Decarbonylative approach to the synthesis of enamides from amino acids: Stereoselective synthesis of the (Z)-aminovinyl-d-cysteine unit of mersacidin

Article abstract of DOI:10.1021/ol203399x

The Pd- and Ni-promoted decarbonylation of amino acid thioesters proceeds smoothly to yield enamides. The synthesis of the (S)-(Z)-AviMeCys subunit of mersacidin, an MRSA-active lantibiotic, via this approach, is described.

Full text of DOI:10.1021/ol203399x

ORGANIC
LETTERS
2012
Vol. 14, No. 4
1030–1033
Decarbonylative Approach to the
Synthesis of Enamides from Amino Acids:
Stereoselective Synthesis of the
(Z)-Aminovinyl-D-Cysteine Unit of Mersacidin
´
Pablo Garcıa-Reynaga, Angela K. Carrillo, and Michael S. VanNieuwenhze*
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington,
Indiana 47505, United States
mvannieu@indiana.edu
Received December 20, 2011
ABSTRACT
The Pd- and Ni-promoted decarbonylation of amino acid thioesters proceeds smoothly to yield enamides. The synthesis of the (S)-(Z)-AviMeCys
subunit of mersacidin, an MRSA-active lantibiotic, via this approach, is described.
The prevalence of antibiotic resistance poses a signifi-
cant public healthproblemand continues toundermine the
achievements that have led to the development of our
current antibiotic arsenal. Among these agents, “last line”
glycopeptide antibiotics, such as vancomycin, have argu-
ably received the most attention in light of the onset of
methicillin-resistant S. aureus (MRSA), a particularly
problematic nosocomial infection. However, the emer-
gence of new resistance mechanisms, coupled with the
paucity of novel antibiotics belonging to new structural
classes, furtherunderscores the need torevitalize the search
for alternative therapeutics.
To address this need, we have initiated a broad research
program based on the chemical synthesis and mechanistic
study of several peptide antibiotics that inhibit bac-
terial peptidoglycan (PG) biosynthesis via mechanisms
that are orthogonal to that utilized by vancomycin.1 One
such candidate is mersacidin (1), a type B lantibiotic pro-
duced ribosomally by Bacillus sp. strain HIL Y-85,54728
and whose in vivo activity against MRSA is comparable to
that of vancomycin.2,3 The discovery that mersacidin’s
bioactivity is uninhibited by vancomycin despite also
forming a 1:1 stoichiometric complex with lipid II
suggests that its mode of action is distinct.
Its unique binding site as well as inhibition of the transgly-
cosylation reaction make it an attractive target for develop-
ment of novel therapeutics because (i) transglycosylation
occurs on the cell surface so cellular penetration of the
antibiotic is not a requirement for activity and (ii) the
transglycosylation reaction utilized in PG biosynthesis is
unique to bacterial cells. With the ultimate goal of delineating
(2) Chatterjee, S.; Chatterjee, D. K.; Jani, R. H.; Blumbach, J.;
Ganguli, B. N.; Klesel, N.; Limbert, M.; Seibert, G. J. Antibiot. 1992,
45, 832.
(3) For recent reviews on lantibiotics, see: (a) Willey, J. M.; van der
Donk, W. A. Annu. Rev. Microbiol. 2007, 61, 477–501. (b) Chatterjee, C.;
Paul, M.; Xie, L.; van der Donk, W. A. Chem. Rev. 2005, 105, 633–683.
(1) Narayan, R. S.; VanNieuwenhze, M. S. Eur. J. Org. Chem. 2007,
2007, 1399.
r
10.1021/ol203399x
Published on Web 02/01/2012
2012 American Chemical Society

the exact mode of action of mersacidin and its variants, as
well as developing novel analogues with increased efficacy,
we have embarked on the total synthesis of 1.
olefins have appeared.18À21 Yet, despite its simplicity, this
approach is hampered the need for strongly basic condi-
tions, which may not be suitable for all substrates. In
addition, these methods may also require access to activated
and/or stereodefined olefins.
