Synthetic studies toward the mannopeptimycins: Synthesis of orthogonally protected β-hydroxyenduracididines

Article abstract of DOI:10.1021/ol100219a

The asymmetric synthesis of the nonproteinogenic amino acids (2S,3S,4-S)-β-hydroxyenduracididine 3 and (2R,3S,4-S)-β- hydroxyenduracididine 4 in orthogonally protected form in 15 total steps from Garner's aldehyde is reported. The former and N-glycosylated form of the latter are found in the glycopeptide antibiotic mannopeptimycin.

Full text of DOI:10.1021/ol100219a

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1680-1683
Synthetic Studies toward the
Mannopeptimycins: Synthesis of
Orthogonally Protected
ꢀ-Hydroxyenduracididines
Kevin S. Olivier and Michael S. Van Nieuwenhze*
Department of Chemistry, Indiana UniVersity, 800 East Kirkwood AVenue,
Bloomington, Indiana 47405-7102
mVannieu@indiana.edu
Received January 27, 2010
ABSTRACT
The asymmetric synthesis of the nonproteinogenic amino acids (2S,3S,4′S)-ꢀ-hydroxyenduracididine 3 and (2R,3S,4′S)-ꢀ-hydroxyenduracididine
4 in orthogonally protected form in 15 total steps from Garner’s aldehyde is reported. The former and N-glycosylated form of the latter are
found in the glycopeptide antibiotic mannopeptimycin.
The rapidly escalating fight against bacterial resistance to
currently available therapies has created an urgent need for
new antibiotic agents with novel modes of action. For
example, Staphylococcus aureus, which has a long history
of acquiring resistance to antibiotics, continues to pose
problems for existing chemotherapeutic agents. In fact,
methicillin-resistant S. aureus (MRSA) infections have been
a significant health problem since the 1960s.1 A recent study
estimated that there were over 94000 cases of invasive
MRSA infection in the United States in 2005.2 While
vancomycin has been an effective drug for treating these
infections, recent identification of MRSA isolates possessing
an intermediate level of resistance to vancomycin has
underscored the need for novel antibiotics that act via
mechanisms that are orthogonal to currently used therapies.1
The mannopeptimycins are a group of cyclic glycopeptides
originally isolated in the 1950s as an antibiotic complex
produced by the LL-AC98 strain of Streptomyces hygro-
scopicus.3 They represent a novel class of lipoglycopeptide
antibiotics that are assembled via a nonribosomal peptide
synthetase (NRPS) pathway and have shown promising
antibacterial activity against multidrug-resistant pathogens.4
Only in 2002 was a report of the complete structural and
stereochemical assignment of the five members of this
complex disclosed. The structures of the mannopeptimycins
and their biological activities are summarized in Table 1.
(1) Lin˜ares, J. J. Clin. Microbiol. Infect. 2001, 7, 8–15.
(2) Klevens, R. M.; Morrison, M. A.; Nadle, J.; Petit, S.; Gershman,
K.; Ray, S.; Harrison, L. H.; Lynfield, R.; Dumyati, G.; Townes, J. M.;
Craig, A. S.; Zell, E. R.; Fosheim, G. E.; McDougal, L. K.; Carey, R. B.;
Fridkin, S. K. JAMA 2007, 298, 1763–1771.
(3) He, H.; Williamson, R. T.; Shen, B.; Graziani, E. I.; Yang, H. Y.;
Sakya, S. M.; Petersen, P. J.; Carter, G. T. J. Am. Chem. Soc. 2002, 124,
9729–9736.
(4) Magarvey, N. A.; Haltli, B.; Greenstein, M.; Hucul, J. A. Antimicrob.
Agents Chemother. 2006, 50, 2167–2177.
10.1021/ol100219a  2010 American Chemical Society
Published on Web 03/16/2010

