Total synthesis of (+)-spongistatin 1. An effective second-generation construction of an advanced EF Wittig salt, fragment union, and final elaboration.

Article abstract of DOI:10.1021/ol034037a

A stereocontrolled, total synthesis of (+)-spongistatin 1 (1) has been achieved. Union of a second-generation EF Wittig salt (+)-3 with the advanced ABCD aldehyde (-)-4, followed by regioselective macrolactonization and global deprotection afforded (+)-sp

Full text of DOI:10.1021/ol034037a

ORGANIC
LETTERS
2003
Vol. 5, No. 5
761-764
Total Synthesis of (+)-Spongistatin 1.
An Effective Second-Generation
Construction of an Advanced EF Wittig
Salt, Fragment Union, and Final
Elaboration
Amos B. Smith, III,* Wenyu Zhu, Shohei Shirakami, Chris Sfouggatakis,
Victoria A. Doughty, Clay S. Bennett, and Yasuharu Sakamoto
Department of Chemistry, Monell Chemical Senses Center,
and Laboratory for Research on the Structure of Matter,
UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
smithab@sas.upenn.edu
Received January 8, 2003
ABSTRACT
A stereocontrolled, total synthesis of (+)-spongistatin 1 (1) has been achieved. Union of a second-generation EF Wittig salt (+)-3 with the
advanced ABCD aldehyde (−)-4, followed by regioselective macrolactonization and global deprotection afforded (+)-spongistatin 1 (1). The
longest linear sequence, 29 steps, proceeded in 0.5% overall yield.
The spongistatins (aka altohyrtins) comprise an architectur-
ally unique family of macrolides that display extraordinary
cytotoxicity against several highly chemo-resistant tumor cell
lines.1 Since their independent isolation by three research
groups,2-4 the spongistatins have been the focus of consider-
able attention in both the chemical and biological communi-
ties, based on their intriguing structures and potent antitumor
activities.5-11 The relative and absolute stereochemistries, first
deduced by Kitagawa,4 were confirmed via the total synthesis
of spongistatin 2 (2) by Evans5 and spongistatin 1 (1) by
Kishi6 (Scheme 1). More recently, we,7 Paterson,8 and
(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.; Sakai, H.; Kihara, N.; Sasaki, T.; Kitagawa, I. Chem. Pharm.
Bull. 1993, 41, 989.
(5) (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.
(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.
(2) (a) Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. L.; Boyd, M. R.
J. Chem. Soc., Chem. Commum. 1993, 1166. (b) 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.
(3) Fusetani, N.; Shinoda, K.; Matsunaga, S. J. Am. Chem. Soc. 1993,
115, 3977.
(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. 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. 1998, 37, 192.
10.1021/ol034037a CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/05/2003

