Enantio- and diastereoselective allylmetalations: An easy and efficient access to the AB spiroketal of spongistatin

Article abstract of DOI:10.1021/ol060812l

A unique combination of highly enantio- and diastereoselective allylmetalations and a one-pot "desacetalization/spiroketalization" have been employed to synthesize the AB spiroketal fragment (C1-C13) of spongistatin in 15 steps and in excellent diastereos

Full text of DOI:10.1021/ol060812l

ORGANIC
LETTERS
2006
Vol. 8, No. 17
3655-3657
Enantio- and Diastereoselective
Allylmetalations: An Easy and Efficient
Access to the AB Spiroketal of
Spongistatin
Florent Allais and Janine Cossy*
Laboratoire de Chimie Organique, Associe´ au CNRS, ESPCI, 10 rue Vauquelin,
F-75231 Paris Cedex 05, France
janine.cossy@espci.fr
Received April 4, 2006
ABSTRACT
A unique combination of highly enantio- and diastereoselective allylmetalations and a one-pot “desacetalization/spiroketalization” have been
employed to synthesize the AB spiroketal fragment (C1 C13) of spongistatin in 15 steps and in excellent diastereoselectivity.
−
In 1993, the isolation of several series of macrolides from
the marine sponges of the genus Spongia such as spongi-
statins, cinachyrolides, and altohyrtins was reported by Pettit
et al. (Figure 1). These compounds exhibit extremely potent
antitumor activity.1-7 The spongistatins (altohyrtins) elicit
extraordinary (subnanomolar) growth inhibition of a variety
of chemoresistant tumor types included in the NCI panel of
60 human cancer cell lines. Human melanoma, lung, brain,
and colon cancers were particularly sensitive to spongistatin
1, whose activity correlates well with the class of microtubule
interactive antimitotics. This remarkable biological profile
and the extremely limited supply of these compounds (400
kg wet weight of Spongia sp. provided only 13.8 mg of
spongistatin) have sparked intense synthetic efforts and there
has been enormous interest in the pharmacology and structure
of these compounds.
Seven total syntheses8 and a number of syntheses of
key substructures9,10 have been reported. The syntheses of
altohyrtin C (identical with spongistatin 2) and altohyrtin A
(spongistatin 1) have served to confirm their structure (Figure
1).5 Partial syntheses have focused on the synthesis of the
(1) Pettit, G. R.; Cichacz, Z. A.; Gao, R.; 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.;
Schmidt, J. M.; Hamol, E.; Bai, R. J. Chem. Soc., Chem. Commun. 1994,
1605.
(3) (a) Kobayashi, M.; Aoki, S.; Kitagawa, I. Tetrahedron Lett. 1994,
35, 1243. (b) Kobayashi, M.; Aoki, S.; Sakai, S.; 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) Aoki, S.; Nemoto, N.; Kobayashi, Y.; Kobayashi, M.; Kitagawa, I.
Tetrahedron 2001, 57, 2289.
(6) Pietruszka, J. Angew. Chem., Int. Ed. 1998, 37, 2629.
(7) Pettit, G. R. J. Nat. Prod. 1996, 59, 812.
Figure 1. Spongistatin family.
10.1021/ol060812l CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/27/2006

