Studies toward a synthesis of epothilone A: Use of hydropyran templates for the management of acyclic stereochemical relationships

Full text of DOI:10.1021/jo961673w

7998
J . Org. Chem. 1996, 61, 7998-7999
two functional domains of the molecules. This achiral
“spacer element” actually complicates prospects for con-
tinuous chirality transfer and seems to call for a strategy
of merging two stereochemically committed substruc-
tures. Herein, we direct our attention to a synthesis of
compound 4, confident that, in principle, such a structure
could be converted to the epothilones themselves, and to
related screening candidates.
Stu d ies tow a r d a Syn th esis of Ep oth ilon e
A: Use of Hyd r op yr a n Tem p la tes for th e
Ma n a gem en t of Acyclic Ster eoch em ica l
Rela tion sh ip s
Dongfang Meng,†,‡ Erik J . Sorensen,†
Peter Bertinato,† and Samuel J . Danishefsky*,†,‡
Laboratory for Bioorganic Chemistry, Sloan-Kettering
Institute for Cancer Research, 1275 York Avenue,
New York, New York 10021, and Department of Chemistry,
Columbia University, Havemeyer Hall,
New York, New York 10027
Received August 30, 1996
Taxol has been approved for chemotherapeutic clinical
application against ovarian carcinomas. It is also un-
dergoing extensive evaluation for other indications.
While taxol is not a curative agent, it is already a useful
chemotherapeutic resource.1
The best indications arising from tissue culture and
in vitro experiments are that taxol functions by inhibition
of cellular mitosis through binding to and stabilization
of microtubule assemblies.2 Presumably, this property
is pertinent to the human patient.
Unfortunately, taxol is far from an ideal drug. Thus,
difficulties with respect to formulation and susceptibility
to multiple drug resistance (MDR) complicate its ap-
plicability.3 At the present writing, no major improve-
ments in drug performance have been realized from any
substantially modified analogs of taxol or its close rela-
tive, taxotere.4
The identification of compound 4 as a synthetic inter-
mediate provided an opportunity to illustrate the power
of hydropyran matrices in addressing problems associ-
ated with the control of stereochemistry in acyclic
intermediates. Some years ago, we described the syn-
thesis of dihydropyrones through what amounts to overall
cyclocondensation of suitably active dienes and aldehydic
heterodienophiles.7
New agents that function by microtubule stabilization
are clearly of great interest.2 In this connection, there
has already been considerable attention directed toward
the bacterial-derived metabolites epothilone A (2) and B
(3), which were first identified as antifungal cytotoxic
agents by Ho¨efle et al.5a,b and subsequently encountered
by a group based at the Merck corporation.6 The report
of the Merck scientists on the epothilones indicated that
they are powerful cytotoxic agents that seem to function
through stabilization of microtubules by binding to taxol-
binding domains. Given the possibilities that these
agents themselves, or appropriately modified derivatives,
might function as alternatives to taxol, attention from
the standpoint of organic synthesis is warranted.
Augmenting the biological rationale for such a venture
are the chemical incentives associated with several novel
structural features of the epothilones. Thus, the presence
of a thiazole moiety, as well as a cis epoxide and geminal
dimethyl groups are among the issues to be addressed.
Not the least intriguing feature is the array of three
contiguous methylene groups that serves to insulate the
High margins of stereoselectivity can be realized in
assembling such matrices (cf. 5 + 6 f 7). Moreover, the
hydropyran platforms service various stereoselective
reactions (see formalism 7 f 8). Furthermore, the
products of these reactions are amenable to ring-opening
schemes, resulting in the expression of acyclic fragments
with defined stereochemical relationships (cf. 8 f 9).8
We describe the application of two such routes for the
synthesis of compound 4. Route 1, which does not per se
involve control over the issue of absolute configuration,
commences with the known aldehyde 10.9 Homologation,
as shown, provided enal 12. Cyclocondensation of 12
with the known diene,10 under BF3 catalysis, led to
racemic dihydropyrone 13. Luche reduction11 of 13
provided compound 14. At this point we were well
positioned to take advantage of our previously introduced
lipase methodology for resolution of glycal derivatives
through enzymatically mediated kinetic resolution.12
Thus, carbinol 14 was treated with lipase 30 and isopro-
penyl acetate (following the prescriptions of Wong),13 and
† Sloan-Kettering Institute for Cancer Research.
‡ Columbia University.
(1) Georg, G. I.; Chen, T. T.; Ojima, I.; Vyas, D. M. Taxane Anticancer
Agents; American Cancer Society: San Diego, 1995.
