Embed Size (px)
Citation preview
The Vinylogous Aldol ReactionSynthesis and Methodology
Evans Group Seminar
February 15, 2002
Jason Burch
I. Biosynthetic VARs
II. Non-directed VARs
III. VARs of Metal Dienolates
IV. Mukaiyama VARs
V. Diastereoselective VARs
VI. Catalytic Enantioselective VARs
Leading References: Casiraghi and Rassu, Chem. Rev. 2000, 100, 1929.Rassu and Casiraghi, Chem. Soc. Rev. 2000, 29, 109.Rassu and Casiraghi, Synlett 1999, 1333.Martin, Tetrahedron 2001, 57, 3221. (Mannich rxns.; not covered)
OM
X
MeRCHO
O
X R
OHMe
01-Cover Slide 2/11/02 4:56 PM
Aldols, Homoaldols and Vinylogous AldolsA Comparison
O
XR1
O
XR1
X
OTMS
OM
XR1
O
X
M
OM
XR1
RCHO
RCHO
RCHO O
X
R1
R
OH
O
X
R1
R
OH
O
XR
OH
Aldol
Homoaldol
Vinylogous Aldol
02-Comparison 2/11/02 4:57 PM
The Vinylogous Aldol Reaction in NatureYohimbine and Reserpine
Cordell, Introduction to Alkaloids, Wiley: New York, 1981; pp. 826-828
NH
N
MeO2CO
H
NH
N
MeO2COH
H
H
NH
N
MeO2COH
H
HNH
N
MeO2COH
H
H
H H
OAr
ReserpineYohimibine
03-VAR in Nature Yohimbine 2/11/02 4:57 PM
The Vinylogous Aldol Reaction in NatureEuphoperfolianes
Appendino, J. Nat. Prod. 1998, 61, 749.
Both α and β were isolated
Me O
O
MeMe
Me
O
AcO
H
AcO
Me
AcOOAc
OH
O
MeMe
MeO
H
AcO
Me
AcO
AcOAcO
MeMe
O
OH
AcO
H
Me
AcO
AcO
MeO
Eupoperfoliane A and BAcO
Jatrophane skeleton
04-VAR in Nature Euphoperf 2/13/02 3:40 PM
Non-Directed Vinylogous Aldol ReactionsIntramolecular Cyclization
O
OMe
O
pTsOH
PhH, ∆ O
OMe
HO
OMe
OH
O
Torgov, Izv. Acad. Nauk SSSR 1964, 1311.
• non-directed aldol reaction: nucleophile (enolate or enol) generated in sub-stoichiometric manner in the presence of the electrophile
• non-directed VAR: very rare since VAR adducts rarely survive conditions of reaction (acid or base catalysis)
• some special cases:
05-Torgov Intramolecular 2/13/02 3:41 PM
Non-Directed Vinylogous Aldol ReactionsCycloaromatization
O
HCl
O
n
O OH
HO
n n
nnn = 1 (55%)n = 2 (29%)
Mayer, Ber. 1956, 89, 1443.
06-Cycloaromatization 2/9/02 1:12 PM
Dienolates from Unsaturated Acid EquivalentsKinetic vs. Thermodynamic Control
• In General
O
X Me
Me
or
O
X
Me
X = OR, OH, NR2
O
X
Me
kineticcontrol
thermo.control
RCHO
RCHO
O
X
Me
R OH
O
X Me
O
X
Me
OH
R
R
OH
+
α-alkylation
γ-alkylation
Casiraghi, Chem. Rev. 2000, 100, 1929.07-General Acid Dienolates 2/12/02 2:12 PM
Metal Dienolates of AmidesKinetic vs. Thermodynamic Control
Snieckus, J. Org. Chem.1981, 46, 2029.
Me
Me NMe2
O1. LDA, -5 °C
2. RCHO
Me
NMe2
O
R
OH
Me
NMe2
O
HO R
+
R
1
2
-5 °C, 5 min1 : 2
-5 °C to rt, overnight1 : 2
N
Ph
nPr
meta
ortho / para
(E)-CH=CHPh
80 : 20
100 : 0
100 : 0
100 : 0
100 : 0
0 : 100
13 : 87
15 : 85
100 : 0
100 : 0
Me
R
OH
NMe2O+
08-Snieckus amides 2/11/02 5:03 PM
Dienolates from Unsaturated Carboxylic AcidsVinylogous Aldol Selectivity Highly Dependant on Metal(s)
Me
Me OH
O
Me OM2
OM1Me
OH
O
PhCHO, THF, -78 °C
OH
Ph
Me
COOH
O
O
Ph Me
OH
Ph
Me
Ph OH
COOH
Me
COOH
A B C D
M M'relative yield
A B C D
LiLiNaKK
SnBu3LiLiLiK
-19554100
-274424-
--5--
100544622-
Cainelli, J. Chem. Soc. Perkin Trans. 1 1973, 400.
