Transcript INTRODUCTION - University of Arizona

INTRODUCTION
In the past, a few d-oxygenated a,b-unsaturated
compounds have been selected as substrates for
research in the filed of Michael addition. One of
the most studied substrates are derived from
glyceraldehyde acetonide (Figure 1).
O
O
O
O
O
RO
O
Figure 1. Examples of substrates with d-oxygen used for Michael addition
PROBLEM
Unfortunately, the electron donating
oxygen makes the b-carbon
electrophilic (Figure 2).
This
molecules as poor substrates for
addition.
nature of dmuch less
makes these
the Michael
OR'
OR'
RO
R
O
RO
R
O
Figure 2. d-Oxygenated a,b-unsaturated substrate with a less electrophilic
b-carbon.
SOLUTIONS
A number of modified conditions have been studied
in the past in order to make some of these poor
substrates, such as d-oxygenated a,b-unsaturated
ketone, work for the Michael additions (Figure 3).
O
O
O
O
Conditions
R2CuLi
R2CuCNLi2
RCu
RCu/TMSCl
RCu/BF3.OEt2
RLi*
O
O
R
OR
OR
Ph
O
R'MgBr/CuBr.Me2S
TMSCl/HMPA
Ph
O
R'
Figure 3. Conditions for poor substrates in Michael addition
*PhLi gives 1,2-product as the major product.
However, with d-oxygenated a,b-unsaturated ester
as the substrates, only limited conditions had been
applied successfully (Figure 4).
O
O
O
RO
O
R'Li
O
RO
O
R'
Figure 4. Modified conditions for Michael Addition with certain substrates.
Unfortunately, when phenyl lithium (PhLi) was used,
NO conjugated product was obtained.
GOALS
Our goal is to find which condition(s) can be applied
to the Michael addition with d-oxygenated a,bunsaturated esters as the substrates.
O
O
O
RO
O
?
O
RO
O
R
RESULTS I
O
O
O Conditions
MeO
O
O
O
MeO
O
O
+ MeO
Ph
O
Ph
Table 1. Michael addition from PhMgBr
Grignard Reagent
PhMgBr
PhMgBr
PhMgBr
PhMgBr
PhMgBr
PhMgBr
PhMgBr
PhMgBr
PhMgBr
PhMgBr
PhMgBr
Additives
CuI
CuI/TMSCl
CuBr.Me2S/Me2S
CuBr.Me2S/Me2S
TMSCl
TMEDA
CuBr.Me2S/Me2S/TMSCl
CuCN/TMSCl
CuCN/TMEDA
CuBr.Me2S/Me2S/TMSCl/LiBr
TMEDA/TMSCl
Temperature (oC)
-78
-78
-78 or -100
-23
-78
-78
-78
-23 to RT
-78
-78
-78
d.e. (%)
73.7
78.3 (84.8)
`
91.6 (>95)
Yield (%)
0
0
0
0
0
0
100
100 (80)
0
80 (73.7)
0
UNEXPECTED RESULTS
COOMe
O
CuBr.Me2S
TMSCl
LiBr
o
-78 C
O
O
O
Ph
O
Ph
O
O PhMgBr
MeO
O
O
Ph
O
LiBr
o
-40 C to RT
O
RESULTS II
O
O
O Conditions
MeO
O
O
O
MeO
O
O
+ MeO
Ph
O
Ph
Table 1. Michael addition from PhLi
Grignard Reagent
PhLi
PhLi
Additives
CuCN
LiBr
Temperature (oC)
-78
-78
d.e. (%)
69.81
19.85
Yield (%)
1.08
8.3
STEREOSELECTIVITY OF
MAJOR PRODUCT
O
O
O
RO
HCl/MeOH
O H
OH
O
Ph
H Ph
J = 12.81 Hz
MECHANISM
RCu
OH
RCu OMe
OMe
O
H H
H
O
H
H
O
O
O
OMe
R
H
H
O
O
H
O
DISCUSSIONS
• PhMgBr INSTEAD PhLi undergoes Michael
Addition
• CuBr.Me2S/Me2S or CuCN as an additive required
• TMSCl is a MUST for this Michael Addition
• TMEDA offered NO assistance at all
• LiBr is NOT necessary for Michael Addition. But
it IMPROVED distereoselectivity
• HMPA, used in other substrates as reported, is
NOT required
ACKNOWLEDGEMENTS
Dr. Victor J.Hruby
Dr. Jon Rainier
NIH and USPHS
SELECTED REFERENCES
• Taylor, R. J. K., Ed. Organocopper Reagents - A Practical Approach, Oxford
University Press, 1994, 362pp.
• Raczko, J. Stereoselective 1,4-addition of Grignard reagents to chiral g-alkoxy-a,bunsaturated ketones, Tetrahedron: Asymmetry, 1997, 8(22), pp3821-3828.
• Leonard, J., Mohialdin, S., Reed, D., Ryan, G and Swain, P. A., Stereoselective
conjugate addition of organolithium and organocopper reagents to d-oxygenated
a,b-unsaturated carbonyl systems derived from glyceraldehyde acetonide,
Tetrahedron, 1995, 51(47), p12843-12858.
• Costa, J. S., Dias, A. G., Anholeto, A. L., Monteiro, M. D.Patrocinio, V. L., and
Costa, R. R., Syn-selective Michael addition of nitromethane derivatives to enolates
derived from (R)-glyceraldehyde acetonide, J. Org. Chem., 1997, 62, pp4002-4006.
• Yechezkel, T., Ghera, E., Ramesh, N. G., and Hassner A., Asymmetric synthesis of
substituted cyclopentanes via Michael initiated ring closure reactions, Tetrahedron:
Asymmtry, 1996, 7(8), pp2423-2436.