Synthesis and use of α-silyl-substituted α-hydroxyacetic acids

Article abstract of DOI:10.1021/ol025911n

(matrix presented) Rhodium-catalyzed oxygen transfer was used to generate benzyl 2-silyl-2-oxoacetates in good yields. The hydrogenation of these compounds led to chiral α-silyl-substituted α-hydroxyacetic acids. Resolution by means of HPLC using a chiral stationary phase afforded an enantiomerically pure representative of this class of compounds, which was successfully applied as a chiral ligand in an asymmetric aldol-type reaction.

Full text of DOI:10.1021/ol025911n

ORGANIC
LETTERS
2002
Vol. 4, No. 13
2265-2267
Synthesis and Use of r-Silyl-Substituted
r-Hydroxyacetic Acids†
,‡
Carsten Bolm,* Andrey Kasyan,‡ Peter Heider,‡ Sandra Saladin,‡
Karlheinz Drauz,§ Kurt Gu1nther, and Christoph Wagner|
Institute of Organic Chemistry, RWTH Aachen, Professor-Pirlet-Str. 1, D-52056
Aachen, Germany, Technology and R+D-Management des Gescha¨ftsbereichs
Feinchemikalien, Degussa AG, Postfach 1345, D-62403 Hanau, Germany, Analytisch
Technische SerVices, Infracor GmbH, Postfach 1345, D-62403 Hanau, Germany, and
Institute of Inorganic Chemistry, Martin-Luther-UniVersity Halle-Wittenberg,
Kurt-Mothes-Str. 2, D-06120 Halle, Germany
carsten.bolm@oc.rwth-aachen.de
Received May 2, 2002
ABSTRACT
Rhodium-catalyzed oxygen transfer was used to generate benzyl 2-silyl-2-oxoacetates in good yields. The hydrogenation of these compounds
led to chiral r-silyl-substituted r-hydroxyacetic acids. Resolution by means of HPLC using a chiral stationary phase afforded an enantiomerically
pure representative of this class of compounds, which was successfully applied as a chiral ligand in an asymmetric aldol-type reaction.
Chiral R-hydroxyacids are important components of natural
products and may be incorporated as diversely modified
building blocks in asymmetric synthesis.1 In past years,
numerous effective methods have been developed in order
to obtain enantiomerically pure R-hydroxyacids.2 In this
communication we describe the synthesis and structure of
R-silyl-substituted R-hydroxyacetic acids 13 and illustrate the
successful implementation of these compounds as ligands
in asymmetric catalysis.
† Dedicated to Professor Dr. G. Quinkert on the occasion of his 75th
birthday.
‡ RWTH Aachen.
The benzyl 2-silyl-2-oxoacetates 2 play a major role in
the synthesis of 1. In general, various practical routes leading
to R-ketoesters are known, including the ozonolysis of
alkynes4a and diazocompounds4b or the oxidation of the latter
§ Degussa AG, Hanau.
Infracor GmbH, Hanau.
| Martin-Luther-University Halle-Wittenberg.
(1) (a) Scott, J. W. In Asymmetric Synthesis; Morrison, J. D., Scott, J.
W., Eds.; Academic Press: New York, 1984; Vol. 4, p 1. (b) Seebach, D.;
Hungerbu¨hler, E. In Modern Synthetic Methods; Scheffold, R., Ed.; Otto
Salle Verlag: Frankfurt, 1980; Vol. 2, p 91. (c) Coppola, G. M.; Schuster,
H. F. Hydroxy Acids In EnantioselectiVe Synthesis; Wiley-VCH: Weinheim,
1997.
(2) (a) Pearson, W. H.; Cheng, M.-C. J. Org. Chem. 1986, 51, 3746. (b)
Seebach, D.; Naef, R.; Calderari, G. Tetrahedron 1984, 40, 1313. (c) Ley,
S. V.; Boons, G.-J.; Downham, R.; Kim, K. S.; Woods, M. Tetrahedron
1994, 50, 7157. (d) Xiang, Y. B.; Snow, K.; Belley, M. J. Org. Chem.
1993, 58, 993. (e) Camps, P.; Perez, F.; Soldevilla, N. Tetrahedron:
Asymmetry 1997, 8, 1877. (f) Wang, Z.; La, B.; Fortunak, J. M.; Meng,
X.-J.; Kabalka, G. W. Tetrahedron Lett. 1998, 39, 5501. (g) Cavelier, F.;
Gomez, S.; Jacquier, R.; Verducci, J. Tetrahedron Lett. 1994, 35, 2891.
(h) Adam, W.; Fell, R. T.; Stegmann, V. R.; Saha-Mo¨ller, C. R. J. Am.