Conclusion: vinylogous aldol adducts favored with more ionic character
09-Dienolate carboxylates 2/12/02 2:51 PM
Metal Dienolates of AldehydesMethods of Enolate Generation
• "traditional" methods of enolization not synthetically useful
RO
H MNR2, low temp.polymerization
THF, etc.
• enolate can be generated in liquid ammonia; highly stable in these conditions but reactivity in these conditions not studied
RO
HKNH2, NH3
ROK
• most common method: cleavage of silyl dienol ethers and dienol acetates
ROR'
MeLi or tBuOK
R' = TMS or Ac
ROM
van der Gen, Tetrahedron Lett.. 1978, 491.Stork, J. Am. Chem. Soc. 1968, 90, 4464.House, J. Org. Chem. 1969, 34, 2324.
10-Aldehyde dienolates 2/11/02 5:04 PM
Metal Dienolates of AldehydesYamamoto's Al-mediated VAR
Yamamoto, J. Am. Chem. Soc. 1998, 120, 813.
O
H
R3
R2
R1
O
H R
+
ATPH (2.2 equiv.)
toluene, -78 °CO
H
R3
R2
R1
O
H R
+ATPH
ATPH
LDA (1.2 equiv.)THF, -78 °C
OR3
R2
R1
O
H R
+ATPH
ATPH
O
H R2
R1 R3
R
OH
O Al
Ph
Ph 3
ATPH =
11-Yamamoto Al VAR 2/14/02 9:18 AM
Metal Dienolates of AldehydesYamamoto's Al-mediated VAR
Yamamoto, J. Am. Chem. Soc. 1998, 120, 813.
O
H
R3
R2
R1
O
H R
+ 1. ATPH (2.2 equiv.), tol, -78 °C O
H R2
R1 R3
R
OH2. LDA (1.2 equiv.), THF, -78 °C
MeCHO
MeCHO
MeCHO
Me
Me
CHO CHO
PhCHO
Me CHO
99%
97%
99%
99%
91%
99%
55%
90%
77%
83%
83%
83%
aldehydeconj.aldehyde
12-Yamamoto Al VAR2 2/14/02 9:17 AM
Metal Dienolates of AldehydesYamamoto's Al-mediated VAR
Yamamoto, J. Am. Chem. Soc. 1998, 120, 813.Casiraghi, Chem. Rev. 2000, 100, 1929.Maruoka, Angew. Chem. Int. Ed. 1998, 37, 3039.
• Rational for enolatization selectivity
MeO
H
Me OATPH
H
ATPH
Hydrogens notaccessible to base
Hydrogens accessibleto base
• has also been suggested that aldol occurs only with uncomplexed aldehyde due to this steric hindrance →carbonyls complexed with ATPH even resistant to addition by MeLi
MM2Models
(Chem3D)
13-Yamamoto Al VAR3 2/14/02 9:15 AM
Metal Dienolates of Aldehydes - Synthetic ApplicationsCallipeltoside Aglycone - Patterson
Patterson, Angew. Chem. Int. Ed. 2001, 40, 603.
O
H
Me
Me
O
H
I
+
1. 2.2 equiv. ATPHtol, -78 °C
2. LDA, THF, -78 °C80%
O
O
Me
Cl
OMeO
Me
OH
Me
H OH
diastereomers separatedat a late stage
OH
Me
H
I
O
14-Callipeltoside Patterson 2/14/02 9:20 AM
Metal Dienolates of EnonesMethods of Enolate Generation
• regiochemical issues
O
O
O
O
O
O
base
R
OH
R
HO R
OH
α'-enolization
γ-enolization
α'-alkylation
α-alkylation
γ-alkylation
Only product observedunder kinetic conditions(i.e. LDA, cold temp)
Can be observed underequilibrating conditions; usually accompanied by elimination (aldol condensation)
RCHO
RCHO
15-Enone dienolates 2/14/02 9:13 AM
Metal Dienolates of EnonesYamamoto's Al-mediated VAR
Yamamoto, J. Am. Chem. Soc. 1998, 120, 813.
