Efficient enantio- and diastereoselective synthesis of enantiopure syn-α-bromo-β-hydroxy-α-methylpropionate esters and their cis-α,β-epoxy derivatives based on a chiral oxazaborolidinone-promoted asymmetric aldol reaction

Article abstract of DOI:10.1016/S0957-4166(00)00089-6

syn-α-Bromo-β-hydroxy-α-methylpropionate esters were prepared in high diastereoselectivity with essentially enantiopure state by employing the chiral oxazaborolidinone-promoted asymmetric aldol reaction with β-bromo-β-methylketene silyl acetal. The subsequent subjection of the α-bromo-β-hydroxy esters to basic conditions led to the quantitative transformation to the corresponding enantiopure cis-α,β-epoxy derivatives. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00089-6

Tetrahedron: Asymmetry 11 (2000) 1537±1542
Ecient enantio- and diastereoselective synthesis of
enantiopure syn-a-bromo-b-hydroxy-a-methylpropionate
esters and their cis-a,b-epoxy derivatives based on a
chiral oxazaborolidinone-promoted asymmetric
aldol reaction
Syun-ichi Kiyooka* and Kazi A. Shahid
Department of Chemistry, Faculty of Science, Kochi University, Akebono-cho, Kochi 780-8520, Japan
Received 31 January 2000; accepted 24 February 2000
Abstract
syn-a-Bromo-b-hydroxy-a-methylpropionate esters were prepared in high diastereoselectivity with
essentially enantiopure state by employing the chiral oxazaborolidinone-promoted asymmetric aldol reaction
with b-bromo-b-methylketene silyl acetal. The subsequent subjection of the a-bromo-b-hydroxy esters to
basic conditions led to the quantitative transformation to the corresponding enantiopure cis-a,b-epoxy
derivatives. # 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
Development of versatile syntheses of enantiopure a-bromo-b-hydroxy esters is required in
order to extend their availability as precursors to a,b-epoxy esters, a-amino-b-hydroxy esters, b-
amino-a-hydroxy esters and so on.1 These studies are, however, limited to anti isomers without
an alkyl substituent at the a-position of the a-bromo-b-hydroxy esters.2 E€ective preparation of
enantiopure a-bromo-b-hydroxy-a-methyl esters is being intensively studied to provide a,a-
disubstituted a-amino acids with a methyl group at the a-position as constituents of biologically
active compounds.3 We disclose herein a highly enantio- and diastereoselective general synthesis
of such a-bromo-b-hydroxy-a-methyl esters realized by using the stereoselective oxaza-
borolidinone-promoted asymmetric aldol reaction with b-bromo-b-methylketene silyl acetal.
* Corresponding author. Fax: (+81)888448360; e-mail: kiyo@cc.kochi-u.ac.jp
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00089-6

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S. Kiyooka, K. A. Shahid / Tetrahedron: Asymmetry 11 (2000) 1537±1542
2. Results and discussion
We were aware that considerably large substituents at the b-position of ketene silyl acetals
brings about the high enantioselectivity (almost >98% ee) in asymmetric aldol reactions in the
4
.
presence of chiral oxazaborolidinone 1, prepared in situ from L-Ts-Val and BH3 THF.
According to the strategy, b-bromo-b-methylketene silyl acetal 2 (bp 73±74ꢀC/0.1 mmHg,
E:Z=1: 2) was chosen as an appropriate silyl nucleophile available for the topic under study. The
reaction of a variety of aldehydes with the silyl nucleophile 2 proceeded in good yields under
standard conditions (CH2Cl2, ^78ꢀC, 15 h, in the presence of a stoichiometric amount of chiral
borane 1) and the results are summarized in Table 1. Very high enantioselectivities were observed
as expected. The considerably high diastereoselection observed is particularly intriguing beyond
the scope of the asymmetric aldol reaction which proceeds independent of the geometry of the
silyl nucleophiles used.4,5 The following transformation (DIBALH reduction and acetalization)
was carried out with respect to syn-3a and then the structure of the acetonide was con®rmed
(Scheme 1). When 3a was ®rst reported as an intermediate for radical reactions in a previous
paper,6 the con®guration was assigned as anti from the misinterpretation of three singlet methyls
in the acetonide derivative. The detailed NOE experiments allowed revision of the structure as syn
after reassignment of the methyls using H±H COSY with Eu(fod)3 shift reagent.
Table 1
Preparation of enantiopure syn-a-bromo-b-hydroxy-a-methylpropionate
esters by chiral oxazaborolidinone-promoted aldol reactions
For a rationale to explain the syn selectivity, a predominant arrangement of the aldehyde car-
bonyl and the silyl nucleophile should be indispensable to a transition state assembly, as depicted
in Scheme 2. Electronic e€ects might be presumably requisite to the arrangement because the steric