chlorodiene side chain would next take advantage of the
Evans tactic involving addition of a fully elaborated allyl-
stannane 5 to a C(42)-C(43) epoxide. Completion of the
synthesis of 1 would then entail TMS protection of the C(41,
42, and 47) hydroxyls, generation of the Wittig phosphonium
salt, union with the advanced ABCD fragment (-)-4,12
regioselective macrolactonization, and global deprotection.
Preparation of the requisite F-ring aldehyde 7 (Scheme 2)
began with a Brown asymmetric crotylboration13 of aldehyde
(-)-914 to furnish homoallylic alcohol (-)-10; the diaste-
reoselectivity was excellent (>20:1). Subsequent benzylation
and acidic removal of the acetonide generated diol (-)-11;
the overall yield for the three steps was 55%. Selective
sulfonation of the primary hydroxyl with 2,4,6-triisopropyl-
benzenesulfonyl chloride (TrisCl), followed by protection of
the secondary hydroxyl as the PMB ether15 afforded alkene
(+)-12. Sharpless asymmetric dihydroxylation16 then led to
an intermediate diol, which upon treatment with NaOMe
achieved ring closure to afford tetrahydropyran (+)-13 in
85% yield (dr, 6:1). Parikh-Doering17 oxidation completed
construction of the C(38)-C(43) tetrahydropyran (+)-7.
Scheme 1
Scheme 2
Crimmins9 have also achieved successful total syntheses in
this area.
The spongistatins possess a striking array of structural
features, including a 42-membered macrolactone incorporat-
ing two spiroketals, a hemiketal, and a tetrahydropyran,
which is subtended by a highly unsaturated side chain. Hav-
ing recently achieved a preparatively useful synthesis of the
advanced ABCD fragment (-)-4,12 we turned to a second-
generation synthesis of the C(29)-C(51) EF Wittig salt (+)-
3. Our strategy called for three subunits 5, 7, and 8. On the
basis of our first-generation syntheses, we envisioned a chela-
tion-controlled addition of known dithiane 811 to F-ring al-
dehyde 7, followed by removal of the acetonide and dithiane
with in situ hemiketalization would provide the EF bis-pyran
6 with the requisite C(38) stereogenicity. Installation of the
As anticipated, efficient fragment union was achieved in
a highly stereocontrolled fashion (>20:1; 51% yield; Scheme
3) via treatment of the cerium anion generated from dithiane
(-)-8 with a premixed solution of aldehyde (+)-7 and zinc
chloride.18 Acidic removal of the acetonide (CSA, MeOH/
H2O, 86%) in (+)-14, followed by dithiane removal employ-
ing the conditions of Fujita19 [Hg(ClO4)2, CaCO3, CH3CN/
H2O, 95%], with concomitant hemiketal formation then
afforded (+)-15 possessing the E and F rings. Selective
protection of the sterically more accessible C(35) hydroxyl
(7) (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.
(8) 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.; Hodgson, A. P.; Norcross, R. D. Angew. Chem., Int. Ed. 2001, 40, 4055.
(9) Crimmins, M. T.; Katz, J. D.; Washburn, D. G.; Allwein, S. P.;
McAtee, L. F. J. Am. Chem. Soc. 2002, 124, 5661.
(10) For synthetic approaches to the spongistatins, see refs 5-9 and
references therein.
(11) Smith, A. B., III; Zhuang, L.; Brook, C. S.; Boldi, A. M.; McBriar,
M. D.; Moser, W. H.; Murase, N.; Nakayama, K.; Verhoest, P. R.; Lin, Q.
Tetrahedron Lett. 1997, 38, 8667.
(13) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919.
(14) Hubschwerlen, C. Synthesis 1986, 962.
(15) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron Lett.
1988, 29, 4139.
(16) Crispino, G. A.; Jeong, K.-S.; Kolb, H. C.; Wang, Z.-M.; Xu, D.;
Sharpless, K. B. J. Org. Chem. 1993, 58, 3785.
(17) Parikh, J. R.; Doering, W. V. E. J. Am. Chem. Soc. 1967, 89, 5505.
(18) The use of cerium chloride serves to suppress enolization; see:
Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya, Y. J.
Am. Chem. Soc. 1989, 111, 4392.
(12) Smith, A. B. III; Doughty, V. A.; Sfouggatakis, C.; Bennett, C. S.;
Koyanagi, J.; Takeuchi, M. Org. Lett. 2002, 4, 783.
(19) Fujita, E.; Nagao, Y.; Kaneko, K. Chem. Pharm. Bull. 1978, 26,
3743.
762
Org. Lett., Vol. 5, No. 5, 2003

