Synthesis of the C16-C28 spiroketal Subunit of spongistatin 1 (altohyrtin A): The pyrone approach

Article abstract of DOI:10.1021/ol005605e

(Equation presented) The synthesis of the CD spiroketal fragment of spongistatin 1 (altohyrtin A) has been accomplished utilizing the addition of a metalated pyrone to an aldehyde and subsequent acid-catalyzed spirocyclization. A stereoselective hydrogena

Full text of DOI:10.1021/ol005605e

ORGANIC
LETTERS
2000
Vol. 2, No. 7
957-960
Synthesis of the C16−C28 Spiroketal
Subunit of Spongistatin 1
(Altohyrtin A): The Pyrone Approach
Michael T. Crimmins* and Jason D. Katz
Venable and Kenan Laboratories of Chemistry, UniVersity of North Carolina at
Chapel Hill, Chapel Hill, North Carolina 27599-3290
crimmins@email.unc.edu
Received February 1, 2000
ABSTRACT
The synthesis of the CD spiroketal fragment of spongistatin 1 (altohyrtin A) has been accomplished utilizing the addition of a metalated
pyrone to an aldehyde and subsequent acid-catalyzed spirocyclization. A stereoselective hydrogenation and subsequent conformational inversion
establish the C19 stereocenter and the axial−equatorial spiroketal center.
The spongistatins,1 altohyrtins,2 and cinachyrolide A3 are
recently isolated members of a new class of antitumor
agents.4 We recently reported the preparation of the C1-
C13 spiroketal (AB) subunit of the potent antitumor agent
spongistatin 15 (altohyrtin A) 1. Several other approaches
to the AB spiroketal,6 CD spiroketal,6a,e,g,7 and EF fragments8
have been reported, and recently the first total syntheses of
altohyrtins A9 and C10 were described.
To date, most approaches to the CD spiroketal have relied
on the thermodynamic equilibration of the anomeric center
to control the spiroketal configuration. Since the CD
spiroketal of spongistatin is an equatorial-axial spiroketal,
thermodynamic control results in a mixture of the diaxial
and equatorial-axial spiroketals in approximately equal
ratios, depending on the reaction conditions. One exception
is the apparent kinetic formation of a 6.5:1 ratio in favor of
the axial-equatorial spiroketal observed by Heathcock.6a
(1) (a) Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. L.; Boyd, M.
R.; Schmidt, J. M.; Hooper, J. N. A. J. Org. Chem. 1993, 58, 1302-1304.
(b) Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. L.; Boyd, M. R.;
Schmidt, J. M.; Hamel, E.; Bai, R. J. Chem. Soc., Chem. Commun. 1994,
58, 1605-1606. (c) Pettit, G. R.; Herald, C.L.; Cichacz, Z. A.; Gao, F.;
Schmidt, J. M.; Boyd, M. R.; Christie, N. D.; Boettner, F. E. J. Chem.
Soc., Chem. Commun. 1993, 1805-1807. (d) Pettit, G. R.; Herald, C.L.;
Cichacz, Z. A.; Gao, F.; Schmidt, J. M.; Boyd, M. R.; Christie, N. D.;
Boettner, F. E. J. Chem. Soc., Chem. Commun. 1993, 1166-1168.
(2) Kobayashi, M.; Aoki, S.; Gato, K.; Kitagawa, I. Chem. Pharm. Bull.
1996, 44, 2142-22149 and references therein.
(6) (a) Heathcock, C. H.; Claffey, M. M. J. Org. Chem. 1996, 61, 7646.
(b) Claffey, M. M.; Hayes, C. J.; Heathcock, C. H. J. Org. Chem. 1999,
64, 8267-8274. (c) Paterson, I.; Oballa, R. M.; Norcross, R. D. Tetrahedron
Lett. 1996, 37, 8581-8584. (d) Paterson, I.; Oballa, R. M. Tetrahedron
Lett. 1997, 38, 8241. (e) Paterson, I.; Wallace, D. J.; Oballa, R. M.
Tetrahedron Lett. 1998, 39, 8545. (f) Paquette, L. A.; Zuev, D. Tetrahedron
Lett. 1997, 38, 5115-5118. (g) Paquette, L. A.; Zuev, D. Org. Lett. 2000,
2, 679-682. (h) Smith, A. B., III; Lin, Q.; Nakayama, K.; Boldi, A.; Brook,
C. S.; McBriar, M. D.; Moser, W. H.; Sobukawa, M.; Zhuang, L.
Tetrahedron Lett. 1997, 38, 8675-8678. (i) Zemribo, R.; Mead K. T.
Tetrahedron Lett. 1998, 39, 3891. (j) Zemribo, R.; Mead, K. T. Tetrahedron
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(3) Fusetani, N.; Shinoda, K.; Matsunoga, S. J. Am. Chem. Soc. 1993,
115, 3977-3981.
(4) (a) Bai, R.; Cichacz, Z. A.; Herald, C. L.; Pettit, G. R.; Hamel, E.
Mol. Pharmacol. 1993, 44, 757-766. (b) Bai, R.; Taylor, G. F.; Cichacz,
Z. A.; Herald, C. L.; Kepler, J. A.; Pettit, G. R.; Hamel, E. Biochemistry
1995, 34, 9714-9721.
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7487-7490.
10.1021/ol005605e CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/07/2000