O
H Ph
+1. ATPH (2.2 equiv.), tol, -78 °C
2. LDA (1.2 equiv.), THF, -78 °C
O
Ph OH
O
70%; 4 : 1 dr(stereochemistrynot determined)
O
H R
+1. ATPH (2.2 equiv.), tol, -78 °C
2. LDA (1.2 equiv.), THF, -78 °C
O
Me
O
R
OH
R = Ph : 86%R = tBu : 99%R = nBu : 73%R = (E)-CH=CHPh : 68%
16-Yamamoto Al VAR enone 2/14/02 9:22 AM
Vinylogous Aldol Reactions of SiloxyfuransEffect of Lewis Acid / Promoters
nPent
OH
O
O
nPent
OH
O
O
+conditions
O
TMSO
+ nPentCHO
Conditions syn : anti yield (%)
SnCl4 (0.4 equiv.), -78 °C
ZnBr2 (0.4 equiv.), 0 °C
ZnCl2 (0.5 equiv.), 0 °C
BF3•OEt2 (0.6 equiv.), -78 °C
TrClO4 (0.1 equiv.), -78 to 0 °C
TMSOTf (0.2 equiv.), -78 °C
TESOTf (0.2 equiv.), -78 °C
76 : 24
66 : 34
68 : 32
81 : 19
79 : 21
82 : 18
82 : 18
88
94
82
95
92
95
93
syn anti
Jefford, Tetrahedron Lett. 1987, 28, 4037.
CsF (1.3 equiv.), -78 to 0 °C
TBAF (0.06 equiv.), -78 °C
27 : 73
33 : 67
68
74
17-Siloxyfurans 2/14/02 9:21 AM
Vinylogous Aldol Reactions of SiloxyfuransRationale of Stereoselectivity - "naked" dienolates
O
O
Jefford, Tetrahedron Lett. 1987, 28, 4037.
O
R H
O
O
O
R H
O
R H
O
O
syn
antiO
O
O
R H
Dipole minimized
18-Siloxyfurans rationale1 2/11/02 5:06 PM
LA
LA
Vinylogous Aldol Reactions of SiloxyfuransRationale of Stereoselectivity - Mukaiyama VARs
O
OTMS
Jefford, Tetrahedron Lett. 1987, 28, 4037.
O
R H
O
OTMS
O
R H
O
R H
O
TMSO
O
OTMS
O
R H
LA
LA
"Diels-Alder like"
syn
anti
19-Siloxyfurans rationale2 2/11/02 5:06 PM
Vinylogous Aldol Reactions of SiloxyfuransSynthetic Applications
D-erthyro-C18-sphingosine - Casiraghi
Spanu and Casiraghi, Tetrahedron Asymm. 1997, 8, 3237.
NBoc
O
OH
O
O
MeMe
NBoc
TBSO
O
O
O
MeMe
+SnCl4, Et2O, -85 °C
80%, >98:2 dr
H
TBSCl, imid.DMF
NBoc
O
OTBS
O
O
MeMe
NBoc
O
OTBS
O
O
MeMe
+
A B
Reaction time A : B
10 hours4 days
12 : 8885 : 15
HO C13H27
OH
NH2
D-erthyro-C18-sphingosine
20-Casiraghi Sphingosine 2/11/02 6:38 PM
Spanu and Casiraghi, Eur. J. Org. Chem. 1999, 1395.
NBoc
O
OH
O
O
MeMe
NBoc
TBSO
O
O
O
MeMe
+SnCl4, Et2O, -85 °C
80%, >98:2 dr
H
NBoc
OTBDPSMeO
OTBSO
CH2Cl2, -80 °C78%, >95:5 dr
0.6 eq. TBSOTf
NBoc
OTBDPS
OHH
O
N
OH
HO
HO
H
OH
Vinylogous Aldol Reactions of SiloxyfuransSynthetic Applications
Indolizidine Alkaloid Analogues - Casiraghi
21-Casiraghi Indolizidines 2/11/02 6:39 PM
Martin, J. Org. Chem. 1998, 63, 7592.
O
OO
SPh
O
O
CO2MeHO
TBDPSO
O
O
TiCl4 (3 equiv.)