AB and CD spiroketals and on the EF tetrahydropyran
moieties.10
Here, we would like to report the synthesis of the AB
spiroketal A, which was planned from ketone B (Scheme
1). It was envisaged that the stereogenic center at C11 will
allylmetal respectively on a â-hydroxy aldehyde and a
â-hydroxy ketone. Furthermore, the use of an enantio-
selective allyltitanation was envisaged to establish the C5
stereogenic center.
The synthesis of the AB ring of spongistatin began with
the opening of the known epoxide 111 with isopropenyl-
magnesium bromide in the presence of CuI (THF, -40 °C)
to afford the homoallylic alcohol 2 in 94% yield (Scheme
2). To control the stereogenic center at C9, compound 2 was
Scheme 1
Scheme 2
be issued from the ring opening of the optically active
epoxide 1 and the C3 and C9 stereogenic centers will be
controlled by using a diastereoselective addition of an
(8) (a) 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. (b) Paterson, I.; Coster, M.;
Chen, D. Y.-K.; Oballa, R. M.; Wallace, D.; Norcross, R. D. Org. Biomol.
Chem. 2005, 3, 2399. (c) Paterson, I.; Coster, M. J.; Chen, D. Y.-K.; Gibson,
K. R.; Wallace, D. J. Org. Biomol. Chem. 2005, 3, 2410. (d) Paterson, I.;
Coster, M. J.; Chen, D. Y.-K.; Acen˜a, J. L.; Bach, J.; Keown, L. E.;
Trieselman, T. Org. Biomol. Chem. 2005, 3, 2420. (e) Paterson, I.; Chen,
D. Y.-K.; Coster, M. J.; Acen˜a J. L.; Bach, J.; Wallace, D. J. Org. Biomol.
Chem. 2005, 3, 2431. (f) Heathcock, C. H.; McLaucghlin, 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. (g) Crimmins, M. T.; Katz, J.
D.; Washburn, D. G.; Allwein, S. P.; McAtee, L. F. J. Am. Chem. Soc.
2002, 124, 5661-5663. (h) Smith, A. B., III; Lai, 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. (i) Evans, D. A.;
Trotter, B. W.; Coleman, P. J.; Coˆte´, B.; Dias, L. C.; Rajapakse, H.; Tyler,
A. N. Tetrahedron 1999, 55, 8671. (j) 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. (k) 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.
converted to the corresponding ketone 3 in 94% yield by
oxidative cleavage (OsO4, NaIO4, 2,6-lutidine, dioxane/
H2O).12 At this stage, the stereospecific introduction of the
C9 stereocenter was attempted by using an allylstannane
synthesized from trimethylallylsilane. When ketone 3 and
trimethylallylsilane were combined by using a number of
different Lewis acids, addition protocols, and precomplex-
ation protocols, only one set of conditions, i.e., a premixed
solution of trimethylallylsilane and SnCl4 in CH2Cl2 at
-78 °C, was found to produce the desired alcohol 4 in
good yield (77%) and with excellent diastereoselectivity
(dr > 99:1) in favor of the syn isomer. The stereochemical
(9) Reviews: (a) Yeung, K.-S.; Paterson, I. Chem. ReV. 2005, 105, 4237.
(b) Paterson, I.; Coster, M. J. Strategies and Tactics in Organic Synthesis;
Elsevier: London, UK, 2004; Vol. 4, p 211.
(10) (a) Crimmins, M. T.; Smith, A. C. Org. Lett. 2006, 8, 1003. (b)
Paterson, I.; Gottschling, D.; Menche, D. Chem. Commun. 2005, 28, 3568.
(c) Lau, C. K.; Crumpler, S.; MacFarlane, K.; Lee, F.; Berthelette, C. Synlett
2004, 13, 2281. (d) Hubbs, J. L.; Heathcock, C. H. J. Am. Chem. Soc. 2003,
125, 12836. (e) Terauchi, T.; Terauchi, T.; Sato, I.; Shoji, W.; Tsukada, T.;
Tsunoda, T.; Kanoh, N.; Nakata, M. Tetrahedron Lett. 2003, 44, 7741. (f)
Gaunt, M. J.; Sneddon, H. F.; Hewitt, P. R.; Orsini, P.; Hook, D. F.; Ley,
S. V. Org. Biomol. Chem. 2003, 1, 15. (g) Smith, A. B. III; Corbett, R. M.;
Pettit, G. R.; Chapuis, J.-C.; Schmidt, J. M.; Hamel, E.; Jung, M. K. Bioorg.
Med. Chem. Lett. 2002, 12, 2039. (h) Crimmins, M. T.; Katz, J. D.; McAtee,
L. C.; Tabet, E. A.; Kirincich, S. J. Org. Lett. 2001, 3, 949. (i) Barrett, A.
G. M.; Braddock, D. C.; Pieter, D.; Andrew, J. P.; Williams, D. J. J. Org.
Chem. 2000, 65, 375. (j) Pietruszka, J. Angew. Chem., Int. Ed. 1998, 37,
2629. (k) Paterson, I.; Wallace, D. J.; Oballa, R. M. Tetrahedron Lett. 1998,
39, 8545. (l) Crimmins, M. T.; Washburn, D. G. Tetrahedron Lett. 1998,
39, 7487. (m) Terauchi, T.; Nakata, M. Tetrahedron Lett. 1998, 39, 3795.
(n) Evans, D. A.; Coleman, P. J.; Dias, L. C. Angew. Chem., Int. Ed. Engl.
1997, 36, 2737. (o) Evans, D. A.; Trotter, B. W.; Coleman, P. J.; Coˆte´, B.
Angew. Chem., Int. Ed. 1997, 36, 2741. (p) Smith, A. B. III; Lin, Q.;
Nakayama, K.; Boldi, A. M.; Brook, C. S.; McBriar, M. D.; Moser, W. H.;
Sobukawa, M.; Zhuang, L. Tetrahedron Lett. 1997, 38, 8675. (q) Paterson,
I.; Oballa, R. M. Tetrahedron Lett. 1997, 38, 8241. (r) Paterson, I.; Oballa,
R. M.; Norcross, R. D. Tetrahedron Lett. 1996, 37, 8581.
assignment was achieved by examination of the 1H and 13
C
NMR spectra13 of ketal 5, obtained from 4 by treatment with
2,2-dimethoxypropane, in the presence of PPTS (0.1 equiv)
in CH2Cl2 at room temperature. Elaboration of the C5-C13
fragment was achieved in a two-step sequence. After
oxidative cleavage of the olefin 5 (OsO4, NaIO4, 2,6-lutidine,
dioxane/H2O), the resulting aldehyde was treated with allyl-
magnesium bromide (Et2O, -78 °C) to provide the desired
alcohol 6 as a 1/1 inseparable mixture of diastereomers
(11) Liu, Y.-J.; Tropp, B. E.; Engel, R. Can. J. Chem. 1993, 71, 206.
(12) Wensheng, Y.; Yan, M.; Ying, K.; Zhengmao, H.; Zhendong, J.
Org. Lett. 2004, 6, 3217.
(13) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I. Acc. Chem.
Res. 1998, 31, 9.
3656
Org. Lett., Vol. 8, No. 17, 2006

