a number of unique structural features including thioether
linkages and dehydrated amino acid side chains.6-8
Concise Preparation of Tetra-orthogonally
Protected (2S,6R)-Lanthionines
Nathaniel I. Martin
Department of Medicinal Chemistry and Chemical Biology,
UniVersity of Utrecht, Sorbonnelaan 16,
3584 CA Utrecht, The Netherlands
FIGURE 1. Structure of the lantibiotic peptide nisin (1).
ReceiVed October 30, 2008
The biosynthetic origin of these structural features involves
the enzymatic dehydration of serine and threonine residues to
dehydroalanine(Dha)anddehydrobutyrine(Dhb),respectively.9-11
Subsequent enzyme-mediated Michael addition of cysteine
thiolates to Dha and Dhb residues generates the thioether cross-
links lanthionine and ꢀ-methyllanthionine respectively (these
moieties provide lantibiotic peptides their family name).12Given
the interest in lantibiotic peptides, various methods for their
synthetic preparation have been pursued. Critical to such
investigations is the ability to incorporate lanthionine residues
containing the (2S,6R) stereochemistry found in nature
(Figure 2).
Lantibiotics are antimicrobial peptides containing the unique
bis-amino acids lanthionine and ꢀ-methyllanthionine. While
previous syntheses of lanthionine have often involved the
coupling of precursors derived from D-serine and L-cysteine,
we here report an inverted strategy whereby D-cysteine and
L-serine are employed as building blocks. This approach
provides for a concise preparation of tetra-orthogonally
protected (2R,6S)-lanthionines while allowing convenient
introduction of orthogonal protecting groups not previously
incorporated into lanthionines.
FIGURE 2. Naturally occurring (2S,6R)-lanthionine and (2S,3S,6R)-
ꢀ-methyllanthionine.
In the only total synthesis of a lantibiotic to date, the Shiba
group utilized a desulfurizing ring-contraction approach to
convert cystines into lanthionines for the preparation of nisin.13
This methodology provides lanthionines in moderate yields and
is not amenable to solid-phase peptide synthesis (SPPS). As an
alterative, dehydro-residues have been incorporated into pep-
tides, after which Michael addition by a neighboring cysteine
thiolate can provide lanthionine-containing peptides.14-17 The
diastereoselectivity of lanthionine bridge formation in such
cases, however, has been shown to be highly dependent upon
preorganization of the peptide, and the desired stereochemical
outcome cannot be guaranteed in all cases. An alternate strategy
toward the synthesis of lantibiotic peptides involves the
The rapid emergence of drug-resistant bacteria poses a serious
threat to human health and underscores the importance of
developing new antibiotics. In this regard, the lantibiotic family
of antimicrobial peptides is rapidly gaining recognition.1-3
Lantibiotics are ribosomally synthesized and highly modified
bacterial defense peptides with potent antibacterial activity
against a wide range of infectious (and drug-resistant) bacteria.4,5
The most thoroughly studied lantibiotic nisin (Figure 1) contains
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der Donk, W. A. Science 2004, 303, 679.
(1) Willey, J. M.; van der Donk, W. A. Annu. ReV. Microbiol. 2007, 61,
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(12) Schnell, N.; Entian, K.-D.; Schneider, U.; Gotz, F.; Zahner, H.; Kellner,
R.; Jung, G. Nature 1988, 333, 276.
(13) 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–
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285–308.
(6) Gross, E.; Morell, J. L. J. Am. Chem. Soc. 1971, 93, 4634–4635.
(7) Kellner, R.; Jung, G.; Sahl, H.-G. Nisin and NoVel Lantibiotics; ESCOM:
Leiden, 1991.
(8) Lian, L. Y.; Chan, W. C.; Morley, S. D.; Roberts, G. C.; Bycroft, B. W.;
Jackson, D Biochem. J. 1992, 283 (Pt 2), 413–420.
(15) Zhou, H.; van der Donk, W. A. Org. Lett. 2002, 4, 1335–1338.
(16) Burrage, S.; Raynham, T.; Williams, G.; Essex, J. W.; Allen, C.; Cardno,
M.; Swali, V.; Bradley, M. Chem. Eur. J. 2000, 6, 1455–1466.
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946 J. Org. Chem. 2009, 74, 946–949
10.1021/jo802415c CCC: $40.75 2009 American Chemical Society
Published on Web 12/02/2008