Improved synthesis of epothilone B employing alkylation of an alkyne for assembly of subunits

Article abstract of DOI:10.1021/ol990248x

(formula presented) A strategy for assembling the two principal modules of epothilone B was developed that merges an allylic bromide with a terminal acetylene to fabricate the C10-C11 bond of the macrocycle. The resulting alkyne was semihydrogenated to gi

Full text of DOI:10.1021/ol990248x

ORGANIC
LETTERS
1999
Vol. 1, No. 9
1431-1434
Improved Synthesis of Epothilone B
Employing Alkylation of an Alkyne for
Assembly of Subunits
James D. White,* Kurt F. Sundermann, and Rich G. Carter
Department of Chemistry, Oregon State UniVersity, CorVallis, Oregon 97331-4003
james.white@orst.edu
Received August 23, 1999
ABSTRACT
A strategy for assembling the two principal modules of epothilone B was developed that merges an allylic bromide with a terminal acetylene
to fabricate the C10−C11 bond of the macrocycle. The resulting alkyne was semihydrogenated to give a seco ester previously employed in
our total synthesis of epothilone B. This new approach affords a more efficient route to the naturally occurring macrolide and to its 9,10-
dehydro analogue.
The extraordinary interest in the macrolides epothilone A
(1) and B (2) reflects a growing awareness that these
fermentation metabolites share a distinctive mechanism of
cytotoxic activity with paclitaxel (Taxol), discodermolide,
and eleutherobin whereby cell division is prevented by
inhibition of microtubule disassembly.1 Alongside ongoing
investigations into the pivotal intracellular events triggered
by epothilones2 have been very active synthetic efforts by
several groups, notably those of Danishefsky3 and Nicolaou.4
These studies have resulted in total syntheses of 1 and 2, as
well as a large ensemble of analogues. In addition, syntheses
of 2 have been described by Schinzer,5 Grieco,6 Mulzer,7
and ourselves.8
(1) (a) Bollag, D. M.; McQuency, P. A.; Zhu, J.; Hensens, O.; Koupal,
L.; Liesch, J.; Goetz, M.; Lazarides, E.; Woods, C. M. Cancer Res. 1995,
55, 2325. (b) Ho¨fle, G.; Bedorf, N.; Steinmetz, H.; Schomburg, D.; Gerth,
K.; Reichenbach, H. Angew. Chem. 1996, 108, 1671; Angew. Chem., Int.
Ed. Engl. 1996, 35, 1567. (c) Gerth, K.; Bedorf, N.; Ho¨fle, G.; Irschik, H.;
Reichenbach, H. J. Antibiot. 1996, 49, 560.
(2) (a) Bollag, D. Exp. Opin. InVest. Drugs 1997, 6, 867. (b) Su, D.-S.;
Balog, A.; Meng, D.; Bertinato, P.; Danishefsky, S. J.; Zheng, Y.-H.; Chou,
T.-C.; He, L.; Horwitz, S. Angew. Chem. 1997, 109, 2178; Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2093.
(3) (a) Balog, A.; Meng, D.; Kamenecka, T.; Bertinato, P.; Su, D.-S.;
Sorensen, E. J.; Danishefsky, S. J.; Angew. Chem. 1996, 108, 2976; Angew.
Chem., Int. Ed. Engl. 1996, 35, 2801. (b) Su, D.-S.; Meng, D.; Bertinato,
P.; Balog, A.; Sorensen, E. J.; Danishefsky, S. J.; Zheng, Y.-H.; Chou, T.-
C.; He, L.; Horwitz, S. B. Angew. Chem. 1997, 109, 775; Angew. Chem.,
Int. Ed. Engl. 1997, 36, 757. (c) Meng, D.; Bertinato, P.; Balog, A.; Su,
D.-S.; Komenecka, T.; Sorensen, E. J.; Danishefsky, S. J. J. Am. Chem.
Our initial synthesis of 2 proceeded via (9Z)-dehydro-12,-
13-deoxyepothilone B (3) with the goal of exploring
Soc. 1997, 119, 10073. (d) Balog, A.; Harris, C.; Savin, K.; Zhang, X.-G.;
Chou, T.-C.; Danishefsky, S. J. Angew. Chem. 1998, 110, 2821; Angew.
Chem., Int. Ed. Engl. 1998, 37, 2675. (e) Harris, C. R.; Kuduk, S. D.; Savin,
K.; Balog, A.; Danishefsky, S. J. Tetrahedron Lett. 1999, 40, 2263.
10.1021/ol990248x CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/07/1999