CH2Cl2, 0 C to rt
40% (<5% combined of other diast.)• all other L.A. tried led to decomp. or
complex diastereomeric mixtures
OOMeO2C
MeO2C
OHMe Me
Ph
OHOOHOOC
HOOC
OHCOOH Me
Ph
RO OHOAc
Zaragozic Acid
CO2MeO
TBDPSO
Vinylogous Aldol Reactions of α-heterofuransSynthetic Applications
Zaragozic Acid Core - Martin
22-Martin Zaragozic Acid 2/14/02 9:24 AM
Vinylogous Mukaiyama Aldol ReactionsEffect of Lewis Acid and Solvent
Kalesse, Tetrahedron Lett. 2001, 42, 1269.
OMe
OTBS
Me H
OOTBS
Me
+Me
OROTBS
Me
OMe
O
solvent-78 °C
1: R = TBS2: R = H
L.A.
Lewis Acid Equiv. Solvent dr Product (Yield (%))
BF3•OEt2
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6H5)3
1.5
1.0
0.5
0.2
0.1
0.2
1.0
CH2Cl2/Et2O (9:1)
CH2Cl2/Et2O (9:1)
CH2Cl2/Et2O (9:1)
CH2Cl2/Et2O (9:1)
CH2Cl2/Et2O (9:1)
CH2Cl2
CH2Cl2/Et2O (9:1)
3:1
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
2 (92)
1 (81)
1 (78)
1 (74)
1 (15)
1 (61), 2 (8)
2 (85)
23-Kalesse L.A. Scan 2/11/02 5:09 PM
Vinylogous Mukaiyama Aldol Reactions - Synthetic Applications(+)-Ratjadone - Kalesse
Kalesse, J. Org. Chem. 2001, 66, 1885.
O
H Me
OTBS
MeB(C6F5)3, -78 °C
80%, 95:5 dr
OTBS
Me
OTBS
Me
MeO
O
OMeH H
Me
OH
OH
Me
Me
Me
O O
(+)-Ratjadone
1.Dibal-H, THF, -78 °C2. mCPBA, NaHCO3 CH2Cl2, 0 °C
85%
OTBS
Me
OTBS
Me
HOO
OMeH H
Me
OH
OH
OH1. TBAF
2. H+
93%
OTBS
MeO
24-Kalesse Ratjdone 2/15/02 10:35 AM
Vinylogous Mukaiyama Aldol ReactionsEffect of Dienolate Stucture
Kalesse, Org. Lett. 2001, 3, 3561.
MeOMe
OTBS
Me
OMe
OTBS
• (Z)-silyl dienolates are good substrates for VMAR
Me
Me CHO
Et2O, B(C6F5)3iPrOH
Me
Me
OMe
OOH
Me
+Me
Me
OH
Me
OMe
O
84%; >20:1 syn <1%; mixture of isomers
• (E)-silyl dienolates, however, are less reactive and unselective
Me
Me CHO
Et2O, BF3•OEt2
Me
Me
OMe
OOH
Me
+Me
Me
OH
Me
OMe
O
51%; 1:1 syn:anti 25%; mixture of isomers• no reaction with B(C6F5)3
25-Kalesse (E) vs. (Z) 2/11/02 5:07 PM
Vinylogous Enoxy Silane ApplicationsMolander's [3+4] and [3+5] Annulations
Molander, J. Am. Chem. Soc. 1993, 115, 830.
R1
TMSO
R2
OMe
OTMS
R1,R2 = H, alkyl
RS
O
RL
O
R3
n+
RS = H, MeRL = alkyl, arylR3 = H, alkyl, ORn = 1,2
O
R3
O
CO2MeRS
RL
TMSOTf (20 mol%)
CH2Cl2, -78 °C50-90 %
n
• Representative Examples
R1
H
H
H
H
Me
H
R2
R1
R2
H
H
HiPr
H
H
R3
H
H
Me
H
H
Me
RS
H
Me
H
H
H
H
RL
PhnPr
MenPrnPr
Me
Yield (%)
87
58
75
73
72
72
dr
>200:1
5:1
13.5:1
25:1
5.4:1
30:1
n
1
1
1
1
1
2
26-Molander Annulation1 2/11/02 11:19 AM
Vinylogous Enoxy Silane ApplicationsMolander's [3+4] and [3+5] Annulations
Molander, J. Am. Chem. Soc. 1993, 115, 830.
