the vinylogous aldol reaction: application in synthesis€¦ · rassu, g.; zanardi, f.; battistini,...
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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.
- Diastereoselective vinylogous aldol reactions - Vinylogous Mukaiyama aldol - Siloxyfurans - Schlessinger's chiral auxillaries
- Catalytic, enantioselective vinylogous aldol reactions - Carreira's Ti(IV) and Cu(I) catalysts - Evans' Cu(II) catalyst
The Aldol Reactions
R
OH O
Aldol AdductR
O
+O
MLn
O
Homoaldol Adduct
R
O
+O
O
Vinylogous Aldol AdductR
O
+O
MLn
R
OH
M
aldol coupling
vinylogous aldol coupling
homoaldol coupling
Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G.; Synlett. 1999, 9, 1333-1350.
R1
R1
R1
R1
R1
enolate
homoenolate
dienolate
OH
RR1
H
H
HH
H
H
The Vinylogous Aldol Reaction in NatureEuphoperfolianes
O
AcO
H
AcO
AcO
AcO
O
O
H+
O
AcO
AcO
AcO
AcO
O
O H
O
AcO
AcO
AcO
AcOO
OH
Jatrophane structure
Both EuphorperfolianeA and B isolated
Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. Rev. 2000, 100, 1929-1972.
The Vinylogous Aldol Reaction In NatureYohimbine and Reserpine
NH
N
OMeO2C
H
H+
NH
N
OHMeO2C
H
NH
N
OHMeO2C
H
NH
N
OMeMeO2C
HH
HO
OMe
OMe
OMe
H
YohimbineReserpine
Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. Rev. 2000, 100, 1929-1972.
Nondirected Vinylogous Aldol Additions
- 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
X
O
Me
Me
X
O Me
R=OH, OR, NR2, H
Base
X
O Me
RCHO
low tempshorter rxn time
RCHO
High templonger rxn time
X
O Me
X
O
OHR
Kinetic Control
ThemoControl
α-alkylation
X
O Me
R
OH
R
OH
+
γ-alkylation
Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. Rev. 2000, 100, 1929-1972.
or
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
Yamamoto's Al-mediated Vinylogous Aldol Reactionwith Aldehydes
R3
R2
R1
H
O
H
R
O
H+
ATPH(2.2 equiv.)
toluene, -78oCR3
R2
R1
H
O
H
R
O
H+ATPH
ATPH
LDA (1.2 equiv.)THF, -78oC
R3
R2
R1
H
O R
O
H+ATPH
R2
R1
H
O
R3
R
OH
ATPH =O Al
3
aluminum tris(2,6-diphenyl)phenoxide
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.
Yamamoto's Al-mediated Vinylogous Aldol ReactionSubstrate Generality
R3
R2
R1
H
O
H
R
O
H+
ATPH (2.2 equiv), tol, -78oC
LDA (1.2 equiv), THF, -78oC
R2
R1
H
O
R3
R
OH
CHO
Me
Me
Me
CHO
Me CHO PhCHO
CHO
CHO
CHO
CHO
Aldehyde
ConjAldehyde
99% 99% 83% 55%
97% 91% 83% 90%
99% 99% 83% 77%
80% 99% 67% 47%
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
R2CHO
R2CHO
Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. Rev. 2000, 100, 1929-1972.
Yamamoto's Al-mediated Vinylogous Aldol Reactionwith Enones
O
+ PhCHOATPH (2.2 Equiv.), tol, -78oCLDA(1.2 equiv.), THF, -78oC
O
OHPhstereochem never determined
O
+ RCHOATPH (2.2 Equiv.), tol, -78oCLDA(1.2 equiv.), THF, -78oC
O
Me R
OH
CO2Me
+ RCHOATPH (2.2 Equiv.), tol, -78oCLDA(1.2 equiv.), THF, -78oC
CO2Me
Me
R
OH
R %YieldPh 86tbutyl 99nbutyl 73(E)-CH=CHPh 68
R %YieldPh 72tbutyl 93nbutyl 38
Saito, S.; Shiozawa, M.; Ito, M.; Yamamoto, H. J. Am. Chem. Soc. 1998, 120, 813-814.
Vinylogous Mukaiyama Aldol Reactions
Christmann, M.; Kalesse, M. Tetrahedron Lett. 2001, 42, 1269-1271.