Given our recent report of the concise synthesis of
orthogonally protected β-MeCys and β-MeLan,22 we en-
visioned the direct synthesis of this AviMeCys unit via
decarbonylation of an activated lanthionine precursor
(Scheme 1). In our efforts toward the chemical synthesis
of mersacidin, we now wish to report our advances in this
area, specifically the expeditious synthesis of the Avi-
MeCys unit directly from the β-MeLan unit.23
The presence of the sensitive S-[(Z)-2-aminovinyl]-3-
methyl-D-cysteine (AviMeCys) linkage in the CD ring
system, as well as the unnatural amino acid (2S,3S)-
β-methylcysteine (β-MeCys) and (2S,3S,6R)-β-methyl-
lanthionine (β-MeLan) fragments in the A, B, and CD
ring systems, renders mersacidin a challenging synthetic
target. The AviMeCys subunit is present in other bio-
active peptides including epidermin,4 thioviridamide,5
and the recently discovered microbisporicin, now con-
sidered the most potent lantibiotic to date.6 Still, at the
time we initiated our studies, no synthesis of the Avi-
MeCys functionality had been reported.7
Although little is known about the function of the
enamide subunit, it appears to have a critical role for the
biological activity of other agents.8,9 As a result, a wide
range of methodologies has arisen to address the issues of
chemo- and stereoselectivity associated with their chemical
synthesis. Given that enamides possess intrinsically mod-
erate reactivity, they may also serve as intermediates for
accessing other functionality.10,11
The concept of a decarbonylative pathway to enamides
is not novel, although its documentation is limited,24À26
probably because it has traditionally been viewed as an
undesirable side reaction. As a result, we took a systematic
approach for optimization of this strategy.27
Our initial approach consisted of evaluating amino acid
chlorides in light of Bubner’s observation that an enamide
byproduct was isolated during the attempted Stille cross-
coupling of Fmoc-Pro-Cl.24,28 Like Bubner, we also ob-
served the lack of enamide formation in the absence of
an organostannane. In search of additives that could
enhance reactivity, we found that nBu4I was very efficient
at promoting the catalytic decarbonylation of Fmoc-
Pro-Cl, while only traces of the desired product were
observed with NaI, presumably an artifact of its low
solubility in organic solvents. The efficiency of this process
is highlighted by the observation that Fmoc-Pro-OH could
be activated in situ with diphenylphosphoryl chloride to
give high yields of the pyrroline product. Unfortunately,
when these conditions were applied to the synthesis of
cysteine-derived enamides, only the enamine byproduct
arising from β-elimination (i.e., desulfurization) was ob-
served. CuI was added in an effort to sequester thiol
byproducts and suppress the potential for poisoning of
the Pd catalyst. However, this only increased the amount
of the elimination byproduct that was generated. Further-
more, only decomposition was observed in the attempted
decarbonylation of Fmoc-Ser(OBn)-Cl and Fmoc-Val-Cl.
Scheme 1. Retrosynthetic Analysis of the Enamide Unit
Methods that have been developed for the synthesis of
enamides include the Curtius rearrangement,12 Peterson
olefination,13 vinyl transfer,14 hydrometalation of alkynes,15
radical decarboxylation,16 and radical addition to ynamides.17
Most recently, several reports of transition-metal-catalyzed
cross-coupling reactions between amides and activated
€
(4) Allgaier, H.; Jung, G.; Werner, R. G.; Schneider, U.; Zahner, H.
Angew. Chem., Int. Ed. 1985, 24, 1051.
(5) Hayakawa, Y.; Sasaki, K.; Adachi, H.; Furihata, K.; Nagai, K.;
(18) Dehli, J. R.; Legros, J.; Bolm, C. Chem. Commun. 2005, 973.
(19) Wallace, D. J.; Klauber, D. J.; Chen, C.-y.; Volante, R. P. Org.
Lett. 2003, 5, 4749.
(20) Cesati, R. R.; Dwyer, G.;Jones, R. C.; Hayes, M. P.;Yalamanchili,
P.; Casebier, D. S. Org. Lett. 2007, 9, 5617.
(21) Yuri, B.; Robert, A. B. Angew. Chem. 2008, 120, 2139.
(22) Narayan, R. S.; VanNieuwenhze, M. S. Org. Lett. 2005, 7,
2655.
(23) For a review on recent developments in lantibiotic synthesis, see:
Tabor, A. B. Org. Biomol. Chem. 2011, 9, 7606–7628.
(24) Crisp, G. T.; Bubner, T. P. Synth. Commun. 1990, 20, 1665.
(25) Goto, T.; Onaka, M.; Mukaiyama, T. Chem. Lett. 1980, Vol.9
709.
