A modular approach to marine macrolide construction. 4. assembly of C36 - C51 and C29 - C44 building blocks and evaluation of key coupling reactions targeting spongistatin 1 (Altohyrtin A)

Article abstract of DOI:10.1021/ol063083i

Routes have been developed for the stereocontrolled elaboration of two highly functionalized sectors of spongistatin 1. The approach to ring F takes advantage of S-alkyl Suzuki - Miyaura coupling to install the C44 - C45 bond. The E-ring pyran moiety was

Full text of DOI:10.1021/ol063083i

ORGANIC
LETTERS
2007
Vol. 9, No. 4
719-722
A Modular Approach to Marine
Macrolide Construction. 4. Assembly of
C36−C51 and C29−C44 Building Blocks
and Evaluation of Key Coupling
Reactions Targeting Spongistatin 1
(Altohyrtin A)
Stephane Ciblat, Jungchul Kim, Catherine A. Stewart, Jizhou Wang,
Pat Forgione, Dean Clyne, and Leo A. Paquette*
EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210
paquette.1@osu.edu
Received December 20, 2006
ABSTRACT
Routes have been developed for the stereocontrolled elaboration of two highly functionalized sectors of spongistatin 1. The approach to ring
F takes advantage of B-alkyl Suzuki Miyaura coupling to install the C44 C45 bond. The E-ring pyran moiety was generated by acylation of
an -sulfonyl carbanion, the stereogenic centers of which were incorporated by sequential asymmetric aldol reactions.
−
−
r
More than 10 years have elapsed since the spongipyran
marine macrolides have been characterized1-3 and their
extraordinary inhibitory capacity against many human cancer
cell lines defined.4 The outstanding potency of these structur-
ally unique macrolides has generated substantial interest in
the total synthesis of spongistatin 1 (1, X ) Cl) and 2 (1, X
) H),5 as well as their AB and CD spiroketal sectors, and
the constituent E and F rings. Our own efforts in this area
have consisted of the development of an expeditious enan-
tioselective route to C1-C28 (see framed sector of 1),6 with
the intent of conjoining this major eastern fragment to a
properly functionalized C29-C51 subunit. An early vision
of this merger involved deployment of the B-alkyl Suzuki-
Miyaura cross-coupling reaction7 as a means for convenient
installation of the C44-C45 bond that links the vinyl chloride
side chain to ring F. In recent years, this protocol has gained
increasing acceptance in natural product synthesis8 but has
(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.; 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.; 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. (e) Pettit, G. R. Pure Appl.
Chem. 1994, 66, 2271.
(2) (a) Kobayashi, M.; Aoki, S.; Kitagawa, I. Tetrahedron Lett. 1994,
35, 1243. (b) Kobayashi, M.; Aoki, S.; Sakai, H.; Kawazoe, K.; Kihara,
N.; Sasaki, T.; Kitagawa, I. Tetrahedron Lett. 1993, 34, 2795. (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, K.; Kitagawa, I.
Chem. Pharm. Bull. 1996, 44, 2142.
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(4) Pettit, G. R. J. Nat. Prod. 1996, 59, 812.
10.1021/ol063083i CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/18/2007

