Magnesium bromide diethyl etherate mediated highly diastereoselective aldol reaction between an aldehyde and a silyl enol ether

Article abstract of DOI:10.1246/cl.2001.190

High yield and excellent diastereoselectivity in the formation of methyl (2R,3R,5R,6S)-2,6-dibenzyloxy-7-(t-butyldimethylsiloxy)-3-hydroxy-5-(4-methoxybe nzyloxy)-4,4-dimethylheptanoate 3 and methyl (2R,3R,4S)-2,4-dibenzyloxy-3-hydroxypentanoate 7 are achieved by aldol reaction between (Z)-2-benzyloxy-1-methoxy-1-(trimethylsiloxy)ethene 1 and chiral alkoxy aldehydes using three equivalents of MgBr₂·OEt₂. The following mechanism of the above aldol reaction proposes that MgBr₂·OEt₂ activated both chiral alkoxy aldehydes and silyl enolate, that is, magnesiumu enolate, formed by transmetalation from silyl enolate and MgBr₂·OEt₂, reacted with MgBr₂·OEt₂-chelated alkoxy aldehydes via the six-membered cyclic transition state.

Full text of DOI:10.1246/cl.2001.190

190
Chemistry Letters 2001
Magnesium Bromide Diethyl Etherate Mediated Highly Diastereoselective Aldol Reaction
between an Aldehyde and a Silyl Enol Ether
Hidehiko Fujisawa, Yasuhiro Sasaki, and Teruaki Mukaiyama*
Department of Applied Chemistry, Faculty of Science, Science University of Tokyo, Kagurazaka, Shinjyukuku,Tokyo 162-8601
(Received November 22, 2000; CL-001062)
High yield and excellent diastereoselectivity in the formation
of methyl (2R,3R,5R,6S)-2,6-dibenzyloxy-7-(t-butyldimethyl-
siloxy)-3-hydroxy-5-(4-methoxybenzyloxy)-4,4-dimethylhep-
tanoate 3 and methyl (2R,3R,4S)-2,4-dibenzyloxy-3-hydroxypen-
tanoate 7 are achieved by aldol reaction between (Z)-2-benzy-
loxy-1-methoxy-1-(trimethylsiloxy)ethene 1 and chiral alkoxy
aldehydes using three equivalents of MgBr2·OEt2. The following
mechanism of the above aldol reaction proposes that MgBr2·OEt2
activated both chiral alkoxy aldehydes and silyl enolate, that is,
magnesiumu enolate, formed by transmetalation from silyl eno-
late and MgBr2·OEt2, reacted with MgBr2·OEt2-chelated alkoxy
aldehydes via the six-membered cyclic transition state.
Stereoselective synthesis of chiral polyhydroxylated acyclic
compounds is one of the important topics in modern organic syn-
thesis. Aldol reactions between carbonyl compounds and several
silyl enolates bearing a protected hydroxy group at α-position are
useful tools for the synthesis of diol units with two carbon exten-
sion.1 Based on this method, stereoselective aldol reaction
between 1, derived from methyl 2-benzyloxyacetate, and optical-
ly active trialkoxy aldehyde 2 was employed as a key step in
preparing chiral polyoxy ester 3,2 in our synthesis of the B ring
system of Taxol which possessed a 2,3,5,6-anti,anti,anti rela-
tive configuration. It was reported briefly from our Laboratory
that 3 was obtained in high yield with excellent diastereoselec-
tivity by the MgBr2·OEt2-mediated aldol reaction. Here, we
would like to describe a characteristic feature of MgBr2·OEt2-
mediated aldol reaction between chiral alkoxy aldehydes and α-
alkoxy silyl ketene acetals.
While working on the above mentioned aldol reactions
between 1 and 2, it was found that the desired aldol adduct 3 was
obtained in poor yields when typical Lewis acids such as TiCl4 or
SnCl4 were used. It was supposed that these results were attrib-
uted to the strong coordinations of Lewis acids to the aldehydes
bearing oxygenated functional groups to deactive the Lewis
acids. At the same time, silyl enolates bearing benzyloxy group
at α-position decreased their nucleophilic ability in comparision
with the reactivity of the enolates not bearing benzyloxy group.
After screening various Lewis acids, it was interestingly found
that the desired diastereomer was selectively formed by using
MgBr2·OEt2. Of the four possible diastereomeric aldol products,
only two diastereomers 3 and 4 were obtained under the present
reaction conditions while the other two diastereomers 2,3-
anti,3,5-syn,5,6-anti and 2,3,5-syn,syn,5,6-anti isomers were not
detected. Formation of diastereomers 3 and 4 is explained by
considering a selective attack of enolate 1 from si face of alde-
hyde 2, that is, the coordination of aldehyde 2 to MgBr2·OEt2
caused to inhibit re face attack of the enolate, and thus the 3,5-
anti isomer is expected to form selectively.
result (97%, 3:4=41:1) was obtained when reactions were car-
ried out at –19 °C using MgBr2·OEt2 whose amount exceeded
the combined quantity of aldehyde plus silyl enolate3 (Table 1,
entry 2). The high reactivity and selectivity in the present
experiment suggested that MgBr2·OEt2 activated not only alde-
hyde as a Lewis acid but also the silyl enolate forming the cor-
responding magnesium enolate by metal exchange under the
reaction conditions. Although several metal salts such as TiCl4,
and Bu2BOTf were already known to be able to form the corre-
sponding metal enolates by metal exchange with silyl enolate,4
this type of transmetalation with magnesium salts has not been
reported to the best of our knowledge.5
In order to examine the above mentioned transmetalation,
silyl enolate 1 was treated with MgBr2·OEt2 in toluene-d8 at
room temperature and the formation of trimethylsilyl bromide
1
was observed by H NMR measurement.6 This indicated that
the magnesium enolate was formed readily and it behaved as a
nucleophile in the formation of aldols.
Further, there are two factors to achieve the excellent
diastereoselectivity: that is, a) formyl face selectivity by the
chelation control of MgBr2·OEt2,7 and b) stereoselectivity via
the six membered cyclic transition state8 involving magnesium
enolate. It was assumed that the high diastereoselectivity in the
present aldol reaction using MgBr2·OEt2 would be performed by
the concurrent effect of a) and b). By this combined effect, aldol
reaction using MgBr2·OEt2 was expected to afford the aldols in
higher yields and diastereoselectivity compared with the cases
obtained by using conventional Lewis acids or metal enolates.
To verify the above assumption, the double facial diastereo-
selectivity in the MgBr2·OEt2-mediated aldol reaction of chiral
O-benzyl lactaldehyde 5 was examined and compared to the
results with that of the reactions using other Lewis acids and
silyl or other metal enolates.9 Then, it was found that high yield
and excellent diastereoselectivity were achieved only when
After carefull optimization of reaction conditions, the best
Copyright © 2001 The Chemical Society of Japan

