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Direct Carbon-Carbon Bond Formation via Reductive Soft Elimination: A Kinetically Controlled syn-Aldol Addition of a-Halo Thioesters and Enolizable Aldehydes
Scott J. Saur, Michelle R. Garnsey, and Don M. ColtartJ. Am. Chem. Soc. 2010, 132, 13997-13999
Direct Carbon-Carbon Bond Formation via Soft Enolization; Aldol Addition of a-Halogenated Thioesters
Julianne M. Yost, Rachel J. Alfie, Emily M. Tarsis, Insun Chong, and Don M. ColtartChem. Commun. 2010, Advance Article
Antoinette NibbsShort Literature Presentation
6 December 2010
Don M. Coltart1989-1993: B.Sc. (Honors) Biochemistry, University of Manitoba
1993-1995: M.Sc. Chemistry, University of ManitobaAdvisor: Dr. J. L. Charlton
1995-2000: Ph.D. Chemistry, University of AlbertaAdvisor: Dr. D. L. J. Clive
2001-2004: CRI (Cancer Research Institute)/NSERC (National Science and Engineering Research Council of Canada)/AHFMR (Alberta Heritage Foundation for Medical Research) Postdoctoral Fellow, Memorial Sloan-Kettering Cancer Center,Advisor: Dr. S. J. Danishefsky
2004 to present: Assistant Professor, Duke University, Dept. of Chemistry
Direct Aldol Reaction
"long-standing yet unrealized goal"
side reactions between the base and the electrophile
R1Y
O
Y = OR, SR
R2 CHO basedirect aldol
R1
OH
Y
O
R2
Direct Aldol Reaction
Hauser, C. R.; Puterbaugh, W. H. J. Am. Chem. Soc. 1951, 73, 2972
The Long-Standing Goal
enolate generation time-consumingrequire anhydrous conditions
require low temperatures with strong bases
Traditional Methods
generates nucleophile in situreactions carried out open to air in untreated solvents
proceed at room temperature with milder bases
Reductive Soft Enolization
R1Y
O
Y = OR, SR
R2 CHO basedirect aldol
R1
OH
Y
O
R2
Aldol Reactions
Considerations
chemoselectivity R1Y
O
Y = OR, SR
R2 CHO non-basic means of enolization
stereoselectivity most easily managed when reaction is under kinetic control
R1Y
O
Y = OR, SR
R2 CHO basedirect aldol
R1
OH
Y
O
R2
Soft Enolization
O
X
O
X
base O
X
O
X
R
O
Cl O
X
O
X
O R
Problem: more acidic than starting material
solution: single-step acylation in the presence of excess base (works only if base does not react destructively with acid chloride)
O
X
O
X
2base O
X
O
X
O RR
O
Cl
Rathke, M.W.; Cowan, P.J. J. Org. Chem. 1985, 50, 2622
O
OEt
O
EtO
O
OEt
O
EtO
O R
R
O
Cl
MgCl2, 2 Et3N
MeCN, 25 °C12 h
up to 92% yield
Coltartʼs System
chemoselectivity via reductive soft enolization of a-halo thioesters
R1SR3
OR2
OH
SR3
O
R1
syn aldol
R2 CHOR3P, Mg2+
X
R1SR3
O
X
Mg2+
PR3
chemoselective enolization X- +PR3 R1
SR3
OMg2+
R2 CHOkinetic addition
