Thionyl Chloride-Mediated Synthesis of tert-Butyl ((S)-1-((R)-Oxiran-2-yl)-2-phenylethyl)carbamate with Boc-Involved Neighboring Group Participation

Article abstract of DOI:10.1080/00397911.2015.1014917

A convenient, high-yielding preparation of tert-butyl ((S)-1-((R)-oxiran-2-yl)-2-phenylethyl)carbamate is described. An efficient chiral inversion as the key step is furnished via Boc-involved neighboring group participation mediated by thionyl chloride. This preparation has significant advantages over the previously reported methods with respect to simplicity, cost efficiency, yield, and purification procedure as well as industry reliability.

Full text of DOI:10.1080/00397911.2015.1014917

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Thionyl Chloride–Mediated Synthesis
of tert-Butyl ((S)-1-((R)-Oxiran-2-yl)-2-
phenylethyl)carbamate with Boc-
Involved Neighboring Group Participation
Tao Lia, Mei Meia, Hongjun Gaob, Yuanqiang Lib, Yongliang Yana &
Daqing Cheb
a Zhejiang Jiuzhou Pharmaceutical Science and Technology Co.,
Zhejiang Province, China
Click for updates
b Zhejiang Jiuzhou Pharmaceutical Co., Zhejiang Province, China
Accepted author version posted online: 09 Feb 2015.Published
online: 09 Feb 2015.
To cite this article: Tao Li, Mei Mei, Hongjun Gao, Yuanqiang Li, Yongliang Yan & Daqing Che (2015)
Thionyl Chloride–Mediated Synthesis of tert-Butyl ((S)-1-((R)-Oxiran-2-yl)-2-phenylethyl)carbamate
with Boc-Involved Neighboring Group Participation, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 45:10, 1183-1189, DOI:
10.1080/00397911.2015.1014917
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1014917
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Synthetic Communications1, 45: 1183–1189, 2015
Copyright © Zhejiang Jiuzhou Pharmaceutical Co. Ltd.
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2015.1014917
THIONYL CHLORIDE–MEDIATED SYNTHESIS OF
TERT-BUTYL ((S)-1-((R)-OXIRAN-2-YL)-2-
PHENYLETHYL)CARBAMATE WITH BOC-INVOLVED
NEIGHBORING GROUP PARTICIPATION
Tao Li,1 Mei Mei,1 Hongjun Gao,2 Yuanqiang Li,2
Yongliang Yan,1 and Daqing Che2
1Zhejiang Jiuzhou Pharmaceutical Science and Technology Co.,
Zhejiang Province, China
2Zhejiang Jiuzhou Pharmaceutical Co., Zhejiang Province, China
GRAPHICAL ABSTRACT
Abstract A convenient, high-yielding preparation of tert-butyl ((S)-1-((R)-oxiran-2-yl)-2-
phenylethyl)carbamate is described. An efficient chiral inversion as the key step is furnished
via Boc-involved neighboring group participation mediated by thionyl chloride. This
preparation has significant advantages over the previously reported methods with respect
to simplicity, cost efficiency, yield, and purification procedure as well as industry reliability.
Keywords Chiral inversion; chiral retention; neighboring group participation; thionyl
chloride
INTRODUCTION
Chiral N-protected a-amino epoxides or their derivatives are key building
blocks or essential starting materials for a series of HIV protease inhibitors,
including atazanavir,[1,2] ritonavir,[3] fosamprenavir,[4] darunavir,[5] saguinavir,[6]
amprenavir,[7] and nelfanavir.[8] As a result, the synthesis of related compounds
has attracted considerable attention from both academia and the pharmaceutical
industry in recent years.
The optically active tert-butyl ((S)-1-((R)-oxiran-2-yl)-2-phenylethyl)carbamate
(1)[9] is one of the most important examples. Carbamate 1 can be prepared by epox-
idation of the related alkenes,[10,11] which are usually synthesized via aldehydes by
Received September 25, 2014.
Address correspondence to Hongjun Gao or Yuanqiang Li, Zhejiang Jiuzhou Pharmaceutical Co.
Ltd., Waisha Road 99, Jiaojiang District, Taizhou City 318000, Zhejiang Province, PR China. E-mail:
hjgao@outlook.com; yqli@zbjz.cn
1183

