ORGANIC
LETTERS
2007
Vol. 9, No. 8
1489-1492
Chemoenzymatic Approaches toward
Dechloroansamitocin P-3†
Axel Meyer,‡ Marco Bru
1
njes,‡ Florian Taft,‡ Thomas Frenzel,‡ Florenz Sasse,§ and
Andreas Kirschning*,‡
Institut fu¨r Organische Chemie, Leibniz UniVersita¨t HannoVer, Schneiderberg 1B,
30167 HannoVer, Germany, and Helmholtzzentrum fu¨r Infektionsforschung (HZI),
Mascheroder Weg 1, 38124 Braunschweig, Germany
andreas.kirschning@oci.uni-hannoVer.de
Received January 29, 2007
ABSTRACT
The enantioselective total synthesis of proansamitocin, a key biosynthetic intermediate of the highly potent antitumor agent ansamitocin P-3,
is described which bears a diene-ene RCM as the key macrocyclization step. Feeding of proansamitocin to an AHBA block mutant Actinosynnema
pretiosum (HGF073) yielded ansamitocin P-3 as well as dechloroansamitocin P-3, the latter also being formed upon fermentation in the presence
of 3-amino-5-methoxybenzoic acid.
Maytansine, first isolated from the Ethiopian plant Maytenus
serrata,1,2 and the related ansamitocins P-1 to P-4,3-5 which
are of microbial origin (Actinosynnema pretiosum), consist
of a 19-membered macrolactam ring and differ in the side
chain at C-3. They inhibit growth of different leukaemia cell
lines as well as human solid tumors at very low concentra-
tions (10-3 to 10-7 µg/mL) by inhibiting tubulin polymeri-
zation. However, the clinical development of maytansinoids
had to be stopped in phase II2a,6 due to gastrointestinal side
effects and neurotoxicities.4b,7
† Dedicated to E. Winterfeldt on the occasion of his 75th birthday.
‡ Leibniz University Hannover.
§ Helmholtzzentrum fu¨r Infektionsforschung (HZI).
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R. M.; Karim, A.; Gilmore, C. J.; Haltiwanger, R. C.; Bryan, R. F. J. Am.
Chem. Soc. 1972, 94, 1354-1356. (b) Kupchan, S. M.; Komoda, Y.;
Branfman, A. R.; Sneden, A. T.; Court, W. A.; Thomas, G. J.; Hintz, H. P.
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(Colubrina texensis; Rhamnaceae and Trewia nudiflora; Euphorbiaceae):
(a) Reider, P. J.; Roland, D. M. In The Alkaloids; Brossi, A., Ed.; Academic
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Total synthesis approaches5,8 contributed little to our
knowledge of the structure-activity relationships; this
(4) A mutant of A. pretiosum spp. auranticum provided 15 additional
ansamitocines: (a) Izawa, M.; Tanida, S.; Asai, M. J. Antibiot. 1981, 34,
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E. Chem. Pharm. Bull. 2004, 52, 1-26.
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(8) (a) Paterson, I.; Mansuri, M. M. Tetrahedron 1985, 41, 3569-3624.
(b) A recent review of the synthetic approaches is given in ref 5b.
(3) (a) Higashide, E.; Asai, M.; Ootsu, K.; Tanida, S.; Kozai, Y.;
Hasegawa, T.; Kishi, T.; Sugino, Y.; Yoneda, M. Nature 1977, 270, 721-
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10.1021/ol0702270 CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/23/2007