A facile method for the synthesis of enantiopure α-unsubstituted β- hydroxy esters

Article abstract of DOI:10.1016/S0957-4166(00)00109-9

One-pot deacylation-debromination reactions involving the transesterification of the initial chiral α-bromo-β-hydroxy thioimide aldol adducts and subsequent Al-Hg mediated reductive cleavage of the C-Br bond allow for a facile synthesis of enantiopure β-h

Full text of DOI:10.1016/S0957-4166(00)00109-9

Tetrahedron: Asymmetry 11 (2000) 1797±1800
A facile method for the synthesis of enantiopure
a-unsubstituted b-hydroxy esters
Ying-Chuan Wang, Jia-Yang Hwang, Yih-Cheng Chen,
Shang-Chi Chuang and Tu-Hsin Yan*
Department of Chemistry, National Chung-Hsing University, Taichung, Taiwan 400, Republic of China
Received 21 February 2000; accepted 14 March 2000
Abstract
One-pot deacylation±debromination reactions involving the transesteri®cation of the initial chiral a-bromo-
b-hydroxy thioimide aldol adducts and subsequent Al±Hg mediated reductive cleavage of the C±Br bond
allow for a facile synthesis of enantiopure b-hydroxy esters. # 2000 Published by Elsevier Science Ltd.
1. Introduction
As a consequence of the importance of enantiomerically pure aldol adducts, considerable e€ort
has been directed toward the development of asymmetric syntheses of homochiral a-unsubstituted
b-hydroxy carboxylate compounds1,2 and the use of homochiral b-hydroxy esters as key building
blocks in the synthesis of drugs and natural products.3 Asymmetric aldol additions are one-step
routes to chiral a-unsubstituted b-hydroxy carboxylates. However, the stereocontrol observed in
metal-assisted aldolizations of chiral unsubstituted enolates of the `acetate' type are not as good
as those obtained from a-substituted metal enolates.1,4 Quite recently, Yamamoto has developed
a chiral acetate ester which adds to a variety of aldehydes in good to excellent yield (57±90%)
with excellent diastereoselectivity (94±99% de).5 The other main general solution to this problem
is based on the incorporation of an auxiliary substituent in the a-position.4 The ease of access to
chiral a-sulfenylated and bromohydrin aldol adducts of 85±99% ee makes the conversion of
a-substituted aldol adducts into a-unsubstituted b-hydroxy carboxylates a useful transformation.
The recently developed catalytic hydrogenolysis4,6 and tri-n-butyltin hydride mediated radical
cleavage of the carbon±bromine bond a€orded b-hydroxy esters in good to excellent yields.7 Our
recent discovery of a one-pot process for the asymmetric bromination±aldolization of acetate
thioimide enolate provided an incentive to ®nd uses for the chiral bromohydrin aldol adducts.8
We report here on a facile process for the conversion of chiral bromohydrin aldols to enantiopure
b-hydroxy esters.
* Corresponding author. E-mail: thyan@mail.nchu.edu.tw
0957-4166/00/$ - see front matter # 2000 Published by Elsevier Science Ltd.
PII: S0957-4166(00)00109-9