Chem. Soc. 1998, 120, 708. (i) Yamamoto, Y.; Kin, H.; Suzuki, I.; Asao,
N. Tetrahedron Lett. 1996, 37, 1863. (j) Kirschning, A.; Dra¨ger, G.; Jung,
A. Angew. Chem. 1997, 109, 253; Angew. Chem., Int. Ed. Engl. 1997, 36,
253. (k) Chang, J.-W.; Jang, D.-P.; Uang, B.-J.; Liao, F.-L.; Wang, S.-L.
Org. Lett. 1999, 1, 2061.
(3) To the best of our knowledge, only one other compound of this class
has been reported before. However, in contrast to our work, this derivative
had a quartenary R-carbon bearing an additional methyl group at C2, and
it was obtained via an entirely different synthetic route (alkyne oxidation).
Murray, R. W.; Singh, M.; Rath, N. P. Acta Crystallogr., Sect. C 1996, 52,
1282.
(4) (a) Schank, K.; Beck, H.; Werner, F. HelV. Chim. Acta 2000, 83,
1611. (b) Sekiguchi, A.; Ando, W. J. Chem. Soc., Chem. Commun. 1979,
575.
10.1021/ol025911n CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/30/2002

substrates using MCPBA5 or dioxiranes.6 Furthermore,
photooxidative reactions have also been described.7 Catalytic
variants are particularly attractive and are gaining attention
due to their unusual chemoselectivity.8 On this basis, we
chose the rhodium-catalyzed reaction of benzyl 2-silyl-2-
diazoacetates 39 with propylene oxide 48a to prepare 2. The
benzyl 2-silyl-2-oxoacetates 2 were obtained in good yields,
and the best results were found for 2b and 2c (up to 95%,
Table 1). In contrast, 3e proved inert to these reaction
on charcoal. To our surprise, this reaction led to the formation
of the novel R-triorganylsilyl-R-hydroxyacetic acids 1 (Table
2) in up to 89% yield. This result was unexpected, since
Table 2. Synthesis of R-Triorganylsilyl-R-hydroxyacetic Acids
1
Table 1. Synthesis of Benzyl 2-Silyl-2-oxoacetates 2
entry
diazoester
R1/2
R3
product
yield (%)
entry
2
product
yield (%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
Me
Et
Me
Et
2a
2b
2c
5
82
89
95
91
1
2
3
4
a
b
c
f
1a
1b
1c
6f
78
85
89
67
Me
Me
iPr
Me
Ph
Ph
tBu
Thex
iPr
Ph
Me
Ph
3f
2g
2h
85
88
81
3g
3h
prior work involving hydrogenation of R-ketobenzyl esters
resulted in debenzylation with formation of the corresponding
R-ketoacids.11 In the case of the dimethylphenylsilyl deriva-
tive 2f, the reaction behavior was even completely reversed,
such that the benzyl ester 6f was obtained solely via reduction
of the R-keto group.
conditions, most probably because of steric hindrance, and
the diazocompound 3d underwent an intramolecular C-H
insertion reaction to form silacyclobutane 5.10
An X-ray crystal structure analysis confirmed the constitu-
tion of the racemic R-silyl-substituted R-hydroxyacetic acid
1c (Figure 1).12 The Si-C1 bond 1.927(2) Å in rac-1c is
Scheme 1
Next, we studied the palladium-catalyzed reduction of the
silylketoesters 2 using molecular hydrogen and palladium
(5) (a) Thorsett, E. D. Tetrahedron Lett. 1982, 23, 1875. (b) Garcia, F.
S.; Cebria´n, G. M. P.; Lo´pez, A. H.; Herrara, F. J. L. Tetrahedron 1998,
54, 6867.
(6) (a) Darkins, P.; McCarthy, N.; McKervey, M. A.; O’Donnell, K.;
Ye, T.; Walker, B. Tetrahedron: Asymmetry 1994, 5, 195. (b) Saba, A.
Synth. Commun. 1994, 24, 695.
Figure 1. Molecular crystal structure of rac-1c. Selected distances
[Å] and angles [deg]: Si-C1 1.927(2), O1-C1 1.427(3), C2-C1
1.492(3), C2-O2 1.209(3), C2-O3 1.320(3); C2-C1-Si 114.67-
(15), O1-C1-Si 109.75(15), O1-C1-C2 111.5(2), C5-Si-C1
112.58(12), C4-Si-C3 110.14(19), C3-Si-C5 111.04(15), C4-
Si-C5 110.80(16).
(7) (a) Sekiguchi, A.; Kabe, Y.; Ando, W. Tetrahedron Lett. 1979, 871.
(b) Sekiguchi, A.; Kabe, Y.; Ando, W. J. Org. Chem. 1982, 47, 2900.
