Stereoselective synthesis of orthogonally protected α- methylnorlanthionine

Article abstract of DOI:10.1021/ol060993r

As the unusual amino acid norlanthionine (nor-Lan) has previously been incorporated into cyclic peptide analogues of the ring C of lantibiotic nisin, we report here the stereoselective synthesis of the new (S,R)- and (R,R)-α-methylnorlanthionines (α-Me-no

Full text of DOI:10.1021/ol060993r

ORGANIC
LETTERS
2006
Vol. 8, No. 13
2855-2858
Stereoselective Synthesis of
Orthogonally Protected
r
-Methylnorlanthionine
Alberto Avenoza,* Jesu´s H. Busto, Gonzalo Jime´nez-Ose´s, and
Jesu´s M. Peregrina*
Departamento de Qu´ımica, UniVersidad de La Rioja, Grupo de S´ıntesis Qu´ımica de La
Rioja, U.A.-C.S.I.C., E-26006 Logron˜o, Spain
alberto.aVenoza@dq.unirioja.es
Received April 26, 2006
ABSTRACT
As the unusual amino acid norlanthionine (nor-Lan) has previously been incorporated into cyclic peptide analogues of the ring C of lantibiotic
nisin, we report here the stereoselective synthesis of the new (S,R)- and (R,R)- -methylnorlanthionines ( -Me-nor-Lan). The orthogonally
protected derivatives of these compounds have also been prepared. The key step in the synthesis of these bisamino acids was the SN2
opening reaction of the corresponding cyclic sulfamidates with the SH group of appropriately protected -cysteine derivatives.
r
r
L
The increasing problem of antibiotic resistance has high-
lighted the imperative demand for novel antimicrobial agents.
Lantibiotics, lanthionine- or methyllanthionine-containing
antibiotics, such as nisin, duramycin, and subtilin are
produced by Gram-positive bacteria1 and are promising
candidates to address this problem. Lanthionine is an unusual
bis-R-amino acid that consists of two alanyl residues bridged
by a thioether linkage (Figure 1). In contrast to the labile
disulfide bond of cystine, the monosulfur bridge of lan-
thionine is chemically far stronger. For this reason, thioether-
bridged peptides can be regarded as stable analogues of
cystine bridges and lanthionine2 and analogues3 have there-
fore been incorporated into medicinally relevant peptides as
(1) Reviews: (a) Guder, A.; Wiedemann, I.; Sahl, H.-G. Biopolymers
2000, 55, 62. (b) van Kraaij, C.; de Vos, W. M.; Siezen, R. J.; Kuipers, O.
P. Nat. Prod. Rep. 1999, 16, 575. (c) Breukink, E.; de Kruijff, B. Biochim.
Biophys. Acta 1999, 1462, 223. (d) Sahl, H.-G.; Bierbaum, G. Annu. ReV.
Microbiol. 1998, 52, 41. (e) Jung, G. Angew. Chem., Int. Ed. Engl. 1991,
30, 1051. (f) Chatterjee, Ch.; Paul, M.; Xie, L.; van der Donk, W. A. Chem.
ReV. 2005, 105, 633 and references therein. (g) Patton, G. C.; van der Donk,
W. A. Curr. Opin. Microbiol. 2005, 8, 543.
(2) (a) O¨ sapay, G.; Prokai, L.; Kim, H.-S.; Medzihradszky, K. F.; Coy,
D. H.; Liapakis, G.; Reisine, T.; Melacini, G.; Zhu, Q.; Wang, S. H.-H.;
Mattern, R.-H.; Goodman, M. J. Med. Chem. 1997, 40, 2241. (b) Melacini,
G.; Zhu, Q.; O¨ sapay, G.; Goodman, M. J. Med. Chem. 1997, 40, 2252. (c)
Polinsky, A.; Cooney, M. G.; Toy-Palmer, A.; O¨ sapay, G.; Goodman, M.
J. Med. Chem. 1992, 35, 4185. (d) O¨ sapay, G.; Goodman, M. J. Chem.
Soc., Chem. Commun. 1993, 1599. (e) Paul, M.; van der Donk, W. A.
MinireV. Org. Chem. 2005, 2, 23. (f) Matteucci, M.; Bhalay, G.; Bradley,
M. Tetrahedron Lett. 2004, 45, 1399. (g) Bregant, S.; Tabor, A. B. J. Org.
Chem. 2005, 70, 2430.
Figure 1. Representation of some lanthionine derivatives.
10.1021/ol060993r CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/20/2006

