Catalytic Reactions Application Towards Enantioselective ... … · Application Towards Enantioselective Catalytic Reactions ... - enzymes modulate the pKa of a substrate to match
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The Nature of the Hydrogen Bond and its Application Towards Enantioselective
Catalytic Reactions
Lead Material:Steiner, T. Angew. Chem. Int. Ed. 2002, 41, 48.Pihko, P. M. Angew. Chem. Int. Ed. 2004, 43, 2062.Jeffrey, G. A.; Saenger, W. Hydrogen Bonding in Biological Structures, Springer-Verlalg, New York, 1991.
Jamie TuttleMacMillan Group
2/02/05
A brief introduction to various hydrogen bond applications
! Examples of hydrogen bonding are incredibly common
- Mineralogy, material science, organometallics, biochemistry, organic chemistry, supramolecular chemistry molecular medicine and pharmacy
! Many important structural functions
- Stabilizes protein folding, organizes DNA, organizes water and carbohydrates
N
NN
N
HN
N
N
O
O
H
H
A T
N
HN
NH
N
O
O
NH
O
HO
H
parallel protein beta sheets DNA
Garrett,R. H. and Grisham, C. M. Biochemistry, Harcourt Brace College, Orlando, 1995.
O
HO
H
HOH
H
HO
O
! Being discovered and elaborated on in bioorganic, organic and inorganic chemistries
HO
HOHO
H
H
OHHO
OH
H
carbohydrates
Saenger, J. W. Hydrogen Bonding in Biological Structures, Springer-Verlag, New York, 1991.
M X
N
H
HCl
Au
ClCl
Cl
N
Ph
Ph
H
Crabtree, R. H. et al. Inorg. Chem. 1995, 34, 3474.
H
Hydrogen bonds and reactivity
! Lewis acid activator
! Transition state organizer
O H+O O
NO O
NO
H HH
! Reaction lubricant
- Initially seen in enzymes and is now be utilized in current synthesis- Provide a route for asymmetric catalysis- Dual reactivity
- LUMO lowering catalysis
- Can provide a source of energy to facilitate a reaction- Completes a "circuit" to allow for reaction to occur
! The proposed interaction
- Charge transfer occurs from an electron lone pair from an acceptor (A) to the antibonding orbital of a donor (D) hydrogen bond
! " D#$#
The three major types of H bonds and important parameters
! General Characteristics
- The "normal" hydrogen could also be termed as the "weak strong" or "strong weak" H bond
interaction type
Strong Moderate Weak
bond lengths (A)H- - -A
lengthening of X–H (A)
X–H vs. H- - -A
X- - -A (A)
directionality
bond angles
bond energy (kcal/mol)
1H downfield shift
strongly covalent
mostly electrostatic
electrostatic/dispersed
1.2–1.5 1.5–2.2 2.2–3.3
0.08 – 0.25 0.02 – 2.2 >2.2
X–H ~ H- - -A X–H<H- - -A X–H << H- - -A
2.2–2.5 2.5–3.2 >3.2
strong moderate weak
170–180 >130 >90
15–40 4–15 <4
14–22 <14
°
°
°
(°)
Qualitative properties H bond lengths
! Strong hydrogen bonds
! Moderate hydrogen bonds
! Weak hydrogen bonds
X H Ad1 d1
d1 ~ d2
pKa X ~ pKa A
X H X H XX
X H X H XX
similarly
X H Ad1 d1
d1 < d2, X–H is long compared to weak bonds
X H Ad1 d1
d1 < d2, X–H is shorter than in moderate H bonds
O
H
H
H O
H
H
pKa ~ –1.7
O
O
R
H
O
O
R
pKa ~ 4.76
- C–H donor groups are most widely studied, includes the H-bond pi interaction- generally regarded as electrostatic/dispersed- ability to form bifurcated and trifurcated structures
- A reasonable way of thinking about the H-Bond is as a frozen proton transfer event- Currently no widely accepted theoretical method for predicting H bonds exists
Steiner, T. Angew. Chem. Int. Ed. 2002, 41, 48.