1184
T. LI ET AL.
Wittig reactions (route 1).[12] It can also be obtained via an intramolecular
[13]
=
Mitsunobu reaction (4, Y OH)
or via a direct intramolecular nucleophilic
cyclization (4, Y ¼ halogen, etc.)[14] (route 2). An intramolecular SN2 nucleophilic
substitution leads to 1 with a configuration inversion on the 2-positioned carbon atom
when the sec-hydroxyl group of tert-butyl ((2S,3S)-3,4-dihydroxy-1-phenylbutan-2-
yl)carbamate (5) is protected with methylsulfonyl chloride (route 3).[2,14g,15] In
addition, the sec-OH group of tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbu-
tan-2-yl)carbamate (7) can be inversed via a intermolecular Mitsunobu reaction[16]
or SN2 nucleophilic substitution with CsOAc,[11] followed by hydrolysis and cycliza-
tion to furnish 1 (route 4). It is also intriguing to find a recently reported transform-
ation from carbamate 7 via an in situ–formed oxazolidinone 10[17] (route 5).
From the perspective of pharmaceutical production, routes 4 and 5 are highly
appreciated because of their high efficiency and convenience, since these routes start
from commercially available L-phenylalanine or tert-butyl ((2S,3S)-4-chloro-3-
hydroxy-1-phenylbutan-2-yl)carbamate (7). However, it is regretful to find that
the generation of triphenylphosphine oxide as the major by-product is always
troublesome and cannot be removed easily (route 4). In addition, methylsulfonyl
esters from methylsulfonyl chloride and alcohols show obvious structural alerts for
genotoxicity[18] so that methylsulfonyl chloride and its ester derivatives are now
not recommended to be involved in the drug production. Thus it is highly desirable
to further improve route 4 and 5 in order to develop a more industrially economical,
convenient, and reliable process.
RESULTS AND DISCUSSION
Thionyl chloride was reported to react with various alcohols to form
chlorosulfite esters.[19] When tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-
2-yl)carbamate (7) was treated with excess thionyl chloride in methyl tert-butyl ether
(MTBE) followed by heating to 55 °C, it was surprising to find the formation of
(4S,5R)-4-benzyl-5-(chloromethyl)oxazolidin-2-one (10),[17] which was clean enough
for the next step after a usual workup. Protection with Boc2O could furnish
(4S,5R)-tert-butyl 4-benzyl-5-(chloromethyl)-2-oxooxazolidine-3-carboxylate (11) in
overall 70–75% yield for two steps, followed by hydrolysis under strongly basic con-
ditions to give the target compound tert-butyl ((S)-1-((R)-oxiran-2-yl)-2-phenylethyl)
carbamate (1) with more than 92% yield and 99.3% purity. With this process, the
target product 1 could be easily obtained through usual workups and crystalliza-
tions, making it highly suitable for large-scale production[20] (Scheme 2).
The reaction mechanism of the key step was proposed as follows: Thionyl
chloride reacted with 7 to give chlorosulfite esters 12. Probably the newly formed
=
chlorosulfite ester bond was repelled by intramolecular C O bond of Boc group
followed by further rearrangement to form (4S,5R)-4-benzyl-5-(chloromethyl)
oxazolidin-2-one (10) with highly efficient chiral inversion. The high efficiency of this
SN2 reaction was proved by spiking high-performance liquid chromatography
(HPLC) study of compound 10 (crude) and its diastereoisomer (4S,5S)-4-benzyl-5-
(chloromethyl)oxazolidin-2-one (14),[21] which indicated that the diastereoselectivity
was as high as 297:1 in this key step. Further, the quality of tert-butyl ((S)-1-((R)-
oxiran-2-yl)-2-phenylethyl)carbamate (1) was considered to be a key factor to

