J. Am. Chem. Soc. 1998, 120, 5319-5320
5319
conducting extractive and chromatographic isolation procedures
at 4 °C under an inert atmosphere. With these modifications,
the efficiency of the transformation has more than doubled, such
that (+)-2 is obtained reproducibly in 65-72% yield after
chromatographic purification. The aglycone (2) was prepared
with the objective of implementing a final-stage glycosylation
reaction for the synthesis of 1 using a suitably protected glycosyl
donor. Although 1 readily decomposes when separated from its
binding protein, mildly acidic conditions are tolerated. For this
reason these conditions were chosen for the proposed coupling
and deprotection steps.7 In this regard, the Schmidt trichloro-
acetimidate method was felt to be an ideal procedure for the
glycosylation reaction in light of its versatility and, more
importantly, for the mildly acidic conditions used in the coupling
reaction.8 Reports of the use of the Schmidt methodology for
the synthesis of 2-amino sugars have primarily described the use
of a 2-azido substituent as a latent amino functionality.8,9 This
was felt not to be a viable option in the present case because of
the incompatibility of the chromophore with conditions for the
reduction of the azide and as well for the monomethylation of
the resultant amine. We therefore chose to employ a glycosyl
donor containing a preexisting 2-methylamino group and focused
on the selection of protective groups for this functionality and
for the two hydroxyl groups. A goal was to remove all protective
groups in a single operation after glycosylation, an approach that
was dictated by the unstable nature of the chromophore.
Total Synthesis of (+)-Neocarzinostatin
Chromophore
Andrew G. Myers,* Jun Liang, Marlys Hammond,
Philip M. Harrington, Yusheng Wu, and Elaine Y. Kuo
DiVision of Chemistry and Chemical Engineering
California Institute of Technology
Pasadena, California 91125
ReceiVed February 20, 1998
The chromoprotein enediyne antibiotics are characterized by
the high reactivity of their “enediyne” chromophore components,
a feature that greatly complicates the development of synthetic
routes to these agents.1 To date, no chromoprotein chromophore
has been synthesized, although notable achievements in this area
have been reported.2,3 We describe below a total synthesis of
(+)-neocarzinostatin chromophore, the first of the enediyne
antibiotics to be characterized.4 The route employed makes use
of an atypical protocol for the introduction of a 2-amino sugar
that may find broader applicability in the synthesis of other
aminoglycosides.
After extensive experimentation, we determined that the C-3
and C-4 hydroxyl groups were best masked as triethylsilyl (TES)
ethers,10 but we were unable to find a suitable means to protect
the N-methylamino group. Carbamates such as 2-(3,5-dimethoxy-
phenyl)propyloxycarbonyl led to oxazolidinone formation during
the coupling reaction, while t-Boc and 2-(trimethylsilyl)ethoxy-
carbonyl (TEOC) groups were found to be too robust to be cleaved
under conditions that 1 would survive. Bulky groups, such as
N-bis(4-methoxyphenyl)methyl, tended to block attack of the
glycosyl acceptor from the R-face, so that the undesired â-ano-
meric products predominated. Eventually, we were led to
question whether an N-methylamino protective group was neces-
sary at all. Despite the obvious appeal of such a strategy, we
were unaware of any examples in which the trichloroacetimidate
method had been conducted in the presence of a free amino group
and had concerns about the viability of such a proposal given
that the coupling is promoted by substoichiometric Brφnsted or
Lewis acids that might be inactivated by reaction with the
amine.11,12
In prior work, we described an enantioselective synthesis of
(+)-neocarzinostatin chromophore aglycone ((+)-2)5 involving
as the final step a novel reductive deoxygenation of the epoxy
alcohol 3 using triphenylphosphine, iodine, and imidazole.6 This
transformation has since been markedly improved by the intro-
duction of a low-temperature (-10 °C) methanol quench and by
(1) Reviews: (a) Smith, A. L.; Nicolaou, K. C. J. Med. Chem. 1996, 39,
2103. (b) Grissom, J. W.; Gunawardena, G. U.; Klingberg, D.; Huang, D.
Tetrahedron 1996, 52, 6453.
(2) (a) Myers, A. G.; Harrington, P. M.; Kuo, E. Y. J. Am. Chem. Soc.
1991, 113, 694. (b) Myers, A. G.; Harrington, P. M.; Kwon, B.-M. J. Am.
Chem. Soc. 1992, 114, 1086.
(3) For leading references to other synthetic studies of 1 and related model
systems, see: (a) Wender, P. A.; Harmata, M.; Jeffrey, D.; Mukai, C.; Suffert,
J. Tetrahedron Lett. 1988, 29, 909. (b) Hirama, M.; Fujiwara, K.; Shigematu,
K.; Fukazawa, Y. J. Am. Chem. Soc. 1989, 111, 4120. (c) Suffert, J.