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Y.-C. Wang et al. / Tetrahedron: Asymmetry 11 (2000) 1797±1800
2. Results and discussion
Previous reports from our laboratory have documented the utility of acetate thioimide 2 for the
construction of homochiral bromohydrin aldols 3.8 The bromination±aldolization of acetate
thioimide enolate to a variety of aldehydes was carried out by a standard procedure.8 With chiral
bromohydrins 3 in hand, the stage was set for establishing the feasibility of Al±Hg as a mild
reducing reagent to e€ect chemoselective cleavage of the C±Br bond in 3. However, attempts to
reductively cleave the C±Br bond in 3 resulted in a complex mixture as a consequence of the
instability of the a-bromo thioimide aldol adducts. The above problems were circumvented by
the bromo thioimide aldol adducts 3 being ®rst converted to the stable benzyl a-bromo esters 4,8
and reductive debromination then performed at this stage. Simply adding Al±Hg (mercury
content ꢀ2.5%) to the bromo ester 4a led to clean debromination within 30 min to give b-hydroxy
ester 5a in 91% isolated yield (Scheme 1). Aldol adduct 4b derived from benzaldehyde gave a
similar result. Thus, the same conditions e€ected deacylation±debromination of 4b to a€ord 96%
overall yield of b-hydroxy ester 5b. Extension of these observations to other unsaturated a-bromo
esters con®rms their generality. Our attention next turned to exploring the chemoselective cleav-
age of the C±Br bond of bromo esters 4c±e, which by virtue of the sensitivity of the unsaturation
within a molecular framework demand mild reduction conditions (Scheme 1). Fortunately, we
found that the Al±Hg promoted debromination not only resulted in the suppression of ole®n
saturation, which is a major problem with H2/Pd/C, but also a€orded complete control for the
desired mode of reductive cleavage. Potential dehydroxybromination in the intermediate carbanion
does not appear to compete kinetically with carbon±hydrogen formation. Most gratifyingly, the
transesteri®cation±debromination approach to the conversion of the initial homochiral bromo-
hydrin aldols to b-hydroxy esters could be accomplished in a one-pot procedure in good to
excellent yields. The simplicity of this one-pot procedure is exempli®ed by the details given for the
case of 3b in the Experimental. The enantiomeric excesses of these b-hydroxy esters were mea-
sured by direct comparison to the racemic esters and analyzed by chiral HPLC. The analyses by
HPLC on a Chiralcel OD column (Daicel Chemical Industries) indicated that b-hydroxy esters
5a±e were essentially enantiomerically pure (>99% ee).
Scheme 1.

Y.-C. Wang et al. / Tetrahedron: Asymmetry 11 (2000) 1797±1800
1799
3. Conclusions
Unlike the reported debromination conditions employed, such as catalytic hydrogenolysis
(H2/Pd±C) and tri-n-butyltin hydride mediated reduction, the Al±Hg mediated chemoselective
cleavage of the C±Br bond allows for a mild transformation of bromohydrin aldols into b-hydroxy
esters in the presence of sensitive functionality. Synthetically, the present studies o€er an ecient
and high-yielding asymmetric synthesis of enantiopure a-unsubstituted b-hydroxy esters.
4. Experimental
4.1. General
Diisopropylethylamine and dichloromethane were dried by distillation under N2 from calcium
hydride. TiCl4 (1 M in CH2Cl2) was used as received. All aldehydes were freshly distilled prior to
use. Unless otherwise noted, all non-aqueous reactions were carried out under a dry nitrogen
atmosphere with oven-dried glassware. Flash chromatography was done on E. Merck silica gel 60
(230±400 mesh). Concentrations for rotation data are given as g/100 mL of solvent. Diastereomeric
excesses (de) were determined by HPLC on a Chiralcel OD column (Daicel Chemical Industries).
4.2. General procedure for the deacylation±debromination reactions of 3
Aluminum amalgam was prepared from granular aluminum (ꢀ40 mesh, 0.1 g), which was
immersed, all at once, into an aqueous solution of HgCl2 (1%, 2.5 mL). After shaking for 10 s,
the grey amalgamated metal was washed with distilled water (10 mL) and used at once. To a
solution of 3b (390 mg, 1 mmol) and PhCH2OH (1.2 mmol) in CH3CN or CH2Cl2 (4 mL) at 0ꢁC
was added a solution of DMAP (0.2 mmol) in 0.5 mL of CH2Cl2. The mixture was stirred at that
temperature for 4 h, and aluminum amalgam was added followed by water (0.2 mL). After stir-
ring for 30 min at 0ꢁC, the mixture was ®ltered and the residue was washed with two 10 mL portions
of CH2Cl2. The combined organic extracts were washed with 5% HCl and brine. The organic
layer was dried (MgSO4), ®ltered, and concentrated in vacuo to give b-hydroxy ester 5b and
recovered 1. New compounds have been satisfactorily characterized spectroscopically, and elemental
composition has been established by high-resolution mass spectroscopy or combustion analysis.
4.3. Phenylmethyl (S)-3-hydroxyhexanoate 5a
1H NMR (400 MHz, CDCl3) ꢀ 7.39±7.32 (m, 5H), 5.13 (s, 2H), 4.04±3.99 (m, 1H), 2.77 (bs,
1H), 2.53 (dd, J=16, 3.2 Hz, 1H), 2.44 (dd, J=16, 9.2 Hz, 1H), 1.52±1.32 (m, 4H), 0.90 (t, J=7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) ꢀ 172.02, 131.55, 128.46, 128.22, 128.13, 127.52, 68.94,
25
D
calcd for C13H19O3 223.1335, found 223.1342.
66.53, 41.65, 34.26, 17.79, 13.52; ‰ꢁŠ +19.7 (c 1.8, CH2Cl2); high-resolution MS (FAB+) m/e
4.4. Phenylmethyl (R)-3-hydroxy-3-phenylpropanoate 5b
1H NMR (400 MHz, CDCl3) ꢀ 7.43±7.22 (m, 10H), 5.22 (s, 2H), 5.20 (dd, J=8.8, 4.0 Hz, 1H),
2.88 (dd, J=16.0, 8.8 Hz, 1H), 2.82 (dd, J=16.4, 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) ꢀ
171.79, 142.21, 135.28, 128.40, 128.36, 128.16, 128.05, 127.63, 125.49, 70.26, 66.57, 43.39; HPLC

