Determination of absolute configuration of a metabolite (-)- hydroxyhexamide from acetohexamide, syntheses of (-)- and (+)- hydroxyhexamides and (-)- and (+)-acetoxyhexamides

Article abstract of DOI:10.1016/S0957-4166(98)00436-4

Enantioselective acetylation of (±)-4-(1- hydroxyethyl)benzenesulfonamide 6 with 'Acylase I' (No. A 2156) from Aspergillus melleus in the presence of vinyl acetate gave (R)-4-(1- acetoxyethyl)benzenesulfonamide 7 (98% ee) and (S)-6 (98% ee). Both (S)-6 and (R)-7 were individually converted to the (S)-hydroxyhexamide 2 (>99% ee) and (R)-hydroxyhexamide 2 (>99% ee), respectively. The absolute configuration of a metabolite (-)-hydroxyhexamide 2 from acetohexamide 1 was found to be S based on unequivocal chemical methods including X-ray analysis.

Full text of DOI:10.1016/S0957-4166(98)00436-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 4331–4340
Determination of absolute configuration of a metabolite
(−)-hydroxyhexamide from acetohexamide, syntheses of (−)- and
(+)-hydroxyhexamides and (−)- and (+)-acetoxyhexamides
Hiroyuki Akita,a,∗ Katsumi Kurashima,b Masako Nozawa,a Shigeo Yamamura,a Kenzi Seri b
and Yorishige Imamura c
aSchool of Pharmaceutical Sciences, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan
bCentral Research Laboratory, Godo Shusei Co., Ltd, 250, Nakahara, Kamihongo, Matsudo, Chiba 271-0064, Japan
cFaculty of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, Kumamoto 862-0973, Japan
Received 29 September 1998; accepted 23 October 1998
Abstract
Enantioselective acetylation of (ꢀ)-4-(1-hydroxyethyl)benzenesulfonamide 6 with ‘Acylase I’ (No. A 2156)
from Aspergillus melleus in the presence of vinyl acetate gave (R)-4-(1-acetoxyethyl)benzenesulfonamide 7
(98% ee) and (S)-6 (98% ee). Both (S)-6 and (R)-7 were individually converted to the (S)-hydroxyhexamide 2
(>99% ee) and (R)-hydroxyhexamide 2 (>99% ee), respectively. The absolute configuration of a metabolite (−)-
hydroxyhexamide 2 from acetohexamide 1 was found to be S based on unequivocal chemical methods including
X-ray analysis. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Acetohexamide 4-acetyl-N-(cyclohexylcarbamoyl)benzenesulfonamide 1 is widely used as an oral
antidiabetic drug possessing a moderate duration of action.1 When this drug is administered in
humans and rabbits, acetohexamide undergoes conversion to an active metabolite 4-(1-hydroxyethyl)-
N-(cyclohexylcarbamoyl)benzenesulfonamide 2 in the body. It was reported that (−)-hydroxyhexamide
2 is more pharmacologically active and has a longer elimination half-life than the parent drug.2 Stereo-
selective reduction of 1 using the enzyme3a,b present in the cytosol of rabbit liver was also reported to
give enantiomerically pure (−)-2.3a Although (−)-hydroxyhexamide 2 from human urine was assumed
to possess the L-configuration,1 there is no information concerning the detailed determination of the
absolute configuration of (−)-2 so far. We now describe the unequivocal determination of the absolute
∗
Corresponding author. E-mail: akita@phar.toho-u.ac.jp
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00436-4

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structure of (−)-hydroxyhexamide 2 and the syntheses of (−)- and (+)-hydroxyhexamides 2, and (−)- and
(+)-acetoxyhexamides, 4-(1-acetoxyethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamides 3 based on an
enzymatic method in order to find a more pharmacologically active drug (Scheme 1).
Scheme 1.
