The Vinylogous Aldol Reaction: Application in Synthesis Audrey Chan Literature Presentation 11/16/04 Lead References: Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. Rev. 2000, 100, 1929-1972. Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G. Synlett. 1999, 9, 1333-1350.
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The Vinylogous Aldol Reaction:Application in Synthesis
Audrey ChanLiterature Presentation
11/16/04
Lead References: Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. Rev. 2000, 100, 1929-1972. Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G. Synlett. 1999, 9, 1333-1350.
Outline
- Relevance of vinylogous aldol additions in natural products
- Non-directed vinylogous aldol additions
-Vinylogous aldol reaction of metal dienolates - Kinetic vs. Thermodynamic conditions - γ-selectivity with amides, carboxylic acids, aldehydes and ketones.
- In a nondirected aldol reaction, the nucleophilic species (enolate or enol) is generated in a substoichiometric way in situ, namely, in the presence of its complimentary electrophilic carbonyl partner.
- Nondirected vinylogous aldol reactions are rare since VAR adducts rarely survive reaction conditions (strong acid/base catalysis)
- Reaction conditions favor higher conjugation such as crontonatization and polymerization
Example:
O
O
OMe
O
O
OMeTsOH
C6H6, Δ
H+
H
H
O
MeO
OH
This is the first intramolecular vinylogous aldol reaction reported
Gaidamovich, N.N.; Torgov, I.V. Izv. Acad. Nauk. SSSR 1964, 1311.
Nondirected Vinylogous Aldol ReactionCycloaromatization and Crotonization
O
H2SO4
O
+
1:1
O
O OH
OOH2H
OHH+
OH HO H2OH
A B
OO
HO
H2O
H B
A
Kinetic vs. Thermodynamic Control of the Vinylogous Aldol Reaction
Kinetic vs. Thermodynamic Control of dienolates of Amides
Me
Me
N
O
Me
Me
LDA Me
N
O
Me
Me
Li
RCHO
THF, -5oC-78oC
Me
N
O
Me
Me
Me
N
O
Me
MeHO R
OH
R+
A B
R -5oC, 5 min -5oC to rt overnight A:B A:B
Ph
O
O
OMe
OMe
Prn
N
80:20 0:100
88:12 0:100
82:18 0:100
100:0 13:87
100:0 15:85
Majewski, M.; Mpango, G.B.; Thomas, M.T.; Wu, A.; Snieckus, V. J. Org. Chem. 1981, 46, 2029-2045.
Dienolates of Unsaturated Carboxylic AcidsVinylogous Aldol Selectivity Highly dependent on Metal(s)
Me
Me
OH
O Me
OM2
OM1 Me
OH
O
PhCHO, THF, -78oC
Ph
OH Me
CO2H
O
O
Ph Me
Ph
OH Me
CO2H
Me
OH
O
OHPh
A B C D
M1 M2 Relative Yields A B C D
Li SnBu3 - - - 100Li Li 19 27 - 54Na Li 5 44 5 46K Li 54 24 - 22K K 100 - - -
- Formation of the γ-alkylated vinylogous aldol adduct is favored with more ionic character counterions.
- The cis regioselectivity of the γ-alkylated product is because the trans-γ-alkylated product is destabilized by allylic strain between the β-methyl and the oxygen atom of the carboxyl.
Cainelli, G.; Cardillo, G.; Contento, M.; Trapani, G.; Umani-Ronchi, A. J. Chem. Soc. Perkin Trans. 1 1973, 400-404.
Ways to Generate Dienolate from Vinylogous Aldehydes
- Traditional method of enolization of vinylogous aldehydes: not synthetically useful
H
O
R
MNH2, THF
low temppolymerization
- An alternative method uses liquid ammonia to generate highly stable enolates but reactivity with carbonyl compounds was never studied
H
O
R
KNH2, NH3
H
OK
R
- The more common method uses methyl lithium and potassium t-butoxide to generate the metal dienolate from silyl dienol ethers and dienol acetates
H
OR1
RMeLi or ButOK
H
OM
R
R1=TMS or Ac
van der Gen, A. Tetrahedron Lett. 1978, 491-494Stork, G.; Hudrlik, P.F. J. Am. Chem. Soc. 1968, 90, 4464-4465
Saito, S.; Shiozawa, M.; Ito, M.; Yamamoto, H. J. Am. Chem. Soc. 1998, 120, 813-814.
- The bulky Lewis acid and carbonyl compounds self-assemble to form complexes where the carbonyl can either be protected toward Nu attack or activated toward selective deprotonation.
Saito, S.; Shiozawa, M.; Ito, M.; Yamamoto, H. J. Am. Chem. Soc. 1998, 120, 813-814.
- The bulky lewis acid is able to block any α-enolization from occurring therefore only γ-enolization results producing only γ-alkylated product.