Shin-ya, K. J. Antibiot. 2006, 59, 1.
(6) Castiglione, F.; Lazzarini, A.; Carrano, L.; Corti, E.; Ciciliato, I.;
Gastaldo, L.; Candiani, P.; Losi, D.; Marinelli, F.; Selva, E.; Parenti, F.
Chem. Biol. 2008, 15, 22.
(7) For a recent review of AviCys-containing lantibiotics, see: Sit,
C. S.; Yoganathan, S.; Vederas, J. C. Acc. Chem. Res. 2011, 44, 261–268.
(8) Yet, L. Chem. Rev. 2003, 103, 4283.
(9) Wu, Y.; Liao, X.; Wang, R.; Xie, X.-S.; De Brabander, J. K. J.
Am. Chem. Soc. 2002, 124, 3245.
(10) Carbery, D. R. Org. Biomol. Chem. 2008, 6, 3455.
(11) Matsubara, R.; Kobayashi, S. Acc. Chem. Res. 2008, 41, 292.
(12) Kuramochi, K.;Osada, Y.; Kitahara, T. Tetrahedron 2003, 59, 9447.
(13) Furstner, A.; Brehm, C.; Cancho-Grande, Y. Org. Lett. 2001, 3,
3955.
(26) Yang, H.; Li, H.; Wittenberg, R.; Egi, M.; Huang, W.; Liebeskind,
L. S. J. Am. Chem. Soc. 2007, 129, 1132.
ꢀ
(27) Min, G. K.; Hernandez, D.; Lindhardt, A. T.; Skrysdstrup, T.
Org. Lett. 2010, 12, 4716–4719.
(14) Brice, J. L.; Meerdink, J. E.; Stahl, S. S. Org. Lett. 2004, 6, 1845.
(15) Buissonneaud, D.; Cintrat, J.-C. Tetrahedron Lett. 2006, 47,
3139.
(16) Wang, X.; Porco, J. A. J. Org. Chem. 2001, 66, 8215.
(17) Banerjee, B.; Litvinov, D. N.; Kang, J.; Bettale, J. D.; Castle,
S. L. Org. Lett. 2010, 12, 2650.
(28) We note that ref 27, highlighting a qualitatively analogous
approach using Pd catalysis, appeared during the course of our study.
Our method requires lower reaction temperatures (rt with most Ni
catalyst systems) and utilized simple phosphine ligands. In addition,
we also observed the desired (Z)-selectivity for cysteine- and serine-
based substrates in contrast to the results reported in ref 27.
Org. Lett., Vol. 14, No. 4, 2012
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Table 1. Scope and Limitations of the Decarbonylative Synthesis of Enamides from N-Protected Amino Acids
a For reaction conditions, see Supporting Information. b Prepared from either Ni(COD)2 and PPh3 or Pd(OAc)2 and P(OEt)3. c Isolated yields.
d Prepared in situ with DCC/PhSH. e Based on recovered starting material. f Mixture of isomers (External:Internal (E)/Internal (Z) = 10:5.8:0.1).
The isolation of dehydroalanine as a byproduct from
decarbonylation reactions with Cys-derived acid chlo-
rides, coupled with the lack of generality of this process,
prompted us to examine milder activating groups for the
amino acid derived esters. Although a range of common
activating groups, including -OSu, -OCOR, -OOBt, -OAt,
and -OPy, gave only traces of product at best, the 2-pyridyl
thioester showed promise. While trace amounts of the
desired enamide were observed under Mukaiyama’s
conditions,25 added DPEPhos as a ligand with Ni(COD)2
asthe precatalystyielded 15% of the vinyl sulfidewith37%
of the product resulting from sulfur abstraction.
Even more promising was thioester activation,29 which
allowed for the efficient decarbonylation of Fmoc-Pro-SPh
(4j). When these conditions were applied to Fmoc-Cys(Me)-
(29) Wenkert, E.; Chianelli, D. J. Chem. Soc., Chem. Commun. 1991,
627.
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Org. Lett., Vol. 14, No. 4, 2012

SPh, high yields of the decarbonylation product were ob-
served, albeit as the trapped thioaminal, along with reduced
amounts of the undesired desulfurization byproduct.
