diaminopimelyl-D-alanyl-D-alanine (Park’s nucleotide) to
prenylpyrophosphoryl-N-acylmuramyl-L-Ala-γ-D-glu-meso-
DAP-D-Ala-D-Ala (lipid I). MraY is inhibited by nucleoside-
based complex natural products such as muraymycin,
liposidomycin, caprazamycin, and capuramycin.8 Capura-
mycin (1) and its analogs exhibited significant mycobacterial
growth inhibitory activities in Vitro and in ViVo (Scheme 1)
capuramycin.11 Their synthesis requires 22 linear steps from
diisopropylidene-D-glucofuranose, and relatively lengthy
synthesis of the manno-pyranuroate glycosyl donor. We now
report a concise total synthesis of capuramycin that is
amenable to performing comprehensive medicinal chemistry
studies based on the core structure of capuramycin.
In our preliminary synthetic studies of the advanced
intermediate ii (Scheme 1), glycosylation of the cyanohydrin
5a with ꢀ-D-manno-pyranuronate imidate i provided the
desired R-linked mannuronic acid derivative with very low
yield (5-15%) even after extensive optimization efforts.
Moreover, E2 elimination to form the 4′′-enopyranosiduronic
acid derivative ii did not give satisfactory results (35-45%
with DBU).12 Based on the preliminary studies summarized
in Scheme 1, we revised the synthetic route for capuramycin
(1) in which we envisioned performing glycosylation of the
cyanohydrin 5a with the tetraacetyl thio-R-D-mannopyra-
noside 6, followed by one-pot oxidation of the C-6′′ alcohol
and elimination of the acetate at the C-4′′ position to form
the R,ꢀ-unsaturated aldehyde 12. The revised synthetic route
for capuramycin illustrated in Scheme 1 would allow for the
synthesis of the intact molecule from readily accessible
building blocks with a minimum number of protecting group
manipulations.
Scheme 1. Preliminary Studies on Glycosylation of 5a and the
Revised Synthetic Strategy for Capuramycin (1)
Scheme 2 illustrates our synthetic route for capuramycin
(1). The partially protected uridine 213 was converted to the
2-O-acetyl-3-O-methyl-uridine derivative 3 through monom-
ethylation using nBu2SnO, acetylation, and detritylation
reactions. The primary alcohol of 3 was oxidized under
Pfitzner-Moffatt conditions (DCC, Cl2CHCO2H, DMSO)14
to provide the corresponding aldehyde 4, which was utilized
after passing through a SiO2 plug. The aldehyde 4 was
unstable against Brønsted and Lewis bases (i.e., Et3N,
DABCO, cinchona alkaloids, triphenylphosphine, and triph-
enylphosphine oxide). Because of the instability of 4 when
exposed to bases, we explored cyano addition reactions of
carbonyl molecules promoted by Lewis acids15 or under
neutral conditions. Several Lewis acid promoted trimethyl-
silylcyanations of 4 were examined. In all cases, cyanohydrin
synthesis furnished a mixture of 5a and 5b in favor of
undesired 5b with moderate yields.16 For example, the
cyanosilyation of 4 with ZnI2 (100 mol %) gave rise to a
mixture of the cyanohydrins in 60% yield with a 5a/5b ratio
of ∼1:2 after desilylation. The same reaction with the (S)-
or (R)-BINOL-Ti(OiPr)4 complex resulted in a 5a/5b selec-
tivity of ∼1:1.5 regardless of the configuration of BINOL.
On the contrary, the addition of TMSCN to 4 with 10 mol%
of Ti(OiPr)4 in CH2Cl2-H2O (1%) provided a mixture of
and very low toxicity in mice.9 Moreover, a capuramycin
analog killed M. tuberculosis much faster than other first-
line TB drugs (>90% of the bacilli were killed within 48 h)
and thus could dramatically reduce the time frame for
effective anti-TB chemotherapy.10 Therefore, capuramycin
and its congeners have been considered important lead
molecules for the development of a new drug for MDR-TB
infections. However, extensive SAR studies of capuramycins
to improve pharmacokinetic properties have been limited due
to difficult modifications of the desired position(s) of the
complex natural product with biologically interesting func-
tional groups. Consequently, it is essential to establish a
concise and convergent synthesis of capuramycin that is
amenable to synthesis of analogs for SAR studies. To date,
Knapp and Nadan have reported the only total synthesis of
(11) Knapp, S.; Nandan, S. R. J. Org. Chem. 1994, 59, 281.
(12) Uncharacterizable byproducts were isolated in addition to the over-
deacetylation products.
(8) (a) Timothy, D. H.; Lloyd, A. J.; Roper, D. I. Infect. Disor.: Drug
Targets 2006, 6, 85. (b) Dini, C. Curr. Top. Med. Chem. 2005, 5, 1221. (c)
Uridat, E.; Zhang, J.; Aszodi, J. Bioorg. Med. Chem. Lett. 2002, 12, 1209.
(d) Dini, C.; Drochon, N.; Feteanu, S.; Guillot, J. C.; Peixoto, C.; Aszodi,
J. Bioorg. Med. Chem. Lett. 2001, 11, 529.
(13) Ito, T.; Ueda, S.; Takaku, H. J. Org. Chem. 1986, 51, 931.
(14) (a) Ranganathan, R. S.; Jones, G. H.; Moffatt, J. G. J. Org. Chem.
1974, 39, 290. (b) Pfitzner, K. E.; Moffatt, J. G. J. Am. Chem. Soc. 1963,
85, 3027.
(15) (a) North, M. Tetrahedron: Asymmetry 2003, 14, 147, and references
therein. (b) Krueger, C. A.; Kuntz, K. W.; Dzierba, C. D.; Wirschun, W. G.;
Gleason, J. D.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 1999,
121, 4284. (c) Mori, M.; Imma, H.; Nakai, T. Tetrahedron Lett. 1997, 38,
6229.
(9) (a) Koga, T.; Fukuoka, T.; Harasaki, T.; Inoue, H.; Hotoda, H.;
Kakuta, M.; Muramatsu, Y.; Yamamura, N.; Hoshi, M.; Hirota, T. J.
Antimicro. Chemother. 2004, 54, 755. (b) Yamaguchi, H.; Sato, S.; Yoshida,
S.; Takeda, K.; Itoh, M.; Seto, H.; Otake, N. J. Antibiot. 1986, 39, 1047.
(10) Reddy, V. M.; Einck, L.; Nacy, C A. Antimicro. Agents Chemther.
2008, 52, 719.
(16) The stereochemistry of 5a was established by the advanced Mosher
method, see Supporting Information.
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Org. Lett., Vol. 11, No. 11, 2009