Spongistatin synthetic studies. Evolution of a scalable synthesis for the EF fragment of (+)-spongistatin 1 exploiting a petasis-ferrier union/rearrangement tactic

Article abstract of DOI:10.1021/ol048418f

(Chemical Equation Presented) An efficient, stereocontrolled, and scalable second-generation synthesis of (+)-3, an advanced EF subtarget for the total synthesis of (+)-spongistatin 1, has been achieved. Highlights of the strategy include preparation of t

Full text of DOI:10.1021/ol048418f

ORGANIC
LETTERS
2004
Vol. 6, No. 20
3637-3640
Spongistatin Synthetic Studies.
Evolution of a Scalable Synthesis for
the EF Fragment of (
Exploiting a Petasis
Rearrangement Tactic
+
)-Spongistatin 1
Ferrier Union/
−
Amos B. Smith, III,* Chris Sfouggatakis, Dimitar B. Gotchev, Shohei Shirakami,
David Bauer, Wenyu Zhu, and Victoria A. Doughty
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 August 10, 2004
ABSTRACT
An efficient, stereocontrolled, and scalable second-generation synthesis of (
+
)-3, an advanced EF subtarget for the total synthesis of (
+)-
spongistatin 1, has been achieved. Highlights of the strategy include preparation of the F-ring pyran via a Petasis−Ferrier union/rearrangement
sequence and installation of the chlorodiene side chain employing a cyanohydrin alkylation. The longest linear sequence, 26 steps, proceeds
in 8.3% overall yield.
The spongistatins comprise a unique family of architecturally
complex marine macrolides which display extraordinary
cytotoxicity.1 Since their isolation,2-4 the spongistatins have
attracted wide attention among both the chemical and
biological communities based on their intriguing structures
and potent antitumor activities.5 The first total syntheses of
spongistatin 2 (2) by Evans6 and spongistatin 1 (1) by Kishi7
confirmed the relative and absolute stereochemical assign-
ments proposed by the Kitagawa group4 (Scheme 1).
(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.
(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) See refs 8-11 for a list of synthetic studies towards the spongistatins.
10.1021/ol048418f CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/03/2004

Scheme 1
Scheme 2
membered macrolide framework, 24 stereogenic centers, and
a delicate triene side chain.
Recently, we reported a first-generation synthesis of (+)-
spongistatin 1 (1)8b exploiting an advanced C(29)-C(51) EF
Wittig salt. We have since redesigned the EF synthetic
strategy with two purposes in mind. First, we sought a
preparatively more effective synthesis of the EF fragment
by addressing some of the deficiencies encountered in our
earlier work. Second, we wished to exploit the modified
Petasis-Ferrier union/rearrangement tactic developed in our
laboratory to assemble the F-ring tetrahydropyran.12 With
these goals in mind, EF fragment (+)-3 was envisioned to
arise via the stereoselective allylation of bis-pyran iodide
(+)-5 with chlorodiene aldehyde 6 (Scheme 1). Further
synthetic analysis of (+)-5 revealed known dithiane (-)-
8,13 which, on the basis of our first-generation synthesis,8
would be coupled to F-ring aldehyde (+)-7, employing
chelation control to install the C(38) hydroxyl stereoselec-
tively. F-ring aldehyde (+)-7, in turn, would be assembled
by way of the Petasis-Ferrier union/rearrangement tactic.
Preparation of F-ring aldehyde (+)-7 (Scheme 2) began
with the TMSOTf-promoted14 union of bis-silyl â-hydroxy
acid (-)-915 with (4Z)-heptenal to afford dioxanone (-)-10
(86%, dr 12:1).16 Petasis-Tebbe methylenation (Cp2TiMe2)17
and exposure of the resulting enol ether to Me2AlCl to trigger
the Petasis-Ferrier rearrangement furnished pyranone (-)-
11 as a single isomer18 in 77% yield (two steps). After
considerable experimentation, introduction of the C(42)
Subsequent total syntheses now include those from the
Smith,8 Paterson,9 Crimmins,10 and Heathcock11 laboratories.
Structurally, the spongistatins possess a striking array of
features, which include two spiroketal moieties, a highly
substituted bis-tetrahydropyran unit encased in a 42-
(6) (a) Evans, D. A.; Coleman, P. J.; Dias, L. C.Angew. Chem., Int. Ed.
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.
(7) (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.
(8) (a) 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. (b) Smith, A. B., III; Zhu, W.; Shirakami, S.;
Sfouggatakis, C.; Doughty, V. A.; Bennett, C. S.; Sakamoto, Y. Org. Lett.
2003, 5, 761.
(9) Paterson, I.; Chen, D. Y.-K.; Coster, M. J.; Acena, 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.
(10) Crimmins, M. T.; Katz, J. D.; Washburn, D. G.; Allwein, S. P.;
McAtee, L. F. J. Am. Chem. Soc. 2002, 124, 5661.
(11) (a) Heathcock, C. H.; Hubbs, J. L. J. Am. Chem. Soc. 2003, 125,
12836. (b) Heathcock, C. H.; McLaughlin, M.; Medina, J.; Hubbs, J. L.;
Wallace, G. A.; Scott, R.; Claffey, M. M.; Hayes, C. J.; Ott, G. R. J. Am.
Chem. Soc. 2003, 125, 12844.
(12) (a) Ferrier, R. J.; Middleton, S. Chem. ReV. 1993, 93, 2779. (b)
Petasis, N. A.; Lu, S.-P. Tetrahedron Lett. 1996, 37, 141. (c) Smith, A. B.,
III; Verhoest, P. R.; Minbiole, K. P.; Lim, J. L. Org. Lett. 1999, 1, 909 and
references therein.
(13) 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.
(14) Seebach, D.; Imwinkelried, R.; Stucky, G. HelV. Chim. Acta 1987,
70, 448.
(15) Prepared in two steps exploiting Evans oxazolidinone chemistry;
see the Supporting Information.
(16) Upon scale-up, TfOH (∼9 mol %) was added, as the reaction does
not proceed otherwise, suggesting that adventitious water was more
pronounced on small scale thereby generating TfOH in situ.
(17) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392.
(18) The stereochemistry in (-)-11 was established on the basis of NOEs
observed between the C(39), C(40), and C(43) hydrogens.
3638
Org. Lett., Vol. 6, No. 20, 2004

