A Novel Syn th etic Rou te to Ch ir a l
γ-La cta m s fr om r-Am in o Acid s via
Rh -Ca ta lyzed In tr a m olecu la r C-H
In ser tion
Cheol Hwan Yoon, David L. Flanigan,
Byong-Don Chong, and Kyung Woon J ung*
F IGURE 1. The structures of lactacystin and (-)-pramanicin.
Department of Chemistry, University of South Florida,
4202 East Fowler Avenue, Tampa, Florida 33620-5250
SCHEME 1
kjung@chuma.cas.usf.edu
Received May 25, 2002
Abstr a ct: Highly functionalized γ-lactams are key inter-
mediates for the synthesis of numerous biologically signifi-
cant natural products. We herein described the synthesis of
various chiral γ-lactams via intramolecular C-H insertion
of R-diazo-R-(phenylsulfonyl)acetamides derived from R-ami-
no acids, which possess various functional groups. The
cyclizations were highly regio- and stereoselective to afford
chiral γ-lactam motifs in high yields.
a
Key: (1) HCl (g), MeOH; (2) PhSCH2CO2H, DIC, imidazole,
DMF, rt; (3) NaBH4, LiCl, THF-MeOH (1:1); (4) Me2C(OMe)2, cat.
p-TsOH, benzene, reflux; (5) m-CPBA, CH2Cl2; (6) p-ABSA, DBU,
CH3CN.
The pyrrolidinone (γ-lactam) functionality is a preva-
lent theme in various natural product syntheses, and
serves as a crucial intermediate for numerous natural
products. For example, lactacystin (1)1 and pramanicin
(2)2 possess highly functionalized γ-lactam cores (Figure
1). Although a vast number of synthetic methods have
been reported to date, syntheses of chiral γ-lactams seem
to be limited and inefficient, resulting in lengthy and
costly synthetic sequences.3,4
SCHEME 2
Recently, we developed intramolecular C-H insertion
of R-diazo-R-(phenylsulfonyl)acetamides to afford γ-lac-
tams with high regio- and stereoselectivities.5 Regarding
chiral pyrrolidinones, we considered R-amino acids ver-
satile chiral starting materials, which possess a variety
of functional groups and are commercially available,
usually in both enantiomeric forms. To our surprise, an
extensive literature search revealed that various R-diazo
amides derived from R-amino acids were poor substrates
for ring closures through C-H insertions, due to compet-
ing side reactions and poor regio- and stereoselectivities.6
We herein describe an efficient synthesis of chiral γ-lac-
tams with R-diazo-R-(phenylsulfonyl)acetamides derived
from R-amino acids using our developed methodology.
As shown in Scheme 1, cyclization precursor 5 was
prepared from (L)-phenylalanine (3) in 6 steps, and then
subjected to Rh(II)-catalyzed C-H insertion cyclization.7
Remarkably, the diazo compound 5 was smoothly con-
verted to the desired trans γ-lactam 6 as a single isomer
in 91% yield without the formation of â-lactam or
aromatic cycloaddition products.8
The observed stereochemical outcomes are rationalized
in Scheme 2. During the insertion reaction, the confor-
mationally restricted metallocarbenoid 7 adopts the s-cis
conformer due to the severe nonbonded interaction
between the gem-dimethyl group and the carbonyl sub-
(1) For a review of lactacystin, see: Corey, E. J .; Li, W.-D. Chem.
Pharm. Bull. 1999, 47, 1 and references therein.
(2) Barrett, A. G.; Head, J .; Smith, M. L.; Stock, N. S.; White, A. J .
P.; Williams, D. J . J . Org. Chem. 1999, 64, 6005 and references therein.
(3) (a) Meyers, A. I.; Snyder, L. J . Org. Chem. 1993, 58, 36. (b)
Knaus, E. E.; Wei, Z.-Y. Tetrahedron Lett. 1993, 34, 4439. (c) Gennari,
C.; Pain, G.; Moresca, D. J . Org. Chem. 1995, 60, 6248. (d) Kanazawa,
A.; Gillet, S.; Delair, P.; Greene, A. E. J . Org. Chem. 1998, 63, 4660.
(e) Yee, N. K.; Nummy, L. J .; Byrne, D. P.; Smith, L. L.; Roth, G. P. J .
Org. Chem. 1998, 63, 326. (f) Wang, J .; Hou, Y.; Wu, P.; Qu, Z.; Chan.
A. S. C. Tetrahedron Asymmetry 1999, 10, 4553. (g) Zimmer, R.; Ziemer,
A.; Gruner, M.; Brudgam, I.; Hartl, H.; Reissig, H.-U. Synthesis 2001,
1649.
(4) For syntheses of chiral pyrrolidinones via C-H insertion, see:
(a) Doyle, M. P.; Protopopova, M. N.; Winchester, W. R.; Daniel, K. L.
Tetrahedron Lett. 1992, 33, 7819. (b) Wee, A. G. H.; Liu, B.; Mcleod,
D. D. J . Org. Chem. 1998, 63, 4218. (c) Anada, M.; Hashimoto, S.-I.
Tetrahedron Lett. 1998, 39, 79.
(5) Yoon, C. H.; Zaworotko, M. J .; Moulton, B.; J ung, K. W. Org.
Lett. 2001, 3, 3539.
(7) General procedure for C-H insertion reactions: Rh2(OAc)4 (11
mg, 2.5 mol %) was added to a solution of an R-diazo-R-(phenylsulfonyl)-
acetamide (1 mmol) in dry CH2Cl2 (20 mL, C ) 0.05 M). The mixture
was refluxed for 12 h under N2, cooled to rt, and concentrated. The
residue was chromatographed to give a γ-lactam.
(8) Padwa, A. P.; Austin, D. J .; Price, A. T.; Semones, M. A.; Doyle,
M. P.; Protopopova, M. N.; Winchester, W. R.; Tran, A. J . Am. Chem.
Soc. 1993, 115, 8669.
(6) (a) Zaragoza, F.; Zahn, G. J . Prakt. Chem. 1995, 292. (b) Doyle,
M. P.; Kalinin, A. V. Tetrahedron Lett. 1996, 37, 1371.
10.1021/jo0259717 CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/15/2002
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J . Org. Chem. 2002, 67, 6582-6584