An aldol approach to the synthesis of the EF fragment of spongistatin 1.

Article abstract of DOI:10.1021/ol015652m

A synthesis of the C29-C51 fragment of spongistatin 1, containing the E and F rings, has been completed. The approach relies on four diastereoselective aldol additions and an asymmetric glycolate alkylation to establish eight of the eleven stereogenic centers. The intact chlorodiene side chain was appended by a Lewis acid catalyzed addition of an allylstannane to an epoxy enol ether.

Full text of DOI:10.1021/ol015652m

ORGANIC
LETTERS
2001
Vol. 3, No. 6
949-952
An Aldol Approach to the Synthesis of
the EF Fragment of Spongistatin 1
Michael T. Crimmins,* Jason D. Katz, Laura C. McAtee, Elie A. Tabet, and
Steven J. Kirincich
Venable and Kenan Laboratories of Chemistry, The UniVersity of North Carolina at
Chapel Hill, Chapel Hill, North Carolina 27599-3290
crimmins@email.unc.edu
Received February 2, 2001
ABSTRACT
A synthesis of the C29−C51 fragment of spongistatin 1, containing the E and F rings, has been completed. The approach relies on four
diastereoselective aldol additions and an asymmetric glycolate alkylation to establish eight of the eleven stereogenic centers. The intact
chlorodiene side chain was appended by a Lewis acid catalyzed addition of an allylstannane to an epoxy enol ether.
Spongistatin 1 was isolated from the marine sponge Spongia
sp. in 1993 by Pettit.1 Subsequently Pettit,2 Kitagawa,3 and
Fusetani4 have discovered additional members of this class
of potent antitumor agents. The spongistatins (altohyrtins)
have been found to be extraordinarily effective against a
variety of chemoresistant tumor types, which comprise the
NCI panel of 60 human cancer cell lines. Human melanoma,
lung, brain, and colon cancers were found to be especially
sensitive to spongistatin 1. The activity of the spongistatins
correlates well with the class of microtubule interactive
antimitotics.5 The unique structures, the unprecedented
biological activity, and the limited supply of the spongistatins
have prompted substantial effort toward their total synthe-
(1) 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.
(2) Pettit, G. R.; Cichacz, Z. A.; Herald, C. L.; Gao, F.; Boyd, M. R.;
Figure 1. Structures of spongistatins 1 and 2.
Schmidt, J. M.; Hamel, E.; Bai, R. J. Chem. Soc., Chem. Commun. 1994,
1605.
sis.6-19 Several laboratories have reported progress toward
the synthesis of the spongistatins, and three independent total
(3) Kobayashi, M.; Aoki, S.; Sakai, H.; Kawazoe, K.; Kihara, N.; Sasaki,
T.; Kitagawa, I. Tetrahedron Lett. 1993, 34, 2795. Kobayashi, M.; Aoki,
S.; Kitagawa, I. Tetrahedron Lett. 1994, 35, 1243. Kobayashi, M.; Aoki,
syntheses have been documented. The total syntheses by
Evans20 and Kishi21 served to confirm the structures of
spongistatin 2 (altohyrtin C, 2) and spongistatin 1 (altohyrtin
A, 1), respectively, and a recent report from the Smith group
S.; Sakai, H.; Kihara, N.; Sasaki, T.; Kitagawa, I. Chem. Pharm. Bull. 1993,
41, 989.
(4) Fusetani, N.; Shinoda, K.; Matsunoga, S. J. Am. Chem. Soc. 1993,
115, 3977.
(5) Pettit, G. R. J. Nat. Prod. 1996, 59, 812.
10.1021/ol015652m CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/28/2001

