A new synthetic approach to efavirenz through enantioselective trifluoromethylation by using the ruppert-prakash reagent

Article abstract of DOI:10.1002/ejoc.201101038

The organocatalyzed asymmetric synthesis of efavirenz was achieved in five steps from a commercially available substrate through the operationally simple, enantioselective trifluoromethylation of an alkynyl ketone by using the Ruppert-Prakash reagent. The present method provides the first example of the enantioselective synthesis of efavirenz by using a direct trifluoromethylation approach. The organocatalyzed asymmetric synthesis of efavirenz was achieved in five steps from a commercially available substrate through the operationally simple, enantioselective trifluoromethylation of an alkynyl ketone by using the Ruppert-Prakash reagent. The present method provides the first example of the enantioselective synthesis of efavirenz by using a direct trifluoromethylation approach.

Full text of DOI:10.1002/ejoc.201101038

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101038
A New Synthetic Approach to Efavirenz through Enantioselective
Trifluoromethylation by Using the Ruppert–Prakash Reagent
Hiroyuki Kawai,[a] Takashi Kitayama,[a] Etsuko Tokunaga,[a] and Norio Shibata*[a]
Keywords: Inhibitors / Asymmetric synthesis / Fluorine / Organocatalysis
The organocatalyzed asymmetric synthesis of efavirenz was
achieved in five steps from a commercially available sub-
strate through the operationally simple, enantioselective tri-
fluoromethylation of an alkynyl ketone by using the Rup-
pert–Prakash reagent. The present method provides the first
example of the enantioselective synthesis of efavirenz by
using a direct trifluoromethylation approach.
reported the first catalytic asymmetric synthesis of efavirenz
by using a very unique semiautocatalytic system.[4] The rea-
gent cocktail for this asymmetric transformation is basically
the same as that used in the stoichiometric reaction, but the
amount of chiral amino alcohol ligand can be reduced to
substoichiometric quantities by the additional use of sub-
stoichiometric quantities of the enantiomerically pure (S)-
product as an inherent part of the catalytic system. This
semiautocatalytic procedure provides the high enantio-
selectivity of the product; however, the reagent cocktail, in-
cluding organometallic reagents and two chiral sources, is
required. We disclose herein the catalytic asymmetric syn-
thesis of efavirenz (1) based on the operationally simple,
organocatalyzed enantioselective trifluoromethylation of an
Introduction
Efavirenz, (S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihy-
dro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one (1), is a
potent, non-nucleoside, reverse-transcriptase inhibitor of
HIV-1 and has been used in combination with other antiret-
rovirals for the treatment of HIV infection.[1] Efavirenz has
a stereogenic quaternary carbon center bearing a CF3
group with the (S) configuration. Biological evaluation of
optically active efavirenz (1) revealed that the (R) enantio-
mer exhibits virtually no activity.[2] Therefore, establishment
of the quaternary carbon center with the (S) configuration
in an asymmetric manner is a main challenge for the syn-
thesis of 1. Synthesis of efavirenz has been examined by
several groups through the asymmetric addition of met-
alated acetylene to aryl trifluoromethyl ketone as a key step
(Figure 1, route a).[3] Stoichiometric quantities of a chiral
amino alcohol ligand, diethylzinc, and trifluoroethanol as
an additive are required for this transformation, and the
development of catalytic variants of this process has been a
long-standing problem. In 2011, Carreira and co-workers
Figure 1. Two synthetic strategies for the enantioselective synthesis
of efavirenz (1): (a) Building block and (b) direct trifluoromethyl-
ation approaches.
[a] Department of Frontier Materials, Graduate School of
Engineering, Nagoya Institute of Technology
Gokiso, Showa-ku, Nagoya 466-8555, Japan
Fax: +81-52-735-7543
E-mail: nozshiba@nitech.ac.jp
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101038.
Scheme 1. Asymmetric synthesis of efavirenz (1).
