Enantioselective synthesis of unsymmetrical benzoins from (S)-mandelic acid enolate and aromatic aldehydes

Article abstract of DOI:10.1016/j.tetlet.2004.08.168

Highly enantioenriched unsymmetrical benzoins are obtained from (S)-mandelic acid. The reaction of the lithium enolate of the 1,3-dioxolan-4-one derived from optically active (S)-mandelic acid and pivalaldehyde with aromatic aldehydes proceeds readily to

Full text of DOI:10.1016/j.tetlet.2004.08.168

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8039–8042
Enantioselective synthesis of unsymmetrical benzoins from
(S)-mandelic acid enolate and aromatic aldehydes
*
´ ´ ´
Gonzalo Blay, Isabel Fernandez, Belen Monje and Jose R. Pedro
´ ` ´
Departament de Quımica Organica, Facultat de Quımica, Universitat de Valencia, Dr. Moliner 50,
E-46100 Burjassot (Valencia), Spain
`
`
Received 29 July 2004; revised 27 August 2004; accepted 31 August 2004
Available online 17 September 2004
Abstract—The reaction of the lithium enolate of the 1,3-dioxolan-4-one derived from optically active (S)-mandelic acid and pival-
aldehyde with aromatic aldehydes proceeds readily to give the corresponding aldol products in good yields and diastereoselectivities.
Subsequent hydroxyl protection, basic hydrolysis of the dioxolanone, oxidative decarboxylation of the a-hydroxyacid moiety, and
hydroxyl deprotection provides chiral unsymmetrical benzoins with high enantiomeric excesses.
Ó 2004 Elsevier Ltd. All rights reserved.
Chiral unsymmetrically substituted benzoins constitute
a valuable class of building blocks in organic and pharma-
ceutical chemistry due to their bifunctional nature and
especially to the fact that they have a stereogenic center
amenable to further synthetic manipulation.1
metallophosphites.12 A very interesting highlight on cat-
alyzed reactions of acyl anion equivalents has been also
published very recently by the same author.13
We have reported a highly diastereoselective Michael
reaction of the (S)-mandelic acid enolate using a,b-
unsaturated carbonyl compounds as acceptors and the
transformation of the corresponding adducts into highly
enantioenriched 2-substituted 1,4-dicarbonyl com-
pounds14 (Scheme 1). Formally this synthesis involves
the use of (S)-mandelic acid as source of chiral informa-
tion and as source of the benzoyl anion. In this reaction
(S)-mandelic acid exerts the stereochemical control in
the newly created stereogenic centers through its previ-
ous conversion into (2S,5S)-cis-2-tert-butyl-5-phenyl-
1,3-dioxolan-4-one (2) derived from pivalaldehyde
(Seebach principle of self-regeneration of stereo-
centers),15 and it acts as a masked benzoyl anion
through an oxidative decarboxylation of the a-hydroxy-
acid moiety.16
Generally the racemic compounds are prepared by
cross-benzoin condensation from aromatic aldehydes
in a reaction catalyzed by cyanide ions2 or quaternary
thiazolium salts ylide derived.3 This condensation has
been recognized as a reaction that involves masked acyl
anion equivalents as intermediates and in fact several
kinds of masked acyl anion, such as O-protected cyano-
hydrins,4 a-(dialkylamino)nitriles,5 cyanophosphates,6
dithioacetals,7 and acylsilanes8 among other have been
also used in addition reactions to carbonyl compounds
to give a-hydroxyketones. However, only a few efficient
enantioselective synthesis of benzoins have been
described so far.9 Recently Enders10 and co-workers
have developed a new chiral triazolium salt as precata-
lyst in the synthesis of symmetrical benzoins, Muller11
and co-workers have reported the first asymmetric
cross-benzoin condensation leading to a new donor–
acceptor concept for enzymatic cross-coupling reactions
of aldehydes and Johnson has described the enantio-
selective cross-silyl benzoin reaction catalyzed by
O
O
H
LDA
H
O
+
R1
R2
O
But
Ph
R1
O
R1
O
O
1.Hydrolysis
H
O
Ph
R2
Keywords: Dioxolanones; Self-regeneration of stereocenters; Aldol
reaction; Oxidative decarboxylation.
R2
O
But
Ph
2. Ox.Decarbox.
O
*
Corresponding author. Tel.: +34 964544329; fax: +34 963544328;
e-mail: jose.r.pedro@uv.es
Scheme 1.
0040-4039/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.168