described the most recent synthesis of spongistatin 2, as well
as a formal synthesis of spongistatin 1.22
Scheme 2
Our strategy for the synthesis of the C29-C51 fragment
containing the E and F pyran rings focused on the assembly
of the three subunits 4, 5, and 6. It was envisioned that an
F ring methyl ketone 4 might undergo a diastereoselective
aldol addition to syn â-silyloxy aldehyde 5 to establish the
C35 stereogenic center. Subsequently, the entire chlorodiene
side chain would be attached through the addition of
allylstannane 6 to a C42-C43 epoxide, as executed by Evans
with the deschloro derivative.20 The synthesis of the F ring
Scheme 1
methyl ketone 4 was accomplished as illustrated in Scheme
2. The C40-C41 stereocenters and the C38-C39 stereo-
centers were introduced by two sequential aldol additions.
By using our recently developed modification of the Evans
aldol,23 exposure of N-propionyloxazolidinethione 7 to
titanium tetrachloride and (-)-sparteine followed by the
addition of 3-butenal,24 syn aldol adduct 8 was produced in
94% yield in >98:2 diastereoselectivity.25 The hydroxyl was
protected as its TBS ether, the auxiliary was reductively
(6) 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. 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. 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.
(7) Claffey, M. M.; Heathcock, C. H. J. Org. Chem. 1996, 61, 7646.
Hayes, C. J.; Heathcock, C. H. J. Org. Chem. 1997, 62, 2678. Claffey, M.
M.; Hayes, C. J.; Heathcock, C. H. J. Org. Chem. 1999, 64, 8267. Wallace,
G. A.; Scott, R. W.; Heathcock, C. H. J. Org. Chem. 2000, 65, 4145.
(8) Paterson, I.; Oballa, R. M.; Norcross, R. D. Tetrahedron Lett. 1996,
37, 8581. Paterson, I.; Oballa, R. M. Tetrahedron Lett. 1997, 38, 8241.
Paterson, I.; Keown, L. E. Tetrahedron Lett. 1997, 38, 5727. Paterson, I.;
Wallace, D. J.; Gibson, K. R. Tetrahedron Lett. 1997, 38, 8911. Paterson,
I.; Wallace, D. J.; Oballa, R. M. Tetrahedron Lett. 1998, 39, 8548.
(9) Paquette, L. A.; Zuev, D. Tetrahedron Lett. 1997, 38, 5115. Paquette,
L. A.; Braun, A. Tetrahedron Lett. 1997, 38, 5119.
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Hermitage, S. A.; Roberts, S. M.; Watson, D. J. Tetrahedron Lett. 1998,
39, 3567. Kary, P. D.; Roberts, S. M.; Watson, D. J. Tetrahedron:
Asymmetry 1999, 10, 213. Kary, P. D.; Roberts, S. M. Tetrahedron:
Asymmetry 1999, 10, 217.
(11) Crimmins, M. T.; Washburn, D. G. Tetrahedron Lett. 1998, 39, 7487.
Crimmins, M. T.; Katz, J. D. Org. Lett. 2000, 2, 957.
(12) Terauchi, T.; Nakata, M. Tetrahedron Lett. 1998, 39, 3795.
(13) Lemaire-Audoire, S.; Vogel, P. Tetrahedron Lett. 1998, 39, 1345.
Lemaire-Audoire, S.; Vogel, P. J. Org. Chem. 2000, 65, 3346.
(14) Zemribo, R.; Mead, K. T. Tetrahedron Lett. 1998, 39, 3895.
(15) Fernandez-Megia, E.; Gourlaouen, N.; Ley, S. V.; Rowlands, G. J.
Synlett 1998, 991.
(16) Micalizio, G. C.; Roush, W. R. Tetrahedron Lett. 1999, 40, 3351.
Micalizio, G. C.; Pinchuk, A. N.; Roush, W. R. J. Org. Chem. 2000, 65,
8730.
(18) Samadi, M.; Munoz-Letelier, C.; Poigny, S.; Guyot, M. Tetrahedron
Lett. 2000, 41, 3349.
(19) Terauchi, T.; Terauchi, T.; Sato, I.; Tsukada, T.; Kanoh, N.; Nakata,
M. Tetrahedron Lett. 2000, 41, 2649.
(20) Evans, D. A.; Trotter, W.; Coleman, P. J.; Coˆte´, B.; Dias, L. C.;
Rajapakse, H. A.; Tyler, A. N. Tetrahedron 1999, 55, 8671. Evans, D. A.;
Coleman, P. J.; Dias, L. C. Angew. Chem., Int. Ed. Engl. 1997, 36, 2738.
Evans, D. A.; Trotter, B. W.; Coˆte´, B.; Coleman, P. J. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2741. Evans, D. A.; Trotter, B. W.; Coˆte´, B.; Coleman,
P. J.; Dias, L. C.; Tyler, A. N. Angew. Chem., Int. Ed. Engl. 1997, 36,
2744.
(21) Guo, J.; Duffy, K. J.; Stevens, K. L.; Dalko, P. I.; Roth, R. M.;
Hayward, M. M.; Kishi, Y. Angew. Chem., Int. Ed. Engl. 1998, 37, 187.
Hayward, M. M.; Roth, R. M.; Duffy, K. J.; Dalko, P. I.; Stevens, K. L.;
Guo, J.; Kishi, Y. Angew. Chem., Int. Ed. Engl. 1998, 37, 192.
(22) Smith, A. B., III; Doughty, V. A.; Lin, Q.; Zhuang, L.; McBriar,
M. D.; Boldi, A. M.; Moser, W. H.; Murase, N.; Nakayama, K.; Sobukawa,
M. Angew. Chem., Int. Ed. 2001, 40, 191. Smith, A. B., III; Lin, Q.;
Doughty, V. A.; Zhuang, L.; McBriar, M. D.; Kerns, J. K.; Brook, C. S.;
Murase, N.; Nakayama, K. Angew. Chem., Int. Ed. 2001, 40, 196.
(23) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org.
Chem. 2001, 65, 894. Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am.
Chem. Soc. 1997, 119, 7883-7884.
(24) Crimmins, M. T.; Kirincich, S. J.; Wells, A. J.; Choy, A. L. Synth.
Commun. 1998, 28, 3675. Crimmins, M. T.; Choy, A. L. J. Am. Chem.
Soc. 1999, 121, 5663.
1
(25) All new compounds were characterized by H and 13C NMR, IR,
and optical rotation. Yields are for isolated, chromatographically purified
products.
(17) Anderson, J. C.; McDermott, B. P. Tetrahedron Lett. 1999, 40, 7135.
950
Org. Lett., Vol. 3, No. 6, 2001

