Spongistatin synthetic studies. An efficient, second-generation construction of an advanced ABCD intermediate

Article abstract of DOI:10.1021/ol017273z

(formula presented) A short, efficient, and stereocontrolled synthesis of (-)-4, an advanced ABCD subunit of the spongistatins, has been achieved. Central to the synthetic strategy is the multicomponent linchpin union of silyl dithianes with epoxides to access both the AB and CD fragments. Fragment coupling was then achieved via an efficient stereoselective aldol reaction. The linear sequence required 22 steps and proceeded in 4.0% overall yield.

Full text of DOI:10.1021/ol017273z

ORGANIC
LETTERS
2002
Vol. 4, No. 5
783-786
Spongistatin Synthetic Studies. An
Efficient, Second-Generation
Construction of an Advanced ABCD
Intermediate
Amos B. Smith, III,* Victoria A. Doughty, Chris Sfouggatakis, Clay S. Bennett,
Jyunichi Koyanagi, and Makoto Takeuchi
Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
smithab@sas.upenn.edu
Received December 19, 2001
ABSTRACT
A short, efficient, and stereocontrolled synthesis of (−)-4, an advanced ABCD subunit of the spongistatins, has been achieved. Central to the
synthetic strategy is the multicomponent linchpin union of silyl dithianes with epoxides to access both the AB and CD fragments. Fragment
coupling was then achieved via an efficient stereoselective aldol reaction. The linear sequence required 22 steps and proceeded in 4.0%
overall yield.
The spongistatins (aka altohyrtins) comprise a family of
unique, architecturally complex bisspiroketal macrolides,
which display extraordinary cytotoxicity.1 Since their inde-
pendent isolation by three research groups,2-4 the spongist-
atins have been the focus of considerable attention in both
the chemical and biological communities, based on their
intriguing structures and potent antitumor activities.5 The
relative and absolute stereochemistries, first deduced by
Kitagawa,4 were confirmed via the total syntheses of
spongistatin 1 (1) by Kishi6 and spongistatin 2 (2) by Evans
(Figure 1).7 More recently, we8 and Paterson9 have also
(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. (b)
Pettit, G. R. Pure Appl. Chem. 1994, 66, 2271. (c) Bai, R.; Taylor, G. F.;
Cichacz, Z. A.; Herald, C. L.; Kepler, J. A.; Pettit, G. R.; Hamel, E.
Biochemistry 1995, 34, 9714.
(2) (a) Pettit, G. R.; Tan, R.; Gao, F.; Williams, M. D.; Doubek, D. L.;
Boyd, M. R.; Schmidt, J. M.; Chapuis, J.-C.; Hamel, E.; Bai, R.; Hooper,
J. N. A.; Tackett, L. P. J. Org. Chem. 1993, 58, 2538. (b) Pettit, G. R.;
Cichacz, Z. A.; Gao, F.; Herald, C. L.; Boyd, M. R. J. Chem. Soc., Chem.
Commun. 1993, 1166. (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. (d) Pettit, G. R.; Herald, C. L.; Cichacz,
Z. A.; Gao, F.; Boyd, M. R.; Christie, N. D.; Schmidt, J. M. Nat. Prod.
Lett. 1993, 3, 239. (e) Pettit, G. R.; Cichacz, Z. A.; Herald, C. L.; Gao, F.;
Boyd, M. R.; Schmidt, J. M.; Hamel, E.; Bai, R. J. Chem. Soc., Chem.
Commun. 1994, 1605.
(3) Fusetani, N.; Shinoda, K.; Matsunaga, S. J. Am. Chem. Soc. 1993,
115, 3977.
(4) (a) Kobayashi, M.; Aoki, S.; Sakai, H.; Kawazoe, K.; Kihara, N.;
Sasaki, T.; Kitagawa, I. Tetrahedron Lett. 1993, 34, 2795. (b) Kobayashi,
M.; Aoki, S.; Kitagawa, I. Tetrahedron Lett. 1994, 35, 1243. (c) Kobayashi,
M.; Aoki, S.; Sakai, H.; Kihara, N.; Sasaki, T.; Kitagawa, I. Chem. Pharm.
Bull. 1993, 41, 989. (d) Kobayashi, M.; Aoki, S.; Gato, Kitagawa, K. I.
Chem. Pharm. Bull. 1996, 44, 2142.
(5) See ref 8a and also ref 9 for a list to date of synthetic studies towards
the spongistatins.
(6) (a) 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. (b)
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.
10.1021/ol017273z CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/02/2002