structural variants in the C9-C11 region of the macrocycle
for analogue purposes. On the assumption that this domain
is not intimately associated with the pharmacophore of the
epothilones,9 our expectation is that 3 should retain good
biological activity.10 On the other hand, introduction of a
double bond at ∆9,10 distorts the macrocycle in a way that
no longer permits overlay of the C9-C11 section of 3 with
that of 2. In particular, the introduction of C9-C10 unsat-
uration changes the antiperiplanar arrangement around these
atoms in 2 to a syn coplanar alignment in 3. The interplay
of ring conformation with functional appendages offers a
new avenue for probing structure-activity relationships in
the epothilones that suggest new lines for analogue develop-
ment.
by a p-methoxybenzyl ether for directing the Z enolate of
an ethyl ketone to the re face of an R-methyl aldehyde.
Phosphonium bromide 4 was obtained through homologation
of allylic bromide 7, prepared by a sequence in which both
E-trisubstituted alkene units were introduced with complete
stereoselectivity. Although Wittig coupling of 4 and 5
proceeded efficiently on a >1 mmol scale, this reaction
proved difficult to effect on smaller quantities of reactants.
Consequently, we sought an alternative means for fusing the
available subunits into 6. This led to a plan in which a
connection was to be forged between 7 or the corresponding
alcohol 8 (via its mesylate) and a terminal alkyne represent-
ing the C1-C10 portion of 3. A potential consequence of
this approach was a new series of epothilone analogues
embodying a CtC unit across C9-C10.
Our previous strategy for assembling the requisite precur-
sor to 3 invoked a Wittig olefination that merged the two
components 4 and 5 into the seco ester 6 (Scheme 1). The
Scheme 1
Aldehyde 5 was reacted with the anion of dimethyl
diazophosphonate11 to give alkyne 9 in good yield. Coupling
of the copper(I) derivative of 9 with either bromide 7 or the
mesylate of 8 required extensive experimentation (Table 1)
Table 1. Coupling of 9 with 7 and 8
equiv coupling
yield of
10 (%)a
of 9
partner
reagents/conditions
1.1
1.1
1.1
1.1
7
7
7
8
5% CuI, TBAB, K2CO3, DMFb
20% CuI, Aliquot 336, K2CO3, DMF
50% CuI, pyrrolidine, DMF
(a) Ms2O, Et3N, DMF
8
11
0c
(b) 10% CuI, Na2CO3, TBAB, DMF
(a) Ms2O, Et3N, CH2Cl2
(b) 20% CuI, Na2CO3, TBAB, DMF
5% CuI, Et3N, Et2O-DMF
5% CuI, Et3N, Et2O-DMF
34
aldehyde 5 was prepared by a double stereodifferentiating
anti-Felkin aldol condensation that hinged upon chelation
1.1
8
42
24
60
1.1
2.0
7
7
(4) (a) Yang, Z.; He, Y.; Vourloumis, D.; Vallberg, H.; Nicolaou, K. C.
Angew. Chem. 1997, 109, 170; Angew. Chem., Int. Ed. Engl. 1997, 36,
166. (b) Nicolaou, K. C.; Sarabia, F.; Ninkovic, S.; Yang, Z. Angew. Chem.
1997, 109, 539; Angew. Chem., Int. Ed. Engl. 1997, 36, 525. (c) Nicolaou,
K. C.; Winssinger, N.; Pastor, J. A.; Ninkovic, S.; Sarabia, F.; He, Y.;
Vourloumis, D.; Yang, Z.; Li, T.; Giannakakou, P.; Hamel, E. Nature 1997,
387, 268. (d) Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, F.;
Roschangar, F.; Sarabia, F.; Ninkovic, S.; Yang, Z.; Trujillo, J. I. J. Am.
Chem. Soc. 1997, 119, 7960. (e) Nicolaou, K. C.; Ninkovic, S.; Sarabia,
F.; Vourloumis, D.; He, Y.; Vallberg, H.; Finlay, M. R. V.; Yang, Z. J.
Am. Chem. Soc. 1997, 119, 7974. (f) Nicolaou, K. C.; He, Y.; Vourloumis,
D.; Vallberg, H. Yang, Z. Angew. Chem. 1996, 108, 2554, Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2399. (g) Nicolaou, K. C.; Hepworth, D.; Finley,
M. R. V.; King, N. P.; Werschkun, B.; Bigot, A. Chem. Commun. 1999,
519.
a Based on 7 or 8. b Jeffery, T. Tetrahedron Lett. 1989, 30, 2225.
c Product was exclusively 11.
but was found to give dienyne 10 in good yield when a
mixture of ether and DMF was employed as solvent.
However, even under rigorously anhydrous and anaerobic
conditions, small amounts of the diyne 11 resulting from
Glaser coupling12 of 9 were detected. Our goal with 10 was
(5) (a) Schinzer, D.; Limberg, A.; Bauer, A.; Bo¨hm, O. M.; Cordes, M.
Angew. Chem. 1997, 109, 543; Angew. Chem., Int. Ed. Engl. 1997, 36,
523. (b) Schinzer, D.; Bauer, A.; Schieber, J. Synlett 1998, 861.
(6) May, S. A.; Grieco, P. Chem. Commun. 1998, 1597.
(7) Mulzer, J.; Mantoulidis, A.; O¨ hler, E. Tetrahedron Lett. 1998, 39,
8633.
(8) White, J. D.; Carter, R. G.; Sundermann, K. F. J. Org. Chem. 1999,
64, 684.
(9) Ojima, I.; Chakravarty, S.; Inoue, T.; Lin, S.; He, L.; Horwitz, S. B.;
Kuduk, S. D.; Danishefsky, S. J. Proc. Natl. Acad. Sci. U.S.A. 1999, 96,
4256.
to continue the synthesis with this alkyne in the form of its
cobalt complex 12, in the hope that the alkyne could be
1432
Org. Lett., Vol. 1, No. 9, 1999