Eur. J. Org. Chem. 2011, 5959–5961
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5959

H. Kawai, T. Kitayama, E. Tokunaga, N. Shibata
SHORT COMMUNICATION
aryl alkynyl ketone by using the Ruppert–Prakash reagent, and quinine-based catalyst 9d having an anthracyl group
(trifluoromethyl)trimethylsilane (Me3SiCF3), in the key gave disappointing results (Table 1, Entries 3 & 4). Catalyst
step. This strategy had not been examined for the synthesis 9e slightly improved the ee value to 23% (Table 1, Entry 5).
of 1 (Figure 1, route b) and efavirenz was synthesized by When the reaction was performed in the presence of 9f, tri-
our approach from commercially available aryl aldehyde 2 fluoromethylated product 5 was obtained with a higher
in five steps (Scheme 1).
enantioselectivity of 33% (Table 1, Entry 6). Cinchonidine
derivative 9g, having a N-3,5-bis(trifluoromethylbenzyl)
group, was found to be the most effective catalyst providing
5 in high yield of 88% with an acceptable 50%ee (Table 1,
Entry 7).
Results and Discussion
Our group has been engaged in the development of ef-
ficient methods for the enantioselective synthesis of fluo-
roorganic compounds over the last decade.[5,6] Recently, we
developed the first enantioselective trifluoromethylation of
alkynyl ketones with Me3SiCF3.[7] By employing an ammo-
nium salt derived from cinchonine and Me4NF as a cata-
lyst, we efficiently condensed a wide range of alkynyl
ketones 7 and Me3SiCF3 to provide trifluoromethylated
propargyl alcohols 8 having a quaternary carbon center in
very high enantiomeric excess. This outcome allowed us to
envisage the organocatalytic asymmetric synthesis of 1. In
practice, however, the reverse selection of the stereochemis-
try of 8 should be achieved to give access to 1 (Scheme 2).
Table 1. Enantioselective trifluoromethylation of 4.[a]
Entry
Catalyst 9
Time [h]
Yield [%][b]
ee [%][c]
1[d]
2
9a
9b
9c
9d
9e
9f
48
2
8
17
6
30
2
72
86
74
32
94
60
88
4
0
5
3
4[d]
5
0
23
33
50
6[d]
7[e]
Scheme 2. Enantioselective trifluoromethylation of alkynyl ketones
with Me3SiCF3 catalyzed by a cinchonine derivative and Me4NF.
9g
[a] The reaction of 4 with Me3SiCF3 (2.0 equiv.) was carried out in
the presence of catalyst 9 (10 mol-%) and Me4NF (20 mol-%) in
toluene/CH2Cl2 (2:1) at –60 °C, unless otherwise noted. [b] Isolated
yield. [c] The ee values were determined by chiral HPLC. [d] The
reaction was carried out by warming from –60 to –30 °C. [e] The
reaction was carried out at –40 °C.
The problem is the lack of availability of a mirror image
of cinchonine. We hence considered using cinchonidine and
quinine as catalyst templates, which both possess an ap-
proximately mirror-image molecular structure of cinchon-
ine. Starting alkynyl ketone 4 was prepared from commer-
cially available 5-chloro-2-nitrobenzaldehyde (2) in two
steps. Namely, the addition of zinc cyclopropyl acetylide to
2 afforded corresponding alcohol 3 in 89%. Oxidation of
alcohol 3 with Dess–Martin periodinane in CH2Cl2 pro-
vided 4 in 93% yield (from 2 to 4 in Scheme 1).
We started our investigation with the trifluoromethyl-
ation of 4 in the presence of a catalytic amount of Me4NF
with Me3SiCF3 in toluene/CH2Cl2 (2:1) and screened a
broad range of ammonium bromides derived from cin-
chonidine and quinine (Table 1). We first attempted the re-
action of 4 in the presence of a catalytic amount of 9a,
which is a dimeric compound derived from cinchonidine.
However, this attempt gave a disappointing result: trifluoro-
methylated adduct 5 was obtained in 72% with 4%ee
(Table 1, Entry 1). The reaction was next attempted by
using 9b derived from quinine. Trifluoromethylated adduct
5 was formed in 86% with no chiral induction (Table 1, En-
With enantiomerically enriched 5 in hand, the transfor-
mation of 5 into 1 was carried out (Scheme 1). The chemo-
selective reduction of the nitro group was successfully
achieved by iron in the presence of acetic acid in THF/
MeOH (2:1) to furnish the corresponding amino alcohol 6
in 77% without losing a chloride substituent on the benzene
ring. The enantiopurity of amino alcohol 6 was easily in-
creased from 50 to 94%ee by a single recrystallization
(hexane/CH2Cl2). Treatment of 6 with 4-nitrophenylchloro-
formate under basic conditions resulting in the formation
of p-nitrophenylcarbamate followed by closure of the ring
afforded efavirenz (1) in an excellent yield of 96%.