tion12 tactics, an efficient synthesis of an ABCD fragment
could be achieved as outlined in Figure 1. In this Letter we
describe a second-generation approach to subunit 4, which
sets the stage for efficient syntheses of both spongistatins 1
and 2, as well as numerous analogues for further biological
study.
Construction of the AB spiroketal fragment 5 called for
linchpin union of epoxides 7 and 9, the former prepared in
nearly identical fashion as our first-generation synthesis
except for selection of the 2-naphthylmethyl protecting group,
recently introduced by Spencer, Gaunt, and Yu.13,14
Epoxide (+)-9 in turn was prepared in 7 steps via coupling
epoxide (-)-17 (Scheme 1) with hydrazone (-)-19 (Scheme
Scheme 1
2), exploiting a Shapiro coupling tactic. To this end,
Sharpless epoxidation of commercially available 13, followed
by in situ silyl protection furnished known epoxide (-)-
Scheme 2
Figure 1.
achieved successful total syntheses of 1 and 2. Structurally,
the spongistatins possess a striking array of features, includ-
ing a 42-membered macrolactone incorporating two spiro-
ketals, a hemiacetal, and a pyran, which is subtended by a
highly unsaturated side chain.
Recognizing the power of the anti-aldol reaction to unite
the AB and CD fragments, as exploited to great advantage
by Evans,7 Paterson,9 and Heathcock,10 we reasoned that with
our multicomponent linchpin11 and iodocarbonate cycliza-
14.15,16 Treatment with vinyl cuprate, formation of the mixed
BOC carbonate, and execution of our iodocarbonate cycliza-
tion protocol12 then led to (+)-16 as a readily separable
mixture (7:1) of diastereomers favoring the desired syn
isomer. Basic methanolysis provided epoxide (-)-17.
Ketone (+)-18 was next prepared via protection of Roche’s
ester (PMBTCA, p-TsOH) (Scheme 2), followed by forma-
tion of the Weinreb amide, employing the Merck protocol17
(7) (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.; Coˆte´, B.; Coleman,
P. J. Angew. Chem., Int. Ed. Engl. 1997, 36, 2741. (c) 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. (d) Evans, D. A.; Trotter, B. W.; Coleman,
P. J.; Coˆte´, B.; Dias, L. C.; Rajapakse, H. A.; Tyler, A. N. Tetrahedron
1999, 55, 8671.
(8) (a) 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; (b) 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.
(9) Paterson, I.; Chen D. Y.-K.; Coster, M. J.; Acen˜a, J. L.; Bach, J.;
Gibson, K. R.; Keown, L. E.; Oballa, R. M.; Trieselmann, T.; Wallace, D.
J.; Norcross, R. D. Angew. Chem., Int. Ed. 2001, 40, 4055.
(10) Claffey, M. M.; Hayes, C. J.; Heathcock, C. H. J. Org. Chem. 1999,
64, 8267.
(12) (a) Duan, J. J.-W.; Smith, A. B., III. J. Org. Chem. 1993, 58, 3703.
(b) Bartlett, P. A.; Meadows, J. D.; Brown, E. G.; Morimoto, A.; Jernstedt,
K. K. J. Org. Chem. 1982, 47, 4013.
(13) Gaunt, M. J.; Yu, J.; Spencer, J. B. J. Org. Chem. 1998, 63, 4172.
(14) See Supporting Information.
(15) Gao, Y.; Hanson, R. M.; Klonder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(16) Behnke, D.; Hennig, L.; Findeisen, M.; Welzel, P.; Mu¨ller, D.;
Thormann, M.; Hofmann, H.-J. Tetrahedron 2000, 56, 1081.
(17) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling,
U. H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461.
(11) Smith, A. B., III; Boldi, A. M. J. Am. Chem. Soc. 1997, 119, 6925.
784
Org. Lett., Vol. 4, No. 5, 2002

