N-heterocyclic carbene catalyzed C-C bond cleavage in redox esterifications of chiral formylcyclopropanes

Article abstract of DOI:10.1002/anie.200601919

(Chemical Equation Presented) A clean break: An N-heterocyclic carbene catalyzes the ring-opening of chiral non-racemic formylcyclopropanes, with simultaneous oxidation of the aldehyde function and without the need for stoichiometric reagents. The activated carboxylate intermediate is trapped by a variety of nucleophiles, thus leading to chiral esters, thioesters, or carboxylic acids (see scheme; DBU = 1,8-diazabicyclo-[5.4.0]undec-7-ene, EWG = electron-withdrawing group, Nu = nucleophile.)

Full text of DOI:10.1002/anie.200601919

Angewandte
Chemie
Organocatalysis
organocatalyst, thus leading to esters and thioesters via the
intermediacy of catalytically generated activated carboxylates
[Eq. (1); DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, elec-
tron-withdrawing group (EWG) = ketone, ester, amide, or
nitro].
DOI: 10.1002/anie.200601919
À
N-Heterocyclic Carbene Catalyzed C C Bond
Cleavage in Redox Esterifications of Chiral
Formylcyclopropanes**
Stephanie S. Sohn and Jeffrey W. Bode*
Dedicated to Professor Michael P. Doyle
Ring-opening reactions of small, strained molecules translate
the high degree of stereoselectivity inherent in the synthesis
of diverse cyclic structures into the establishment of absolute
stereochemistry in acyclic systems.[1] A disadvantage of many
ring-opening processes, which are formally reduction reac-
tions, is the necessity of stoichiometric reagents that are often
expensive or toxic metals. To address this limitation, we
recently developed an organocatalytic redox opening of a,b-
epoxyaldehydes with concomitant oxidation of the aldehyde
and subsequent esterification.[2,3] This efficient process trans-
forms widely available, enantioenriched epoxides into a
variety of value-added products, including anti-propionate
aldol adducts under mild, practical conditions.
At the onset of our studies, it was unclear if the stabilized
acyl anion equivalents expected to be formed by addition of
an NHC catalyst to a formylcyclopropane would lead to ring-
opening reactions in preference to benzoin dimerizations,[8]
especially under the protic conditions mandated by redox
esterification processes. We selected readily prepared, enan-
tiomerically enriched formylcyclopropane 1 as a model
substrate for reaction development. Initial efforts confirmed
our trepidation that simple thiazolium- and triazolium-
derived NHCs would prove inefficient or prefer competing
pathways (Scheme 1). However, we were pleased to find that
our mesityl-substituted triazolium salt 7,[3b] which deters
In seeking to extend the concept of catalytic cyclic-to-
acyclic stereochemical translation of readily prepared, enan-
tiopure starting materials, we were attracted to the recent
advances made by Kunz and MacMillan on the direct, highly
enantioselective synthesis of formylcyclopropanes with the
commercially available organocatalyst (2S)-indoline-2-car-
boxylic acid.[4] We reasoned that an efficient method for
redox esterifications that involves opening the cyclopropane
unit would result in a concise approach to enantioenriched b-
substituted carboxylic acid derivatives, an attractive class of
chiral building blocks with few methods for their general,
asymmetric preparation.[5] To achieve this transformation,
however, we required the cleavage of a carbon–-carbon bond
lacking heteroatom functionalities,[6] a process that normally
requires strong reducing agents and vigorous conditions even
in highly strained systems.[7] We now report the successful
Scheme 1. The influence of NHC precatalysts on catalytic redoxesterifications of
formylcyclopropane 1. The starting aldehyde was recovered in reactions with lower
conversion. Mes=2,4,6-trimethylphenyl.
À
development of C C-bond-cleaving ring-openings of formyl-
cyclopropanes mediated by an N-heterocyclic carbene (NHC)
nucleophilic reactions of the catalytically generated acyl
anion equivalent, serves as a highly active precatalyst for ring-
opening esterifications of formylcyclopropanes in excellent
yield. A screen of solvents, bases, reaction temperatures, and
catalyst loadings revealed the optimal conditions. Weaker
bases (NEt3, Hünigꢀs base) proved less efficient at ambient
temperature but worked well at 608C. We selected THFas the
optimal solvent, but comparable conversions and rates were
observed in EtOAc, CH2Cl2, and toluene. Careful studies
using GC and HPLC with chiral columns confirmed the
preservation of the stereochemistry at the b-position.
NHC-catalyzed ring-opening reactions of trisubstituted
formylcyclopropanes proceeded with a wide range of sub-
stitution patterns in the presence of 5 mol% 7 and 20 mol%
DBU (Table 1). The necessary substrates were available in a
single, convenient step from the corresponding sulfur ylides,
[*] S. S. Sohn, Prof. Dr. J. W. Bode
Department of Chemistry and Biochemistry
University of California
Santa Barbara, CA (USA)
Fax: ( +1)805-893-4120
E-mail: bode@chem.ucsb.edu
Homepage: http://www.chem.ucsb.edu/~bodegroup/