O/N–H bonded species are 2–4 kcal/mol higher with neutralspecies and 15 kcal/mol higher in charged species
- moderate bonds have both weak and strong characteristics and tends to be blurred depending upon the experimental treatment- generally regarded as electrostatic
!+!"
The types of hydrogen bond geometries
! Two centered hydrogen bonds
! Three centered hydrogen bonds or bifurcated H bond
! Four centered hydrogen bonds or trifurcated H bond
X H A
X H
A
A
X H A
A
A
N
H
H
A3
A2
A1
- most understood and reasearched
- most examples are found in biology, especially carbohydrates (~25%) and amino acids (over 25%)
NH(CH2CH2OH)3N
H
O
OO=
H- - -O, 2.14–2.35 AN- - -O, 2.71–2.86A
- Rare, found in molecules that have a high density of donors and acceptors - Also found in biology
F H F
NH3H Bn
HOH OH
Hydrogen bond energies
Steiner, T. Angew. Chem. Int. Ed. 2002, 41, 48.
! Energies for some gas phase dimers
F H F
H2O H OH2
H3N H NH3
OH H OH
H4N OH2
H4N Bn
HOH Cl
COOH OCOH
HOH OH2
NCH OH2
HOH Bn
F3C OH2
MeOH Bn
NH3 Bn
HCCH OH2
H2CCH2 OH
HSH H2S
CH4 FCH3
Dimer Energy (kcal/mol)
39
33
24
23
19
17
13.5
Dimer Energy (kcal/mol)
7.4
4.7–5.0
3.8
3.2
3.1
2.8
2.2
2.2
1.0
1.1
0.2
- strong H bonds, HOH- - -Cl is borderline
-moderate to weak hydrogen bonds
! Comparing to other covalent BDE
H2C CH2
Ph I
Et I
Me H
HO OH
t-BuO Ot-Bu
I I
BDE
171
105
65
53
BDE
51
38
36
- the strongest H bonds start to take on a covalent nature!
Donor/Acceptor Strengths
! Relative donor strengths
- General rule: donor strength is increased by neighboring electron-withdrawing groups and decreased by electron donating groups
O–H > N–H > S–H > C–H
oxygen subclass
H3O+ > O=C–OH > Ph–OH > Csp3–OH > H2O > OH–
nitrogen subclass
Im+N–H > R3N+–H > R2NH+–H > Csp2N–H > Csp3NH > N–NH2
carbon subclass
Cl3CH > C –H > (RN2)2Csp2 –H > (Cl, C)C–sp3 –H > R2C –H > R3C –H > O –CH3 >CH3CH2 –H
! Relative acceptor strengths
oxygen subclass
OH– > COO– > H2O > Csp3–OH >Ph–OH > C–NO2 > M–CO
nitrogen subclass
Csp3–NH2 > R2N–H > R3N–H > CN > Csp2NH2 > C=N–S
halogen subclass
F– > C–F > Cl– >Br– > I–
- General rule: acceptor strength is increased by neighboring electron-donating groups and decreased by electron donating groups withdrawing groups
Steiner, T. Angew. Chem. Int. Ed. 2002, 41, 48.
- These trends are highly dependent on acceptor/donor pairings
Other interesting characteristics
! Cooperativity
!"X H A
!+ !"
X H!" !+
X H!" !+
Y H!" !+
- Charges flow through the X–H sigma bonds. The net result is an overall strengthening of both sigma bonds by ~ 20%- This effect drives the clustering of polar groups (e.g. carbohydrates)- Anticooperativity
! Donor directionality
- the main feature distinguishing a H bond from van der Waals interaction is its preference for linearity- degree of directionality depends on polarity of donor, O–H>C
! Acceptor directionality
H>C=CCH2>CH3
Steiner, T. Angew. Chem. Int. Ed. 2002, 41, 48.
