Synthesis of Novel Picolylamine Template Catalysts and its Applications in Asymmetric Aldol Reactions Muhammad Naveed Umar A thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy In Chemistry Approved Thesis Committee Prof. Dr. Thomas Nugent Professor of Organic Chemistry Jacobs University Bremen Prof. Dr. Nikolai Kuhnert Professor of Organic Chemistry Jacobs University Bremen Prof. Dr. Zia-Ur-Rehman Professor of Chemistry Quaid-I-Azam University Islamabad,Pakistan Date of Defense: September 29, 2010 School of Engineering and Science, Jacobs University Bremen, Germany.
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Synthesis of Novel Picolylamine Template Catalysts and its Applications in Asymmetric
Aldol Reactions
Muhammad Naveed Umar A thesis submitted in partial fulfillment of the requirements for the degree of
Doctor of Philosophy
In Chemistry
Approved Thesis Committee Prof. Dr. Thomas Nugent Professor of Organic Chemistry Jacobs University Bremen
Prof. Dr. Nikolai Kuhnert
Professor of Organic Chemistry Jacobs University Bremen
Prof. Dr. Zia-Ur-Rehman
Professor of Chemistry Quaid-I-Azam University
Islamabad,Pakistan
Date of Defense: September 29, 2010 School of Engineering and Science, Jacobs University Bremen, Germany.
I
Declaration I herewith declare that this thesis is my own work and that I have used only the sources listed. No part of this thesis has been accepted or is currently being submitted for the conferral of any degree at this university or elsewhere. Muhammad Naveed Umar Jacobs University Bremen Germany
II
Dedication This dissertation is dedicated to my late Father (M. Umar Khan) with out his moral support and encouragement I could not come so far to do my highest degree in my academics.
III
Acknowledgement
All the work reported in this thesis have been carried out at the Department of Chemistry, School of Engineering and Science, Jacobs University, Bremen, Germany since joining here in March 2007 till March 2010. I would like to thank Jacobs University for the financial support from University of Malakand and all the laboratory facilities during my stay here. In this regard I would like to thank Prof. Dr. h. c. Bernhard Kramer for approving my admission in PhD. I would like to convey my kind regards to my supervisor Prof. Thomas C. Nugent and thank him for all his kind suggestions and deeply appreciate his skillful guidance throughout my research. It was due to his relentless efforts that I could master the various techniques and learn to solve the different scientific challenges that came by my way. Lastly, I would also acknowledge his patience and kind understanding. I would thank Prof. Nikolai Kuhnert for his kind consent to become the internal examiner of this thesis. I would also thank Dr.Zia Ur Rehman Department of chemistry, Quaid-i-azam university Islamabad, for his kind consents to become the external examiner of this thesis. All my deepest veneration goes to my parents, brothers and sisters for everything that they have given to me. I would convey my regards and special thanks to my wife Tahira Naveed who gave me full support and sacrifice. My sincere appreciation goes to all my lab mates, Dr. Abhijit Ghosh, Dr. Mohamed El-Shazly, Mohammad Shoaib, A. Alvaradomendez, Abdul Sadiq, Dan Hu, Ahtaram Bibi, Amna Bibi, Andrei Dragan, Andrei Iosub and Daniela Negru for their constant help and encouragement in all respect. I would also thank Mrs. Müller for her continuous help. I would also thank all professors and colleagues in Pakistan. Especially I would like to thank to Prof. Nasim hasan Rama, Prof. Aurangzeb Hassan and Prof. Javed Zaidi for their support and help over the past years. I would like to thank my brother Jehangir Umar and all friends at Jacobs University, Masooma, Ibrahim, Abu Nasar, Majid, Raafiq, Noor Muhammad, Imran, Wakeel, Tariq, Aasim, Amir, Zia, Nawab and Farhan for their continuous support. Muhammad Naveed Umar
IV
Abbreviations Ac Acetyl AcOH Acetic acid aq. Aqueous Ar Aryl Bs Broad singlet (1H-NMR) BINOL 1,1'-Bi-2-naphthol BINAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl. BOC tert-Butyl carbamates iBu iso-Butyl nBu n-Butyl conv. Conversion cat. Catalyst CDCl3 Deuterated chloroform COD Cycloctadiene d Doublet (1H-NMR) dd Doublet of doublet (1H-NMR) DCM Dichloromethane de Diastereomeric excess DIBAL-H Diisobutyl aluminium hydride DME 1,2-Dimethoxyethane DMF N,N’-Dimethylfomamide DMSO Dimethylsulfoxide 2,4-DNBSA 2,4-dinitrobenzene sulfonic acid DNP Dinitro phenol δ Chemical shift (1H-NMR) ee Enantiomeric excess equiv. Equivalent ESI Electron spray ionization (Mass spectroscopy) Et Ethyl EtOH Ethanol EtOAc Ethylacetate GC Gas chromatography h Hours HPLC High performance liquid chromatography HRMS High resolution mass spectrometry Hz Hertz J Coupling constant (1H-NMR) KHMDS Potassium hexamethyldisilazide LDA Lithium diisopropylamide m Multiplate (1H-NMR) M Molar MBA Methyl Benzyl Amine Me Methyl min. Minutes MS Molecular sieves MS Mass spectroscopy MTBE Methyl-tert-butyl ether MW Molecular weight
V
m/z Mass/charge m Meta NaOtBu Sodium tert-butoxide NBD N-Bornadiene NMR Nuclear Magentic Resonance 1-NSA 1-naphthalen sulfonic acid Na-DBS Sodium dodecyl benzene sulfonate o Ortho p Para Pd-C Palladium on carbon Ph Phenyl iPr iso-Propyl nPr n-Propyl Pt-C Platinum on carbon pyr Pyridine q Quartet (1H-NMR) Raney-Ni Raney-Nickel Ref. Reference Rh-C Rhodium on carbon s Singlet (1H-NMR) t Triplet (1H-NMR) t-Bu tert-Butyl tert Tertiary temp Temperature TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography TMS Trimethylsilane Ts Tosyl TsOH p-Toluenesulfonic acid TBuLi tert-Butyllithium Ti(OiPr)4 Titanium(IV) isopropoxide
VI
Synthesis of Novel Picolylamine Template Catalysts and its applications in Asymmetric Aldol Reactions Abstract The synthesis of enantiomerically pure compounds is one of the major areas of organic chemistry, with emphasis on the elaboration of commodity chemicals into high value enantiopure advanced building blocks. Asymmetric organocatalysis, where chiral organic molecules catalyze enantioselective reactions, has grown explosively and become a main focus of research. In the past 5 years different chiral primary amine derived organocatalysts, usually based on naturally occurring cinchonine alkaloids, have been shown for asymmetric Aldol, Michael, Mannich and α-amination reactions. The results have been impressive but many substrates remain untested or are still challenging, and will be required to overcome the limitations of the non-modular, fixed, cinchonia template. To try and overcome these problems, we have designed and synthesized pyridine-primary amine bifunctional catalysts with a similar juxtaposition of vital functionality as cinchonia alkaloids. The important design feature is the modular nature of the new organocatalysts in combination with the brevity of their synthesis. Our chiral pyridine-primary amine catalysts are likely candidates for Aldol reactions, Michael additions, α-amination of ketones, and Mannich reactions. These catalysts are able to generate chiral enamines, carbanion equivalents, in situ which would then undergo reactions with different available electrophiles to give α-modified carbonyl products. A pyridine based 1,2-diamine containing only one stereogenic center has been identified for fast aldol reactions (16-48h). Using 2-5 mol% of (R)- or (S)-PicAm-2a, cyclohexanone (3.3 equiv) readily undergoes aldol reactions with o-,m- p-substituted aromatic aldehyde partners (limiting reagents), including the poor electrophile 4-methylbenzaldehyde (95-99% ee). Further more, functionalized cyclic ketone substrates have been converted into four aldol products using the lowest catalyst loading (5.0 mol%) to date with the highest yield and enatioselectivity.
VII
Table of Contents Acknowledgment. III List of Abbreviations. IV Abstract. VI CHAPTER 1 Introduction 1. Asymmetric Organocatalysis-------------------------------------------------------------1 1.1. Principles----------------------------------------------------------------------------------1 1.1.1 Lewis Base Catalysis-------------------------------------------------------------------2 1.1.2 Lewis Acid Catalysis-------------------------------------------------------------------2 1.1.3 Brønsted Base Catalysis ---------------------------------------------------------------3 1.1.4 Brønsted Acid Catalysis ---------------------------------------------------------------4 1.2. Enamine Catalysis------------------------------------------------------------------------6 1.2.1 Asymmetric Aldol Reaction-----------------------------------------------------------7 1.2.2 Asymmetric Mannich Reaction-------------------------------------------------------8 1.2.3 Asymmetric Michael Reaction--------------------------------------------------------9 1.2.4 Asymmetric α-Amination--------------------------------------------------------------9 1.2.5 Asymmetric α-Alkylation-------------------------------------------------------------10 1.2.6 Asymmetric α-Chlorination----------------------------------------------------------10 1.3. Iminium Catalysis-----------------------------------------------------------------------11 1.3.1 Diels-Alder Reaction------------------------------------------------------------------11 1.3.2 [ 3+2] Cycloaddition -----------------------------------------------------------------12 1.3.3 Friedal Craft Alkylation--------------------------------------------------------------12 1.3.4 Asymmetric Hydride Transfer-------------------------------------------------------13 1.3.5 Mukaiyama-Michael Addition-------------------------------------------------------13 1.4. Aim of Work-----------------------------------------------------------------------------13 References Chapter 1-------------------------------------------------------------------14 CHAPTER 2 2.1. Historical Perspective of Aldol Chemistry----------------------------------------17 2.2. Mechanism of Aldolases-------------------------------------------------------------18 2.3. Enamine-Catalyzed Aldol reactions-------------------------------------------------19 2.3.1 Proline-catalyzed Aldol reactions---------------------------------------------------19 2.3.2 Proline-Catalyzed Acetone Aldol Reaction----------------------------------------21 2.3.3 Substituted Ketone Donors in the Proline-Catalyzed Aldol Reaction----------24 2.3.4 Proline-Catalyzed Hydroxy- Dihydroxy and Substituted Hydroxyacetone Aldol Reaction-----------------------------------------------------------------------------------------26 2.3.5 Ketone Electrophiles, Proline-Catalyzed Aldol Reaction------------------------27 2.3.6 Aldehyde Donors in the Proline-Catalyzed Aldol Reaction----------------------28 2.4. Modern Trends and Development of New Bifunctional Organocatalysts------32 2.4.1 Proline Base Catalysts for Acetone Aldol Reaction------------------------------34 2.4.2 Non-Proline Base Catalysts for Acetone Aldol Reaction------------------------38 2.4.3 Benzaldeyde Acceptor in Acetone Aldol Reaction-------------------------------39 2.4.4 p-MeO-benzaldeyde Acceptor in Acetone Aldol Reaction---------------------40 2.4.5 Cyclohexanone as Aldol Donor (Proline Based Catalysts)----------------------44 2.4.6 Non-proline Derived Catalysts for Cyclohexanone and p-nitrobenzadehyde Aldol Reactions---------------------------------------------------------------------------------46 2.4.7 Catalysts for Cyclohexanone and less Reactive Aldehyde Aldol reactions-----48
2.4.8 Catalysts for Cyclohexanone and Alkyl Aldehyde Aldol Reactions---------49 2.4.9 Catalysts for Cyclopentanone and p-nitrobenzaldehyde Aldol Reaction----49 2.4.10 Catalysts for 2-butanone and p-nitrobenzaldehyde Aldol Reaction----------50 2.4.11 Catalysts for Hydroxyacetone Aldol Reaction----------------------------------51 2.4.12 Catalysts for Dihydroxyacetone Aldol Reaction--------------------------------52 2.4.13 Catalysts for Halogenated and Sulfur-containing Substrates------------------52 2.4.14 Catalysts for Ketone Electrophiles in Aldol Reaction--------------------------53 2.4.15 Catalysts for Aldehyde-aldehyde Aldol Reaction--------------------------------58 2.4.16 Catalysts for Special Ketone (N-Boc-piperidone) Aldol Reaction-------------59 Conclusion-----------------------------------------------------------------------------60 References Chapter 2-----------------------------------------------------------------61 CHAPTER 3 3. Results and Discussions-------------------------------------------------------------------70 3.1 Strategies for the Synthesis of Targetted Catalysts-----------------------------------71 3.1.1 Synthesis of Pyridyl-primary Diamine using Chiral Phenyl Glycinol-----------71 3.1.2 Synthesis of Pyridyl-primary Diamine using Tert-butyl Sulfinamide-----------72 3.1.3 Synthesis of pyridyl-primary Diamine Catalysts via Classical Resolution-----73 3.1.4 Synthesis of pyridyl-primary Diamine Catalysts by Reductive Amination-----74 3.2 PicAm-2a Catalyzed Aldol Reactions -------------------------------------------------75 Conclusion --------------------------------------------------------------------------------82 References Chapter 3---------------------------------------------------------------------83
CHAPTER 4 Experimental 4.1 Procedure for Synthesis of Ketones----------------------------------------------------85 4.2 Procedure for the Synthesis of Racemic PicAm--------------------------------------86 4.3 Resolution of Racemic PicAm----------------------------------------------------------86 4.4 General Procedure for Racemic Aldol Formation------------------------------------87 4.5 General Procedure for Enantioselective Aldol Reaction-----------------------------88 Spectral Data and Figures----------------------------------------------------------------95 References Chapter 4--------------------------------------------------------------------125
1. Asymmetric Organocatalysis Asymmetric organocatalysts, the use of low molecular weight organic molecules to promote asymmetric reactions have gained large interest in the last years.[1-4] The first asymmetric organocatalytic reaction was reported by Bredig and Fiske in 1912.[5] They reported that addition of HCN to benzaldehyde is accelerated by alkaloids, specifically quinine and quinidine. In 2000 List et al. used (S)-proline as a simple organic molecule for the direct asymmetric aldol reaction.[6] After this report many research groups all over the world became engaged in organocatalysis.[6-21] (S)-proline has been applied in many reactions such as the Mannich,[22-29] Michael,[30-33] electrophilic α-amination,[34-36] Diels-Alder,[37-39] Baylis-Hillman,[35] aza-Morita-Baylis-Hillman,[40,41] α-selenenylation,[42] oxidation,[43-49] chlorination[50] and many other reactions.[51, 52] In this chapter I will give some examples of these enamine and iminium catalysis for understanding. 1.1. Principles Chemical reaction catalyzed by a small organic molecule in the absence of a metal atom.[53] are refered to as organocatalytic reactions. An organocatalyst is responsible for transferring chirality into a prochiral substrate through a well defined transition state.[54] Metal containing enzymes or organometallic catalysts can also be used for chiral induction. The metal as well as the ligand play an important role in stereoselectivity. By changing the ligands one can tune the reactivity. An ideal catalyst regardless whether it is an organocatalyst or not should have the following characteristics: 1) High catalytic activity 2) Easy availability 3) Low price 4) Low molecular weight 5) Easy separation from product 6) Recycling after reaction workup 7) Non toxic 8) Stability 9) High turn over frequency Most of the organocatalysts usually do not require inert conditions and further more organocatalysts can be comparatively cheaper than organometallic catalysts and enzymes. Most of organocatalysts can be broadly classified as Lewis acid, Lewis base, Bronsted acid and Bronsted base.[55] Lewis base catalyst initiates the catalytic cycle by nucleophilic attack on the substrate. The resulting complex undergoes reaction and gives product and the catalyst. Similarly a Lewis acid catalyst activates substrate as an electrophile. However Bronsted base and Bronsted acid catalysis is initiated by protonation or deprotonation respectively.
CHAPTER 1
2
1.1.1 Lewis Base Catalysis Lewis base catalysis is the process by which an electron pair donor increases the rate of a reaction by interacting with an acceptor atom in one of the reagents or substrates.[56] Lewis base organocatalysts mostly contain S, N, O and P heteroatoms. Their mechanism is to convert the substrate either in an electrophilic or nucleophilic manner. Thus carbonyl compounds can be transferred by amines into iminium ions (electrophiles) and enamines (nucleophiles). They are typical reactive intermediates of Lewis base catalysis. Iminium Catalysis The active species in an iminium catalysis is iminium ion formed by reversible reaction of an amine catalyst with a carbonyl substrate. MacMillan et al. synthesized imidazolidinone organocatalyst 35 (Fig. 5) which catalyzes the reaction through iminium ion intermediate. See details in (1.3) Enamine Catalysis The reactive species in an enamine catalysis is an enamine formed by deprotonation of an iminium ion (primarily formed from a carbonyl compound and an amine) which then reacts with various electrophiles. See details in (1.2) 1.1.2 Lewis Acid Catalysis A Lewis acid is defined as a species which can act as electron pair acceptor. Phase transfer catalysts (PTC) are a class of organocatalyst which can be considered as Lewis acid catalyst. These catalysts facilitate the migration of a reactant in a heterogeneous system from one phase into another phase where the reaction can take place. Phase transfer catalysts fulfill the concept of Lewis acid Lewis base complexes during the catalytic process. For instance N-benzyl cinchonium 1 (Figure 1) was the first chiral phase transfer catalyst and was used for asymmetric α-methylation of indanone.[57] The X-ray and molecular modeling studies of benzyl cinchonium ion shows that C-OH bond of quinoline and N-benzyl group lie in one plane (Figure 2). The negative charge is delocalized into the two phenyl ring. The OH group provides ionic attraction via hydrogen bonding to the indanone anion. Ion pairing between indanone anion and benzyl cinchonium cation formed which is important for asymmetric induction. O’Donnell et al.[58, 59] did asymmetric synthesis of amino acids by phase transfer catalytic alkylation of glycine derivatives using this approach. Later on, Lygo and Corey synthesized cinchonidium salts 2. Shi et al.[60] did enatioselective epoxidation of olefins by synthesizing chiral dioxirane from chiral ketone catalyst and oxone as oxidant.
CHAPTER 1
3
N
N
OH
N
N
O
ClBr
1 2
Figure 1: Phase Transfer Catalysis
Figure 2: Transition State for asymmetric α-methylation of indanone 1.1.3 Brønsted Base Catalysis A Brønsted base catalytic cycle is initiated by deprotonation of the substrate. Strecker reaction and cyanohydrin synthesis are most common examples of Bronsted base catalysis. Inone et al. reported hydrocyanation of aldehydes by using peptide catalyst 4[61] (Scheme 1a). Lipton and coworker[62] did strecker reaction using N-benzhydryl imines 5 to α-aminonitrites (Scheme 1b). C2-symmetric guanidine 6 was used by Corey and Grogan[63] in Strecker reaction. In all these examples HCN interacts with nitrogen base through H-bonding and then carbonyl or imine coordinates with the catalyst. Bronsted base catalysis for the Michael reaction has also been achieved by guanidine derivatives using a prochiral glycine substrate. Tan et al. recently reported the development of chiral bicyclic guanidine 12 as a versatile Brønsted base catalyst for enantiselective Michael reaction in dithiomalonates and β-keto thioesters.[64]
N
N
O
ClOCl
Cl
H3CO
H
3
CHAPTER 1
4
HNNH
NH
NH
O
ONH2
N N
NOH
Ph
Ph PhN
N
NH
4 5 6
N
N
NH
t
N
O
O
Et
OMe
OMeO
O
But Bu
OMe
OMeO
O
N
O
O
Et
H
20 mol%, Toluene, rt20% yield, 47% ee
12
13 14
15
+
Scheme 2: Micheal addition catalysed by bicyclic guanidine 12 1.1.4 Brønsted Acid Catalysis Brønsted acids are substances that can donate a proton. A Brønsted acid catalytic cycle is initiated by protonation of the substrate. Catalysis through hydrogen bonding[65, 66] and enzymatic catalysis where H-bonding is involved in transition state can be described as general Brønsted acid catalysis. Jacobsen et al. developed Strecker reactions,[67, 68] Mannich reactions,[69] and hydrophosphonylation[70] reactions by the use acid catalysts. These catalysts actually form hydrogen bonds with imines through bridging. Takemoto et al. used the chiral thiourea catalyst 18 with neighboring effect of tertiary amines giving Henry[71] and Michael reactions[72] (Scheme 2). The Morita-Baylis-Hillman reaction[73] (Scheme 3) was catalyzed by BINOL-derived Bronsted acid 17. The Brønsted acid may serve to
H
N Ph
Ph
CN
HN Ph
Ph
4 (2 mol%) HCN
MeOH, -78 oC97%7
8>99% ee
OPh
NO
Ph+ CO2Me 5 (20 mol%)
20 oC, 90%
OPh
NO
Ph
MeO2C
9 10 11
1a
1b
Scheme 1: Hydrocyanation and Strecker reaction catalyzed by BrØnsted catalysts 4 and 5
Figure 3: Bronsted base catalysts
CHAPTER 1
5
promote the conjugate addition step of the reaction and then remain hydrogen bonded to the resulting enolate in the enantioselectivity determing aldehyde addition step.
HN
NH
NHO
O
N H
HO
O
OOHOH
CF3
CF3
CF3
CF3
NNH
NH
S
CF3
CF3
16
17
18 Figure: 3 Brønsted base catalysts
NO2+ EtO2C CO2Et 18 (10 mol%)
toluene rt86% yield
NO2
EtO2C CO2Et
93% ee
O O
+
Et3P (20 mol%)
17 (10 mol%)THF, -10 oC
80%
OH O
90% ee
19 20 21
22 2324
Scheme 3: Michael and MBH reaction catalyzed by Brønsted acid catalysts 18 and 17
CHAPTER 1
6
1.2. Enamine Catalysis An electrophilic substitution reaction of an α-H atom in carbonyl compounds catalyzed by primary or secondary amines through an enamine intermediate is enamine catalysis. Enamine catalysis in a last few years has emerged as an independent field in asymmetric organocatalysis and a powerful strategy in asymmetric synthesis. There are two types of enamine catalysis. It depends on the class of electrophile used. 1) Electrophiles containing double bond such as aldehydes, imines, michael acceptors etc are inserted into the R-C-H bond of the carbonyl compound via nucleophilic addition reaction of the enamine intermediate (Scheme 4a). Electrophiles containing a single bond such as alkyl halide react in a nucleophilic substitution reaction and lead to a stoichiometric product (Scheme 4b).
1.2.1. Asymmetric Aldol Reaction Aldol reaction is the most common C-C bond forming reaction which is catalyzed by both acids and bases. Aldol reaction can be intramolecular and intermolecular. The first example of the catalytic asymmetric aldol reaction was the Hajos-Parrish-Eder-Sauer-Wiechert cyclization[74]. Hajos found that (S)-proline is an effective catalyst for intramolecular aldol reaction of triketones (Scheme 5). Enolexo aldolization is generally more common in aldol reaction. List and coworkers developed highly enantioselective enolexo aldolization of dicarbonyl compounds[75] (Scheme 5). The first amine catalyzed asymmetric intermolecular aldol reaction was introduced by List et al. in 2000.[6, 28, 76-78] The reaction was between acetone and aldehydes with catalytic amounts of proline (Scheme 5).