(i-PrMgCl, MeOMeNH‚HCl), which both avoids the use of
pyrophoric trimethylaluminum and is readily amenable to
scale-up. Addition of methyl-magnesium bromide furnished
ketone (+)-18. Formation of the trisyl hydrazone (-)-19
(trisyl hydrazide, THF, 90%),18-20 followed by deprotonation
with 2 equiv of t-BuLi, and introduction of the lithium anion
derived from epoxide (-)-17 resulted in diol (+)-20 (88%
yield). Importantly, this reaction can be carried out on a
multiple-gram scale. Completion of the synthesis of (+)-9
entailed removal of the silyl ether (TBAF, 98%), formation
of epoxide (+)-21 (trisylimidazole, NaH, THF, 73%),21 and
silyl protection (TESCl, imid., 98%).
experiments revealed that spiroketal (-)-23 indeed possessed
the thermodynamically most stable bisaxial configuration.
Selective acetylation of the secondary hydroxyl followed by
TES protection of the tertiary hydroxyl and removal of the
naphthylmethyl group (catalytic transfer hydrogenolysis) then
led to (-)-24. Of considerable note, the naphthylmethyl
group was removed in the presence of a PMB ether, an exo-
methylene, a TES ether, an acetate, and the spiroketal. Two-
step oxidation, followed in turn by TIPS protection of the
derived acid to afford (-)-25, removal of the PMB group
(DDQ, 91%), and Dess-Martin periodinane oxidation
completed construction of aldehyde (-)-5, which because
of the unstable nature was used directly in the Evans aldol
(vide infra).
Studies on the linchpin union of (-)-7 and (+)-9 began
by employing (+)-9 as the first epoxide (Scheme 3). Lithiated
Linchpin assembly of the CD spiroketal fragment 6
employed epoxide (+)-10 as in our first-generation synthe-
sis,8,22 beginning with (R)-glycidol.23 Construction of the
second epoxide (-)-12 began with inexpensive (L)-malic acid
(Scheme 4). Highlights of this sequence included oxidation
Scheme 3
Scheme 4
employing TEMPO/trichloroisocyanuric acid, a method
recently reported by Giacomelli et al.,24,25 excellent 1,3-anti
selectivity (>10:1)26 in the Keck alkylation protocol27 with
known allyl stannane 2628 [Ti(Oi-Pr)4/BINOL] to afford (-)-
27, and a one-pot Kishi epoxide construction.29
Pleasingly, the multicomponent union of (-)-10 and (-)-
12 again proceeded in good yield to furnish (+)-28 (Scheme
5).30 Methylation of the hydroxyl was followed in turn by
2-TES-1,3-dithiane, however, did not react with the epoxide;
only elimination products and recovered epoxide (+)-9 were
observed. To circumvent this problem, the order of epoxide
coupling was reversed, with the lithium anion of epoxide
(+)-21 serving as the second component. This tactic provided
the desired coupled product (+)-22 in 58% yield. Impor-
tantly, the sequence removed the need for silyl protection,
thereby shortening the longest linear sequence by one step.
To our delight, in situ spiroketalization occurred upon
removal of both the dithiane and silyl ethers in (+)-22 with
Hg(ClO4)2‚4H2O to furnish spiroketal (-)-23 as the sole
product in 83% yield (Scheme 3). Careful NOESY NMR
(22) Smith, A. B., III; Zhuang, L.; Brook, C. S.; Lin, Q.; Moser, W. H.;
Trout, R. E. L.; Boldi, A. M. Tetrahedron Lett. 1997, 38, 8671.
(23) Large-scale preparation of this valuable intermediate was carried
out using Jacobsen’s kinetic resolution methodology; see: Furrow, M. E.;
Schaus, S. E.; Jacobsen, E. N. J. Org. Chem. 1998, 68, 6776.
(24) De Luca, L.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2001, 3,
3041-3043.
(25) Hanessian, S.; Ugolini, A.; Dube´, D.; Glamyan, A. Can. J. Chem.
1984, 62, 2146.
(26) Treatment with both chelating and nonchelating Lewis acids only
afforded a 2.6-2.2:1 ratio of anti/syn diastereomers.
(27) (a) Keck, G. E.; Krishnamurthy, D.; Grier, M. C. J. Org. Chem.
1993, 58, 6543. (b) Keck, G. E.; Tarbet, K. H.; Gerachi, L. S. J. Am. Chem.
Soc. 1993, 115, 8467. (c) Molinski, T. F.; Searle, P. A. J. Am. Chem. Soc.
1996, 118, 9422.
(18) Cusack, N. J.; Reese, C. B.; Risius, A. C.; Roozpeikar, B.
Tetrahedron 1976, 32, 2157.
(19) Chamberlin, A. R.; Stemke, J. E.; Bond, F. T. J. Org. Chem. 1978,
43, 147.
(20) Initial studies employing the tosyl hydrazone did not lead to the
desired deprotonation.
(21) The use of tosyl imidazole, a more commonly employed reagent
for this type of transformation, led to competitive sulfonation of the
secondary hydroxyl after epoxide formation, as well as recovered starting
material.
(28) Keck, G. E.; Wager, C. A.; Wager, T. T.; Savin, K. A.; Covel, J.
A.; McLaws, M. D.; Krishnamurthy, D.; Cee, V. Angew. Chem., Int. Ed.
2001, 40, 231.
(29) A 20:1 mixture of diastereomers was obtained. This minor diaste-
reomer resulted from competitive tosylation at the secondary hydroxyl
followed by displacement of the tosylate.
(30) The reaction proved sensitive to oxygen on small scale. Use of oxy-
clear argon improved the reproducibility of the reaction.
Org. Lett., Vol. 4, No. 5, 2002
785