proteinogenic amino acids (D-tyrosine and ꢀ-D-hydroxyen-
duracididine) are glycosylated with mannose residues; the
former is glycosylated with an R-(1,4)-linked-bis-manno-
pyranosyl pyranoside11,12 and the latter is N-glycosylated
with an R-linked mannose residue.
Table 1. Structures and Activities of the Mannopeptimycins
An important element of any effort directed toward the
total synthesis of mannopeptimycin is development of an
efficient asymmetric synthesis of the novel ꢀ-hydroxyen-
duracididine residues 3 and 4 with appropriate orthogonal
protecting groups. Each of these residues is densely func-
tionalized, every carbon atom in the amino acid backbone
is heteroatom-substituted, and features three contiguous
stereocenters. Synthetic routes to either of these unusual
amino acids have yet to be reported. Our interest in studying
the influence of structure on the biological activity of the
mannopeptimycins required an efficient and robust synthetic
route to each of the ꢀ-hydroxyenduracididines. Herein, we
detail our synthetic route to these mannopeptimycin building
blocks.
Given that the hydroxyenduracididines differ only in the
stereochemical configuration at C-2, it was envisaged that
they could be accessed from a common advanced intermedi-
ate. Our strategy, which is depicted in Scheme 1, involved
Scheme 1. Synthetic Strategy
Mannopeptimycins ꢀ-ε are active against a wide range
of Gram-positive bacteria, including methicillin-resistant
Staphylococcus aureus (MRSA) and vancomycin-resistant
Enterococcus faecium.5,6 A semisynthetic analogue of the
mannopeptimycins AC98-6446 has shown significantly
greater potency than the natural mannopeptimycins against
MRSA, VRE, penicillin-resistant Streptococcus pneumoniae,
and glycopeptide intermediate S. aureus.6-8 Mechanism of
action studies have shown that mannopeptimycin interferes
with the late stages of bacterial cell wall synthesis, most
likely the transglycosylation reaction, possibly through
binding to lipid II.9
The peptide core of the mannopeptimycins is composed
of six amino acid residues of alternating D- and L-amino
acids, three of which are nonproteinogenic. Two of these
nonproteinogenic amino acids, the ꢀ-hydroxyenduracididines,
have not been found in any other natural product although
the biosynthetic pathway used for their construction is
currently being studied.4,10 In addition, two of these non-
the preparation of the R-nosylate ester 2, which was
subsequently manipulated to provide each of the hydroxy-
enduracididine diastereomers. Nosylate 2 could be accessed
via Sharpless asymmetric dihydroxylation13 of an ap-
propriately derivatized enoate precursor (e.g., 11) followed
by selective activation of the R-hydroxyl group via nosyla-
tion.14 The (2S,3S,4′S)-diastereomer 3 (L-absolute configu-
ration) could be accessed via direct azide displacement of
the nosylate group in 2. Conversion of nosylate 2 to an
epoxide intermediate followed by nucleophilic ring-opening
(10) Haltli, B.; Tan, Y.; Magarvey, N. A.; Wagenaar, M.; Yin, X.;
Greenstein, M.; Hucul, J. A.; Zabriskie, T. M. Chem. Biol. 2005, 12, 1163–
(5) He, H. Appl. Microbiol. Biotechnol. 2005, 67, 444–452
(6) Weiss, W. J.; Murphy, T.; Lenoy, E. B.; Young, M. Antimicrob.
Agents Chemother. 2004, 48, 1708–1712
(7) Petersen, P. J.; Wang, T. Z.; Dushin, R. G.; Bradford, P. A.
Antimicrob. Agents Chemother. 2004, 48, 739–746
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Ashcroft, J. S.; Graziani, E. I.; E., K. F.; Bradford, P. A.; Petersen, P. J.;
Wheless, K. L.; How, D.; Torres, N.; Lenoy, E. B.; Weiss, W. J.; Lang,
S. A.; Projan, S. J.; Shlaes, D. M.; Mansour, T. S. J. Med. Chem. 2004, 47,
S. Eur. J. Org. Chem. 2008, 2895.
(13) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483–2547.
(14) (a) Fleming, P. R.; Sharpless, K. B. J. Org. Chem. 1991, 56, 2869–
2875. (b) Denis, J.; Correa, A.; Greene, A. E. J. Org. Chem. 1990, 55,
1957–1959. (c) Watson, K. G.; Fung, Y. M.; Gredley, M.; Bird, G. J.;
Jackson, W. R.; Gountzos, H.; Matthews, B. R. J. Chem. Soc., Chem.
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(9) Ruzin, A.; Singh, G.; Severin, A.; Yang, Y.; Dushin, R. G.;
Sutherland, A. G.; Minnick, A.; Greenstein, M.; May, M. K.; Shlaes, D. M.;
Bradford, P. A. Antimicrob. Agents Chemother. 2004, 48, 728–738.
Org. Lett., Vol. 12, No. 8, 2010
1681