Scheme 3
Scheme 4
protected as the tetra-TES ether to provide (+)-17 in high
yield over the four steps. Partial side-chain introduction began
with ozonolysis of alkene (+)-17 employing a reductive
workup, followed without isolation by treatment with Es-
chenmoser’s salt26 to afford enal (+)-18. Completion of
allylation precursor (+)-5 was then achieved by 1,2-reduction
of the aldehyde and conversion of the derived alcohol to the
allyl iodide.
Initial attempts to install the chlorodiene moiety focused
on a tin-mediated Barbier27 allylation between iodide (+)-5
and known chlorodiene aldehyde 68b (Scheme 4). Precedent
for this construction derives from the Paterson group
synthesis of spongistatin 1,9 wherein the boron enolate
generated from an EF bis-pyran methyl ketone was coupled
to aldehyde 6 to set the C(47) hydroxyl stereochemistry with
high selectivity employing substrate control.28 In an effort
to exploit this stereochemical bias, we treated a premixed
solution of iodide (+)-5 [or bromide (+)-19] and aldehyde
6 with SnCl2‚2H2O to affect coupling. However, after
significant effort, at best we obtained only a 42% yield of
20, produced as a mixture (∼1:1) of C(47) alcohols. All other
conditions (i.e., various metal sources, solvents, and tem-
peratures) proved unsuccessful.
Having exhausted most, if not all options directed at side
chain installation via allylation chemistry, we decided to alter
our strategy by incorporating the chlorodiene moiety as a
nucleophile rather than as an electrophile. To this end, TMS-
cyanohydrin 21 (Scheme 5)29 was prepared and treated with
LiHMDS at low temperature, followed by addition of allyl
iodide (+)-5 [or bromide (+)-19]. Initial attempts to affect
this coupling, however, resulted in cyanohydrin decomposi-
tion with recovery of the allyl halide. Subsequent deuterium
studies revealed that the anion derived from cyanohydrin 21
is highly unstable, decomposing rapidly at low temperatures.
Suspecting that the instability of the anion derived from
cyanohydrin 21 was due to the unsaturation, we prepared
hydroxyl group was achieved by treatment of the potassium
enolate derived from (-)-11 with oxaziridine (+)-1219 to
provide R-hydroxy ketone (+)-13 in 78% yield after base-
promoted epimerization (K2CO3, MeOH) of the C(40) methyl
substituent. Silylation,20 selective axial reduction, and an
acidic workup to remove the TMS group then furnished diol
(+)-14 in 85% yield (two steps, dr 7:1).21 Completion of
the F-ring aldehyde (+)-7 was then achieved by formation
of the bis-benzyl ether, oxidative removal of the p-methox-
yphenyl group, and Parikh-Doering22 oxidation (99%, three
steps).
As anticipated, efficient fragment union was achieved via
treatment of the cerium anion generated from dithiane (-)-8
with a premixed solution of aldehyde (+)-7 and zinc
chloride23 to afford (+)-15 as a single isomer24 (68%; Scheme
3). Acidic removal of the acetonide, followed by dethioket-
alization with in situ formation of the E-ring hemiketal,
afforded the EF bis-pyran (+)-16. Selective silylation at
C(35), formation of the methyl ketal, and reductive deben-
zylation25 then led to an intermediate polyol which was
(19) Davis, F. A.; Kumar, A.; Chen, B.-C. J. Org. Chem. 1991, 56, 1143.
(20) Silylation at C(42) served to minimize chelation-control in the
reduction, which otherwise resulted in poor selectivity.
(21) Watanabe, Y.; Ogasawara, T.; Nakahira, H.; Matsuki, T.; Ozaki, S.
Tetrahedron Lett. 1988, 29, 5359.
(22) Parikh, J. R.; Doering, W. V. E. J. Am. Chem. Soc. 1967, 89, 5505.
(23) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya,
Y. J. Am. Chem. Soc. 1989, 111, 4392.
(24) The C(38) stereochemistry was confirmed by Mosher ester analysis;
see: Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. (b) Ohtani,
I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,
4092.
(25) Ireland, R. E.; Smith, M. G. J. Am. Chem. Soc. 1988, 110, 854.
(26) Schreiber, J.; Maag, H.; Hashimoto, N.; Eschenmoser, A. Angew.
Chem., Int. Ed. Engl. 1971, 10, 330.
(27) Imai, T.; Nishida, S. A. Synthesis 1993, 395.
(28) This is in the 1,5-syn sense, opposite to 1,5-anti stereoinduction
observed for boron aldol reactions of simple â-alkoxy ketones, suggesting
in this case, the overwhelming contribution from the more remote
stereocenters; see ref 9.
(29) Prepared by treatment of 6 with TMSCN and ZnI2; see: (a) Stork,
G.; Maldonado, L. J. Am. Chem. Soc. 1971, 93, 5286. (b) Evans, D. A.;
Truesdale, L. K. J. Chem. Soc., Chem. Commun. 1973, 55.
Org. Lett., Vol. 6, No. 20, 2004
3639