TMSO
OMe
OTMS
H
O
Ph
O
O
O
CO2MeH
Ph
TMSOTf
H
O
Ph
O
TMS
O
OTMS
Ph
OOTMS
Ph
H
OTMS
CO2Me
O
PhOTMS
CO2Me
• Mechanism
27-Molander Annulation2 2/9/02 9:20 AM
[3+n] Enoxy Silane Annulation - Synthetic ApplicationsMolander's Annulation - Davanone and Dactylol
MeH
O
O1. Chan's Diene
TMSOTfCH2Cl2, -78 °C
2. LiCl, DMSO75%
O
Me
O
OMe H
O Me
Me
Me
(±)-Davanone
CHO
O
Me
MeMe 2. LiCl, DMSO60%
single diast.
O
H
Me
O
Me
Me
H
Me
Me
Me
Me
HO
(+)-Dactylol
Molander, Tetrahedron 1999, 55, 617.Molander, J. Org. Chem. 1995, 60, 4559.
1. Chan's DieneTrSbCl6
CH2Cl2, -78 °C
28-Molander Datylol/Davanone 2/15/02 10:32 AM
Diastereoselective Vinylogous Aldol ReactionsSchlessinger's Chiral Dienolate - First Generation
CO2Me
Me
NH
Me
Me
+tBuOH, 83 °C
90%N
Me
OMe
O
Me
Me
1. LDA / THF2. iPrCHO; -78 to 0 °C 86%; 97:3 dr
O
O
NMe
MeMe
Me
Me
1. Li/NH3; tBuOH
2. mCPBA, Al2O3 pyridine
OH
Me
MeMe
OHC
Schlessinger and Springer, J. Org. Chem. 1986, 51, 3073.29-Schlessinger 1st Gen 2/11/02 5:10 PM
Diastereoselective Vinylogous Aldol ReactionsSchlessinger's Chiral Dienolate - Second Generation
Schlessinger, J. Org. Chem. 1996, 61, 3226.
• Problem with previous auxillary: very expensive, and difficult to prepare on large scale - solution: proline-derived auxillary
NH
OMe
Me
OMeO
+
tBuOH, ∆
76% NMe
O
OMe
EtEtMeO
1. LDA, THF, -78 °C2. iPrCHO 89%; 99:1dr
O
Me
O
N
EtEtMeO
Me
Me
1. NaCNBH3
2. mCPBA 82%
O
Me
O
Me
Me
Me
Me
30-Schlessinger 2nd Gen 2/11/02 5:11 PM
Diastereoselective Vinylogous Aldol ReactionsSchlessinger's Chiral Dienolate - Second Generation
Schlessinger, J. Org. Chem. 1996, 61, 3226.Williard and Schlessinger, J. Am. Chem. Soc. 1988, 110, 7901.
NMe
OLi
OMe
EtEtMeO
O
Me
O
N
EtEtMeO
Me
MeO
H iPr
2 3View down C3-C2 bond
View from top
=
MM2Models
(Chem3D)
31-Schlessinger 2nd Gen2 2/12/02 5:49 PM
Diastereoselective Vinylogous Aldol ReactionsSchlessinger's Chiral Dienolate - Second Generation
Schlessinger, J. Org. Chem. 1996, 61, 3226.
• Substrate Generality
NMe
O
OMe
EtEtMeO
O
R
Me
O
N
EtEtMeO
1. LDA, THF, -78 °C
2. RCHO
R Yield (%) dr
tBu
Cy
nPr
(E)-CH=CHMe
(E)-CH=CHPh
(E)-CH=CHSnBu3
83
83
57
74
74
68
99:1
99:1
97:3
99:1
98:2
99:1
32-Schlessinger 2nd Gen3 2/11/02 5:12 PM
Diastereoselective Vinylogous Aldol Reactions Synthetic ApplicationsVirginiamycin M2 - Schlessinger
Schlessinger, J. Am. Chem. Soc. 1996, 118, 3301.
O
Me
O
N
EtEtMeO
Me
Me
1. Li, NH3, tBuOH, THF
2. mCPBA, pyr, -78 to 0 °C
75%
OHC
Me
Me
Me
OH
1. N-Troc-D-Proline DCC, DMAP, CH2Cl22. NH2SO3H, NaClO2 THF, H2O
72%
O
NHO
O
N
O
O
MeO
O
Me
Me
Me
N
H
Virginiamycin M2O
O
MeO
Me
Me
NTroc
HO
33-Schlessinger Virginiamycin 2/11/02 6:53 PM
Diastereoselective Vinylogous Aldol ReactionsSchlessinger's Chiral Dienolate - Effect of Oxygenation
Schlessinger, J. Org. Chem.. 1998, 63, 9089.