2. Results and discussion
Treatment of the commercially available 4-ethylbenzenesulfonyl chloride 4 with ammonia followed
by oxidation gave 4-acetylbenzenesulfonamide 5 in 55% yield, which was reduced with NaBH4 to
afford (ꢀ)-4-(1-hydroxyethyl)benzenesulfonamide 6 in 95% yield. Acetylation of (ꢀ)-6 gave (ꢀ)-4-(1-
acetoxyethyl)benzenesulfonamide 7 in 87% yield, which was treated with cyclohexylisocyanate in the
presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to provide (ꢀ)-acetoxyhexamide 3 in 97% yield.
Alkaline hydrolysis of (ꢀ)-3 with K2CO3 in MeOH afforded (ꢀ)-hydroxyhexamide 2 in 90% yield,
whose spectral data (1H NMR) were identical with those of the reported (−)-2 (Scheme 2).
Scheme 2.
From a screening experiment for enantioselective esterification of (ꢀ)-6 with vinyl acetate using
various kinds of lipase and acylase, the commercially available enzyme, ‘lipase PL 679 and 266’ from
Alcaligenes sp. and ‘Acylase I’ (No. A 2156) from Aspergillus melleus was found to be effective. When
(ꢀ)-6 was exposed to the ‘lipase PL 679’ in the presence of vinyl acetate at 33°C, acetylated product
22
(+)-7 {47%, [α]D25 +87.7 (c 0.285, MeOH) corresponds to 99% ee} and unchanged (−)-6 {50%, [α]D
−27.9 (c 0.211, MeOH) corresponds to 91% ee} were obtained (Table 1, entry 1). In the case of using the
‘lipase PL 266’ from Alcaligenes sp. and the ‘Acylase I’ (No. A 2156), the results are shown in entry 2
and entry 3, respectively.
When the ‘Acylase I’ was employed at 33°C, the reaction proceeded extremely slowly and required 11
days to complete (entry 3). However, when this reaction was carried out at 40°C for 43 h, the reaction

H. Akita et al. / Tetrahedron: Asymmetry 9 (1998) 4331–4340
4333
Table 1
Asymmetric acetylation of (ꢀ)-6 with enzymes
Figure 1. NMR assignment of (Y)-6-(R)-MTPA
was found to be accelerated and the temperature effect clearly appeared to give (+)-7 (43%, 98% ee)
and (−)-6 (54%, 77% ee). The unchanged (−)-6 (77% ee) was again exposed to the same conditions as
mentioned above for 72 h to afford (+)-7 (14%, 44% ee) and (−)-6 (81%, 98% ee). The enantiomeric
purity of the enzymatic reaction products was determined by HPLC on a Chiralcell OD and AS columns
(250 mm×4.6 mm).
In order to determine the absolute configurations of (−)-6 and (+)-7, tentative absolute configurations
of both (−)-6 and (+)-7 are defined to be X and Y, respectively. Alkaline hydrolysis of the acetoxy
23
compound (Y)-(+)-7 with MeONa in MeOH gave the hydroxy compound (Y)-(+)-6 {95% [α]D
+31.9 (c 0.320, MeOH) corresponds to >98% ee}, which was treated with (S)-(+)-α-methoxy-α-
trifluoromethylphenylacetyl chloride [(S)-(+)-MTPACl]4 in pyridine to afford the (Y)-6-(R)-MTPA ester
25
(76% yield). The unchanged (X)-(−)-6 {[α]D −30.6 (c 0.301, MeOH) corresponds to 98% ee} was
also converted into the corresponding (X)-6-(R)-MTPA ester (89% yield). Chemical shifts due to the
secondary methyl group and aromatic protons (Ha and Hb) of both (Y)-6-(R)-MTPA and (X)-6-(R)-
MTPA are assigned as shown in Figs. 1 and 2, respectively, based on the NOE experiments. The NMR
spectrum of (Y)-6-(R)-MTPA was the same as those of the postulated (X)-6-(S)-MTPA because of the
enantiomeric relationship of (Y)-6-(R)-MTPA and (X)-6-(S)-MTPA. The differences (∆δ) of chemical
shifts due to both (X)-6-(S)-MTPA and (X)-6-(R)-MTPA are shown in Table 2.