by azide would provide access to the (2R,3S,4′S)-diastere-
omer 4 (D-absolute configuration).14a
Given these limitations, we chose to protect the remaining
nitrogen atom of 9 with the (triisopropylsilyloxy)methyl
(Tom) group.16 Thus, olefin 9 was treated with Tom-Cl
(KHMDS, toluene, 1 h) to provide the Tom-protected olefin
10 in modest yield. Olefin 10 was subjected to a dihydroxy-
lation/oxidative cleavage sequence (OsO4, NMO, THF/H2O/
t-BuOH then NaIO4, CH2Cl2/H2O) and the crude aldehyde
was treated with methyl (triphenylphosphoranylidene)acetate
at low concentration in THF to give enoate 11 in 71% overall
yield and a 17:1 product ratio favoring the desired (E)-isomer.
Sharpless asymmetric dihydroxylation (AD-mix R, t-BuOH/
H2O) proceeded cleanly to provide a single diol diastereomer
12. Monosulfonylation of diol 12 (Nos-Cl, Et3N, CH2Cl2,
-40 to 0 °C) proceeded smoothly to provide nosylate 2 in
71% yield.14a
The synthesis of nosylate 2 commenced with olefin 6,15
which was prepared by Wittig olefination of (S)-Garner’s
aldehyde. As detailed in Scheme 2, acidic cleavage of the
Scheme 2. Synthesis of Common Intermediate 2
The nosylate intermediate 2 was then transformed into
othogonally protected (2S,3S,4′S)-diastereomer 3 (ꢀ-L-hy-
droxyenduracididine) in two steps (Scheme 3).
Scheme 3. Synthesis of the Diastereomeric
ꢀ-Hydroxyenduracididines from Common Intermediate 2
N,O-acetonide and N-Boc protecting groups (6 N HCl, 1 h)
was followed by guanidinylation with N,N′-bis-(benzyloxy-
carbonyl)-S-methylisothiourea 7 (HgCl2, Et3N, DMF, 4 d)
to afford alcohol 8 in 45% overall yield from 6. Cyclization
of 8 under Mitsunobu conditions (DIAD, Ph3P, THF, -15
°C) provided alkene 9 that contained the 2-iminoimidazo-
lidine group in partially protected form.
At this juncture, orthogonal protection of the remaining
nitrogen atom of the 2-iminoimidazolidine was required
in order to ensure that it could be selectively unmasked
for subsequent glycosylation. Since the remainder of the
synthetic route would leverage the Sharpless asymmetric
dihydroxylation reaction and subsequent electrophilic
activation/displacement reactions, the choice of protection
for this nitrogen must satisfy several requirements. First,
it must not contain electrophilic functionality capable of
reacting with nearby hydroxyl groups that would be
introduced with Sharpless asymmetric dihydroxylation.
Second, it must not contain nucleophilic functionality that
would be capable of displacing either of the activated
hydroxyl groups. Third, it must be selectively cleaved
under mild conditions that will not also cleave the
neighboring Cbz-protecting groups. These restrictions rule
out a number of commonly used protecting groups (e.g.,
carbamates, amides, benzyl, etc.).
Nucleophilic displacement of the nosylate in 2 with sodium
azide (NaN3, DMF, 50 °C, 78%) provided an intermediate
azido alcohol which was subjected to a one-pot Staudinger
reduction (Ph3P, THF/H2O, 4 h) and Boc protection (Boc2O,
NaHCO3, 12 h) to provide building block 3 in 62% overall
yield from the intermediate azido alcohol.
Whereas 3 was prepared via inversion of the stereochem-
ical configuration at C-2, its epimer 4 was obtained by double
inversion at that center, as outlined in Scheme 3. Conversion
of 2 to epoxide 13 (KHMDS, THF/tol, -78 °C, 59%)
followed by nucleophilic ring opening in the presence of
sodium azide and pyridinium p-toluenesulfonate (DMF, 44%)
afforded an intermediate azido alcohol which was converted
to the orthogonally protected (2R,3S,4′S)-diastereomer 4 (ꢀ-
D-hydroxyenduracididine) via the aforementioned Staudinger
reduction/Boc-protection procedure.
In conclusion, we have completed the first chemical
synthesis of the (2S,3S,4′S)- and (2R,3S,4′S)-hydroxyendura-
(15) Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K. Synthesis 1998,
1707–1709.
(16) Pitsch, S.; Weiss, P. A.; Stutz, J. A.; Wu, X. HelV. Chim. Acta
2001, 84, 3773–3795.
1682
Org. Lett., Vol. 12, No. 8, 2010

cididines in orthogonally protected form. Access to each of
these nonproteinogenic amino acids will assist efforts directed
at total synthesis of members of the mannopeptimycin class
of lipoglycopeptide antibiotics and aid semisynthetic efforts
directed toward identification of mannopeptimycin deriva-
tives with improved biological activity profiles. Furthermore,
these novel amino acids will support efforts directed toward
elucidating the mode of action and binding site(s) utilized
by the mannopeptimycins. Our results from these studies will
be presented in due course.
Acknowledgment. Financial support provided by the
National Institutes of Health (AI 059327) and Indiana
University is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and tabulated spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL100219A
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