1.2.2. Asymmetric Mannich Reaction The Mannich reaction is a useful transformation in the synthesis of nitrogenous compounds[79-82] in which two carbonyl compounds and one amine react to form β-amino carbonyl compounds. The reaction can be described as direct or indirect. In 2000, List demonstrated the first efficient proline catalyzed direct three component asymmetric Mannich reaction of ketones with p-anisidine and aldehydes.[22, 76, 83, 84] (Scheme 6). Hydroxyacetone 46 was used as ketone and corresponding syn the 1,2-amino alcohol 49 was obtained in high yield and enantioselectivity.[85]
Scheme 6: Asymmetric Mannich Reaction catalyzed by L-proline
OH
O
46
H
O
O2N
+ +OMe
H2N37 (20-30 mol%)
DMSO, rt97%47 48
OH
NHPMPO
NO249
Scheme 5: Asymmetric Aldol Reaction catalyzed by L-Proline
O
H
OOHO37 (20-30 mol%)
DMSO, rt97%
39 40 4196% ee
HH
O O
37 (10 mol%)
CH2Cl2, rt95%
H
O OH
H
O
+
42 43
H
O
4044
37 (20-30 mol%)
DMSO, rt97%
99% ee, 10 : 1 dr
OH
H
O
4599% ee, 24 : 1 dr
+
CHAPTER 1
9
1.2.3. Asymmetric Michael Reaction Michael reaction is the conjugative addition of nucleophiles, in particular carbon nucleophiles to the β-position of α,β-unsaturated carbonyl compounds for C-C bond formation.[86] The first enamine catalytic asymmetric intermolecular Michael reaction was developed by List et al. in 2001.[30, 83] The addition of unsaturated ketones to nitro olefins was found to proceed in the presence of catalytic amounts of proline. Fonseca and List published a catalytic asymmetric intramolecular Michael reaction of aldehydes.[87] Formyl enones 55 readily cyclized by MacMillan catalyst 34 (Figure 5) in catalytic amounts (Scheme7). 1.2.4. Asymmetric α-Amination Asymmetric C-N bond formation in organic synthesis plays a vital role because of its applications and importance in biological compounds. Direct stereoselective introductions of nitrogen electrophiles into the α-position of carbonyl compounds give valuable chiral molecules such as α-amino acid and β-amino alcohols.[84] Jorgensen et
Scheme 7: Asymmetric Michael Reaction catalyzed by Macmillan catalyst 34
H
O34 (5 mol%)
THF, rt99%
H
O
5097% ee, 24 : 1 dr
PhO Ph
O
51
N
NH
O
Ph
N
NH
O
Ph
N
NH2
O
Ph
N
NH2
O
Ph
NH
CO2HNH
CO2H
Cl
X
3233
34 (X= Cl)35 (X= CF3CO2)
36
37 38
Figure 5: Organocatalysts Employing Enamine and Iminium Ions
CHAPTER 1
10
al.[34] and List[35] in 2002 reported direct asymmetric α-amination of aldehydes. Azodicarboxylate 53 was used as nitrogen source with 10 mol % of (S)-proline (Scheme 8). 1.2.5. Asymmetric α-Alkylation C-C σ-bond formation through α-alkylation of carbonyl compounds is important in organic synthesis. Chiral phase transfer catalysts are most commonly used for asymmetric α-alkylations. List et al.[88] in 2004 introduced catalytic asymmetric intramolecular α-alkylation of aldehydes. This was the first example of enamine catalysis where nucleophilic substitution takes place. Proline was not good in selectivity but (S) α-methyl proline turned out to be an efficient catalyst (Scheme 9). 1.2.6. Asymmetric α-Chlorination α-Chlorinated carbonyl compounds are important precursors for a number of products because of their synthetic transformation into many amino acid derivatives and optically active epoxides. First chiral α-chlorination of aldehydes was done independently by MacMillan[50] and Jorgensen[89] in 2004. MacMillan used TFA salt of chiral imidazolidinone 35 (Figure 5) as catalyst for chiral asymmetric α-chlorination of aldehydes with the perchlorinated quinone 58 as chlorinating agent (Scheme 10).
Scheme 9: Asymmetric α-alkylation
IOHC
EtO2CEtO2C
38 (10 mol%)Et3N, CHCl3, -30 oC 92%
OHC
EtO2CEtO2C
55 5695% ee
Scheme 10: Asymmetric α-Chlorination catalyzed by MacMillan catalyst 35
H
On -Hex +
O
ClCl
ClCl
ClCl
35 (5 mol%)
acetone, -30 oC71% yield
H
On -Hex
Cl
59585792% ee
Scheme 8: Asymmetric α -amination catalyzed by L-proline
HiPr
O(1) 37 (10 mol%)
52
+ N CO2BnNBnO2C
53(2) CH3CN, 0 oC, rt
EtOH, Na 99%
HON
NH
CO2Bn
iPr
CO2Bn
96% ee54
CHAPTER 1
11
1.3. Iminium Catalysis Schiff in 1864 discovered that primary amines during the condensation of aldehydes and ketones give imines[90] which exist as iminium ions and secondary amines give iminium cations (Scheme 11). In the field of iminium ion catalysis secondary amines are more dominant because of specific amine catalyst mechanism. Iminium salts are more electrophilic than aldehydes and ketones. Iminium salt activates the carbonyl group for nucleophilic attack. Iminium ion catalysis has been now well established and a conceptual class of organocatalysis. The iminium catalytic cycle for nucleophilic additions is shown in (Scheme 11). It is initiated via iminium ion formation from α, β -unsaturated aldehyde and the catalyst. Conjugate addition of a nucleophile gives an enamine intermediate, which upon hydrolysis provides the product. 1.3.1. Diels-Alder Reaction In the Diels-Alder reaction an active iminium ion is formed from the dienophile that reacts with the diene to give the Diels-Alder product. Activation of α,β-unsaturated carbonyl compound 67 through iminium ion in Diels-Alder reaction was introduced by Baum et al. in 1976[91] but that was not enantioselective. MacMillan in 2000 developed iminium ion catalyzed stereoselective Diels-Alder reaction (Scheme 12) by chiral imidazolidinone 32 (Figure 5) with high stereoselectivity. In the assumed transition state the hydrogen atom in α-position of the aldehyde 69 avoids unfavourable interaction with
Scheme 11: Iminium Catalysis
H
N
H
N
- H2O
NH
60H
O
65
X
+ H2O
H
N
62
H∗
O
63
X
R
X
Nu-H
R Nu
HX
61
R NuR Nu
R
64
CHAPTER 1
12
the geminal methyl groups of the catalyst and the diene approaches the iminium ion from the Si face.
1.3.2. [3+2] Cycloaddition α,β-Unsaturated aldehydes 70 are poor substrates for Lewis acid catalyzed [3+2] cycloadditions,[92] because the nitrone 71 undergoes unfavourable coordination with Lewis acids. This problem can be overcome by organocatalysis. Thus the imidazolidone catalyst 32 (Scheme 13) forms iminium ions with the carbonyl group reversibly, resulting in the cycloaddition. The [3+2] cycloaddition of α,β-unsaturated aldehydes and nitrones was introduced by MacMillan et al. in 2000 (Scheme 13). 1.3.3. Friedel-Craft Alkylation Macmillan used imidazolidinone catalyst 32 (Figure 5) in Friedel Crafts alkylation of pyrroles.[93] This catalyst can be used in the synthesis of alkylation products of pyrroles, indoles and benzene ring systems and induces chirality. In this case the α,β-unsaturated aldehydes act as a source of electrophile. N-methyl pyrrole react with several α,β-unsaturated aldehydes to give Friedel Crafts product in good selectivity (Scheme 14).
Scheme 12: Diels-Alder Reaction catalyzed by MacMillan catalyst 32
+ Ph O32 (5 mol%)
MeOH-H2O, 23oC99% yield
PhCHO
93% ee, 1.3 : 1 dr
N
N
O
Ph
R1R2
X1
66 6768
69
H
O
R1
32 (20 mol%)
73
+ NMe
R3
R2
74TFA / TCA / CNA 68-90%
N
R3
R2R1
O
HMe
H
7587-97% ee
Scheme 14: Friedel-Craft Alkylation catalyzed by MacMillan catalyst 32
Scheme 13: [3+2] Cycloaddition catalyzed by MacMillan catalyst 32
H
O
R1
+ N
R2
O R3
32 (20 mol%)
HClO4/TfOH 98%
ON
H
O R2
R1
R3
99% ee, 4 :1 99 : 1 endo : exo70 71 72
CHAPTER 1
13
1.3.4. Asymmetric Hydride Transfer List in 2004 reported a novel strategy for the hydrogenation of enals.[94] He reduced enals in enantioselective fashion[95] using imidazolidinone trifluoroacetate salt 35 (Figure 5) producing saturated aldehydes (Scheme 15). 1.3.5. Mukaiyama-Michael Addition MacMillan in 2003 reported Mukaiyama-Michael type reaction in which furan 79 can be used as a nucleophile.[96] Furan 79 and related structures undergo 1,2-addition by chiral Lewis acid catalysis while chiral amine catalyzed coupling allows 1,4-addition to give product 80. The 2,4-dinitrobenzoic acid (DNBA) salt of catalyst 32 actually reacts with aliphatic α,β substituted enals and cinnamaldehye giving 99% ee (Scheme 16). 1.4. Aim of Work It is evident that asymmetric organocatalysis using a diamine is a rapidly developing research field in organic synthesis. This research field has gained much interest in last few years. We have come to know that a very less importance has been given to pyridyl-primary diamine as organocatlysts and mostly research has been done on cinchona based, proline based or natural amino acid based catalysts. These pyridyl-primary diamine are new in this area, so we focussed on this novel class of catalysts for aldol and Micheal reactions. So far there is no work has been done on such catalysts so we planed to synthesize this type of novel catalysts. We synthesized them and we used them in different asymmetric reactions to investigate the synergestic effect on stereoselectivity and rate of reaction. In the second chapter I will discuss the detail history of asymmetric aldol reaction.
H
O
R
76
+
NH
i
OMeMeO
OO HH
-Pr
35 (10mol%)TFA77-90%
H
O
R
78
H
7790-96% ee
Scheme 15: Asymmetric Hydride transfer
H
O
R1
73
O
OTMS
R2
32 (20mol%)DNBA73-87%
79
OO
H
O
R2R1
8084-99% ee
+
Scheme 16: Mukaiyama-Michael Addition
CHAPTER 1
14
References Chapter 1 [1] G. Guillena, C. Najera, D. J. Ramon, Tetrahedron: Asymmetry 2007, 18, 2249. [2] H. Pellissier, Tetrahedron 2007, 63, 9267. [3] G. Guillena, D. J. Ramon, Tetrahedron: Asymmetry 2006, 17, 1465. [4] P. I. Dalko, L. Moisan, Angew. Chem. Int. Ed. 2004, 43, 5138. [5] G. Bredig, Biochem. Z. 1912, 7. [6] (a)B. List, W. Notz J. Am. Chem. Soc., Vol. 2000 122, 7387 (b)B. List, Tetrahedron 2002, 58, 5573. [7] E. R. Jarvo, S. J. Miller, Tetrahedron 2002, 58, 2481. [8] W. Notz, F. Tanaka, C. F. Barbas, Acc. Chem. Res. 2004, 37, 580. [9] K. Sakthivel, W. Notz, T. Bui, C. F. Barbas, J. Am. Chem. Soc. 2001, 123, 5260. [10] J. T. Suri, S. Mitsumori, K. Albertshofer, F. Tanaka, C. F. Barbas, J. Org. Chem. 2006, 71, 3822. [11] C. Grondal, D. Enders, Tetrahedron 2006, 62, 329. [12] J. T. Suri, D. B. Ramachary, C. F. Barbas, Organic Lett. 2005, 7, 1383. [13] I. Ibrahem, A. Cordova, Tetrahedron Lett. 2005, 46, 3363. [14] R. I. Storer, D. W. C. MacMillan, Tetrahedron 2004, 60, 7705. [15] J. Casas, H. Sunden, A. Cordova, Tetrahedron Lett. 2004, 45, 6117. [16] Q. Pan, B. Zou, Y. Wang, D. Ma, Org. Lett. 2004, 6, 1009. [17] A. B. Northrup, I. K. Mangion, F. Hettche, D. W. C. MacMillan, Angew. Chem. Int. Ed. 2004, 43, 2152. [18] C. Allemann, R. Gordillo, F. R. Clemente, P. H. Y. Cheong, K. N. Houk, Acc. Chem. Res. 2004, 37, 558. [19] R. Thayumanavan, F. Tanaka, C. F. Barbas, Org. Lett. 2004, 6, 3541. [20] C. Pidathala, L. Hoang, N. Vignola, B. List, Angew. Chem. Int. Ed. 2003, 42, 2785. [21] T. Bui, C. F. Barbas, Tetrahedron Lett. 2000, 41, 6951. [22] B. List, J. Am. Chem. Soc. 2000, 122, 9336. [23] A. Cordova, W. Notz, G. F. Zhong, J. M. Betancort, C. F. Barbas, J. Am. Chem. Soc. 2002, 124, 1842. [24] W. Notz, F. Tanaka, S. Watanabe, N. S. Chowdari, J. M. Turner, R. Thayumanavan, C. F. Barbas, J. Org. Chem. 2003, 68, 9624. [25] N. S. Chowdari, J. T. Suri, C. F. Barbas, Org. Lett. 2004, 6, 2507. [26] Y. Hayashi, W. Tsuboi, I. Ashimine, T. Urushima, M. Shoji, K. Sakai, Angew. Chem. Int. Ed. 2003, 42, 3677. [27] A. Cordova, Synlett 2003, 1651. [28] B. List, R. A. Lerner, C. F. Barbas, J. Am. Chem. Soc. 2000, 122, 2395. [29] B. List, P. Pojarliev, W. T. Biller, H. J. Martin, J. Am. Chem. Soc. 2002, 124, 827. [30] B. List, P. Pojarliev, H. J. Martin, Org Lett 2001, 3, 2423. [31] J. M. Betancort, C. F. Barbas, Org. Lett. 2001, 3, 3737. [32] D. Enders, A. Seki, Synlett 2002, 26. [33] I. K. Mangion, D. W. C. MacMillan, J. Am. Chem. Soc. 2005, 127, 3696. [34] A. Bogevig, K. Juhl, N. Kumaragurubaran, W. Zhuang, K. A. Jorgensen, Angew. Chem. Int. Ed. 2002, 41, 1790. [35] B. List, J. Am. Chem. Soc. 2002, 124, 5656.
CHAPTER 1
15
[36] J. T. Suri, D. D. Steiner, C. F. Barbas, Organic Lett. 2005, 7, 3885. [37] G. Sabitha, N. Fatima, E. V. Reddy, J. S. Yadav, Adv. Synth. Catal. 2005, 347, 1353. [38] R. Thayumanavan, B. Dhevalapally, K. Sakthivel, F. Tanaka, C. F. Barbas, Tetrahedron Lett. 2002, 43, 3817. [39] D. B. Ramachary, N. S. Chowdari, C. F. Barbas, Tetrahedron Lett. 2002, 43, 6743. [40] N. Utsumi, H. L. Zhang, F. Tanaka, C. F. Barbas, Angew. Chem. Int. Ed. 2007, 46, 1878. [41] J. Vesely, P. Dziedzic, A. Cordova, Tetrahedron Lett. 2007, 48, 6900. [42] J. Wang, H. Li, Y. Mei, B. Lou, D. Xu, D. Xie, H. Guo, W. Wang, J. Org. Chem. 2005, 70, 5678. [43] G. Zhong, Angew. Chem., Int. Ed. 2003, 42, 4247. [44] S. P. Brown, M. P. Brochu, C. J. Sinz, D. W. C. MacMillan, J. Am. Chem. Soc. 2003, 125, 10808. [45] Y. Hayashi, J. Yamaguchi, K. Hibino, M. Shoji, Tetrahedron Lett. 2003, 44, 8293. [46] A. Bogevig, H. Sunden, A. Cordova, Angew. Chem. Int. Ed. 2004, 43, 1109. [47] Y. Hayashi, J. Yamaguchi, T. Sumiya, K. Hibino, M. Shoji, J. Org. Chem. 2004, 69, 5966. [48] Y. Hayashi, J. Yamaguchi, T. Sumiya, M. Shoji, Angew. Chem., Int. Ed. 2004, 43, 1112. [49] A. Cordova, H. Sunden, A. Bogevig, M. Johansson, F. Himo, Chem. Eur. J. 2004, 10, 3673. [50] M. P. Brochu, S. P. Brown, D. W. C. MacMillan, J. Am. Chem. Soc. 2004, 126, 4108. [51] S. Wallbaum, J. Martens, Tetrahedron: Asymmetry 1993, 4, 637. [52] M. T. Rispens, C. Zondervan, B. L. Feringa, Tetrahedron: Asymmetry 1995, 6, 661. [53] H. Pracejus, H. Matje, J. Prakin. Chem. 1964, 24, 195. [54] P. I. Dalko, L. Moisan, Angew. Chem. Int. Ed. 2001, 40, 3726. [55] J. Seayad, B. List, Organic & Biomolecular Chemistry 2005, 3, 719. [56] E. Denmark Scott, L. Beutner Gregory, Angew. Chem. Int. Ed. 2008, 47, 1560. [57] U. H. Dolling, P. Davis, E. J. J. Grabowski, J. Am. Chem. Soc. 1984, 106, 446. [58] M. J. Odonnell, W. D. Bennett, S. D. Wu, J. Am. Chem. Soc. 1989, 111, 2353. [59] M. J. O'Donnell, Acc. Chem. Res. 2004, 37, 506. [60] H. Tian, X. She, J. Xu, Y. Shi, Org. Lett. 2001, 3, 1929. [61] K. Tanaka, A. Mori, S. Inoue, J. Org. Chem. 1990, 55, 181. [62] M. S. Iyer, K. M. Gigstad, N. D. Namdev, M. Lipton, J. Am. Chem. Soc. 1996, 118, 4910. [63] E. J. Corey, M. J. Grogan, Org. Lett. 1999, 1, 157. [64] W. Ye, Z. Jiang, Y. Zhao, S. L. M. Goh, D. Leow, Y.-T. Soh, C.-H. Tan, Adv. Synth. Catal. 2007, 349, 2454. [65] P. R. Schreiner, Chem. Soc. Rev. 2003, 32, 289. [66] P. M. Pihko, Angew. Chem. Int. Ed. 2004, 43, 2062. [67] M. S. Sigman, E. N. Jacobsen, J. Am. Chem. Soc. 1998, 120, 4901. [68] M. S. Sigman, P. Vachal, E. N. Jacobsen, Angew. Chem. Int. Ed. 2000, 39, 1279. [69] A. G. Wenzel, E. N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 12964. [70] G. D. Joly, E. N. Jacobsen, J. Am. Chem. Soc. 2004, 126, 4102. [71] T. Okino, S. Nakamura, T. Furukawa, Y. Takemoto, Organic Lett. 2004, 6, 625.
CHAPTER 1
16
[72] T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003, 125, 12672. [73] N. T. McDougal, S. E. Schaus, J. Am. Chem. Soc. 2003, 125, 12094. [74] Z. G. Hajos, D. R. Parrish, J. Org. Chem. 1974, 39, 1615. [75] C. Agami, J. Levisalles, C. Puchot, Chem. Commun. 1985, 441. [76] B. List, Synlett 2001, 1675. [77] W. Notz, B. List, J. Am. Chem. Soc. 2000, 122, 7386. [78] B. List, P. Pojarliev, C. Castello, Org Lett 2001, 3, 573. [79] M. Arend, B. Westermann, N. Risch, Angew. Chem. Int. Ed. 1998, 37, 1044. [80] M. M. B. Marques, Angew. Chem. Int. Ed. 2006, 45, 348. [81] M. Shibasaki, S. Matsunaga, J. Organomet. Chem. 2006, 691, 2089. [82] A. Cordova, Acc. Chem. Res. 2004, 37, 102. [83] B. List, Acc. Chem. Res. 2004, 37, 548. [84] R. O. Duthaler, Angew. Chem. Int. Ed. 2003, 42, 975. [85] S. C. Bergmeier, Tetrahedron 2000, 56, 2561. [86] B. E. Rossiter, N. M. Swingle, Chem. Rev. 1992, 92, 771. [87] M. T. H. Fonseca, B. List, Angew. Chem. Int. Ed. 2004, 43, 3958. [88] N. Vignola, B. List, J. Am. Chem. Soc. 2004, 126, 450. [89] N. Halland, A. Braunton, S. Bachmann, M. Marigo, K. A. Jorgensen, J. Am. Chem. Soc. 2004, 126, 4790. [90] R. W. Layer, Chem. Rev. 1963, 63, 489. [91] J. S. Baum, H. G. Viehe, J. Org. Chem. 1976, 41, 183. [92] W. S. Jen, J. J. M. Wiener, D. W. C. MacMillan, J. Am. Chem. Soc. 2000, 122, 9874. [93] N. A. Paras, D. W. C. MacMillan, J. Am. Chem. Soc. 2001, 123, 4370. [94] W. Yang Jung, T. Hechavarria Fonseca Maria, B. List, Angew. Chem. Int. Ed. 2004, 43, 6660. [95] J. W. Yang, M. T. H. Fonseca, N. Vignola, B. List, Angew. Chem. Int. Ed. 2005, 44, 108. [96] S. P. Brown, N. C. Goodwin, D. W. C. MacMillan, J. Am. Chem. Soc. 2003, 125, 1192.
CHAPTER 2
17
As we know that organocatalysis has emerged as a best tool to catalyze a vaierty of reactions as discussed in chapter 1. Asymmetric aldol reaction is a good method for the construction of carbon–carbon bonds in an enantioselective fashion. Initially this reaction has been done in a stoichiometric fashion to control the various aspects of chemo-, diastereo-, regio- and enantioselectivity but use catalytic amount of a chiral catalyst fulfill the above aspects. This chapter present the development of direct catalytic asymmetric aldol methodologies, including organocatalytic strategies. New methods have improved the reactivity, selectivity and substrate scope of the direct aldol reaction. 2.1. Historical Perspective of Aldol Chemistry In 1872 the first aldol reaction was done by Wurtz,[1] one of the most powerful transformations in organic chemistry. In this process the two carbonyl partners unites to give β-hydroxyketones with up to two new stereocenters (Scheme 1). In aldol reactions there are still a lot of challenges for example chemo-, regio-, diastereo-, and enantioselectivity to the synthetic chemist, which has encouraged development of many powerful stoichiometric processes to explain these issues.[2] With the development of these organocatalysts methods we can avoid the production of stoichiometric by-products while maintaining the high levels of control available from stoichiometric processes provides an atom economical alternative for these important transformations.[3]
A large number of, catalysts for the aldol reaction have been reported in recent years, including enzymes,[4] catalytic antibodies[5] and small molecules.[6–8] The focus of this chapter will be on small molecule catalysts, including organocatalysts proceeding via enamine mechanism.