Conclusions
We herein disclosed the organocatalyzed asymmetric syn-
try 2). Sterically demanding tBu quininium derivative 9c thesis of efavirenz by an operationally simple procedure in-
5960
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 5959–5961

A New Synthetic Approach to Efavirenz
[4] N. Chinkov, A. Warm, E. M. Carreira, Angew. Chem. 2011,
123, 3014–3018; Angew. Chem. Int. Ed. 2011, 50, 2957–2961.
[5] a) N. Shibata, S. Mizuta, H. Kawai, Tetrahedron: Asymmetry
2008, 19, 2633–2644; b) N. Shibata, T. Ishimaru, S. Nakamura,
T. Toru, J. Fluorine Chem. 2007, 128, 469–483; c) N. Shibata,
T. Furukawa, D. S. Reddy, Chem. Today 2009, 27, 38–42; d) N.
Shibata, S. Mizuta, T. Toru, J. Synth. Org. Chem. Jpn. 2008,
66, 215–228; e) N. Shibata, J. Synth. Org. Chem. Jpn. 2006,
64, 14–24; f) S. Mizuta, N. Shibata, T. Sato, H. Fujimoto, S.
Nakamura, T. Toru, Synlett 2006, 2, 267–270; g) S. Mizuta, N.
Shibata, S. Ogawa, H. Fujimoto, S. Nakamura, T. Toru, Chem.
Commun. 2006, 2575–2577; h) S. Mizuta, N. Shibata, M. Hib-
ino, S. Nagano, S. Nakamura, T. Toru, Tetrahedron 2007, 63,
8521–8528; i) S. Mizuta, N. Shibata, S. Akiti, H. Fujimoto, S.
Nakamura, T. Toru, Org. Lett. 2007, 9, 3707–3710; j) H. Ka-
wai, A. Kusuda, S. Mizuta, S. Nakamura, Y. Funahashi, H.
Masuda, N. Shibata, J. Fluorine Chem. 2009, 130, 762–765; k)
H. Kawai, A. Kusuda, S. Nakamura, M. Shiro, N. Shibata,
Angew. Chem. 2009, 121, 6442–6445; Angew. Chem. Int. Ed.
2009, 48, 6324–6327; l) H. Kawai, K. Tachi, E. Tokunaga, M.
Shiro, N. Shibata, Angew. Chem. 2011, 123, 7949–7952; Angew.
Chem. Int. Ed. 2011, 50, 7803–7806; m) T. Furukawa, T. Nishi-
mine, E. Tokunaga, K. Hasegawa, M. Shiro, N. Shibata, Org.
Lett. 2011, 13, 3972–3975; n) S. Noritake, N. Shibata, S. Naka-
mura, T. Toru, M. Shiro, Eur. J. Org. Chem. 2008, 3465–3468;
o) A. Matsnev, S. Noritake, Y. Nomura, E. Tokunaga, S. Naka-
mura, N. Shibata, Angew. Chem. 2010, 122, 582–586; Angew.
Chem. Int. Ed. 2010, 49, 572–576.
[6] For selected papers on trifluoromethylation by other groups,
see: a) G. K. S. Prakash, A. K. Yudin, Chem. Rev. 1997, 97,
757–786; b) R. P. Singh, J. M. Shreeve, Tetrahedron 2000, 56,
7613–7632; c) J.-A. Ma, D. Cahard, Chem. Rev. 2008, 108,
PR1–PR43; d) T. Billard, B. R. Langlois, Eur. J. Org. Chem.
2007, 891–897; e) K. Iseki, T. Nagai, Y. Kobayashi, Tetrahedron
Lett. 1994, 35, 3137–3138; f) T. Hagiwara, T. Kobayashi, T.