O S
- for stong hydrogen bonds, the direction is the same as if a hypothetical proton transfer reaction occurred
- rule of thumb: the electron density on oxygen and nitrogen are diffuse enough that linear geometries are favored
! Mixed strong/weak interactions
O H X HO H
O
F
OHOH
- difficult to assess structural importance
The CH ! " interaction– a weak hydrogen bond
! Intramolecular properties
Nishio, M. et al. The CH/# Interaction Evidence, Nature and Consequences, Wiley-VCH, Inc., New York, 1998.
H
H H
n(H2C) OH (CH2)nOH (CH3)n
n = 1,2 in most cases
OH
! Intermolecular properties
H
H H
H
H
stabilized 2–4 kcal/mol
acceptor substituent effects: NO2<Br<Cl<H~Et<Me<NH2donor substituent effects: CO,NMe,O, for C6H5CH2XCHMe2
O
H
H
O
H
H
H
HH
H
C
H
HH
H
acceptor substituent effects: Cl<D<CD3<p-(CD3)2<o-(CD3)2<(CD3)6 for C6H6-nXn/CHCl3 donor substituent effects: NO2<Br<Cl<H<Me<NH2 for C6H6/CH3C6H4Y
! Reactivity effects
C5H11
O
O R
OO
O
R = Me S:R 50:50 p-C6H5C6H4NH S:R 92:8
- remote functionalization reactions, diastereofacial and enantiofacial selectivity are all possible
O
RPh H
CH2
R' Ph
Mg
Cl
RPh
HO HR R' %ee
Me Me
t-Bu i-Pr
38
91
Corey, E. J. et al. J. Am. Chem. Soc. 1972, 94, 8616. Mosher, H. S. et al. J. Org. Chem. 1964, 29, 37.
The low barrier hydrogen bond in enzymes
! General characteristics
Cleland, W. W. et al. J. Bio. Chem. 1998, 273, 25529.
Cleland, W. W. Arch. Biochem. Biophy. 2000, 382, 1.
- basically the same as a strong hydrogen bond- enzymes modulate the pKa of a substrate to match that of the amino acid residue to which it is bonded
O H OO H O
O OH O OH
Ser195 O H NN H
O
O
Asp102
His57
! Chymotrypsin, a serine protease, and its weak hydrogen/LBHB catalytic cycle
Ser195 O H NN H
O
O
Asp102
His57O
NHRpeptidyl+ peptide
Ser195 O NN H
O
O
Asp102
His57O
NHRpeptidyl
H
– H2NR
Ser195 O NN H
O
O
Asp102
His57O
peptidyl
active site ground state compression event occurs
LBHB forms increases pKaimidizole
acylated system begins to reset
Long before round bottom flasks, enzymes roamed the earth
! Hydrogen bonded scaffold acts as cataytic site for protease activity
Northrop, D. B. Acc. Chem. Res. 2001, 34, 790.
Bachovchin, W. W. et al. Science 1997, 278, 1128.
O
O H O
O
HO
O
O H O
O
HO
O
O H O
O
HO
O
O H O
O
HO
O
O H O
O
HO
OH
O H O
O
1 2 3 4
5 6 7
O
RHN R O
RHN R O
RHN R
O
RHN R
O
R
N R
!"!" !" !"
!" !"