Scheme 5
Scheme 6
24 (Scheme 6).30 Pleasingly, modified cyanohydrin 24
underwent clean deprotonation and coupled readily to iodide
(+)-5. Subsequent hydrolysis of the cyanohydrin moiety (KF,
MeOH), accompanied by desilylation at C(29) and C(49),
afforded â-hydroxy ketone 25 in high yield (97%, 2 steps),
as an inconsequential mixture (∼1:1) of alcohols. Elimination
of the C(49) hydroxyl with concomitant formation of the
C(29) iodide was then achieved upon treatment of â-hydroxy
ketone 25 to iodination under buffered conditions (I2, PPh3,
imid). Iodoketone (+)-26 was obtained in 88% yield.
Asymmetric reduction employing the Corey protocol31 then
established the C(47) hydroxyl stereogenicity32 to furnish
(+)-27 in both good yield and with excellent selectivity
(80%, dr > 10:1). Notably, this transformation was success-
fully achieved in the presence of the sensitive chlorodiene
moiety, as well as the exomethylene and the primary iodide.
Silylation followed by Wittig salt formation completed the
synthesis of the fully functionalized C(29)-C(51) EF frag-
ment (+)-3 for (+)-spongistatin 1.
The synthesis of (+)-3, achieved with a longest linear
sequence of 26 steps (8.3% overall yield) from â-hydroxy
acid (-)-9, represents a dramatic improvement in yield
compared to our first-generation total synthesis of spong-
istatin 1 (24 steps, 1.8% overall yield).8b Completion of a
second-generation synthesis of (+)-spongistatin 1 is now
envisioned to be achieved in a fashion similar to our first-
generation approach [i.e., Wittig union of (+)-3 with ABCD
(-)-4,33 followed by desilylation, regioselective Yamaguchi
cyclization,6d,34 and global deprotection].
synthesis of the advanced EF fragment of (+)-spongistatin
1. The synthesis features construction of the F-ring pyran
aldehyde (+)-7 employing a modified Petasis-Ferrier union/
rearrangement sequence developed in our laboratory.12c Also
noteworthy is the effective installation of the highly sensitive
chlorodiene moiety using the cyanohydrin approach. Comple-
tion of a second-generation total synthesis of (+)-spongistatin
1 will be disclosed in due course.
Acknowledgment. Financial support was provided by the
NIH (NCI) through Grant No. CA-70329, by Postdoctoral
Fellowships from the Uehara Memorial Foundation and the
JSPS for research abroad to S.S. and by a Royal Society
Fulbright Fellowship to V.A.D.
In summary, we have achieved an efficient, stereocon-
trolled, and most importantly, scalable second-generation
(30) See the Supporting Information for the preparation of 24.
(31) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.
(32) The C(47) stereochemistry was confirmed by chemical correlation
to an intermediate prepared in our previous synthesis.
(33) The synthesis of (-)-4 was previously disclosed; see: Smith, A.
B., III; Doughty, V. A. D.; Sfouggatakis, C.; Bennett, C. S.; Koyanagi, J.;
Takeuchi, M. Org. Lett. 2002, 4, 783.
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.
(34) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
OL048418F
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Org. Lett., Vol. 6, No. 20, 2004