Chemistry Letters 2001
191
whereas the intermediates C1 and C2 are the models organized
by the concurrent effects of a) and b). When MgBr2·OEt2
worked only as a Lewis acid, it was not possible to differentiate
the two transition states L1 and L2 which resulted in the forma-
tion of a mixture of two diastereo isomers 6 and 7. That is, the
reaction would have proceeded in parallel via L1 and L2, and
the mixture of diastereomers 6 and 7 was formed without per-
fect preference. With respect to the C1 and C2, the latter
should be dominant to C1 because of the steric hindrance of C1;
thus, the diastereomer 7 should be obtained via C2. The result
shown in Table 2 shows the ratio of the products 7 and 6 goes
up to 98:1 indicating that the aldol reaction would procced via
the transition state C2.
Magnesium halides mediated aldol reactions were reported
by some groups7 using the magnesium salts simply as Lewis
acids. Among those reported examples, Corey et al. recently
reported on the magnesium iodide mediated aldol reaction with
interesting double-face selectivity in the total synthesis of lacta-
cystin.12 It is noted that, the results described here suggest a
novel and efficient highly diastereoselective aldol reactions
which are promoted by the double activation of aldehyde and
silyl ethers with MgBr2·OEt2
This work was supported by Grant-in-aid for Scientific
Research the Ministry of Education, Science, Sports and Culture.
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