ORGANIC
LETTERS
2011
Vol. 13, No. 15
4028–4031
Synthesis of L-epi-Capreomycidine
Derivatives via CꢀH Amination
Tetsuya Tanino, Satoshi Ichikawa,* and Akira Matsuda
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku,
Sapporo 060-0812, Japan
Received June 9, 2011
ABSTRACT
The L-epi-capreomycidine (Cpm) derivatives were efficiently and stereoselectively synthesized via nitrene CꢀH insertion starting from a readily
available D-Tyr. Design of a substrate that takes into account hydrogen bonding is a critical feature in order to achieve high selectivity. Our
synthetic strategy could be a new access to epi-Cpm and its derivatives, which are found in several biologically active natural products.
The muraymycins (MRYs) (Figure 1), isolated from a
culture broth of Streptomyces sp.,1 are members of a class of
naturally occurring 60-N-alkyl-50-β-O-aminoribosyl-C-gly-
cyluridine antibiotics.2 The MRYs having a lipophilic side
chain have been shown to exhibit excellent antimicrobial
activity against Gram-positive bacteria. In particular, the
efficacy of the MRYs in S. aureus infected mice repre-
sents a promising lead for the development of new anti-
bacterial agents. The MRYs involve a cyclic guanidine amino
acid, L-epi-capreomycidine (Cpm). Most of the previous
syntheses of the Cpm class of amino acids were racemic.3
Although an elegant asymmetric synthesis of L-Cpm has
been reported by the Williams group,4 only a few asymmetric
Figure 1. Structures of muraymycin D2.
and stereoselectivesynthesesof itsepimer, L-epi-Cpm, have
been reported.5 Recently, we accomplished the first total
synthesis of MRY D2 (1) and its epimer.6 The L-epi-Cpm
moiety was synthesized via the nitrene CꢀH insertion7 of
(1) (a) McDonald, L. A.; Barbieri, L. R.; Carter, G. T.; Lenoy, E.;
Lotvin, J.; Petersen, P. J.; Siegel, M. M.; Singh, G.; Williamson, R. T.
J. Am. Chem. Soc. 2002, 124, 10260–10261. (b) Carter, G. T.; Lotvin,
J. A.; McDonald, L. A. WO 2002085310 A2.
(2) (a) Ochi, K.; Ezaki, M.; Iwani, M.; Komori, T.; Kohsaka, M. EP-
333177, 1989. (b) Yoshida, Y.; Yamanaka, H.; Sakane, K. JP H05ꢀ78385, 1993.
(3) (a) Bycroft, B. W.; Cameron, D.; Johson, A. W. J. Chem. Soc.
1971, 3041–3049. (b) Bycroft, B. W.; Cameron, D.; Croft, L. R.; Johson,
A. W. Chem. Commun. 1968, 1301–1302. (c) Yamashita, A.; Norton,
E. B.; Mansour, T. S. Synth. Commun. 2004, 34, 795–803.
(4) (a) DeMong, D. E.; Williams, R. M. Tetrahedron Lett. 2001, 42,
3529–3532. (b) DeMong, D. E.; Williams, R. M. J. Am. Chem. Soc. 2003,
125, 8561–8565.
(5) Teshima, T.; Konishi, K.; Shiba, T. Bull. Chem. Soc. Jpn. 1980,
53, 508–511.
(6) Tanino, T.; Ichikawa, S.; Shiro, M.; Matsuda, A. J. Org. Chem.
2010, 75, 1366–1377.
(7) For recent reviews, see: (a) Davies, H. M. L.; Beckwith, R. E. J.
Chem. Rev. 2003, 103, 2861–2903. (b) Davies, H. M. L.; Antoulinakis.,
E. G. J. Organomet. Chem. 2001, 617ꢀ618, 47–55.
r
10.1021/ol201527k
Published on Web 07/07/2011
2011 American Chemical Society