Remote effects in macrolide formation through ring-forming olefin metathesis: An application to the synthesis of fully active epothilone congeners

Full text of DOI:10.1021/ja964275j

J. Am. Chem. Soc. 1997, 119, 2733-2734
2733
Communications to the Editor
Scheme 1
Remote Effects in Macrolide Formation through
Ring-Forming Olefin Metathesis: An Application to
the Synthesis of Fully Active Epothilone Congeners
Dongfang Meng,†,‡ Dai-Shi Su,† Aaron Balog,†
Peter Bertinato,† Erik J. Sorensen,†
Samuel J. Danishefsky,*,†,‡ Yu-Huang Zheng,§
Ting-Chao Chou,§ Lifeng He,| and Susan B. Horwitz|
Laboratories for Bioorganic Chemistry
and Biochemical Pharmacology
Sloan-Kettering Institute for Cancer Research
1275 York AVenue, New York, New York 10021
Department of Molecular Pharmacology
The Albert Einstein College of Medicine
Bronx, New York 10461
Scheme 2a
ReceiVed December 12, 1996
Recently, we achieved the first synthesis of epothilone A
(structure 1).1 Aside from numerous chemical issues which
must be addressed in accomplishing such a synthesis, interest
in the epothilone class of compounds is further heightened by
claims (thus far based solely on in Vitro measurements) that
the epothilones may constitute a useful group of anticancer
agents, operating through the same mechanism of action as
paclitaxel.2 It has further been suggested, again on the basis
of in Vitro data, that the epothilones offer advantages relative
to paclitaxel in terms of ease of formulation and potency toward
drug resistant cell lines.
In our synthesis of epothilone A (1), we passed through the
desoxycompound 2Z. We showed, for the first time, that the
action of dimethyldioxirane on compound 2Z results in a highly
diastereoselective epoxidation, providing compound 1. The
strategy we employed to construct compound 2Z provided strict
control over the geometry of the C12-C13 double bond through
a B-alkyl Suzuki coupling reaction of cis vinyl iodide 3 with
an appropriate borane (Scheme 1).
The studies described herein focused on a different method
for the construction of desoxyepothilone A (2Z). In particular,
we investigated the possibility of a ring-forming olefin metath-
esis reaction to construct the C12-C13 bond.3 We were
particularly mindful of a precedent furnished by Hoveyda et
al.3b It was hoped that such an assembly strategy involving
components of the type 6 and 8 might lead to an even more
direct route to the natural series and analogs thereof. These
studies became of particular interest when it was found,
surprisingly, that desoxyepothilone A (2Z) has the full biological
actiVity of epothilone A as manifested through independent
inVestigations at the leVel of cytotoxicity and polymerization of
a Key: (a) (i) 3-butenylmagnesium bromide, Et2O, -78 to 0 °C
(92%); (ii) thiocarbonyldiimidazole, DMAP, 95 °C; (iii) Bu3SnH, AlBN,
C6H6, 80 °C (83% for two steps); (iv) (CF3CO2)2IC6H5, MeOH, THF;
(v) pTSA, dioxane, H2O, 50 °C (85% for two steps).
stable microtubules in the absence of GTP. Herein we describe
a straightforward route to reach substrates needed for olefin
metathesis. We also disclose the results of these cyclizations
which indicate a remarkable sensitivity to permutations of
functionality and stereochemistry at centers far removed from
the site of olefin metathesis. Finally, we describe some early
but exciting SAR results which indicate that significant structural
variances can be introduced in this series with maintenance of
full biological function.
Our new strategy commences with aldehyde 4, a substance
available in multigram quantities.1b,c An important technological
advance in the area was registered when it was found that
subjection of aldehyde 4 to the catalytic asymmetric allylation
protocol previously described by Keck leads to 5 in >95%
enantiomeric excess (Scheme 2).4 As an aside, we note that 5
was converted in two steps to the previously mentioned vinyl
iodide 3, thereby effecting a major economy in the earlier
synthesis. For purposes to be described, compound 5 was
simply converted to the ester 6. The pre-acyl construct 8 was
assembled from the dithiane aldehyde 71a,b in the manner
indicated in Scheme 2. We thus had in hand the two subunits
required to study ring forming olefin metathesis en route to the
C12-C13 bond.
† Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for
Cancer Research.
‡ Department of Chemistry, Columbia University, Havemeyer Hall, New
York, NY 10027.
§ Laboratory for Biochemical Pharmacology, Sloan-Kettering Institute
for Cancer Research.
| The Albert Einstein College of Medicine.
(1) (a) Balog, A.; Meng, D.; Kamenecka, T.; Bertinato, P.; Su, D.-S.;
Sorensen, E. J.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 1996, 35,
2801. (b) Meng, D.; Sorensen, E. J.; Bertinato, P.; Danishefsky, S. J. J.
Org. Chem. 1996, 61, 7998. (c) Bertinato, P.; Sorensen, E. J.; Meng, D.;
Danishefsky, S. J. J. Org. Chem. 1996, 61, 8000.
The compounds 6 and 8 were joined through a simple
intermolecular aldol addition. That this reaction produced an
approximately 1:1 mixture of the epimers 9 and 10 was per se
(2) See: Ho¨fle, G.; Bedorf, N.; Steinmetz, H.; Schomberg, D.; Gerth,
K.; Reichenbach, H. Angew. Chem., Int. Ed. Engl. 1996, 35, 1567 and
references therein.
(3) (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28,
446. (b) Houri, A. F.; Xu, Z.; Cogan, D. A.; Hoveyda, A. H. J. Am. Chem.
Soc. 1995, 117, 2943.
(4) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993,
115, 8467.
S0002-7863(96)04275-8 CCC: $14.00 © 1997 American Chemical Society

