Metal carbene-promoted sequential transformations for the enantioselective synthesis of highly functionalized cycloheptadienes

Article abstract of DOI:10.1021/ja045173t

A two-step, three-component coupling of an alkyne, enol ether, and vinyl diazoester was accomplished by use of successive metal carbene-catalyzed transformations. This efficient approach to cycloheptadienes is both diastereo- and enantioselective. Kinetic

Full text of DOI:10.1021/ja045173t

Published on Web 01/14/2005
Metal Carbene-Promoted Sequential Transformations for the Enantioselective
Synthesis of Highly Functionalized Cycloheptadienes
Liang Deng, Anthony J. Giessert, Oksana O. Gerlitz, Xing Dai, Steven T. Diver,* and
Huw M. L. Davies*
Department of Chemistry, UniVersity at Buffalo, the State UniVersity of New York, Buffalo, New York 14260-3000
Received August 10, 2004; E-mail: hdavies@buffalo.edu
The development of sequential organometallic transformations1
offers exciting opportunities for the rapid access to structurally com-
plex targets. Ring synthesis through modular, complexity-building
reactions in a catalytic and stereocontrolled manner is a tremendous
challenge. In this communication, we describe a two-step, three-
component coupling strategy between alkynes, vinyl ethers, and
vinyldiazoacetates for the enantioselective synthesis of highly
functionalized cycloheptadienes (eq 1).
by Rh2(S-DOSP)4 (1 mol %) gave a promising result. A single
cyclopropane 3 was formed in 71% yield, >94% de, and 95% ee.
Thus, the rhodium carbenoid selectively reacted with (E)-1 instead
of (Z)-1 even though the cyclopropanation was occurring at the
other double bond of the diene.
After having determined that a chemoselective and stereoselective
cyclopropanation was possible, the reaction of diene 1 with the
vinyldiazoacetate 5 was examined (eq 3). The Rh2(S-DOSP)4-
catalyzed reaction was very efficient, but the product now was the
cycloheptadiene 6A, which was formed in 75% yield, 90% de, and
92% ee. This suggests that the vinylcarbenoid did not fully
distinguish between dienes (Z)-1 and (E)-1 in the initial cyclopro-
panation step, because the cycloheptadiene diastereomer formed is
controlled by the alkene geometry.5 The Rh2(S-DOSP)4 reaction
of 5 was also applied to the benzoyl derivative 4 (eq 3). Again, a
stereoselective reaction was obtained, forming 6B in 69% yield,
82% de, and 87% ee.
Scheme 1. Two-Step Synthesis of Cycloheptadienes
The three-component coupling of eq 1 involves two powerful
metal carbene-promoted couplings, applied together in a two-step
sequence. The first step is based on the enyne metathesis2 between
various alkynes and vinyl ethers to form 3-substituted-1-alkoxy-
1,3-dienes A, developed by the Diver group (Scheme 1).3 The
reaction uses the second generation Grubbs’ carbene complex (Ru
gen-2),4 tolerates a variety of heteroatom functionality on the alkyne,
and provides a simple and rapid synthesis of electron-rich 1,3-dienes
A. The second step of the sequence is the (Rh2(S-DOSP)4)-catalyzed
[4 + 3] cycloaddition between vinyldiazoacetates B and dienes A
to from cycloheptadienes, developed by the Davies group.5 By
combining the strengths of these two reactions, a stereoselective
synthesis of cycloheptadienes is possible. The products can also
be obtained in high enantiomeric purity even when starting with
racemic alkynes and isomeric mixtures of dienes.
The combined transformation would be even more powerful if
it was possible to achieve kinetic resolution in addition to the alkene
geometry discrimination. To explore this possibility, the reaction
of 7 with 5 was next examined. It was anticipated that double
diastereodifferentiation might be observed since the diene and
catalyst each possess facial bias. The matched reaction catalyzed
by Rh2(R-DOSP)4 resulted in the formation of 9 in 65% yield >94%
de (right side, Scheme 2). In contrast, the mismatched reaction with
Rh2(S-DOSP)4 was very ineffective, resulting in the formation of
an undetermined 2:1 mixture of diastereomers 8 in 19% yield.
Scheme 2. Double Diastereodifferentiation
For the two step, three-component coupling to be successful,
the rhodium vinylcarbenoid must undergo selective reactions to
