was obtained from the spirolactam (()-2 derived from
a Staudinger reaction between the acid chloride of
N-carbonyloxybenzyl-L-proline and N-methyl-2-[[(1E)-
phenylmethylene]amino]acetamide. Our combined inter-
est in the area of â-turn mimetics7 and the synthetic use
of D- and L-proline led us to explore an optically active
approach to proline-derived 5.4-spiro â-lactams.8,9
Novel Asym m etr ic Ap p r oa ch to
P r olin e-Der ived Sp ir o-â-la cta m s
Alisher B. Khasanov,† Michele M. Ramirez-Weinhouse,‡
Thomas R. Webb,†,§ and Mohan Thiruvazhi*,†
Department of Chemistry Research, ChemBridge Research
Laboratories and ChemBridge Corporation,
16981 Via Tazon, San Diego, California 92127
mohan.thiruvazhi@chembridgeresearch.com
Received April 6, 2004
Abstr a ct: We describe a novel asymmetric approach using
Staudinger chemistry to proline-derived spiro-â-lactams. A
chiral group at C-4 of the acid chloride of proline directs the
stereoselectivity of Staudinger chemistry and later is sac-
rificed to obtain optically active 5.4-spiro-â-lactams. The
scope, limitations, and mechanistic rationale for the observed
results of Staudinger Chemistry of the acid chloride of
4-alkyl(aryl)sulfonyloxy-L-proline with imines are also dis-
cussed.
While asymmetric Staudinger chemistry of optically
active acid chloride of D- or L-proline with achiral imines
is impossible due to the loss of stereochemistry at C-2,10
the use of chiral ketenes11 or chiral imines12 are viable
options. We have developed a strategy that exploits the
asymmetric center resident in C-4 of trans-4-hydroxy-L-
proline to influence the diastereoselectivity in the
Staudinger reaction and which may be sacrificed after
the fact. Whereas, utilization of the asymmetry resident
in C-4 of proline to influence the stereoselectivity in
Staudinger was reported by Croce and Rosa,13 the concept
of sacrificing the asymmetry to eventually deliver opti-
cally active “proline-derived” Staudinger products from
achiral imines is novel. We herein present the details of
the first direction to such a strategy highlighting the fact
that our results are similar in regards to the configura-
tion at the spiranic carbon of the predominant product
(vide infra), but are in contrast with the overall outcome
from those of Croce and Rosa’s possibly due to differences
in mechanistic pathways predetermined by the reaction
conditions employed.14-16
The conceptual approach of peptidomimetics uses
peptides and proteins as leads to discover novel classes
of compounds of biological importance. One approach to
the advancement of a peptide lead to a therapeutically
desirable small molecule drug uses cyclic peptide deriva-
tives and conformational constraints as logical steps in
the process.1 Conformational constraints induced on
introduction of cyclic amino acids (such as proline) into
peptides or proteins is enhanced by quarternization of
the stereocenter. Efficient methods were developed to
synthesize such unusual amino acids, and one such
method was recently published by Kawabata et al.2
Alonso et al. combined the features of a spiro system3
and R,R-disubstituted â-lactams4 to propose the introduc-
tion of a 5.4-spirolactam, which was validated using high-
level ab initio calculations and thereby introduced (()-1
as a novel â-turn mimetic.5,6 The tripeptidic â-turn (()-1
(7) Chianelli, D.; Kim, Y.-C.; Lvovskiy, D.; Webb, T. R. Bioorg. Med.
Chem. 2003, 11, 5059-5068.
(8) This work was presented at 225th National Meeting of the
American Chemical Society, New Orleans, LA, 2003; Abstract ORGN
452.
* Corresponding author.
(9) The “R” and “S” configurations at the spiranic carbon of spiro-
lactam induce different conformations when incorporated in a pep-
tide: (a) Brown, J . R.; Clegg, S. P.; Ewan, G. B.; Hagan, R. M.; Ireland,
S. J .; J ordan, C. C.; Porter, B.; Ross, B. C.; Ward, P. In Molecular
Recognition: Chemical and Biochemical Problems; Roberts, S. M., Ed.;
Royal Society of Chemistry Special Publication No. 78; Royal Society
of Chemistry: Lechtworth, 1989; pp 94-111. (b) Ward, P.; Ewan, G.