S. Kiyooka, K. A. Shahid / Tetrahedron: Asymmetry 11 (2000) 1537±1542
1539
Scheme 1.
Scheme 2. A transition state assembly to syn
bulkiness of bromo and methyl substituents (van der Waals radii) is nearly the same.7 This
reaction is unexpectedly useful for the synthesis of such enantiopure compounds. In addition, it
is practically useful that the major syn isomers can be easily puri®ed by simple ¯ash column
chromatography on silica gel.
Table 2
Stereospeci®c transformation of syn-a-bromo-b-hydroxy esters to
tri-substituted cis-a,b-epoxy estersa

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S. Kiyooka, K. A. Shahid / Tetrahedron: Asymmetry 11 (2000) 1537±1542
Scheme 3. The observed NOEs
We can, furthermore, demonstrate a facile utility of the enantiopure syn-3 compounds by
transformation of them to tri-substituted cis-epoxy esters, which are also versatile synthetic
intermediates. By treatment of sodium ethoxide in ethanol, syn-3 was converted to the corre-
sponding tri-substituted cis-epoxy ester 4 in good yields, as shown in Table 2. The reaction takes
place in a stereospeci®c manner so that a single product is produced. All stereochemistries in this
paper were recon®rmed by NOEs between the hydrogen and the methyl in all cis-epoxides
(Scheme 3).
3. Conclusion
An ecient enantio- and diastereoselective synthesis of enantiopure syn-a-bromo-b-hydroxy-a-
methylpropionate esters was conveniently realized and the following transformation also pro-
ceeded to the corresponding enantiopure tri-substituted cis-a,b-epoxy esters in high yields.
4. Experimental
4.1. General
Unless otherwise noted, materials were obtained from commercial suppliers and were used
without further puri®cation. Tetrahydrofuran (THF) was distilled from sodium/benzophenone
immediately prior to use. All reactions involving organometallic reagents were conducted under
an argon atmosphere. IR spectra were determined with a JASCO FT/IR-5300 Fourier transform
1
infrared recording spectrophotometer. H NMR spectra were determined on a JEOL JNM-LA
400 (a superconducting, 400 MHz, FT instrument) spectrometer. Chemical shifts are expressed in
1
parts per million down®eld from internal tetramethylsilane. Signi®cant H NMR data are tabu-
lated in the following order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet),
coupling constant(s) in hertz, number of protons. 13C NMR spectra were measured at 100 MHz
with a JOEL JNM-LA 400 spectrometer. High-pressure liquid chromatography (HPLC) was
done with a JASCO Model PU-980 liquid chromatograph.
4.2. A typical procedure of chiral oxazaborolidinone-promoted asymmetric aldol reactions with
b-bromo-b-methylketene silyl acetal 2
To a solution of N-(p-toluenesulfonyl)-S-valine (1.5 g, 5.5 mmol) in dry CH2Cl2 (25 mL) at 0ꢀC
.
was added BH3 THF (5.0 mL, 5.0 mmol, 1 M in THF). The solution was stirred for 30 min at
0ꢀC, then additionally for 30 min at rt. The solution was cooled to ^78ꢀC and benzaldehyde (0.5
mL, 5.0 mmol) in CH2Cl2 (1 mL) was added slowly over 5 min. After stirring for 5 min, 2 (1.77 g,
7.0 mmol) in CH2Cl2 (2 mL) was added dropwise over 5 min, the reaction mixture was stirred for

