Catalytic generation of activated carboxylates: Direct, stereoselective synthesis β-hydroxyesters from epoxyaldehydes

Article abstract of DOI:10.1021/ja047407e

The catalytic generation of activated carboxylates from epoxyaldehydes enables the direct, stereoselective synthesis of β-hydroxyesters under mild, convenient reaction conditions. In addition to providing a new method for the synthesis of anti-aldol adducts, this chemistry unveils a mechanistically viable solution to the catalytic, waste-free synthesis of esters. Copyright

Full text of DOI:10.1021/ja047407e

Published on Web 06/15/2004
Catalytic Generation of Activated Carboxylates: Direct, Stereoselective
Synthesis of â-Hydroxyesters from Epoxyaldehydes
Kenneth Yu-Kin Chow and Jeffrey W. Bode*
Department of Chemistry and Biochemistry, UniVersity of California, Santa Barbara, California 93106-9510
Received May 3, 2004; E-mail: bode@chem.ucsb.edu
Table 1. Optimization of Reaction Conditions for the Synthesis of
anti-â-Hydroxyesters from Epoxyaldehydesa
Synthetic methods for the preparation of carboxylic acid deriva-
tives typically rely on the stoichiometric preparation of an activated
carboxylate followed by reaction with an appropriate nucleophile.1
While these protocols have found widespread utility for the
synthesis of esters and related compounds, they suffer from
disadvantages including the need to employ significant molar
excesses of the coupling reagents and the formation of large
amounts of byproducts. To overcome these limitations, chemists
have sought catalytic methods for effecting esterifications and
amidations. Although some success has been found through the
use of Lewis2 or Brønsted3 acids at high temperature, there remains
a great need for truly catalytic methods under mild reaction
conditions.4
As part of a program aimed at developing new approaches to
stereoselective, atom-economical esterifications and amidations, we
now document the catalytic, diastereoselective synthesis of â-hy-
droxy esters from R,â-epoxy aldehydes. In addition to providing a
new method for the preparation of these important structural motifs
from readily available starting materials, this chemistry unveils a
mechanistically viable solution to the catalytic generation of
activated carboxylates (Scheme 1).
entry
solvent
time/h
yieldb4/%
dr 4(anti:syn)c
1d
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DMF
EtOH
CH3CN
none
15
15
4
48
89
77
72
88
68
75
76
8:1
13:1
12:1
12:1
3.5:1
7:1
3e
4f
5
4
15
15
15
15
6
7
8
12:1
8:1
a All reactions were performed on a 0.5 mmol scale at 0.5 M. DIPEA )
diisopropylethylamine; DBU ) 1,8-diazabicyclo[5.4.0]undec-7-ene. b Iso-
lated yield following chromatography. c Determined by GC analysis of
unpurified reaction mixtures. d 3-Benzyl-5-(2-hydroxyethyl)-4-methyl thia-
zolium chloride (10 mol %) was used as catalyst. e 20 mol % DIPEA. f 8
mol % DBU.
optimal. A screen of alternative catalysts and reaction conditions
led to our selection of readily prepared thiazolium precatalyst 110
and operationally convenient reaction parameters: 30 °C, 0.5 M,
10 mol % 1, and 8 mol % DIPEA (entry 2). The reaction was
accelerated by increased amounts of base (entry 3) or the use of
DBU (entry 4), albeit with slightly diminished chemical yields. Of
interest was the solvent-dependent, and notably high, diastereose-
lectivity of catalytic carboxylate generation: catalytic reactions in
CH2Cl2 (entries 2-4) or CH3CN (entry 7) reliably formed the anti-
â-hydroxy ester in >12:1 diastereoselectivity.11,12
Scheme 1
We have found this reaction to be general for a variety of
i
epoxyaldehydes and alcohols. Thus BnOH, PrOH, and CD3OD
reacted with 2 to give the anti-â-hydroxyesters in good yield and
diastereoselectivity (Table 2, entries 1-3). Substrates lacking an
R-alkyl group gave the corresponding acetate-aldol adduct (entry
4). An aliphatic example provided the expected products in good
yields and stereoselectivity (entries 5). This chemistry also offers
a valuable approach to enantiomerically pure â-alkyl-â-hydroxy-
esters, which are difficult to obtain via other methods (entry 6).13
The catalytic generation of activated carboxylates is not limited
to epoxide substrates. For example, R,â-aziridinylaldehyde 14 gave
the desired N-tosyl-â-aminoester 15 in 53% yield under standard