H H H
O
O H O
O O
O H O
O
HO
H
H
HO
H
H
- compounds 1–3 each contain low barrier hydrogen bond.- electron flow model theory- LBHB theory- Alzheimer #-secretase/HIV
+H2O
An example of enzyme mimicry–chemists are learning how to use H bonds
! A porphyrin-esque approach towards H2O2 activation
N
N N
N
MES
MES
Mn
MES
O
Me
Me
CO2H
t-Bu
t-Bu
catalyst
O0.2 mol% catalyst
25 eq. 1,5 dicyclohexylimidazole147 eq. H2O2
CH2Cl2, RT, 3h
70% yield
Nocera, D. G. et al. J. Am. Chem. Soc. 2003, 125, 1866.
t-Bu
Me
Me
t-Bu
Mn
O
OO
HH
t-Bu
Me
Me
t-Bu
Mn
O
O
OO
active speciesH bonded intermediateproton coupled electron transfer
- Control experiments indicate complex greatly increases rate of epoxidation- Did not completely rule out any free radical degradation pathways
A non-heme example of O2 activation
! The first reported example of an iron complex activation of molecular oxygen
Borovik, A. S.; Macbeth, C. E. et al. Science 2000, 289, 938.
FeN N
O
N
N
O
NMe
MeMe
ON
Me MeMe
HH
O
N Me
MeMe
H
III
NNH
NH
Me
O MeMe
3
1) KH (4 eq.) DMA, Ar, RT2) KH (3 eq.) DMA, Ar, RT3) Fe(OAc)2 DMA, Ar, RT4) O2 (0.5 eq.)5) H2O, RT
- Homolysis of the O2 bond creates the high spin Fe-oxo species- Produces a crystallizable-stable oxygen radical species, stabilized by hydrogen bonding- Compare this to similar cytochrome p450 species that oxidize C-H bonds via similar intermediates
Hine and co-workers develop the first hydrogen bond activated reaction
O O
Hine, J.; Ahn, K. J. Org. Chem. 1987, 52, 2083.Hine, J. et al. ibid. 1985, 50, 5096.
O
O
NO
Me
Me
Me
H
H
! The initial idea was based on stable hydrogen bonded crystal structures
PO
N
N
NMeMe
Me
Me
Me Me
OO
Me
Me
- A comparison of 1,8 biphenylenediol (pKa = 8.01) to m-nitrophenol (pKa = 8.36) indicated the diol bound 50 x's stronger.
! Rate studies provide convincing proof of a stable hydrogen bond catalyst
Et2NHO
OH
NEt
Et
butanone
aromatic alcoholcatalyst
phenolp-Cl-phenolm-Cl-phenol
m-nitrophenolp-cyanophenolp-nitrophenol
catechol1-biphenylenol
8-methoxy-1-biphenylenol1,8-biphenylenediol
105kc, M-2s-1 pKa
6.07.78.214.315.317.011.911.57.375
9.999.419.128.367.977.159.368.649.158.01
- The only yield reaction was set-up using 57 mol% catalyst and provided the product, after 15 days at 35 °C, in 86% yield.
- The aryl groups of both donor and acceptor are planar.
- used 3.75 eq. catalyst
Application of Hine's discovery
! Kelly catalyzes the Diels Alder reaction
Kelly, T. R. et al. Tet. Lett. 1990, 31, 3381.
n-Pr n-Pr
NO2NO2
CHCl3, 10 min. RTMe
O
COCH3
90% (3% bgd.)
- Other dienes: 2,3-dimethylbutadiene, 1-methoxybutadiene
- Other dienophiles: acrolein, 2-methylacrolein, 3-methylacrolein, 3-phenyl acrolein, methylacrylate
OH OH
- Esters and methoxydienes work poorly.
n-Pr n-Pr
NO2NO2
O OO
O
R
Me
H HOMe
- The methoxy substituent competes with aldehydes for H bonding
10 eq. 1 eq.
(0.4–0.5 mol eq.)
Another conceptual step leads to a hydrogen bonding framework
! A purely crystallographic analysis of urea scaffold/carbonyl structures
Etter, M. C.; Panunto, T. W. J. Am. Chem. Soc. 1988, 110, 5896.
NH
NH
O
X Y
ZXNO2CF3NO2NO2
YNO2CF3HH
ZHHHNO2
- Finds that ortho EWG's have most prominent effect and may induce aryl–H/CO bonding.
Etter, M. C. Acc. Chem. Res. 1990, 23, 120.