By applying the reported empirical rule5 to elucidate the absolute configuration of secondary alcohols,
the present data indicate that the absolute configuration of (X)-6 is found to be S as shown in Fig. 3
and hence X and Y are S and R, respectively. Thus, the absolute configuration of (+)-7 was determined
to be R. This assumption was confirmed by X-ray single crystal structure analysis of (+)-7 as shown
in Fig. 4. A crystal of (+)-7, crystallizing from ethylacetate–diethyl ether by slow evaporation of the
solvent, with an approximate size of 0.4×0.2×0.5 mm3 was employed. The compound crystallizes in

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H. Akita et al. / Tetrahedron: Asymmetry 9 (1998) 4331–4340
Figure 2. NMR assignment of (X)-6-(R)-MTPA
Table 2
The differences (∆δ) of chemical shifts due to both (X)-6-(S)-MTPA and (X)-6-(R)-MTPA
Figure 3. Determination method of absolute configuration of (X)-6 based on empirical rule
Figure 4. ORTEP diagram of (+)-7
the monoclinic space group P21 with a=10.366(1) Å, b=5.0776(8) Å, c=11.9674(8) Å and β=106.114(6)
deg; V=605.1(1) Å3, Z=2, Dc=1.335 g cm−3, µ=24.03 cm−1. The intensities were measured on a Rigaku
AFC7R diffractometer in the ω−2θ scan mode. The total 1081 reflections utilizing CuKα radiation
(λ=1.54178 Å) and 1020 unique reflections were used for the structure determination. The structure was
solved by direct methods SIR926 and refined by full matrix least squares with anisotropic displacement
parameters for the non-hydrogen atoms. The positions of the hydrogen atoms were obtained from
difference Fourier maps and refined isotropically. The final R1-value is 0.036 for 981 reflections with
I>2.00 σ−(I). The absolute configuration was established using the Flack parameter [x=0.04(8)].7 Fig. 4
shows a view of the molecule with the numbering system.
The result of the enantioselective esterification of (ꢀ)-6 with the ‘lipase PL’ from Alcaligenes sp.
was explained by applying the reported empirical rules8 to predict which enantiomer possessing a

H. Akita et al. / Tetrahedron: Asymmetry 9 (1998) 4331–4340
4335
secondary hydroxy group reacts faster in lipase-catalyzed reactions by comparing the relative sizes of
substituents at the stereocenter. A methyl group seems to be a relatively small size substituent (M) and
the benzenesulfonamide moiety appears to be the relatively large sized substituent (L) (Scheme 3).
Scheme 3.
Thus both optically active (S)-(−)-6 (98% ee) and (R)-(+)-7 (98% ee) were individually converted
22
to (S)-(−)-hydroxyhexamide 2 {[α]D −19.6 (c 0.214, CHCl3) corresponds to >99% ee} and (R)-(+)-
hydroxyhexamide {[α]D23 +21.8 (c 0.220, CHCl3) corresponds to >99% ee} 2, respectively, by the same
method as for the synthesis of (ꢀ)-2. Physical data of the synthetic (S)-(−)-2 were identical with those
{[α]D −19.9 (c 0.5, CHCl3)} of (−)-hydroxyhexamide 23a obtained by the enantioselective reduction
20
of acetohexamide using the enzyme present in the cytosol of rabbit liver (Scheme 4).
Scheme 4.