(2) Schiff, P. B.; Fant, J .; Horwitz, S. B. Nature (London) 1979, 277,
665.
(3) Landino, L. M.; Macdonald, T. L. In The Chemistry and Phar-
macology of Taxol® and its Derivatives; Farin, V., Ed.; Elsevier: New
York, 1995; Chapter 7, p 301.
(4) Gueritte-Voegelein, F.; Guenard, D.; Dubois, J .; Wahl, A.;
Marder, R.; Muller, R.; Lund, M.; Bricard, L.; Potier, P. In Taxane
Anticancer Agents; Georg, G. I., Chen, T. T., Ojima, I., Vyas, D. M.,
Eds.; American Cancer Society: San Diego, 1995; Chapter 14, p 189.
(5) (a) Gerth, K.; Bedorf, N.; Ho¨fle, G.; Irschik, H.; Reichenbach, H.
J . Antibiot. 1996, 49, 560. (b) Ho¨fle, G.; Bedorf, N.; Steinmetz, H.;
Schomburg, D.; Gerth, K.; Reichenbach, H. Angew. Chem., Int. Ed.
Engl. 1996, 35, 1567.
(7) Danishefsky, S. J . Aldrichim. Acta 1986, 19, 59.
(8) Danishefsky, S. J . Chemtracts 1989, 2, 273.
(9) (a) Shafiee, A.; Mazloumi, A.; Cohen, V. I. J . Heterocycl. Chem.
1979, 16, 1563. (b) Schafiee, A.; Shahocini, S. J . Heterocycl. Chem.
1989, 26, 1627.
(6) Bollag, D. M.; McQueney, P. A. Zhu, J .; Hensens, O.; Koupal,
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S0022-3263(96)01673-8 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 23, 1996 7999
the reaction was stopped after ca. 48% conversion,
providing acetate 15 in addition to the enantiomerically
related free glycal 16. Compound 15 was further ad-
vanced to the p-methoxybenzyl (PMB)-protected system
17. At this juncture, reaction of 17 with dimethyldiox-
irane14 generated an intermediate (presumably the cor-
responding glycal epoxide) that, upon treatment with
sodium metaperiodate, gave rise to aldehyde formate 18.
Lewis acid-promoted allylation of 18 afforded carbinol 19
in which the formate ester had nicely survived. Unfor-
tunately, 19 was accompanied by its anti stereoisomer
(not shown here) (4:1). Although this 4:1 mixture of
diastereomers was obtained in an excellent yield of 98%,
it was not possible to obtain the desired stereoisomer 19
in pure form at this stage. Mesylation of the secondary
alcohol, followed by deprotection (see 19 f 20) and
cyclization, as indicated, gave compound 4, a substance
that could be separated from the stereoisomeric trans
epoxide.
Needless to say, in this synthesis, only ca. half of the
dihydropyrone was secured through the process of kinetic
resolution. While, in theory, several of our synthetic
strategems contemplate the possible use of each enanti-
omer of 15 to reach epothilone itself, we sought to
implement another route to allow for full enantiomeric
convergence. The logic of this route is that the chirality
of a “dummy” stereogenic center is communicated to the
emerging pyran following previously established prin-
ciples of tunable diastereoselection in the cycloconden-
sation reaction.7,8 We proceeded as follows. Cyclocon-
densation of lactaldehyde derivative 2115 with the
indicated diene, under ostensible chelation control, af-
forded 22. The side chain ether could then be converted
to the methyl ketone 25 as shown (see 22 f 23 f 24 f
25). Finally, an Emmons condensation of 25 with the
phosphine oxide 2616 as shown in Scheme 4 afforded
compound 27 as a single geometrical isomer. A straight-
forward protecting group adjustment then afforded the
previously encountered 17. This route cogently illus-
trates the concept of stereochemical imprinting through
a carbon center that eventually emerges in planar form
after conferring enantioselection to subsequently derived
stereocenters. The use of the dihydropyrone-based logic
for securing the stereochemical elements of the epothi-
lones, as well as the identification of a possible strategy
for macrocyclization will be described in the paper that
follows.
Ack n ow led gm en t. This work was supported by
NIH Grant No. CA 28824. Postdoctoral Fellowships are
gratefully acknowledged by E.J .S. (NSF, CHE-9504805)
and P.B. (NIH, CA 62948).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectroscopic data for the compounds illustrated
in the reactions (compounds 12-15, 17-20, 4, and 22-27) (9
pages).
J O961673W
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