Synthetic utility of bowl-shaped tris(2,6-diphenyl-benzyl)silyl glyoxylate as a stable glyoxylate: Application to highly diastereoselective aldol reactions

Article abstract of DOI:10.1016/S0040-4039(02)02557-1

A stable glyoxylate can be successfully applied to both syn- and anti-selective aldol reactions by using two different kinds of ordinary Lewis acids. Thus, treatment of bowl-shaped tris(2,6-diphenylbenzyl)silyl glyoxylate 1 with enol silyl ether under the influence of BF₃·OEt₂ gave syn-aldol product, while the use of TiCl₄ afforded anti-aldol product with >97% selectivity.

Full text of DOI:10.1016/S0040-4039(02)02557-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 281–284
Synthetic utility of bowl-shaped tris(2,6-diphenylbenzyl)silyl
glyoxylate as a stable glyoxylate: application to highly
diastereoselective aldol reactions
Seiji Shirakawa and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan
Received 4 October 2002; revised 5 November 2002; accepted 8 November 2002
Abstract—A stable glyoxylate can be successfully applied to both syn- and anti-selective aldol reactions by using two different
kinds of ordinary Lewis acids. Thus, treatment of bowl-shaped tris(2,6-diphenylbenzyl)silyl glyoxylate 1 with enol silyl ether under
the influence of BF3·OEt2 gave syn-aldol product, while the use of TiCl4 afforded anti-aldol product with >97% selectivity. © 2002
Elsevier Science Ltd. All rights reserved.
Glyoxylates are extremely useful compounds in organic
synthesis, and introduction of various nucleophiles,
particularly in an asymmetric manner to prochiral gly-
oxylates, affords optically active a-hydroxy esters of
biological and synthetic importance.1–3 However, this
advantage is seriously diminished by the intrinsic insta-
bility of glyoxylates due to the facile hydration and
self-polymerization for very reactive aldehyde moiety,4
and hence fresh distillation of glyoxylates before use is
often necessary for their smooth transformation with
nucleophiles. Apparently, however, such inconvenience
curtails the synthetic potential of the otherwise very
useful glyoxylate substrates. In this context, we are
interested in the possibility that certain bowl-shaped
substituents5–8 might be highly effective in stabilizing
the aldehyde moiety of glyoxylates from the undesired
hydration and polymerization without loss of reactivity
toward nucleophiles. Here we wish to report the synthe-
sis of bowl-shaped tris(2,6-diphenylbenzyl)silyl glyoxy-
late
1
(TDS glyoxylate; TDS=tris(2,6-diphenyl-
benzyl)silyl),6 by which the synthetic utility of glyoxyl-
ates is considerably increased as exemplified by both
syn- and anti-selective aldol reactions, hitherto not
observable with ordinary glyoxylates.
Scheme 1. Synthesis of TDS glyoxylate 1.
Keywords: diastereoselectivity; aldol reaction; glyoxylate; enol silyl ether.
* Corresponding author. Tel./fax: +81 75 753 4041; e-mail: maruoka@kuchem.kyoto-u.ac.jp
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02557-1