Scheme 1: The direct catalytic asymmetric aldol and issues of selectivity
2.2. Mechanism of Aldolases In biological systems, the aldol reaction is accomplished by two types of aldolases, classified by their different mechanisms (Scheme 2).[9] Type I aldolases function via an enamine mechanism, in which an enzyme lysine residue reacts with the donor component 8 to generate an enamine (B) in the active site. This enamine (C) then attacks the acceptor electrophile (9) to give iminium adduct D. Hydrolysis frees the substrate from the enzyme and releases the aldol adduct 10. Type II aldolases catalyze the aldol reaction by activation of the donor substrate 8 with an active site histidine-bound zinc ion. This
Scheme 2: Mechanism of type I (RAMA FDP) and type II (fructose-1-phosphate) aldolases[9]
OP
O OHHN
OO
Lys229
Ser271O
PO O
OH
OOH
Ser271
OP
O OHHN
OO
Lys229
OPO
OHO
OO
H
OP
O OHN
OO
Lys229
OPO
OO
H
Lys107 Lys107
OH
H+
OP
O OHN
OO
Lys229
Ser271
OP
O OHO
OOO
PO
O
OO
Ser271
OHR
OH
OH
Type I
Type II
R= OPO32-
OP
O OHO
OO
ZnHis155 His94
His92
HO O
Glu73
OOH
HO
PO OH
O
OO
Ser271 ZnHis155 His94
His92
HH
OHO H O
Tyr113
OP
O OHO
OO
ZnHis155 His94
His92
OHOH
R= H
B
A
8
E F
11
G
10
C
9
CHAPTER 2
19
acidifies the a-proton, allowing for facile generation of zinc enolate F. Activation of the carbonyl of the acceptor 11 through hydrogen-bonding is followed by attack of the zinc enolate to provide aldol adduct G. Protonation and decomplexation yields aldol adduct 10. These biological processes have provided a template for the development of small molecule catalysts. Indeed, most of the reported catalytic systems fall into these two mechanistic classes. Nature’s aldolases inspire chemists to create small molecule which can work selectively and efficiently. 2.3. Enamine-catalyzed aldol reactions Small molecule catalysts which take advantage of an enamine mechanism analogous to the type I aldolases comprise the vast majority of reported methods for carrying out direct catalytic asymmetric aldol reactions. As these approaches have been discussed previously,[10–24] the goal of this chapter will be to highlight different type of organocatalyst which are working via enamine catalysis. This chapter will not focus on design parameters such as catalyst immobilization,[25–35] attaching hydrophobic groups to the catalyst,[30,36–38] reactions in micelles,[39,40] host–guest catalytic systems,[41,42] or the use of ionic liquids[43–54] or surfactants,[55–60] which can be found elsewhere.[12,13] Instead, this chapter will highlight what is currently possible synthetically and what challenges remain undislosed for enamine-based catalysts. 2.3.1 Proline-catalyzed aldol reactions The first report of a direct asymmetric aldol reaction catalyzed by a small molecule was the Hajos–Parrish–Eder–Sauer–Wiechert cyclization, disclosed in 1971 (Scheme 3).[61,62] This intramolecular aldol cyclization proceeded with only 3 mol% proline 13 to give the cyclized product 14 in excellent yield and enantioselectivity. Unfortunately, both the yield and the enantioselectivity dropped for the 6-membered ring substrate 15. Amino acids such as proline are particularly appealing catalysts, due to their natural abundance and low cost. The Hajos–Parrish–Eder–Sauer–Wiechert reaction is an enol-endo aldolization. Enol-exo cyclizations are also possiblec using proline catalysis. In 2003 List and co-workers reported the enol-exo cyclization of a variety of dialdehydes, such as 17, yielding 6-membered rings (18) in high yields, diastereo- and enantioselectivities. Five-membered rings (20) were formed with reduced diastereo- and enantioselectivities (Scheme 4).[63,64] List has also demonstrated that transannular intramolecular cyclizations are possible using catalytic proline, though the enantioselectivity was not high. Using modified catalyst 22 (Scheme 4) the enantioselectivity was greatly improved. The utility of this transannular cyclization was demonstrated in List’s synthesis of (+)-hirsutene (24). The first intermolecular proline-catalyzed direct aldol reaction was described by List and co-workers in 2000 (Table 1)[65]
Scheme 4: Proline-catalysed enol-exo and tranannular cyclizations.[63,64]
NH
CO2H
3 mol%
DCM, 8-16h13
NH
CO2H
3 mol%
DMF, 72h13
CHOCHOOH
OHCOHC
CHO
OHOHC
95%10 : 1 dr99% ee
85%2 : 1 dr79% ee (anti)37% ee (syn)
17 18 19 20
O
O
H
H
NH
CO2H
10 mol%
OH
H
H
H
O
22
DMSO, 15h HH
H
21 23 2484%98 : 2 dr
(+)-hirsutene
F
CHAPTER 2
21
Table 1: Proline-catalyzed acetone aldola
2.3.2 Proline-catalyzed acetone aldol reaction Using 20–30 mol% L-proline and a 4 : 1 solution of DMSO: acetone, the desired aldol adducts 27 were obtained. Aryl aldehydes were good substrates for this reaction, as were branched aliphatic substrates, which gave the highest yields and enantioselectivities. α-unbranched aldehydes were less successful substrates, giving low yields and moderate enantioselectivity after tuning of the reaction conditions to prevent aldehyde self-condensation.[66] Unfortunately, even under these optimized conditions (employing neat acetone or chloroform as cosolvent for 3–7 days), the cross-aldol condensation product 4 (Scheme 1) was a significant by-product, resulting in low overall yield. Despite the low yield and modest enantioselection of this process, the simplicity and mildness of these reaction conditions is exceptional. This methodology was used by List and co-workers to complete the synthesis of (S)-ipsenol (28), a sex pheromone of the bark beetle. The acetone aldol has also been used for the syntheses of 4-hydroxypipecolic acid derivative 29[67] and carboxylic acid 30, a building block for the synthesis of epothilone.[68] A great deal of research has clarified the mechanism of the proline-catalyzed aldol reaction, which is essentially that of a class I aldolase (Scheme 5).[24,61,69–105] The accepted mechanism for the intermolecular process begins with rate-limiting enamine formation (A), followed by carbonyl addition, activated by the carboxylic acid of proline (B), followed by hydrolysis of iminium ion C to give aldol adduct 27.
aReferences are given for each product as superscript. D-Proline was used
NH
CO2H
20-30 mol%
O
R H
O+
25 26 DMSO, 8-16hexcess
R
OH O
27
OOH
O2N
O
Ph
OH
OOH
OOH
i-Pr
OOHi-Pr
OHi-Pr
O
OH
OOOTBS
OOH
N H
HN3
PMPO
HN
NPMP
OHHH
O
27a65
68% yield76% ee
27b65
62% yield72% ee
27c65
97% yield96% ee
27d66
34% yield73% ee
28(S)-ipsenol
29
30
27e67
62% yieldsingle diastereomer
27f68
75% yield99% ee
CHAPTER 2
22
O
HR
ONH
CO2HR
OH OR
OR
H
OH O
R
RH
O
R
NO
O
R
26 31+
1332 33 34
+ +
+ +
35 36 Scheme 6 : Side products obtained in the proline-catalyzed aldol reaction. The addition step has a similar energy barrier as the enamine formation, indicating that under different conditions or with different substrates, the rate-determining step may be the addition step. In fact, recent kinetic evidence obtained by Armstrong and Blackmond et al. indicates that under the reaction conditions studied, the addition step is rate determining.[106] Several by-products have been observed in the proline-catalyzed acetone aldol reaction that lead to reduced yields, including aldol condensation (yielding enone 33), and the
Scheme 5: Mechanism of the intermolecular proline-catalysed aldol76
NH
CO2H
O
26O
R
OH
27
R
OH N CO2H
N R H
O
25
R
O
H
O
O
H
H2O
13H2O
N CO2H
B
CA
CHAPTER 2
23
aldol reaction and condensation of the aldehyde component, which generates adducts 34 and 35, respectively (Scheme 6). Additionally, oxazolidinone 36 derived from the aldehyde component 31 has been observed. To achieve high yields of the desired adduct 32, acetone is used in a large excess to prevent homodimerization of the aldehyde and catalyst kill events, such as the formation of oxazolidinone 36. A beneficial effect of water in small amounts was first reported by Pihko and co-workers.[107,108] Armstrong and Blackmond et al. have recently clarified the role of water in the reaction (Scheme 7).[109]
They demonstrated that water actually decreases the rate of the reaction, as it must be extruded before the rate-limiting step (Scheme 5), but off cycle processes are shut down significantly in the presence of water, thereby giving an overall positive effect on the yield of the desired aldol product 27. By shifting the equilibrium between aldehyde 25 and iminium ion A toward aldehyde 25 with added water, the formation of by-products can be largely avoided (Scheme 7). Formation of oxazolidinone 37 and oxazole 38 (derived from decarboxylation of iminium ion A, followed by addition of ammonium ylide B to another equivalent of aldehyde 25) is largely prevented in this way. An alternative mechanism for proline-catalyzed reactions was proposed in 2007 by Seebach et al. (Scheme 8).[110] The authors propose that oxazolidinones, which are observable by NMR, are key players in the catalytic cycle.
NH
CO2HR H
O
25
13H2O
R
N CO2
H
B
A
NO
O
R 37
CO2
R
N
HR H
O
25
NO
R
R 38
Scheme 7: Off-cycle processes that are ameliorated by the addition of water.106
CHAPTER 2
24
NH
CO2HR,
O
39
13H2O
N
A
R,
O
R
E
40
R
O
O
R,
R
R H
O
25
N
C
O
O
R,
R
E
H2O
regioselective enamine formation
NO
R,
R
O
EB
Scheme 8 : Alternative oxazolidinone mechanism proposed by Seebach and Eschenmoser et al. 110 Their proposed mechanism begins by formation of oxazolidinone A by condensation of proline with the donor componant 39. Regioselective formation of an enamine, either by E2 elimination or through a two-step iminium formation and intramolecular proton transfer sequence, then undergoes a trans addition to an electrophile (approach from the Re face) to generate oxazolidinone C. Hydrolysis then gives the desired product 40. This mechanistic proposal differs greatly from the List-Houk model in that the key step is triggered by a γ-lactonization process and does not involve activation of the acceptor componant by the catalyst. This model is difficult to apply to the aldol reaction in which facial selectivity of the aldehyde, and not facial selectivity of the enamine is the relevant question. It is not obvious how this model would account for the high facial selectivity observed in the proline-catalyzed aldol reaction, nor is the question addressed by the authors, who limit their discussion to induction of enantioselectivity at the α-position. Also, this model can only be applied to catalysts bearing a free carboxylic acid group, which can participate in oxazolidinone formation. 2.3.3 Substituted ketone donors in the proline-catalyzed aldol reaction The proline-catalyzed aldol reaction was extended to ketones other than acetone in 2001 (Table 2).[22,66] Since the ketone was required in near solvent quantities, the reaction was limited to simple ketone substrates, such as cyclohexanone and cyclopentanone, for practical reasons. The anti aldol adducts 42 were favored over the syn configuration in most cases. For cyclic ketones, only one enamine geometry is possible, the E enamine A. The orientation of the aldehyde when approaching this enamine, therefore, gives rise to the diastereoselectivity. The orientation depicted in A is generally favored, as it avoids
CHAPTER 2
25
steric clashes with the alkyl group on the other side of the enamine, as long as RS is smaller than this alkyl group. Cyclohexanone tends to give higher diastereoselectivities than cyclopentanone, as do aliphatic aldehydes when compared to aromatic aldehydes. These reactions are typically run for 3 days with 10–30 mol% catalyst, indicating that the reaction rate is rather slow. The original conditions reported by Barbas et al.[111] for the synthesis of aldol adduct 42 were improved upon by using the solvent-free conditions reported by Hayashi et al. to give the cyclohexanone adduct 42a in 73% yield, 9:1 dr and in >99% ee favoring the anti isomer.[112] The cyclopentanone aldol catalyzed by proline has been used for the synthesis of adduct 42f, which was used for the synthesis of the antimalarial (+)-(11R, 12S)-mefloquine hydrochloride.[113] In 2001 Barbas and co-workers described the use of proline with 2-butanone, an unsymmetrical ketone.[111] Under the reaction conditions (20 mol% catalyst, 0.1 M substrate in 1:4 ketone : DMSO, ambient temperature for 1–2 days) only the linear product was observed. The authors suggest that the formation of the kinetic enamine is rate-limiting, resulting in observation of only the linear product. Interestingly, employing N-ethyl-N-methylimadazolium trifluoromethanesulfonate ([emim][OTf]), an ionic liquid, rather than using DMSO as solvent led to isolation of the branched product, with a strong preference for the anti diastereomer.[46,114]
Table 2: Substituted ketone donors in the proline-catalyzed aldol reactiona
NH
CO2HR1 H
O
O
+R2 R3
O
OH
O2N
R2 R3
O
R1
OH
10-30 mol%
13
25 41 42
O
Ph
OH OOH OOHOH O
OH O
N
CF3
F3COOH
OOH
O2N
OOH
n-Bu
OOH
OH
OOH
OH
OOH
OH
Cl
O O
OOH
OBn O O
OOH
OMe
MeO
O O
OOH
O O
OOH
O2N O O
OOHN
O
O OTBS
OOH
O2NOTBS
OOH
OTBS
42a111,112
65% (73%)1.7:1 (9:1) anti: syn89% (99%) ee (anti)67% ee(syn)
42b22
85% 1:1 anti: syn86% ee (anti)76% ee (syn)
42c22
68% 20:1 anti: syn97% ee (anti)
42d22
41% 7:1 anti: syn86% ee (anti)89% ee (syn)
42e22
77% 3:1 anti: syn95% ee (anti)20% ee (syn)
42f113
69% 1: 6.8 anti: syn74% ee (anti)71% ee (syn)
42g111
60% 80% ee
42h111
65% 77% ee
42i111
65% 58% ee
42j115
38% 1.7:1 anti: syn97% ee (anti)84% ee (syn)
42k115
62% 20:1 anti: syn99% ee (anti)
42l115
95% 1.5:1 anti: syn67% ee (anti)32% ee (syn)
42m118
40% 98:2 anti: syn97% ee (anti)
42n117
69% 94:6 anti: syn93% ee (anti)
42o121
75% 10:1 anti: syn98% ee (anti)
42p121
89% 6:1 anti: syn93% ee (anti)
42q121
75% 55:1 anti: syn98% ee (anti)
42r122
86% 90:7:3 anti:syn:linear90% ee (anti)15% ee (syn)
42s122
86% 20:10:70 anti:syn:linear43% ee (anti)
aReferences are given for each product as superscript
CHAPTER 2
26
NH
CO2H
CHO
OMe
13
DMSO, 12h
OH
O
4544
OMe4684%5:1 anti:syn
OOH
OH
OH
OH
O
O
HO
HO
47brassinolide
Scheme 9 : Use of the proline-catalyzed hydroxyacetone aldol reaction for the synthesis of brassinolide.[116]
2.3.4 proline-catalyzed hydroxy- dihydroxy and substituted hydroxyacetone aldol reaction Hydroxyacetone has also been used successfully as a donor for the proline-catalyzed direct aldol reaction, using similar reaction conditions (20–30 mol% catalyst, 0.1 M substrate in 1:4 ketone:DMSO, ambient temperature for 1–3 days).[115] Formation of the branched products is observed, with high diastereoselectivity for α-branched aldehydes, and lower diastereoselectivity observed for aryl aldehydes and α-unbranched aldehydes. Low yields were observed for α-unbranched aldehydes, similar to the acetone aldol. This reaction has been used for a formal synthesis of the steroidal plant-growth inhibitor brassinolide (Scheme 9).[116] The dihydroxyacetone derivative 2,2-dimethyl-1,3-diox-5- one has also been used successfully as a donor in the proline-catalyzed aldol reaction.[117–119] In 2005 Enders and Grondal reported a highly anti-selective aldol reaction that can be used to generate protected sugar derivatives in high enantioselectivity by selecting the appropriate aldehyde substrate. Aldol adduct 42m, for example, is a protected L-ribulose derivative. Gratifyingly, only one equivalent of the ketone donor was needed to obtain the desired adducts in good yields, employing 30 mol% proline as catalyst. Previous work by Barbas and co-workers demonstrated that unprotected dihydroxyacetone could be used and gave good diastereoselectivity, however, the aldol adducts obtained were racemic in this case.[120] Later in the same year as the Enders and Grondal report, Barbas and co-workers disclosed similar reaction conditions for the use of 2,2-dimethyl-1,3-diox-5-one, demonstrating that the reaction proceeded well with aliphatic, aromatic, and even protected phthalimide substrates using 20 mol% proline.[121] Aliphatic aldehydes gave higher diastereoselectivity than aromatic derivatives. It is notable that the α-unbranched derivative 42o was obtained in high yield, in contrast to the adduct derived from reaction of this aldehyde with acetone or cyclohexanone. The discovery of these simple reaction conditions for the use of a protected form of dihydroxyacetone in a direct catalytic aldol reaction has opened up new synthetic routes for the synthesis of various sugar derivatives.
CHAPTER 2
27
A protected variant of hydroxyacetone has also been used to generate diols in which one of the alcohols is differentiated from the other with a protecting group. TBS protected hydroxyacetone undergoes anti-selective aldol addition with aromatic substrates.[122] Aldol adduct 42r is obtained with 90% ee, however, the ee was lower for other aromatic aldehydes (for example, 40% ee was obtained when benzaldehyde was used). α,β-unsaturated aldehydes gave either no yield or gave predominantly the linear isomer, such as adduct 42t. The ee in this case was also quite low. Table 3: Ketone electrophiles in the proline-catalyzed aldol reactiona
R1 R2
O
+R3 R3
O NH
CO2H
13R3 R3
O
R1
OHR2
OHO
ON
50(S)-oxybutynin48 41
O O
OO
O
OHOF3C OH OOHEtO2C OF3C OH
O2N
O(OEt2)P OHO
OP OHO
(i-PrO2)O(OEt2)P OH
O
MeO
49
49a118
57% yield94% ee
49b123
98% yield64% ee
49c124
79% yield96% ee20:1 dr
49d126
75% yield84% ee
49e127
91% yield97% ee
49f127
60% yield96% ee
49g127
32% yield86% ee
10-50%
aReferences are given for each product as superscript 2.3.5 Ketone electrophiles, proline-catalyzed aldol reaction Proline catalysis has also been used for reactions with highly activated ketone electrophiles 48 (Table 3). The self-condensation of 2,2-dimethyl-1,3-diox-5-one was observed by Enders and Grondal, producing adduct 49a in 94% ee.[118] Zhang and co-workers reported the use of α-trifluoromethyl ketones for the synthesis of aldol adducts such as 49b with only 10 mol% proline with excellent yields, though the best ee observed was 64%.[123] Maruoka demonstrated the feasibility of using α-keto esters as electrophiles with cyclohexanone as donor in 2005.[124] Aldol adduct 49c was obtained in excellent enantio- and diastereoselectivity, although 50 mol% catalyst was needed to achieve these excellent results. Adduct 49c was taken on to complete the synthesis of a key intermediate for the synthesis of (S)-oxybutynin 50. The research groups of Zhang and
CHAPTER 2
28
Shao reported the use of α-keto esters as electrophiles for the acetone aldol catalyzed by proline in 2006 using 60 and 50 mol% proline, respectively.[125,126] α-Keto phosphonates have also been used as substrates for the proline-catalyzed acetone aldol, yielding the desired aldol adducts 49 in high yield and enantioselectivity when electron-deficient aldehydes are employed as the acceptors, using a catalyst loading of 20 mol%.127 Electron-rich aromatic substrates, however, gave lower yields due to their lower reactivity. Adduct 49g was obtained in only 32% yield using 50 mol% proline. 2.3.6 Aldehyde donors in the proline-catalyzed aldol reaction Aldehydes can also be used as donors for the proline catalyzed aldol reaction. Barbas et al. first noted the trimerization of acetaldehyde 51 in 10% yield and 90% ee (Scheme 10).[128] Dienal 53 was isolated together with the interesting trimer 52.
NH
CO2H
H
O13
51
catalytic
H
O OH
5210%90% ee
H
O
+
53
Scheme 10 : Trimerization of acetaldehyde.128
Table 4 : Aldehyde donors in the proline-catalyzed aldol reactiona
NH
CO2HR1 R2
O
R3
H
O
48 31+
10-50 mol%
R1 H
O
R3
OHR213
54
EtO2C H
OOHEtO2C
EtO2C H
OOHEtO2C
EtO2C H
OOHEtO2C
PhF3C H
OOHEtO2C
H
OOH
H
OOH
H
OOH
n-Bu
H
OOH
OBn
BnOH
OOH
OMOM
MOMOH
OOH
OTBS
TBSO
H
OOHTIPSO
H
OOHBnO
i-Pr
H
OOH
OTIPS
H
OOH
OBnH
OOHS
S
H
OOHS
SH
OOH
OTBS
S
Sn-hexyl H
OOHN
i-Pr
H
OOHN
n-Bu
O
O O
O
54a129
90% yield90% ee
54b129
94% yield88% ee
54c129
97% yield90% ee
54d129
98% yield1.5 : 1 dr67%, 81% ee
54e130
80% yield4 : 1 dr99% ee
54f130
88% yield3 : 1 dr97% ee
54g130
80% yield24 : 1 dr99% ee
54h133
73% yield4 : 1 dr98% ee
54i133
42% yield4 : 1 dr96% ee
54j133
62% yield3 : 1 dr88% ee
54k133
75% yield4 : 1 dr99% ee
54l132
64% yield4 : 1 dr94% ee
54m133
43% yield8 : 1 dr99% ee
54n133
33% yield7 : 1 dr96% ee
54o136
85% yield16 : 1 dr99% ee
54p136
75% yield20 : 1 dr97% ee
54q136
52% yield13 : 1 dr70% ee
54r138
89% yield6 : 1 dr97% ee
54s137
92% yield6 : 1 dr95% ee
aReferences are given for each product as superscript The first proline-catalyzed cross-aldol reaction of aldehyde donors was reported by Jørgensen et al. (Table 4).[129] Using 50 mol% proline, aldehydes were coupled with non-enolizable α-keto esters to give α-chiral aldehydes 54. While adducts 54a and 54b were isolated in good enantioselectivity, the phenyl substituted adduct 54c was found to be racemic. The trifluoromethyl derivative 54d was isolated in poor diastereoselectivity with moderate enantioselectivity. Northrup and MacMillan reported a remarkable breakthrough for the cross-aldol reaction of aldehydes in 2002.[130] Using slow addition of the donor aldehyde (2 equivalents) to
CHAPTER 2
29
the acceptor aldehyde the desired cross-aldol products 54 could be obtained in excellent yields and enantioselectivities with only 10 mol% proline. The diastereoselectivity was moderate with α-unbranched or aromatic acceptor aldehydes and excellent with α-branched acceptor aldehydes. Even remarkably similar aldehydes gave exclusively the desired cross-aldol adduct, such as adduct 54f. The acceptor substrate (in the case where the aldehydes are different) in each case is either non-enolizable or generates a less reactive enamine. In this way the dimerization of the acceptor aldehyde is suppressed. Pihko and Erkkila used this methodology for a short synthesis of prelactone B (Scheme 11).[131] MacMillan and co-workers also used this method for the synthesis of callipeltoside C.[132] In 2004 MacMillan and co-workers extended this methodology to the dimerization of protected α-hydroxy aldehydes to give highly functionalized aldehydes.[133] These substrates could themselves be used in a subsequent Mukaiyama aldol to give protected sugar derivatives.[134] Mangion and MacMillan used this methodology to complete the synthesis of (_)-littoralisone (Scheme 12).[135] Cross-aldol reactions with aliphatic aldehyde donors could also be used to give the desired aldol adducts, even with sterically-hindered donor aldehydes (adduct 54l for example). When more hindered aldehydes, such as isobutyraldehyde, that do not readily participate in enamine formation, are employed, both triisopropylsilyl- and benzyl-protected hydroxyacetaldehyde can be used as the donor component in the cross-aldol reaction, albeit in rather low yields. Storer and MacMillan reported the use of α-thioacetal aldehydes as acceptors for the cross-aldol reaction of aldehydes in 2004.[136]
H
O
H
O
+
55 56
NH
CO2H
1. 10 mol%
DMF, 40 h, 5 oC2. TBSOTf,2,6-Lutidine
H
O OTBS
5761% yield40:1 anti:syn>99% ee
O
O
HO
58Prelactone B
H
O+
55
H
O
59
OPMB NH
CO2H
10 mol%
DMF, 40 h, 5 oCH
O OH
OPMB O
OTBS
CO2MeOMeH
O
A
6048% yield12:1 syn:syn>19:1 Felkin:anti-Felkin99% ee
61
H
O
OTIPS
13
13
NH
CO2H
10 mol%
DMF, 40 h, 5 oC
H
O
6375% yield99% ee
OH
OTIPSTIPSO
62
O O
Cl3C NH
BOMeTIPSO
HO
O
OH OH
MeO O
Cl
O O
OHOH
MeO
A
B
64 65Callipeltoside C
ent-13
Scheme 11 : Application of aldehyde aldol reaction in the synthesis of prelactone B and callipeltoside C [131, 132]
CHAPTER 2
30
OBnH
OH
OBn
O
54h
BnO
O
O
TMSO
BnO
O
O
O
OH OBnOBn
HO
OH
H
H
O
O
OO
O
O
OH
OH
OH
H
H
(-)-littoraalisone68
6765% yield
1. 66
2. MgBr2.OEt2
Scheme 12 : MacMillan's direct aldol-Mukaiyama aldolsequence: application to the synthesis of (-)-littoralisone.[135]
Table 5 : Pyranose formation with proline catalyst[135,136]
H R
O
+ H
O
25 55
NH
CO2H
1. 10 mol%
4 oC to rt2. MnO2, EtOAc
OO R
OH69
OO Et
OH
69a53% yield33% ee
OO
OH69b32% yield12% ee
OO
OH69a24% yield11% ee
i-Pr i-Bu
13
The highly functionalized products 54o–q were formed in moderate to excellent yields, and in excellent diastereo- and enantioselectivities with a variety of aldehyde donors. Tanaka et al. reported the use of a protected nitrogen-containing aldehyde for the production of adduct 54r,s in 2004.[137] The nitrogen-containing aldehyde could also be used as the donor. Aldehyde cross-trimerizations have also been reported for the synthesis of complex products in only one step from simple substrates. Barbas and co-workers reported the trimerization of alkyl aldehydes in 2002 using syringe-pump addition of two equivalents of propionaldehyde to one equivalent of the acceptor aldehyde (Table 5).[138] The trimers were isolated after oxidation to the corresponding lactones 69 (The proposed relative configuration was later corrected by Cordova et al.139 The trimers were isolated in rather low and disappointingly low ee, but given the simplicity of the reaction conditions and
CHAPTER 2
31
the amazing complexity generated in a single reaction, the transformation is exceptional. The authors note that the ee of the reaction degrades with time, for example 69a was obtained in 47% ee after 10 h at 4 oC. Cordova and co-workers reported a similar reaction with considerably higher enantioselectivity in 2005 (Table 6).[139] By altering the reaction conditions they were able to increase the enantioselectivity considerably, likely by shutting down the racemization observed under the conditions described by Barbas. Cordova observed that the ee was highly dependent on the reaction conditions and was best controlled by portion-wise addition of propionaldehyde. By separating the two sequential aldol steps, and using the opposite enantiomer for the second step, they were able to effectively shut down the retro-aldol for the first step, and thereby increase the enantioselectivity. This also allowed them to vary the three component aldehydes. The yields are rather low, but given the rapid assembly of complexity, the modest yield is easily compensated for. Table 6: Two steps polyketide synthesis139
H
O
+ H R2
O
31 25
NH
CO2H
10 mol%
O OH
OH71
R1 DMFH R2
O OH
R1
70
NH
CO2H
10 mol%
ent-13
DMF
H
O
55
R2
R1 Me
O OH
OH
Et
Me Me
O OH
OH
Me Me
O OH
OH
BnO Me
BnO
71a29%yield99% ee
71b41%yield99% ee
71c39%yield99% ee
13
H
O
72
NH
CO2H
10 mol%
OBn DMF, 4d H
O OH
OBn54h51% yield4:1 dr98% ee
13OBn +
O OH
OH
BnO OBn
BnO
7341%yield99% ee
Scheme 13 : Proline-catalyzed sugar synthesis140
Remarkably, this trimerization was expanded to the synthesis of sugars by Cordova and co-workers in 2005 (Scheme 13).[140,141] For this class of aldehyde it appears that the retro-aldol is not problematic. Using only 10 mol% L-proline, 41% of protected hexose 73 was generated in excellent enantioselectivity, together with 51% of the dimmer 54h. A
CHAPTER 2
32
large non-linear effect was observed for this reaction, with proline of only 40% ee generating the product hexose 73 in >99% ee. This observation led the authors to propose a model for the evolution of homochirality, in which simple amino acids with low levels of enantiomeric excess amplify this small imbalance of one enantiomer to homochirality through prebiotic gluconeogenesis. The ability of such a simple molecule to generate such high levels of complexity is truly remarkable. Given the low cost and abundance of proline, as well as its wide scope, it is certainly the first choice for any enamine-catalyzed reaction, including the direct catalytic aldol reaction. 2.4. Modern Trends and Development of New Difunctional Organocatlysts Despite the utility of proline for carrying out a wide range of aldol reactions, a great deal of effort has been exerted for the development of new catalysts. The long reaction times and poor results with certain substrates, such as α-unbranched aldehydes, have led numerous researchers to develop more reactive catalysts, as well as design catalysts that will not undergo oxazolidinone formation, which is the major catalyst deactivation pathway (Scheme 6 and 7). The need for high catalyst loadings, large excesses of ketone and long reaction times when using proline as catalyst has at times been imputed to its low solubility in the reaction media, and therefore many catalyst designs incorporate increased lipophilicity. New catalyst designs have also provided access to isomers not favored using reported proline-catalyzed conditions. The initial screen of catalysts reported by List and co-workers in 2000 for the asymmetric aldol of acetone with p-nitrobenzaldehyde 74 illustrates the effect of a number of different modifications of the proline structure (Table 7).[65,66] Primary amino acids histidine (75), tyrosine (76), phenylalanine (77), and valine (78) provide less than 10% yield of the desired adduct 27a. Methylation of valine to produce an acyclic secondary amine (79) did not improve the yield. Both the azetidine (80) and piperidine (81) were inferior to the pyrrolidine structure of proline (13).
