Combined C-H functionalization/cope rearrangement with vinyl ethers as a surrogate for the vinylogous Mukaiyama aldol reaction

Article abstract of DOI:10.1021/ja2051155

Vinyl ethers selectively undergo the combined C-H functionalization/Cope rearrangement reaction via an s-cis/boat transition state. With chiral dirhodium catalysts, products are generated in a highly diastereoselective and enantioselective fashion. This r

Full text of DOI:10.1021/ja2051155

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Combined CÀH Functionalization/Cope Rearrangement with
Vinyl Ethers as a Surrogate for the Vinylogous Mukaiyama
Aldol Reaction
Yajing Lian and Huw M. L. Davies*
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
S Supporting Information
b
Scheme 1. Carbenoid Approaches to Vinylogous Aldols
ABSTRACT: Vinyl ethers selectively undergo the com-
bined CÀH functionalization/Cope rearrangement reac-
tion via an s-cis/boat transition state. With chiral dirhodium
catalysts, products are generated in a highly diastereoselec-
tive and enantioselective fashion. This reaction can be
considered as a surrogate to the traditional vinylogous
Mukaiyama aldol reaction. Effective kinetic resolution has
been achieved, leading to the recovery of a cyclic vinyl ether
with axial chirality of high enantiomeric purity.
CÀsynHthfuetnicctisotrnaatleizgaietisonusheadsftohrempoatkeinngtianlattourrealvoplruotdiouncitzseatnhde
pharmaceutical targets.1 Rhodium-catalyzed carbenoid CÀH inser-
tion is one of the most effective methods for stereoselective CÀH
functionalization.2 Of particular interest is the possibility of using
the CÀH functionalization as a disconnection strategy that is
complementary to the conventional transformations used in or-
ganic synthesis.1 Intermolecular CÀH functionalization by means
of carbenoid-induced CÀH insertion has been shown to be
complementary to the aldol reaction,3 Mannich reaction,4 Claisen
condensation,5 Michael addition,6 and Claisen rearrangement.3a In
this paper, we describe how the combined CÀH functionalization/
Cope rearrangement (CHCR) reaction can be applied as a surro-
gate to the vinylogous Mukaiyama aldol reaction.
The vinylogous Mukaiyama aldol reaction has been widely
used in organic synthesis.7 It has the potential to generate highly
functionalized products containing two newly formed stereogenic
centers. In recent years, several protocols have been developed to
achieve this transformation in an enantioselective manner.8 Even
with these advances, controlling both the diastereoselectivity and
the enantioselectivity of the vinylogous Mukaiyama aldol reaction
is still a challenge. Recently, Panek9 reported a carbenoid approach
for generating the typical syn products of a vinylogous Mukaiyama
aldol reaction through a two-step sequence involving a rhodium-
catalyzed asymmetric SiÀH insertion between vinyldiazoace-
tates and silanes followed by a Lewis acid-catalyzed crotylation
(Scheme 1). The CÀH functionalization approach described
herein complements the Panek approach, leading to a highly
stereoselective method for the formation of the typical anti
products of the vinylogous Mukaiyama aldol reaction.
chair10aÀf or an s-cis/boat10g transition state to generate indepen-
dently the two possible diastereomers (eqs 1 and 2). Recent
computational studies revealed that the reaction proceeds through
a concerted but highly asynchronous hydride transfer/CÀC bond-
forming process, and there is a potential energy surface bifurcation
between the CHCR reaction and the competing direct CÀH
insertion reaction.11 As a result, controlling the reaction to select the
CHCR pathway over the direct CÀH insertion is challenging.
Only a few substrate systems to date favor a clean CHCR
reaction, and the majority of these are cyclohexadiene and
dihydronaphthalene derivatives.10aÀf Therefore, a major chal-
lenge in this field is to broaden the scope of substrates that
selectively undergo the CHCR reaction.
The new methodology arises from the CHCR reaction between
allylic CÀH bonds and vinyldiazoacetates.10 This reaction typically
generates products with two new stereocenters. With suitable
substrate design, the reaction can proceed through either an s-cis/
Received: June 2, 2011
Published: July 08, 2011
r
2011 American Chemical Society
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Scheme 2. Rationalization of Substrate Scope Design
Figure 1. Structures of Rh2(S-DOSP)4 and Rh2(S-PTAD)4.
substrates reacted through a similar transition state and trajectory
of approach.
We recently reported that disubstituted cyclopentenyl deriva-
tives smoothly undergo the CHCR reaction via a boat transition
state.10g Evaluation of the s-cis/boat transition state model11 led
us to the realization that acyclic trisubstituted vinyl ethers might
be ideal substrates for the CHCR reaction because steric repul-
sion with the catalyst “wall” would be avoided in an s-cis/boat
transition state (Scheme 2). If this were indeed the case, the
scope of the CHCR reaction would be greatly broadened because
vinyl ethers are readily accessible from the corresponding
ketones via the Wittig reaction.