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S. Shirakawa, K. Maruoka / Tetrahedron Letters 44 (2003) 281–284
Scheme 2. Alkylation of TDS glyoxylate 1 with Grignard reagents.
The requisite TDS glyoxylate 1 can be conveniently
synthesized from TDS-Br6a in a two-step sequence as
shown in Scheme 1. The TDS glyoxylate 1 thus pre-
pared is found to be stable toward self-polymerization
and hydration even in the presence of water. This
stability is attributable to the existence of an appropri-
ate molecular pocket around the otherwise reactive
aldehyde moiety, and this influence is in accord with
the unusually high field shift (l=8.38) of aldehyde
Another interesting feature of TDS glyoxylate 1 is its
applicability to the Lewis acid-promoted diastereoselec-
tive aldol reactions with enol silyl ethers or ketene silyl
acetals.11 Indeed, both syn- and anti-selective aldol
reactions of TDS glyoxylate 1 are achievable using two
different kinds of ordinary Lewis acids. For example,
treatment of TDS glyoxylate 1 with enol silyl ether 5a
(2 equiv.) under the influence of BF3·OEt2 (2 equiv.) at
0°C afforded a syn-aldol product (syn-6a) in 99% yield
with virtually complete selectivity. On the other hand,
using TiCl4 (2 equiv.) at −78°C a totally opposite
anti-aldol product (anti-6a) was obtained in 43% yield
(Scheme 3; Table 1, entries 1 and 4).2c,12 It should be
noted, however, that treatment of freshly distilled ethyl
glyoxylate 7 with enol silyl ether 5a under the influence
of BF3·OEt2 or TiCl4 afforded the aldol product 8a
with low diastereoselectivity (syn/anti=47:53ꢀ57:43;
entries 5 and 6). Other examples including various enol
silyl ethers and ketene silyl acetal are listed in Table 1.
Several characteristic features of the present
diastereoselective aldol reactions follow: (1) In general,
high syn- and anti-selectivity can be observed in the
aldol reaction of TDS glyoxylate 1 under the influence
of BF3·OEt2 and TiCl4, respectively. However, simple
ethyl glyoxylate 7 showed low diastereoselectivity under
similar reaction conditions. A similar tendency was also
observed with ketene silyl acetal (entries 21ꢀ24). (2)
Both syn- and anti-selectivity of aldol products 6
derived from TDS glyoxylate 1 were independent of the
geometry of enol silyl ethers (entries 7, 8, 11, and
14).2c,12 (3) syn-Selective aldol reactions of TDS glyoxyl-
ate 1 with BF3·OEt2 is not sensitive to the reaction
temperature (entry 11 versus 12). (4) Among other
Lewis acids, Me2AlCl showed the preferential syn-selec-
tivity (entries 2 and 13), while only low diastereoselec-
tivity was observed in the case of SnCl4 (entry 3).
1
proton in the H NMR spectrum [cf. freshly distilled
ethyl glyoxylate 7: l=9.40 (CHꢀO)].9
The reactivity of TDS glyoxylate 1 was examined in
both ordinary nucleophilic and electrophilic alkyla-
tions. For example, treatment of TDS glyoxylate 1 with
Grignard reagent (2 equiv. of PhMgBr, allylMgBr, and
MeMgI) in THF at 0°C for 1ꢀ2 h gave rise to the
corresponding a-hydroxy esters 2aꢀ2c in high yields
(Scheme 2). In the case of methylation, the initially
formed a-hydroxy ester partially rearranged to a-siloxy
acid 3 in 10% yield. The TDS group of a-hydroxy ester
2a can be readily cleaved to mandelic acid quantita-
tively by treatment with HF·Py in THF at 50°C for 5 h
with recovery of the TDS group as TDS-F.6a,10
BF3·OEt2-promoted ene reaction and allylation of TDS
glyoxylate 1 afforded corresponding a-hydroxy esters 4
and 2b, respectively, in high yields. Moreover, noncata-
lyzed allylation of TDS glyoxylate 1 with allyl-
tributyltin was also effected at 100°C for 4 h to furnish
2b in 81% yield.
Since both syn- and anti-selectivities of aldol products 6
can be achieved irrespective of the geometry of enol
silyl ethers, the present reactions are most likely to
Scheme 3. Diastereoselective aldol reactions of glyoxylate 1 under the influence of BF3·OEt2 or TiCl4.

S. Shirakawa, K. Maruoka / Tetrahedron Letters 44 (2003) 281–284
Table 1. Diastereoselective aldol reactions of glyoxylatesa
283
Entry
Glyoxylate
Silyl ether
Lewis acid
Conditions (°C, h)
Yield (%)b (syn/anti)c
1
2
3
4
5
6
7
8
1
5a
BF3·OEt2
Me2AlCl
SnCl4
TiCl4
BF3·OEt2
TiCl4
BF3·OEt2
TiCl4
BF3·OEt2
TiCl4
BF3·OEt2
BF3·OEt2
Me2AlCl
TiCl4
BF3·OEt2
TiCl4
BF3·OEt2
TiCl4
BF3·OEt2
TiCl4
BF3·OEt2
TiCl4
BF3·OEt2
TiCl4
0, 0.5
99 (\97:B3)
84 (\97:B3)
92 (53:47)
43 (B3:\97)
84 (47:53)
28 (57:43)
88 (94:6)
−78, 1
−78, 1
−78, 1
0, 0.5
−78, 1
0, 0.5
−78, 1
0, 0.5
−78, 1
0, 0.5
−78, 5
−78, 1
−78, 1
0, 0.5
−78, 1
0, 0.5
−78, 1
0, 0.5
−78, 1
0, 0.5
7
1
7
1
Z-5b
E-5b
80 (3:97)
9
40 (53:47)
55 (45:55)
99 (77:23)
55 (75:25)
74 (67:33)
74 (5:95)
49 (49:51)
57 (50:50)
99 (72:28)
82 (10:90)
65 (44:56)
62 (50:50)
97 (90:10)
98 (7:93)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
7
1
7
1
7
5c
5d
−78, 1
0, 0.5
−78, 1
58 (47:53)
22 (44:56)
a The aldol reaction was carried out with silyl ether (2 equiv.) in the presence of Lewis acid (2 equiv.) in CH2Cl2 under the given reaction
conditions.
b Isolated yield.
c Determined by 1H NMR analysis.
proceed via acyclic transition states.13 The syn-selectiv-
ity under the influence of BF3·OEt2 is explained by the
steric repulsion between bulky siloxy moiety of TDS
glyoxylate 1 and R1 of enol silyl ethers (Scheme 4,
A>B). On the other hand, the anti-selectivity using
TiCl4 is ascribed to the steric interaction between TiCl4
and R1 of enol silyl ethers (C<D).14 Such an anti-selec-
tive aldol reaction, which is independent of the geome-
try of enol silyl ethers, is relatively rare.11b,15
Acknowledgements
This work was supported by a Grant-in-Aid for Scien-
tific Research (No. 13853003) from the Ministry of
Education, Culture, Sports, Science and Technology,
Japan.
Scheme 4. Assumed transition states for syn- and anti-selec-
tivity.

284
S. Shirakawa, K. Maruoka / Tetrahedron Letters 44 (2003) 281–284
8. Another example of bowl-shaped silyl compounds with
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