CHAPTER 2
33
Table 7 : Initial catalyst screening for acetone aldol reaction65,66
H
O2N
O
+
O
26excess74
O2N 27a
OH O30-40 mol%catalyst
DMSO, 4-24h
H2N CO2H
HN
N
H2N CO2H
HO
H2N CO2H H2N CO2H NH
CO2HMe
NH
CO2HNH
CO2HNH
CO2H NH
CONH2
S
NH
CO2H
NH
CO2H
HO
NH
CO2H
t-BuO
NH
CO2H
AcO
NH
CO2H
HO
75<10% yield
76<10% yield
77<10% yield
78<10% yield
79<10% yield
8055% yield40% ee
1368% yield76% ee
81<10% yield
82<10% yield
8367% yield73% ee
8485% yield78% ee
8550% yield62% ee
8670% yield74% ee
8750% yield-62% ee
Changing the carboxylic acid to an amide (82) also gave little reactivity. The thiazolidium carboxylate (83) gave similar, though slightly inferior results. Interestingly, proline derivative 84 gave a higher yield and enantioselectivity than proline itself. The tert-butyl ether derivative 85 gave lower yield and enantioselectivity, as did the acylated derivative 86, though to a lesser extent. Diastereomer 87 provided the opposite enantiomer, with reduced yield and selectivity. A number of other amino acids and small peptides have been evaluated as alternate catalysts for the direct catalytic asymmetric aldol reaction (Table 8).[15,142–150] The reaction between acetone and p-nitrobenzaldehyde has been used in this field as a model system to evaluate catalyst activity and is a convenient way to compare the performance of the multitude of available catalysts. Among the amino acids and peptides screened, L-Pro-L-Pro-L-Asp–NH2, reported by Wennemers and co-workers, gave the best results.148 The catalyst loading could be significantly decreased to 1 mol% to give the desired adduct ent-27a in 99% yield and 80% ee after 4 hours, using acetone as solvent. Compared to the other reported amino acids and small peptides, this is a significant increase in catalytic activity. Interestingly, this catalyst gives the opposite enantiomer
CHAPTER 2
34
than that obtained via proline catalysis, an observation the authors trace to the secondary structure of this catalyst. Table 8: Screening of amino acids and small peptides for acetone aldol reactiona
aReferences are given for each product as superscript Many catalysts have been developed based on the structure of proline (Table 9). Some of the common modifications to the proline structure include increasing the hydrophobicity to improve solubility in organic solvents and modification of the carboxylic acid to a variety of other hydrogen-bonding groups. Other trends include adding steric bulk and stereocenters to enhance the enantioselectivity. Many of these catalysts require numerous steps for their synthesis, and this should be considered when choosing a catalyst. Proline, on the other hand, is abundant and inexpensive, and therefore new catalyst designs must provide significant improvements to surpass the utility of proline, both in terms of selectivity and reactivity. 2.4.1 Proline base Catalysts for Acetone Aldol reaction One of the earliest designed catalysts was reported by Barbas et al. in 2001.[111] Using 20 mol% of catalyst 88 over the course of 1–2 days, adduct 27a was isolated in improved enantioselectivity when compared to proline, but the reactivity of this catalyst was rather low, reflected in the high catalyst loading, long reaction times and the need to use acetone as a cosolvent. Yamamoto et al. reported the use of catalyst 89 for the direct catalytic aldol reaction in 2001.[151,152] With only 3 mol% catalyst 89, adduct 27a was obtained in moderate yield and ee after 2 hours. Despite this improved reactivity, acetone was still used as solvent under the optimized conditions. In 2003, Gong and Wu et al. reported the
CHAPTER 2
35
use of 20 mol% of catalyst 90 over the course of 1–2 days.[153,154] The enantioselectivity obtained was quite good, though the reactivity was not high, and acetone was again needed as solvent. Hartikka and Arvidsson reported the use of tetrazole 91 for the direct catalytic aldol of acetone with aldehyde 74,[155,156] a catalyst that was reported in the same year by Saito and Yamamoto et al. for reaction with chloral and trifluoroacetaldehyde.[157] A catalyst loading of 5 mol% and reaction time of 40 hours with acetone as a cosolvent gave the product 27a in 82% yield and 79% ee. Sulfonylcarboxamide catalyst 92 was reported in 2004 by Berkessel and co-workers.[158] The catalyst was used in 30 mol% loading with acetone as a cosolvent over the course of 1 day to yield the desired adduct 27a in excellent yield and enantioselectivity. Benzoimidazole catalyst 93, reported by Landais and Vincent et al.,[159] could be used with a catalyst loading as low as 2 mol%, together with trifluoroacetic acid, in neat acetone over the course of 1 day to give the desired adduct 27a in 87% yield and 82% ee. In 2005 Gong et al. reported an extremely enantioselective catalyst 94 possessing a chiral diester sidechain.[160] Using only 2 mol% 94 the aldol reaction yielded adduct 27a in 62% yield and in 99% ee. The reaction was carried out in neat acetone over the course of 1–2 days, indicating that the reactivity was still rather low. Chimni and co-workers reported the use of proline derivative 95 in 2005.[161,162] The reaction conditions required the use of 20 mol% 95 in wet acetone over the course of 40 hours. Unfortunately the enantioselectivity was lower than that obtained using proline alone. Thioamide 96, reported by Gryko and Lipinski, delivered adduct 27a in 62% yield and 84% ee using acetone as solvent and 20 mol% catalyst loading after 68 hours.[163,164] Ley and co-workers reported sulfonylcarboxamide catalyst 97, similar to catalyst 92, which gave adduct 27a in 100% yield and 92% ee, using acetone as solvent and 20 mol% catalyst loading over 1–2 days.[165] Camphorsulfonyl-derivative 98 was disclosed by Bellis and Kokotos in 2005.[166] The catalyst could be used in 10 mol% loading with an equal molar amount of triethylamine with acetone as a cosolvent over 18–24 hours yielding adduct 27a in 71% yield and 90% ee. Kokotos et al. also reported sulfonylcarboxamide catalyst 99 in the same year, similar to catalysts 92 and 97, which gave adduct 27a in 63% yield and in 90% ee using 20 mol% catalyst and an equivalent amount of triethylamine, with acetone as a cosolvent over the course of 18–24 hours.[167] C2-Symmetric stilbene derivative 100 was disclosed by Zhao and co-workers in 2005.[168] The catalyst was used in 10 mol% loading in acetone over 12–24 hours, delivering adduct 27a in 88% yield and 98% ee.
CHAPTER 2
36
Table 9: Proline base catalysts for acetone aldol reactiona
H
O
O2N+
O
74 26
Catalyst
OH
O2N27a
S
NH
CO2HNH
N.TfOH
NH
O
HN
HO
Ph
Ph
NH HN N
NN
NH O
HN S
O Oi-Pr
i-Pr i-Pr
NH HN
N NH
O
HN
HO
CO2Et
CO2EtNH O
NH
Ph
.HBrNH S
NH
Ph
NH O
HN S
Ph
O O
NH OH
O
OSO
O
O
NH O
HN S
O O
Me
NH
NHO
HN
PhPhO
HN
NH
PO
OEtOEt N
H O
HN N
Bn
O HN
.TFANH
CO2H
NH
CO2HHO2C NH O
HN OH
Ph Ph
i-Bu
NH
NHO
HNO
CF3NMe2
NH
OHN
NH HN
O O
HN
NH
NH O
HN
NH2
NH OH
O
TBSO
OH
NH
OHN
NH
NHO
HNO
NH
O
HN
HO
Ph
Ph
TBSO
HO OH
NH
OMe
OO
HN
NH O
NH(OPh)2P O
NH
O
HN
HO
CO2Et
CO2Et
TBSO
NH
O
HNN
N
NH S
HN
NH
NHO
N
PhPh
(n-C5H11)2 NH
O
HN
PhO
HO
t-Bu.TFA
88111
Barbas 200160% yield86% ee
89151,152
Yamamoto 2001,0260% yield88% ee
90153,154
Gong and Wu 200366% yield93% ee
91155,156
Arvidsson 2004,0582% yield79% ee
92158
Berkessel 200499% yield95% ee
93159
Landais and Vincent 200487% yield82% ee
94160
Gong 200562% yield99% ee
95161,162
Chimni 200586% yield50% ee
96163,164
Gryko 200562% yield84% ee
97165
Ley 200599% yield92% ee
98166
Kokotos 200571% yield90% ee
99167
Kokotos 200563% yield90% ee
100168
Zhao 200588% yield98% ee
101169
Amedjkouh 200669% yield82% ee
102170
Sun and Wu 200695% yield96% ee
103171
Zhao 200687% yield95% ee
104172
Wu 200691% yield65% ee
105173
Singh 200670% yield99% ee
106174
Xiao 200657% yield77% ee
107175
Benaglia 200692% yield90% ee
108176
Najera 200692% yield88% ee
109177
Zhou 200680% yield51% ee
110178
Hayashi 200663% yield67% ee
111179,180
Latanzi 200799% yield70% ee
112181
Xiao 200771% yield66% ee
113182
He and Gong 200757% yield91% ee
114183
Luliano 200799% yield80% ee
115184
Li 200865% yield72% ee
NH
O
HN
NO2
O2NNO2
116185
Shirai 200890% yield85% ee
117186
Gong 200885% yield71% ee
118187
Xiao 200897% yield92% ee
119188
Najera 200880% yield80% ee
120189
Da 200996% yield94% ee
121191
Fu 200990% yield80% ee
O
aReferences are given for each product as superscript Phosphonate catalyst 101 was reported in 2006 by Diner and Amedjkouh to give the opposite enantiomer of adduct 27a in 69% yield and 82% ee.[169] The catalyst was used in 20 mol% loading with acetone as cosolvent over the course of 1 day. Sun and Wu et al. disclosed hydrazide catalyst 102 for the direct catalytic aldol in 2006.[170] With 20 mol% of catalyst 102 and an equal amount of trifluoroacetic acid, employing acetone as a cosolvent over 7 hours the desired adduct 27a was obtained in 95% yield and in 96% ee. Zhao et al. reported 4-disubstituted proline derivative 103 in 2006 for the direct catalytic aldol reaction.[171] Using 10 mol% of this catalyst with acetone as cosolvent over 2 days the adduct 27a was obtained in 87% yield and 95% ee. C2-Symmetric proline derivative 104, together with an equal amount of triethylamine, was employed by Wu and co-workers in 2006.[172] The catalyst was used in 30 mol% loading and the reaction was run in acetone as solvent over 30 hours to deliver the desired adduct 27a in 91% yield but in only 65% ee. Singh et al. reported the highly selective catalyst 105 in 2006.[173] Using 10 mol% catalyst in acetone for 1–2 days the product 27a was obtained in 70% yield and 99% ee. Catalyst 106 was reported for the asymmetric aldol reaction by Xiao and co-workers.[174] The catalyst was used in 20 mol% loading with 40 mol% acetic acid over 18 hours to give the adduct 27a in 57% yield and 77% ee. Binaphthyl-derivative 107, disclosed by Benaglia and co-workers, can be used in 10 mol% with acetone as solvent over 88 hours to deliver adduct 27a in 92% yield and in 90% ee.[175] A C2-symmetric binaphthyl derivative 108 was disclosed by Najera and co-workers, used in 10 mol% loading along
CHAPTER 2
37
with 20 mol% benzoic acid, with acetone as cosolvent over 36 hours. These conditions delivered the adduct 27a in 92% yield and in 88% ee.[176] Zhou and Zhou et al. reported the use of spiroderivative 109, employing only 1 mol% catalyst over 4 hours in acetone.[177] This increased reactivity resulted in an 80% yield of adduct 27a, but unfortunately only in 51% ee. Hayashi et al. reported the utility of silyl protected 4-hydroxyproline 110 in 2006 for the direct catalytic asymmetric aldol reaction.[178] The catalyst loading used was 10 mol% with 5 equivalents of acetone in water over 18 hours. The adduct 27a was obtained in 63% yield and 67% ee. Binaphthyl derivative 111 was reported in 2007 by Lattanzi et al.[179,180] The catalyst was used in 5 mol% loading using only 3 equivalents of acetone over 10 hours to deliver the adduct in 99% yield and in 70% ee. Catalyst 112, reported by Xiao in 2007, was used in 20 mol% loading with an equal amount of acetic acid.[181] The reaction was run in brine with 10 equivalents of acetone over 39 hours to yield adduct 27a in 71% yield and 66% ee. He and Gong et al. disclosed the use of 5 mol% catalyst 113 using acetone as solvent over 60 hours.[182] The adduct 27a was obtained in 57% yield with 91% ee. Iuliano and co-workers reported the synthesis and use of steroid-derived catalyst 114 containing a D-proline tethered to the 6-membered ring.[183] The catalyst was tested for reactivity in the direct catalytic aldol reaction with p-nitrobenzaldehyde 74. The catalyst was used in 5 mol% loading with acetone as a cosolvent over the course of 2 days. The reaction yield was not given, but proceeded in complete conversion to give adduct 27a in 80% ee. Phosphoramide catalyst 115 was reported in 2008 by Li and co-workers.[184] With 10 mol% catalyst, an equal amount of N-methylmorpholine and 6 equivalents of acetone the product 27a was obtained in 65% yield and 72% ee. Trinitroanilide catalyst 116 was reported by Shirai and co-workers in 2008.185 The reaction was performed using HMPA as solvent with 30 equivalents of water and 20 equivalents of acetone to give the adduct 27a in 90% yield and 85% ee after 4 days. Catalyst 117, which is similar to catalyst 94, was reported by Gong et al. in 2008.[186] Using only 1 mol% catalyst loading and 2 equivalents of acetone the adduct was obtained in 85% yield and 71% ee after 14 hours. Cinchona alkaloid derivative 118 was reported by Xiao et al. in 2008.[187] Similar conditions were reported by Liu and co-workers in 2009.[188] The reaction was carried out using 10 mol% catalyst 118 and 20 mol% acetic acid in acetone over the course of 1–3 days to deliver adduct 27a in excellent yield and in 92% ee. Najera and co-workers reported the use of prolinethioamide 119 for the direct catalytic asymmetric aldol reaction in 2008.[189] The reaction conditions consisted of using 5 mol% of catalyst 119 for 2 days, yielding adduct 27a in 80% yield and 80% ee. In 2009, Da and co-workers reported the use of stilbene catalyst 120.[190] Using only 1 mol% catalyst, together with an equal amount of 2,4-dinitrophenol, and 10 equivalents of acetone a 96% yield of adduct 27a was obtained in 94% ee after 20 hours. Fu and co-workers reported the use of catalyst 121 in 2009. Adduct 27a was obtained in 90% yield in 80% ee using 10 mol% catalyst loading and only two equivalents of acetone.[191] Although many of these catalysts have successfully improved the enantioselectivity of the aldol reaction between acetone and p-nitrobenzaldehyde, reactivity remains a problem. Da’s catalyst 120 gives perhaps the best combination of low catalyst loadings, good yield, and good enantioselectivity amongst the reported catalysts. The catalyst can be made in three steps with 76% overall yield. There is still a great deal of room for improvement in terms of reactivity, as the reaction times are almost uniformly very long (days). The need for huge excesses of the ketone
CHAPTER 2
38
component is also a huge drawback in cases in which the ketone is of more value than acetone. 2.4.2 Non-Proline base Catalysts for Acetone Aldol reaction A variety of catalysts have been reported that are not based on the structure of proline (Table 10). Maruoka reported binaphthyl catalyst 122 in 2005, which catalyzes the aldol reaction between p-nitrobenzaldehyde 74 and acetone using 5 mol% 122 with 27 equivalents of acetone in 82% yield and with 95% ee over the course of 1 day.[192] Later the same group reported the use of the highly substituted biphenyl catalyst 123 which could be used in as little as 0.5 mol% to give the desired adduct 27a in 90% yield and 96% ee, although the reaction took 2–3 days to complete and required the use of acetone as solvent to achieve these results.[193] In 2007 Teo reported the use of siloxy serine derivative 124 for the direct catalytic aldol reaction with cyclic ketones.[194] Unfortunately, the yield and selectivity were low when applied to acetone. Luo and co-workers reported the use of a primary amine catalyst 125 for the asymmetric aldol.[195] Using 10 mol% catalyst with 20 equivalents of acetone, adduct 27a was obtained in 94% yield and 95% ee after 20–72 hours. Liu et al. reported the use of cinchona alkaloid derivative 126 for use with cyclic ketones in 2007.[196] When applied to acetone, the catalyst 126 gave disappointingly low yield and enantioselectivity. Binaphthyl catalyst 127 was reported by Liu and Luo et al. in 2008.[197] The catalyst 127 was used in a 10 mol% loading with 20 mol% trifluoroacetic acid using acetone as solvent to deliver adduct 27a in 43% yield and 94% ee. The rest of the material was almost entirely the aldol condensation product, rather than unreacted starting aldehyde 74. Bispidine catalyst 128 was reported by Feng and Hu et al. in 2008 and applied to the acetone aldol with p-nitrobenzaldehyde 74.[198] Using 30 mol% catalyst 128 in acetone with 30 mol%
CHAPTER 2
39
Table 10: Non-proline base catalysts for acetone aldol reactiona
H
O
O2N+
O
74 26
Catalyst
O2N27a
NH
CO2H
MeO
MeO
NH
CO2HMeO
MeO
OMe
OMe
OTBDPSCO2H
NH2 N
NH2.TfOH N
H2N N
NPh
H2N
NH N O
H2N Ph NH2N.TFA
O
H2N
NHPh
i-Bu
i-BuHO Ph
H2N NHTf
Ph
122192
Marouka 200582% yield95% ee
123193
Marouka 200690% yield96% ee
124194
Teo 200742% yield41% ee
125195
Luo and Cheng 200794% yield95% ee
OOH
126196
Liu 200725% yield56% ee
127197
Luo and Liu 200843% yield94% ee
128198
Feng and Hu 200870% yield91% ee
129199
Shao 200871% yield87% ee
130200
Da 200982% yield96% ee
131201
Miura and Imai 200961% yield29% ee
aReferences are given for each product as superscript 3,3',5,5'-tetrabromobiphenol as an additive adduct 27a was obtained in 70% yield with 91% ee after 2 days. Binaphthyl derivative 129, disclosed by Shao et al. in 2008, was used in only 3.5 mol% catalyst loading with 20 equivalents of acetone.[199] The aldol adduct 27a was obtained in 71% yield and 87% ee after 2 days. In 2009, Da et al. reported the use of catalyst 130 for the asymmetric aldol.[200] When applied to p-nitrobenzaldehyde 74 and acetone, the reaction proceeded with 82% yield and 96% ee. The reaction conditions included the use of 20 mol% catalyst 130 and 20 mol% 2,4-dinitrophenol in acetone as solvent over the course of 26 hours. Triflamide catalyst 131 was reported in 2009 for use with cyclic ketones.[201] Unfortunately, when the reaction conditions were applied to acetone, both the yield and enantioselectivity were disappointingly low. Among the non-proline derived catalysts, the biphenyl catalyst 123 of Maruoka and the cyclohexanediamine catalyst 125 of Luo and Cheng stand out. Although the Maruoka catalyst 123 is the more active, the simplicity of Luo and Cheng’s catalyst 125, which can be synthesized in far fewer steps, make it an appealing choice. 2.4.3 Benzaldeyde Acceptor in Acetone Aldol reaction Given the high reactivity of p-nitrobenzaldehyde 74 relative to typical aldehydes, it is an excellent substrate for finding reactivity initially, but it is less useful as a measure of the
CHAPTER 2
40
general applicability of a catalyst for less reactive (and more typical) substrates. For this reason the reactivity of various catalysts using benzaldehyde (132) as an acceptor have been compared (Table 11). Proline was found to catalyze this reaction in 62% yield and in 72% ee using 30–40 mol% catalyst loading with acetone as cosolvent for 2–8 hours (Table 1). Among the catalysts described, many do not surpass this level of reactivity and enantioselectivity.[142,148,151,156,161,162,170,172,177,179,185,202,203] Among those that do are thiazole 88,[111] stilbene derivative 90,[153] diester 94,[160] C2-symmetric catalyst 100,[168] 4-disubstituted proline derivative 103,[171] prolinamide 134,[173,204] binaphthyl derivative 107,175 diamine 125,[195] cinchona alkaloid derivative 118,[187] sulfonamide 135,[205] and 4-hydroxy proline derivative 136.[206] Singh’s catalyst 134 was used in an analogous fashion to derivative 105 (Table 9). Sulfamide catalyst 135, also developed by Singh,[205] was used in 5 mol% loading using 4 equivalents of acetone to give adduct 27b in 75% yield with 89% ee after 20–52 hours. Among the catalysts reported with benzaldehyde 132, the 4-hydroxyproline catalyst 136 of Nakano and Takeshita stands out for its high yield and enantioselectivity.[206] With only 5 mol% catalyst (using acetone as solvent) adduct 27b was obtained in 99% yield and >99% ee in 36 hours. Interestingly, although the enantioselectivity of the catalytic system remained excellent, the yield of the reaction dropped to 48% when cyclohexanecarboxaldehyde was used. Notably, although Wennemers catalyst L-Pro-L-Pro-L-Asp–NH2 gave decreased enantioselectivity, the catalyst could be used in only 1 mol% loading.[148] 2.4.4 p-MeO-benzaldeyde Acceptor in Acetone Aldol reaction When the even more electron-rich aromatic aldehyde p-methoxybenzaldehyde 137 was used, reactivity dropped off significantly for many of the catalysts (Table 12). Singh’s prolinamide catalyst 134 and Nakano and Takeshita’s catalyst 136, using identical conditions as described above, retained their high activity and excellent enantioselectivity. These catalysts should make excellent choices for use with aromatic aldehydes when the enantioselectivity afforded by proline is deemed to be insufficient for one’s purposes.