B. Eur. Patent 0 360 390 A1, 1989. (c) Reference 3a.
(10) Staudinger reaction proceeds via ketene mechanism when base
is used in conjunction with an acid chloride. In the absence of a base,
a direct attack of the imine on acid chloride is the first step in the
mechanism.
† ChemBridge Research Laboratories.
‡ Current address: Pfizer Global Research & Development-La J olla
Laboratories, Discovery Technologies, 10614 Science Center Drive
(CB6), San Diego, CA 92121.
§ ChemBridge Corp.
(1) Olson, G. L.; Bolin, D. R.; Bonner, M. P.; Bo¨s, M.; Cook, C. M.;
Fry, D. C.; Graves, B. J .; Hatada, M.; Hill, D. E.; Kahn, M.; Madison,
V. S.; Rusiecki, V. K.; Sarabu, R.; Sepinwall, J .; Vincent, G. P.; Voss,
M. E. J . Med. Chem. 1993, 36, 3039-3049.
(2) Kawabata, T.; Kawakami, S.; Majumdar, S. J . Am. Chem. Soc.
2003, 125, 13012-13013.
(3) (a) Ward, P.; Ewan, G. B.; J ordan, C. C.; Ireland, S. J .; Hagan,
R. M.; Brown, J . R. J . Med. Chem. 1990, 33, 1848-1851. (b) Hinds,
M. G.; Welsh, J . H.; Brennand, D. M.; Fisher, J .; Glennie, M. J .;
Richards, N. G. J .; Turner, D. L.; Robinson, J . A. J . Med. Chem. 1991,
34, 1777-1789. (c) Mu¨ller, G.; Hessler, G.; Decornez, H. Y. Angew.
Chem., Int. Ed. 2000, 39, 894-896.
(4) Palomo, C.; Aizpurua, J . M.; Benito, A.; Galarza, R.; Khamrai,
U. K.; Vazquez, J .; Pascual-Teresa, B.; Nieto, P. M.; Linden, A. Angew.
Chem., Int. Ed. 1999, 38, 3056-3058.
(5) Alonso, E.; Lopez-Ortiz, F.; Del Pozo, C.; Peralta, E.; Mac´ıas, A.;
Gonza´lez, J . J . Org. Chem. 2001, 66, 6333-6338.
(6) For references on 5.n-spirolactams (where n * 4), see: Ferna´n-
dez, M. M.; Diez, A.; Rubiralta, M.; Montenegro, E.; Casamitjana. N.;
Kogan, M. J .; Giralt, E. J . Org. Chem. 2002, 67, 7587-7599 and
references therein.
(11) For the first efficient approach, see: (a) Evans, D. A.; Sjogren,
E. B. Tetrahedron Lett. 1985, 26, 3787-3790. (b) Evans, D. A.; Sjogren,
E. B. Tetrahedron Lett. 1985, 26, 3783-3786.
(12) For first report on this approach, see: Hubschwelen, C.; Scgmid,
G. Helv. Chim. Acta 1983, 66, 2206-2209.
(13) Croce, P. D.; Rosa, C. L. Tetrahedron: Asymmetry 1999, 10,
1193-1199.
(14) For variety of mechanistic possibilities for Staudinger reaction,
see: Georg, G. I.; Ravikumar, V. T. In The Organic Chemistry of
â-lactams; Georg, G. I., Ed.; VCH: New York 1992; pp 295-368.
(15) For theoretical study on ketene mechanistic pathway, see: (a)
Coss´ıo, F. P.; Arrieta, A.; Lecea, B.; Ugalde, J . M. J . Am. Chem. Soc.
1994, 116, 2085-2093. (b) Cossio, F. P.; Ugalde, J . M.; Lopez, X.; Lecea,
B.; Palomo, C. J . Am. Chem. Soc. 1993, 115, 995-1004. (c) Venturini,
A.; Gonza´lez, J . J . Org. Chem. 2002, 67, 9089-9092.
10.1021/jo049430o CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/21/2004
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J . Org. Chem. 2004, 69, 5766-5769