In preliminary pharmacological studies, both hydroxyhexamides, (S)-2 and (R)-2, showed a potent
hypoglycemic effect after oral administration in mice and rats. The efficancies of these two compounds
were almost equivalent. The hypoglycemic effects of these two compounds were dose-dependent, early
onset and of significantly short duration. The acetates (S)-3 and (R)-3 were about 200 times more potent
than acetohexamide in insulin secretion activities in cultured pancreatic β-cells. The two acetates (S)-
3 and (R)-3 seemed to be absorbed quickly after oral administration in several species of experimental
animals, and showed potent and short lasting hypoglycemic effects. The detailed pharmacological studies
will be reported in a forthcoming paper.

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3. Experimental
3.1. General
All melting points were measured on a Yanaco MP-3S micro melting point apparatus and are
1
uncorrected. H NMR spectra were recorded on a JEOL EX 400 spectrometer. Spectra were taken with
5–10% (w/v) solution in (CD3)2SO with Me4Si as an internal reference. The mass spectra (EIMS) were
obtained with a JEOL JMS-AX 500 spectrometer. IR spectra were recorded on a JASCO FT/IR-300
spectrometer. The HPLC system was composed of two SSC instruments [ultraviolet (UV) detector 3000B
and flow system 3100]. Optical rotations were measured with a JASCO DIP-370 digital polarimeter. All
evaporations were performed under reduced pressure. For column chromatography, silica gel (Kieselgel
60) was employed.
3.2. 4-Acetylbenzenesulfonamide 5
4-Ethylbenzenesulfonyl chloride 4 (23 g, 0.112 mol) was added to an aqueous ammonia solution (120
ml) with stirring and the mixture was heated at 40°C for 30 min. After cooling, the reaction mixture was
diluted with satd brine, extracted with ethyl acetate and dried over MgSO4. Evaporation of the organic
solvent gave a crude 4-ethylbenzenesulfonamide, which was used for the next reaction without further
purification. To a stirred and cooled (0°C) solution of chromium trioxide (CrO3, 56.72 g, 0.567 mol) in
a mixed solvent [AcOH (40 ml) and H2O (40 ml)] was added a solution of sulfonamide in AcOH (360
ml) and the mixture was warmed to ambient temperature and stirred for 3 h. After isopropyl alcohol
(500 ml) was added to the reaction mixture, the whole mixture was condensed under reduced pressure to
give a crude residue. This was diluted with H2O and extracted with AcOEt. The organic layer was dried
over MgSO4 and evaporated to give an oily product, which was chromatographed on silica gel (200 g,
n-hexane:AcOEt=1:1) to afford 5. Recrystallization of 5 from AcOEt gave colorless needles of 5 (12.42
g, 55% yield from 4). 5: mp 178–179°C; IR (Nujol): 3307 (NH2), 1666 cm−1 (C_O); 1H NMR: δ 2.63
(3H, s), 7.55 (2H, br, s), 7.95, 8.12 (each 2H, d, J=8.2 Hz). Anal. found: C, 47.96; H, 4.59; N, 6.91.
Calcd. for C8H9NO3S: C, 48.23; H, 4.55; N, 7.03%.
3.3. (ꢀ)-4-(1-Hydroxyethyl)benzenesulfonamide 6
To a stirred solution of 5 (1.988 g, 10 mmol) in MeOH (10 ml) at 0°C was added NaBH4 (465
mg, 12.3 mmol) and the whole mixture was stirred for 30 min. This was diluted with satd brine and
extracted with AcOEt. The organic layer was dried over MgSO4 and evaporated to give a residue. This
was chromatographed on silica gel (60 g, AcOEt) to afford crystals of (ꢀ)-6 (1.916 g, 95%), which
were recrystallized from AcOEt–n-hexane to give colorless needles of (ꢀ)-6. (ꢀ)-6: mp 125–126°C; IR
(Nujol): 3481 (OH), 3330, 3254 cm−1 (NH2); 1H NMR: δ 1.33 (3H, d, J=6.4 Hz), 4.79 (1H, dq, J=4.2,
6.4 Hz), 5.32 (1H, d, J=4.2 Hz), 7.26 (2H, s), 7.51, 7.77 (each 2H, d, J=8.5 Hz). Anal. found: C, 47.65;
H, 5.46; N, 6.91. Calcd. for C8H11NO3S: C, 47.75; H, 5.51; N, 6.96%. The racemate (ꢀ)-6 was analyzed
to provide well separated peaks (20 and 32 min) of each enantiomer using a Chiralcel OD (4.6 mm×250
mm) under the following analytical conditions [eluent, n-hexane:EtOH (5:1); detection, UV at 254 nm;
flow rate, 1.0 ml/min].

