Total synthesis of (-)-discodermolide: An application of a chelation- controlled alkylation reaction

Full text of DOI:10.1021/jo9708093

6098
J . Org. Chem. 1997, 62, 6098-6099
Tota l Syn th esis of (-)-Discod er m olid e: An
Ap p lica tion of a Ch ela tion -Con tr olled
Alk yla tion Rea ction
Scott S. Harried, Ge Yang, Marcus A. Strawn,1 and
David C. Myles*
Department of Chemistry and Biochemistry, UCLA, Los
Angeles, California 90095-1569
Received May 9, 1997
The polyhydroxylated lactone (+)-discodermolide (ent-
1) is a potent microtubule-stabilizing agent with antitu-
mor activity similar to that of taxol. In this communi-
cation, we describe the total synthesis of (-)-disco-
dermolide (1) using chelation-controlled alkylation reac-
tion as the key coupling. Like taxol,2 ent-1 arrests the
cell cycle at the G2/M boundary and promotes the
formation of microtubules.3 In addition to our own
work4,5 several partial syntheses of discodermolide have
appeared.6 Total syntheses of discodermolide have been
described by Schreiber and co-workers7 and Smith and
co-workers.8
We adopted a highly convergent strategy to 1, discon-
necting the C-7/8 and C-15/16 bonds to give three key
subunits, structures 2-4 (Figure 1). The key coupling
reaction (C-15/16) was envisioned to occur via a diaste-
reoselective alkylation reaction between the anion of
ethyl ketone 4 and allylic iodide 3. A metal-promoted
coupling of a C-8 Z-vinyl iodide with a C-7 aldehyde was
expected to complete the carbon backbone of 1.
Chelation of the â′-alkoxy moiety in enolate 5 (Figure
2) fixes the enolate in a rotational isomer that displays
the R′-methyl group in a position that blocks one face of
the enolate. In their synthetic efforts directed toward
discodermolide, both Schreiber and co-workers7 and
Heathcock and co-workers6b examined the formation of
the C-15 to C-16 bond by way of alkylation. They found
that for their substrates where P′ was p-methoxybenzyl,
the alkylation of ethyl ketones analogous to ketone 4 gave
the stereochemistry opposite to that required for disco-
dermolide. Both groups overcame this obstacle via a two-
step alkylation protocol. Based on our own work4 and
these results, the diastereoselectivity of this type of
alkylation is dependent on a number of factors including
temperature, solvent, counterion, and protecting group
P′ at the â′ position of the ketone.
F igu r e 1.
F igu r e 2.
methylpropionate. We took advantage of the chelating
ability of the methoxymethyl protecting group in the key
alkylative coupling to form the C-15 to C-16 bond and in
the chelation-controlled reduction of the C-17 ketone and
to facilitate introduction of the C-19 carbamate late in
the synthesis.
We found that treatment of 7 with lithium hexameth-
yldisilazide and 1 equiv of tetramethylethylenediamine
in THF at -78 °C followed by addition of allylic iodide 8
led to smooth chelation-controlled alkylation. The dias-
tereoselectivity of this reaction shows a remarkable
solvent dependence, affording the desired diastereomer
as the major component of a 6:1 mixture, in 70%, using
the mixed solvent system 45:55 hexanes:THF. Our
assignment of the structure of the major diastereomer
was strengthened by the reversal of selectivity (1:18)
when using the nonchelating Na+ counterion during the
alkylation. We later established the validity of this
assignment via the total synthesis. Using chelation-
controlled reduction of ketone 9 with LAH and lithium
iodide in ether at -78 °C, we established the C-17 alcohol
stereochemistry with >8:1 diastereoselectivity. Silylation
of the secondary alcohol (Tips-OTf, TEA) followed by
selective hydrogenolysis of the C-9 benzyl ether9 (Ra/Ni,
H2) then afforded C-9 to C-21 synthon 10 in 71% yield
and facilitated separation of all minor diastereomers from
10.
After extensive investigation into alternative strate-
gies, we found that the Nozaki-Kishi coupling10 of a C-8
Z-vinyl iodide to aldehyde 13 had emerged as the best
option. To prepare the required vinyl iodide, we oxidized
the C-9 alcohol (10) using tetrapropylammonium perru-
thenate (TPAP) in 10% acetonitrile in CH2Cl2.11 We
immediately treated this material with iodomethylene-
triphenylphosphorane12 to obtain the vinyl iodide in 85%
yield with ca. 20:1 Z:E selectivity. Oxidative cleavage
The partners in the chelation-controlled alkylation
used for the synthesis of discodermolide were ethyl
ketone 7 and allylic iodide 8 (Figure 3). We have
previously described syntheses of both 74 and 85 via short
sequences starting from methyl (S)-(+)-3-hydroxy-2-
(1) Pfizer Undergraduate Summer Research Fellow, 1994.
(2) Schiff, P. B.; Frant, J .; Horwitz, S. B. Nature 1979, 665.
(3) ter Harr, E.; Kowalski, R. J .; Hamel, E.; Lin, C. M.; Longley, R.
E.; Gunasekera, S. P.; Rosenkranz, H. S.; and Day, B. W. Biochemistry
1996, 35, 243 and references therein.
(4) Yang, G.; Myles, D. C. Tetrahedron Lett. 1994, 35, 1313.
(5) Yang, G.; Myles, D. C. Tetrahedron Lett. 1994, 35, 2503.
(6) (a) Paterson, I.; Wren, S. P. J . Chem. Soc., Chem. Commun. 1993,
1790. (b) Clark, D. L.; Heathcock, C. H. J . Org. Chem. 1993, 58, 5878.