8040
G. Blay et al. / Tetrahedron Letters 45 (2004) 8039–8042
OH
O
1. Separation
ArCHO (3)
O
H
ButCHO
H+
O
H
O
H
H
HO2C
HO
Ar
O
2. MEMCl, Pri2NEt
O
LDA
Ph
But
Ph
Ph
But
2
(+)-1
4
OMEM
OMEM
OH
OMEM
Ar
O
TiCl4
O2, ButCHO
Co complex
H
O
KOH
EtOH-H2O
HO2C
HO
Ph
Ph
Ar
Ar
Ar
O
But
Ph
Ph
O
O
5
8
7
6
Scheme 2.
In this letter we wish to report the diastereoselective
addition of the (2S,5S)-1,3-dioxolan-4-one 2 to aromatic
aldehydes 3 and the transformation of the resulting
aldol products 4 into highly enantioenriched unsym-
metrical benzoins 8 (Scheme 2).
separately in (S)-(+)-benzoin and comparison of the spe-
cific rotations sign with that of a commercially available
authentic sample.18 Consequently, the stereochemistry
of this carbon should be R in both minor diastereomers
4a-D and 4a-B, which would differ in the stereochemis-
try of the quaternary carbon of the dioxolanone ring.19
Initial studies were carried out using benzaldehyde (3a).
Treatment of 2 with a freshly prepared solution of LDA
(1.25equiv) in THF at ꢀ78°C, followed by addition of a
solution of benzaldehyde (1.25equiv) in THF at ꢀ78°C,
stirring for 1h and quenching with aq NH4Cl at ꢀ78°C,
As the final objective of our synthetic sequence is the
preparation of enantioenriched unsymmetrical benzoins,
and since the quaternary stereogenic center in the dioxol-
anone ring is lost in further stages of the synthesis, the
overall stereoselectivity depends exclusively on the facial
diastereoselection with regards to the aldehyde carbonyl
group, that is, 4a-A and 4a-C lead to the (S)-benzoin,
while 4a-B and 4a-D would lead to the (R)-benzoin. This
is given by the ratio (A+C)/(B+D) that are shown in the
last column of Table 1.
gave aldol product 4a in 84% yield.17
A
1H NMR
analysis of the reaction mixture revealed the presence
of three out of four possible diastereomers for 4a in a
ratio 14:0:76:10, one of them being strongly predomi-
nant (Table 1, entry 1). Careful flash chromatography
allowed to obtain pure the two major aldols 4a-A and
4a-C.
Attempts to improve these results were also performed
using other solvents (ethyl ether, toluene) as well as in
the presence of additives (HMPA or DMPU), which
modifies the enolate aggregation state.20 However simi-
lar results were obtained in all cases regarding both
the yield and facial diastereoselectivity.
The stereochemical structures of these two diastereo-
mers were elucidated by NOE experiments, which
showed that in the case of 4a-C the phenyl group of
mandelic acid remains syn to the t-Bu group whilst in
the case of 4a-A both groups are anti. The absolute
stereochemistry of the newly formed quaternary carbon
was then assigned to be R for aldol 4a-C and S for aldol
4a-A upon the consideration that the absolute configu-
ration of the dioxolanone carbon bearing the t-Bu group
in 2 is S and it keeps unaltered from 2 to 4.
On the basis of the above preliminary survey, two other
aromatic aldehydes were treated with the lithium enolate
derived from 2 in THF at ꢀ78°C without additives
(Table 2). The reaction of 2 with para-tolualdehyde 3b
gave the corresponding aldol products 4b in goods yields
and with slightly higher facial diastereoselectivity than
the reaction with benzaldehyde whilst the reaction with
para-chlorobenzaldehyde (3c) gave the aldol products 4c
with somewhat lower yield and facial diastereoselectivity.
The absolute configuration of the hydroxyl-supporting
carbon atom in the side chain could not be determined
at this stage, but it was shown to be S in both major ald-
ols, 4a-C and 4a-A after conversion of these compounds
Table 1. Aldol reaction of (2S,5S)-1,3-dioxolan-4-one 2 with benzaldehyde 3a under various conditions
Entry
Solvent
Additive
Addition
4a Yield (%)a
Ratio A:B:C:Db
Ratio (A+C)/(B+D)c
1
2
3
THF
THF
Diethyl ether
—
—
—
Di:r0e:c7t6:10
Inverse
Direct
72
8414 90:10
20
70
28:2:58:12
19:1:62:18
18:3:72:7 90:10
86:14
81:19
4Diethyl ether–toluene
—
Direct
5
6
7
8
9
THF
THF
THF
THF
THF
HMPA (3equiv)
HMPA (3equiv)
DMPU (3equiv)
HMPA (6equiv)
DMPU (6equiv)
Direct
Inverse
Direct
Direct
Direct
75
70
26:11:55:8
13:13:68:6
92:8
81:19
81:19
7437:2:55:6
70
68
18:8:67:7
16:0:78:6
85:15
94:6
a Yields refer to isolated product.
b Ratio determined by 1H NMR.
c See text. Aldols A and C lead to (S)-benzoin, aldols B and D would lead to (R)-benzoin.