As a result of the anticipated selectivity problems with
thermodynamic control of the anomeric center, we sought a
different approach to the CD spiroketal unit. A stereoselective
hydrogenation of an unsaturated spiroketal 3 was chosen to
kinetically establish the required axial-equatorial spiroketal
configuration of the C16-C28 spiroketal subunit 2 (Figure
1). Enone 3 would be prepared through initial metalation of
mentation of this strategy for the synthesis of the C16-C28
fragment of spongistatin 1 is reported here.
The synthesis began with the preparation of aldehyde 5
from commercially available (S)-benzyl glycidyl ether 6, as
illustrated in Scheme 1. Epoxide opening of 6 with vinyl-
Scheme 1
magnesium bromide in the presence of CuI, followed by
protection of the secondary alcohol as the p-methoxybenzyl
ether, gave alkene 7 in excellent yield.12 Oxidative cleavage
of the alkene with osmium tetraoxide and sodium periodate
produced 90% of the desired aldehyde 5.
With aldehyde 5 in hand, modification of 2,6-dimethyl-
γ-pyrone 4, which serves as the C ring of the spiroketal
fragment, was initiated. Lithiation of 2,6-dimethyl-γ-pyrone
4 with lithium diisopropylamide and subsequent addition of
aldehyde 5 produced pyrone aldol adduct 8 in 73% yield
(Scheme 2). Protection of the secondary alcohol as the tert-
butyldimethylsilyl ether followed by oxidative cleavage of
the p-methoxybenzyl ether yielded hydroxypyrone 9 in 64%
yield over two steps.
Elaboration of the other methyl group of pyrone 8 proved
to be more challenging. A variety of metalation conditions
on several differentially protected forms of pyrone 8 were
surveyed. Most reaction conditions resulted in low conversion
to the aldol adduct (about 20%) with a mass recovery of
about 50%. During the course of these experiments, it was
found that the mass recovery could be improved to 90% by
utilizing LiCl as an additive and lowering the reaction
temperature to -98 °C. Ultimately it was discovered that
the presence of a free hydroxyl in the substrate, which
resulted in the formation of a dianion, was important for
acceptable conversions. As shown in Table 1, the only cases
with yields over 30% were those where the pyrone contained
a free hydroxyl on the side chain.
Figure 1. Retrosynthetic analysis.
pyrone 4 and sequential addition to aldehyde 5 and pro-
pionaldehyde. An acid-catalyzed cyclization11 of the resultant
hydroxypyrone would give the spiroenone 3. The imple-
(7) (a) Heathcock, C. H.; Hayes, C. J. J. Org. Chem. 1997, 62, 2678.
(b) Paterson, I.; Wallace, D. J.; Gibson, K. R. Tetrahedron Lett. 1997, 38,
8911. (c) Paquette, L. A.; Braun, A. Tetrahedron Lett. 1997, 38, 5119-
5122. (d) Smith, A. B., III; Zhuang, L.; Brook, C. S.; Lin, Q.; Moser, W.
H.; Trout, R. E. L.; Boldi, A. Tetrahedron Lett. 1997, 38, 8671-8674.
(8) (a) Heathcock, C. H.; Ott, G. R. Org. Lett. 1999, 1, 1475. (b) Paterson,
I.; Keown, L. E. Tetrahedron Lett. 1997, 38, 5727-5730. (c) Lemaire-
Audoire, S.; Vogel, P. Tetrahedron Lett. 1998, 39, 1345-1348. (d) Smith,
A. B., III; Zhuang, L.; Brook C. S.; Boldi, A.; McBriar, M. D.; Moser, W.
H.; Murase, N.; Nakayama, K.; Verhoest, P. R.; Lin, Q. Tetrahedron Lett.
1997, 38, 8667-8670. (e) Hermitage, S. A.; Roberts, S. M.; Watson, D. J.
Tetrahedron Lett., 1998, 39, 3567. (f) Kary, P. D.; Roberts, S. M.; Watson,
D. J. Tetrahedron: Asymmetry 1999, 10, 213. (g) Kary, P. D.; Roberts, S.
M. Tetrahedron: Asymmetry 1999, 10, 217. (h) Fernandez-Megia, E.;
Gourlaouen, N.; Ley, S. V.; Rowlands, G. J. Synlett 1998, 991. (i) Micalizio,
G. C.; Roush, W. R. Tetrahedron Lett. 1999, 40, 3351. (j) Dunkel, R.; Treu,
J.; Hoffmann, H. M. R. Tetrahedron: Asymmetry 1999, 10, 1539.
(9) (a) Guo, J.; Duffy, K. J.; Dalko, P. I.; Roth, R. M.; Hayward, M. M.;
Kishi, Y. Angew. Chem., Int. Ed. 1998, 37, 187-192. (b) Hayward, M.
M.; Roth, R. M.; Duffy, K. J.; Dalko, P. I.; Steverns, K. L.; Guo, J.; Kishi,
Y. Angew. Chem., Int. Ed. 1998, 37, 192-196.
Table 1. Second Aldol Reactions on Pyrones
958
Org. Lett., Vol. 2, No. 7, 2000