Scheme 1. Syntheses of R-Me-nor-Lan (2S,2′R)-4 and (2R,2′R)-4 as Hydrochloride Derivativesa
a Reagents and conditions: (a) (i) DBU, DMF, 50 °C, 1 h; (ii) 2 N HCl/CH2Cl2 (1:1), 25 °C, 10 h. (b) (i) LiOH‚H2O, MeOH/H2O (3:2),
25 °C, 24 h; (ii) 12 N HCl, reflux, 12 h.
conformational constraints. The syntheses of lanthionine
(Lan) and methyllanthionine (Me-Lan) monomers for use
in peptide synthesis are nontrivial because of the requirement
of orthogonal protection of the two amine groups and the
two carboxylic acid functions. Despite this, however, several
synthetic approaches to these compounds have been de-
scribed in recent years.2,4 Nevertheless, the synthesis of the
isomer norlanthionine (nor-Lan), which consists of an alanyl
and a â-alanyl residue (Figure 1), has to the best of our
knowledge only been reported by the group of Tabor,5 and
this was incorporated into a cyclic peptide analogue of the
ring C of lantibiotic nisin.6
In this sense, the development of a new and efficient
synthesis of norlanthionine derivatives seems to be of interest.
As part of our ongoing program aimed at the synthesis of
restricted peptides, we decided to pursue approaches to
R-methylnorlanthionines because of their potential biological
importance.
reported. The opening reaction of the starting sulfamidate
at the quaternary carbon center with the thiol group of a
suitably protected cysteine derivative is the key step in the
synthetic pathway.
Initially, and taking into account the excellent results
obtained in the opening reaction of the easily accessible chiral
building block (R)-1 with nucleophiles,7 particularly with
sulfur nucleophiles,8 we performed the SN2 reaction with
commercial N-Boc-L-cysteine methyl ester (R)-2 using DBU
as a base and DMF as a solvent at 50 °C for 1 h, followed
by acid hydrolysis of the sulfamic acid intermediate.
Purification of the crude product by column chromatography
gave the corresponding protected R-Me-nor-Lan 3 in excel-
lent yield (98%) with a dr > 20:19 (Scheme 1).
Bearing in mind that the protecting groups on derivative
3 are not suitable for peptide synthesis, we used this
compound to obtain the free R-Me-nor-Lan 4. Weinreb
amide hydrolysis of 3 with LiOH, followed by acid hydroly-
sis with 12 N HCl under reflux gave (2S,2′R)-R-Me-nor-
Lan 4 as the hydrochloride derivative. The other diastereo-
isomer was obtained by the same sequence of reactions but
starting from the chiral building block (S)-1 and giving the
protected (2R,2′R)-R-Me-nor-Lan 3, which was hydrolyzed
to (2R,2′R)-R-Me-nor-Lan 4 (Scheme 1).
We wish to report here new and efficient syntheses of
(2S,2′R)- and (2R,2′R)-R-methylnorlanthionine (R-Me-nor-
Lan) in diastereomerically pure form starting from the
corresponding cyclic R-methylisoserine-derived sulfamidate
as a chiral building block. The preparation of the orthogonally
protected derivatives of the target compounds is also
Given that an orthogonal protecting group plan will be
required for the future regioselective manipulation of these
important diastereomerically pure core residues, R-Me-nor-
Lan, we considered changing the protecting groups on the
starting materials: the chiral sulfamidate-derived building
blocks and the cysteine derivatives.
(3) (a) Yu, L.; Lai, Y.; Wade, J. V.; Coutts, S. M. Tetrahedron Lett.
1998, 39, 6633. (b) Feng, Y.; Pattarawarapan, M.; Wang, Z.; Burgess, K.
Org. Lett. 1999, 1, 121. (c) Rew, Y.; Malkmus, S.; Svensson, C.; Yaksh,
T. L.; Chung, N. N.; Schiller, P. W.; Cassel, J. A.; DeHaven, R. N.;
Goodman, M. J. Med. Chem. 2002, 45, 3746. (d) Mustapa, M. F. M.; Harris,
R.; Mould, J.; Chubb, N. A. L.; Schultz, D.; Driscoll, P. C.; Tabor, A. B.
Tetrahedron Lett. 2002, 43, 8363. (e) Smith, N. D.; Goodman, M. Org.
Lett. 2003, 5, 1035.
(4) Some examples: (a) Narayan, R. S.; VanNieuwenhze, M. S. Org.
Lett. 2005, 7, 2655. (b) Swali, V.; Matteucci, M.; Elliot, R.; Bradley, M.
Tetrahedron 2002, 58, 9101. (c) Zhu, X.; Schmidt, R. R. Eur. J. Org. Chem.
2003, 4069. (d) Shao, H.; Wang, S. H.; Lee, C.; O¨ sapay, G.; Goodman, M.
J. Org. Chem. 1995, 60, 2956.
(5) (a) Mustapa, M. F. M.; Harris, R.; Mould, J.; Chubb, N. A. L.;
Schultz, D.; Driscoll, P. C.; Tabor, A. B. Tetrahedron Lett. 2002, 43, 8363.
(b) Mustapa, M. F. M.; Harris, R.; Bulic-Subanovic, N.; Elliott, S. L.;
Bregant, S.; Groussier, M. F. A.; Mould, J.; Schultz, D.; Chubb, N. A. L.;
Gaffney, P. R. J.; Driscoll, P. C.; Tabor, A. B. J. Org. Chem. 2003, 68,
8185.
To this end, the amide and carbamate groups of sulfami-
date (R)-1 were hydrolyzed to give sulfamidate (R)-5. The
(7) (a) Avenoza, A.; Busto, J. H.; Corzana, F.; Jime´nez-Ose´s, G.;
Peregrina, J. M. Chem. Commun. 2004, 980. (b) Building block (R)-1 was
obtained in two steps from the Weinreb amide of methacrylic acid with an
overall yield of 78%.
(8) Avenoza, A.; Busto, J. H.; Jime´nez-Ose´s, G.; Peregrina, J. M. J. Org.
Chem. 2006, 71, 1692.
(9) The diastereomeric purity of opening products (2R,2′R)-3, (2S,2′R)-
3, (2S,2′R)-20, and (2R,2′R)-20 was determined by 1H NMR spectroscopy,
and a sole stereoisomer was detected: dr > 20:1.
(6) Mustapa, M. F. M.; Harris, R.; Esposito, D.; Chubb, N. A. L.; Mould,
J.; Schultz, D.; Driscoll, P. C.; Tabor, A. B. J. Org. Chem. 2003, 68, 8193.
2856
Org. Lett., Vol. 8, No. 13, 2006