N
O
OMe
EtEtMeO
OTMSE
O
R
OTMSE
O
N
EtEtMeO
1. LDA, THF, -78 °C
2. RCHO
R Yield (%) dr
tBu
iPr
Ph
(E)-CH=CHEt
(E)-CH=CHSnBu3
(Z)-CH=CHSnBu3
93
73
84
78
76
75
98:2
98:2
99:1
98:2
98:2
99:1
34-Schlessinger oxygenation 2/12/02 5:49 PM
Diastereoselective Vinylogous Aldol Reactions Synthetic Applications
(+)-KDO - Schlessinger
Schlessinger, J. Org. Chem. 1998, 63, 9089.
O
OTMSE
O
N
EtEtMeO
SnBu3
HCl / THF
78%O
OTMSE
O
O
O
O
O
OMe
Me
OsO4, NMO
90%, >95:5 dr
O
O
O
OMe
Me
OH
OH
O
OH
OHHO
OH
HO COOH
(+)-KDO35-Schlessinger KDO 2/13/02 6:02 PM
OTBS
Diastereoselective Vinylogous Aldol Reactionsα-alkylation / Cope rearrangement strategy
Black, Tetrahedron Lett. 1996, 37, 4471.
• Problem: imide auxiliaries give α-alkyation with dienolates
• Solution: aldol followed by siloxy-Cope rearrangement
O
O N
OBBu2
Bn
O
O N
O
Bn
OTBSO
H OPh
1.
2. TBSCl, imid.OPh
OPhXcOC
COXc
TBSO OPh
vs.
140 °C
O
Xc
OPh OTBS
OPh
OTBS
Xc O
A
B
86%, 31:1 A : B
36-Black Aldol/Cope 2/11/02 5:20 PM
Catalytic Asymmetric Vinylogous Aldol ReactionsCarreira Ti(IV) Catalyst
Carreira, J. Am. Chem. Soc. 1995, 117, 12360.Carreira, J. Am. Chem. Soc. 1994, 116, 8837.
N
OO
tBu
Br
OO
O
tBu
tBu
Ti
catalyst
O O
OTMS
Me Me
2. CF3COOH
O O
O
Me Me
HO1. 1-3 mol% cat., RCHO Et2O, 0 °C
R
Aldehdye Yield (%) ee (%)
CHOiPr3Si
PhCHO
PhCHO
PhCHO
Bu3SnCHO
86
83
88
97
79
91
84
92
80
92
37-Carreira Ti CAVM 2/9/02 9:22 AM
Catalytic Asymmetric Vinylogous Aldol ReactionsCarreira Copper Catalyst
Carreira, J. Am. Chem. Soc. 1998, 120, 837.
O O
OTMS
Me Me
2. CF3COOH
O O
O
Me Me
HO1. 2 mol% CuF(S)-tolBinap, RCHO, THF, -78 °C
R
Aldehdye Yield (%) ee (%)
92
91
93
83
48
94
94
94
85
91
Cu(OTf)2 + TBAT + (S)-tolBinap
PhCHO
furfural
p-OMePhCHO
(E)-PhCH=CHCHO
(E)-MeCH=CHCHO
38-Carreira Cu CAVM 2/11/02 5:50 PM
Catalytic Asymmetric Vinylogous Aldol ReactionsCarreira Copper Catalyst - Mechanistic Insights
Carreira, Angew. Chem. Int. Ed. 1998, 37, 3124.
OTMS
O
CuF(tolBinap)TMSF
O
O
R
OCuL*
RCHO
O
Me Me
OTMS
OO
Me Me
OCuL*
OO
Me Me
O
Me Me
O
O
R
OTMS O
Me Me
Support for Cu enolate:
1. CuOtBu(S)-tolBinap equally good catalyst2. ReactIR observation of signals which are "consistent" with A (1690 and 1550 cm-1)
A
CuF2(tolBinap)
OTMS
R
ROCCOR
39-Carreira Cu CAVM2 2/13/02 6:04 PM
Carreira's CAVM - Synthetic ApplicationsTowards Amphotericin - Carreira
Carreira, Tetrahedron Lett. 1998, 39, 7013.