Fuchigami, Main Group Chem. 1997, 2, 13–15; g) H. Nagao,
Y. Yamane, T. Mukaiyama, Chem. Lett. 2007, 36, 666–667; h)
H. Zhao, B. Qin, X. Liu, X. Feng, Tetrahedron 2007, 63, 6822–
6826; i) L. M. Yagupolskii, N. V. Kondratenko, G. N. Timo-
feeva, J. Org. Chem. USSR 1984, 20, 103–106; j) T. Umemoto,
S. Ishihara, Tetrahedron Lett. 1990, 31, 3579–3582; k) J.-J.
Yang, R. L. Kirchmeier, J. M. Shreeve, J. Org. Chem. 1998, 63,
2656–2660; l) P. Eisenberger, S. Gischig, A. Togni, Chem. Eur.
J. 2006, 12, 2579–2586; m) E. Magnier, J.-C. Blazejewski, M.
Tordeux, C. Wakselman, Angew. Chem. 2006, 118, 1301–1304;
Angew. Chem. Int. Ed. 2006, 45, 1279–1282.
volving the enantioselective trifluoromethylation of alkynyl
ketone 4 with the Ruppert–Prakash reagent based on the
combination of the ammonium bromides of cinchona alka-
loids with Me4NF. Because the reported synthesis of efavir-
enz is based on a building block approach using organome-
tallic reagents, this is the first example of the asymmetric
synthesis of efavirenz by the direct introduction of the tri-
fluoromethyl group.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization data, copies of the
NMR spectra, and HPLC traces.
Acknowledgments
This study was financially supported in part by a Grants-in-Aid
for Scientific Research from the Ministry of Education, Science,
Sports and Culture, Japan (21390030, 22106515, Project No. 2105:
Organic Synthesis Based on Reaction Integration). We also thank
TOSOH F-TECH for the gift of Me3SiCF3 and the Asahi Glass
Foundation for partial support.
[1] a) D. L. Romero, Ann. Rep. Med. Chem. 1994, 29, 123–132; b)
J. C. Adkins, S. Noble, Drugs 1998, 56, 1055–1064; c) B. G.
Gazzard, Int. J. Clin. Pract. 1999, 53, 60–64; d) E. de Clercq,
Rev. Med. Virol. 2009, 19, 287–299.
[2] J. W. Corbett, S. S. Ko, J. D. Rodgers, S. Jeffrey, L. T. Bacheler,
R. M. Klabe, S. Diamond, C.-M. Lai, S. R. Rabel, J. A. Saye,
S. P. Adams, G. L. Trainor, P. S. Anderson, S. K. Erickson-Viit-
anen, Antimicrob. Agents Chemother. 1999, 43, 2893–2897.
[3] a) A. S. Thompson, E. G. Corley, M. F. Huntington, E. J. J.
Grabowski, Tetrahedron Lett. 1995, 36, 8937–8940; b) M. E.
Pierce, R. L. Parsons Jr., L. A. Radesca, Y. S. Lo, S. Silverman,
J. R. Moore, Q. Islam, A. Choudhury, J. M. D. Fortunak, D.
Nguyen, C. Luo, S. J. Morgan, W. P. Davis, P. N. Confalone, J.
Org. Chem. 1998, 63, 8536–8543; c) L. Tan, C.-Y. Chen, R.
Tillyer, E. J. J. Grabowski, P. J. Reider, Angew. Chem. 1999, 111,
724–727; Angew. Chem. Int. Ed. 1999, 38, 711–713; d) L. Tan,
C.-Y. Chen, Enantiomer 1999, 4, 599–608; e) C. Y. Chen, R. D.
Richard, L. Tan, PCT Int. Appl., WO9851676, 1998 [Chem.
Abstr. 1999, 130, 24851]; f) A. Thompson, E. G. Corley, M. F.
Huntington, E. J. J. Grabowski, J. F. Remenar, D. B. Collum, J.
Am. Chem. Soc. 1998, 120, 2028–2038; g) A. Choudhury, J. R.
Moore, M. E. Pierce, J. M. Fortunak, I. Valvis, P. N. Confa-
lone, Org. Process Res. Dev. 2003, 7, 324–328; h) E. J. J. Gra-
bowski, Chirality 2005, 17, S249–259.
[7] H. Kawai, K. Tachi, E. Tokunaga, M. Shiro, N. Shibata, Org.
Lett. 2010, 12, 5104–5107.
Received: July 17, 2011
Published Online: September 14, 2011
Eur. J. Org. Chem. 2011, 5959–5961
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5961