number of type A lantibiotics including nisin,6 subtilin,7
epidermin,8 and gallidermin.9 Analogues of the B-ring,
containing lanthionine instead of methyllanthionine, have
been prepared in several laboratories via cyclization of a Cys
onto a Dha residue.3 The authentic B-ring has so far only
been prepared using desulfurization of the corresponding
cyclic disulfide.10 Investigation of its formation via a
stereoselective Michael addition first required a general and
facile route to (Z)-dehydrobutyrine.
yield. Only one diastereomer was detected, suggesting that
the product was formed via a clean SN2 reaction instead of
an elimination-addition sequence (vide infra). Dipeptide 4
was synthesized by solution-phase chemistry. As anticipated,
upon oxidation only the (Z)-isomer of Dhb was observed in
the crude reaction mixture. Importantly, no γ-elimination to
give allylglycine was detected. The product peptide was
isolated in 83% yield after purification by silica gel flash
chromatography.14
Encouraged by these results we sought to apply the
methodology to Fmoc-based solid-phase peptide synthesis
(SPPS).15 Fmoc-(2R,3S)-3-methyl-Se-phenylselenocysteine
(9) was prepared as illustrated in Scheme 2. Fmoc-threonine
Because dehydroamino acids are unstable and result in
low coupling yields,11 masked residues are usually employed
during peptide synthesis and converted to the dehydroamino
acids late in the synthetic route, preferably after global
deprotection. Dhb residues have typically been incorporated
into peptides via the activation and elimination of threonine
derivatives.12 Such an approach, however, is not compatible
if the target contains unmodified Ser and Thr residues. We
recently reported a facile, site-specific, and chemoselective
method for introduction of Dha residues via the chemo-
selective oxidative elimination of selenocysteine derivatives.3b
Given the well-known syn stereochemistry of selenoxide
elimination,13 extension of our methodology to the prepara-
tion of (Z)-Dhb demanded an enantioselective synthesis of
(2R,3S)-3-methyl-Se-phenylselenocysteine.
Scheme 2
The target compound was synthesized as depicted in
Scheme 1. Boc-protected threonine was converted to the
Scheme 1
was protected as the diphenylmethyl (Dpm) ester, and the
hydroxyl group was activated as before. Displacement of the
(5) (a) Polinsky, A.; Cooney, M. G.; Toy-Palmer, A.; Osapay, G.;
Goodman, M. J. Med. Chem. 1992, 35, 4185. (b) Osapay, G.; Goodman,
M. J. Chem. Soc., Chem. Commun. 1993, 1955. (c) Mayer, J. P.; Zhang, J.;
Groeger, S.; Liu, C.-F.; Jarosinski, M. A. J. Pept. Res. 1998, 51, 432. (d)
Osapay, G.; Prokai, L.; Kim, H. S.; Medzihradszky, K. F.; Coy, D. H.;
Liapakis, G.; Reisine, T.; Melacini, G.; Zhu, Q.; Wang, S. H.; Mattern, R.
H.; Goodman, M. J. Med. Chem. 1997, 40, 2241.
(6) Gross, E.; Morell, J. L. J. Am. Chem. Soc. 1971, 93, 4634.
(7) Gross, E.; Kiltz, H. H.; Nebelin, E. Hoppe-Seyler’s Z. Physiol. Chem.
1973, 354, 810.
(8) Allgaier, H.; Jung, G.; Werner, R. G.; Schneider, U. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 1051.
(9) Kellner, R.; Jung, G.; Hoerner, T.; Zaehner, H.; Schnell, N.; Entian,
K. D.; Goetz, F. Eur. J. Biochem. 1988, 177, 53.
benzyl ester, and its hydroxyl group was activated with
p-toluenesulfonyl chloride. Nucleophilic displacement of the
tosyl group of 2 with phenylselenolate afforded 3 in 67%
(2) (a) Bro¨tz, H.; Bierbaum, G.; Reynolds, P. E.; Sahl, H. G. Eur. J.
Biochem. 1997, 246, 193. (b) Breukink, E.; Wiedemann, I.; van Kraaij, C.;
Kuipers, O. P.; Sahl, H. G.; de Kruijff, B. Science 1999, 286, 2361.
(3) (a) Toogood, P. L. Tetrahedron Lett. 1993, 34, 7833. (b) Okeley, N.
M.; Zhu, Y.; van der Donk, W. A. Org. Lett. 2000, 2, 3603. (c) Burrage,
S.; Raynham, T.; Williams, G.; Essex, J. W.; Allen, C.; Cardno, M.; Swali,
V.; Bradley, M. Chem.-Eur. J. 2000, 6, 1455.
(4) (a) Nakajima, K.; Oda, H.; Okawa, K. Bull. Chem. Soc. Jpn. 1983,
56, 520. (b) Wakamiya, T.; Shimbo, K.; Sano, A.; Fukase, K.; Shiba, T.
Bull. Chem. Soc. Jpn. 1983, 56, 2044. (c) Wakamiya, T.; Oda, Y.; Fukase,
K.; Shiba, T. Bull. Chem. Soc. Jpn. 1985, 58, 536. (d) Shiba, T.; Wakamiya,
T.; Fukase, K.; Sano, A.; Shimbo, K.; Ueki, Y. Biopolymers 1986, 25, S11.
(e) Fukase, K.; Kitazawa, M.; Sano, A.; Shimbo, K.; Horimoto, S.; Fujita,
H.; Kubo, A.; Wakamiya, T.; Shiba, T. Bull. Chem. Soc. Jpn. 1992, 65,
2227.
(10) Fukase, K.; Wakamiya, T.; Shiba, T. Bull. Chem. Soc. Jpn. 1986,
59, 2505.
(11) For a review, see: Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis
1988, 3, 159.
(12) For examples, see: (a) Fukase, K.; Kitazawa, M.; Sano, A.; Shimbo,
K.; Fujita, H.; Horimoto, S.; Wakamiya, T.; Shiba, T. Tetrahedron Lett.
1988, 29, 795. (b) Li, K. W.; Wu, J.; Xing, W.; Simon, J. A. J. Am. Chem.
Soc. 1996, 118, 7237.
(13) (a) Sharpless, K. B.; Young, M. W.; Lauer, R. F. Tetrahedron Lett.
1973, 1979. (b) Reich, H.; Renga, J. M.; Reich, I. L. J. Am. Chem. Soc.
1975, 97, 5434.
(14) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
(15) (a) Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149. (b) Atherton,
E.; Sheppard, R. C. Solid-Phase Peptide Synthesis, A Practical Approach;
2nd ed.; Pierce Chemical Company: Rockford, IL, 1989.
1336
Org. Lett., Vol. 4, No. 8, 2002