carboxylic acid function of this compound was transformed
into benzyl and allyl esters to obtain sulfamidates (R)-6 and
(R)-7, respectively (Scheme 2).
14 and (2R,2′R)-17, respectively, which are also com-
mercially available (Scheme 3).
Scheme 3. Synthesis of Cysteine Derivativesa
Scheme 2. Synthesis of Chiral Sulfamidate-Derived Building
Blocks 5-10a
a Reagents and conditions: (a) (Boc)2O, TEA, CH2Cl2, 25 °C,
14 h. (b) Bu3P, THF, H2O, 25 °C, 4 h. (c) (i) (COCl)2, ClCH2CH2Cl,
DMF, 0 °C, 2 h; (ii) BnOH, DIEA, 25 °C, 3 h. (d) (i)
Cl3CCH2OCOCl, dioxane, NaOH, 0-25 °C, 14 h; (ii) (COCl)2,
ClCH2CH2Cl, DMF, 0 °C, 2 h; (iii) BnOH, DIEA, 25 °C, 3 h.
The synthesis of the known cysteine derivative10 (R)-16
from cystine (2R,2′R)-14 was performed by a new procedure
that involved esterification of the carboxylic acids with
benzyl alcohol in the presence of oxalyl chloride and
dichloroethane as a solvent to give (2R,2′R)-15, followed
by clean cleavage of the disulfide bridge with Bu3P (Scheme
3).
a Reagents and conditions: (a) (i) LiOH‚H2O, MeOH/H2O (3:
2), 25 °C, 24 h; (ii) 2 N HCl. (b) (i) SOCl2, reflux, 4 h; (ii) BnOH,
TEA, CH2Cl2, 25 °C, 16 h. (c) Allylic alcohol, HCl, 70 °C, 3 h.
t
(d) PMB-Br, BuOK (1.0 equiv), THF, 25 °C, 24 h. (e) PMB-
Br, tBuOK (7.5 equiv), THF, 25 °C, 24 h. (f) tBuOK, THF, 25 °C,
24 h.
On the other hand, the synthetic route to compound (R)-
19 from cystine (2R,2′R)-17 started from the protection of
the amino group as the trichloroethoxycarbonyl (Troc)
carbamate in a basic medium. The carboxylic acid groups
of the corresponding cystine derivative were then activated
as acid chlorides to incorporate the benzyl group as an ester
function with benzyl alcohol to give compound (2R,2′R)-
18, which was readily transformed into the desired protected
cysteine (R)-19 by treatment with Bu3P (Scheme 3).
In an effort to synthesize orthogonally protected R-Me-
nor-Lan, we initially explored the use of cysteine (R)-13 as
a nucleophile to open cyclic sulfamidate (R)-6 under different
conditions. Unfortunately, all attempts failed, probably
because of internal attack of SH or NHBoc groups on the
The NH function of compound (R)-7 was protected with
the p-methoxybenzyl group (PMB) by reaction with p-
methoxybenzyl bromide (PMB-Br) in the presence of 1.0
t
equiv of BuOK as base in THF. This reaction yielded
sulfamidate (R)-8 as the major product, accompanied by
sulfamidate (R)-9 as a result of the transformation of the
allyl ester into the tert-butyl ester. Treatment of sulfamidate
(R)-7 under the conditions described above, but using 7.5
t
equiv of BuOK, gave compound (R)-9 exclusively. Alter-
natively, compound (R)-9 could also be obtained in two steps
from (R)-7, via (R)-10, by transesterification and subsequent
N-alkylation (Scheme 2).
As far as the cysteine derivatives are concerned, com-
mercially available L-cystine bisallyl ester di(p-toluen-
sulfonate) salt (2R,2′R)-11 was used to give cysteine deriva-
tive (R)-13 in two steps. This procedure involved the
generation of Boc carbamate (2R,2′R)-12 followed by
cleavage of the disulfide bond with tri-n-butylphosphine
(Bu3P). Moreover, two other protected cysteine derivatives
(R)-16 and (R)-19 were synthesized from L-cystines (2R,2′R)-
1
allyl ester (as detected by H NMR). Taking this fact into
account, we decided to change the protecting groups, i.e.,
the allyl ester in the sulfamidate building block and the
benzyl ester in the cysteine moiety. Moreover, the NH
(10) (a) Humphrey, R. E.; McCrary, A. L.; Webb, R. M. Talanta 1965,
12, 727. (b) Trost, B. M.; Braslau, R. J. Org. Chem. 1988, 53, 532.
Org. Lett., Vol. 8, No. 13, 2006
2857