CHO
O
O O
OTMS
Me Me
+
1. CuF(S)-tolBinap (2 mol%)-78 °C, THF
2. CF3COOHO
O O
O
Me Me
HO
O
H
O O
OTBS
Me Me
1. CuF(R)-tolBinap (2 mol%)-78 °C, THF
2. CF3COOH
O
O O
O
Me Me
HO
O O
Me Me
TBDPSO
40-Amphotercin1 Carreira 2/11/02 6:55 PM
Carreira's CAVM - Synthetic ApplicationsTowards Amphotericin - Carreira
Carreira, Tetrahedron Lett. 1998, 39, 7013.
O
H
O O
OTBS
Me Me
O O
Me Me
TBDPSO
O
O
Me
Me
Me OH
OMycosamine
HO O OH OH
OH
OH OH
OH
COOH
O O
OH
O O
OTBSTBDPSO
Me Me Me Me
41-Amphotercin2 Carreira 2/11/02 6:55 PM
Carreira's CAVM - Synthetic ApplicationsVirginiamycin M2 - Campagne
Campagne, Tetrahedron Lett. 2001, 42, 5195.
O
HN
HO
O
N
O
O
MeO
O
Me
Me
Me
N
Virginiamycin M2
O O
TMSO
Me Me
Me
NHBOc+
1. CuF(R)-tolBinap THF, -78 °C
2. PPTS, MeOH, rt80% 81% ee
OHOO
O
Me Me
OHC
Me
NHBoc
NHBocMOMO
O
N
O
Me
OMe
O
42-Campagne Virginiamycin 2/11/02 6:55 PM
Catalytic Asymmetric Vinylogous Aldol ReactionsCarreira's Catalyst for Other Dienolates - Campagne
Me
OEt
OTMS
+ RCHO10 mol% CuF(S)-tolBinap
THF, rt
Me
OEt
O
R
OTMS
Aldehyde Yield (%) ee (%)
CHO
CHO
CHO
CHO
80
70
35
68
70
48
56
77
Campagne, Tetrahderon Lett. 1999, 40, 5507.43-Campagne CAVM 2/12/02 5:51 PM
Catalytic Asymmetric Vinylogous Aldol ReactionsCarreira's Catalyst for Other Dienolates - Campagne
Me
OEt
OTMS
Me
OEt
O
R
OTMS
Campagne, J. Org. Chem. 2001, 66, 4295.
CuF(tolBinap)
Me
OEt
OCuL*
TMSF
Me
OEt
O
R
OCuL*
RCHO
Me
OEt
OTMS
Is Silylation Important in Selectivity???
44-Campagne CAVM Cat. Cycle 2/11/02 5:35 PM
Campagne's CAVM - Synthetic ApplicationsOctalactin A - Campagne
Campagne, Synlett 2000, 221.
10 mol% CuF(S)-tolBinap
THF, rt90%, 80%ee
Me
Me
OHC+
OTMS
EtO
Me
O
EtO
Me
OH
Me
Me
O
Me
OTBS
Me
MeMe
O
Me
OH
Me
MeMe
O
O
HO
Me
O
45-Campagne Octalactin 2/11/02 6:56 PM
Catalytic Asymmetric Vinylogous Aldol ReactionsSynthesis of Lactones with Other Silyl Dienolates - Campagne
OMe
OTMS
+ RCHO
CuF(S)-tolBinap10 mol%
THF, rt OMe
O
R
OH
Me
Me
O
Me
O
R
+
1 2
Aldehyde Yield (%)(1 + 2)
ratio (1/2) ee (%) of 1
Benzaldehyde
2-napthaldehyde
2,3-dimethoxybenzaldehyde
2-furaldehdye
(E)-cinnamaldehyde
isobutyraldehyde
85
95
87
60
60
95
86/14
80/20
81/19
50/50
70/30
64/36
87
85
91
86
82
91
E,Z-mix
Campagne, Org. Lett. 2001, 3, 3807.46-Campagne CAVM lactones 2/12/02 5:52 PM
Catalytic Asymmetric Vinylogous Aldol ReactionsEvans' Cu(II)box and pybox Catalysts
NO
N N
O
Ph Ph
Cu
N
OO
N
Me Me
tBu tBuCu
BnO
OH
O
O
2+
2 SbF6 -
2+
2 TfO -
BnO
O
O
OTMS
EtO
OH
O
O
O
Me
H
1.
10 mol%-78 °C, CH2Cl2
2. 1 N HCl / THF
+
EtO
O
O
OTMS
Me+
93%, 91:9 anti:syn92% ee (anti)
O2. 1 N HCl / MeOH
93%, 95:5 anti:syn99% ee (anti)
1.
