Highly diastereoselective TiCl4 mediated addition of (E)-cinnamyl(tributyl)tin to α-keto esters

Article abstract of DOI:10.1016/S0040-4039(02)00417-3

Highly syn-(87-98%) diastereoselective addition of (E)-cinnamyl(tributyl)tin to α-keto esters under the influence of titanium tetrachloride, leading to the isolation of pure alkyl syn-2-aryl-2-hydroxy-3-phenylpent-4-enoates in 50-80% yields, is described.

Full text of DOI:10.1016/S0040-4039(02)00417-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2987–2990
Highly diastereoselective TiCl mediated addition of
4
(
E)-cinnamyl(tributyl)tin to a-keto esters
Deevi Basavaiah* and Bandaru Sreenivasulu
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
Received 19 November 2001; revised 12 February 2002; accepted 28 February 2002
Abstract—Highly syn-(87–98%) diastereoselective addition of (E)-cinnamyl(tributyl)tin to a-keto esters under the influence of
titanium tetrachloride, leading to the isolation of pure alkyl syn-2-aryl-2-hydroxy-3-phenylpent-4-enoates in 50–80% yields, is
described. © 2002 Elsevier Science Ltd. All rights reserved.
Allylation of carbonyl compounds using various allyltin
reagents has become a well established methodology for
the stereoselective construction of carbonꢀcarbon
bonds providing an elegant synthesis of homoallylic
of a suitable methodology for diastereoselective synthe-
ses of tertiary-a-hydroxy acids/esters. Accordingly, we
have undertaken a research program to examine the
reaction of (E)-cinnamyl(tributyl)tin with a-keto esters,
with a view to understanding the stereochemical out-
come of this reaction. As a preliminary study, we first
examined the reaction of allyl(tributyl)tin with repre-
sentative a-keto esters under the influence of titanium
tetrachloride, which provided the desired tertiary-
homoallylic alcohols in good yields (Eq. (1)).
1
–9
alcohols.
It is also well established in the literature
that the reaction of various crotyl and cinnamyltin
reagents with a variety of aldehydes provides the corre-
sponding homoallylic alcohols with high diastereoselec-
1,10–13
tivities under the influence of selected Lewis acids.
However, the application of a-keto esters, yet another
class of electrophiles, has not been studied systemati-
cally in such reactions and there are only a few reports
in the literature describing the reaction of a-keto esters
(
pyruvate esters) with crotyltin reagents with low
14,15
diastereoselectivities.
To the best of our knowledge,
the reaction of (E)-cinnamyl(tributyl)tin with a-keto
1
6–21
(1)
diastereoselective synthesis of alkyl syn-2-aryl-2-
hydroxy-3-phenylpent-4-enoates via the reaction
between a-keto esters and (E)-cinnamyl(tributyl)tin
under the influence of titanium tetrachloride.
Tertiary-a-hydroxy acids and their derivatives consti-
tute an integral part of many biologically active
2
2–25
molecules
and hence the development of convenient
methodologies for the diastereoselective synthesis of
such compounds continues to attract the attention of
organic chemists. It occurred to us that the reaction of
cinnamyl(tributyl)tin with a-keto esters under the
appropriate conditions might result in the development
Keywords: allylation; titanium tetrachloride; a-keto esters; cinnamyl-
(tributyl)tin; diastereoselectivity.
*
Corresponding author.
Figure 1. ORTEP diagram of compound 2a.
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00417-3