Me
OOTBS
Me
OTBS
OMe
Lewis AcidMe
OROTBS
Me
OMe
O
Lewis Acid Solvent/temp dr % Yield (pdt)
BF3 OEt2 (1.5 eq.) CH2Cl2/Et2O(9:1), -78oC 3:1 92 (1)B(C6H5)3 (1.0 eq.) CH2Cl2/Et2O(9:1), -78oC 95:5 85 (1)B(C6F5)3 (1.0 eq.) CH2Cl2/Et2O(9:1), -78oC 95:5 81 (2)B(C6F5)3 (0.5 eq.) CH2Cl2/Et2O(9:1), -78oC 95:5 78 (2)B(C6F5)3 (0.2 eq.) CH2Cl2/Et2O(9:1), -78oC 95:5 74 (2)B(C6F5)3 (0.1 eq.) CH2Cl2/Et2O(9:1), -78oC 95:5 15 (2)B(C6F5)3 (0.2 eq.) CH2Cl2, -78oC 95:5 8 (1), 61(2)
1: R=H2: R=TBS
- 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
Me
(no reaction with B(C6F5)3)
Me
Rationale:
H Me
O
R HTBSO
MeO
H Me
O
R H
Me H
O
R H
H Me
O
R H
OTBSMeO OMeTBSO OMeTBSO
-E-dienolate -Z-dienolate
H
H
Vinylogous Mukaiyama Aldol ReactionA Synthetic Application: (+)-Ratjadone
O
Me
Me
OTBSMeO
OTBS
B(C6F5)3, -78oC,9:1 CH2Cl2/Et2O
95:5, 80%
MeO
O OTBS
Me
Me
OTBS
1. Dibal-H, THF, -78oC2. m-CPBA, NaHCO3, CH2Cl2, 0oC
85%
OTBS
Me
Me
OTBSO1. TBAF, THF, 88%
2. amberlyst-15, THF93%
O
Me
OH
OH
OHMe
O
Me
OH
OH
Me
Me
Me
O O
Me
HO
(+)-Ratjadone
Bhatt, U.; Christmann, M.; Quitschalle, M.; Claus, E.; Kalesse, M. J. Org. Chem. 2001, 66, 1885-1893
H
HH
H H
Vinylogous Aldol Reaction with Siloxyfuransand Lewis Acids
+R H
O
O
O
RO
Me3SiO
OH
O
O
R
OH
LA +
Syn Anti
Entry RCHO LA/Conditions Syn:Anti % Yield
1 SnCl4, -78oC, 2h 76:24 88 2 ZnBr2, 0oC, 2h 66:34 94 3 ZnCl2, 0oC, 2h 68:32 82 4 BF3Et2O, -78oC, 2h 81:19 95 5 R= npentyl TrClO4, -78 to 20oC, 4h 79:21 92 6 TMSOTf, -78oC, 2h 82:18 95 7 TESOTf, -78oC, 2h 82:18 93 8 CsF, -78 to 20oC, 4h 27:73 68 9 nBu4N+F-, -78oC, 4h 33:67 74 10 nBu4N+F-, -78 to 20oC, 4h 22:78 70
- When R = CH2Ph, i-Pr, n-Bu, same results observed under similar conditions as entries 7, 9, and 10.
Jefford, C.H.; Jaggi, D.; Boukouvalas, J. Tetrahedron Lett. 1987, 28, 4037-4040.
Vinylogous Aldol Reaction with SiloxyfuransRationale of selectivity
Under Lewis Acid conditions:
O
R H
O
H
Me3SiO
LA OOSiMe3
O
H
R
LA
H
Syn
O
R H
OH
OSiMe3
LA
O
R H
O
OSiMe3
H
LA
OH
O
H
R
LAOSiMe3
Anti
O
R H
O
OSiMe3
H
LA
Jefford, C.H.; Jaggi, D.; Boukouvalas, J. Tetrahedron Lett. 1987, 28, 4037-4040.
H
H
Vinylogous Aldol Reaction with SiloxyfuransRationale of selectivity
Under flouride conditions for desilylation:
O
R H
O
H
O
OO
OH
R H
Syn
O
R H
OH
O
O
R H
O
O
H OH
O
H
R
O
Anti
O
R H
O
O
H
Jefford, C.H.; Jaggi, D.; Boukouvalas, J. Tetrahedron Lett. 1987, 28, 4037-4040.
H
H
Vinylogous Aldol Reaction with SiloxyfuransA Synthetic Application: D-erythro-C18-sphingosine
Spanu, P.; Rassu, G.; Pinna, L.; Battistini, L.; Casiraghi, G. Tetrahedron Asymm. 1997, 8, 3237-3243.
N
TBSOBoc
O
OO
MeMe
+SnCl4, Et2O
-85oC80%, >98:2 dr
N
O
HO
OO
MeMeBoc
TBSCl, DMFimidazole
N
O
TBSO
OO
MeMeBoc
N
O
TBSO
OO
MeMeBoc
HO
NH2
OH
C13H27
D-erythro-C18-sphingosine
+
Reaction Time A:B %Yield (A:B)10h 12:88 -- 4d 85:15 75:minor amt
A B
H
Diasteroselective Vinylogous Aldol Reaction with Chiral AuxillaryFirst Generation of Chiral Vinylogous Urethane
Adams, A.D.; Schlessinger, R.H.; Tata, J.R.; Venit, J.J. J. Org. Chem. 1986, 51, 3070-3073.
