Denmark's Base Catalyzed Aldol/Allylation

40 Pages·2003·0.11 MB·English

by  Dave Evans

Denmark’s Base Catalyzed Aldol/Allylation
Evans’ Group Seminar
November 21th, 2003
Jimmy Wu
Lead References:
Denmark, S. E. Acc. Chem. Res., 2000, 33, 432
Denmark, S. E. Chem. Comm. 2003, 167
Denmark, S. E. Chem. Rev. 2003, 103, 2763
Denmark, S. E. JOC, 1998, 63, 9517
Background
O OH
OM O
+
Me
X R
Xc H R c
Me
• Requires stoichiometric amounts of covalently bound auxiliaries
O OH
O MLn*
OTMS
+ R1O R
Me
R1O H R Me
• Ligand is often deactivating
• Diastereoselectivity can be high but are often variable
S O OH
S O MLn*
O
Me + S N R
Base
S N
H R Me
• Number of literature examples is still limited.
Lewis Base Activated Aldol
OM O
O OH
H R
R
G* (Activating Group)
G* G*
OM OM O
H R
Must react via a closed
Must be more reactive
than non-bound substrate T.S. to obtain good
selectivities
General Reaction Overview
Me
Ph
N
O
P
N
N
Ph
O OH
SiCl
3 O Me
O
+
R R1
Me H R1
R
Me
• E enolsilane ---> anti product
• Highly diastereoselective (up to 99:1 anti/syn)
• Highly enantioselective (up to 98% ee)
• Z enolsilane ---> syn product
• Highly diasteroselective (up to 18:1 syn/anti)
• Highly enantioselective (up to 98% ee)
How It All Started
Si
O O OH
t-Bu
RCHO
X X R
Me Me
• Wanted to exploit the concept of “strain-release Lewis acidity”
< 109.5o
L Nu- L
Si Si
L
L Nu
tetrahedral trigonal bipyramid
Literature Examples
F3C CF3 F3C CF3
O O
Nu Et N
M 4 M Nu
O O
F3C CF3 F3C CF3
M = Si and Ge
Ligand C-O(Ge) –2.6o
• Germanium compound is able to catalyze the ene reaction
while silicon is not.
Martin, J. C. JOC, 1981, 46, 1049
Denmark, S. E. Organometallics, 1990, 9, 3015
Strain-Release Catalyzed Aldol
Si O OH O OH
1. RCHO, CHCl , RT
t-Bu O 3
+
MeO R MeO R
Me
2. HF/THF
MeO
Me Me
entry R E/Z yield syn/anti
1 Ph 0/100 80 42/58
2 Ph 95/5 94 95/5
3 cinnamyl 89/11 95 93/7
4 n-pentyl 89/11 91 93/7
5 cyclohexyl 89/11 85 >99/1
• Also worked for thiosilylketene acetals but both E and Z gave syn
selectivity.
• Amide derived enolsilanes were unselective.
Denmark, S. E. JACS, 1994, 116, 7026
Mechanistic Studies
Si Si Si
H C O O O O O
3 CH CD
3 3
Me
H C H CO R H CO R
3 3 3
Me Me
Me Me Me
PhCHO
Si Si
Si
O O O O
D C O CD CH
3 3 3
Me
D CO R D C R
D C 3 3
3
Me Me Me Me
Me
• Must go through a trigonal bipyramidal T.S. with internal transfer of
silicon
• Analagous studies with KOt-Bu as a catalyst revealed complete
deuterium scrambling. Cannot go through an octahedreal T.S.
Denmark, S. E. JACS, 1994, 116, 7026
T.S. Models
t-Bu
H
Si
O
Ph
O
syn diastereomer
Me
OMe
• Closed boat-like T.S.
• Pentacoordinate silicon
•Evans proposes similar T.S. in Zr based aldol (Evans, D. A. TL, 1980, 21,
3975.
2nd Generation of LB Catalyzed Aldol
OSiCl O OH
3
chiral LB
Ph Ph R
RCHO
Me Me
• Trichlorosilane required for sufficient Lewis acidity
• Silicon can expand valency by 2
• Simultaneous activation of Nu- and El+ via closed T.S.
• Facial selectivity comes from chiral base