chains. Preclinical studies6 demonstrated that maytansinoids
are strong antitumor agents as a result of binding to tubulin,
thereby shutting down tubulin polymerization.7 They inhibit
growth of different leukaemia cell lines as well as human
solid tumors at very low concentrations (10-3 to 10-7 µg/
mL). Despite promising toxicity tests in different animal
models,6 the clinical development of maytansinoids had to
be stopped in phase II2a,8 because of gastrointestinal side
effects and neurotoxicities.4b,6,9
However, given the high intrinsic potency of this class of
natural products, efforts to develop them into clinically useful
agents still continue. Particularly promising are the initial
results toward increasing their selectivity by conjugating the
ansamitocins to tumor-targeted antibodies.10
cyclized by an amide synthase (gene asm9)15,16 to yield the
cyclic 19-membered macrocyclic lactam, proansamitocin 2
(Scheme 1).17 A closer study of the substrate specificity of
this key enzyme could pave the way for a chemoenzymatic
strategy toward new macrocyclic analogues of proansami-
tocin.
Therefore, we first decided to prepare the N-acetylcys-
teamine derivative 1b to explore whether it is a substrate
for this cyclase before generating analogues of seco-
proansamitocin to study the substrate specificity of the amide
synthase.
Retrosynthetic analysis of 1b led us to vinyl iodide 6 and
alkene 7, which are supposed to be connected by Pd(0)-
catalyzed cross-coupling, preferentially by the Heck reaction
(Scheme 2).
The potent antitumor activity of the maytansinoids stimu-
lated substantial synthetic work that from 1980 on led to
several total syntheses.11 Because of their complexity these
syntheses contributed little to our knowledge of the structure-
activity relationships; this was basically collected from
semisynthetic work starting with the natural products.2a,e
However, recent cloning and sequencing of the ansami-
tocin (asm) biosynthetic gene cluster from Actinosynnema
pretiosum by Floss and co-workers12 has paved the way for
the detailed analysis of ansamitocin biosynthesis at the
genetic and biochemical levels. This may provide a tool for
the chemoenzymatic synthesis of maytansine analogues
carrying backbone structural modifications that are not easily
accessible by chemical means. The biosynthesis involves the
assembly of the carbon framework on a type I modular
polyketide synthase13 from 3-amino-5-hydroxybenzoic acid
(AHBA)14 through chain extension by one “glycolate”, three
propionate, and three acetate units. The last PKS module
holds the seco-proansamitocin 1a, which is released and
Scheme 2 a
(6) Issell, B. F.; Crooke, S. T. Cancer Treat. ReV. 1978, 5, 199-207.
(7) (a) Remillard, S.; Rebhun, L. I.; Howie, G. A.; Kupchan, S. M.
Science 1975, 189, 1002-1005. (b) Mandelbaum-Shavit, F.; Wolpert-
DeFilippes, M. K.; Johns, D. G. Biochem. Biophys. Res. Commun. 1976,
72, 47-54. (c) Hamel, E. Pharm. Ther. 1992, 55, 31-51. (d) Ootsu, K.;
Kozai, Y.; Takeuchi, M.; Ikeyama, S.; Igarashi, K. Tsukamoto, K.; Sugino,
Y.; Tashiro, T.; Tsukagoshi, S.; Sakurai, Y. Cancer Res. 40 1980, 1707-
1717.
(8) (a) Thigpen, J. T.; Ehrlich, C. E.; Creasman, W. T.; Curry, S.;
Blessing, J. A. Am. J. Clin. Oncol. (CCT) 1985, 6, 273-275. (b) Thigpen,
J. T.; Ehrlich, C. E.; Conroy, J.; Blessing, J. A. Am. J. Clin. Oncol. (CCT)
1985, 6, 427-430. (c) Ravry, M. J.; Omura, G. A.; Birch, R. Am J. Clin.
Oncol. (CCT) 1985, 8, 148-150.
a PG ) protective group.
Fragment 6 originates from commercially available 3,5-
dihydroxybenzoic acid (8). Alkene 7 is further simplified to
aldehyde 9, which is disconnected to the three starting
building blocks 10-12.
This strategy has to make use of two asymmetric acetate
aldol reactions and requires an optimized protecting group
strategy, because a thioester moiety, a keto, a phenolic, and
an amino group have to be taken into consideration.
Furthermore, the target molecule is prone to conjugation of
the diene unit with the keto group, epimerization at C-10,
and â-elimination next to the thioester.
(9) Significant insecticidal activity of various maytansinoids, probably
due to a feeding deterrent effect was also encountered: Madrigal, R. V.;
Zilkowski, B. W.; Smith, C. R., Jr. J. Chem. Ecol. 1985, 11, 501-506 and
references therein.
(10) (a) Chari, R. V.; Martell, B. A.; Gross, J. L.; Cook, S. B.; Shah, S.
A.; Bla¨ttler, W. A.; McKenzie, S. J.; Goldmacher, V. S. Cancer Res. 1992,
52, 127-131. (b) Okamoto, K. Harada, K.; Ikeyama, S.; Iwasa, S. Jpn. J.
Cancer Res. 1992, 52, 761-768. (c) Liu, C.; Tadayoni, B. M.; Bourret, L.
A.; Mattocks, K. M.; Derr, S. M.; Widdison, W. C.; Kedersha, N. L.;
Ariniello, P. D.; Goldmacher, V. S.; Lambert, J. M.; Bla¨ttler, W. A.; Chari,
R. V. J. Proc. Nat. Acad. Sci. U.S.A. 1996, 93, 8618-8623.
(11) A recent review of the synthetic approaches is given in ref 5b.
(12) Yu, T.-W.; Bai, L.; Clade, D.; Hoffmann, D.; Toelzer, S.; Trinh,
K. Q.; Xu, J.; Moss, S. J.; Leistner, E.; Floss, H. G. Proc. Nat Acad. Sci.
U.S.A. 2002, 99, 7968-7973.
(13) (a) Hopwood, D. A. Chem. ReV. 1997, 97, 2465-2497. (b) Khosla,
C.; Gokhale, R. S.; Jacobsen, J. R.; Cane, D. E. Annu. ReV. Biochem. 1999,
68, 219-253. (c) Staunton, J.; Weisman, K. J. Nat. Prod. Rep. 2002, 18,
380-416 and references therein.
(14) Hatano, K.; Akiyama, S.-I.; Asai, M.; Rickards, R. W. J. Antibiot.
1982, 35, 1415-1417.
Thus, starting from benzoic acid 8, intermediate benzyl
bromide 13 was prepared by a set of standard reactions that
(15) Yu, T.-W.; Shen, Y.; Doi-Katayama, Y.; Tang, L.; Park, C.; Moore,
B. S.; Hutchinson, C. R.; Floss, H G. Proc. Natl. Acad. Sci. U.S.A. 1999,
96, 9051-9056.
(16) Stratmann, A.; Toupet, C.; Schilling, W.; Traber, R.; Oberer, L.;
Schupp, T. Microbiology 1999, 145, 3365-3375.
(17) Spiteller, P.; Bai, L.; Shang, G.; Carroll, B. J.; Yu, T.-W.; Floss, H.
G. J. Am. Chem. Soc. 2003, 125, 14236-14237.
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