In order to test the hypothesis presented above, the Rh2(S-
PTAD)4-catalyzed reaction of siloxyvinyldiazoacetate 1 with vinyl
ether 2 (eq 3) was examined. Rh2(S-PTAD)4 is known to be an
effective catalyst for the enantioselective reaction of siloxyvinyl-
diazoacetates such as 1, and when the reaction was conducted at
À20 °C with 1 mol % catalyst, followed by desilylation and
diazotization, diazoacetoacetate 3 was formed as a single diaster-
eomer in 91% overall yield with 94% ee over three steps. 1 is one
of the best vinylcarbenoid precursors with regard to favoring the
CHCR reaction over the direct CÀH insertion, but the 91% yield
of 3 is much higher than the yields obtained in the previous study
using cyclopentene substrates.10g
The CHCR reaction with acyclic ether 7 deserves further
comment. In previous studies, effective CHCR reactions were
limited to cyclic substrates, as otherwise, significant amounts of
products from the competing direct CÀH insertion were
obtained.14 Ether 7 represents a nice example of an effective
CHCR reaction occurring in an acyclic system. The geometry of
the newly formed trisubstituted double bonds in 21 is consistent
with the hypothesis that the reaction proceeds through an s-cis/
boat transition state (Scheme 3).11 The resulting geometry of the
enoate is characteristic of whether the reaction occurs on the s-cis
vinylcarbenoid [to form the (E)-enoate] or the s-trans vinylcar-
benoid [to form the (Z)-enoate].14 The anti diastereoselectivity is
indicative of a boat transition state,11 and the geometry of the
trisubstituted double bond is set through positioning of the
methyl group away from the rhodium“wall” in the transitionstate.
The reactions of donor/acceptor carbenoids are very sensitive
to steric and electronic effects,2b and this is also the case with the
CHCR reaction. These controlling influences were readily seen in
the reaction of 8 with an isomeric mixture of 22a and 22b (eq 4).
Each isomer has two possible allylic sites for CÀH functionaliza-
tion, yet product 23 was formed as the major product in 60% yield.
Yields of <10% for the other CHCR products were observed. The
methoxy group blocks attacks at the allylic site cis to it,2a which
means that the methyl site (H2) in 22a and the methylene site
(H4) in 22b are not prone to CÀH functionalization. The CHCR
reaction is initiated by a hydride transfer event.11 Thus, the
methylene site (H1) in 22a is more reactive than the primary
methyl group (H3) in 22b because the methylene site would be
better at stabilizing buildup of positive charge in the transition
state. Once again, the CÀH functionalization was highly stereo-
selective, as 23 was formed with >30:1 dr and 94% ee.
On the basis of the promising result with 1, we then focused on
whether this reaction could be applied to a range of vinyl ethers
and vinyldiazoacetates. Previous studies have shown that Rh2(S-
DOSP)4 (Figure 1) is the optimum chiral catalyst for asymmetric
reactions with trans-vinyldiazoacetates.12 The Rh2(S-DOSP)4-
catalyzed reaction of trans-styryldiazoacetate 8 with vinyl ether
2 generated the CHCR product 13 as a single diastereomer in
good yield with extremely high asymmetric induction (Table 1,
entry 1). This transformation was then successfully applied to a
variety of trans-vinyldiazoacetates and vinyl ethers, as sum-
marized in Table 1. In all cases, a single diastereomer of the
CHCR product was produced in good yield (67À89%) with
excellent enantioselectivity (in the majority cases greater than
98% ee). Traces of the direct CÀH insertion products were
observed in the crude reaction mixtures in some cases, but
the amounts were never more than 10% of the total amount of
CÀH functionalization products. The absolute configuration of
product 14 wasunambiguouslyassignedbyX-raycrystallography.13
The stereochemical outcome is consistent with the CHCR
reaction proceeding via a boat transition state. The stereochem-
ical configurations of the other CHCR products (13 and 15À21)
were tentatively assigned on the assumption that all of the
There have been a few reported examples of substrates capable
of undergoing two carbenoid reactions, resulting in the rapid
generation of synthetic complexity.15 We recognized that if the
CHCR reaction were to be initiated at a primary methyl site of a
vinyl ether such as 24, then the resulting 1,2-disubstituted alkene 25
would be sterically accessible for a subsequent cyclopropanation
(eq 5). Inorder to test this possibility, the Rh2(S-DOSP)4-catalyzed
reaction of ether 24 with an excess of trans-styryldiazoacetate 8 was
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Table 1. Substrate Scope in the Reaction of Vinyl Ethers with
Vinyldiazoacetates
Scheme 3. Transition State Analysis with an Acyclic
Substrate
Scheme 4. Proposed Transition State for the Kinetic
Resolution
a The diastereoselective ratio was >30:1 in all reactions.