2
988
D. Basa6aiah, B. Sreeni6asulu / Tetrahedron Letters 43 (2002) 2987–2990
(2)
Next, we selected ethyl phenylglyoxylate (1a) as a sub-
strate for reaction with (E)-cinnamyl(tributyl)tin. The
best results were obtained when a solution of ethyl
phenylglyoxylate (1a) (1 mM) and titanium tetra-
tolylglyoxylate
diastereoselectivity. The syn-diastereoselectivity in these
reactions may be explained by considering the transi-
tion state models as described in Scheme 1.
(1h)
provides
slightly
inferior
3
0
chloride (1 mM) in dichloromethane was treated with
1
(
E)-cinnamyl(tributyl)tin (1.1 mM) (normal addition)
In conclusion, for the first time this methodology
describes highly diastereoselective addition of (E)-cin-
namyl(tributyl)tin to a-keto esters in the presence of
titanium tetrachloride, leading to the isolation of pure
alkyl syn-2-aryl-2-hydroxy-3-phenylpent-4-enoates in
at room temperature for 6 h thus providing the
required tertiary-homoallylic alcohol i.e. ethyl syn-2,3-
diphenyl-2-hydroxypent-4-enoate (2a) in 80% yield after
28
26,27
column chromatography.
The syn-stereochemistry
of compound 2a was confirmed by single crystal X-ray
5
0–80% yields.
2
9
data (Fig. 1). With a view to understanding the
generality of the reaction, we carried out the reaction of
representative a-keto esters (1b–h) with (E)-cinnamyl-
Acknowledgements
(
tributyl)tin in the presence of titanium tetrachloride
under similar conditions. These reactions were found to
27
be highly syn-diastereoselective (87–98%).
The
We thank CSIR (New Delhi) for funding this project.
We thank UGC (New Delhi) for a Special Assistance
Program in Organic Chemistry in the School of Chem-
istry, University of Hyderabad. B.S. thanks CSIR (New
Delhi) for financial support. We also thank the
National Single Crystal X-ray Facility, School of
Chemistry, University of Hyderabad funded by DST
(New Delhi). We thank Dr. T. P. Radhakrishnan for
helpful discussions regarding X-ray crystal structures.
required pure syn-tertiary-homoallylic alcohols i.e.
alkyl syn-2-aryl-2-hydroxy-3-phenylpent-4-enoates (2b–
g) [while 2h was obtained as a colorless liquid as a
mixture of diastereomers (syn:anti/87:13) after purifica-
tion] were isolated in 50–66% yields as colorless solids
after purification by column chromatography (Eq. (2)
and Table 1). From Table 1 it is clear that both
methyl and ethyl esters of a-keto acids provide almost
similar diastereoselectivities, however iso-propyl p-
2
7
Table 1. Reaction of (E)-cinnamyl(tributyl)tin with a-keto esters: synthesis of alkyl syn-2-aryl-2-hydroxy-3-phenylpent-4-
a,b,c
enoates
Productd
Mp (°C)e
Yield (%)
f
syn:antig
Keto ester
Ar
R
h
1
1
1
1
1
1
1
1
a
b
c
d
e
f
Phenyl
p-Tolyl
p-Bromophenyl
p-Methoxyphenyl
Phenyl
p-Tolyl
p-Bromophenyl
p-Tolyl
Et
Et
Et
Et
Me
Me
Me
i-Pr
2a
98–100
87–89
84–86
93–95
96–98
102
80
55
63
54
66
50
51
\98:B2
97:3
97:3
\98:B2
93:7
90:10
2b
2c
2d
2e
2f
g
h
2g
2h
110–112
–
\98:B2
i
i
i
56
87:13
a
All reactions were carried out on a 1 mM scale (a-keto ester). To a stirred solution of a-keto ester (1 mM) and titanium tetrachloride (1 mM)
1
in dichloromethane was added (E)-cinnamyl(tributyl)tin (1.1 mM) (normal addition) at 0°C and stirred at room temperature for 6 h.
b
1
13
All products (2a–h) were characterized by IR, H NMR (200 MHz), C NMR (50 MHz) and elemental analyses; compounds 2a and 2g were
also characterized by mass spectral analysis.
c 1
H NMR spectra of the crude products (2a–h) clearly indicated the presence of the starting materials i.e. keto esters (1a–h) in :11, 28, 17, 36,
0, 33, 39, 30%, respectively. In fact, we isolated the starting materials (the a-keto esters) in 29 and 31% yields in the case of 1d and 1g,
respectively.
1
d
27
The isolated products were obtained as colorless solids with pure syn stereochemistry after column chromatography (silica gel, 1.5% EtOAc
in hexanes).
e
f
Melting points are of the pure syn diastereomers.
Yields of the pure syn isomeric products (based on a-keto esters) after column chromatography.
This ratio was determined by H NMR studies of the crude products.
The structure and stereochemistry of compound 2a were established by single crystal X-ray data (crystallization from hexanes).
The compound 2h was isolated (as a mixture of diastereomers) as a colorless liquid after column chromatography.
g
h
i
1
27

D. Basa6aiah, B. Sreeni6asulu / Tetrahedron Letters 43 (2002) 2987–2990
2989
Scheme 1.
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was assigned in analogy with 2a. The H NMR spectrum
8
9
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6
singlets at l 2.22 & 2.35 (:87:13) for CH protons (tolyl
3
methyl) and two singlets at l 3.90 & 3.98 (:13:87) for the
1
1
3
OH proton. Also, the C NMR spectrum of the purified
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1
4
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1
1
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1
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1
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1
1
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2
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1
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2
990
D. Basa6aiah, B. Sreeni6asulu / Tetrahedron Letters 43 (2002) 2987–2990
28. We have assigned syn stereochemistry to the molecules
Road, Cambridge, CB2 1EZ, UK. (For compound 2a
CCDCc173594). Crystal data for 2a: empirical formula,
shown below (the 2-hydroxy group and 3-phenyl groups
are on the same side in the extended conformation).
C H O ; formula weight, 296.35; crystal color, habit:
19 20 3
colorless, prism; crystal dimensions, 0.48×0.48×0.36 mm;
crystal system, monoclinic; lattice type, primitive; lattice
parameters, a=18.237(4) A
,
, b=5.7783 (12) A
,
, c=16.679
3
(
21
3) A
,
; i=115.67 (3); V=1584.1 (6) A
,
; space group, P
3
/C (No. 14); Z=4; Dcalcd=1.243 g/cm ; F =632.00;
Mo K )=0.71073 A; residuals, R=0.0494, wR =0.1040.
30. A similar mechanism for allylation reactions is known in
the literature. See Ref. 1.
ooo
2
(
,
a
29. Detailed X-ray crystallographic data is available from the
Cambridge Crystallographic Data Center, 12 Union