CHAPTER 2
41
Table 11: Use of benzaldehyde for the acetone aldol reactiona
H
O
+
O
132 26
Catalyst
27b
S
NH
CO2HNH
N.TfOH
NH
O
HN
HO
Ph
Ph88111
Barbas 200160% yield89% ee
89151,152
Yamamoto 2001,0237% yield83% ee
90153
Gong and Wu 200351% yield83% ee
NH HN N
NN
91155,156
Arvidsson 2004,0569% yield65% ee
NH
O
HN
HO
CO2Et
CO2EtNH O
NH
Ph
.HBr
94160
Gong 200568% yield98% ee
95161,162
Chimni 200524% yield78% ee
NH
NHO
HN
PhPhO
HN
NH O
HN N
Bn
O HN
.TFANH
CO2H
NH
CO2HHO2C NMe2
NH
OHN
NH HN
O O
HN
NH
NH O
HN
NH2
OH
NH
OHN N
H
O
HNN
N
100168
Zhao 200569% yield90% ee
102170
Sun and Wu 200617% yield90% ee
103171
Zhao 200687% yield86% ee
104172
Wu 200674% yield56% ee
107175
Benaglia 200691% yield71% ee
108202
Najera 200675% yield65% ee
109177
Zhou 200672% yield19% ee
111179
Latanzi 200751% yield57% ee
NH
O
HN
NO2
O2NNO2
116185
Shirai 20088% yield78% ee
118187
Xiao 200861% yield80% ee
N
NH2.TfOH
125195
Luo and Cheng 200756% yield95% ee
NH
O
HN Ph
135205
Singh 200875% yield89% ee
Me NHSO2PhNH O
HN
136206
Nakano and Takeshita 200999% yield99% ee
HO
Ph
Ph
OH
Ph
NH O
HN
133203
Tanimori 200424% yield78% ee
MePh
OH
NH O
HN
134173,204
Singh 2006, 200783% yield99% ee
Ph
Ph
OH
Ph
H2NOH
O
78142
Amedjkouh 200550% yield72% ee
L-Pro-L-Pro-L-Asp-NH2148
Wennemers 200569% yield78% ee
OOH
aReferences are given for each product as superscript
CHAPTER 2
42
Table 12: Use of p-methoxybenzaldehyde for the acetone aldol reactiona
H
O
+
O
137 26
Catalyst
MeO42u
NH HN N
NN
91155,156
Arvidsson 2004,0565% yield62% ee
NH
NHO
HN
PhPhO
HN
NH
CO2H
NH
CO2HHO2C
100168
Zhao 200552% yield96% ee
103171
Zhao 200631% yield84% ee
104172
Wu 200643% yield47% ee
N
NH2.TfOH
125195
Luo and Cheng 200721% yield93% ee
NH O
HN
136206
Nakano and Takeshita 200995% yield98% ee
HO
Ph
Ph
OH
Ph
NH O
HN
134173
Singh 2006, 200775% yield99% ee
Ph
Ph
OH
Ph
MeO
OOH
aReferences are given for each product as superscript As noted in the case of catalyst 136, the results obtained can vary widely with the substrate employed. α-branched aldehydes are among the best substrates for proline catalysis, delivering adduct 27c in 97% yield and 96% ee (Table 1). Although many alternate catalysts give good results, they have not improved upon the high yield and enantioselectivity, coupled with the ready availability, of proline (Table 13). α-unbranched aldehydes are problematic in the proline-catalyzed aldol reaction. When isovaleraldehyde is used as a substrate, adduct 27d is obtained in 34% yield and 73% ee (Table 1). Very few reports of α-unbranched aldehyde substrates have been disclosed with alternate catalysts, and these show no significant improvement (Table 14).
CHAPTER 2
43
Table 13: Catalysts examined for the acetone aldol with isobutyr aldehydea
H
O
+
O
138 26
Catalyst
27c
S
NH
CO2HNH
O
HN
HO
Ph
Ph
88111
Barbas 200161% yield94% ee
90153
Gong and Wu 200343% yield98% ee
NH HN N
NN
91156
Arvidsson 2004,0579% yield99% ee
NH
O
HN
HO
CO2Et
CO2Et94160
Gong 200575% yield99% ee
NH
CO2HNH O
HN
NH2
NH
O
HNN
N
103171
Zhao 200675% yield95% ee
109177
Zhou 200650% yield73% ee
118187
Xiao 20085% yield
NH O
HN
133203
Tanimori 200422% yield80% ee
MePh
OH
NH O
HN
134173,204
Singh 2006, 200762-78% yield99% ee
Ph
Ph
OH
PhL-Pro-L-Pro-L-Asp-NH2148
Wennemers 200575% yield91% ee
OOH
aReferences are given for each product as superscript Table 14: Aldol reactios with α-unbranched aldehydesa
RH
O
+
O
31 26
Catalyst R
32
NH
O
HN
HO
Ph
Ph
90153
Gong and Wu 2003R= CH(CH3)247% yield87% ee
NH O
HN
14015
Wennemers 2003R= C(CH3)324% yield70% ee
OOH
NH
O
HN
HO
Ph
Ph
90153
Gong and Wu 2003R= CH2CH317% yield87% ee
NH
NH2
OCO2H
O
NH O
N
ONH
NH2
O
CO2H13915
Wennemers 2003R= C(CH3)328% yield73% ee
aReferences are given for each product as superscript
CHAPTER 2
44
2.4.5 Cyclohexanone as Aldol Donor (Proline Based Catalysts) Many catalysts have been evaluated for the reaction between cyclohexanone and p-nitrobenzaldehyde (Table 15). This reaction is highly successful using proline as catalyst delivering adduct 42a in 73% yield, with a 9:1 anti:syn ratio and >99% ee (Table 2). Diastereoselectivity with cyclic ketones is not always high when employing proline, however, particularly with other aromatic aldehydes. Among the reported catalysts, stilbene derivative 100,[168] pyrrolidine 142,[207] binaphthyl catalyst 108,[176] hydrazide 102,[208] binaphthyl catalyst 107,[175] silylated proline derivative 143,[178] cyclohexanediamine 112,[174] 4-disubstituted proline catalyst 103,[171] aryl prolinamide 144,[209] binaphthyl derivative 111,[180] prolinamide 145,[146] binaphthyl catalyst 147,[210] prolinamide 148,[211,212] diester 117,[186] phosphine oxide 151,[213] prolinamide 121,[191] and thiourea 152,[214] gave particularly good results. Of these, pyrrolidine 145, binaphthyl catalyst 147, prolinamide 148, diester 117 and thiourea 152 gave the best combination of high yield, diastereoselectivity and enantioselectivity. Phosphine oxide catalyst 146[215] and oxazoline 149,[216] two novel catalyst designs, did not give improved results. The reaction conditions used by Zhao employing stilbene catalyst 100 were the same as used previously (10 mol% catalyst loading).[168] Sun’s pyrrolidine catalyst 142 was used in 20 mol% loading, using cyclohexanone as a cosolvent over the course of 4 hours.[207] Sun also reported the use of hydrazide catalyst 102 for use with cyclohexanone as the donor. These conditions employed 20 mol% catalyst with cyclohexanone as cosolvent for 1 hour.[208] Binaphthyl catalyst 107 was used in 10 mol% loading using cyclohexanone as solvent over 88 hours.[175] The silylated catalyst 143 was used in 10 mol% with 5 equivalents of cyclohexanone over 18 hours.[178] Xiao reported the use of 20 mol% of catalyst 112, along with 20% acetic acid, with cyclohexanone as cosolvent over the course of 6–24 hours.[174] The 4-disubstituted proline catalyst 103 was used in 10 mol% catalyst loading, as before.[171] Aryl prolinamide catalyst 144, reported by Sathaporvajana and Vilaivan in 2007, was used in 10 mol% loading with 2 equivalents of cyclohexanone and a reaction time of 1 day.[209] Lattanzi reported in 2007 that 10 mol% of binaphthyl catalyst 111 with 3 equivalents of cyclohexanone yielded adduct 42a in 65 hours.[180] Prolinamide catalyst 145 was used in 20 mol% with 20 mol% acetic acid using
CHAPTER 2
45
Table 15 : Catalysts for aldol reaction of cyclohexanone and p-nitrobenzaldehydea
H
O
+
O
74 141
Catalyst
S
NH
CO2H
88111
Barbas 200156% yield1.7: 1anti:syn90% ee (anti)69% ee (syn)
NH
O
HN
HO
CO2Et
CO2Et94160
Gong 200583% yield95 : 5 anti:syn79% ee (anti)
NH
NHO
HN
PhPhO
HN
NH O
HN N
Bn
O HN
.TFANH
CO2H
NH
CO2HHO2C
NMe2
NH
OHN
NH HN
O O
HN
NH
OH
NH
OHN
NH
O
HNN
N
100168
Zhao 200578% yield97:3 anti:syn93% ee (anti)
102208
Sun 200699% yield99 : 1 anti:syn98% ee (anti)
103171
Zhao 200690% yield9: 1 anti:syn94% ee (anti)92% ee (syn)
104172
Wu 200655% yield2: 3 anti:syn87% ee (anti)88% ee (syn)
107175
Benaglia 200691% yield98 : 2 anti:syn95% ee (anti)
108176
Najera 200699% yield99 : 1 anti:syn97% ee (anti)6% ee (syn)
111180
Latanzi 200786% yield98 : 2 anti:syn92% ee (anti)
118187
Xiao 200899% yield93 : 7 anti:syn76% ee (anti)
NH
O
HN Ph
135205
Singh 200895% yield9 : 1 anti:syn81% ee (anti)
Me NHSO2Ph
NH O
HN
134173,204
Singh 2006, 200769-85% yield87: 13 anti:syn91% ee (anti)
Ph
Ph
OH
Ph
O2N
OH O
O2N42a
NH O
HN S
O O
99165
Ley 200588% yield1:1.5 anti:syn63% ee (anti)90% ee (syn)
NH
PO
OEtOEt
101169
Amedjkouh 200691% yield2 : 1 anti:syn96% ee (anti)97% ee (syn)
NH
O
OH
N
NH
O
OH
TBDPSO
NH
NHO
HNO
112174
Xiao 200681% yield98 : 2 anti:syn97% ee (anti)
NH
O
HN F
HOCl
NH O
NH(OPh)2P O
NH
O
HN
HO
CO2Et
CO2Et
TBSO
115184
Li 200841% yield96 : 4 anti:syn90% ee (anti)
117186
Gong 200899% yield99 : 1 anti:syn99% ee (anti)
NH
NHO
N
PhPh
(n-C5H11)2NH
O
HN
PhO
HO
t-Bu.TFA
120190
Da 200984% yield79 : 21 anti:syn93% ee (anti)
121191
Fu 200999% yield99 : 1 anti:syn94% ee (anti)
NH
N.TfOH
89151,152
Yamamoto 2001,0297% yield74:26anti:syn96% ee (anti)61% ee (syn)
142207
Sun 200699% yield99 : 1 anti:syn99% ee (anti)
143178
Hayashi 200686% yield20 : 1 anti:syn99% ee (anti)
144209
Vilaivan 200791% yield94: 6 anti:syn97% ee (anti)35% ee (syn
NH
O
HN Me
PhHN ONH
PO
PhPh
147210
Ma 200899% yield92 : 8 anti:syn99% ee (anti)
NO
HNOH
NH O
NH
O2N
145146
Peng 200898% yield98 : 2 anti:syn93% ee (anti)
146215
Liu 200873% yield69 : 31 anti:syn85% ee (anti)
.HBr148211,212
Chimni 200892% yield94 : 6 anti:syn95% ee (anti)
NH
O
N
OHN
t-Bu
149216
Doherty and Knight 200888% yield75 : 25 anti:syn84% ee (anti)
NH O
HN
Bn
Ph
OH
PhHO
150206
Nakano and Takeshita 200943% yield89 : 11 anti:syn96% ee (anti)
PO
HNNH
NH
O
NH
HO
O
NH
HO
O
NHHO
151213
Wang and Pan 200989% yield85 : 15 anti:syn97% ee (anti)
NH
O
HN
TBDPSO
HN NH
S O
152214
Chen 200995% yield96 : 4 anti:syn99% ee (anti)
aReferences are given for each product as superscript cyclohexanone as a cosolvent with a reaction time of 24–72 hours.[146] Binaphthyl catalyst 147 was used by Ma and co-workers in 10 mol% loading with 5 equivalents of cyclohexanone in 72 hours.[210] Chimni’s catalyst 148 was used in 20 mol% loading with 5 equivalents of cyclohexanone with a reaction time of 1 day.[211,212] Gong’s catalyst 117 was used in only 1 mol% loading with 2 equivalents of cyclohexanone, over the course of 5 hours.[186] The phosphine oxide catalyst 151, containing three proline units, was used in 2 mol% loading.[213] Despite this low catalyst loading, the reaction took 72–120 hours to complete. Thiourea catalyst 152 was used in 20 mol% loading with 2 equivalents of cyclohexanone over the course of 1.5 days.[214] Of these catalysts, Gong’s diester catalyst 117 appears to be not only highly selective, but also the most reactive. Although primary amino acids give poorer selectivity than proline for the aldol reaction in many cases, in certain instances they show improved results. In the Hajos–Parrish– Eder–Sauer–Wiechert of substrate 153 (S)-phenylalanine gave superior results for the aldol condensation (Scheme 14).[217] Ethyl ketone 155 also gave superior results with (S)-phenylalanine as catalyst.[218]
CHAPTER 2
46
O
O
O
N
O
O
N
O
O
Catalyst 1 N HClO4MeCN, 80 oC
with (S)-proline10 days 67% yield27% ee
with (S)-phenylalanine40 h 82% yield86% ee
with (S)-prolineDMSO,5 days, 65% oC32% ee
with (S)-phenylalanine1N HClO4 MeCN 80 oC, 40 h95% ee
O
Catalyst
O
O
153 154
155 156
Scheme 14 : Improved reactivity and enantioselectivity with primary amine catalysts for sterically-hindered substrates. [217, 218] 2.4.6 Non-proline derived catalysts for cyclohexanone and p-nitrobenzaldehyde aldol reactions The above results suggest that with more hindered ketones, primary amines may have an advantage over secondary amines. This has led many investigators to evaluate primary amine catalysts for the reaction of cyclohexanone 141 with p-nitrobenzaldehyde 74 (Table 16). Among the catalysts examined, protected threonine catalyst 159,[219] cinchona derivative 126,[196] cyclohexyl catalyst 160,[220] protected serine derivative 124,[194] binaphthyl catalyst 129,[199] triflamide catalyst 131[201] and stilbene catalyst 161221 gave good results. Unprotected amino acids tryptophan 158[222] and histidine 75,[223] and dipeptide 157,[224] gave inferior results. The conditions used for the threonine catalyst 159, as reported by Lu and co-workers, required only 2 mol% catalyst loading and 2 equivalents of cyclohexanone for 20 hours.[219] The cinchona derivative 126 was used in 10 mol% loading with 15 mol% triflic acid, using cyclohexanone as solvent over the course of 9 hours.[196] Maruoka’s catalyst 160 was used in 5 mol%, though the reaction took 3–4 days.220 Shao’s catalyst 129 could be used in only 3.5 mol% with 3 equivalents of cyclohexanone over 10 hours.[199] Triflamide catalyst 131 was used in 10 mol% loading with 10 equivalents of cyclohexanone over the course of 2 days.[201] Lai’s catalyst 161 was used in 10 mol% with 10 equivalents of cyclohexanone over the course of 12 hours.[221] Among these catalysts, the silylated threonine catalyst 159 gives perhaps the best combination of good reactivity, good selectivity, and ease of synthesis.