H. Akita et al. / Tetrahedron: Asymmetry 9 (1998) 4331–4340
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3.4. (ꢀ)-4-(1-Acetoxyethyl)benzenesulfonamide 7
To a stirred and cooled (−10°C) solution of (ꢀ)-6 (1.806 g, 8.97 mmol) in pyridine (50 ml) was
added acetyl chloride (1.051 g, 13.39 mmol) and the whole mixture was stirred for 2 h at −10°C. This
was diluted with 2 M aqueous HCl and extracted with AcOEt. The organic layer was washed with satd
aqueous NaHCO3 and dried over MgSO4. Evaporation of the organic solvent gave a residue. It was
chromatographed on silica gel (60 g, n-hexane:AcOEt=3:1) to provide crystals of (ꢀ)-7 (1.918 g, 87%),
which were recrystallized from EtOH to give colorless needles of (ꢀ)-7. (ꢀ)-7: mp 135.5–136.5°C; IR
(Nujol): 3312, 3210 (NH2), 1714 cm−1 (c O); 1H NMR: δ 1.47 (3H, d, J=6.8 Hz), 2.06 (3H, s), 5.82 (1H,
q, J=6.8 Hz), 7.35 (2H, br, s), 7.55, 7.80 (each 2H, d, J=8.0 Hz). Anal. found: C, 49.51; H, 5.39; N, 5.83.
Calcd. for C10H13NO4S: C, 49.37; H, 5.39; N, 5.76%. The racemate (ꢀ)-7 was analyzed to provide well
separated peaks (22 and 26 min) of each enantiomer using a Chiralcel AS (4.6 mm×250 mm) under the
following analytical conditions [eluent, n-hexane:EtOH (5:1); detection, UV at 254 nm; flow rate, 1.0
ml/min].
3.5. (ꢀ)-4-(1-Acetoxyethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide 3
A mixture of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2.211 g, 14.52 mmol) and (ꢀ)-7 (2.354 g,
9.68 mmol) in benzene (50 ml) was stirred for 30 min at room temperature, and cyclohexylisocyanate
(1.816 g, 14.51 mmol) was added and the whole mixture was stirred for 1 h at room temperature. This was
diluted with 6 M aqueous HCl, and extracted with AcOEt. The organic layer was dried over MgSO4 and
evaporated to give an oily product, which was chromatographed on silica gel (60 g, n-hexane:AcOEt=2:1)
to afford (ꢀ)-3 (3.474 g, 97%). Recrystallization of (ꢀ)-3 from AcOEt–Et2O gave colorless needles of
1
(ꢀ)-3. (ꢀ)-3: mp 137–138°C; IR (Nujol): 3309, 3251 (NH2), 1731, 1689 cm−1 (C_O); H NMR: δ
1.09–1.23 (5H, m), 1.48 (3H, d, J=6.4 Hz), 1.57–1.67 (5H, m), 2.07 (3H, s), 3.24–3.32 (1H, m), 5.84
(1H, q, J=6.4 HZ), 6.36 (1H, d, J=7.7 Hz), 7.58, 7.88 (each 2H, d, J=7.6 Hz), 10.36 (1H, br, s). Anal.
found: C, 55.59; H, 6.54; N, 7.67. Calcd. for C17H24N2O5S: C, 55.42; H, 6.57; N, 7.60%.