(8) (a) Martin, M. G.; Ganem, B. Tetrahedron Lett. 1984, 25, 251. (b)
McKenna, C. E.; Levy, J. N. J. Chem. Soc., Chem. Commun. 1989, 246.
(c) Solbakken, M.; Skramstad, J. Acta Chem. Scand. 1993, 47, 1214.
(9) (a) For the synthesis of 3 from benzyl 2-diazoacetates with triorga-
nylsilyltriflates, see: Bolm, C.; Kasyan, A.; Drauz, K.; Gu¨nther, K.; Raabe,
G. Angew. Chem. 2000, 112, 2374; Angew. Chem. Int. Ed. 2000, 39, 2288.
(b) The synthesis of the required triorganylsilyltriflates was accomplished
according to: Uhlig, W. Chem. Ber. 1992, 125, 43.
(10) (a) For an analogous reactivity, see: Maas, G.; Bender, S. Chem.
Commun. 2000, 437. (b) An excellent overview of silyl-substituted carbenes
may be found in: Maas, G. In The Chemistry of Organic Silicon
Compounds; Rappoport, Z., Apeloig, Y., Eds.; Wiley: Chichester, 1998;
Vol. 2, Part 1, Chapter 13, p 703.
significantly longer than those between the silicon atom and
C3 [1.861(3) Å], C4 [1.863(3) Å], and C5 [1.893(3) Å]; the
last three lengths fall within the range that is considered
average for a bond between a four-coordinate Si atom and
(11) Hilbert, J. M.; Fedor, L. J. Org. Chem. 1978, 43, 452.
Org. Lett., Vol. 4, No. 13, 2002
2266

an sp3-hybridized carbon atom [1.863(24) Å].13 Analogous
observations were made in the case of the crystal structure
of a comparably protected R-amino acid.9
between benzaldehyde 7 and silylketeneketal 8 in the
presence of 10 mol % (+)-1a and a borane-THF complex
was chosen to test this hypothesis (Scheme 3).16 Running
The study was further extended in order to resolve racemic
1a into its enantiomers. However, this was initially unsuc-
cessful, and the first enantiomerically pure R-triorganylsilyl-
R-hydroxyacetic acid was finally obtained via a three-step
strategy (Scheme 2). First, R-ketoester 2a was reduced to
Scheme 3
Scheme 2
the reaction with an in situ generated CAB-type17 catalyst
showed a considerably high asymmetric induction, producing
(S)-9 in 86% ee.18
This result opens up the possibility of using chiral
R-triorganosilyl-R-hydroxyacids in other catalytic reactions,
and extending their scope as a new class of ligands.19
In conclusion, we have synthesized the novel R-silyl-
substituted R-hydroxyacetic acids and proved their structure
by means of X-ray crystallography. Moreover, the synthetic
utility of these compounds as ligands in asymmetric catalysis
has been illustrated. Further applications are currently
underway and will be reported in due course.
R-hydroxybenzyl ester rac-6a using sodium borohydride in
THF at 0 °C, and second, the enantiomers of the latter
compound were separated using preparative HPLC.14 There-
after, a palladium-catalyzed hydrogenolytic debenzylation of
the (+)-enantiomer of 6a afforded (+)-1a in 76% yield.15
Next, we were interested in determining whether the
R-silylated R-hydroxyacetic acids could be used as chiral
ligands in asymmetric catalysis. The aldol-type reaction
Acknowledgment. We are grateful to the Deutsche
Forschungsgemeinschaft (SPP 1118, Graduiertenkolleg 440)
and the Fonds der Chemischen Industrie for financial support.
A.K. thanks Degussa for a postdoctoral fellowship.
(12) The crystallographic data for the compound (rac-1c) was deposited
as Supporting Information at the Cambridge Crystallographic Data Centre
under the publication no. CCDC-174123. Copies may be obtained free of
charge from the following location in Great Britain: CCDC, 12 Union Road,
Cambridge CB2 1EZ (FAX: (+44) 1223-336-033. E-mail: deposit@
ccdc.cam.ac.uk).
(13) F. H. Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen,
A. G.; Taylor, R. J. Chem. Soc., Perkin Trans. 2 1987, S1.
(14) HPLC separation. Analytic: Chiralpak AS (Daicel); 4.6 mm × 250
mm; isohexane/2-propanol 95:5; 215 nm; 0.5 mL/min; 25 °C, tR (-)-6a
11.6 min, tR (+)-6a: 25.3 min. Preparative: as for analytic separation but
using 40 mm × 250 mm, 225 nm, and 40 mL/min
Supporting Information Available: Experimental pro-
cedures and full characterization (1H and 13C NMR data, MS,
IR, and CHN analyses) for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL025911N
(15) (a) Synthesis of rac-2-tert-Butyldimethylsilyl-2-hydroxyacetic
Acid (1c). To a stirring and degassed solution of 3c (580 mg, 2 mmol9)
and propylene oxide (2 mL) in dry toluene (10 mL) at rt was added [Rh2-
(OAc)4] (18 mg, 0.04 mmol, 2 mol %). The reaction mixture was heated to
40 °C and was left stirring at this temperature for 48 h. After the mixture
cooled to room temperature, the solvent was removed in vacuo, and the
crude silylketoester was purified by flash chromatography on silica gel (25:1
petroleum ether/ethyl acetate) to give 524 mg (95%) of 2c as yellow oil.
