Concise Asymmetric Synthesis of (+)-CP-99,994
and (+)-L-733,060 via Efficient Construction of
Homochiral syn-1,2-Diamines and syn-1,2-Amino
Alcohols
Run-Hua Liu,† Kai Fang,‡ Bing Wang,*,†
Ming-Hua Xu,*,‡ and Guo-Qiang Lin*,†,‡,§
Department of Chemistry, Fudan UniVersity, 220 Handan Road,
Shanghai 200433, Institutes of Biomedical Sciences, Fudan
UniVersity, 138 Yixueyuan Road, Shanghai 200032, and
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Road, Shanghai 200032, China
FIGURE 1. Biologically active 1,2-diamines and 1,2-amino alcohols.
99,994 and (+)-L-733,060, their valuable biological profiles
have stimulated immense interests in their syntheses.7-9 To date,
most asymmetric syntheses of 1 and 2 were based on chiron
approach, the stereochemical outcomes of which relied more
or less on substrate control. It is also noteworthy that only a
handful of synthetic routes were applicable to both 1 and 2,8d,f,h,i
whereas the majority were devoted to only one of them. Hence,
a general, flexible, and efficient synthesis of the two is still
highly desirable.
ReceiVed February 5, 2008
One of the most straightforward methods to construct vicinal
diamines or vicinal amino alcohols is the direct pinacol-type
imine-imine or imine-aldehyde reductive coupling, respec-
tively. Recently we have developed an efficient SmI2-induced
reductive coupling of N-tert-butanesulfinyl imines10 with alde-
hydes to yield virtually enantiopure anti-1,2-amino alcohols.11
An efficient asymmetric synthesis of human NK-1 SP
receptor antagonists (+)-CP-99,994 and (+)-L-733,060 was
achieved starting from a common chiral intermediate (5).
Our route featured the SmI2-induced reductive coupling of
N-tert-butanesulfinyl imine (7) with aldehyde (6) as the key
step as well as pivotal transformations of the anti-1,2-amino
alcohol thus obtained to homochiral syn-1,2-amino alcohol
and syn-1,2-diamine for the asymmetric synthesis of 2,3-
disubstituted piperidines.
(5) (a) Koepfli, J. B.; Mead, J. F.; Brockman, J. A., Jr. J. Am. Chem.
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(7) For synthesis of racemic CP-99,994, see: (a) Desai, M. C.; Thadeio,
P. F.; Lefkowitz, S. L. Tetrahedron Lett. 1993, 34, 5831. For synthesis of
racemic L-733,060, see: (b) Ref 4, (c) Tomooka, K.; Nakazaki, A.; Nakai,
T. J. Am. Chem. Soc. 2000, 122, 408. For formal synthesis of 1 or 2, see:
(d) Calvez, O.; Langlois, N. Tetrahedron Lett. 1999, 40, 7099. (e) Stadler,
H.; Bo¨s, M. Heterocycles 1999, 51, 1067. (f) Lee, J.; Hoang, T.; Lewis, S.;
Weissman, S. A.; Askin, D.; Volante, R. P.; Reider, P. J. Tetrahedron Lett.
2001, 42, 6223. (g) Bodas, M. S.; Upadhyay, P. K.; Kumar, P. Tetrahedron
Lett. 2004, 45, 987. (h) Tsai, M.-R.; Chen, B.-F.; Cheng, C.-C.; Chang,
N.-C. J. Org. Chem. 2005, 70, 1780. (i) Okada, A.; Shibuguchi, T.; Ohshima,
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Tetrahedron Lett. 1999, 40, 5071. (b) Yamakazi, N.; Atobe, M.; Kibayashi,
C. Tetrahedron Lett. 2002, 43, 7979. (c) Tsuritani, N.; Yamada, K.-I.;
Yoshikawa, N.; Shibasaki, M. Chem. Lett. 2002, 276. (d) Huang, P.-Q.;
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Tetrahedron Lett. 2007, 48, 7838. For synthesis of ent-1, see: (h) Lemire,
A.; Grenon, M.; Pourashraf, M.; Charette, A. B. Org. Lett. 2004, 6, 3517.
(i) Takahashi, K.; Nakano, H.; Fujita, R. Tetrahedron Lett. 2005, 46, 8927.
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Eur. J. 2006, 12, 466.
1,2-Amino alcohol and 1,2-diamine scaffolds are important
and ubiquitous structural features in natural products and
therapeutical agents possessing a wide variey of biological
activities,1 as well as chiral ligands and auxiliaries for asym-
metric synthesis (Figure 1).2 For example, (+)-CP-99,994 (1)3
and (+)-L-733,060 (2)4 are potent and selective human neu-
ronkinin-1 substance P receptor antagonists. Febrifugine (3) is
well-known for its antimalarial effect.5 Recently, Linezolid (4)6
was successfully marketed as a new antibiotic. For (+)-CP-
† Department of Chemistry, Fudan University.
‡ Chinese Academy of Sciences.
§ Institutes of Biomedical Sciences, Fudan University.
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10.1021/jo8002979 CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/11/2008
J. Org. Chem. 2008, 73, 3307-3310
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