not yet been utilized in pursuit of the spongistatins. In this
report, we show that reaction occurs smoothly and efficiently
between an alkylborane residing in a fully functionalized
F-ring setting and a vinyl iodide consisting of the partially
polyunsaturated side chain.
Scheme 1. Vinyl Iodide Syntheses
Our advance on vinyl iodides 7 and 8 began with ring
cleavage of (R)-glycidol (2) by reaction of its pivalate ester
with lithium trimethylsilylacetylide as earlier described9
(Scheme 1). Following liberation of the terminal alkyne,
conversion to the 2-iodo-1-alkene was conveniently ac-
complished with 9-iodo-9-BBN.10 Hydroxyl protection as the
TBS derivative and reduction of the pivalate ester then set
the stage for oxidation to aldehyde 5 and three-carbon chain
extension involving 2,3-dichloropropene and indium powder
in DMF.11 The availability of 7 in this manner was
anticipated to provide more advanced intermediates having
a C44-C51 side chain less sensitive to degradation than its
trienyl counterpart. In this connection, the dehydration of 6
to give 8 proved uneventful when performed with the Martin
sulfurane reagent.12
The elaboration of ring F involved preliminary conversion
of carbinol 913 to its methyl ester 10. We came to favor the
three-step sequence shown in Scheme 2 because it delivered
10 efficiently without complications attributable to epimer-
ization. The critical particulars surrounding generation of the
exo-olefin consisted of sequential mild acidic hydrolysis to
(5) (a) Review: Yeung, K.-S.; Paterson, I. Chem. ReV. 2005, 105, 4237.
(b) See also: Ball, M.; Gaunt, M. J.; Hook, D. F.; Jessiman, A. S.;
Kawahara, S.; Orsini, P.; Scolaro, A.; Talbot, A. C.; Tanner, H. R.; Yamanoi,
S.; Ley, S. V. Angew. Chem., Int. Ed. 2005, 44, 5433. (c) Guo, J.; Duffy,
K. J.; Stevens, K. L.; Dalko, P. I.; Roth, R. M.; Hayward, M. H.; Kishi, Y.
Angew. Chem., Int. Ed. 1998, 37, 187. (d) Hayward, M. H.; Roth, R. M.;
Duffy, K. J.; Dalko, P. I.; Stevens, K. L.; Guo, J.; Kishi, Y. Angew. Chem.,
Int. Ed. 1998, 37, 192. (e) 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. (f) 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. (g) Smith, A. B., III; Doughty, V. A.; Sfouggatakis, C.; Bennett, C.
S.; Koyanagi, J.; Takeuchi, M. Org. Lett. 2002, 4, 783. (h) Smith, A. B.,
III; Zhu, W.; Shirakami, S.; Sfouggatakis, C.; Doughty, V. A.; Bennett, C.
S.; Sakamoto, Y. Org. Lett. 2003, 5, 761. (i) Paterson, I.; Chen, D. Y.-K.;
Coster, M. J.; Aceua, 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. (j) Crimmins, M. T.; Katz, J. D.;
Washburn, D. G.; Allwein, S. P.; McAtee, L. F. J. Am. Chem. Soc. 2002,
124, 5661. (k) Evans, D. A.; Coleman, P. J.; Dias, L. C. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2738. (l) Evans, D. A.; Trotter, B. W.; Coˆte´, B.;
Coleman, P. J. Angew. Chem., Int. Ed. Engl. 1997, 36, 2741. (m) 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. (n) Evans, D. A.; Trotter, B.
W.; Coleman, P. J.; Coˆte´, B.; Dias, L. C.; Rajapakse, H. A.; Tyler, A. N.
Tetrahedron 1999, 55, 8671.
Scheme 2. Crafting of the F Ring
(6) (a) Paquette, L. A.; Zuev, D. Tetrahedron Lett. 1997, 38, 5115. (b)
Paquette, L. A.; Braun, A. Tetrahedron Lett. 1997, 38, 5119. (c) Zuev, D.;
Paquette, L. A. Org. Lett. 2000, 2, 679.
(7) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Suzuki,
A. J. Organomet. Chem. 1999, 576, 147.
(8) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int.
Ed. 2001, 40, 4544.
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720
Org. Lett., Vol. 9, No. 4, 2007