3.6. (ꢀ)-4-(1-Hydroxyethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide 2
To a solution of (ꢀ)-3 (2.884 g, 7.83 mmol) in MeOH (40 ml) was added K2CO3 (2.167 g, 15.6
mmol) and the whole mixture was stirred for 12 h at room temperature. The reaction mixture was
diluted with 6 M aqueous HCl, and extracted with AcOEt. The organic layer was dried over MgSO4
and evaporated to give a residue. This was diluted with substantial amounts of MeOH and evaporated
to give a residue, which was chromatographed on silica gel (60 g, n-hexane:AcOEt=1:2) to afford (ꢀ)-
2 (2.319 g, 90%). Recrystallization of (ꢀ)-2 from AcOEt gave colorless needles of (ꢀ)-2. (ꢀ)-2: mp
143–144°C; IR (Nujol): 3527 (OH), 3346, 3057 (NH2), 1658 cm−1 (C_O); 1H NMR: δ 1.07–1.28 (5H,
m), 1.33 (3H, d, J=6.4 Hz), 1.47–1.66 (5H, m), 3.25–3.34 (1H, m), 4.80 (1H, dq, J=6.4, 3.9 Hz), 5.39
(1H, d, J=3.9 Hz), 6.33 (1H, d, J=7.8 Hz), 7.55, 7.84 (each 2H, d, J=8.3 Hz), 10.30 (1H, br, s). Anal.
found: C, 54.94; H, 6.82; N, 8.49. Calcd. for C15H22N2O4S: C, 55.19; H, 6.79; N, 8.58%.
3.7. General procedure of enantioselective acetylation of (ꢀ)-6
A suspension of (ꢀ)-6 (100 mg) and lipase (100 mg) in vinyl acetate (20 ml) was incubated at 33°C
for an adequate time as shown in Table 1. After the reaction mixture was filtered, the precipitate was
washed with AcOEt. The combined organic layer was dried over MgSO4 and evaporated. The residue

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H. Akita et al. / Tetrahedron: Asymmetry 9 (1998) 4331–4340
was chromatographed on silica gel (10 g) to give acetate (+)-7 from n-hexane:AcOEt (2:1) eluent and
25
alcohol (−)-6 from n-hexane:AcOEt (1:1) eluent, respectively. (+)-7: [α]D +87.7 (c 0.285, MeOH)
22
corresponds to 99% ee (Table 1, entry 1). (−)-6: [α]D −27.9 (c 0.211, MeOH) corresponds to 96% ee
(Table 1, entry 1). The retention times of (+)-7 and (−)-6 were 22 and 32 min by means of HPLC analysis,
respectively.
3.8. Large scale experiment of enantioselective acetylation of (ꢀ)-6
(i) A suspension of (ꢀ)-6 (9.98 g) and ‘Acylase I’ (No. A 2156, 10 g) from Aspergillus melleus in vinyl
acetate (800 ml) was stirred at 40°C for 43 h. After the reaction mixture was filtered, the precipitate was
washed with AcOEt. The combined organic layer was dried over MgSO4 and evaporated. The residue
was chromatographed on silica gel (300 g) to give crystals of (+)-7 (5.20 g, 43%, 98% ee) from n-
hexane:AcOEt (3:1) eluent and crystals of (−)-6 (5.38 g, 54%, 77% ee) from n-hexane:AcOEt (1:1)
eluent, respectively. Recrystallization of (+)-7 from AcOEt–Et2O gave colorless needles of (+)-7 (4.68
g). (+)-7: mp 97–98°C, [α]D24 +88.8 (c 0.313, MeOH) corresponds to 98% ee.