[**] This study was supported by the National Science Foundation
(CHE-0449587) and the California Cancer Research Coordinating
Committee. J.W.B. is grateful to Amgen and Richard and Leslie
Anderson for additional support. We are grateful to Sean Riznikove,
John Unger, and Bruce Lipshutz (UCSB) for assistance with the
chiral GC analyses.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: NHC-catalyzed redoxesterifications of chiral, enantiomerically enriched formylcyclopropanes. [a]
Entry
1
RCHO
NuH
Product
T [8C]
ee [%]
Yield [%][b]
90
MeOH
23
89[c]
89[d]
93[c]
90[d]
83[c]
77[d,e]
83[c]
81[d]
93[c,e]
2
MeOH
MeOH
MeOH
40
40
40
87
84
96
3[d]
4
5
6
MeOH
40
23
95
99
C12H25SH
88[c]
88[d]
88[c]
87[d]
7[f]
H2O
23
92
[a] Unless otherwise indicated, all reactions were performed on a 0.2–0.8-mmol scale at 0.5m in THF with 5 mol% 7 and 20 mol% DBU for 15 h.
[b] Yields of the isolated products following chromatography. [c] The ee values were assessed by chiral GC or HPLC analysis of the major diastereomer
of the starting cyclopropane. [d] The ee values were assessed by chiral HPLC or GC analysis of the product ester. [e] Minor cyclopropane diastereomer
(ꢀ10%) was present in the starting aldehyde. [f] DBU=1.2 equiv.
unsaturated aldehydes, and a commercially available amino
acid catalyst, thus rendering the two-step MacMillan cyclo-
propanation/redox ring-opening reaction a highly efficient
method for the preparation of acyclic, enantiomerically
enriched b-substituted carboxylic acid derivatives. Impor-
tantly, this strategy is amenable to a full range of substituent
types, including aromatic, aliphatic, and unsaturated moieties.
Although we have focused on alcohol nucleophiles, thiols also
proved to be highly reactive, thus leading to synthetically
useful thioesters poised for further transformation (Table 1,
entry 6).[9] Water, in conjunction with 1.2 equivalents of DBU,
made possible the direct preparation of the corresponding
acid (Table 1, entry 7). At the present stage of development,
attempts to use primary or secondary amine nucleophiles led
to complex reaction mixtures.
The NHC-catalyzed ring-opening reaction leads to the
formation of enolate 9.[13] Under our present conditions, this
species is most likely quenched by rapid proton transfer to
lead to a more stabilized, catalyst-bound enolate 10 (or its
corresponding enol), which undergoes protonation and tau-
tomerization to form acyl triazolium activated carboxylate 11
(Scheme 2). A reaction performed with five equivalents of
MeOD resulted in the quantitative incorporation of a single
deuterium atom, as a mixture of diastereomers, adjacent to
the ketone moiety. Quenching the reaction at partial con-
version leads to the recovery of the starting aldehyde
deuterated at the acyl carbon atom, thus demonstrating that
the NHC catalyst can react reversibly with the formylcyclo-
propane. These observations would be consistent with a
hydride-shift mechanism; however, an experiment in which
an enantioenriched substrate gave a racemic product cur-
rently disfavors this pathway, at least for the substitution
pattern examined.[14]
We prepared a range of formylcyclopropanes bearing
electron-deficient functional groups to probe the require-
ments for an electron sink in the cyclopropane substrates
(Table 2). These findings suggest a wide scope for interfacing
this process with emerging methods for the catalytic, enan-
tioselective synthesis of chiral formylcyclopropanes.[10–12]
In summary, we have described the first NHC-organo-
À
catalyzed C C bond-cleavage reaction that is useful for the
synthesis of enantiomerically enriched esters and thioesters
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Table 2: Further scope of NHC-catalyzed redoxesterifications of formylcyclopropanes. [a]
Keywords: esterifications ·
N-heterocyclic carbenes ·
organocatalysis · ring-opening ·
synthetic methods
.
Entry
RCHO
NuH
Product
T [8C]
Yield[b] [%]
81
1
C12H25SH
40
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MeOH
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C12H25SH
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23
23
23
23
60
95
98
90
95
–
3[d]
4
5
6
[c]
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all two-step process for the synthesis of enantioenriched
carboxylic acid derivatives is notable for proceeding from
simple starting materials under mild, nearly neutral condi-
tions without reagents or reaction by-products.
Received: May 15, 2006
Published online: July 26, 2006
Angew. Chem. Int. Ed. 2006, 45, 6021 –6024
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Communications
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À
[13] For elegant, metal-promoted C C bond-forming reactions from
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[14] The enantiomerically enriched substrate was prepared by a
chiral NHC-catalyzed kinetic resolution of a racemic mixture of
formylcyclopropanes; further studies on the use of chiral NHCs
for the enantioselective transformation of formylcyclopropanes
will be reported in due course.
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