Scheme 3
Scheme 4
ee), albeit the yields were at best modest (ca. 33%).
Application of a bis-zirconium catalyst23 led to a marked
improvement in yield (69%), furnishing homoallylic alcohol
(-)-23 with similar enantioselectivity (97% ee). Silylation
(TMSCl, imid., 78%), followed by removal of the pivaloate
moiety (DIBAL) and installation of the 2,4-dichlorobenzoate
(DCBCl, Pyr., 70%, two steps) then afforded (+)-24.
Completion of the fully functionalized allyl stannane side
chain (+)-5 was achieved by exposure of (+)-24 to Pd(PPh3)4
and Bu3SnAlEt2.24 Importantly, the chlorodiene moiety was
not compromised under the palladium conditions.
Side chain installation proceeded readily via the Evans
precedent (Scheme 5);5 specifically, epoxidation of bis-pyran
(+)-6 with dimethyldioxirane in methylene chloride, fol-
lowed in turn by treatment with allylstannane (+)-5 in the
presence of Bu3SnOTf and then KF (MeOH/THF) provided
(+)-25 as a single isomer in good yield (73%; 3 steps).
(TBSOTf, 2,6-lutidine, 90%) next provided an intermediate
TBS ether. Removal of the C(29) and C(41) benzyl ethers
in the presence of a PMB group, as now required, proved
difficult. Precedent for such chemoselectivity has been ob-
served by Hirota20 for phenolic hydroxyls, using a Pd/C-
pyridine catalyst. In our case this protocol resulted in no reac-
tion. We reasoned that the pyridine may compete with the
benzyl group for access to the active palladium surface, and
thus a bulkier pyridine derivative might be more appropriate.
Pleasingly, clean debenzylation was achieved in the presence
of the C(42) PMB group via transfer hydrogenation, using
2,6-lutidine as an additive. Methanolysis of the intermediate
triol then afforded methyl ketal (+)-16 in high yield for the
two steps. Exhaustive silylation (TESOTf, CH2Cl2, 86%),
followed by medium-pressure hydrogenolysis (500 psi)
removed the PMB group to furnish alcohol (+)-17. Enol
ether (+)-6 was then generated in two steps via triflation
(Tf2O, Pyr.) and elimination (LDA) of triflic acid.
Scheme 5
For the required allylstannane side chain (+)-5 (Scheme
4), our departing point entailed coupling commercially avail-
able allyl chloride 18 with ethyl glyoxalate in the presence
of catalytic BiCl3 (0.12 equiv); ester 19 was obtained in 62%
yield.21 Mesylation (MsCl, Et3N) of the hydroxyl group,
followed by elimination (DBU) of methanesulfonic acid then
provided the R,â-unsaturated ester 20 (89%, two steps).
Reduction with DIBAL next led to an intermediate alcohol
that upon oxidation yielded aldehyde 21 in 89% yield (two
steps). Initial attempts to couple 21 with stannane 22 using
the Keck protocol22 resulted in high enantioselectivity (98%
(20) Sajiki, H.; Kuno, H.; Hirota, K. Tetrahedron Lett. 1997, 38, 399.
(21) Wada, M.; Ohki, H.; Abiba, K. Bull. Chem. Soc. Jpn. 1990, 63,
1738.
Org. Lett., Vol. 5, No. 5, 2003
763

Selective sulfonation of the primary hydroxyl group with
TrisCl (2,6-di-tBu-4-methylpyridine, DMAP, 93%) next
furnished (+)-26. Interestingly, use of the less hindered bases
such as Et3N or Hu¨nig’s base resulted in lower yields of the
primary sulfonate, in conjunction with hydrolysis of the
C(37) methyl ketal. Conversion of (+)-26 to the iodide (LiI,
2,6-lutidine, 94%), protection of the three secondary hy-
droxyls (TMSOTf, 2,6-lutidine, 99%), and reaction with PPh3
(Li2CO3, 93%) then completed assembly of the EF Wittig
salt (+)-3. The synthesis of the fully functionalized EF
fragment was thus achieved employing 24 steps in the longest
linear sequence, with an overall yield of 1.8%.
After removal of the TMS and TIPS groups (KF, MeOH/
THF, quant.), selective protection5,9 of the C(47) hydroxyl
(TESCl, imid., Et3N, 94%) provided (+)-30. Regioselec-
tive macrolactonization5-9 then led to the desired 42-
membered macrolide as the sole product in high yield (81%).
Global deprotection7 employing dilute aqueous HF completed
the total synthesis of (+)-spongistatin 1 (1), which was
identical in all respects (500 MHz 1H, 125 MHz 13C
NMR, HRMS, IR and chiroptic properties) to the literature
data.1,8
In conclusion, we have achieved an effective, second-
generation stereocontrolled total synthesis of (+)-spongistatin
1 (1), highlighted by a highly selective dithiane addition to
F-pyran aldehyde (+)-7, the construction of allylstannane
(+)-5, and the efficient union of fragments. The synthesis
proceeded in 29 steps for the longest linear sequence (based
on the EF subunit), with an overall yield of 0.5%. Impor-
tantly, the linear sequence for our second-generation syn-
thesis [18 steps shorter than our previously reported formal
synthesis of spongistatin 1 (1)]7a is highly competitive with
the other published approaches.
For (+)-spongistatin 1 (1), fragment assembly was achieved
via Wittig coupling of (+)-3 with advanced aldehyde (-)-
412 to provide (+)-28 in 64% yield, employing a modifica-
tion of the conditions reported by Paterson (Scheme 6).8
Scheme 6
Acknowledgment. Financial support was provided by the
NIH (NCI) through grant CA-70329, by Postdoctoral Fel-
lowships from the Uehara Memorial Foundation and the
JSPS for research abroad (2002) to S.S., 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.
OL034037A
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