3518
J. Am. Chem. Soc. 1998, 120, 3518-3519
Scheme 1
Synthesis of the Enediyne Aglycon
(()-Calicheamicinone
Ian Churcher, David Hallett, and Philip Magnus*
Department of Chemistry and Biochemistry
UniVersity of Texas at Austin
Austin, Texas 78712
ReceiVed January 14, 1998
The unusual structure, potent antitumor activity, and in Vitro
mechanism of action of calicheamicin 1 has attracted a great deal
of attention (Scheme 1).1 To date, four syntheses of the aglycon
calicheamicinone 2 have been reported by the groups of Dan-
ishefsky,2 Nicolaou,3 and Clive (2 reports).4 The former two
groups have also synthesized calicheamicin.5,6 Our own synthetic
studies, based upon an η2Co2(CO)6-propargylic aldol cyclization
to form the 10-membered enediyne ring, produced 15 [TBS
instead of TES] (Scheme 2) as the pivotal intermediate, but not
in sufficient quantities to readily explore the full range of
protection-deprotection options that were necessary to complete
the synthesis of 2.7 Consequently, it was decided to examine a
different route that would supply gram amounts of 15. While
there is a substantial literature describing the various strategies
that have been developed for the synthesis of 2, it is notable that
the potentially most direct approach, namely one based upon an
o-quinone monoketal has not been reported.8 The Danishefsky
route most closely parallels a quinone monoketal strategy but uses
the Becker-Adler spiro-epoxide reaction,9 which requires deletion
of one carbon atom (C-14) and replacement by a two-carbon side
chain (C-14,15).
Scheme 2
The phenol 3 was prepared from commercially available
5-methoxysalicylic acid in four standard steps.10 Oxidation of 3
with PhI(OAc)2/MeOH11 gave the o-quinone monoketal 4 (87%),
which was treated with 4a to give 5 (76%) (Scheme 2). Removal
of the TIPS group to give 6 and protection of the tertiary hydroxyl
(1) Enediyne Antibiotics as Antitumor Agents; Borders, D. B., Doyle, T.
W., Eds.; Dekker, Inc.: New York, 1995.
(2) Cabal, M. P.; Coleman, R. S.; Danishefsky, S. J. J. Am. Chem. Soc.
1990, 112, 3253. Haseltine, J. N.; Cabal, M. P.; Mantlo, N. B.; Iwasawa, N.;
Yamashita, D. S.; Coleman, R. S.; Danishefsky, S. J.; Schulte, G. K. J. Am.
Chem. Soc. 1991, 113, 3850.
(3) Smith, A. L.; Pitsinos, E. N.; Hwang, C.-K.; Mizuno, Y.; Saimoto, H.;
Scarlato, G. R.; Suzuki, T.; Nicolaou, K. C. J. Am. Chem. Soc. 1993, 115,
7612.
(4) Clive, D. L. J.; Bo, Y.; Tao, Y.; Daigneault, S.; Wu, Y.-J.; Meignan G.
J. Am. Chem. Soc. 1996, 118, 4904.
(5) Hitchcock, S. A.; Boyer, S. H.; Chu-Moyer, M. Y.; Olson, S. H.;
Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 1994, 33, 858. Shair, M. D.;
Danishefsky, S. J. J. Org. Chem. 1996, 61, 16.
(6) Nicolaou, K. C.; Hummel, W.; Nakada, M.; Shibayama, K.; Pitsinos,
E. N.; Saimoto, H.; Mizuno, Y.; Baldenius, K.-U.; Smith, A. L. J. Am. Chem.
Soc. 1993, 115, 7625. Nicolaou, K. C.; Hummel, W.; Pitsinos, E. N.; Nakada,
M.; Smith, A. L.; Shibayama, K.; Saimoto, H. J. Am. Chem. Soc. 1992, 114,
10082.
(7) Magnus, P.; Miknis, G. F.; Press: N. J.; Grandjean, D.; Taylor, G. M.;
Harling, J. J. Am. Chem. Soc. 1997, 119, 6739.
(8) For recent extensive reviews, see: Lhermitte, H.; Grierson, D. S.
Contemp. Org. Synth. 1996, 3, 41; 1996, 3, 93.
(9) Adler, E.; Brasen, S.; Miyake, H. Acta Chem. Scand. 1971, 25, 2055.
Becker, H.-D.; Bremholt, T.; Adler, E. Tetrahedron Lett. 1972, 13, 4205.
(10) Bromination of I gave II, which was converted into III. Prolonged
exposure of III to Cu/NaOH/H2O gave IV, which on treatment with EtOH/
SOCl2 provided 3 (overall yield 59%).
group as a TES ether resulted in 7 (83% from 5). Reduction of
7 using DIBAL-H/toluene gave 8, which on oxidation with Dess-
Martin (D-M) periodinane12 gave the aldehyde 9 (93% from 7).
Exposure of 9 to LiN(TMS)2/THF at -78 °C gave 10 and 11
(1:4), which were directly oxidized (D-M) to the crystalline
ketone 12. Reduction with DIBAL-H/toluene at -78 °C produced
the desired 12R-alcohol 10 (69% from 9; 11 could not be detected
by 1H NMR). Treatment of 10 with PPTS in aqueous dioxane at
60 °C gave 13 (94%), which on exposure to BCl3/CH2Cl2/heptane
and workup with basic Al2O3/CH2Cl2 gave 14 (94%).13
(11) Pelter, A.; Elgendy, S. Tetrahedron Lett. 1988, 29, 677. Kita, Y.;
Tohma, H.; Kikuchi, K.; Inagaki, M.; Yakura, T. J. Org. Chem. 1991, 56,
435.
(12) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. Meyer, S.
D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549.
S0002-7863(98)00154-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/28/1998