1. no competing enolization of aldehyde2. beneficial stability of Mg enolate
shelf-stable latent enolate
R1Y
O
Y = OR, SR
R2 CHO basedirect aldol
R1
OH
Y
O
R2
Initial Studies
SPh
O
C10H7
OH
SPh
O
C10H7
MgI2, PPh3I
O
HCH2Cl2
78%
Effect of Thioester on Diastereoselectivity
Pirrung, M. C.; Heathcock, C. H. J. Org. Chem. 1980, 45, 1728
Pioneering Work by Heathcock and Pirrung
SR
O
Ph
OH
SR
O
Ph
MgI2, PPh3I
O
H
MeCH2Cl2 Me
Ph
OH
SR
O
Me
Initial Studies
SPh
O
C10H7
OH
SPh
O
C10H7
MgI2, PPh3I
O
HCH2Cl2
78%
S
OI
Me
83%3:1
yieldsyn:anti
S
OI
MeS
OI
MeS
OI
Me
Me
MeMe
Me
Me
i-Pr
i-Pr i-Pr
85%3.7 : 1
78%15.3 : 1
89%>20 : 1
Effect of Thioester on Diastereoselectivity
SR
O
Ph
OH
SR
O
Ph
MgI2, PPh3I
O
H
MeCH2Cl2 Me
Ph
OH
SR
O
Me
Aldehyde Scope
yieldsyn:anti
Ph
O
H C10H7
O
H C6H11
O
H C3H7
O
H C7H15
O
H
89> 20:1
65%> 20:1
87%> 20:1
68%> 20:1
77%> 20:1
O
HPh
68%> 20:1
80%> 20:1
72%> 20:1
62%> 20:1
89%> 20:1
O
HPh
O
H
O
H
O
O
H
BocHN
yieldsyn:anti
S
O
Ph
OH
SAr
O
R
MgI2, PPh3I
O
H
MeCH2Cl2 Me
i-Pr
i-Pr
i-Pr
Aldehyde Scope
S
O
Ph
OH
SAr
O
R
MgI2, PPh3I
O
H
MeCH2Cl2 Me
i-Pr
i-Pr
i-Pr
S
O OH
SAr
OMgI2, PPh3I
O
H
MeCH2Cl2
60% Me
i-Pr
i-Pr
i-Pr
OTBSMe
Me
single diastereomerOTBS
Me
Me
Kinetic Reactivity Studies
sole product
confirms the predicted stability of aldolate intermediatesupports notion of kinetically controlled addition
S
O
C10H7
O
SPh
O
C10H7
MgI2, PPh3I
O
H
i-Pr i-Pr Mg
Me
CHO1.
2. H3O+
C10H7
OH
SPh
OOH
SPh
O
Me
18 hr
X
Stereochemical Model
I
H MeRS O
Mg
I
H MeSO
MgR
Me
OMg
SRMeOMg
SR
R1CHOR1CHO
OMgO
SR
MeR1
H
OMgO
SR
MeR1
H
R1
OH
SR
O
MeR1
OH
SR
O
Me
the bulkier the R group on the thioester, the more syn product is formed
Initial Studies
SPh
O
C10H7
OH
SPh
O
C10H7
MgI2, PPh3I
O
HCH2Cl2
78%
S
OI
Me
83%3:1
yieldsyn:anti
S
OI
MeS
OI
MeS
OI
Me
Me
MeMe
Me
Me
i-Pr
i-Pr i-Pr
85%3.7 : 1
78%15.3 : 1
89%>20 : 1
Effect of Thioester on Diastereoselectivity
SR
O
Ph
OH
SR
O
Ph
MgI2, PPh3I
O
H
MeCH2Cl2 Me
Ph
OH
SR
O
Me
Conclusions
direct addition is a reductive soft enolization process
developed the first Mg2+ promoted direct addition of a-halo thioesters to enolizable aldehydes to produce B-OH thioesters
syn-selective nature of this reaction is opposite than that obtained for simple (thio)esters using amide bases
kinetically controlled addition step allows for direct, stereocontrolled aldol
SR2
O
R3
OH
SR2
O
R3
MgI2, PPh3
I
O
HR1
CH2Cl2 R1
PR3
R1SR3
O
X
Mg2+ chemoselective enolization
X- +PR3 R1SR3
OMg2+
NHC-Promoted Darzens Reactions
Ph H
O
Cl
O
F
1. NHC (15 mol %) n-BuLi (14 mol %), THF
2. solvent, 25 °C
O
F
PhO
Cl
O
F
Ph
OH
21-44% yieldup to 22% ee
up to 1.8 : 1 dr
aldol product
X
O
R2R1
OH
what is it good for?