NH
Me
Me
CO2Me
Me
tBuOH
83oC+
90%N
OMe
OMe
Me
1. LDA/THF
2. CHO
Me
Me
-78oC to 0oC
N
O
O
Me
Me
Me
Me
Me
86%, 97:3 dr
O
HO
N
O
Me
N
H
O
O
O
N
O
Me
Me
Me
(-)-Virginiamycin M2
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
N
OMe
O LDA/THF
-78oC to 0oC
MeOMe
Me
N
O
O
Me
MeOMe
Me
RRCHOMe
R % Yield dr
n-propyl 57% 96:4Cy 83% 98:2t-Butyl 83% 99:1(E)-CH=CHCH3 74% 96:4 (E)-CH=CHPh 74% 96:4 (E)-CH=CHSnBu3 68% 99:1
Li, Y.J.; Von Langen, D.J.; Schlessinger, R.H. J. Org. Chem. 1996, 61, 3226-3227.
Catalytic Asymmetric Aldol ReactionCarreira's Ti(IV) Catalyst
Singer, R.A.; Carreira, E.M. J. Am. Chem. Soc. 1995, 117, 12360-12361.
O O
Me O
Me Me
LDA, THF
Me3SiCl
O O
OSiMe3
Me Me
RCHO+
1. catalyst (1-3 mol%) Et2O, 0oC, 4h
2. THF/TFA
O O
O
Me Me
R
OH
N
O
tBu
BrOTi
OO
O
tBu
tBu
Catalyst:Aldehyde % Yield % ee
iPr3Si CHO
tBuMe2SiO CHO
PhCHO
MeCHO
PhCHO
Bu3SnCHO
PhCHO
86 91
97 94
88 92
95 92
83 84
97 80
79 92
Catalytic Asymmetric Vinylogous Aldol ReactionCarreira's Cu catalyst
O O
OSiMe3
Me Me
+RCHO
1. 2 mol% (S)-Tol-BINAP-CuF2THF, -78oC
2. acidic work-up
O O
Me Me
OH
R O
BINAP + Cu(OTf)2 + TBAT
P(C6H4-pCH3)2
P(C6H4-pCH3)2CuF2
Aldehyde % Yield % ee
S
O
MeCHO
PhCHO
Me
CHO
CHO
CHO
CHO
92 94
86 93
98 95
91 94
48 91
74 65
Kruger, J.; Carreira, E.M. J. Am. Chem. Soc. 1998, 120, 837-838.
Catalytic Asymmetric Vinylogous Aldol ReactionMechanistic study for Carreira's Cu catalyst
CuF2(S)-tol-BINAP CuF(S)-tol-BINAP +O O
OTMS
Me Me
TMSF
O O
Me Me
OCuLn
RCHO
O O
Me Me
OR
OCuLnO O
OTMS
Me Me
O O
Me Me
OR
OTMS
Pagenkopf, B.L.; Kruger, J.; Stojanovic, A.; Carreira, E.M. Angew. Chem. Int. Ed. 1998, 37, 3124-3126.
R1
OTMS
OHCCHO
Support for Mechanism:
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
for the aldol adduct.
Catalytic Asymmetric Vinylogous Aldol ReactionA Synthetic Application: Amphotericin
O
CHOO O
OSiMe3
Me Me 1. 2 mol% CuF2(S)-Tol-BINAP THF, -78oC
2. Acid workup+
1. 2 mol% CuF2(R)-Tol-BINAP THF, -78oC2. Acid workup
OH OO
O
Me Me
O
OH OO
O
Me Me
O
O O
H
O
OSitBuMe
Me Me
O O
Me Me
tBuPh2SiO +
Kruger, J.; Carreira, E.M. Tetrahedron Lett. 1998, 39, 7013-7016.
OMycosamine
OCO2H
OH
OHOH
OH
OH
O
O
Me
Me
Me
HO OH
OH
AmphotericinH
Catalytic Asymmetric Vinylogous Aldol ReactionCarreira's Cu Catalyst: Synthesis of Lactones
Bluet, G.; Bazan-Tejeda, B.; Campagne, J.M. Org. Lett. 2001, 3, 3807-3810.
