Communications
previously reported lithium enolate of 15 with iodide 14 in
This study serves to underscore the potential applicability
of directed total synthesis, even in a multistep setting, in the
quest for new substances of material clinical benefit. The
current research environment tends to favor recourse to
massive numbers of compounds for screening, in preference
to smaller numbers of more carefully crafted, hypothesis-
driven candidate structures. However, there is much to be
learnt from natural products, and these warrant close and
continuing study.
THF, followed by removal of the silyl protecting group,
afforded 16 in 81% yield and with high diastereoselectivity
(d.r. > 25:1). Compound 16 was advanced in two steps to 17 as
shown.
With 11 and 17 in hand, the route to 5 was clear based on
chemistry first developed in our discovery phase.[16] The key
ring-closing metathesis reaction of 18 was carried out in
toluene in the presence of the second-generation Grubbs
catalyst (Scheme 3).[22–26] The reaction afforded the trans
Received: July 11, 2003 [Z52361]
Published Online: September 11, 2003
Please note: Minor changes have been made to this manuscript since
its publication in Angewandte Early View. The Editor.
Keywords: antitumor agents · conformation analysis ·
.
epothilones · natural products · structure–activity relationships
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Scheme 3. Final steps of the synthesis of 5. Reagents and conditions:
a) EDCI, DMAP, CH2Cl2, 11, 08C!RT, 86% based on 11; b) second-
generation Grubbs catalyst, toluene, 1108C, 20 min, 71%;
c) 1. KHMDS, 20, THF, ꢀ788C!ꢀ208C, 70%; 2. HF·pyridine, THF,
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chloride, DMAP=4-(dimethylamino)pyridine.
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isomer 19 exclusively in 71% yield. Installation of the thiazole
moiety, as shown in Scheme 3, was followed by removal of the
two silyl protecting groups with HF·pyridine to give 5.
Compound 5 was converted into 3 in high yield by reduction
of the C9–C10 double bond. Gram quantities of these
structurally novel epothilones have been prepared by total
synthesis in our laboratory.
At the moment there are no grounds on which to argue
that the strikingly superior performance of 5 arises from
factors other than the significantly improved pharmacokinetic
and bioavailability features that were designed into the
molecule through the medium of chemical synthesis. How-
ever, the possibility that the results reflect new (or enhanced)
drug–target interactions is the object of continuing study. New
areas of analogue synthesis are accessible through permuta-
tions of the late-stage olefination (e.g. 19 + 20) by the use of
other phosphonates. In this way, new design features that
result in enhanced pharmaceutical properties are being
explored further.
[11] For more information about clinical trials of dEpoB, visit:
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It is important to keep in mind that the ultimate purpose
of the chemotherapeutic arm of cancer research is to provide
clinically valuable treatment for patients with neoplastic
diseases. Only progression to clinical trials can establish the
value of any of the new epothilone agents with regard to this
central goal.
[21] R. Noyori, T. Ohkuma, M. Kitamura, H. Takaya, N. Sayo, H.
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