COMMUNICATIONS
2.50 (dd, J 1.6, 16.2 Hz, 1H), 1.89 ± 1.93 (m, 1H), 1.73 ± 1.81 (m, 2H),
1.60 ± 1.63 (m, 1H), 1.55 (brs, 1H, OH), 1.28 ± 1.40 (m, 3H); 13C NMR
(100 MHz, CDCl3, 258C): d 143.47, 129.73, 126.68, 119.18, 116.49, 113.43,
72.67, 53.93, 33.16, 32.96, 27.80, 25.31, 23.35; HR-MS (CI): calcd (found) for
re- and si-Face-Selective Nitroaldol Reactions
Catalyzed by a Rigid Chiral Quaternary
Ammonium Salt: A Highly Stereoselective
Synthesis of the HIV Protease Inhibitor
Amprenavir (Vertex 478)**
C13H17NO [M ]: 204.1388 (204.1397).
Received: February 3, 1999 [Z12991IE]
German version: Angew. Chem. 1999, 111, 2054 ± 2056
E. J. Corey* and Fu-Yao Zhang
Keywords: antiviral agents ´ azaxylylenes ´ cycloadditions ´
heterocycles ´ stereocontrol
The development of therapeutically useful HIV protease
inhibitors has been one of the major contributions of synthetic
and medicinal chemistry to human well-being during this
decade.[1, 2] Since several of these agents possess chiral
substituted 1,3-diamino-2-hydroxypropyl segments as a cen-
tral structural subunit, for example, the phenylalanine-related
subunit 1, considerable research effort has been directed at
methods for their synthesis.[3, 4] Described herein is a new
strategy for stereocontrol in the synthesis of subunits of type 1
and a specific application with a practical synthesis of
amprenavir (2),[5, 6] an important second generation HIV
[1] E. M. Burgess, L. McCullagh, J. Am. Chem. Soc. 1966, 88, 1580 ± 1581.
[2] a) M. Lancaster, D. J. H. Smith, J. Chem. Soc. Chem. Commun. 1980,
471 ± 472; b) K. Wojciechowski, Tetrahedron 1993, 49, 7277 ± 7286.
[3] Y. Ito, S. Miyata, M. Nakatsuka, T. Saegusa, J. Am. Chem. Soc. 1981,
103, 5250 ± 5251.
[4] a) R. D. Bowen, D. E. Davies, C. W. G. Fishwick, T. O. Glasbey, S. J.
Noyce, R. C. Storr, Tetrahedron Lett. 1982, 23, 4501 ± 4504; b) J. M.
Â
Wiebe, A. S. Caille, L. Trimble, C. K. Lau, Tetrahedron 1996, 52,
11705 ± 11724; see also c) E. Foresti, P. Spagnolo, P. Zanirato, J. Chem.
Soc. Perkin Trans. 1, 1989, 1354 ± 1356.
[5] For a general review of Diels ± Alder additions with other types of
azadienes, see L. Tietze in Top. Curr. Chem. 1997, 189, 1 ± 120.
[6] The substrates 1a ± 1c of Scheme 1 were prepared from o-amino-
benzyl alcohol by the sequence: 1) N-acylation or N-sulfonylation,
and 2) conversion of the resulting benzyl alcohol into the correspond-
ing chloride by reaction with thionyl chloride in dichloromethane.
[7] a) Crystal structure data for 4: C12H13NO2; monoclinic; P21c; a
14.972(7), b 5.599(3), c 13.403(5) ; a 90, b 114.93(3), g
908; Z 4; R1 [I > 2s(I)] 0.0386; b) crystal structure data for 8:
C14H15NO2; monoclinic; P21c; a 17.7653(11), b 9.1414(6), c
15.4356(10) ; a 90, b 115.5670(10), g 908; Z 8; R1 [I >
2s(I)] 0.0481; c) crystal structure data for 6: C12H12NO2Cl; mono-
clinic; P21n; a 6.2128(5), b 12.1974(12), c 14.4788(13) ; a 90,
b 98.188(3), g 908; Z 4; R1 [I > 2s(I)] 0.0601. Crystallographic
data (excluding structure factors) for the structures reported in this
paper have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication nos. CCDC-113239/113240/
113241. Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK
(fax: (44)1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).