CHAPTER 2
47
Table 16 : Non-proline derived catalysts for the aldol reaction of cyclohexanone with p-nitrobenzaldehydea
H
O
+
O
74 141
Catalyst
O2N
OH O
O2N42a
OTBDPSCO2H
NH2
NHTf
N
H2N N
NH2N.TFA
H2N NHTf
Ph
124194
Teo 200795% yield87 : 13 anti: syn 98% ee (anti)
126196
Liu 200799% yield9.2 : 1 anti: syn 99% ee (anti)65% ee (syn)
129199
Shao 200896% yield98 : 2 anti: syn 98% ee (anti)
131201
Miura and Imai 200992% yield82 : 18 anti: syn 90% ee (anti)
H2NHN
OHO
O
H2NOH
O
NH
H2NOH
O
HN
N
OTBSCO2H
NH2
EtO2C
NH2
H2N NH2
Ph Ph
157224
Cordova 200573% yield8 : 1 anti: syn 91% ee (anti)
158222
Lu 200691% yield5 : 1 anti: syn 96% ee (anti)
75223
Amedjkouh 200766% yield1 : 1 anti: syn 31% ee (anti)48% ee (syn)
159219
Lu 200799% yield10 : 1 anti: syn 96% ee (anti)
160220
Marouka 200873% yield93 : 7 anti: syn 97% ee (anti)
161221
Lai 200985% yield3 : 1 anti: syn -93% ee (anti)
aReferences are given for each product as superscript
CHAPTER 2
48
2.4.7 Catalysts for Cyclohexanone and less reactive aldehyde aldol reactions With less reactive aldehydes such as benzaldehyde 132 or p-methoxybenzaldehyde 137, much poorer results were obtained with most of the catalysts (Table 17). Singh’s catalyst 105 retained good reactivity, however, even with p-methoxybenzaldehyde 137.[173] Armstrong’s aryl ether catalyst 162 also showed good reactivity, and was needed in only 2 mol% loading with only one equivalent of cyclohexanone, though the reaction still took 2 days to complete.[41] The cyclohexyldiamine catalyst 112,[174] anilide catalyst 144,[209]
protected threonine derivative 159,[219] sulfamide 135,[205] dipeptide catalyst 145,[146] diester catalyst 117,[186] 4-hydroxyproline derivative 150,[206] and Fu’s catalyst 121[191] all gave fair results as well. The reaction conditions for these catalysts have been given above. Table 17 : Catalysts for less reactive aldehydes with cyclohexanonea
H
O
+
O
141
Catalyst
NH O
HN N
Bn
O HN
.TFANMe2
NH
OHN
NH HN
O O
HN
NH102208
Sun 2006107175
Benaglia 2006 108176
Najera 2006R = H99% yield4.3 : 1 anti:syn90% ee (anti)
NH
O
HN Ph
135205
Singh 2008
Me NHSO2Ph
R
OH O
O2N
NH
NHO
HNO
112174
Xiao 2006R = H72% yield85 : 15 anti:syn83% ee (anti)
NH
O
HN
PhO
HO
t-Bu.TFA
121191
Fu 2009R = H72% yield92 : 8 anti:syn84% ee (anti)
NH
O
HN Me
PhHN O145146
Peng 2008R = H98% yield81 : 19 anti:syn87% ee (anti)
NH O
HN
Bn
Ph
OH
PhHO
150206
Nakano and Takeshita 2009R = H70% yield96 : 4 anti:syn96% ee (anti)
P
O
NHNH
NH
O
NH
OH
O
NH
OH
O
NHOH
151213
Wang and Pan 2009
NH
O
HN
TBDPSO
HN NH
S O
152214
Chen 2009
R= H, 132R= OMe, 137
R= H, 42bR= OMe, 42v
NH
O
OH
TBDPSO
NH
O
OH
NNH O
HN OH
Ph Ph
i-Bu
105173
Singh 2006, 2007
H2NOH
O
NH
158222
Lu 2006R = H47% yield78 : 1 anti:syn89% ee (anti)
N
H2N N
H2N NHTf
Ph
126196
Liu 2007
131201
Miura and Imai 2009
OTBSCO2H
NH2
H2N NH2
Ph Ph
159219
Lu 2007R = OMe54% yield5 : 1 anti:syn93% ee (anti)
161221
Lai 2009R = H15% yield19 : 1 anti:syn-90% ee (anti)
OTBDPSCO2H
NH2
124194
Teo 2007
NH
O
HN
HO
CO2Et
CO2Et
TBSO
117186
Gong 2008R = H75% yield99 : 1 anti:syn92% ee (anti)
NH
O
N
OHN
t-Bu
149216
Doherty and Knight 2008R = H59% yield83 : 17 anti:syn7% ee (anti)
NH2N.TFA
129199
Shao 2008
NH
O
OH
ONH
O
HN F
HOCl
144209
Vilaivan 2007R = H68% yield88 : 12 anti:syn90% ee (anti)29% ee (syn
NHTfEtO2C
NH2
160220
Marouka 2008R = H53% yield96 : 4 anti:syn98% ee (anti)
NH O
NH
O2N
.HBr
148211,212
Chimni 2008R = H62% yield87 : 13 anti:syn82% ee (anti)
NH
NHO
N
PhPh
(n-C5H11)2
120190
Da 2009R = OMe10% yield92 : 8 anti:syn79% ee (anti)
143178
Hayashi 2006
R = H78% yield13 : 1 anti:syn99% ee (anti)
R = OMe21% yield5 : 1 anti:syn96% ee (anti)
R = H80% yield99 : 1 anti:syn93% ee (anti)
R = OMe57% yield1 : 1 anti:syn87% ee (anti)
R = H84% yield94 : 6 anti:syn92% ee (anti)
R = OMe39% yield96 : 4 anti:syn93% ee (anti)
142207
Sun 2006R = H81% yield97 : 3 anti:syn99% ee (anti)
R = OMe28% yield95 : 5 anti:syn97% ee (anti)
R = H69-85% yield94 : 6 anti:syn99% ee (anti)
R = OMe69-85% yield98 : 2 anti:syn99% ee (anti
16241
Armstrong 2007R = H84% yield9 : 1 anti:syn94% ee (anti)
R = H31% yield1 : 1 anti:syn86% ee (anti)54% ee (syn
R = OMe19% yield3.7 : 1 anti:syn89% ee (anti)14% ee (syn
R = H63% yield86 : 14 anti:syn92% ee (anti)
R = OMe41% yield81 : 19 anti:syn90% ee (anti)
R = H82% yield98 : 2 anti:syn96% ee (anti)
R = OMe60% yield93 : 7 anti:syn85% ee (anti) R = H
61% yield94 : 6 anti:syn94% ee (anti)
R = OMe23% yield95 : 5 anti:syn90% ee (anti)
R = H68% yield78 : 22 anti:syn87% ee (anti)
R = OMe43% yield83 : 17 anti:syn95% ee (anti)
R = H23% yield84 : 16 anti:syn89% ee (anti)
R = OMe12% yield87 : 13 anti:syn92% ee (anti)
R = H55% yield97 : 3 anti:syn94% ee (anti)
R = OMe26% yield85 : 15 anti:syn80% ee (anti)
aReferences are given for each product as superscript
CHAPTER 2
49
2.4.8 Catalysts for Cyclohexanone and Alkyl aldehyde aldol reactions Proline is an excellent catalyst for aldol reactions of cyclohexanone with alkyl aldehydes, especially α-branched aldehydes (Table 2). Use of more elaborate catalysts has been reported, but with generally worse results than using proline itself (Table 18). Silyl derivative 143[178] and binaphthyl catalyst 107[175] give high yields for cyclohexanecarboxaldehyde, but other aldehydes give poor yields, though with excellent selectivities. Proline also gives high diastereo- and enantioselectivity, however, and remains the preferred catalyst for such substrates, due to its ready availability. Table 18 : Aldol reactions with alkyl aldehydesa
R H
O
+
O
141
Catalyst
NMe2
NH
OHN
107175
Benaglia 2006R = C6H1188% yield>98 : 2 anti:syn87% ee (anti)
R
OH O
NH
O
OH
TBDPSO
143178
Hayashi 2006, 2007
NH
O
HN
HO
Ph
Ph
TBSO
113182
He and Gong 2007
25 163
R = CH2CH(CH3)254% yield20 : 1 anti:syn99% ee (anti)
R = C6H1176% yield20 : 1 anti:syn99% ee (anti)
R = n-pentyl 21% yield>20 : 1 anti:syn 96% ee (anti)
R = CH(CH3)2 29% yield>20 : 1 anti:syn 99% ee (anti)
R = C6H1140% yield99 : 1 anti:syn99% ee (anti)
R = CH(CH3)2 38% yield>99 : 1 anti:syn>99% ee (anti)
aReferences are given for each product as superscript 2.4.9 Catalysts for Cyclopentanone and p-nitrobenzaldehyde aldol reaction When cyclopentanone is used as a donor in the proline catalyzed asymmetric aldol reaction poor diastereoselectivity is observed. Many of the developed catalysts have been applied to this substrate, and fortunately, several catalysts were found with improved diastereoselectivity for the anti diastereomer (Table 19). Singh’s sulfamide catalyst 135,[205] Shirai’s trinitrocatalyst 116,[185] Shao’s binaphthyl catalyst 129,[199] Maruoka’s cyclohexyl catalyst 160,[220] Miura and Imai’s triflamide catalyst 131201 and Chen’s thiourea catalyst 152[214] all showed improved diastereoselectivity over the 1:1 selectivity observed for proline. Of these catalysts, Maruoka’s gives the best balance of selectivity and yield. Interestingly, several catalysts showed selectivity for the syn adduct 42f, including hydrazide 102,[170] binaphthyl catalyst 108,[176] anilide catalyst 144,[209]
CHAPTER 2
50
cyclohexanediamine catalyst 125[195] and Da’s stilbene catalyst 130.[190] Luo and Cheng’s catalyst 125 is remarkable in its selectivity, and should prove quite useful for the synthesis of syn products. Table 19 : Catalysts used in the aldol reaction between cyclopentanone and p-nitrobenzaldehydea
H
O
O2N+
O
74 164
Catalyst
OH
O2N42f
S
NH
CO2H NH
O
HN
HO
Ph
PhNH HN
N NH
O
HN
HO
CO2Et
CO2Et NH
NHO
HN
PhPhO
HN
NH O
HN N
Bn
O HN
.TFA
NH
NHO
HNO
CF3NH HN
O O
HN
NH
OH
NH
OHN
NH
NHO
HNO
NH
NHO
N
PhPh
(n-C5H11)2 NH
O
HN
PhO
HO
t-Bu.TFA
88111
Barbas 200163% yield1.6 : 1 anti:syn63% ee (anti)60% ee (syn
90151
Yamamoto 2001, 200288% yield43 : 57 anti:syn84% ee (anti)5% ee (syn
93159
Landais and Vincent 200467% yield1 : 1 anti:syn88% ee (anti)86% ee (syn
94160
Gong 200585% yield1 : 1 anti:syn93% ee (anti)3% ee (syn
100168
Zhao 200562% yield40 : 60 anti:syn82% ee (anti)18% ee (syn
102170
Sun and Wu 200695% yield1 : 3 anti:syn67% ee (anti)74% ee (syn
106174
Xiao 200668% yield48 : 52 anti:syn56% ee (anti)99% ee (syn
108176
Najera 200698% yield1 : 2 anti:syn85% ee (anti)61% ee (syn
111180
Latanzi 200798% yield35 : 65 anti:syn92% ee (anti)62% ee (syn
112181
Xiao 200775% yield35 : 65 anti:syn92% ee (anti)
NH
O
HN
NO2
O2NNO2
116185
Shirai 200887% yield71 : 29 anti:syn96% ee (anti)54% ee (syn
120190
Da 200997% yield63 : 37 anti: syn 77% ee (anti)
121191
Fu 200990% yield55 : 45 anti: syn 91% ee (anti)41% ee (syn)
O
NH O
HN S
165165
Ley 200585% yield1 : 1.8 anti:syn41% ee (anti)36% ee (syn
O O
Me
NH
O
HN F
HOCl
144209
Vilaivan 200796% yield33 : 67 anti:syn79% ee (anti)67% ee (syn
NH
PO
OH
166169
Amedjkouh 200651% yield1 : 1 anti:syn46% ee (syn)
OH
NH
CO2H103171
Zhao 200671% yield46 : 54 anti:syn94% ee (anti)45% ee (syn
H2NOH
O
NH
158222
Lu 200674% yield1 : 1 anti: syn 78% ee (anti)
OTBDPSCO2H
NH2N
NH2.TfOH
124194
Teo 200778% yield55 : 45 anti:syn84% ee (anti)
125195
Luo and Cheng 200799% yield1 : 9 anti:syn98% ee (syn)
NH2N.TFA
O
H2N
NHPh
i-Bu
i-BuHO
Ph
H2N NHTf
Ph
129199
Shao 200891% yield9 : 1 anti:syn92% ee (anti)
130190
Da 200982% yield1 : 2 anti: syn 93% ee (anti)
131201
Miura and Imai 200971% yield71 : 29 anti: syn 88% ee (anti)
NH O
NH
O2N
.HBr
148211,212
Chimni 200874% yield56 : 44 anti:syn73% ee (anti)
NH
O
HN Ph
135205
Singh 200875% yield92 : 8 anti:syn93% ee (anti)
Me NHSO2Ph
NH
O
HN
TBDPSO
HN NH
S O
152214
Chen 200972% yield77 : 23 anti: syn 82% ee (anti)
NHTfEtO2C
NH2
160220
Marouka 200899% yield92 : 8 anti: syn 93% ee (anti)
H2N NH2
Ph Ph
161221
Lai 200958% yield1 : 1.3 anti: syn 64% ee (syn)
aReferences are given for each product as superscript 2.4.10 Catalysts for 2-butanone and p-nitrobenzaldehyde aldol reaction When proline was used with 2-butanone 167 and p-nitrobenzaldehyde 74, the linear adduct 42h was obtained in 65% yield and 77% ee (Table 2). Many catalysts have been applied to this reaction enhancing both the yield and selectivity of the linear adduct 42h, but also providing access to both diastereomers of the branched adduct 168 (Table 20). The linear product was favored by catalysts 88,[111] 90,[154] 99,[165] 94,[160] 107,[225] 103,[171] 108,[176,226] 148,[211] 117,[186] and 128.[198] Among these catalysts, Najera’s binaphthyl amine 108 provided the linear adduct 42h with the best yield and selectivity. Xiao’s cyclohexanediamine catalyst 112, on the other hand, gave the branched product 168 with excellent selectivity for the anti diastereomer, though with only moderate selectivity for
CHAPTER 2
51
the branched product over the linear.[181] The enantioselectivity for catalyst 112 was also high. Trinitroanilide catalyst 116 also favors the anti adduct, but the reaction conditions are less appealing, as HMPA is used as solvent.185 Thiourea catalyst 152 also provides the anti adduct in good selectivity.[214] Luo and Cheng’s cyclohexanediamine catalyst 125 gave the syn adduct in excellent selectivity and yield.[195] With these developments, each aldol adduct isomer can be synthesized with good selectivity. Luo and Cheng’s diamine catalyst 125 displays very interesting selectivity (Table 21). When unsymmetrical ketones are employed, such as 2-butanone 167, the adduct (42x for example) resulting from reaction through the more substituted enamine is observed, producing the syn branched isomer 42. When 3-hexanone is used, the adduct resulting from the least sterically-hindered enamine (42u) is formed almost exclusively. When 2-pentanone is used, there is a competition between reaction through the more highly substituted enamine and the less sterically-hindered enamine. The major product resulted from reaction through the less hindered enamine, yielding 42v in 5:1 selectivity. When the ketone was made even more hindered the selectivity increased dramatically, for example, in the case of adduct 42w the selectivity was greater than 20:1. Benzyl protected hydroxyacetone also gave excellent selectivity for the syn branched product 42y. Luo and Cheng’s catalyst 125 provides a very useful selectivity unavailable from proline. Table 20 : Catalysts used in the aldol reaction between 2-butanone and p-nitrobenzaldehydea
H
O
O2N+
O
74 167excess
Catalyst
OH
O2N42h
S
NH
CO2H NH
O
HN
HO
Ph
Ph
NH
O
HN
HO
CO2Et
CO2Et
NH O
HN S
O O
NH
CO2H
NH HN
O O
HN
NH
NH
NHO
HNO
NH
O
HN
HO
CO2Et
CO2Et
TBSONH
O
HNN
N
88111
Barbas 200160% yieldlinear only74% ee
90154
Gong and Wu 200463% yield (linear)<5% branched 88% ee (linear)
94160
Gong 20051.3 : 1 linear : branched99 : 1 anti : syn99% ee (anti)98% ee (linear)
99165
Ley 200548% yield (linear) 77% ee (linear)
103171
Zhao 200643% yield3.3 : 1 linear : branched95 : 5 anti : syn99% ee (anti)88% ee (linear)
108176, 226
Najera 200696% yield50 : 1 linear : branched100 : 0 anti : syn31% ee (anti)96% ee (linear)
112181
Xiao 200774% yield1 : 2.9 linear : branched97 : 3 anti : syn93% ee (anti)
NH
O
HN
NO2
O2NNO2
116185
Shirai 200890% yield38 : 62 linear : branched98 : 2 anti : syn99% ee (anti)93% ee (linear)
117186
Gong 200830% yield (linear)78% ee (linear)
118187
Xiao 200885% yield1 : 1.7 linear : branched93 : 7 anti : syn98% ee (anti)75% ee (linear)
O
+
OH
O2N168
O
NH
O
HN
TBDPSO
HN NH
S O
152214
Chen 200958% yield93 : 7 anti : syn98% ee (anti)
N
NH2.TfOH
125195
Luo and Cheng 200795% yield1 : 9 linear : branched1 : 10 anti : syn96% ee (syn)
O
H2N
NHPh
i-Bu
i-BuHO Ph
130200
Da 200985% yield1 : 3 linear : branched1 : 2 anti : syn88% ee (syn)
NH O
NH
O2N
.HBr
148211
Chimni 200863% yield (linear)50% ee (linear)
NH
O
HN Me
PhHN O145146
Peng 200890% yield1 : 1.5 linear : branched9 : 1 anti : syn96% ee (anti)53% ee (linear)
NH N O
H2N Ph
128198
Feng and Hu 200860% yield1.4 : 1 linear : branched2 : 1 dr90% ee (linear)96% ee (branched)
NMe2
NH
OHN
107225
Benaglia 2006, 200790% yield70 : 30 linear : branched99 : 1 anti : syn95% ee (linear)
aReferences are given for each product as superscript 2.4.11 Catalysts for Hydroxyacetone aldol reaction When hydroxyacetone is used as a donor under proline catalysis, good diastereoselectivity is observed with α-branched aldehydes, favoring the anti branched isomer, but some aryl (particularly ortho-chlorobenzaldehyde) and α-unbranched aldehydes result in poor diastereoselectivity. Silyl protected hydroxyacetone, as well as methylated derivatives,[227] also gave the anti branched isomer selectively. A variety of catalysts have been tested with hydroxyacetone and protected derivatives (Table 22).
CHAPTER 2
52
When hydroxyacetone was used as substrate, diester catalyst 95 gave excellent selectivity for the linear isomer, with excellent enantioselectivity.[228] Other catalysts were not very selective with unprotected hydroxyacetone.[111,168,224,229] Wu and Zhao’s primary amine catalyst 175 gave the syn isomer in 4:1 selectivity with 80% ee.[230] Luo and Cheng’s catalyst 176 gave even higher selectivity for the syn isomer.[231] Silyl protected hydroxyacetone was also used as a substrate with threonine derivatives 173[219] and 174,[232] both of which favored the syn branched isomer in excellent enantioselectivity. Methyl and benzyl protected hydroxyacetone were also used, and depending on the chosen catalyst, could be obtained in either the anti or syn configuration. Binaphthyl catalysts 108,[227,233] 172,[175] and 111,[180] as well as thioamide 119[189] all gave the anti isomer selectively. The syn isomer was obtained when threonine derivative 174 or primary-tertiary amine catalyst 176 was used. All three isomers are now available through judicious choice of protecting group and catalyst. 2.4.12 Catalysts for Dihydroxyacetone aldol reaction Dihydroxyacetone and its protected derivatives have also been used with many different catalysts. Proline gives the anti derivative with excellent selectivity with a variety of aldehydes. When untethered dihydroxyacetone derivatives are used only binaphthyl catalyst 108 gave the anti isomer with moderate selectivity (Table 23).[227] The syn isomer, on the other hand, is favored by a variety of primary amine catalysts including threonine derivative 174,[232] cyclohexyl catalyst 125,[195,234] primary-tertiary amine catalyst 176,[231] and amino alcohols 179,[235] 180,[60] and 130.[200] When tethered dihydroxyacetone derivative 2,2-dimethyl-1,3-dioxan-5-one (177, R = -CMe2-) was used, only the anti isomer was observed with all of the catalysts.[236] When the anti isomer is desired, proline should be the catalyst of choice, as it gives good selectivity as is inexpensive. When the syn isomer is desired, a number of primary amine catalysts can be used. Diamine catalyst 125 is particularly useful, as it can be used in the lowest catalyst loading (10 mol%). 2.4.13 Catalyst for Halogenated and sulfur-containing substrates Thioether and halogenated ketone derivatives have also been examined (Table 24). When α-chloroacetone was used as a substrate, the anti branched product was obtained in excellent selectivity with a variety of catalysts,[180,237] though only good yield was obtained with the binaphthyl catalyst 108[180,238] and the trinitroanilide catalyst 116.[185] α-Fluoroacetone was used as a substrate with Gong’s diester catalyst 94,[228,239] and was
CHAPTER 2
53
Table 21 : Lou and Cheng`s syn selective aldol195
N
NH2.TfOHR1 H
O
O
+R2 R3
O
OH
O2N
R2 R3
O
R1
OH
10 mol%
25 4142
125
10 mol% m-NO2PhCO2H
OOH
O2N
OOH
O2N
OOH
OBn
OOH
O2N
20-72 h20 equiv.
42u75% yield>20 : 1 branched : linear4 : 1 syn : anti96% ee
42v92% yield1 : 5 branched : linear88% ee
42w56% yield1 : >20 branched : linear85% ee
42x53% yield4 : 1 branched : linear5 : 1 syn : anti92% ee
42y98% yield20 : 1 branched : linear9 : 1 syn : anti97% ee
capable of yielding either the branched product in 2:1 dr or the linear product, depending on the reaction conditions. When water was added, the linear adduct 183 was favored, while running the reaction in dry THF gave the branched adduct 182. A thioether-substituted ketone was also used as a substrate, both with the diester catalyst 94 and with binaphthyl catalyst 108. Both catalysts favor the linear product 183, with diester catalyst 94 giving slightly better selectivity. A number of interesting substrates other than aryl and alkyl aldehydes have been employed for the direct catalytic aldol reaction (Scheme 15). The use of enals 185 and 186 was reported by Maruoka using binaphthyl amino acid 123 in the aldol reaction with acetone.[192] The adducts were obtained in 73% yield with 90% ee and 81% yield with 96% ee, respectively. Saito and Yamamoto et al. demonstrated the use of chloral 187 and trifluoroacetaldehyde ethyl hemiacetal 188 as acceptors using tetrazole catalyst 91 in 2004. The authors used a variety of ketones with these acceptors, including α-ketoester 189 and methyl aryl ketones 190 with yields between 55–93% and with 82–97% ee.[157] Zhang and Wang et al. have used methyl aryl ketones 190 as well, employing triflamide catalyst 191.[240] Trifluoroacetaldehyde ethyl hemiacetal 188 was also used by Gong et al. as an acceptor using cyclohexanone as the donor. The authors found that prolinamide catalyst 82 gave the best results.[241] Acetal derivatives 192 were employed by Luo and Cheng et al. using cyclohexanediamine catalyst 125, giving the desired adducts in 30–98% yield and with 49–99% ee.[242] Ynone donor 193 was used by Gouverneur and co-workers with aromatic aldehydes as acceptors employing sulfonamide catalyst 99. The adducts were obtained in 26–90% yield, 3:1–19:1 dr, and 77–95% ee.[243] The reaction appears to be limited to electron-poor aryl aldehydes. This collection of interesting substrates should prove useful for the synthesis of more functionalized products. 2.4.14 Catalyst for ketone electrophiles in aldol reaction There have been a few reports of ketone electrophiles in the direct catalytic asymmetric aldol reaction (Table 25). Tomasini et al. used catalyst 195 with isatin, a highly reactive
CHAPTER 2
54
and non-enolizable ketone to give the aldol adduct 194 in 92% yield and 72% ee.[244] Luo and Gong et al. developed pyridine catalyst 196 for the aldol reaction of acetone with α-keto acids.[245,246] The aldol adducts were obtained in excellent yield and enantioselectivity, even when an enolizable substrate was used. Feng et al. reported the use of stilbene catalyst 100 with α-keto esters.[247] When R1 = Ph and R2 = CO2Me, the aldol adduct was obtained in 92% yield and in 93% ee. Binaphthyl catalyst 127 also was used for example, when R1 = p-MeO-Ph and R2 = CO2Me, the aldol adduct was obtained in 98% yield and 96% ee.[197] Bispidine catalyst 128 was used with benzoyl phosphonates.[198] When R1 = p-NO2-Ph and R2 = P(O)(OEt)2, the α-hydroxyphosphonates was obtained in 90% yielded and 98% ee. Thiophene catalyst 197 was used for substituted isatins, such as 4,6-dibromoisatine, which yielded the desired adduct 194 in 99% yield and 95% ee.[248] Table 22 : Hydroxyacetone aldol reactions and protected derivativesa
H
O
O2N+
O
74 169
Catalyst
OH
O2N170
S
NH
CO2H
NH
NHO
HN
PhPhO
HN88111
Barbas 2001R = H52% yield branched only1 : 1 anti : syn95% ee (anti)50% ee (syn)
100168
Zhao 2005R = H90% yield 1 : 1.3 branched : linear 66% ee (syn)97% ee (linear)
O
OROR
OH
O2N
OOR
+
171
NH HN
O
NH HN
O O
HN
NH
OH
NH
OHN
95228
Gong 2007
108227, 233
111180
Latanzi 2007R = Me62% yield (branched)85 : 15 branched : linear 84 : 16 anti : syn84% ee (anti)
NH S
HN
119188
Najera 2008R = Bn90% yield 89 : 11 anti : syn91% ee (anti)43% ee (syn)
L-Pro-L-Phe-L-Phe-L-Phe-L-Phe-OMe L-Ala-L-Phe-
NH HN
O O
HN
172175
Benaglia 2006R = Me91% yield 98 : 2 anti : syn 91% ee (anti)
CO2H
NH2
OTBDPS
173219
Lu 2007R = TBS92% yield 1 : 8 anti : syn 98% ee (anti)
CO2H
NH2
Ot-Bu
174232
Barbas 2007
Ph NNH2
176231
luo and Cheng 2009
.TfOHNH
HO PhPh
HN
ONH2
TBDPSO
175230
Wu and Cheng 2009R = H91% yield 1 : 4 anti : syn80% ee (syn)
Gong 2004229
R = H97% yield 1 : 3.6 branched : linear 1.6 : 1 anti : syn30% ee (anti)87% ee (linear)
Cordova 2005224
R = H93% yield branched only1 : 1 anti : syn75% ee (anti)
R = Me88% yield 5 : 1 branched : linear7 : 1 anti : syn 92% ee (anti)
Najera 2006R = Bn96% yield 88 : 12 branched : linear83 : 17 anti : syn 86% ee (anti)
HO
CO2Et
CO2Et
R = Me79% yield 1 : 3 anti : syn92% ee (syn)39% ee (anti)
R = H95% yield (linear)<5% branched 95% ee
R = Bn79% yield 1 : 3 anti : syn94% ee (syn)35% ee (anti)
R = TBS82% yield 1 : 5 anti : syn95% ee (syn)7% ee (anti)
R = H81% yield 1 : 7 anti : syn94% ee (syn)
R = Bn93% yield 1 : 9 anti : syn98% ee (syn)
aReferences are given for each product as superscript
CHAPTER 2
55
Table 23 : Dihydroxyacetone aldol reactionsa
H
O
O2N+
O
74 177
Catalyst
OH
O2N178
O
OR OR
NH HN
O O
HN
NH 108227
Najera 2006R = H86% yield 50 : 1 branched : linear3 : 1 anti : syn82% ee (anti)82% ee (syn)
NH
CO2H
TBDPSO
143236
Hayashi 2006, 2007R = -CMe2
-
77% yield 14 : 1 anti : syn95% ee (anti)benzaldehyde used as acceptor
L-Ala-L-PheCordova 2005224
R = -CMe2-
88% yield 5 : 1 anti : syn99% ee (anti)
L-Val-L-PheCordova 2005224
CO2H
NH2
Ot-Bu
174232
Barbas 2007
Ph NNH2
176231
Luo and ChengR = H95% yield 1 : 30 anti : syn95% ee (syn)
.H3PW12O40
N
NH2.TfOH
125195, 234
Luo and Cheng 2008
O
H2N
NHPh
i-Bu
i-BuHO Ph
130200
Da 2009R = H48% yield 1 : 7 anti : syn95% ee (syn)
EtO2C
NH2
NHTfNH
OH2N
OH
PhPh
i-Bu
18060
Gong 2008R = H78% yield 1 : 14 anti : syn95% ee (syn)
159220
Marouka 2008R = -CMe2
-
99% yield 9 : 1 anti : syn98% ee (anti)
NH
OH2N
OH
PhPh
Ph
179235
Barbas 2008
O t-Bu
OR OR
R = -CMe2-
51% yield 15 : 1 anti : syn99% ee (anti)
R = H53% yield 1 : 1 anti : syn70% ee (anti)
R = Bn94% yield 1 : 4 anti : syn93% ee (syn)
R = TBS85% yield 1 : 5 anti : syn93% ee (syn)
R = H, R´ = Et 97% yield 3 : 97 anti : syn99% ee (syn)
R = -CMe2-
R´ = 90% yield 6 : 1 anti : syn94% ee (anti)
n-decanyl R = H78% yield 1 : 6 anti : syn92% ee (syn)62% ee (anti)
R = TBS81% yield 1 : 5 anti : syn87% ee (syn)
aReferences are given for each product as superscript
CHAPTER 2
56
Table 24 : Halogenated and sulfur-containing substratesa
NH HN
O O
HN
NH
108180, 238
Najera 2007X = Cl86% yield99 : 1 branched : linear>99 : 1 anti : syn90% ee (anti)
OH
NH
OHN
111180
Latanzi 2007X = Cl41% yield (branched)95 : 5 branched : linear95 : 5 anti : syn85% ee (anti)
NH
O
HN
HO
CO2Et
CO2Et
94228, 239
Gong 2007X = SMe72% yield (linear)5% yield (branched)95% ee (linear)
NH
O
HN
NO2
O2NNO2
116185
Shirai 2008X = Cl90% yield92 : 8 branched : linear94 : 6 anti : syn98% ee (anti)21% ee (syn)80% ee (linear)
NH
O
HN
184237
Gong 2006X = Cl57% yield7 : 1 branched : linear7 : 1 anti : syn91% ee (anti)
H
O
O2N+
O
74 181
Catalyst
OH
O2N182
O
X X
OH
O2N
OX
+
183
X = F96% yield 98 : 2 branched : linear2 : 1 anti : syn95% ee (anti)
aReferences are given for each product as superscript
CHAPTER 2
57
PhCl
H
O
HO2CMe
H
O
HO CCl3
OH
EtO CF3
OH
O
OEtO
Ar
O
OMe
OMeO
R
O
OMOMMe
NH
NHTf
191240
185192 186192 187157 188157,241
189157 190157,240 192242 193243
Scheme 15 : Additional acceptors and donors Isatin itself gave the aldol adduct in 99% yield, however, the product was obtained in only 3% ee. Nakamura and Toru et al. used this methodology for the synthesis of (R)-convolutamydine A (198). Non-enolizable and highly reactive ketone derivatives have been used successfully with proline as well, which should be the first choice of catalyst for most substrates (Table 3). Table 25 : Ketone electrophiles in the acetone aldol reactiona
R1 R2
O O
48 26
+OOH
R2
R1
194
catalyst
NH
O
O
X
X
X= H, isatinX= Br, 2,6-dibromoisatine
NH
O
Br
Br
HOO
198248
(R)-convolutamydine A
NH
NHO
HN
PhPhO
HN
100247
Feng 2007R1 = PhR2 = CO2Me92% yield93% ee
NH N O
H2N Ph
128198
Feng and Hu 2008R1 = P-NO2-PhR2 = P(O)(OEt)290% yield98% ee
NPh
H2N
127197
Liu and Luo 2008R1 = P-OMe-PhR2 = CO2Me98% yield96% ee
NH O
HN OBn
OPh
195244
Tomasini 2005isatine was used as acceptor92% yield72% ee
NH O
HN
196245, 246
Luo and Gong 2006, 2007R1 = PhR2 = CO2H>99% yield93% ee
N
NH O
HN
S
197248
Nakamura and Toru 20084,6-dibromoisatinwas used as acceptor99% yield95% ee
O O
S
.TFA
R1 = BnR2 = CO2H75% yield98% ee
aReferences are given for each product as superscript
CHAPTER 2
58
Table 26 : Aldehyde donors in self-aldol and cross-aldol reactionsa
R1 H
O
+
O
25 31
CatalystH R1
OH O
H
199
N
NH
NHN
H
N.TfOH
89151,152
R2 R2
CO2NH2
82251
Hayashi 2007R1 = EtR2 = Me23% yield1 : 1.3 anti : syn78% ee (anti)74% ee (syn)
PO
HNNH
NH
O
NH
HO
O
NH
HO
O
NHHO151213
Wang and Pan 2009R1 = p-NO2-PhR2 = i-Pr34% yield87 : 13 anti : syn97% ee (anti)R1 = p-NO2-PhR2 = n-Bu64% yield82 : 18 anti : syn80% ee (anti)
NH
NHSO2CF3
202252
Maruoka 2007R1 = R2 = Me73% yield1 : 12 anti : syn98% ee (syn)
H
OH O
Et MeO2N N
H OH
F3C CF3
CF3
CF3203253, 254
Hayashi 2008R1 = p-NO2-PhR2 = H85% yield96% ee (anti)R1 = MeR2 = H56% yield82% ee (anti)
MeO
Pht-Bu
200249
MacMillan 2004
201
R1 = EtR2 = Me86% yield 4 : 1 anti : syn94% ee
R1 = R2 = 86% yield 4 : 1 anti : syn94% ee
i-Prn-Bu
R1 = CH2OTIPSR2 = OTIPS84% yield1 : 4 anti : syn 92% ee
Barbas 2004250
96% yield62 : 38 anti : syn91% ee (anti)75% ee (syn)
p-OMe-Ph
aReferences are given for each product as superscript 2.4.15 Catalyst for aldehyde-aldehyde aldol reaction Aldehyde cross-aldol reactions have been achieved with a number of different catalysts (Table 26). MacMillan et al. first described the cross-aldol reaction with proline,[130] and later reported the use of catalyst 200 for the reaction.[249] The reaction proceeds with good yield and enantioselectivity for a wide array of substrates, favoring the anti isomer. Proline, however, is also a good catalyst for this reaction, and is less expensive to employ (Table 4). Barbas et al. reported the use of diamine 89, together with an equal amount of trifluoroacetic acid, for the creation of quaternary stereocenters adjacent to an aldehyde (201).[250] The reaction works well with electronpoor aryl aldehydes, but the yields are lower for benzaldehyde and other more electron-rich aryl aldehydes. The diastereoselectivity is only moderate with this catalyst, and future developments should improve this highly useful reaction. Hayashi et al. reported the use of prolinamide 82 for the self-aldol reaction of propanal in an aqueous environment, which was followed by reduction of the resulting aldehyde with sodium borohydride to give the diol.[251] Unfortunately low diastereoselectivity and yield was obtained under these conditions. Maruoka’s binaphthyl catalyst 202 gave very impressive results when applied to the cross-aldol reaction.[252] Unlike proline, catalyst 202 produces the syn diastereomer in good diastereoselectivity, yield and enantioselectivity. This provides a complement to the proline catalyst, making the selective production of either diastereomer possible. Prolinol 203, reported by Hayashi et al. in 2008, has been reported for the use of acetaldehyde in self-aldol and cross-aldol reactions.[253,254] Hayashi demonstrated that proline itself was an inefficient catalyst for this reaction (which was followed by sodium borohydride reduction of the resulting aldehyde) giving very little of the desired adducts. The use of catalyst 203 allows the substrate scope of enamine-catalyzed cross-aldol reactions to be extended to the use of acetaldehyde. Wang and Pan et al. have also used their phosphine oxide catalyst 151 for the cross-aldol reaction, but this catalyst appears to have no advantage over use of the far simpler catalyst proline.[213] The aldehyde self- and cross-aldol reaction may now be used for a variety of aldehydes, including α-branched and α -unbranched aldehydes, and even acetaldehyde. The syn diastereomeric products are also now available, providing access to an ever-growing family of products.