ether 27a) (eq 6). The unreactive vinyl ether 27a was recovered
in 40% isolated yield with 98% ee. Thus, the Rh2(S-DOSP)4-
catalyzed reaction between 27a and 8 displays a very high level of
kinetic resolution. A similar kinetic resolution was achieved with
the methyl-substituted substrate 27b, but the stereoselectivity
was not as pronounced. The CHCR product 28b was produced
with 92% ee, and the recovered vinyl ether 27b was obtained with
60% ee. This kinetic resolution approach provides a convenient
way of making enantiopure cyclic vinyl ethers with axial chirality.
The asymmetric synthesis of this type of compound is typically
challenging, and the only successful previous approach required
the use of chiral Wittig reagents as stoichiometric reagents.18 The
absolute and relative configurations of products 28a and 28b
were unambiguously assigned by X-ray crystallography13 and
found to be consistent with the CHCR reaction proceeding
though an s-cis/boat transition state.11
examined. This resulted in the formation of product 26 containing
four newly formed contiguous stereocenters, two of which are
quaternary. 26 was formed in 53% yield as a single diastereomer
with 99% ee. The relative configuration of the cyclopropane in 26
was determined by nuclear Overhauser effect (NOE) analysis,
while the absolute configuration of 26 was tentatively assigned on
the basis of the expected s-cis/boat transition state model and the
predictive transition state model for the cyclopropanation.16 This
reaction indicated that both the CHCR and cyclopropanation
reactions occurred in a highly stereoselective fashion, as only one
diastereomer of the product was observed. The reaction represents
the first example of initiation of the CHCR reaction by attack at a
methyl CÀH bond.
A reasonable mechanism that would be consistent with the
kinetic resolution is shown in Scheme 4. The Rh2(S-DOSP)4 is
proposed to adopt a D2-symmetric structure, and the substrate
would approach only from the front face.12 The CHCR reaction
would proceed through a boat transition state as shown.11 The R
group in the substrate would need to point away from the
carbenoid to avoid steric interference. This controlling element
must be severe for 27a when R = phenyl, as only one enantiomer
Donor/acceptor carbenoids have been shown to be capa-
ble of kinetic resolution, desymmetrization, and enantiomer
differentiation.10a,b,g,17 To explore the possibility of kinetic
resolution in the CHCR reaction, the reaction between phenyl-
substituted substrate 27a and 0.6 equiv of diazo compound 8 in
the presence of Rh2(S-DOSP)4 was examined (eq 6). This
generated the CHCR product 28a as a single diastereomer with
99% ee in good isolated yield (94% based on one enantiomer of
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of the substrate reacts, leading to products with high stereo-
chemical control. When the R group is methyl, the steric
interference is not as dramatic, which would account for the
moderate kinetic resolution with 27b.
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In conclusion, vinyl ethers have been demonstrated to be
excellent substrates for the CHCR reaction. The reaction pro-
ceeds through an s-cis/boat transition state, leading to the
formation of products having defined stereochemistry that might
typically be approached by the vinylogous Mukaiyama aldol
reaction. These studies demonstrate that asymmetric CÀH
functionalization by the CHCR reaction can compete with a
classic strategic reaction for organic synthesis. Furthermore, the
studies underscore the subtle steric and electronic influences that
allow the CHCR reaction to be highly regio-, diastereo-, and
enantioselective.
’ ASSOCIATED CONTENT
S
Supporting Information. Full experimental data for the
b
compounds described in the paper and X-ray crystallographic
data (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(11) Hansen, J. H.; Gregg, T. M.; Ovalles, S. R.; Lian, Y.; Autschnach,
J.; Davies, H. M. L. J. Am. Chem. Soc. 2011, 133, 5076.
’ AUTHOR INFORMATION
(12) Hansen, J. H.; Davies, H. M. L. Coord. Chem. Rev. 2008, 252,
545.
(13) The crystal structures of 14, 28a, and 28b have been deposited
at the Cambridge Crystallographic Data Centre, and the deposition
numbers CCDC 827302, 827300, and 827301 have been allocated
correspondingly.
Corresponding Author
hmdavie@emory.edu
’ ACKNOWLEDGMENT
This research was supported by the National Science Founda-
tion under the Center for Chemical Innovation in Stereoselective
CÀH Functionalization (CHE-0943980) and by the National
Institutes of Health (GM080337). We thank Dr. Ken Hardcastle
for the X-ray crystallographic structure determination.
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