H
N
OH
2
R2
OH
2
R1NH
N
O
N
3
R3
SO2
NH2
O
(2R or 2S)
1
2
protease inhibitor with a number of clinical advantages over
first generation agents. The method currently being used to
produce 2 involves the activation of the carboxyl group of N-
tert-butoxycarbonylphenylalanine and transformation to the
corresponding diazomethyl ketone with diazomethane as a
key element.[7] Because of the intrinsic hazards of this step a
safer alternative seems preferable.
The sequence utilized for the synthesis of amprenavir is
summarized in Scheme 1. N,N-Dibenzyl-(S)-phenylalaninal
(3)[8] in tetrahydrofuran (THF) was added to a mixture of
quaternary ammonium salt 4,[9, 10] nitromethane, and finely
divided potassium fluoride in THF with stirring. After 6 h the
nitro alcohol 5 was isolated in 86% yield by flash chromatog-
raphy on silica gel.[10] The more polar C(2) diastereomer of 5
was isolated in 5% yield, which indicated a 17:1 diastereo-
selectivity for the nitroaldol reaction.[11] In contrast, the
nitroaldol reaction of 3 in the presence of tetra-n-butylam-
monium fluoride[8c] afforded a mixture of 5 and the C(2)
diastereomer with only 4:1 diastereoselectivity under the
same reaction conditions. Treatment of nitro alcohol 5 with
2.5 equivalents of NiCl2 and 25 equivalents of NaBH4 in
methanol at 08C for 10 min with vigorous agitation provided
Å
[8] S. Omura, A. Nakagawa, Tetrahedron Lett. 1981, 22, 2199 ± 2202.
[9] a) M. L. Hill, R. A. Raphael, Tetrahedron 1990, 46, 4587 ± 4594; b) Y.
Morimoto, H. Shirahama, Tetrahedron 1996, 52, 10609 ± 10630.
[10] Chiralpak AD column (Daicel Chemical Industries); flow rate:
1
0.7 mL min
; eluent: 6% iPrOH in hexane; UV detection at
254 nm; tR[()-8] 26.4 min, tR[( )-8] 30.0 min.
[11] The substrates 3, 5, and 7 were prepared starting from the corre-
sponding allylic alcohols by the sequence: 1) conversion into chlor-
oformates by reaction with phosgene, 2) treatment of the chlorofor-
mates with o-aminobenzyl alcohol, and 3) conversion of the resulting
hydroxy carbamates into the corresponding chlorides with thionyl
chloride (see experimental section for details). 3-Chloro-2-methyl-2-
propen-1-ol was prepared according to A. Mooradian, J. B. Cloke, J.
Am. Chem. Soc. 1946, 68, 785 ± 789; L. F. Hatch, J. J. Russ, L. B.
Gordon, J. Am. Chem. Soc. 1947, 69, 2614 ± 2616. Enantiomerically
pure (R)-2-cyclohexen-1-ol was prepared by kinetic resolution with
lipase as described by T. Fukazawa, T. Hashimoto, Tetrahedron:
Asymmetry 1993, 4, 2323 ± 2326.
[*] Professor E. J. Corey, Dr. F.-Y. Zhang
Department of Chemistry and Chemical Biology
Harvard University
12 Oxford Street, Cambridge, Massachusetts, 02138 (USA)
Fax: (1)617-495-0376
[**] This research was supported by grants from the National Science
Foundation and the National Institutes of Health. We thank Mr.
David Barnes-Seeman for the graphic illustrations in Figures 1 and 2.
Angew. Chem. Int. Ed. 1999, 38, No. 13/14
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1433-7851/99/3813-1931 $ 17.50+.50/0
1931