distinguish between the mixture of dienes derived from the enyne
metathesis. Donor/acceptor substituted carbenoids are capable of
chemoselective reactions and are highly discriminating as compared
to the conventional carbenoids lacking a donor group.6 The reaction
of 1 with methyl p-bromophenyldiazoacetate (2) was used to begin
exploring the chemoselectivity issues (eq 2). The reaction catalyzed
The above results indicate that the [4 + 3] cycloaddition could
lead to effective kinetic resolution of the racemic dienes (Table 1).
This led to the formation of cycloheptadienes ent-9, 10, and 11 in
40-64% isolated yield with high enantioselection (85-99% ee),
although the diastereoselectivity was considerably lower (50-82%
de).
9
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J. AM. CHEM. SOC. 2005, 127, 1342-1343
10.1021/ja045173t CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Kinetic Resolution with Chiral Rh2(S-DOSP)4 Catalyst
R1
R2
product
yield, %
de, %
ee, %
Ac
Bz
Ac
Ph
Ph
ent-9
10
11
64
40
54
50
82
50
99
95
85
CHdCHPh
Figure 1. Model for stereoselectivity
would also be expected to have a significant effect on face
selectivity in the cyclopropanation (see D).8 Assuming that attack
over the phenyl group is disfavored both for the (S)-substrate and
for the (R)-catalyst, then selective cyclopropanation of the re face
will occur, leading to a strongly matched reaction. Once the
divinylcyclopropane C has been formed in a stereoselective manner,
the cycloheptadiene 9 will inevitably be formed stereoselectively
because the Cope rearrangement of divinylcyclopropanes proceeds
through a well-defined boat transition state.
The selectivity of the reaction of E-vinyl ether is so pronounced
that under appropriate conditions it is possible to recover cleanly the
Z-diene. As can be seen in the reaction of 7 with 5 (1.5 equiv), com-
plete consumption of (E)-7 can be achieved through cyclopropana-
tion-Cope rearrangement, leaving (Z)-7 which was recovered in
40% yield (eq 5).
These studies demonstrate that a highly stereoselective three-com-
ponent ring synthesis can be accomplished by conjoining two pow-
erful metal carbene-mediated transformations. Furthermore, the high-
ly discriminating Rh2(DOSP)4 catalyst selects diene topology and
can differentiate propargylic stereochemistry in an effective kinetic
resolution. By applying these reactions in sequence, highly stereo-
selective synthesis of complex cycloheptadienes can be achieved.
To determine the absolute stereochemistry of these reactions,
the Rh2(R-DOSP)4-catalyzed reaction of 7 with 2 was examined (eq
6). This resulted in the formation of the cyclopropane 12 in 58%
yield, >94% de, and 92% ee. In this case, the presence of the aryl
group serves two purposes. First, it precludes Cope rearrangement,
permitting assignment of facial selectivity in the cyclopropanation
step. Second, the presence of the heavy atom allows the assignment
of absolute stereochemistry by crystal structure determination.
Recrystallization of 12 enriched the material to >99% ee whose
X-ray crystal structure revealed that it was the drawn stereoisomer
12. The assigned stereochemistry of the cycloheptadienes is based
on the well-precedented analogous enantioinduction for the cyclo-
propanation with vinyldiazoacetates,7 followed by a divinylcyclo-
propane rearrangement occurring through a boat transition state.5
Acknowledgment. This work was supported by the National
Science Foundation (CHE-0350536 for H.M.L.D. and CHE-
0092434 for S.T.D). We thank Dr. Philip Coppens for the use of
his X-ray crystallography equipment.
Supporting Information Available: Full experimental data for the
compounds described in this paper, 1H and 13C spectra of selected
compounds, and X-ray crystallographic data for 12. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
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The chemoselectivity of the carbenoid transformations can be
rationalized as illustrated in Figure 1. The diene E-7 is more reactive
that the Z-isomer, and this is more pronounced as the size of the
3-substituent increases. With large 3-substituents, the E-diene would
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