2734 J. Am. Chem. Soc., Vol. 119, No. 11, 1997
Communications to the Editor
Scheme 3
Scheme 4a
of no consequence, since the latter could be converted to the
former through an oxidation/reduction sequence (i.e., 10 f 11
f 9) (Scheme 3). Indeed, much was learned chemically and
biologically from having both the 3S (cf. 9) and 3R (cf. 10)
series available to us. From the core compounds 9 and 10, we
could easily fashion substrates 12-14. We were then in a
position to study the ring-forming olefin methathesis (ROM)
reaction (Scheme 4).
Cyclization reactions were conducted under the conditions
shown in Scheme 4 for compounds 9, 10, and 12-14. As seen,
we could readily obtain products containing the E C12-C13
double bond (see formation of 19E,Z). However, at this writing
the highest ratio for the Z product is only 1.7:1 (see formation
of 18E,Z). We note that, with all protecting groups identical,
the proportion of E product increases upon changing from the
3S to 3R series (see formation of 19E,Z and 20E,Z). Similarly,
keeping C-3 and C-7 constant but permutating C-5 (see ROM
substrates 13 and 14) affords more of the Z olefin product (see
formation of 18E,Z and 2E,Z).
a Key: (a) RuBnCl2(PCy3)2 (50 mol %), C6H6, 0.001 M, rt, 24 h;
(b) TESCl, imidazole, DMF, (80%); (c) pyridine hydrofluoride, THF,
rt; (d) (i) pyridine hydrofluoride, pyridine, THF, rt, (93%); (ii) TBSOTf,
2,6-lutidine, -35 °C, (95%); (iii) Dess-Martin periodinane, (87%)
(TBS ) tert-butyldimethylsilyl; TPS ) triphenylsilyl; TES ) trieth-
ylsilyl).
In summary, a route to (E)- and (Z)-desoxyepothilones using
ROM technology has been accomplished. Through this and
related methodology to be described soon, highly biologically
active congeners have been obtained, and a total synthesis driven
mapping of the SAR of epothilones is well underway.
Acknowledgment. This research was supported by the National
Institutes of Health (grant numbers CA-28824 (S.J.D.) CA-39821
(S.B.H.)). Postdoctoral fellowship support is gratefully acknowledged
by E.J.S. (NSF, CHE-9504805), A.B. (NIH, CA-GM 72231), P.B. (NIH,
CA 62948). We gratefully acknowledge Dr. George Sukenick (NMR
Core Facility, Sloan-Kettering Institute) for NMR and mass spectral
analyses.
Using this chemistry, we could easily access the fully
deprotected cis-desoxyepothilone A (2Z). Of course, this work
constitutes a second synthesis of 2Z and a formal total synthesis
of 1.5 It is noteworthy that the concise route to enantiomerically
pure vinyl iodide 3 (see Scheme 2) renders our initial approach
to 2Z more practical. Nevertheless, the ROM chemistry
described herein provides an eminently more workable route
to trans-desoxyepothilone A (2E). Remarkably, compound (2E)
is fully actiVe as measured by cytotoxicity and microtubule
assays. Perhaps equally surprising, biological actiVity is
abrogated in the 3R compounds 21Z and 3-epi-epothilone A
(3-epi-1).6
Supporting Information Available: Preparation of substrates for
olefin methathesis (9, 10 and 12-15) and compounds 21Z and 3-epi-
epothilone A and relevant biological data (IC50 values) as well as all
relevant spectral data for compounds 2-21 (43 pages). See any current
masthead page for ordering and Internet access instructions.
JA964275J
(5) It has been brought to our attention through the popular media that
another total synthesis of epothilone A has been subsequently completed
utilizing ring-closing olefin metathesis. Nicolaou, K. C.; et al. Angew.
Chem., Int. Ed. Engl. 1997, 37, 166.
(6) The compound 3-epi-epothilone A was produced by treatment of
3-epi-desoxyepothlone A (21Z) with dimethyldioxirane at -35 °C.