S. Kiyooka, K. A. Shahid / Tetrahedron: Asymmetry 11 (2000) 1537±1542
1541
15 h at ^78ꢀC, and 10% hydrochloric acid (5 mL) was added to quench the reaction. The reaction
mixture was allowed to warm to rt and evaporated to a concentrated residue. The residue was
diluted with ether and the phases were separated. The organic phase was washed with satd
NaHCO3 aq. solution and brine, dried over MgSO4, and evaporated in vacuo. Flash column
chromatography (7% ethyl acetate/hexane) provided separately the pure aldols of syn-3a and
anti-3a with a ratio of 7:1 (Rf values 0.4 and 0.3, respectively, on silica gel TLC with 20% ethyl
acetate in hexane) (1.18 g, 82%).
22
D
1
Compound syn-3a: ‰ꢀŠ +10.1 (c 1.48, CHCl3). IR (®lm) 3508, 1734 cm^1. H NMR (CDCl3,
400 MHz): ꢁ 1.30 (t, J=7.07, 3H), 1.75 (s, 3H), 3.27 (d, J=3.16, 1H), 4.24 (q, J=7.07, 2H), 5.23
(d, J=2.92, 1H), 7.25±7.51 (m, 5H). 13C NMR (CDCl3, 100 MHz): ꢁ 13.79, 22.55, 62.40, 67.67,
77.16, 127.90, 128.00, 128.51, 136.86, 170.46. Anal. calcd for C12H15O3Br: C, 50.19; H, 5.27.
Found: C, 50.21; H, 5.31.
22
Compound syn-3b: ‰ꢀŠ ^10.7 (c 3.66, CHCl3). IR (®lm) 3506, 1735 cm^1. H NMR (CDCl3,
1
D
400 MHz): ꢁ 0.88 (d, J=6.8, 3H), 1.06 (d, J=6.60, 3H), 1.32 (t, J=7.07, 3H), 1.76 (septet,
J=6.84, 1H), 1.88 (s, 3H), 2.52 (br.s, 1H), 3.94 (d, J=6.09, 1H), 4.25 (m, 2H). 13C NMR
(CDCl3, 100 MHz): ꢁ 13.72, 19.22, 20.41, 21.83, 30.95, 62.08, 69.37, 78.99, 170.62. Anal. calcd for
C9H17O3Br: C, 42.70; H, 6.77. Found: C, 42.77; H, 6.64.
22
Compound syn-3c: ‰ꢀŠ +45.0 (c 0.77, CHCl3). IR (®lm) 3508, 1732 cm^1. H NMR (CDCl3,
1
D
400 MHz): ꢁ 1.24 (t, J=7.07, 3H), 1.62±1.85 (m, 2H), 1.82 (s, 3H), 2.73 (d, J=4.64, 1H), 2.66±
2.73 (m, 1H), 2.96 (ddd, J=9.52, 4.88, 14.16, 1H), 4.01 (ddd, J=4.16, 1.96, 10.04, 1H), 4.20 (q,
J=7.07, 2H), 7.17±7.38 (m, 5H). 13C NMR (CDCl3, 100 MHz): ꢁ 13.76, 22.45, 32.53, 32.54,
62.24, 67.71, 74.86, 126.00, 128.41, 128.46, 141.40, 170.57. Anal. calcd for C14H19O3Br: C, 53.34;
H, 6.08. Found: C, 54.00; H, 6.13.
22
Compound syn-3d: ‰ꢀŠ +21.5 (c 1.81, CHCl3). IR (®lm) 3504, 1736 cm^1. H NMR (CDCl3,
1
D
400 MHz): ꢁ 0.84 (t, J=7.07, 3H), 1.22 (t, J=7.07, 3H), 1.12±1.28 (m, 1H), 1.30±1.42 (m, 2H),
1.49±1.61 (m, 1H), 1.72 (s, 3H), 2.51 (d, J=4.40, 1H), 3.94 (dd, J=4.40, 9.52, 1H), 4.17 (m, 2H).
13C NMR (CDCl3, 100 MHz): ꢁ 13.75, 13.79, 19.68, 22.26, 33.86, 62.15, 68.17, 75.38, 170.59.
Anal. calcd for C9H17O3Br: C, 42.70; H, 6.77. Found: C, 43.21; H, 6.55.
22
Compound syn-3e: ‰ꢀŠ +2.3 (c 3.49, CHCl3). IR (®lm) 3462, 1736 cm^1. H NMR (CDCl3,
1
D
400 MHz): ꢁ 0.0 (s, 6H), 0.82 (s, 9H), 1.23 (t, J=7.07, 3H), 1.54±1.67 (m, 2H), 1.78 (s, 3H), 3.35
(d, J=2.93, 1H), 3.71±3.82 (m, 2H), 4.15 (dt, J=2.88, 9.28, 1H), 4.18 (q, J=7.07, 2H). 13C NMR
(CDCl3, 100 MHz): ꢁ ^5.54, ^5.50, 13.83, 18.16, 23.00, 25.83, 34.35, 61.19, 62.19, 66.57, 74.55,
170.51. Anal. calcd for C14H29O4BrSi: C, 45.52; H, 7.91. Found: C, 45.86; H, 7.73.
4.3. A typical procedure of stereospeci®c transformation of syn-a-bromo-b-hydroxy esters to cis-
a,b-epoxy esters
To a solution of syn-3a (574 mg, 2.0 mmol) in EtOH (10 mL) was added sodium ethoxide (1 M
soln in EtOH) and the reaction mixture was stirred for 2 h at rt. The reaction mixture was
evaporated in vacuo. The resulting residue was dissolved in ether, washed with water, and dried
over MgSO4. After evaporation of the solvent, the crude material was puri®ed by ¯ash column
chromatography (4% ethyl acetate/hexane) to provide cis-4a (358.4 mg, 87%) as a colorless oil.
22
D
1
Compound cis-4a: ‰ꢀŠ +34.4 (c 1.01, CHCl3). IR (®lm) 1749 cm^1. H NMR (CDCl3, 400
MHz): ꢁ 0.92 (t, J=7.07, 3H), 1.72 (s, 3H), 3.93 (m, 2H), 4.02 (s, 1H), 7.10±7.39 (m, 5H). 13C
NMR (CDCl3, 100 MHz): ꢁ 13.70, 19.41, 61.01, 62.85, 63.69, 126.26, 127.90, 128.12, 133.68,
168.45. Anal. calcd for C12H14O3: C, 69.88; H, 6.84. Found: C, 70.02; H, 6.69.