removed with LiBH4, and the resulting primary alcohol was
oxidized to the aldehyde with the Dess-Martin periodinane26
to provide the aldehyde 9 in preparation for the second aldol
addition. Treatment of the aldehyde 9 with the dibutylboryl
enolate derived from 10, followed by oxidative workup of
the aldolate under carefully controlled conditions,27 provided
the aldol adduct 11 in 74% yield as a single observable
diastereomer. Initial attempts to close the pyran ring by
oxidative cleavage of alkene 11 to the corresponding
aldehyde with subsequent cyclodehydration to the enol ether
met with poor results. We attributed this to participation by
the oxazolidinone acyl group during the dehydration step.
To avoid this problem, the oxazolidinone was reductively
removed and the primary alcohol was selectively protected
as the pivalate to provide alkene 12 in 70% overall yield.
Oxidative cleavage of the alkene followed by dehydration
of the resultant hemiketal with phosphorus oxychloride20
cleanly delivered the enol ether 13. Reduction of the pivalate
unmasked the primary alcohol, which was oxidized to
aldehyde 14. Without purification, aldehyde 14 was exposed
to methylmagnesium chloride in ether.28 The mixture of
diastereomeric secondary alcohols was then oxidized with
the Dess-Martin periodinane26 to provide the desired methyl
ketone 4 in 80% yield.
removed to give the primary alcohol 17. Finally, the alcohol
was oxidized to the aldehyde under Dess-Martin condi-
tions26 (immediately prior to the ensuing aldol reaction) to
afford the required aldehyde 5.
Synthesis of the third and final subunit, allyl stannane 6,
proved to be a difficult undertaking. A number of possible
approaches to the allylstannane 6 were investigated but were
generally thwarted as a result of the sensitivity of the
chlorodiene unit to strongly basic reagents. Ultimately, the
successful strategy outlined in Scheme 4 was developed. The
Scheme 4
The C29-C35 aldehyde 5 was prepared as illustrated in
Scheme 3. Once again, we took advantage of the titanium
Scheme 3
C47 stereocenter was established through an asymmetric
glycolate alkylation recently reported from our laboratory.29
Alkylation of the sodium enolate of N-acyloxazolidinone 18
with the allyl iodide 19 delivered allylic chloride 20 in 86%
yield (>98:2 diastereoselectivity). Careful reduction of the
oxazolidinone with lithium borohydride avoided both reduc-
tion of the carbon-chlorine bond and transfer of the silyl
ether producing alcohol 21 in good yield. Oxidation of the
alcohol to the aldehyde was followed immediately by
addition of the allylindium species generated from 2-chloro-
3-iodopropene.21,30 The resultant mixture of alcohols 22 was
exposed to the Martin sulfurane21,31 to effect dehydration to
the chlorodiene 23. Attempts to displace the allylic chloride
with Bu3SnLi failed to deliver the allylstannane. Use of other
allylic leaving groups also met with extensive decomposition
when they were treated with basic reagents. We then turned
tetrachloride-(-)-sparteine mediated aldol addition.23 Expo-
sure of aldehyde 14, readily available from 1,5-pentanediol,
to the chlorotitanium enolate of N-acyloxazolidinethione 15
resulted in a highly selective aldol reaction to give 16 in
85% yield (>98:2 diastereoselectivity). The alcohol was
protected as its TES ether, and the auxiliary was reductively
(26) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4156.
(27) Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J.
Am. Chem. Soc. 1990, 112, 7001.
(28) Crimmins, M. T.; Al-awar, R. S.; Vallin, I. M.; O’Mahony, R.;
Hollis, W. G., Jr.; Bankaitis-Davis, D. M.; Lever, J. G. J. Am. Chem. Soc.
1996, 118, 7513.
(29) Crimmins, M. T.; Emmitte,; K. A., Katz, J. D. Org. Lett. 2000, 2,
2165.
(30) Yi, X.-H.; Meng, Y.; Li, C.-J. Tetrahedron Lett. 1997, 38, 4731.
(31) Arhart, R. J.; Martin, J. C. J. Am. Chem. Soc. 1972, 94, 5003.
Org. Lett., Vol. 3, No. 6, 2001
951