obtained in 82% yield. We have to point out that the hydroxy
group at C7 will be the precursor of a ketone, necessary to
build up the spiroketal and, in consequence, the control of
the stereogenic center is not necessary. After silylation of
the hydroxy group at C7 (TBSOTf, 2,6-lutidine, CH2Cl2, -78
°C), the fully protected triol 7 was isolated in 87% yield
(Scheme 2).
spectra of 11 showed a signal at 98.33 ppm, demonstrating
the syn relationship for the hydroxy groups at C3 and C5.13
The precursor of the spiroketal, ketone 13, was synthesized
in two steps from 11 (Scheme 4). Deprotection of the
Scheme 4
The transformation of the C5-C13 fragment 7 into the
C1-C13 fragment 11 utilized an enantioselective allyl-
titanation and a diastereoselective allylmetalation of a
â-hydroxy aldehyde (Scheme 3).
Scheme 3
hydroxy group at C7 (TBAF, THF) afforded the free alcohol
12, which was oxidized by using Pyr‚SO3 (TEA, DMSO/
CH2Cl2) to provide ketone 13 in 81% overall yield over two
steps as a single isomer. It is worth noting that other oxidants
such as PCC, IBX, or Dess-Martin periodinane led to the
decomposition of 12. Acidic treatment of 13 with a catalytic
amount of PPTS in a 1:1 mixture of CH2Cl2/MeOH at room
temperature led to a one-pot process (i.e., deprotection-
spiroketalization) to furnish the desired thermodynamic AB
spiroketal 14 in 73% yield (Scheme 4). Extensive NMR
studies (1H NMR, 13C NMR, NOESY) and comparison with
Crimmins’ similar spiroketal10a showed that compound 14
is in full agreement with the structure of the C1-C13 AB
spiroketal ring system of spongistatin.
The synthesis of the AB spiroketal fragment of spongistatin
has been achieved in 15 steps with an overall yield of 24%
and with excellent diastereoselectivity starting from known
(S)-2-(2-benzyloxyethyl)oxirane and by using a unique
combination of highly enantioselective and diastereoselective
allylmetalations.
At first, an oxidative cleavage of the olefin in 7 (OsO4,
NaIO4, 2,6-lutidine, dioxane/H2O) led to the corresponding
aldehyde, which was not purified but directly treated with
the highly enantioface selective allyltitanium complex (S,S)-
I14 (Scheme 1) to produce the desired homoallylic alcohol 8
with a good diastereoselectivity (96%, dr > 98:2) (Scheme
3). By using a similar strategy to the one employed to
transform ketone 3 into syn-1,3-diol 4, compound 8 was
converted into diol 10 by first performing an oxidative
cleavage yielding aldehyde 9, and then a treatment of crude
9 with a premixed solution of trimethylallylsilane and SnCl4
in CH2Cl2 at -78 °C produced syn-diol 10 in high yield and
excellent diastereoselectivity (91% yield, dr > 99:1). Protec-
tion of 10 (2,2-dimethoxypropane, PPTS, CH2Cl2) led to the
bisacetonide 11 (97% yield). Examination of the 13C NMR
Acknowledgment. F.A. thanks the ARC (French Re-
search Association against Cancer) for financial support.
Supporting Information Available: Experimental pro-
cedures and full analytical data (including 1H and 13C
spectra). This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-Streit, P.;
Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114, 2321.
OL060812L
Org. Lett., Vol. 8, No. 17, 2006
3657