Scheme 2
Lithiation of hydroxypyrone 9 in the presence of LiCl and
of steric shielding by the pivaloate and the directing effect
of the free hydroxyl. The resultant diaxially substituted C
ring underwent ring inversion, as shown in Scheme 4, to
addition of excess propionaldehyde afforded dihydroxypy-
rone aldol adduct 10 in 63% yield. This mixture of
diastereomers contains all of the required carbons for the
C16-C28 fragment. Exposure of the mixture to catalytic
trifluoroacetic acid in benzene afforded a 1:1.5 mixture of
the spiroenones 11 and pyrone 10. This mixture was readily
separated by flash chromatography, and the spiroenone was
ultimately obtained in greater than 80% yield after recycling.
Scheme 4
The benzyl ether of 11a was then cleaved by hydrogena-
tion over Pd(OH)2, and the resulting primary alcohol was
selectively protected as pivalate ester 3 in 74% yield over
the two steps (Scheme 3). The spiroenone was hydrogenated
Scheme 3
provide axial-equatorial spiroketal 12 with the configuration
required for the CD ring of spongistatin 1. The C17 hydroxyl
was then protected as the acetate, and the ketone was
stereoselectively reduced with L-Selectride to furnish alcohol
13, which has all of the stereocenters required for the CD
spiroketal ring. The C21 hydroxyl was converted to methyl
ether 14 by treatment with Me3OBF4 and 2,6-di-tert-butyl-
4-methylpyridine.
(10) (a) Evans, D. A.; Coleman, P. J.; Dias, L. C. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2738. (b) Evans, D. A.; Trotter, B. W.; Cote, B.;
Coleman, P. J. Angew. Chem., Int. Ed. Engl. 1997, 36, 2741. (c) Evans, D.
A.; Trotter, B. W.; Cote, B.; Coleman, P. J.; Dias, L. C.; Tyler, A. N. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2744. (d) Evans, D. A.; Trotter, B. W.;
Coleman, P. J.; Cote, B.; Dias, L. C.; Rajapakse, H. A.; Tyler, A. N.
Tetrahedron 1999, 55, 8671-8726.
(11) (a) Crimmins, M. T.; O′Mahony, R.; J. Org. Chem. 1990, 55, 5894-
5900. (b) Crimmins, M. T.; Washburn, D. G.; Katz, J. D.; Zawacki, F. J.
Tetrahedron Lett. 1998, 39, 3439-3442.
1
(12) All new compounds were characterized by H and 13C NMR, IR,
and optical rotation. Yields are for isolated, chromatographically purified
products.
over Pd/C, resulting in addition of hydrogen to the double
bond solely from the equatorial face due to a combination
(13) Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43,
2480.
Org. Lett., Vol. 2, No. 7, 2000
959