Scheme 5
Scheme 6
construction of the fully elaborated ABCD aldehyde (-)-4.
The synthesis of (-)-4 was achieved with a longest linear
sequence of 22 steps (4.0% overall yield) and with average
yield per step of 87%. Four well precedented steps8b (Wittig
coupling, selective silyl deprotection, macrolactonization, and
global deprotection) should lead to the spongistatins. Im-
portantly, the linear sequence for our second generation
synthesis is 15 steps shorter than our previous synthesis of
the C(23) epimeric ABCD aldehyde8a and is highly competi-
tive with other published approaches to the ABCD sub-
unit.6a,7d,31,32
To confirm the structure, and in particular the stereochem-
istry of (-)-4 initially based on extensive NOESY analysis,
we completed a two-step chemical correlation with an
advanced Paterson intermediate,9,14,33 which further consti-
tutes a formal total synthesis of spongistatin 1 (1).
In conclusion, we have achieved a short, efficient, and
stereocontrolled synthesis of the ABCD fragment (-)-4 of
the spongistatins, highlighted by application of both our
iodocarbonate cyclization and muliticomponent linchpin
coupling of silyl dithianes. AB and CD fragment union was
then achieved via a stereoselective aldol reaction.
removal of the silyl groups (p-TsOH) and hydrolysis of the
dithiane moiety (CAN), the latter providing a mixture of
spiroketals (+)-29 and 30 (4:1), favoring undesired axial-
axial spiroketal (+)-29.
We reasoned that the introduction of additional hydroxyl
functionality would permit use of the calcium perchlorate/
perchloric acid equilibration protocol discovered in our first
generation synthesis.8a,22 Toward this end, dihydroxylation
of the olefin (OsO4, NMO), followed by treatment of the
mixture with calcium perchlorate/perchloric acid, and then
1,2-diol cleavage via NaIO4 afforded a separable mixture of
(+)-31 and (-)-32 (1:4), now favoring the desired axial-
equatorial spiroketal (-)-32; silyl protection (TBSOTf)
completed the synthesis of the CD spiroketal ketone (-)-6.
Stereochemical assignments for both spiroketals (+)-31 and
(-)-32 were again confirmed by detailed NOESY NMR
analysis.14
Aldol union7d,10,31 of the AB and CD fragments was next
achieved, as anticipated by the earlier precedent of Evans,
both in good yield (64%) and with high anti-selectivity (9:
1) (Scheme 6). Acetylation of the derived alcohol, followed
by removal of the benzyl group and oxidation, completed
Acknowledgment. Financial support was provided by the
NIH (NCI) through grant CA-70329 and by a Royal Society
Fulbright Fellowship to V.A.D.
Supporting Information Available: Spectroscopic and
analytical data and selected experimental procedures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL017273Z
(32) Zuev, D.; Paquette, L. A. Org. Lett. 2000, 2, 679.
(33) We thank Professor I. Paterson for providing spectroscopic data
for the correlation compound.
(31) Paterson, I.; Wallace, D. J.; Oballa, R. M. Tetrahedron Lett. 1998,
39, 8545.
786
Org. Lett., Vol. 4, No. 5, 2002