produce diol 11, regiocontrolled formation of primary iodide
12,14 silyl protection of the remaining hydroxyl group,18 and
dehydroiodination with DBU in C6H6 at 60 °C.15 The borane
reagent was in turn generated by the action of 9-BBN-H
on the exo-methylene intermediate.16 At this point, recourse
was made to the combined capabilities of PdCl2(dppf) and
K3PO4 to deliver in 55% overall yield a product identifiable
by spectroscopic means as 14. The coupling constant of 9.3
Hz observed between H42 and H43 was especially diagnostic
of their trans-diaxial relationship. During subsequent scrutiny
of further chemical manipulations, we became aware of the
lability of 14 and congeners thereof. These complications
were resolved by replacement of the labile OTMS group in
14 by the more robust OTBS group as in 15 before
proceeding forward.
70:30 mixture of aldols rich in the syn isomer. Chromato-
graphic purification followed protection as the TES ether.
Sequential lithium borohydride reduction to the primary
alcohol 20 and oxidation with IBX19 led to aldehyde 21. At
this point, we made recourse to the tin(II) enolate of
thiazolidinethione 22 for the purpose of generating 23. The
involvement of a highly chelated transition state in this
instance requires that the absolute configuration of 22 be
opposite to that of 17. Indeed, the Fujita-Nagao protocol20
functioned very effectively to furnish 23 as the sole product
in 96% yield. Reductive removal of the chiral auxiliary and
subsequent generation of iodide 25 made possible the
ultimate acquisition of sulfone 26.
Construction of the required building block began by
acylating the carbanion of sulfone 26 with acid chloride 27,
as generated from 10 via saponification and subsequent
exposure to 1-chloro-N,N-2-trimethylpropenylamine.21 Oxi-
dation of the resulting 28 with the reactive dichlorinated
oxaziridine 29 introduced by Williams22 gave rise to the
R-diketone (Scheme 4). The latter was treated directly with
Our complementary thrust began with the operational
proposition that the E-ring pyran subunit could be correlated
to a terminal sulfone defined by 26, the stereogenic centers
in which were to be installed by means of asymmetric aldol
reactions (Scheme 3). Following the generation of aldehyde
Scheme 3. Elaboration of Sulfone 26
Scheme 4. Synthesis of the Completely Assembled Bispyran
31
p-toluenesulfonic acid to bring about chemoselective removal
of the TES group. Acetonide hydrolysis in a solvent system
of THF and ethylene glycol followed to induce cyclization
(14) Prisbe, E. J.; Smejkal, J.; Verheyden, J. P. H.; Moffatt, J. G. J.
Org. Chem. 1976, 41, 1836.
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Soc. 2001, 123, 9974.
(16) Rajan Babu, T. V.; Reddy, G. S. J. Org. Chem. 1986, 51, 5458.
(17) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 77, 83.
(18) Inoue, T.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1980, 53, 174.
(19) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019.
(20) Nagao, Y.; Hagiwara, Y.; Kumagai, T.; Ochiai, M.; Inoue, T.;
Hashimoto, K.; Fujita, E. J. Org. Chem. 1986, 51, 2391.
(21) Devos, A.; Re´mion, J.; Frisque-Hesbain, A.-M.; Colens, A.; Ghosez,
L. Chem. Commun. 1979, 1180.
16 from 1,5-pentanediol, its exposure to the dibutylboron
enolate of 1717,18 gave rise in a 94% combined yield to a
(22) (a) Williams, D. R.; Robinson, L. A.; Amato, G. S.; Osterhout, M.
H. J. Org. Chem. 1992, 57, 3740. (b) Williams, D. R.; Coleman, P. J.;
Nevill, C. R.; Robinson, L. A. Tetrahedron Lett. 1993, 34, 7895.
(12) Arhart, R. J.; Martin, J. C. J. Am. Chem. Soc. 1972, 94, 5003.
(13) Cho, I. H.; Paquette, L. A. Heterocycles 2002, 58, 43.
Org. Lett., Vol. 9, No. 4, 2007
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to lactol 30. Our ability to preserve the integrity of the labile
OTBS group at C34 in this manner is notable. When
formation of the methyl glycoside was found to be precluded
because of the proximal ketone carbonyl, generation of
primary iodide 31 followed immediately.
The lessons learned in this study are expected to be useful
in our continuing studies aimed at developing a synthetic
entry to spongistatin 1. Applications toward this goal are
currently being pursued.
Acknowledgment. Financial support was generously
provided by the S. T. Li Foundation, Eli Lilly Company,
and Sanofi-Aventis Pharmaceuticals.
Supporting Information Available: Detailed experi-
mental procedures and spectral characterization of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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