(ii) A suspension of (−)-6 (4.47 g, 77% ee) and ‘Acylase I’ (No. A 2156, 4.47 g) in vinyl acetate
(360 ml) stirred again at 40°C for 72 h. After the reaction mixture was filtered, the precipitate was
washed with AcOEt. The combined organic layer was dried over MgSO4 and evaporated. The residue
was chromatographed on silica gel (150 g) to give crystals of (+)-7 (0.766 g, 14%, 44% ee) from n-
hexane:AcOEt (3:1) eluent and crystals of (−)-6 (3.61 g, 81%, 98% ee) from n-hexane:AcOEt (1:1)
eluent. Recrystallization of (−)-6 from AcOEt–Et2O gave colorless needles of (−)-6 (3.126g). (−)-6: mp
127–127.5°C, [α]D25 −30.2 (c 0.324, MeOH) corresponds to 98% ee.
3.9. (+)-4-(1-Hydroxyethyl)benzenesulfonamide 6
To a stirred and cooled (0°C) solution of (+)-7 (2.183 g, 8.97 mmol, 98% ee) in MeOH (60 ml) was
added MeONa (0.97 g, 18 mmol) and the whole mixture was stirred for 12 h at room temperature. The
reaction mixture was diluted with 6 M aqueous HCl, extracted with AcOEt and washed with satd brine.
The organic layer was dried over MgSO4 and evaporated to give a residue, which was chromatographed
on silica gel (60 g, n-hexane:AcOEt=1:1) to afford (+)-6 (1.765 g, 97%). Recrystallization of (+)-6 from
23
AcOEt–Et2O gave colorless needles of (+)-6 (1.59 g). (+)-6: mp 126–127°C; [α]D +31.9 (c 0.320,
MeOH) corresponds to 98% ee.
3.10. (Y)-6-(R)-MTPA ester
To a stirred solution of (Y)-(+)-6 (30.4 mg, 0.15 mmol) in pyridine (1 ml) was added (S)-MTPACl
(57 mg, 0.23 mmol) and the whole mixture was stirred for 12 h at room temperature. The reaction
mixture was diluted with H2O at 0°C, and extracted with AcOEt. The organic layer was washed with 2
M aqueous HCl and satd aqueous NaHCO3. The organic layer was dried over MgSO4 and evaporated to
give a residue, which was chromatographed on silica gel (5 g, n-hexane:AcOEt=2:1) to afford the (Y)-
1
6-(R)-MTPA ester (48 mg, 76%). (Y)-6-(R)-MTPA ester: H NMR (CDCl3): δ 1.58 (3H, d, J=6.6 Hz),
3.47 (3H, s), 5.04 (2H, br s), 6.13 (1H, q, J=6.6 Hz), 7.35–7.47 (5H, m), 7.48, 7.92 (each 2H, d, J=8.6
Hz).

H. Akita et al. / Tetrahedron: Asymmetry 9 (1998) 4331–4340
4339
3.11. (X)-6-(R)-MTPA ester
To a stirred solution of (Y)-(+)-6 (20.1 mg, 0.10 mmol) in pyridine (1 ml) was added (S)-MTPACl (38
mg, 0.15 mmol) and the whole mixture was stirred for 12 h at room temperature. The reaction mixture
was worked up in the same way as for the synthesis of the (Y)-6-(R)-MTPA ester to afford the (X)-6-(R)-
1
MTPA ester (37 mg, 89%). (X)-6-(R)-MTPA ester: H NMR (CDCl3): δ 1.63 (3H, d, J=6.6 Hz), 3.56
(3H, s), 4.94 (2H, br, s), 6.11 (1H, q, J=6.6 Hz), 7.34–7.44 (5H, m), 7.40, 7.86 (each 2H, d, J=8.6 Hz).