G. Blay et al. / Tetrahedron Letters 45 (2004) 8039–8042
8041
Table 2. Aldol reaction of (2S,5S)-1,3-dioxolan-4-one 2 with several aromatic aldehydes 3 under optimized conditionsa
Entry
Ar
4
4 Yield (%)b
Ratio A:B:C:Dc
Ratio(A+C)/(B+D)d
C Yield (%)e
1
2
3
Ph
4-MeC6H4
4-ClC6H4
:0:746a:10
4b
4c
8414 90:10
60 (9)
86
60
22:0:70:8
22:0:61:17
92:8
83:17
57
32
a Optimized conditions refer to those indicated in entry 1 of Table 1.
b Combined yield of all four diastereomers.
c Ratio determined by 1H NMR.
d See text. Aldols A and C lead to (S)-benzoin, aldols B and D would lead to (R)-benzoin.
e Isolated yield of pure diastereomer C. Entry 1, in brackets: Isolated yield of diastereomer A.
Table 3. Synthesis of (S)-benzoinsa from aldols 4
Entry
Starting 4
Hydroxyl protection
Hydrolysis
Product
Yield (%)b
Ox. decarboxylation
MEM cleavage
c
Product
Yield (%)b
Product
Yield (%)b
Product
Yield (%)b
[a]D
1
2
3
4
4a-C
4a-A
4b-C
4c-C
5a-C
5a-A
5b-C
5c-C
70
89
75
69
6a-C
6a-A
6b-C
6c-C
97
86
96
80
7a
7a
7b
7c
62
60
66
62
8a
8a
8b
8c
85
85
90
80
+110 (c 1.3)
+110 (c 1.3)
+104( c 1.0)
+69 (c 0.6)
a In the case of 8a, configuration determined by comparison with an authentic sample. In the case of 8b and 8c, assigned on the basis of a uniform
reaction mechanism. In all the cases, higher than 95% ee were determined by 1H NMR experiments with shift reagent (see text).
b Yields refer to isolated product.
c Optical rotations measured in acetone.
In the case of these two aldol products 4b and 4c, we
performed the isolation of only the major diastereoiso-
mers 4b-C and 4c-C, respectively, by silica gel flash
chromatography.
-
O
O
O
N
N
N
N
+
Co
NMe4
O
Me Me
With the aldol products 4 in our hands we carried out
the protection of the hydroxyl group in order to avoid
the retro-aldol reaction during the basic hydrolysis of the
1,3-dioxolan-4-one moiety and a possible over-oxida-
tion21 during the oxidative decarboxylation of the a-
hydroxyacid moiety. This protection was carried out
by reaction of aldols 4 with MEM-chloride and diiso-
propylethylamine in acetonitrile at reflux temperature
to afford MEM derivatives 5, with good yields.22
Figure 1. Co(III) ortho-phenylene-bis(N0-methyloxamidate) complex.
sample of enantiomerically pure benzoin.18 The configu-
ration of 8b and 8c was assigned as S on the basis of a
uniform reaction mechanism.
In summary, we have developed a strategy for the asym-
metric aldol reaction of a masked benzoyl anion equiv-
alent with aromatic aldehydes that formally involves the
use of (S)-mandelic acid as the source of chiral informa-
tion and as source of benzoyl anion. This strategy
appears as a convenient method for the synthesis of
highly enantioenriched unsymmetrical benzoins
Once the hydroxyl group was protected as MEM deriv-
ative, we carried out the basic hydrolysis of the dioxol-
anone moiety to obtain the corresponding a-hydroxy
acids 6 in almost quantitative yield.
The oxidative decarboxylation of the a-hydroxyacid
moiety was carried out using a catalytic procedure
developed in our laboratory, which employs oxygen as
terminal oxidant in the presence of pivalaldehyde and
of a catalytic amount of the Co(III) ortho-phenylene-
bis(N0-methyloxamidate) complex (Fig. 1).23 Under
these conditions the MEM-protected benzoins 7a, 7b,
and 7c were obtained, respectively, with fair to good
yields (Table 3). Finally the MEM-protected benzoins
were treated with TiCl4 in order to remove the MEM
protecting group: This reaction proceeded in good yield
to provide highly enantioenriched benzoins (ee > 95%)
as proven by 1H NMR experiments using the chiral
lanthanide shift reagent Eu(hfc)3 under conditions previ-
ously optimized for a racemic mixture.
Acknowledgements
This work was financially supported by the Spanish
Government (MCYT, project BQU 2001-3017) and
in part by Generalitat Valenciana (AVCYT, groups
03/168). B.M. thanks MCYT for a grant (FPI program).
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