CHAPTER 2
59
2.4.16 Catalyst for special ketone (N-Boc-piperidone) aldol reaction A number of interesting substrates for example N-Boc-piperidone have been employed for the direct catalytic aldol reaction (Table 27). The use of 204 in the aldol reaction with aromatic aldehydes have been reported by Pihko.[108] The adduct 207 was obtained in 40% yield with 74% ee by using L-proline (10 mol%) after long reaction time of 5 days. Xiao et al. demonstrated the use of derivative of proline 106[174] (20 mol%) and acetic acid 40 mol% to afford adducts 206 and 207 in 86 and 80% yields respectively by using 5:1 ketone:aldehyde ratio. Gryko et al. reported thioprolinamide 96[255] as an efficient catalyst for N-Boc-piperidone aldol reaction. They used 2:1 ketone aldehydes ratio and 10 mol% of thioprolinamide. Bolm reports D-proline[256], Liu phosphinyloxide[215] Najera BINAM-L-proline.[99,189] These type of interesting substrates should prove useful for the synthesis of more functionalized products. Table 27 : N-Boc-piperidone as aldol donora
N
O
Boc 204
+R
H
O
205
NH
OHO
ent-13108
Pihko 2006R= Cl40% yield4:1 anti:syn74% ee
NH
OHO
13255
Bolm 2007R = NO250% yield86:14 anti:syn55% ee
NH2 S
HN Ph
CF3CO2
Gryko 2007R = NO296% yield60:40 anti:syn91% ee
NHNH
O
NCOCF3H
106174
Xiao 2006R = NO290% yield96:4 anti:syn96% ee
R= Cl80% yield97:3 anti:syn95% ee
NHP
O
O
PhPh
146215
Liu 2008R = NO243% yield69:31 anti:syn80% ee
NHNH O
O
NH
NH10899
Najera 2008R = NO277% yield92:8 anti:syn90% ee
NHNH
S
119189
Alonso and Najera 2009R = NO256% yield98:2 anti:syn80% ee
96256
NBoc
O OH
R
R= NO2 206R= Cl 207
Catalyst
aReferences are given for each product as superscript
CHAPTER 2
60
Conclusion Enamine-catalysis is a hot field, and its impact on the direct aldol reaction is far-reaching. The scope of this reaction has been extended from the original report of acetone as a donor to include more substituted ketones, cyclic ketones, unsymmetrical ketones, β-keto esters, aryl ketones, ynones, and even aldehydes. The acceptor component can be a variety of different aldehydes and highly reactive ketone derivatives. Importantly, the selectivity of the reaction has been extended to include production of isomers not observed when proline is used, through the development of alternate catalysts. Selective formation of linear and branched products is possible, as well as control over the diastereoselectivity. One of the remaining challenges is the development of more reactive catalysts, as the need for excess donor component, high catalyst loadings, and long reaction times remains a problem for most of the described methods.
CHAPTER 2
61
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3. Result and discussion Based on the earlier reported literature regarding the usefulness of bifunctional catalysts, our main goal was to synthesize a new class of chiral diamines which are based on tertiary-primary diamines, can be synthesized in a short number of steps and allow a large number of derivatives of pyridyl-primary diamine to be synthesized with the specific intent to using them as enantioselective catalysts. Regarding the tertiary amine of the diamine, we chose to focus on a pyridine based diamine. Various asymmetric aldol reactions catalyzed by chiral primary-tertiary diamines have been reported.[1-8] But these catalysts have some disadvantages: i) many can not be easily modified for optimized performance, ii) few bifunctional templates have been introduced (cinchona alkaloid based, proline based, amino acid base) leaving creative space for new generations of perhaps more effective catalysts and or catalysts that can work with presently challenging substrates. Consequently, we decided to focus on the synthesis of pyridyl-primary diamine bifunctional catalysts (Figure 1), which would be attractive alternative of the diamine catalysts used in the past.[2-8] Our catalyst ideas come from considering a simple achiral bifunctional template: picolyl amine. Chiral derivatives therefore would be straight forward to synthesize allow a high degree of modularity. Figure 1: Chiral Pyridyl-primary diamine catalysts synthesized
N NN
Ph
Ph
N
NH2NH2
NH2
NH2
2b 2d2a
2e
NNH2
NR1
NH2
RPicolylamine Chiral version
NNH2
2c
NNH2
2f
NNH2
2g
1 2
Based on theoretical knowledge and reported literature, we thought that our synthesized catalysts hold the potential to induce enantioselective Aldol reactions and mechanistically related reactions, e.g Michael, Mannich etc. For the synthesis of these target catalysts different strategies were present in the literature. In the following paragraphes we show previously publishes routes leading to chiral versions of our organocatalyst template.
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71
3.1 Strategies for the Synthesis of Targeted Catalysts One convenient starting point for a variety of chiral pyridyl-primary diamines is to synthesize different 2-acyl pyridines (Figure 2). Commercially available are acetyl pyridine 16c and benzoyl pyridine 16f. The ketones (16 a,b,d,e, g) were easily synthesized from commercially available acetyl pyridine 16c (Scheme 1). Figure 2: Corresponding ketones for amine synthesis
N NN
Ph
Ph
N
16b 16d16a
16e
N
16c
N
16f
N
16g
O O O O
O O O
NO
NO
R
ROr RBr, 18-C-6, NaH, toluene, 50 0C
RI, 18-C-6, KOH, CH2Cl2, 25 0C
16c 16 a,b,d,e, g
Scheme 1: Synthesis of various ketones from acetyl pyridine Several methods are available for the synthesis pyridyl-primary diamine catalysts from pyridyl ketones in the literature, some of which are mentioned below. 3.1.1 Synthesis of Pyridyl-primary diamine using Chiral Phenyl Glycinol One of the methods for the synthesis of pyridyl-primary diamine is the use of chiral phenyl glycinol to synthesize a secondary amine and then treating with NaIO4 or Pb(OAc)4 to make the primary amine in high stereoselectivity[9] (Scheme 2).
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72
16c
NO
S- Phenyl glycinolN
N
Ph
OH
Pb(OAc)4or Bleach, EtOH
cat. SOCl2toluene reflux
MgX
R
X = Cl, BrR = F, H N
NH
R
HOPh
s s
N
H2N
R
s
R=F, 73% yield, 92% deR=H, 50% yield, 97% de
17 17b
17C
Scheme 2. Use of Phenyl Glycinol in the Synthesis of pyridyl-primary diamine 3.1.2 Synthesis of Pyridyl-primary diamine using tert-butyl Sulfinamide Another methodology to get chiral pyridyl-primary diamine from ketones is to synthesize the ketimine with a chiral auxiliary tert-butyl sulfinamide, subsequent reduction with sodium borohydride and hydrolysis to afford primary pyridyl amine.[10]
A solution of pyridyl ketone, (R)-2-methylpropane-2-sulfinamide and Ti(OEt)4 in anhydrous THF was heated at 70 oC, for the proper time, then sodium borohydride (2.0 equiv) was added portionwise to a cooled (0 oC) solution of the imine in methanol. After proper time (1-30h) at 25 oC, the reaction was quenched with aqueous ammonium chloride. The crude mixture was extracted with ethyl acetate, the solvent was evaporated under reduce pressure and the enantiopure pryidyl amine was obtained flash chromatography (Scheme 3).
Scheme 3. Use of chiral sulfinamide in the Synthesis of Pyridyl-primary diamine
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73
3.1.3 Synthesis of Pyridyl-primarydiamine Catalysts via Classical Resolution One of the methods to get pyridyl-primary diamine is to make oxime from corresponding ketone, subsequent reduction, and then resolution with chiral D-tartaric acid to enantiopure amine. The ketone is treated with a mixture of hydroxylamine hydrochloride and triethyl amine in ethanol at room temperature and the corresponding oxime formed. Then the oxime are subsequently reduced with Zn powder in the presence of ammonium acetate and ammonium hydroxide to get the corresponding racemic amine[11] (Scheme 4). The racemic pyridyl-primary diamine resolved into its enantiopure R and S forms after several resolutions using D-tartaric acid.
NO
RNH4OAc, Zn,NH2OH.HCl
TEA, ethanol,1h,TBDMSO
NN
RTBDMSO
OH
NNH2
RTBDMSO
R =3-TBDMSO methyl pyridine
ethanol, 3h,reflux
NNH2
RTBDMSO
NNH2
RTBDMSO
D-tartaric acid THF/CH3CN(1:5)
22 23 24
25
Scheme 4: Example of the synthesis of an enantiopure Pyridyl-primary diamine via resolution. Although the above two methods in Scheme 2 and 3 are short steps procedure as compared to classical resolution method but the chiral auxiliary used methods are much expensive and most importantly our ketone 16a failed to react with these chiral auxiliaries to afford imine. So that is why I selected this classical resolution method. By using this methodology we have synthesized enatiopure PicAm 2a starting from commercially available acetyl pyridine 16c. Design of new chiral organocatalysts to achieve efficient asymmetric transformations has become increasingly important in current asymmetric organocatalysis. In particular, development of a novel approach for asymmetric synthesis of enantiomeric products would be very useful from a practical viewpoint by designing different chiral organocatalysts from a commercially available compound. One of our goals is to synthesize chiral organocatalysts 2a-g (Figure 1) starting from acetyl pyridine 16c. The requisite catalyst 2a can be prepared in a 4-step sequence as shown in Scheme 4. We have synthesized chiral pyridylamine 2a starting from acetyl pyridine to synthesized the ketone 16a, conversion to oxime 26 and then reduce with ammonium acetate to afford the desired racemic amine. Different chiral acids were tested to make its salt and recrystalized with 95% ethanol to get enantiopure amine 2a as its D.tartaric salt. Its application was evaluated as chiral catalyst for Aldol reaction.
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N
Ph
Ph
NH2N
Ph
Ph
NH2
NO
18-C-6
Toluene
NaH
Benzyl bromide ΤΕΑ,
NH2OH.HCl
ethanol
NN
Ph
Ph
OH
NH4OAC Zn, ethanol
NNH2
Ph
Ph
rac-2a
D-Tartaric Acid
16c 16a
(R) - 2a
26
(S) - 2a
NO
Ph
Ph
Scheme 5: Synthesis of Catalyst PicAm-2a. 3.1.4 Synthesis of Pyridyl-primary diamine Catalysts (2b-g) by Reductive amination. The catalysts 2b-g have been synthesized by Nugent group by reductive amination method. In this method the corresponding ketones 18, (Scheme 6) were treated with MeO-α-MBA in the presence of Ti(iPrO4) at higher temperature to afford the imine 28 which are further hydrogenated on Pt/C under 10 bar of hydrogen pressure to get the corresponding secondary amine 29. After chromatography two diasteromers were separated and single diasteromer was treated with BCl3 and NaI to afford catalysts (2b-g).[12]
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75
NR
O
18
OMe
H2N
Ti(OiPr4), 60 oC NR
N
OMe
NR
HN
OMe
NR
HN
OMe
+
Chromatography
27
28
29a 29b
NR
NH2
29b
2b-g
H2
deprotection
Scheme 6: Synthesis of Pyridyl-primary diamine by Reductive amination. 3.2 PicAm-2a Catalyzed Aldol Reactions The basic skeleton of our catalyst PicAm-2 is similar to picolyl amine 1 (Figure 1). So we first examined the direct Aldol reaction of cyclohexanone and p-nitrobenzaldehyde catalyzed by picolylamine as a model experiment to get racemic aldol product 3 (Scheme 7). After column chromatography 88% yield was observed. This simple method represents the most convenient method presently known for racemic aldol product formation.
O
H
O
NO2
O
NO225 oC, 0.5M,44h
Picolylamine (20 mol %)
OH
MeOH:H2O
33.3 equiv 1 equiv27 28
Scheme 7: Picolylamine Catalyzed Aldol reaction of Cyclohexanone and 4-nitrobenzaldehyde Scheme 7. Aldol Reaction of Cyclohexanone and p-nitrobenzaldehyde Catalyzed by Picolylamine.
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Using picolylamine (20 mol %) which contain the backbone with our designed amino-pyridine catalyst, we screened different solvents (Table 1) to find the optimum reaction solvent for the reaction of Cyclohexanone and 4-nitrobenzyldehyde (limiting reagent). In polar solvents (H2O, DMSO, NMP, CH2Cl2 MeOH/H2O) at room temperature gave aldol product as compared to the nonpolar solvents (toluene and hexane). A noticeable increase in the reaction rate was attained by the use of MeOH and water (Table 1, entry 8), MeOH/Water (1:1) was found to be superior in terms of reactivity (Entry 9). Table 1. Direct Aldol Reaction of cyclohexanone and p-nitrobenzaldehyde catalyzed by picolylamine in the presence of various solventsa
Foot note. a Reaction conditions: ketone (3.3 equiv), aldehyde (1.0 equiv) at rt, 0.5 M solvent Further we screened our synthesized chiral version of picolylamine catalysts (Figure 1) and we found that catalyst 2a is effective for aldol while catalyst 2f was best for Micheal addition in terms of reactivities as well as enantioselectivities. We next focused our attention on the benchmark enantioselective aldol reaction, addition of cyclohexanone to 4-nitrobenzaldehyde. Using 5 mol % of (S)-PicAm 2a and 2,4-dinitrobenzenesulfonic acid (2,4-DNBSA), various organic solvents (PhMe, CH2Cl2, THF, DMSO, and NMP) were screened. After 16 h at 25 oC little product formation was noted (1-11 area %, HPLC). Protic solvent screening, on the other hand, showed the reaction smoothly proceeded (Table 3). Regarding the diastereomeric ratio, water and brine provided very high drs for the anti-aldol product at 25 oC, while MeOH provided good, but opposite, dr (syn-aldol product favored). Even so, the reactions were incomplete after 22 h (Table 2, compare 8, 11, 13). This was overcome by heating the reaction at 45 oC, without significant consequences for the stereoselectivity (Table 2, e.g. entries 8 and 9). During the reaction of cyclohexanone with 4-nitrobenzaldehyde, the imine of 4-nitrobenzaldehyde and PicAm forms. This non-productive reaction is reversible, but the stated imine co-elutes with one of the syn-aldol products, inflating the HPLC yield area % (it was confirmed by independent synthesis of imine) Nevertheless, appreciation of this situation allowed a more detailed analysis of the chromatograms, and unambiguous relative rates of reaction could be assigned: water ≥ brine >> MeOH.
Foot note. a Reaction conditions: ketone (3.3 equiv), aldehyde (1.0 equiv, 0.5 mmol), (S)-PicAm-2a (5.0 mol%), 2.4-DNBSA (5.0 mol%), unless otherwise stated. bHPLC yield. c1H NMR data of crude product after work-up, major product is anti. d HPLC data (OD-H column)
Further we screened different combination of chiral and achiral acids along with variety of additives (Table 3) with same standard substrate cyclohexanone and 4-nitrobenzaldehyde and we found the use of 2,4-DNBSA and CH3COOH (entry 1), Naphtalensulfonic acid (entry 15), 2,4-DNBSA (entry 19), 2,4-DNBSA and Na-DBS (entry 25) and (D-tartaric acid and Na-DBS entry 35). we repeated these five best conditions and found that these are the five best conditions at 45 oC regarding yield, ee and drs.
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Table 3. Acid and Additive screening for Enantioselective aldol reaction Catalzyed by PicAm-2aa S. No
Foot note. a Reaction conditions: ketone (3.3 equiv), aldehyde (1.0 equiv, 0.5 mmol), (S)-PicAm-2a (5.0 mol%), H2O (0.5 M), 45 oC,unless otherwise stated. bIsolated yield after column chromatography. c1H NMR data of crude product after work-up, major product is anti. d HPLC data (OD-H column) Under the optimized conditions consequently use of acid additive (bifunctional organocatalysis), which can be considered as a flexible modular reaction component for substrate-catalyst optimization as demonstrated shortly.(Table 4) provides a summary for the aldol reaction of cyclohexanone, cyclopentanone and Tetrahydro- thiopyran-4-one with six different aromatic aldehydes. Reaction of cyclohexanone with p-NO2-, p-CF3-, or o-NO2-PhC(O)H permitted high dr and ee (Table 4, products 3, 4, 6). m-Cl-PhC(O)H is less frequently studied and considerably less electrophilic. Under our standard conditions significant quantities of the aldol elimination product were noted in addition to desired product 5 (Table 4). The elimination product was completely suppressed by replacing the 2,4-DNBSA acid additive with 5 mol% each of (S,S)-D-tartaric acid and sodium dodecylbenzenesulfonate (NaDBSA) in a brine reaction medium. An unintended consequence was very slow, but clean, product formation. By further changing the reaction medium from brine to water the reaction rate increased allowing the optimized conditions to be found (Table 4, product 5).
Table 4: Aldol Products of Cyclohexanone, Cyclopentanone and Tetrahydro- thiopyran-4-onea Comd No.