3.12. (S)-4-(1-Acetoxyethyl)benzenesulfonamide 7
To a stirred and cooled (−10°C) solution of (−)-6 (2.187 g, 10.87 mmol) in pyridine (50 ml) was added
acetyl chloride (1.291 g, 16.45 mmol) under ice–NaCl cooling and the whole mixture was stirred for 2 h
at −10°C. The reaction mixture was worked up in the same way as for the synthesis of (ꢀ)-7 to provide
colorless needles of (S)-7 (2.357 g, 89%). (S)-7: mp 98°C, EIMS m/z: 243 (M+), 184 (M+−OCOCH3),
24
1
[α]D −90.4 (c 0.218, MeOH) corresponds to 98% ee. H NMR spectra of (S)-7 were identical with
those of (ꢀ)-7.
3.13. (S)-4-(1-Acetoxyethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide 3
A mixture of DBU (2.211 g, 14.52 mmol) and (S)-7 (2.354 g, 9.68 mmol) in benzene (50 ml) was
stirred for 30 min at room temperature, and cyclohexylisocyanate (1.816 g, 14.51 mmol) was added
and the whole mixture was stirred for 1 h at room temperature. The reaction mixture was worked up
in the same way as for the synthesis of (ꢀ)-3 to afford (S)-3 (3.474 g, 97%). Recrystallization of (S)-3
from AcOEt–Et2O gave colorless needles of (S)-3. (S)-3: mp 116–117°C; EIMS m/z: 368 (M+), 325
(M+−COCH3), [α]D −61.2 (c 0.255, MeOH) corresponds to 98% ee. H NMR spectra of (S)-3 were
identical with those of (ꢀ)-3.
23
1
3.14. (S)-4-(1-Hydroxyethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide 2
To a solution of (S)-3 (2.136 g, 5.80 mmol) in MeOH (40 ml) was added K2CO3 (1.603 g, 11.6 mmol)
and the whole mixture was stirred for 12 h at room temperature. The reaction mixture was worked up in
the same way as for the synthesis of (ꢀ)-2 to afford (S)-2 (1.676 g, 88%). Recrystallization of (S)-2 from
AcOEt–Et2O gave colorless needles of (S)-2. (S)-2: mp 141–143°C; EIMS m/z: 326 (M+), [α]D22 −19.6
(c 0.214, CHCl3) corresponds to >99% ee. 1H NMR spectra of (S)-2 were identical with those of (ꢀ)-2.
3.15. (R)-4-(1-Acetoxyethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide 3
A mixture of DBU (2.69 g, 17.67 mmol) and (R)-(+)-7 (2.859 g, 11.75 mmol) in benzene (50 ml)
was stirred for 30 min at room temperature, and cyclohexylisocyanate (2.22 g, 17.74 mmol) was added
and the whole mixture was stirred for 1 h at room temperature. The reaction mixture was worked up
in the same way as for the synthesis of (ꢀ)-3 to afford (R)-3 (4.189 g, 97%). Recrystallization of (R)-3
from AcOEt–Et2O gave colorless needles of (R)-3. (R)-3: mp 115–116°C; EIMS m/z: 368 (M+), 325
(M+−COCH3), [α]D +61.6 (c 0.216, MeOH) corresponds to 98% ee. H NMR spectra of (R)-3 were
identical with those of (ꢀ)-3.
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H. Akita et al. / Tetrahedron: Asymmetry 9 (1998) 4331–4340
3.16. (R)-4-(1-Hydroxyethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide 2
To a solution of (R)-3 (2.116 g, 5.74 mmol) in MeOH (40 ml) was added K2CO3 (1.588 g, 11.49 mmol)
and the whole mixture was stirred for 12 h at room temperature. The reaction mixture was worked up in
the same way as for the synthesis of (ꢀ)-2 to afford (R)-2 (1.619 g, 86%). Recrystallization of (R)-2 from
AcOEt–Et2O gave colorless needles of (R)-2. (R)-2: mp 141–143°C; EIMS m/z: 326 (M+), [α]D23 +21.8
(c 0.220, CHCl3) corresponds to >99% ee. 1H NMR spectra of (R)-2 were identical with those of (ꢀ)-2.
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