conditions. This result points to a potentially broader scope for
catalytic carboxylate activation and offers an attractive approach
to â-amino acids.14
The inspiration for our catalytic, diastereoselective esterification
is the facility of thiazolium-aldehyde adducts to undergo oxidation
to 2-acyl thiazolium species, which are efficient and well-known
acyl donors, i.e., activated carboxylates.5 While previous studies
have utilized stoichometric oxidants6 or electrochemical conditions,7
we reasoned that incorporation of a reducible functionality into the
aldehyde substrate could set the stage for a catalyst-induced
intramolecular redox reaction. This, in turn, leads to the generation
of the key acyl thiazolium species, poised for reaction with
nucleophiles.8
For initial studies we selected 2,3-epoxyaldehydes, such as 2,
as suitable substrates for reaction development (eq 1). In addition
to the widespread availability of these structures in enantiopure
form,9 the expected â-hydroxyester products are synthetically
valuable building blocks for the construction of natural products
and pharmaceuticals. Preliminary trials employing commercially
available thiazolium salts led to formation of the desired product
(Table 1, entry 1); however, the chemical yield was less than
9
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J. AM. CHEM. SOC. 2004, 126, 8126-8127
10.1021/ja047407e CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Catalytic Esterifications of Epoxyaldehydesa
conditions appears to be related to the transformation of trichlo-
roacetaldehyde to dichloroacetic acid in the presence of cyanide,
reported by Wallach in 1873.15 An apparently similar process,
mediated by a thiamine-dependent enzyme, has also been postulated
for the biosynthesis of clavulanic acid.16 These reports, coupled
with experimental observations, support the catalytic cycle shown
in Scheme 2. Of particular significance is the epoxide-opening step,
which could occur either via a concerted elimination to give 21
from 20 or in a stepwise manner via stabilized anion 19. Reactions
performed in the presence of CD3OD, and quenched at 50%
completion, reveal no deuterium incorporation into recovered 17,
suggesting either a concerted process or a rate-determining depro-
tonation step. Likewise, the stereochemical outcome and additional
isotopic labeling experiments, which produce deuterium incorpora-
tion at the R-position (∼50% incorporation), disfavor a Favorskii-
like or hydride-shift mechanism from intermediate 18 or a
hemiacetal (Table 2, entry 3).
In summary, we have developed a truly catalytic method for the
generation of activated carboxylates from epoxyaldehydes and its
application to a unique esterification process. This mechanistic
prototype invites further applications to stereoselective, waste-free
syntheses of other important carboxylic acid derivatives.
Acknowledgment. The University of California is thanked for
generous financial support.
a Unless otherwise indicated, all reactions were performed on racemic
epoxides at 0.5 M in CH2Cl2 at 30 °C for 15 h using 10 mol % 1, 8 mol
% DIPEA, and 3 equiv of the nucleophile. b Determined by GC analysis of
unpurified reaction mixtures. c Isolated yield following chromatography.
d Determined by 1H NMR analysis of unpurified reaction mixtures.
e Reaction time was 3 h; longer reaction times gave identical results. f 8
mol % DBU was employed. g Enantiomerically enriched (94% ee) epoxide
was used.
Supporting Information Available: Experimental procedures and
characterization data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) The term activated carboxylate is taken to encompass any acyl species
that reacts irreversibly with nucelophiles to give stable carboxylic acid
derivates. Examples include acyl halides, acyl cyanides, and activated
esters.
Scheme 2
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Despite the similarity of the reaction conditions to those typically
used for benzoin reactions, we have yet to observe any trace of the
corresponding acyloin dimers; the only detectable byproducts were
small amounts (∼2% each) of the R,â-unsaturated esters and
oligomeric esters. The reactivity of 2,3-epoxyaldehydes under these
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