! A set of rules for predicting H-bond in various molecules is proposed
Some more interesting facets:- Six membered intramolecular H bond structures are preferred over intermolecular bonding.- After six membered ring bonding, the remaining H donating/accepting groups interact.- 2-aminopyrimidine as an illustrative example.
N N N N
N NH H H H
H
(1) (1)
(4)
(2) (3)
O
O
R
N1 > N2 > acid carbonyl > N3 = N4proton accepting ability
(a) (a)(b) (c)
proton donating abilityOH (acid) > Ha > Hb > Hc
! Free radical allylation
Curran, D. P.; Kuo L. H. J. Org. Chem., 1994, 59, 3259.
NH
NH
O
CF3 CF3
CO2C8H17C8H17O2C
HNS
O
SePh
O
NH
S
O
NH
ArNH
Ar
O
top face shielded
Two mechanistically different reactions, same H bond manifold
Curran, D. P.; Kuo, L. H. Tet. Lett. 1995, 36, 6647
SnBu
AIBN, benzene, 55 °C, 24 h
HNS
O
O
1
eq. 10.250.51.0
trans/cis7.1:111.3:114.1:1
yield707272
! Kinetic studies indicate H bonding accelerates the Claisen rearrangement
O
OMe
E:Z = 2.6:1
1
benzene, 80 °C
O
R
catalyst1
1
1
1
thioureaDMSO
DMSO + 1
eq.0
0.10.41.01.0
5 eq.5eq, 1eq
krel
12.75.022.43-41.91.3
O
(1.25 eq.)
! Parallel library generated catalysts to effect the Strecker reaction were screened to provide the
thiourea scaffold
Jacobsen develops the most efficient and broadly used scaffold to date
Wittkopp, A.; Schreiner, P. R. Chem. Eur. J. 2003, 9, 407. (for some examples of thiourea catalyzed Diels Alder reactions)
Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901.Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2000, 39, 1279. (for substrate scope)
PhHN
NH
NH
O
S
N
HO
t-Bu
OMe
MeMeMe
N
R H
(2 mol%)
toluene, – 78 °C, 24 hTFAA workup
HCN (2 eq.)R
N
CN
O
F3C
RPh
p-OCH3C6H4p-BrC6H42-naphthyl
t-butylc-hexyl
yield (%)789265887077
ee (%)917086888583
- The original goal of the catalyst screen was to incorporate metal binding sites on the scaffold.- Jacobsen, "a sequence of nonobvious modifications in the catalyst structure."
Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012.
Origins of selectivity in the catalyzed Strecker reaction
! NMR solution structure and MOLMOL modelling lead to a set of selection rules
N
HO
Me
Me
O
O Me
Me
Me
HN
O
HN
O
HN
N
Ph
Me
=
Me
- Determined that only the Z-isomer binds the catalyst and is bridged by the urea nitrogens.- Large groups are directed into solvent.- The small group is placed directly into the catalyst.- The N-substituent is directed away from the catalyst.
! Synthesis of B-aryl, B-amino acids via asymmetric Mannich reactions
Jacobsen extends this technology towards other transformations
N
H R
Boc OTBS
OiPr
Ph NNH
NH
O
S
N
HO
t-Bu
MeMeMe
Me
Me
Me
Me(5 mol%)
PrOi R
O NHBoctoluene, 48 h, – 40 to 4 °C
1)
2) TFA, 1 min.
- Tolerates a wide range of aryl groups, no aliphatic examples.- Currently the mechanism is not well understood
Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964.
! Nitro-Mannich reaction
Yoon, T. P.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2005, 44, 466.
Me2NNH
NH
O
SMeMe
Me
NHAcNH
Ph
NO2R1
R2
1 eq. 5 eq.
1 eq. 2 eq.
i-Pr2NEt, toluene4 A mol. sieves
(10 mol%)
PhNO2
NHBoc
R1 R2
%ee: 86-98%yield: 84-99
- Only aryl aldimines are used for the transformation- Suspect the catalysts may activate BOTH reactants.