Tetrahedron Lett. 1990, 31, 7437. (d) Doi, T.; Takahashi, T. J. Org. Chem.
1991, 56, 3456. (e) Hirama, M.; Gomibuchi, T.; Fujiwara, K. J. Am. Chem.
Soc. 1991, 113, 9851. (f) Nakatani, K.; Arai, K.; Terashima, S. Tetrahedron
1993, 49, 1901. (g) Matsumoto, Y.; Kuwatani, Y.; Ueda, I. Tetrahedron Lett.
1995, 36, 3197. (h) Toshima, K.; Ohta, K.; Yanagawa, K.; Kano, T.; Nakata,
M.; Kinoshita, M.; Matsumura, S. J. Am. Chem. Soc. 1995, 117, 10825. (i)
Magnus, P.; Carter, R.; Davies, M.; Elliott, J.; Pitterna, T. Tetrahedron 1996,
52, 6283. (j) Caddick, S.; Delisser, V. M. Tetrahedron Lett. 1997, 38, 2355.
(k) Ferri, F.; Bru¨ckner, R. Liebigs Ann. 1997, 961.
To explore this possibility, the glycosyl donor 413 containing
a free N-methylamino group was synthesized in 10 steps from
tri-O-acetyl-D-galactal (see Supporting Information). Studies of
(6) Following our disclosure of this transformation,5 similar conditions for
the reductive deoxygenation of 2,3-epoxy alcohols were independently reported
by another research group: Dorta, R. L.; Rodr´ıguez, M. S.; Salazar, J. A.;
Sua´rez, E. Tetrahedron Lett. 1997, 38, 4675.
(7) In studies of the stability of authentic neocarzinostatin chromophore,
we observed its rapid decomposition in the presence of 10% HF in acetonitrile
(t1/2 e 30 min), but no evidence of its decomposition in the presence of
HF‚pyridine complex in THF after 2 h at 23 °C (rp-HPLC analysis).
(8) Reviews: (a) Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25,
212. (b) Schmidt, R. R.; Kinzy, W. AdV. Carbohydr. Chem. Biochem. 1994,
50, 21. (c) Schmidt, R. R.; Jung, K.-H. In PreparatiVe Carbohydrate
Chemistry; Hanessian, S., Ed.; Marcel Dekker: New York, 1997; Chapter
12.
(9) (a) Schmidt, R. R.; Grundler, G. Angew. Chem., Int. Ed. Engl. 1982,
21, 781. (b) Grundler, G.; Schmidt, R. R. Liebigs Ann. Chem. 1984, 1826. (c)
Kinzy, W.; Schmidt, R. R. Carbohydr. Res. 1989, 193, 33. (d) Boons, G. J.
P. H.; Overhand, M.; van der Marel, G. A.; van Boom, J.-H. Angew. Chem.,
Int. Ed. Engl. 1989, 28, 1504. (e) Kaneko, T.; Takahashi, K.; Hirama, M.
Heterocycles 1998, 47, 91.
(10) Conditions for the removal of acetonide, cyclopentylidene ketal, and
1,1,3,3-tetraisopropyldisiloxane protective groups for the 1,2-diol, for example,
were found to be incompatible with 1.
(4) Isolation of 1: (a) Napier, M. A.; Holmquist, B.; Strydom, D. J.;
Goldberg, I. H. Biochem. Biophys. Res. Commun. 1979, 89, 635. (b) Koide,
Y.; Ishii, F.; Hasuda, K.; Koyama, Y.; Edo, K.; Katamine, S.; Kitame, F.;
Ishida, N. J. Antibiot. 1980, 33, 342. Chromophore structure: (c) Edo, K.;
Mizugaki, M.; Koide, Y.; Seto, H.; Furihata, K.; Otake, N.; Ishida, N.
Tetrahedron Lett. 1985, 26, 331. Carbohydrate stereochemistry: (d) Edo, K.;
Akiyama, Y.; Saito, K.; Mizugaki, M.; Koide, Y.; Ishida, N. J. Antibiot. 1986,
39, 1615. Chromophore stereochemistry: (e) Myers, A. G.; Proteau, P. J.;
Handel, T. M. J. Am. Chem. Soc. 1988, 110, 7212.
(5) Myers, A. G.; Hammond, M.; Wu, Y.-S.; Xiang, J.-N.; Harrington, P.
M.; Kuo, E. Y. J. Am. Chem. Soc. 1996, 118, 10006.
S0002-7863(98)00588-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/14/1998