The equatorial isomer of the spiroketalization, 11e, was
also readily converted to 14, as shown in Scheme 5. The
Scheme 6
Scheme 5
Support for the stereochemical assignment of the final
product, 2, was obtained by inspection of the NOESY
spectrum (Figure 2). A strong NOE was observed between
benzyl ether was converted to pivalate ester 15 as above,
and the enone was reduced via a catalytic hydrogenation
followed by hydroxyl protection to furnish acetate 16.
Stereoselective reduction of the ketone, and conversion to
the methyl ether, provided spiroketal 17. The C25 silyl ether
was then cleaved using tetrabutylammonium fluoride, and
the resulting secondary alcohol was oxidized under Swern13
conditions to produce ketone 18. The ketone was stereo-
selectively reduced with L-Selectride to the axial alcohol,
which was converted to tert-butyldimethylsilyl ether 14 in
94% yield upon treatment with TBSOTf and 2,6-lutidine at
-78 °C, thereby completing inversion of the C25 stereo-
center. This inverted material could then be combined with
the previously synthesized 14 and carried on to complete
the CD fragment.
Figure 2.
the C19 and C21 axial protons, as well as between the C19
axial proton and C24 equatorial proton and the C21 axial
proton and C24 equatorial proton. This C19-C21-C24 triad
as well as the C22eq-C24ax interaction is diagnostic in
spongistatin 1 as well. The C27 proton was assigned as axial
on the basis of its coupling constants to C26, and similarly,
the equatorial nature of C25 was assigned by its coupling
constants with the C24 and C26 hydrogens.
The C16-C28 axial-equatorial spiroketal fragment of
spongistatin 1 has been prepared in a highly stereoselective
manner from 2,6-dimethyl-γ-pyrone and (S)-benzyl glycidyl
ether. Efforts are underway to connect the AB and CD
spiroketal fragments and complete the synthesis of spongi-
statin 1.
Completion of the CD spiroketal from 14 required only
adjustment of the oxidation state at C17 and a change of the
C28 protecting group. Hydrolysis of both the acetate and
pivaloate esters with sodium hydroxide in methanol afforded
diol 19 in 96% yield (Scheme 6). Selective protection of
the primary hydroxyl as the tert-butyldimethylsilyl ether and
oxidation of the secondary hydroxyl to the ketone under
Swern conditions accessed the fully functionalized C16-
C28 spiroketal fragment 2 in 82% yield over the two steps.
Acknowledgment. This work was supported by a grant
from the National Institute of Health (NCI) (CA63572).
Supporting Information Available: Experimental pro-
cedures and full characterization for compounds 2, 3, 5, and
7-20. This material is available free of charge via the
Internet at http://pubs.acs.org.
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Org. Lett., Vol. 2, No. 7, 2000