>5:1 syn: anti d.r in most cases>92% ee in all cases>90% yield in most cases
! Takemoto develops the Michael reaction of malonates and nitroolefins
Other carbon-carbon bond forming reactions catalyzed by the thiourea scaffold
NO2
HN
HNF3C
CF3
S
NMe2
NO2
EtO2C CO2Et
(0.1 eq)
EtO2C CO2Et
toluene, rt, 24 h 86% yield93% ee
Takemoto, Y. et al. J. Am. Chem. Soc. 2003, 125, 12672.
- aromatic olefins give the best yields and ee in most cases.- aliphatic olefins give decent yields but lower ee. (81% ee in both examples)
! Another variant of the Mannich reaction
N
Ar
P(O)Ph2(0.1 eq.) catalyst above
RCH2NO2 (10 eq.)
(2 eq.)
CH2Cl2, rt
Takemoto, Y. et al. Org. Lett. 2004, 6, 625.
ArNO2
HNP(O)Ph2
yields ranged from 57–87%ee's ranged 63–76% ee
NH
NH
S
N
NO O
NH
NH
S
NMeH
NO O
RH
HR H
Me
! Preparation of imines
One well known and one not-so-well-known H bond reaction
Crabtree, R. H. et al. Chem. Commun., 1999, 2109.
O
NH2Bn
O2S SO2
NH2NH2
1 eq. 11 eq.
NBn
CH2Cl2, –20 °C
MgSO4 anh.
- Only rate of catalyst acceleration was probed.
! Rawal's TADDOL catalyzed Diels Alder cycloaddition
Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 1124, 9662.Rawal, V. H. et al. PNAS, 2004, 101, 5846.
NMe2
TBSO
OH
OH
NaphNaph
NaphNaph
O
OMe
Me
toluene, –78 °C or –40 °C O
TBSO
N
R
Me Me
AcCltoluene/CH2Cl2–78 °C, 15 min.
O
O R
O
O O
OH
CHOMe
H O
(20 mol%)
(2 eq.)
Chiral Bronsted Acid Catalysis! Mannich type reaction
HO
N
PhMe
H
OTMS
OEt
PhNO2
PhNO2
O
OP
OH
O
Akiyama, T. et al. Angew. Chem. Int. 2004, 43, 1566.
PhCO2Et
HN
Me
HO
syn/anti 87:1396% ee (syn)100% yield
1.0 eq. 1.5 eq.
10 mol%
10 more examples
- Only aromatic aldimines are used- All the yields were high, as was syn/anti selectivity.- ee's ranged from 81% – 96%
O
OP
O
O
NO2
NO2
Ar
NH Ar
O
HR
O
OH
OH
Schaus, S. E.; McDougal, N. T. J. Am. Chem. Soc. 2003, 125, 12094.
R
R
CF3
CF3
! Morita-Baylis-Hillman reaction
OHB
R3P
OOH
R
(2 mol%)
Et3P (0.5 eq)THF, –10 °C, 48 h, Ar1 eq. 1 eq.
R =
R = aliphatic, 82 – 96% ee 70 – 88% ee R = conjugated, 67, 81% ee low yields
Chiral Bronsted Acid Catalysis
! Aza Henry reaction
Johnston, J. N. et al. J. Am. Chem. Soc. 2004, 126, 3418.
HN HN
N NH
NH
R1C6H4
NO2
R2
R1C6H4
NO2
HN
R2
BOC
10 mol%
neat, –20 °C
- Syn preferred of anti- Yields range from 51 – 69 %- mechanism unclear
OTf
(4.8 eq)
Conclusions
- The hydrogen bond is a fascinating molecule whose theory of interaction needs further development
- A well of chemical reactivity is filled with possibilities
- Theory is not as important as practice
- May be able to exploit a wide range of interactions to develop an asymmetric, catalytic system
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