to milder methods for allylic substitution reactions. It was
hoped that Trost’s conditions32 for Pd(0)-mediated substitu-
tion might effect the desired transformation. To that end,
the allyl chloride was converted to the allylic benzoate 24.
Exposure of the benzoate to Pd(PPh3)4 and Bu3SnAlEt2
provided the allylstannane 6 without destruction of the
chlorodiene functionality.
Scheme 5
With the three required subunits in hand, it remained to
assemble them into the desired EF fragment of spongistatin
1. Because of our experience with the sensitivity of the
chlorodiene unit, we decided to explore the aldol reaction
between the methyl ketone 4 and the aldehyde 5 prior to
installation of the chlorodiene unit.
While analogous aldol reactions to establish the C35 center
have been reported to result in low diastereoselectivity,7,13,15,16
all but one of these reports utilized the lithium enolate of
the methyl ketone or the silyl enol ether in a Mukaiyama-
type aldol. A single report of the use of a boron enolate of
an analogous methyl ketone had been noted. Ley had
executed a similar aldol addition, albeit in low yield and with
the chiral dialkyl boron chloride [(-)-(Ipc)2BCl].15 Evans33
has demonstrated that boron enolates of â-alkoxy methyl
ketones give 1,5 anti selectivity in aldol additions in contrast
to the 1,5 syn selectivity of the corresponding ethyl ketones.
A twist-boat conformation was proposed for the transition
state of the methyl ketone aldol, while a chair conformation
was invoked to rationalize the reaction for the ethyl ketone.
In addition, Paterson34 has noted 1,4 syn selectivity in the
aldol reaction of boron enolates of R-alkoxy ethyl ketones.
If R-alkoxy ketones behave as the â-alkoxy ketones, a
reversal in selectivity should be observed when switching
from ethyl to methyl ketones. Therefore, in ketone 4, both
the R-alkoxy and the â-alkoxy groups should direct the aldol
addition in the same sense producing a 1,4 anti, 1,5 anti
orientationsthe required stereochemistry for C35 in spongi-
statin 1.
Enolization of the methyl ketone 4 with (C6H11)2BCl and
Et3N in pentane followed by addition of aldehyde 5 led to
the isolation of a single diastereomeric aldol adduct 25
(Scheme 5). Since the sense of diastereoselection could not
be readily determined immediately after the aldol addition,
the aldol adduct 25 was exposed to MeOH, PPTS to cleave
the triethylsilyl ether and effect closure of the E ring pyran
unit to the mixed ketal 26. The coupling constants of the
500 MHz 1H NMR and NOESY spectra of ketal 26
corroborated the assignment of the C35 stereocenter.
Completion of the intact EF fragment was achieved by
first removal of the C29 and C38 benzyl ethers to give triol
27. Protection of the C29, C35, and C38 hydroxyls as
trimethylsilyl ethers produced 28. Enol ether 28 was exposed
to dimethyldioxirane to afford the epoxide 29, which was
treated immediately with allylstannane 6 and Bu3SnOTf
according to the conditions described by Evans.20 A single
diastereomeric product 3 was obtained from the reaction. The
product contained both the intact chlorodiene unit and the
C35 and C38 TMS ethers.
The synthesis of the fully elaborated EF fragment of
spongistatin 1 was completed in 19 linear steps in ap-
proximately 7% overall yield. The approach is highly
convergent and proceeds with high levels of stereocontrol
throughout. The highly selective assembly of the methyl
ketone 4 and aldehyde 5, as well as the demonstration that
the chlorodiene side chain can be incorporated as a single
unit using the Evans allylstannane approach, are noteworthy.
Current efforts are directed toward assembly of the EF
fragment with the AB and CD subunits.11
(32) Trost, B. M.; Herndon, J. W. J. Am. Chem. Soc. 1984, 106, 6835.
Ple´, P. A.; Hamon, A.; Jones, G. Tetrahedron 1997, 53, 3395.
(33) Evans, D. A.; Coleman, P. J.; Coˆte´, B. J. Org. Chem. 1997, 62,
788.
(34) Paterson, I.; Wallace, D. J.; Vela´zquez, S. M. Tetrahedron Lett.
1994, 35, 9083. Paterson, I.; Wallace, D. J. Tetrahedron Lett. 1994, 35,
9087.
Acknowledgment. This research was supported by a
grant from the National Institutes of Health (NCI) (CA63572).
We thank Professor Ian Paterson for helpful discussion.
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Org. Lett., Vol. 3, No. 6, 2001