A highly stereoselective entry to α-hydroxy carboxylic acids using D-fructose diacetonide as a chiral auxiliary

Article abstract of DOI:10.1016/S0040-4039(01)00043-0

Protected α-hydroxy carboxylic acids were synthesized in moderate yield and high diastereoselectivity by alkylation of glycolate ester enolates using a D-fructose-derived chiral auxiliary. The new chiral center was assigned the (R)-configuration based upon comparisons to the literature. Both enantiomers of the auxiliary are readily available.

Full text of DOI:10.1016/S0040-4039(01)00043-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1835–1838
A highly stereoselective entry to a-hydroxy carboxylic acids
using
D-fructose diacetonide as a chiral auxiliary
Hongwu Yu, C. Eric Ballard and Binghe Wang*
Department of Chemistry, Box 8204, North Carolina State University, Raleigh, NC 27695-8204, USA
Received 26 October 2000; accepted 9 January 2001
Abstract—Protected a-hydroxy carboxylic acids were synthesized in moderate yield and high diastereoselectivity by alkylation of
glycolate ester enolates using a D-fructose-derived chiral auxiliary. The new chiral center was assigned the (R)-configuration based
upon comparisons to the literature. Both enantiomers of the auxiliary are readily available. © 2001 Published by Elsevier Science
Ltd.
a-Hydroxy carboxylic acids are important building
blocks for the synthesis of depsides and depsipeptides,
natural products that often exhibit significant biological
activity.1–5 Reported enantioselective routes to a-
hydroxy acids6,7 include reduction of chiral hemi-
acetals,8,9 reduction of a-ketoacids or their deriva-
tives,10–13 hydroxylation of enolates,14,15 O-H insertions
of diazoacetates,16 condensation of trans-1,3-dithiane-
1,3-dioxide with aldehydes,17 osmium-catalyzed dihy-
droxylation/oxidation,18 nucleophilic alkylation of
oxazin-4-ones,19 dynamic kinetic resolution,20 and enzy-
matic resolution.21,22 One very straightforward method
is the stereoselective alkylation of glycolates.23–30 The
most notable reports used 2,5-disubstituted pyrro-
lidine,26 spiro-dioxolanones,27 and Evans oxazolidin-
ones25 as auxiliaries. The first two reports showed that
even less reactive electrophiles (e.g. butyl iodide) gave
excellent yield and good to excellent de for the alkyla-
tions, but they suffer the limitation of being cleaved
under harshly acidic conditions. The last auxiliary gave
excellent yields and diastereoselectivities, but it was
only studied with reactive electrophiles, such as allylic
or propargylic iodides.
It is conceivable that carbohydrates can be used for the
development of readily available and inexpensive chiral
auxiliaries for stereoselective glycolate alkylation. How-
ever, methodologies using carbohydrate-derived auxil-
iaries for other types of ester enolate alkylations have
met with mixed results.31,32 Costa33,34 and Mulzer35
achieved moderate yield and moderate to good de with
a variety of furanose and pyranose derivatives. Koll’s
xylose-derived oxazolidinones generally gave alkyla-
tions in moderate yield and moderate to good stereo-
selectivity.36 Herein, we wish to report our preliminary
results using
D-fructose diacetonide as an auxiliary in
glycolate enolate alkylations for the preparation of
a-hydroxy acids (Scheme 1). The auxiliary, 1,2:4,5-di-
O-isopropylidene-b-D-fructopyranose, is reminiscent of
the epoxidation catalyst developed by Shi and co-work-
Scheme 1.
* Corresponding author. Tel.: 1-919-515-2948; fax: 1-919-515-3757; e-mail: binghe wang@ncsu.edu
–
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)00043-0