(c) Golec, J . M. C.; J ones, S. D. Tetrahedron Lett. 1993, 34, 8159. (d)
Evans, P. L.; Golec, J . M. C.; Gillespie, R. J . Tetrahedron Lett., 1993,
34, 8163. (e) Golec, J . M. C.; Gillespie, R. J . Tetrahedron Lett. 1993,
34, 8167. (f) Paterson, I.; Schlapbach, A. Synlett. 1995, 5, 498.
(7) (a) Nerenberg, J . B.; Hung, D. T.; Somers, P. K.; Schreiber, S. L
J . Am. Chem. Soc. 1993, 115, 12621. (b) Hung, D. T.; Nerenberg, J .
B.; Schreiber, S. L J . Am. Chem. Soc. 1996, 118, 11054.
(8) Smith, A. B.; Qui, Y.; J ones, D. R.; Kobayashi, K. J . Am. Chem.
Soc. 1995, 117, 12011.
(9) Selective reductive debenzylation at C-9 was achieved using
Raney nickel and hydrogen in ethanol. Reductive cleavage of the C-21
PMB ether was minimized under these conditions. No reduction of the
trisubstituted double bond was observed.
(10) J in, H.; Uenishi, J .-I.; Christ, W. J .; Kishi, Y. J . Am. Chem.
Soc. 1986, 108. 5644. (b) Takai, K.; Tagashira, M.; Kuroda, T.; Oshima,
K.; Utimoto, Nozaki, H. J . Am. Chem. Soc. 1986, 108, 6048.
(11) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 50, 639.
(12) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173.
S0022-3263(97)00809-8 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 18, 1997 6099
F igu r e 3.
of the C-21 PMB ether using DDQ proceeded smoothly
(87%) to afford alcohol 11. After TPAP oxidation of
alcohol 11 (85%), we prepared the Z-diene via a modified
Peterson olefination13 to obtain the desired alkene in
>20:1 Z:E selectivity in 70% from 11. After extensive
experimentation, we found that 1 equiv of catecholbora-
nyl chloride and 0.5 equiv of H2O in CH2Cl2 led to
hydrolysis of the methoxymethyl ether and furnished the
desired C-21 alcohol in 60% yield. We prepared carbam-
ate 12 in 80% by treatment of the alcohol with trichlo-
roacetyl isocyanate.14 The transition metal (1% NiCl2 in
CrCl2, DMSO, 5 d) promoted addition of the vinyl iodide
of 12 to aldehyde 1315 proceeded to afford the C-1 to C-24
fragment 14 of discodermolide in 40% yield as a mixture
of C-7 epimers with starting materials 12 and 13
recovered in ca. 30% and 30% yield, respectively. The
diastereoselectivity of this coupling process is ca. 2.5:1.
As with diastereoselective alkylation, we did not prove
the stereochemistry of the major isomer at this point. We
then treated 14 with 10% aqueous HF in acetonitrile for
18 h to remove the C-5 TBDMS ether, effect lactonization,
and remove one of the TIPS ethers. Prolonged exposure
to these conditions did not lead to further desilylation.
Thus, we isolated the monosilyl ether of discodermolide
and treated it with HF/pyridine for 18 h to provide
stereochemically homogeneous (-)-discodermolide in 40%
yield, which could be easily separated from a byproduct
believed to be C-7-epi-discodermolide, isolated in 20%
yield. The (-)-discodermolide obtained from this se-
quence gave an optical rotation opposite in sign and equal
in magnitude to (+)-discodermolide ((-)-1 [R]22 ) -14,
D
c ) 0.28, MeOH; (+)-1 [R]22 ) +14, c ) 0.50, MeOH7b).
D
Our synthetic (-)-discodermolide was identical in all
other respects (1H NMR, 13C NMR, HPLC, IR) to authen-
tic (+)-discodermolide.
This highly convergent synthesis of discodermolide
takes advantage of a chelation-controlled alkylation
reaction to achieve high selection in the key bond
coupling reaction. We have found this method to be
highly useful and are applying it to not only to the
synthesis of structural analogs of discodermolide but also
to the synthesis of other targets.
(13) (a) Tsai, D. J .-S.; Matteson, D. S. Tetrahedron Lett. 1981, 22,
2751. (b) Roush, W. R.; Grover, P. T. Tetrahedron 1992, 48, 1981.
(14) Kocovsky, P. Tetrahedron Lett. 1986, 27, 5521.
Ack n ow led gm en t. The Alfred P. Sloan Foundation,
the University of California, and Pfizer Inc. supported
this research. The authors thank Drs. R. E. Longley and
S. P. Gunasekera of the Harbor Branch Oceanographic
Institution for helpful discussions and for providing
(S.P.G.) a sample of (+)-discodermolide, and Mr. T. Lee
for help in preparing this manuscript.
(15) C-1 to C-7 fragment aldehyde 10 was synthesized from the
known (Brown, H. C.; Bhat, K. S.; Randad, R. S. J . Org. Chem., 1989,
54, 1570 and references therein) crotylboration adduct shown below
via the following sequence: (a) Tips-OTf, TEA, CH2Cl2; (b) Li/NH3; (c)
pivaloyl chloride, TEA, DMAP, CH2Cl2; (d) ozone followed by Ph3P;
(e) allylbis(isopinocamphyl)borane followed by H2O2 and NaOH; (f)
TBDMS-OTf, TEA, CH2Cl2; (g) Dibal-H, CH2Cl2; (h) Dess-Martin
periodinane; (i) NaClO2 followed by CH2N2; (j) ozone followed by Bu3P.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data for compounds 1, 9-14 (33 pages).
information.
J O9708093