TERT-BUTYL ((S)-1-((R)-OXIRAN-2-YL)-2-PHENYLETHYL)CARBAMATE
1185
evaluate this route. On the one hand, the diastereoisomer tert-butyl ((S)-1-((S)-
oxiran-2-yl)-2-phenylethyl)carbamate (15)[22] was easily prepared from compound
7 by a cyclization in the basic condition. Spiking HPLC analysis shown that there
were no obvious diastereoisomer (15) and enantiomer tert-butyl ((R)-1-((S)-oxiran-
2-yl)-2-phenylethyl)carbamate (16)[23] found in the crude product of 1, which also
meant the complete chiral inversion of SN2 conversion in the first step and the com-
plete retention of the other chiral center in the whole process. On the other hand,
further verification in the plant confirmed that the quality of compound 1 could
completely meet the quality specification set before.
CONCLUSION
A new industrially reliable process was developed for the manufacturing of
tert-butyl ((S)-1-((R)-oxiran-2-yl)-2-phenylethyl)carbamate (1). Two important
intermediates were isolated and characterized, and the reaction mechanism was
elucidated. With this process route, product 1 could be conveniently manufactured
with good quality. By preliminary estimate, the manufacture cost could be reduced
at least 20–30% with the current process compared to the early routes. Further study
on the mechanism, process optimization, and process development are still in
progress.
EXPERIMENTAL
(4S,5R)-4-Benzyl-5-(chloromethyl)oxazolidin-2-one (10)[20,24]
tert-Butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate (7) (10.00 g,
33.4 mmol) was dissolved in 100 mL dry MTBE and stirred, followed by addition
of SOCl2 (14.6 mL, 200.4 mmol) at 10–20 °C within about 20 min. The mixture was
heated to 55 °C, kept at this temperature for 8 h, and cooled to 0 °C. Then 50 mL
saturated aqueous NaHCO3 was charged slowly to quench the excess SOCl2. The
mixture was separated and the aqueous layer was extracted with MTBE
(2 × 30 mL). The organic layer was combined, washed with saturated aqueous
NaHCO3 (30 mL) and then brine (30 mL), dried over Na2SO4, filtered, concen-
trated to ca. 100 mL, and then used directly for the next step. NMR spectra were
recorded after drying in a vacuum for 5 h at room temperature. 1H NMR
(400 MHz, TMS, CDCl3) d (ppm) 2.86 (dd, J ¼ 6.8, 13.6 Hz, 1H), 2.96 (dd, J ¼ 7.2,
13.6 Hz, 1H), 3.41 (dd, J ¼ 4.4, 12.0 Hz, 1H), 3.52 (dd, J ¼ 6.0, 11.6 Hz, 1H), 3.96
(dd, J ¼ 6.8, 12.0 Hz, 1H), 4.46 (dd, J ¼ 4.8, 10.0 Hz, 1H), 6.58 (s, 1H), 7.18–7.35
(m, 5H). 13C NMR (CDCl3) d (ppm) 41.5, 44.4, 56.7, 79.4, 127.4, 129.0, 129.3,
135.4, 158.3. ESI-MS: C11H13ClNO2[MþH]þ, calculated 226.0629, found 226.0633.
(4S,5R)-tert-Butyl 4-Benzyl-5-(chloromethyl)-2-oxooxazolidine-3-
carboxylate (11)[20]
To this solution, trimethylamine (TEA; 8.0 mL, 55.4 mmol), Boc2O (8.01 g,
36.7 mmol), and dimethylaminopyridine (DMAP; 0.20 g, 0.165 mmol) were added.
The reaction was kept at 10–20 °C for about 8 h. The mixture was then filtered

1186
T. LI ET AL.
and the cake was washed with cold MTBE to collect the solid. The mother liquor was
washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and con-
centrated in a vacuum to give a solid. The solid was combined and recrystallized in
1
EtOH to afford 11 as a white solid (8.10 g, 74% for 2 steps). H NMR (400 MHz,
TMS, CDCl3) d (ppm) 1.60 (s, 9H), 2.86 (dd, J ¼ 9.6, 13.6 Hz, 1H), 3.28–3.36
(m, 2H), 3.50 (dd, J ¼ 5.6, 12.0 Hz, 1H), 4.36–4.42 (m, 2H), 7.18–7.20 (m, 2H),
7.28–7.36 (m, 3H). 13C NMR (CDCl3) d (ppm) 28.0, 38.9, 44.5, 58.6, 75.0, 84.4,
127.6, 129.1, 129.4, 134.5, 149.0, 151.0. ESI-MS: C16H20ClNNaO4 [MþNa]þ
calculated: 348.0979, found 348.0983.
tert-Butyl ((S)-1-((R)-Oxiran-2-yl)-2-phenylethyl)carbamate
(1)[10,12h,14b,14g,20]
Compound 11 (10.0 g, 31.0 mmol) and KOH (5.25 g, 93.0 mmol) were added
respectively to 25 mL ethanol and cooled to ca. 5 °C. With stirring, KOH in ethanol
was gradually added to the mixture. Then after 30 min the reaction mixture was
concentrated in a vacuum, dissolved in 100 mL ethyl acetate, and washed with water
(30 mL) and brine (30 mL). The organic layer was collected, dried over Na2SO4,
filtered, and concentrated in a vacuum to give a colorless liquid (7.75 g, 95%), which
could also be solidified at ꢀ 20 °C to afford the title product as a white solid.
1H NMR (400 MHz, TMS, CDCl3) d (ppm) 1.39 (s, 9H), 2.58 (s, 1H), 2.70 (dd,
J ¼ 4.4, 4.4 Hz, 1H), 2.85–3.01 (m, 3H), 4.11 (s, br, 1H), 4.53 (s, br, 1H), 7.24–7.30
(m, 5H). 13C NMR (CDCl3) d (ppm) 28.3, 39.8, 44.5, 50.4, 52.6, 79.6, 126.6,
128.5, 129.4, 137.4, 155.5. ESI-MS: C15H21NNaO3 [MþNa]þ, calculated 286.1414,
found 286.1423.
(4 s,5 s)-4-Benzyl-5-(chloromethyl)oxazolidin-2-one (14)[21]
Acetonitrile (15 mL), and boron trifluoride–THF complex (1.0 equiv., 0.70 g)
were added to compound tert-butyl ((S)-1-((R)-oxiran-2-yl)-2-phenylethyl)
carbamate (1) (1.31 g, 5 mmol). The mixture was stirred at 60 °C for ca. 5 h. This
reaction mixture was quenched with water and extracted with dicholormethane
(DCM). The organic layer was combined, dried over Na2SO4, and purified by flash
column chromatography on silica gel (hexane:ethyl acetate ¼ 1:2) to furnish (4S,5S)-
4-benzyl-5-(hydroxymethyl)oxazolidin-2-one as a white solid (0.74 g, 71%). 1H
NMR (400 MHz, TMS, DMSO-d6) d (ppm) 2.69 (dd, J ¼ 8.8, 14.0 Hz, 1H), 2.93 (dd,
J ¼ 5.2, 14.0 Hz, 1H), 3.63–3.64 (m, 2H), 4.12–4.17 (m, 1H), 4.51–4.55 (m, 1H), 5.03–
5.04 (m, 1H), 7.20–7.32 (m, 5H), 7.54 (s, 1H). 13C NMR (DMSO-d6) d (ppm) 35.7,
54.7, 59.5, 79.0, 126.4, 128.6, 129.1, 138.1, 158.2. ESI-MS: C11H14NO3[MþH]þ,
calculated 208.0968, found 208.0975.
(4S,5S)-4-Benzyl-5-(hydroxymethyl)oxazolidin-2-one was dissolved (0.41 g,
2 mmol) in pyridine (5 mL), followed by addition of thiony chloride (5 equiv.,
1.21 g) at 0–10 °C. The reaction was then elevated to 60 °C, and stirred for a further
2 h. The mixture was concentrated in a vacuum, quenched with water, and extracted
with DCM. The organic layer was combined, dried over Na2SO4, and purified by
flash column chromatography on silica gel (hexane = ethyl acetate ¼ 2:1) to
furnish (4S,5S)-4-benzyl-5-(chloromethyl)oxazolidin-2-one (14) as a white solid