function of the sulfamidate was protected with the p-
methoxybenzyl group. Indeed, we assayed the opening
reaction of sulfamidate (R)-8 with cysteine (R)-16, and a
complex mixture of several compounds was obtained.
Fortunately, these problems were solved by using compound
(R)-19 as the protected cysteine and compound (R)-9 as the
sulfamidate building block. The SN2 reaction with DBU as
the base and DMF as the solvent, followed by acid
hydrolysis, gave orthogonally protected R-Me-nor-Lan
(2S,2′R)-20 in excellent yield in diastereomerically pure form
(Scheme 4).
was prepared using the protocol described above but starting
from (S)-1. The opening reaction of (S)-9 with cysteine (R)-
19 gave the orthogonally protected R-Me-nor-Lan (2R,2′R)-
20 in diastereomerically pure form (Scheme 4). Evidently,
the other two diastereomers of R-Me-nor-Lan could be
obtained by following the synthetic pathway described here
but combining the sulfamidates (S)-9 and (R)-9 with the
cysteine moiety (S)-19.
In summary, we have carried out the stereoselective syn-
thesis of the new (S,R)- and (R,R)-R-methylnorlanthionines
(R-Me-nor-Lan). We have also prepared the orthogonally
protected derivatives for peptide synthesis. The key step in
the synthetic pathway for these new bisamino acids was the
SN2 opening reaction of the corresponding chiral cyclic
sulfamidates with the SH group of L-cysteine derivatives.
Taking into account that nor-Lan-containing peptides show
unknown turn conformations, the future inclusion of R-Me-
nor-Lan into peptides will allow the exploration of confor-
mational space which will probably not be available with
the proteinogenic amino acids.
Scheme 4. Synthesis of Orthogonally Protected R-Me-nor-Lan
(2S,2′R)-20 and (2R,2′R)-20a
Acknowledgment. We thank the Ministerio de Educacio´n
y Ciencia (project CTQ2005-06235/BQU and Ramon y Cajal
contract for J.H.B.), Gobierno de La Rioja (project ANGI-
2005/01), and the Universidad de La Rioja (project API-05/
A01 and doctoral fellowship of G.J.-O.).
a Reagents and conditions: (a) (i) (R)-19, DBU, DMF, 50 °C, 1
h; (ii) 20% H2SO4/CH2Cl2 (1:1), 25 °C, 10 h.
Supporting Information Available: Experimental de-
tails, as well as spectroscopic characterization of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
In an attempt to obtain the diastereoisomer of R-Me-nor-
Lan with the (2R,2′R)-configuration, we synthesized the
enantiomer of (R)-9; the sulfamidate building block (S)-9
OL060993R
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Org. Lett., Vol. 8, No. 13, 2006