Dienolates of Vinylogous EnonesKinetic vs. Thermodynamic Conditions
O
R R1Base
α'-enolization
γ-enolization
R
O
R1
R
O
R1
R
O
R1
R
O
R1
R
O
R1
OHR2
R2 OH
R2 OH
α'-alkylation
α-alkylation
γ-alkylation
- Under kinetic conditions (low temp and short time), α'-enolization results, producing α'-alkylation- Under thermodynamic conditions, the extended dienolate forms resulting in either α− or γ-alkylated products
- Lewis Acid and solvent play important roles in the vinylogous Mukaiyama aldol reaction.- The syn product was selectively produced.- The use of the other Lewis Acids such as Ti(OiPr)4, Ti(OiPr)4/Binol, TiCl2(OiPr)2, and TiCl4, gave either no reaction or just decomposition.
H +
Vinylogous Mukiayama Aldol ReactionEffect of Dienolate Structure
Hassfeld, J.; Christmann, M.; Kalesse, M. Org. Lett. 2001, 3, 3561-3564.
- (Z)-dienolates are good substrates producing selective γ-alkylated products
Me
OMe
OTBS
+
Me
Me
OB(C6F5)3, Et2O
iPrOHMe
Me
OH
Me
OMe
O
+ Me
OMe
O
HO
Me
Me
84%, syn: 20:1 <1%, mix of isomers
OMe
OTBS
+
Me
Me
OBF3 OEt2, Et2O Me
Me
OH
Me
OMe
O
+OMe
O
HO
Me
Me
51%, syn/anti: 1:1 25%, mix of isomers
- (E)-dienolates are poor substrates producing mixtures of regiomers and diastereomers
Problems:- Very expensive - Difficult to prepare in large scale
Solution:- Second generation chiral vinylogous urethane prepare
Me
Diastereoselective Vinylogous Aldol Reaction with Chiral AuxillarySecond Generation of Chiral Vinylogous urethane
Li, Y.J.; Von Langen, D.J.; Schlessinger, R.H. J. Org. Chem. 1996, 61, 3226-3227.
NH
OMe
Me
Me
+
CO2Me
Me
83oC76%
N
OMe
O
1. LDA/THF
2. CHO
Me
Me
-78oC to 0oC
89%, 99:1 dr
MeOMe
Me
N
O
O
Me
MeOMe
MeMe
Me
tBuOH
1. NaCNBH3, THF
2. m-CPBA, pyridine
O
O
Me
Me
Me
82%
Me
Diastereoselective Vinylogous Aldol Reaction with Chiral AuxillaryRationale of selectivity
Li, Y.J.; Von Langen, D.J.; Schlessinger, R.H. J. Org. Chem. 1996, 61, 3226-3227.
N
LiO
H3CO
Me
Me
Me
H
OMe
N
OMe
O LDA/THF
CHO
Me
Me
-78oC to 0oC
89%, 99:1 dr
MeOMe
MeN
O
O
Me
MeOMe
MeMe
MeN
OMe
O
MeOMe
Me
Li
-78oC to 0oC
1
2
3
4
N X
OLi
HMe
O Me
H
Me Me
OCH3
- X-ray study only shows 2 as the highly organized enolate stucture - Li is bonded to both the N atom and the O atom - The carbon backbone of the enolate (C1-C4) is significantly twisted about the C2, C3 bond of the enolate.
- 1 does not exist because of severe interaction between C4 vinyl H atom and the chiral arm.
1 2
OMe
OLi
N
Me
Me Me
R1
OR
R= ipropylR1= OMe
RCHO
Me Me
H
HN
Me
H
Me Me
R1
OR
Li
O
OMe
Diastereoselective Vinylogous Aldol Reaction with Chiral AuxillarySubstrate Generality
1. CuOtBu(S)-tol-BINAP worked equally well, therefore confirms the formation of Cu(I) in the mechanism
2. ReactIR shows disappearance of TMS-dienolate (1671 cm-1) and formation Cu-enolate (1690 and 1550 cm-1). Addition of RCHO resulted in replacement of the two bands by a 1720 cm-1
Catalytic Asymmetric Vinylogous Aldol ReactionA Synthetic Application: Callipeltoside A
EtO
OTMS Me
1.N
Cu N
O
N
O
Ph Ph
2+
2SbF6-
2. 1N HCl, THF
(10 mol%), CH2Cl2,-78oC
Evans, D.A.; Hu, E.; Burch, J.D.; Jaeschke, G. J. Am. Chem. Soc. 2002, 124, 5654-5655.
H2O OH2+
H
O
OPMB
EtO
O
Me
OH
OPMB
O
Me
O O
H
O
MeO
Me
Me
OH
H OHO
Me
O OMeO
Me
Me
O
H OH
NH
O
O
Cl
MeO
MeH
Me
Callipeltoside A
93%, 95% ee
Conclusion
- In general, metal dienolates favor α-alkylation under kinetic conditions and γ-alkylation under thermodynamic conditions.
- Yamamoto's ATPH-mediated vinylogous aldol reaction produced selective γ-alkylation.
- In general, siloxyfuran vinylogous aldol reactions favor syn addition under Lewis acid coniditions while anionic equivalent favor anti adduct under desilylation conditions.
- Schlessinger's proline-derived auxillary is useful for diastereoselective vinylogous aldol reactions.
- Carreira's Ti(IV) and Cu(I) catalysts and Evans' Cu(II) catalysts are useful for enantio- selective vinylogous aldol reactions