10 mol%-78 °C, THF
Evans, J. Am. Chem. Soc. 1999, 121, 669.Evans, J. Am. Chem. Soc. 1999, 121, 686.
• addition of CF3CH2OH makes reaction amenable to large scale
47-Evans CAVM 2/11/02 5:38 PM
Catalytic Asymmetric Vinylogous Aldol ReactionsEvans' Cu(II)box and pybox Catalysts
NO
N N
O
Ph Ph
Cu
2+
2 SbF6 -
BnO
O
H
1.
5 mol%-78 °C, CH2Cl2
2. 1 N HCl / THF
+
94%, 92% ee
O
OTMS
O
NO
N N
O
Ph Ph
Cu
2+
2 SbF6 -
BnO
O
H
1.
2.5 mol%-78 °C, CH2Cl2
2. PPTS, MeOH
+
85%, 99% ee
TMSO
OMe
OTMS
Me Me
O
O
O
Me Me
BnO
OH
O
OtBu
O
BnO
OH
Evans, J. Am. Chem. Soc. 1999, 121, 669.48-Evans CAVM2 2/13/02 6:13 PM
Catalytic Asymmetric Vinylogous Aldol ReactionsEvans' Sn(II)box and Cu(II)pybox Catalysts
N
OO
N
Et Et
Sn
X
O
O
O
X
O
O
OTMS
H+
O2. 1 N HCl / EtOAc
1.
10 mol%-78 °C, THF
Evans, Favor, Beauchemin, Hu and Burch; unpublished results
• some new results:
Me
2+
2 TfO -
OH
Me
NO
N N
O
Ph Ph
Cu
2+
2 SbF6 -
PMBO
O
H
1.
2.5 mol%-78 °C, CH2Cl2
2. 1 N HCl / EtOAc
+
93%, 95% ee
Me
OMe
OTMS
MeOPMB
OH
O
MeO
X = OEt: 94%, >50:1 dr; 95% ee = NHPh: 44:1 dr; 97% ee
Slow addition Slow addition
49-Evans CAVM3 2/14/02 9:30 AM
Evans' CAVM - Synthetic ApplicationsAzaspiracid - Evans
Evans, Dunn and Beauchemin; unpublished results
BnO
OH
O
O
BnO
O
O
OTMS
H
10 mol%-78 °C, CH2Cl2
CF3CH2OH
2. 1 N HCl / EtOAc
+
80%, 93:7 anti:syn97% ee (anti)
1. Cu(S,S)PhPybox
PhHN
O
O
O
PhHN
O
O
OTMS
H+
O2. 1 N HCl / EtOAc
10 mol%-78 °C, THF
Me
OH
Me
44:1 dr; 97% ee
1. Sn(R,R)indabox
NCH
OMe OTBS
OPMB
Azaspiracid
50-Azaspiracid Evans 2/14/02 9:28 AM
Evans' CAVM - Synthetic ApplicationsCallipeltoside - Evans
Evans, Hu and Burch; unpublished results
EtO
OTMS Me
O
H
OPMB
+
1. 2.5 mol% Cu(S,S)PhPyBox CH2Cl2, -78 °C, slow addition
2. 1 N HCl, THF 93%, 95% ee
O
O
Me
OMeO
Me
OH
Me
H OH
stereocenter invertedwith cyclization
OH
MeOPMB
EtO
O
OPMB
51-Callipeltoside Evans 2/13/02 6:14 PM
The Vinylogous Aldol ReactionA Summary
OM
X
MeRCHO
O
X R
OHMe
• in general, metal dienolates favor α-alkylation under kinetic conditions and γ-alkylation under
thermodynamic conditions
• exception: Yamamoto's ATPH-mediated vinylogous aldol conditions
• in general, siloxyfurans vinylogous aldol favor syn adducts under lewis acid catalysis and anti
adducts with "naked" dienolates
• exception: Evans' Cu(II) catalyzed additions of siloxyfurans
• Schlessinger's proline-derived auxilliary useful for diastereoselective vinylogous aldol reacitons
• Carreira's Ti(IV) and Cu(I) catalysts and Evans' Cu(II) and Sn(II) catalysts useful for enantioselective
vinylogous aldol reactions of β-oxygenated dienolates; non-oxygenated cases also showing promise
52-Summary 2/15/02 10:32 AM