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Y.-C. Wang et al. / Tetrahedron: Asymmetry 11 (2000) 1797±1800
(Chiralcel OD; 95:5 hexane:isopropyl alcohol; ¯ow rate 1 ml/min; UV 254 nm); tR=21.2 min (S),
25
29.7 min (R); ‰ꢁŠ +28.6 (c 1.8, CH2Cl2); high-resolution MS (FAB+) m/e calcd for C16H16O3
D
257.1178, found 257.1177.
4.5. Phenylmethyl (R)-3-hydroxy-4-pentenoate 5c
1H NMR (400 MHz, CDCl3) ꢀ 7.37±7.31 (m, 5H), 5.86 (ddd, J=17.2, 10.8, 5.6 Hz, 1H), 5.29
(dd, J=17.2, 1.2 Hz, 1H), 5.14 (s, 2H), 5.13 (dd, J=10.8, 1.2 Hz, 1H), 4.57±4.53 (m, 1H), 2.63
(dd, J=16.8, 4.0 Hz, 1H), 2.56 (dd, J=16.8, 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) ꢀ 171.69,
138.49, 135.33, 128.43, 128.20, 128.10, 115.35, 68.89, 66.56, 41.25; ‰ꢁŠ25 +9.7 (c 1.8, CH2Cl2); high-
D
resolution MS (EI) m/e calcd for C12H14O3 206.0943, found 206.0934.
4.6. Phenylmethyl (R)-3-hydroxy-4-methyl-4-pentenoate 5d
1H NMR (400 MHz, CDCl3) ꢀ 7.38±7.30 (m, 5H), 5.14 (s, 2H), 5.01 (s, 1H), 4.86 (s, 1H), 4.48
(dd, J=8.0, 4.4 Hz, 1H), 2.69 (dd, J=15.6, 4.4 Hz, 1H), 2.65 (dd, J=15.6, 8.0 Hz, 1H), 1.79
(s, 3H); 13C NMR (100 MHz, CDCl3) ꢀ 172.11, 145.17, 135.34, 128.46, 128.25, 128.19, 111.49,
71.51, 66.63, 40.14, 18.35; HPLC (Chiralcel OD; 95:5 hexane:isopropyl alcohol; ¯ow rate 1 ml/
25
min; UV 254 nm); tR=14.1 min (S), 19.2 min (R); ‰ꢁŠ +6.2 (c 2.1, CH2Cl2); high-resolution MS
D
(FAB+) m/e calcd for C13H17O3 221.1178, found 221.1181.
4.7. Phenylmethyl (R)-3-hydroxy-5-phenyl-(E)-4-pentenoate 5e
1H NMR (400 MHz, CDCl3) ꢀ 7.42±7.22 (m, 10H), 6.65 (d, J=16.0 Hz, 1H), 6.22 (dd, J=16.0,
6.0 Hz, 1H), 5.17 (s, 2H), 4.78±4.72 (m, 1H), 2.73 (dd, J=16.4, 4.0 Hz, 1H), 2.67 (dd, J=16.4, 8.0
Hz, 1H); 13C NMR (100 MHz, CDCl3) ꢀ 171.65, 136.16, 135.31, 130.72, 129.63, 128.45, 128.39,
25
128.22, 128.13, 127.66, 126.39, 68.88, 66.62, 41.62; ‰ꢁŠ ^1.9 (c 1.1, CH2Cl2); high-resolution MS
D
(EI) m/e calcd for C18H18O3 282.1256, found 282.1260.
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