To a solution of 2c (276 mg, 1 mmol) in ethyl acetate (5 mL) was added
10% Pd/C (10 mg), and the reaction mixture was stirred at room temperature
for 5 h in the presence of a blanket of hydrogen. After filtration, the solvent
was removed in vacuo, and purification via flash chromatography on silica
gel (3:1 petroleum ether/ethyl acetate) afforded 169 mg (89%) rac-1c as a
white solid, mp 101-102 (petroleum ether/ethyl acetate). The molecular
structure of rac-1c in the solid state was confirmed by X-ray crystal
structural analysis.12 (b) Synthesis of (+)-2-Trimethylsilyl-2-hydroxyacetic
Acid [(+)-1a]. To a stirring and degassed solution of 2a (472 mg, 2 mmol)
under argon in dry THF (5 mL) was added NaBH4 at 0 °C (40 mg, 1.1
mmol). The reaction mixture was stirred for another 3 h at room temperature
after the addition was complete. After the solvent was removed in vacuo,
dichloromethane (10 mL) was added to the residue, and the solution was
washed with 3% HCl (20 mL). The organic layer was separated and dried
over anhydrous MgSO4, before the solvent was removed in vacuo. The
pure product was isolated via flash chromatography on silica gel (10:1
petroleum ether/ethyl acetate) to provide 228 mg (48%) of the hydroxyacetic
benzyl ester 6a as a colorless oil. The enantiomers of 6a were separated
via preparative HPLC.14 The (+)-enantiomer of 6a was hydrogenolytically
debenzylated to the hydroxyacetic acid (+)-1a (76% yield) by means of
Pd/C catalysis.
(16) For current overviews of this field, see: (a) Nelson, S. G.
Tetrahedron: Asymmetry 1998, 9, 357. (b) Carreira, E. M. In Comprehen-
siVe Asymmetric Catalysis; Jacobsen, E. N., A. Pfaltz, A., H. Yamamoto,
H., Eds.; Springer: Berlin, 1999; Vol. 3, p 998.
(17) CAB stands for “chiral acyloxyborane” and describes catalysts that
are synthesized from boranes with chiral carboxylic acids (i.e., R-hydroxy-
and R-amino acids). For examples, see: (a) Takasu, M.; Yamamoto, H.
Synlett 1990, 194. (b) Sartor, D.; Saffrich, J.; Helmchen, G. Synlett 1990,
197. (c) Ishihara, K.; Kondo, S.; Yamamoto, H. J. Org. Chem. 2000, 65,
9125 and references therein.
(18) Standard protocol for Aldol-Type Reaction. To the hydroxyacetic
acid (+)-1a (0.1 mmol, 14.8 mg, 0.1 equiv) in propionitrile (1.5 mL) was
added BH3‚THF (100 µL of 1 M solution in THF, 0.1 mmol, 0.1 equiv).
The solution was heated for 1 h at 45 °C and then cooled to -78 °C.
Silylketeneketal 8 (126 µL, 125 mg, 1.2 mmol, 1.2 equiv) was added,
followed by benzaldehyde (106 mg, 1.0 mmol, 1.0 equiv) in propionitrile
(1 mL) using a syringe pump over 3 h. The reaction mixture was stirred
for another 1 h at -78 °C after the addition was complete and then added
to So¨rensen buffer (pH 7) at 0 °C. After the standard purification procedure,
the silyl ether was hydrolyzed to the corresponding â-hydroxyester by using
1 N HCl in THF (5 mL). Flash chromatography on silica gel (3:7 ether/
pentane) afforded 204 mg (92%) of (S)-9. The enantiomer ratio of 9 was
determined by HPLC using a chiral column (Chiralcel-OD; 0.5 mL/min;
95:5 hexane/2-propanol; tR (R)-9 30 min (minor), tR (S)-9 35 min (major).
(19) Recently, it has been shown that R-hydroxyacids with bulky
substituents may be successfully used as chiral ligands in the enantioselective
addition of diethylzinc to benzaldehyde, achieving good ee’s. Bauer, T.;
Tarasiuk, J. Tetrahedron Lett. 2002, 43, 687.
Org. Lett., Vol. 4, No. 13, 2002
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