Inspired by Liebeskind’s work on the Cu(I) carbox-
ylate activation of thioesters,23 we sought to limit the
propensity for SPh deinsertion by taking advantage of
the inherent thiophilicity of Cu(I). Although simple
salts, such as Cu(I) and Cu(OAc), showed limited activ-
ity, high quantities of the desired enamide product 5
were isolated, along with a significant amount of the
sulfur-abstraction product, when copper(I) 3-methyl-
salicylate (CuMeSal) was used. Similar yields were ob-
served with an SiPr ester suggesting that steric hindrance
may not play a significant role in the transition state
leading to thioaminal formation. Under optimized con-
ditions for decarbonylation of Fmoc-Cys-(Me)-SPh,
thioaminal formation was kept to a minimum through
use of PPh3 as a ligand, providing the desired aminovinyl
sulfide in 91% yield after 1 h at rt.
With these promising results in hand, we proceeded to
examine the substrate scope as summarized in Table 1. We
were pleased to find that Pd[P(OEt)3]4 efficiently catalyzed
the formation of conjugated enamides (entries 1À9).
However, moderate yields were observed with amino acids
such as Pro (entries 11À14) and Ser (entry 15). In spite of
near-quantitative recovery of starting material, enamide
yields plateaued to a similar level regardless of whether the
reaction was run at or above rt. Moreover, added CuMeSal
did not have any positive effect on the yield, while only
slightly increased yields were observed when more Pd catalyst
was added to the reaction mixture.
In most instances, the Ni-based approach proved to be
superior and, in general, yielded enamides in good to
excellent yields; some reactions proceeded very effi-
ciently at rt (entries 23À27). This is further highlighted
by the contrast between the good yields obtained for the
Asp- and Val-derived enamides with Ni that were un-
attainable with the Pd catalyst (entries 9, 10, 19, 20). To
the best of our knowledge, these conditions provide a
route to enamides under nonoxidative, nonbasic condi-
tions not reported previously. We did observe, however,
that steric hindrance in the substrate may be a limiting
factor for successful application of this methodology
(cf., entries 18 and 22).
Scheme 2. Synthesis of the AviMeCys Unit of Mersacidin
was critically dependent on the choice of Cu(I) salt and
ligand (Table S2, Supporting Information). While reac-
tions utilizing copper(I) thiophene-2-carboxylate (CuTC)
reproducibly returned good yields of the desired product,
reactions employing CuMeSal resulted in isolation of an
alkene byproduct arising from a desulfurization process.
Product selectivity (i.e., enamide vs desulfurization) was
also strongly influenced by the choice of ligand. Reactions
employing PPh3 provided the desired enamide in good
yields (CuTC additive) while reactions using (o-Tol)3P
provide the desulfurization product exclusively. Bulky, as
well as sigma-donating, ligands also returned higher yields
of the desulfurization byproduct.
Under the optimized conditions, we were pleased to find
that lanthionine 6could be decarbonylated smoothly to yield
aminovinyl cysteine 7 in 75% yield (Scheme 2). More
importantly, the synthetically more relevant subunit 2 could
be prepared in satisfactory yields directly from lanthionine 8
and can be used directly for the synthesis of mersacidin.
In conclusion, we have developed a mild alternative
to the synthesis of enamides that makes use of readily
available amino acid starting materials. This has allowed
efficient access to the AviMeCys fragment of mersacidin.
Future work directed toward the total synthesis of mer-
sacidin as well as attempts to determine the function of the
AviMeCys subunit will be presented in due course.
Acknowledgment. Financial support provided by the
NIH (AI 059327) and Indiana University is gratefully
acknowledged. P.G.-R. thanks Eli Lilly and Company
for fellowship support. We also thank Professor Lanny
Liebeskind (Emory University) and Professor Kenneth
Caulton (Indiana University) for helpful discussions.
A series of thioesters (4sÀu) were prepared in order
to assess the relationship between the proximity of the
protected nitrogen to the thioester and the overall effi-
ciency of the decarbonylation reaction. The data reveal the
possibility of a modest trend toward improved yields with
increasing distance between the two functional groups. In
general, excellent yields of alkene products were observed
with simple alkyl thioesters (entries 23 and 24), an indica-
tion that this approach may be general for the synthesis of
alkenes from thioester precursors.
Supporting Information Available. Experimental details
and spectral data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
The decarbonylation of dipeptide substrate 4w returned
an excellent yield of the desired (Z)-enamide. This result
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
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