Aldol products Time Yield(%)b drc eed( anti)
3 O OH
NO2
16e 92 22 : 1 99
4 O OH
CF3
22 88 12 : 1 99
5 O OHCl
40f 82 5.5 : 1 95g
6 O OH NO2
20 84 30 : 1 98
7 O OH
CH3
24 55 8 : 1 96
8 O OH
NO2
16h 81 1.2 : 1 92 89i
13 O OH
9j 50 6.8 : 1 97
14
S
O OH
NO2
16 92 20 : 1 98
15
S
O OH
26 40 17 : 1 95
a Reaction conditions: ketone (3.3 equiv), aldehyde (1.0 equiv, 0.5 mmol), (S)-PicAm-2a (5.0 mol%), 2,4-DNBSA (5 mol%), H2O (0.5 M), 45 oC,unless otherwise stated. bIsolated yield after column chromatography. c1H NMR data of crude product after work-up, major product is anti. d HPLC data (Chiralpak AS-H or OD-H column) after silica gelchromatography. e performed in brine (0.5 M). f2,4-DNBSA was replaced with 5 mol% each of: (S,S)-D-tartaric acid and NaDBSA.g (R)- PicAm-2a (5.0 mol%) was used. h2,4-DNBSA was replaced with 5 mol% of 1-NSA (1-naphthalenesulfonic acid). i ee of minor diastereostereomer. j Temperature was 60 oC, elimination product observed.
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4-Methylbenzaldehyde is considered a challenging substrate regarding yield, stereoselectivity, and reaction time. Of the thirteen previous reports we are aware of, eleven require a proline based organocatalyst.[13-19] The remaining two organocatalysts are represented by a chiral phosphine oxide (10 mol% loading, 6.6:1 dr, 83% ee, 92% yield)20 and a primary amine (leucine/amide-alcohol (20 mol% loading, 10:1 dr, 92% ee, 50% yield).21 Using our standard conditions we obtained a 55% isolated yield, 8:1 dr, and 96% ee within 24 h (Table 4, product 7). The best performing organocatalysts are proline based, requiring 1-2 mol% loading (yield 42-75%, 88:12 to 99:1 dr, and 87-98% ee).[13,14,16,17] To round out our initial study, we examined cyclopentanone and noted a clear lack of diastereoselectivity (Table 4, product 8). Be this as it may, the ee was good for both diastereomers (92 and 89% ee). For our optimization of this substrate, the acid component was again crucial, albeit not regarding the de, with 1-naphthalenesulfonic acid (1-NSA) providing by far the highest ee. Table 5 : Aldol Products of Cyclohexanone: 2.0 mol% PicAm-2a loading (See Table 4 for Structure).a
Aldol product Time Yield(%)b drc ee (anti)d 3 24 89 15 :1 98 4 32 56 9 : 1 98 6 30 83 30 : 1 98 aFootnote text. Reaction conditions: ketone (3.3 equiv), aldehyde (1.0 equiv, 0.5 mmol), (S)- PicAm-2a (2.0 mol%), 2,4-DNBSA (2.0 mol%), brine (0.5 M), 45 oC.b-d As in Table 4. eThe same reaction, but in water, provided a 17:1 dr. To further test the performance of organocatalyst PicAm-2a, we examined three substrates at the 2.0 mol% catalyst loading (Table 5). Aldol reactions of cyclohexanone with ortho-, meta-, or para-substituted benzaldehydes are good for establishing the potential usefullness of a new catalyst, but the products themselves lack the functional group diversity of drug-like building blocks. Examination of functionalized ketones would begin to address this point and allowed us to realize the inherent high value of our new organocatalyst template. Notably the results outlined in Figure 3 represent the best achieved to date at the lowest catalyst loading (5 mol%) known to date. For example N-Boc-piperidone has been examined by at least eight research groups.[18, 19a, 22a,b,23a,24] Of those, the lowest catalyst loading reported to date is 5 mol%,[18,24b] resulting in product 9 (Figure 3) with an optimal result of 56% yield, >45:1 dr, 80% ee, 72 h.[18] The most favorable 10 mol % result provided a 59% yield, 45:1 dr, 93% ee, 22 h,19a and the best 20 mol% result provided an 86% yield, 45:1 dr, and 98% ee. It was therefore gratifying to see that our catalyst provided improved yield and ee at the low loading of 5 mol% (R)-PicAm-2a (Figure 3, product 9). A similar trend was observed for aldol products 10 and 11. Reaction of N-Boc-piperidone with 4-Cl-benzaldehyde in the presence of 5 mol% (S)-PicAm-2a provided product 10 (55% yield, 66:1 dr, and >99% ee). Two other organocatalyst reports exist for its synthesis, one uses a 10 mol% loading (40% yield, 4:1 dr, 74% ee),[25] while the other uses a 20 mol% loading (80% yield, 97:3 dr, 95% ee).[22a] For the reaction of 4-ketalcyclohexanone with 4-nitrobenzaldyhde we examined the effect of lowering the ketone/aldehyde ratio to 2:1. Using 5 mol% (S)-PicAm-2, product 11 (Figure 3) was obtained in excellent yield (91%), dr (65:1), and ee (98%). Five prior literature reports are noted for product 11.[16,22b,19b,26] One study was clearly superior regarding catalyst loading, using 1 mol% of a trans-4-silylhydroxyproline/amidealcohol (four stereogenic centers), but the yield (75%), dr (9:1), and ee (95%) are considerably lower and the reaction time significantly longer (70 h vs 21 h).[16] In another study, 5
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mol% of a different trans-4-silylhydroxyproline/amide-alcohol resulted in a 90% yield, 45:1 dr, and 94% ee.[19b]
N
O
Boc
or
O
O O
H
O
X
5 mol% PicAm-245 oC
N
O
Boc
O
O O
OH
NO2
NO2
OH O
O O
OH NO2
N
O
Boc
OH
Cl
82% yield16:1 dr 98% eewater 33h3.3/1 ket/ald
81% yield33:1 dr 96% eebrine 35h3.3/1 ket/ald
55% yield66:1 dr 99% eebrine 48h3.3/1 ket/ald
91% yield65:1 dr 98% eebrine 21h2/1 ket/ald
86% yield18:1 dr 91% eebrine 38h3.3/1 ket/ald
9 10
11 12
Figure 3: Approaching drug-like highly fanctionalized aldol products This result was possible when using the ketone in solvent like volumes after four days of reaction. Our final aldol product (12) is reported here for the first time in the literature. Although preliminary, a mechanism justifying the observed diastereo- and enantiocontrol is offered in Figure 4. Whether these type of reactions are occuring in, on, or at the organicwater interface is still a matter of intense discussion in the literature. For now we can say that a concentrated organic phase is observed on the water during our reactions.
X
O OH
X12
(1S, 2R)-anti aldol
NH
Ph
Ph NH
R-PicAm-2a
H
O
Figure 4 : Proposed Transition State Model Conclusions In summary, the 2-picolylamine template has been established as a promising new organocatalyst. A chiral version containing a single stereogenic center, (R)- and (S)-PicAm (2a), has been identified as allowing fast and highly stereoselective anti-aldol product formation at a low catalyst loading (5 mol %). Importantly, PicAm-2a excelled when examining more functionalized ketone substrates. The new template is likely to be amenable to mechanistically related organocatalytic reactions.
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References [1] J. Li, S. Hu, S. Luo, J. Cheng, Eur. J. Org. Chem. 2009, 132. [2] Y. Jia, F. Wua, X. Maa, G. Zhu, C. Da, Tetrahedron Letters 2009, 50, 3059. [3] S. Luo, H. Xu, J. Li, L. Zhang, J. Cheng, J. Am. Chem. Soc. 2007,129, 3074. [4] B. Zheng, Q. Liu, C. Guo, X. Wang, L. He, Org. Biomol. Chem. 2007, 5, 2913. [5] D. Enders, M. Voith, A. Lenzen, A, Angew. Chem. Int. Ed. 2005, 44, 1304. [6] S. Luo, H. Xu, L. Zhang, J. Li, J. P. Cheng, Org. Lett. 2008, 10, 653. [7] J. Zhou, V. Wakchaure, P. Kraft, B. List, Angew. Chem. Int. Ed. 2008, 40, 7656. [8] J. Li, S. Luo, J. Cheng, J. Org. Chem. 2009, 74, 1747. [9] D. Spero, S. Kapadia, J. Org. Chem. 1997, 62, 5537. [10] G. Chelucci, S. Baldino, S. Chessa, G. pinna, F. Soccolini, Tetrahedron: Asymmetry, 2006, 17, 3163. [11] M. Heuvel, T. Berg, R. Kellogg, C. Choma, B. Feringa, J. Org. Chem. 2004, 69, 250. [12] S. D. Boggs, J. D. Cobb, K. S. Gudmundsson, L. A. Jones, R.T. Matsuoka, A. Millar, D. E. Patterson, V. Samano, M. D. Trone, S. Xie, X.-M. Zhou, Org. Proc. Res. Dev. 2007, 11, 539. [13] J. Huang, X. Zhang, D. W. Armstrong, Angew. Chem. Int. Ed. 2007, 46, 9073. [14] F. Giacalone, M. Gruttadauria, P. L. Meo, S. Riela, R. Noto, Adv. Synth. Catal. 2008, 350, 2747. [15] Y.-N. Jia, F.-C. Wu, X. Ma, G.-J. Zhu, C.-S. Da, Tetrahedron Lett. 2009, 50, 3059. [16] J.-F. Zhao, L. He, J. Jiang, Z. Tang, L.-F. Cun, L.-Z. Gong, Tetrahedron Lett. 2008, 49, 3372. [17] S. Gandhi, V. K. Singh, J. Org. Chem. 2008, 73, 9411. [18] (a) D. Almasi, D. A. Alonso, A.-N. Balaguer, C. Nájera, C. Adv. Synth. Catal. 2009, 351, 1123. (b) D. Almasi, D. A. Alonso, C. Nájera, Adv. Synth. Catal. 2008, 350, 2467. [19] (a) M. Gruttadauria, F. Giacalone, A. M. Marculescu, R. Noto, Adv. Synth. Catal. 2008, 350, 1397. b) L. He, J. Jiang, Z. Tang, X. Cui, A.-O. Mi, Y.-Z. Jiang, L.-Z. Gong, Tetrahedron Asymmetry 2007, 18, 265. c) K. Liu, D. Häussinger, W.-D. Woggon, Syn. Lett. 2007, 14, 2298. d) Y. Wu, Y. Zhang, M. Yu, G. Zhao, S. Wang, Org. Lett. 2006, 8, 4417. [20] S. Kotani, S. Hashimoto, M. Nakajima, Syn. Lett. 2006, 7, 1116. [21] X. Ma, C.-S. Da, L. Yi, Y.-N. Jia, Q.-P. Guo, L.-P. Che, F.-C. Wu, J.-R. Wang, W.-P. Li, Tetrahedron Asymmetry 2009, 20, 1419. [22] (a) J.-R. Chen, X.-Y. Li, X.-N. Xing, W.-J. Xiao, J. Org. Chem. 2006, 71, 8198. b) D. Gryko, W. J. Saletra, W. J. Org. Biomol. Chem. 2007, 5, 2148. [23] Loadings of 20 or 30 mol% of commercially available proline have been used for cyclic ketones, respectively see: (a) B. RodrÃguez, A. Bruckmann, C. Bolm, Chem. Eur. J. 2007, 13, 4710. (b) Y. Hayashi, S. Aratake, T. Itoh, T. Okano, T. Sumiya, M. Shoji, Chem. Commun. 2007, 957. [24] (a) X.-W. Liu, T. N. Le; Y. Lu, Y. Xiao, J. Ma, X. Li, Org. Biomol. Chem., 2008, 6, 3997. b) G. Guillena, M. C. Hita, C. Nájera, S. F. Viózquez, J. Org. Chem. 2008, 73, 5933. [25] P. M. Pihko, K. M. Laurikainen, A. Usano, A. I. Nyberg, J. A. Kaavi, J. A. Tetrahedron 2006, 62, 317. [26] (a) S. S. Chimni, S. Singh, D. Mahajan, Tetrahedron Asymmetry 2008, 19, 2276.
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(b) A. Córdova, W. Zou, I. Ibrahem, E. Reyes, M. Engqvist, W.-W. Liao, Chem. Commun. 2005, 3586.
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4. EXPERIMENTAL General Information: Commercial reagents were used as received from Sigma-Aldrich. Routine monitoring of reactions were performed by thin-layer chromatography (TLC) using precoated plates of silica gel 60 F254 and visualized under ultraviolet irradiation (254 nm). Column chromatography separations were performed by with silica gel 60 (0.040-0.063 mm). Petroleum ether with a boiling point range of 60-80 °C was used. Organic extracts were dried over anhydrous sodium sulfate. Evaporation of solvent was performed at reduced pressure. Chemical shifts (δ) were reported in parts per million (ppm) downfield from tetramethylsilane (TMS= 0) or relative to CHCl3 (7.26 ppm) for 1H NMR. Multiplicities are abbreviated as: (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet). Coupling constants are expressed in Hz. FT-IR spectra were obtained on Nicolet Avatar 370 thermonicolet spectrometer. MS data was measured on a Bruker Daltonics HCT Ultra. HRMS were recorded on a Brukar micrOTOF instrument with an ionization potential of 70 eV with ESI positive mode. The enantiomeric excess was determined by HPLC using a Chiralpak AS-H or OD-H column with n-heptane and i-propanol as eluents. 4.1 Procedure for the synthesis of Ketone (16a) 2-benzyl-3-phenyl-1-(pyridine-2yl)propan-1-one (16a). To a 250 ml two neck round bottom flask (dried) was added NaH (4 equiv, 1.2 gm, 48 mmol) in anhydrous toluene (40 ml) at 25 oC, followed by addition of 18-C-6 (0.1 equiv, 0.32gm, 1.2 mmol), and acetyl pyridine 16c (1 equiv,1.35 ml, 12 mmol) stirred for 20 minutes. Then added drop wise benzyl bromide (2.5 equiv, 3.6ml, 30 mmol) by glass syringe. The reaction mixture was stirred at 50 oC for 5-6 hours under inert atmosphere. The reaction was monitored by TLC and GC which showing complete conversion of starting material into new product. The resulting faint yellow reaction mixture was quenched by adding saturated NH4Cl solution at 25 oC. The reaction mixture was extracted with Ethyl acetate. The organic layer was dried over sodium sulphate and concentrate under low vacuum gave yellow oil submitted to flash chromatography eluting with 5 % EtOAc/ hexane to give the desired ketone 4a (3.6 gm) with (68 %) yield as a white solid. 1H NMR (CDCl3, 300 MHz): 2.73-2.78 (dd, J) 7.31 Hz, 2H), 3.13-3.18(dd, J)9.85 Hz, 2H), 4.81-4.88, (pentate 1H), 7.08-7.41 (m, 10H), 7.69-7.73 (m 2H) 7.92-7.93 (d J) 7.79Hz 1H),8.62 (d, J ) 4.12 Hz, 1H ). 13C NMR (CDCl3, 300 MHz): δ 37.2, 47.9, 122.3, 125.9, 126.8, 128.1, 129.1, 136.6, 139.8, 148.8, 153.0, 203.5.
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4.2 Procedure for the Synthesis of Racemic PicAm (2) A mixture of hydroxylammonium chloride (3.0 equiv, 3.33 g, 48.0 mmol) and Et3N (3.0 equiv, 6.69 mL, 48.0 mmol) in EtOH (53 mL) was stirred at room temperature for 30 min.[1] The corresponding ketone (1.0 equiv, 4.82 g, 16.0 mmol) was then added. After heating under reflux for 8 h, the solvent was removed by rotary evaporation and the residue was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude oxime as a brown oil. Without further purification, the crude oxime (1.0 equiv, 5.06 g, 16.0 mmol) was added to EtOH (70 mL) with NH4OAc (1.3 equiv, 1.64g, 20.8 mmol) and NH4OH (59 mL, 25% v/v in H2O). This solution was heated at reflux and zinc powder (5.0 equiv, 5.05 g, 80.0 mmol) was added portion wise over 2 h every 15 min. After refluxing for an additional 8 h, the reaction mixture was cooled to room temperature and concentrated NaOH was added until reaching a pH of 12. After filtration through celite and washing with diethyl ether, the layers were separated. The aqueous layer was further extracted with Et2O. The organic phases were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. After column chromatography, EtOAc/pet ether (1:4), racemic PicAm (2) was afforded as a pure viscous oil (65% yield).[1]
N
Ph
Ph
NH2
(R)-PicAm 2 4.3 Resolution of Racemic PicAm (2) To a stirred solution of unnatural tartaric acid, (S,S)-D-tartaric acid (0.50 equiv, 1.59 g, 10.6 mmol), in a boiling mixture of THF/CH3CN 1:5 (180 mL), was added racemic PicAm (2) (1.0 equiv, 6.4 g, 21.2 mmol).[2] The mixture was gently refluxed (∼70 oC) for 1 h. During this time some precipitation of the salt may occur and is normal. The precipitated salt color, in the solution, is brown. The oil bath was then turned off. In this way the solution was allowed to come to room temperature over ∼1 h. After stirring for an additional 1-2 h at room temperature the precipitate was filtered giving 5.14 g of off-white to brown colored solid. This material was crystallized a total of four more times but now from EtOH/H2O (95:5 vol-to-vol ratio). The EtOH used was Sigma-Aldrich cat. # 32205. Each EtOH/H2O crystallization was performed by dissolving the salt into the minimum volume of 95% ethanol sufficient to dissolve the salt at 70 oC. This was followed by gentle reflux for 1 h, then cooling to 25 oC in a controlled manner over 1 h. This was followed by 2 h of stirring at 25 oC, followed by filtration. Repeat three more times. After the five resolutions (1 with THF/CH3CN and 4 with EtOH/H2O), high vacuum drying furnished the (R)-PicAm 2 salt as a white powder (26% weight recovery, 2.10 g, 99% ee) [Note: salt ratio undetermined]. Before use in reactions, the salt was first converted to the corresponding free amine by addition to EtOAc (75 mL) and NaOH (75 ml, 0.5 M). Further extraction (EtOAc, 50 mL x 2) of the basic aqueous layer, was followed by organic extract combination and concentration (Rot Vap) providing the free
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amine [(R)-PicAm 2] as an oil. This free amine was then dissolved in MeOH and unnatural tartaric acid ((S,S)-D-tartaric acid, 1.0 equiv) was added, this 1:1 salt of (R)-PicAm 2 was used for the reactions as indicated. The absolute configuration was determined by x-ray analysis of the 1:1 salt. The absolute configuration of D-tartaric acid is known, (S,S), and relative to this PicAm 2 was of the R configuration.
The ee of PicAm-2 was determined by chiral HPLC (Chiral OD-H, i-PrOH/heptane 5/95, flow rate = 1 mL/min, λ = 254 nm): tmajor= 10.4 min, tminor = 13.8 min. Free amine (R)-PicAm 2: 1H NMR (400 MHz, CDCl3) (ppm): 1.78 (br s, 2H), 2.45-2.50 (m, 2H), 2.57-2.62 (m, 2H), 2.70-2.76 (m, 1H), 3.97 (d, J = 3.66 Hz, 1H), 7.02-7.26 (m, 12H), 7.54-7.58 (m, 1H), 8.55 (d, J = 5.04 Hz, 1H); 13C NMR (400MHz, CDCl3) (ppm): 34.5, 36.8, 49.2, 56.6, 121.6, 125.7, 125.8, 128.2, 128.3, 129.0, 129.1, 136.0, 141.0, 148.7, 163.9. FT-IR (R)-PicAm Naphthalenesulfonic acid salt: (KBr), νmax: 3441, 3025, 2924, 1593, 1495, 1473, 1181, 1042 cm−1; MS (EI), m/z (relative intensity): 325 [M+Na]+, 100%), 286 [M- NH2] 19.5%; HRMS (ESI-TOF) calculated for C21H22N2 [M+H]+ 303.1856; found: 303.1868. 4.4 General Procedure for Racemic Aldol Formation (3-15) The following procedure can be used to synthesize all of the racemic aldol products shown in this manuscript. To a solution of water and methanol 4.0 mL (1:1 v/v) was added 2-picolylamine (0.40 mmol), aldedyde (2.0 mmol, 1.0 equiv), and ketone (1.5 to 3.3 equiv). This stirred at room temperature for 12-24 h, TLC was used to determine complete reaction. Rf values for each compound can be found in the experimental write ups of the enantioenriched aldol products. The reactions were quenched with a saturated solution of NH4Cl (20-25mL) and the resulting mixture was extracted with EtOAc (30 mL x 2). The combined organic layers were separated, dried over anhydrous sodium sulfate, evaporated to give the crude aldol product. Column chromatography on silica gel using EtOAc/pet ether (1:9) gave the pure aldol product (70-90% yield). Although not examined further in this manuscript, tetrahydro-4H-thiopyran-4-one (see main text,
NNH2
Ph
Ph
(R)-PicAm-2
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Scheme 1, X= S), also readily provided the racemic aldol product under these conditions. Although all reactions were by-product free, this was not true for benzaldehyde, not examined in this manuscript, which afforded the expected aldol product and ~20 % of the corresponding elimination product under the above noted conditions. 4.5 General Procedure for Enantioselective Aldol Reaction (compounds 3-12) Four general reaction conditions were found to be optimal depending on the ketone examined. The limiting reagent was the aldehyde, which was always used at the 0.50 mmol scale: Catalyst mixture A: The 2,4-dinitrobenzenesulfonic acid (2,4-DNBSA) salt of (S)-PicAm 2 (MW=550.58, 13.8 mg, 0.025 mmol, 5.0 mol%) Catalyst mixture B: The 1-naphthalenesulfonic acid (1-NSA) salt of (R)-PicAm 2 (MW=510.65, 12.8 mg, 0.025 mmol, 5.0 mol%). Catalyst mixture C: The 1:1 salt of (S,S)-D-tartaric acid (unnatural tartaric acid) and (R)- PicAm 2 (MW=452.50, 11.3 mg, 0.025 mmol, 5.0 mol%). Sodium dodecylbenezenesulfonate (NaDBSA) (MW= 348.48, 8.7 mg, 0.025 mmol, 5.0 mol%) was additionally added. Catalyst mixture D: The 1:1 salt of (R,R)-L-tartaric acid (natural tartaric acid) and (S)- PicAm 2 (MW=452.50, 11.3 mg, 0.025 mmol, 5.0 mol%). Sodium dodecylbenezenesulfonate (NaDBSA) (MW= 348.48, 8.7 mg, 0.025 mmol, 5.0 mol%) and 2,4-dinitrobenzenesulfonic acid (2,4-DNBSA) (MW=248.17, 6.2 mg, 0.025 mmol, 5 mol%) were additionally added. One of the above catalyst mixtures (A, B, C, or D) was added to distilled water or brine (1.0 mL, 0.5 M). The ketone (1.66 mmol, 3.3 equiv) and aldehyde (0.5 mmol, 1.0 equiv) were then added. This mixture was stirred and heated at 45 oC for the indicated reaction time. [NOTE: extension of the indicated reaction times can be detrimental to the diastereoselectivity (α-keto epimerization), do not extend the reaction time.] The reaction was quenched by simply adding water (10 mL) and EtOAc (10 mL). The resulting aqueous layer was extracted a total of three times with EtOAc (10 mL x 3). The combined organic extracts were dried (Na2SO4), evaporated (Rot Vap), and then exposed to high vacuum for 1 h. The resulting crude product was examined by 1H NMR to determine the dr. The crude material was then purified by column chromatography (EtOAc/ petroleum ether). [Note: During column chromatography almost all of the aldol products epimerize. The α-keto-product epimerization likely occurs via enol induced processes on the acidic silica gel. Attempts to ‘neutralize’ the silica gel using eluent doped with Et3N or pretreatment of the silica gel with NH4OH treated solvent were helpful but did not completely and satisfactorily suppress the noted epimerization. As a consequence 1H NMR data obtained after chromatography shows a lower dr than before chromatography.] The after chromatography 1H NMR data supplied here is only provided
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to confirm the purity of the aldol products. The chromatography purified aldol products were then examined by HPLC to determine their ee. The relative and absolute configurations of the products were determined by comparison with the known 1H NMR data and by direct comparison with the literature available HPLC data for aldol products 3-11 and 13-15, while product 12 is reported here for the first time.
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