MeOMe
OTMS
RCHO10 mol % CuF2(S)-tol-BINAP
THF, rt+ Ph
OH
Me
OMe
O
O
Ph
O
Me
+
Aldehyde % Yield (A+B) Ratio (A/B) A (anti/syn) % ee (Anti)
A B
Benzaldehyde 85 86/14 >98/2 87
2-naphthaldehyde 95 80/20 >98/2 85
2,3-dimethozybenzaldehyde 87 81/19 >98/2 91
2-furaldehyde 60 50/50 >98/2 86
(E)-cinnamaldehyde 60 70/30 >98/2 82
isobutyraldehyde 95 64/36 >98/2 91
Catalytic Asymmetric Vinylogous Aldol ReactionEvans' Cu Catalyst
Evans, D.A.; Kozlowski, M.C.; Murry, J.A.; Burgey, C.S.; Campos, K.R.; Connel, B.T.; Staples,R.J. J. Am. Chem. Soc. 1999, 121, 669-685
Evans, D.A.; Burgey, C.S.; Kozlowski, M.C.; Tregay, S.W. J. Am. Chem. Soc. 1999, 121, 686-699.
BnOH
O1. 1 (2 mol%), CH2Cl2,-93 to -78oC2. PPTS, THF
85%99% ee
+ BnO
OH
BnOH
O1. 1 (5 mol%), CH2Cl2,-78oC2. 1N HCl, THF
94%92% ee
+ BnO
OHO O
Me Me
OSiMe3
Me3SiO
OtBu
OSIMe3
OO
O
Me Me
O
OtBu
O
1 = N
Cu N
O
N
O
Ph Ph
2+
2SbF6-
Catalytic Asymmetric Vinylogous Aldol ReactionEvans' Cu Catalyst: Rationale of Selectivity
Evans, D.A.; Kozlowski, M.C.; Murry, J.A.; Burgey, C.S.; Campos, K.R.; Connel, B.T.; Staples,R.J. J. Am. Chem. Soc. 1999, 121, 669-685
Evans, D.A.; Burgey, C.S.; Kozlowski, M.C.; Tregay, S.W. J. Am. Chem. Soc. 1999, 121, 686-699.
BnOH
O
94%92% ee
+ BnO
OHO O
Me Me
OSiMe3
OO
O
Me Me
1.N
Cu N
O
N
O
Ph Ph
2+
2SbF6-
2. 1N HCl, THF
(10 mol%), CH2Cl2,-78oC
NCu
N
ON
O
Ph
Ph
H
H BnO
O
H
NCu
N
ON
O
Ph
Ph
H
HO
O
H
Bn
Nu (si face) Nu (re face)
BnO
OH OO
O
Me Me
BnO
OH OO
O
Me Me
(S) (R)
2+ 2+
Catalytic Asymmetric Vinylogous Aldol ReactionEvans' Cu Catalyst
BnOH
O
O
1. 1 (10 mol%), CH2Cl2,-78oC2. 1N HCl, THF
93%91:9 anti/syn92% ee (anti)
+
OSiMe3
BnO
O
OH
O
MeOMe
O
O
1. 2 (10 mol%), CH2Cl2,-78oC2. 1N HCl, THF
99%95:5 anti/syn99% ee (anti)
+
OSiMe3
MeO
O
OO
O
Me OH
1 = N
Cu N
O
N
O
Ph Ph
2+
2SbF6- 2 =
2+
OTf -
Me Me
O
N N
O
But tBu
Evans, D.A.; Kozlowski, M.C.; Murry, J.A.; Burgey, C.S.; Campos, K.R.; Connel, B.T.; Staples,R.J. J. Am. Chem. Soc. 1999, 121, 669-685
Evans, D.A.; Burgey, C.S.; Kozlowski, M.C.; Tregay, S.W. J. Am. Chem. Soc. 1999, 121, 686-699.
Cu
Catalytic Asymmetric Vinylogous Aldol ReactionEvans' Cu catalyst: Rationale of Selectivity
BnOH
O
O
1.
93%91:9 anti/syn92% ee (anti)
+
OSiMe3
BnO
O
OH
O
N
Cu N
O
N
O
Ph Ph
2+
2SbF6-
Evans, D.A.; Kozlowski, M.C.; Murry, J.A.; Burgey, C.S.; Campos, K.R.; Connel, B.T.; Staples,R.J. J. Am. Chem. Soc. 1999, 121, 669-685
Evans, D.A.; Burgey, C.S.; Kozlowski, M.C.; Tregay, S.W. J. Am. Chem. Soc. 1999, 121, 686-699.
NCu
N
ON
O
Ph
Ph
H
H BnO
O
HOH
OSiMe3
NCu
N
ON
O
Ph
Ph
H
H BnO
O
H
O
OSiMe3
H
syn anti
2. 1N HCl, THF
(10 mol%), CH2Cl2,-78oC
2+ 2+
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