1836
H. Yu et al. / Tetrahedron Letters 42 (2001) 1835–1838
ers,37 and has been used as a chiral auxiliary in Diels–
Alder reactions.38,39
The alkylation products (2a–c) were hydrolyzed with
LiOH/THF/H2O to give the corresponding products 3
in 96, 98, and 84% isolated yields, respectively. The
configurations of these free acids were assigned as (R)
by comparison of experimentally measured optical rota-
tions to the literature (Table 2).46,47 It should be noted
The auxiliary was obtained from D-fructose following a
literature procedure.37 Its free 3-hydroxyl group was
coupled with 2-benzyloxyacetic acid40 in the presence of
1,3-dicyclohexylcarbodiimide (DCC) and 4-(dimethyl-
amino)pyridine (DMAP) to give compound 1 as white
crystals in 78% yield. Ether and THF were examined as
solvent for the alkylations, but only THF was suitable
because 1 showed poor solubility in ether at low tem-
perature. The initial experiment used LDA for the
deprotonation of 1 at −78°C, followed by alkylation of
the enolate with allyl bromide to give 2a in 59% yield
after silica gel column purification. HPLC analysis
revealed that the alkylation showed moderate
diastereoselectivity with 66% de (Table 1, entry 1). This
result prompted us to test other bases frequently used
in enolate alkylation. With 1.5 equivalents of LiHMDS,
the yield of 2a was 51%, but the de increased to 92%
(Table 1, entry 2). Use of 2 equivalents of LiHMDS
gave similar results (Table 1, entry 3). NaHMDS pro-
vided similar results, but not as good as those with
LiHMDS (Table 1, entry 4). Based on a report that
similar enolates decompose even at −70°C,41 one reac-
tion was performed at −92°C (Table 1, entry 5).
Although the yield increased to 78%, the de decreased
to 86%.
that the auxiliary
L-fructose diacetonide, which should
generate the (S)-configuration during the alkylation,
could be prepared from inexpensive
steps.37,48
L-sorbose in four
In conclusion, the synthesis of protected a-hydroxy
carboxylic acids using compound 1 has been success-
fully carried out. The following features were notable:
(1) the auxiliary 1,2:4,5-di-O-isopropylidene-b-
pyranose was easily obtained on a large scale from an
inexpensive starting material, -fructose; (2) the enolate
D-fructo-
D
alkylation proceeded in high de; (3) the addition of
HMPA increased the yield without sacrificing
diastereoselectivity; and (4) the other enantiomer of the
auxiliary is readily available.37,48 A comparison of the
chiral auxiliaries reported in the literature shows that
this method is comparable with or better than most
approaches. The fructose auxiliary has not been opti-
mized sufficiently to give the excellent yields and
stereoselectivity of Katsuki’s pyrrolidine26 and Pear-
son’s dioxolanone27 methods. It is not quite as selective
as the Evans auxiliary. However, the
D-fructose auxil-
iary offers the advantage of low cost. Considering that
in most reports only a limited number of fairly reactive
electrophiles were examined, it is hard to draw a con-
clusion on the general effectiveness of these chiral auxil-
iaries with a larger number of electrophiles. The
availability of a number of chiral auxiliaries, particu-
larly those available from inexpensive carbohydrates,
will broaden the arsenal of tools available for the
preparation of a-hydroxy acids in a variety of situa-
tions. Further optimization of this auxiliary and its
application to the synthesis of other substituted car-
boxylic acids is in progress.
The enolate derived from 1 with 2 equivalents of LiH-
MDS was alkylated under various conditions with
methyl iodide and benzyl bromide, and the results are
summarized in Table 2. Alkylation with methyl iodide
proceeded in 61% yield and 83% de (Table 2, entry 1).
Reaction with the bulkier benzyl bromide resulted in
53% yield and 98% de (Table 2, entry 2). In the case of
benzyl bromide, addition of a catalytic amount of
sodium iodide42 improved the yield slightly without
decreasing the de (Table 2, entry 3). To study the effect
of enolate aggregation on reactivity and selectivity,
HMPA was added as an additive. It is known that
polar aprotic solvents can dissociate enolate–metal ion
pairs to give a less encumbered, more reactive enolate.43
In most enolate alkylations, the use of HMPA as an
additive increases the reactivity (yield) appreciably at
the expense of decreasing the selectivity (de),23,44 some-
times to the extent of reversing the selectivity.34,45 When
10% HMPA was used in the syntheses of compounds 2,
the yield for each product increased, and the de was
maintained at the same level as without the additive
(Table 2, entries 4 and 6).
Acknowledgements
Financial support from the American Heart Associa-
tion (c9740117N) and the National Institutes of
Health (GM52515) is gratefully acknowledged. C.E.B.
thanks the Burroughs-Wellcome Fund for a graduate
fellowship.
Table 1. Influences of base and temperature on the alkylation
Entry
RX
Base (equiv.)
Temp. (°C)
Yielda (%)
deb (%)
1
2
3
4
5
Allyl bromide
Allyl iodide
Allyl iodide
Allyl iodide
Allyl iodide
LDA (1.5)
−78
−78
−78
−78
−92
59
51
54
41
78
66
92
92
91
86
LiHMDS (1.5)
LiHMDS (2)
NaHMDS (1.5)
LiHMDS (2)
a Isolated yield.
b Determined by HPLC on a Nova-Pak® silica column (3.9×150 mm) using hexanes–ethyl acetate.

H. Yu et al. / Tetrahedron Letters 42 (2001) 1835–1838
Table 2. Effects of reaction conditions on the alkylation at −78°C
1837
Entry
RX
Solvent (additive)
Alkylated product 2
Acid 3
Configuration
Yielda (%)
de (%)
Yielda (%)
1
2
3
4
5
6
MeI
BnBr
BnBr+NaI
MeI
Allyl iodide
Allyl iodide
THF
THF
THF
THF (10% HMPA)
THF
61
53
58
80
54
76
83b
98c
98c
84b
92b
92b
98
84
R46
R47
96
THF (10% HMPA)
a Isolated yield.
b Determined by HPLC on a Nova-Pak® silica column (3.9×150 mm) using hexanes–ethyl acetate.
c Estimated by 1H NMR.
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