X
Asymmetric Aldol Reactions
X
O
OHR1
OH
useful intermediates in total synthesis
Evans, D. A.; Sjogren, E. B.; Weber, A. E.; Conn, R. E.; Tetrahedron Lett., 1987, 28, 39
NO
O
R1 R2
O
X
1. Bu2OTf, Et3N
2. R3CHONO
O
R1 R2
O
ClR3
OH
(Br)
HO
O
NH2
R3
OH
R*2BBr + BrOt-Bu
O 1. Et3N, —78 °C
2. RCHOOt-Bu
O
BrR
OH
Corey, E. J.; Choi, S.Tetrahedron Lett., 1991, 32, 2857
MeMe
NO
SMe
O
TiCl4/DIPEA;
then Br2/DIPEA
MeMe
NO
SHO
Br
Ti
RCHO–78 °C
MeMe
NO
SO
BrHO
RWang, Y.-C.; Su, D.-W.; Lin, C.-M; Tseng, H.L.; Li, C.-L.; Yan, T.-H. Tetrahedron Lett., 1999, 40, 3577
Considerations for Aldol Reactions
Cl
O
R2R1
OH
aldol productO
R2R1
ODarzens product
H
O
Br
O
SPh
MgBr2·OEt2, i-Pr2EtN
CH2Cl230 min
98%1.1 : 1 syn:anti
OH
Br
O
SPh
Aldol Addition of a-Halogenated Thioesters
X
O
OHR1
OH
useful intermediates in total synthesisenolate generation is a stepwise procedure
time-consumingrequire anhydrous conditions
low temperatures
Effect of Halogen Substituent
no appreciable difference
H
O
X
O
SPh
MgBr2·OEt, i-Pr2EtN
CH2Cl25 min
OH
X
O
SPh
Cl
O
SPh
Br
O
SPhI
O
SPh
syn:anticonversion
1.2 : 195
1.1 : 190
1.1 : 185
Control Experiments
H
O
X
O
SPhi-Pr2EtN
CH2Cl272 hr
OH
X
O
SPh
Cl
O
SPh
Br
O
SPh
trace product no productconfirms importance of MgBr2·OEt2
Diastereoselectivity of Aldol
S
O
ClS
O
ClS
O
ClMe
Me
i-Pr
i-Pr i-Pr
S
O
Cl t-Bu
t-Bu t-Bu
syn:anticonversion
1.2 : 198
2.5 : 197
5.2 : 197
4.5 : 190
lower ratio with more bulky thioester
H
O
Cl
O
SR
MgBr2·OEt2i-Pr2EtN
OH
Cl
O
SRCH2Cl2
OH
Cl
O
SR
Aldehyde Substrate Scope
R H
O
Cl
O
S
MgBr2·OEt2i-Pr2EtN
R
OH
Cl
O
SArCH2Cl2
R
OH
Cl
O
SAr
i-Pr
i-Pr
i-Pr
low yield; competing aldehyde self-addition
H
O
H
O
H
O
MeO
H
O
F3C
H
O
O
H
OMe
MeMe
H
O
H
O
H
O
Me
5.2 : 191%
4.0 : 196%
4.0 : 196%
3.7 : 197%
4.2 : 183%
3.2:176%
3.2 : 173%
3.4 : 129%
5.0 : 136%
Conclusions
mild and efficient MgBr2·OEt2-promoted direct aldol employing soft enolization
proceeds without competing Darzens addition
produces a-chloro-b-hydroxy thioesters is moderate-to-high yields and "moderate-to-good dr"
works with aldehydes with enolizable protons
R H
O
Cl
O
S
MgBr2·OEt2i-Pr2EtN
R
OH
Cl
O
SArCH2Cl2
i-Pr
i-Pr
i-Pr