1542
S. Kiyooka, K. A. Shahid / Tetrahedron: Asymmetry 11 (2000) 1537±1542
22
D
Compound 4b: ‰ꢀŠ +23.8 (c 1.30, CHCl3). IR (®lm) 1749 cm^1. 1H NMR (CDCl3, 400 MHz):
ꢁ 0.86 (d, J=6.84, 3H), 1.03 (d, J=6.60, 3H), 1.23 (t, J=7.07, 3H), 1.33±1.46 (m, 1H), 1.50 (s,
3H), 2.55 (d, J=9.52, 1H), 4.18 (m, 2H). 13C NMR (CDCl3, 100 MHz): ꢁ 14.15, 18.25, 19.45,
19.96, 27.85, 60.01, 61.27, 69.62, 170.02. Anal. calcd for C9H16O3: C, 62.76; H, 9.36. Found: C,
62.34; H, 9.57.
22
D
1
Compound 4c: ‰ꢀŠ +32.9 (c 0.42, CHCl3). IR (®lm) 1745 cm^1. H NMR (CDCl3, 400 MHz):
ꢁ 1.27 (t, J=7.07, 3H), 1.54 (s, 3H), 1.90 (m, 2H), 2.73 (dt, J=8.04, 13.88, 1H), 2.84 (ddd,
J=8.76, 6.08, 14.16, 1H), 2.95 (t, J=6.22, 1H), 4.18 (q, J=7.07, 2H). 13C NMR (CDCl3, 100
MHz): ꢁ 14.24, 19.34, 29.87, 32.36, 59.72, 61.49, 63.53, 126.15, 128.37, 128.50, 140.75, 169.93.
Anal. calcd for C14H18O3: C, 71.77; H, 7.74. Found: C, 71.84; H, 7.81.
22
Compound 4d: ‰ꢀŠ +35.8 (c 0.61, CHCl3). IR (®lm) 1746 cm^1. 1H NMR (CDCl3, 400 MHz):
D
ꢁ 0.94 (t, J=7.07, 3H), 1.30 (t, J=7.07, 3H), 1.40±1.61 (m, 4H), 1.56 (s, 3H), 2.92 (t, J=5.86,
1H), 4.24 (q, J=7.07, 2H). 13C NMR (CDCl3, 100 MHz): ꢁ 13.75, 14.21, 19.33, 19.44, 30.03,
59.51, 61.33, 64.08, 170.11. Anal. calcd for C9H16O3: C, 62.76; H, 9.36. Found: C, 63.10; H, 9.29.
22
D
1
Compound 4e: ‰ꢀŠ +12.9 (c 2.80, CHCl3). IR (®lm) 1749 cm^1. H NMR (CDCl3, 400 MHz):
ꢁ 0.0 (s, 6H), 0.83 (s, 9H), 1.23 (t, J=7.07, 3H), 1.51 (s, 3H), 1.65±1.79 (m, 2H), 3.04 (dd, J=6.12,
6.12, 1H), 3.70 (m, 2H), 4.17 (m, 2H). 13C NMR (CDCl3, 100 MHz): ꢁ ^5.34, 14.15, 18.19, 19.28,
25.79, 31.31, 59.28, 59.92, 61.31, 61.85, 169.96. Anal. calcd for C14H28O4Si: C, 50.30; H, 9.79.
Found: C, 49.97; H, 9.83.
Acknowledgements
This work was supported by Grant-in-Aids for Scienti®c Research (Grant Nos. 9554046 and
10640525) from the Ministry of Education, Science, Culture and Sports.
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