TERT-BUTYL ((S)-1-((R)-OXIRAN-2-YL)-2-PHENYLETHYL)CARBAMATE
1187
(0.31 g, 70%). 1H NMR (400 MHz, TMS, CDCl3) d (ppm) 2.71 (dd, J ¼ 12.8,
11.6 Hz, 1H), 3.10 (dd, J ¼ 3.2, 13.2 Hz, 1H), 3.77 (dd, J ¼ 8.0, 11.6 Hz, 1H), 3.85
(dd, J ¼ 5.6, 11.6 Hz, 1H), 4.10–4.16 (m, 1H), 4.84–4.89 (m, 1H), 5.12 (br, 1H),
7.19 (d, J ¼ 7.2 Hz, 2H), 7.26–7.38 (m, 3H); 13C NMR (CDCl3) d (ppm) 35.5, 40.0,
56.0, 77.7, 127.5, 129.0, 129.3, 136.0, 157.3. ESI-MS: C11H13ClNO2 [MþH]þ, calcu-
lated 226.0629, found 226.0635.
tert-Butyl ((S)-1-((S)-Oxiran-2-yl)-2-phenylethyl)carbamate (15)[22]
Compound 7 (3.0 g, 10.0 mmol) and KOH (1.68 g, 30.0 mmol) was added
respectively to 20 mL ethanol and cooled to ca. 5 °C. With stirring, KOH in ethanol
was gradually added to the mixture. The reaction was stirred for another 1 h and
then concentrated in a vacuum. The crude mixture was dissolved in 40 mL ethyl
acetate, washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered,
and concentrated in a vacuum to give a white solid (2.42 g, 92%). 1H NMR
(400 MHz, TMS, CDCl3) d (ppm) 1.38 (s, 9H), 2.76 (br, 1H), 2.78–2.81 (m, 1H),
2.87–2.99 (m, 3H), 3.70 (s, br, 1H), 4.49 (s, br, 1H), 7.21–7.31 (m, 5H). 13C NMR
(CDCl3) d (ppm) 28.3, 37.6, 46.9, 52.6, 53.2, 79.6, 126.7, 128.6, 129.5, 136.8, 155.3.
ESI-MS: C15H21NNaO3 [MþNa]þ, calculated 286.1414, found 286.1418.
ACKNOWLEDGMENTS
We thank Min Li, Yinli Lv, Weixia Liu, Wenlong Wang, and Xiangjun Wang
for their support with NMR, HPLC, and LC-MS analysis. We also thank Jun He
and Hai Sun for their help in the manuscript preparation.
SUPPORTING INFORMATION
1
Full experimental detail, H and 13C NMR spectra, HPLC conditions, and
charts for this article can be accessed on the publisher’s website.
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