unmasked after macrocyclization. Unfortunately, although
12 was easily prepared by treatment of 10 with dicobaltoc-
tacarbonyl, attempts to saponify the methyl ester of 12 led
to complex mixtures (Scheme 2).
Scheme 3
Scheme 2
resultant triene 6, after saponification, gave the corresponding
carboxylic acid, which underwent clean deprotection of the
C15 TBS ether to yield seco acid 19.14 Macrolactonization
under Yamaguchi conditions15 followed by removal of the
remaining pair of TBS ethers furnished 3 (Scheme 4). The
Scheme 4
In an effort to circumvent this problem, the terminal ester
of 9 was replaced by an aldehyde in the guise of acetal 13.
The latter was synthesized by oxidative cleavage of alkene
14 followed by protection of aldehyde 15 as its ethylene
acetal. After hydrogenolysis of 16, the resultant alcohol 17
was oxidized to 18 which was reacted with dimethyl
diazophosphonate11 to afford 13 (Scheme 3). Disappointingly,
13 yielded no coupled product with bromide 7 under
conditions that had been successful with 9.
Finally, to bring this sequence into convergence with our
previously published pathway to 2,8 alkyne 10 was semihy-
drogenated over Lindlar catalyst. An important requirement
for success in this reaction was that it be carried out in
hexane.13 Other solvents gave little or no reaction. The
(10) The results of bioassay studies with 3 will be disclosed indepen-
dently.
(11) Gilbert, J. C.; Weerasooriya, V. J. Org. Chem. 1982, 47, 1837.
(12) Eglinton, G.; McCrae, W. In AdVances in Organic Chemistry,
Methods and Results; Raphael, R. A., Taylor, E. C., Wynberg, H., Eds.;
Interscience: New York, 1963; Vol. 4, p 225.
(13) The importance of a hydrocarbon solvent for acetylene semihydro-
genation was pointed out by Lindlar himself, see: Freifelder, M. Practical
Catalytic Hydrogenation, Techniques and Applications; Wiley-Inter-
science: New York, 1971; p 99.
latter has previously been reduced with diimide to yield 12,-
13-deoxyepothilone B,8 and epoxidation of this material with
(14) Selectivity is attributed to a sterically favorable transilylation
involving the carboxylate anion; the resultant silyl ester is hydrolyzed during
aqueous workup.
(15) Inanaga, J.; Kirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
Org. Lett., Vol. 1, No. 9, 1999
1433

dimethyldioxirane as described by Danishefsky3b afforded
2.
Supporting Information Available: Experimental pro-
cedures for the preparation of 8, 9, and 6. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We are grateful to the National
Institutes of Health (GM50574) for financial support. R.G.C.
was the recipient of a National Institutes of Health Postdoc-
toral Fellowship (F32CA76743).
OL990248X
1434
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