Synthesis of the C(2)-C(13) fragment (the A-B spiroketal unit) of spongistatin 1 (altohyrtin A): use of a common intermediate for the synthesis of both spongistatin spiroketals.

Article abstract of DOI:10.1021/ol026688x

[reaction: see text] A convergent synthesis of 14 corresponding to the A-B spiroketal core of spongistatin 1 has been accomplished via an iodo-spiroketalization reaction of glycal 9, which was synthesized in three steps from a late-stage intermediate used

Full text of DOI:10.1021/ol026688x

ORGANIC
LETTERS
2002
Vol. 4, No. 21
3723-3725
Synthesis of the C(2)−C(13) Fragment
(The A−B Spiroketal Unit) of
Spongistatin 1 (Altohyrtin A): Use of a
Common Intermediate for the Synthesis
of Both Spongistatin Spiroketals
Edward B. Holson and William R. Roush*
Department of Chemistry, UniVersity of Michigan, 930 North UniVersity,
Ann Arbor, Michigan 48109
roush@umich.edu
Received August 7, 2002
ABSTRACT
A convergent synthesis of 14 corresponding to the A−B spiroketal core of spongistatin 1 has been accomplished via an iodo-spiroketalization
reaction of glycal 9, which was synthesized in three steps from a late-stage intermediate used in our synthesis of the C−D spiroketal fragment
of spongistatin 1. Elaboration of 14 to the A−B spiroketal 15 was accomplished in three steps.
The spongistatins are a unique class of marine polyether
macrolactone metabolites that were isolated in 1993.1-6 This
class of compounds has demonstrated excellent antimitotic
activity against numerous cancer cell lines. Due to their
complex structural features, limited availability, and potent
cytotoxicity, these compounds have generated considerable
interest from synthetic chemists.7 Total syntheses of two
members from this class of compounds have been reported.8-12
We have previously described syntheses of the E-F bis-
pyran13 and the C-D spiroketal,14 and here we describe a
synthesis of the other major structural fragment, the A-B
spiroketal (15). Our synthesis of 15 constitutes a second
example of the iodo-spiroketalization methodology used in
our synthesis of the C-D spiroketal and, moreover, utilizes
a late-stage intermediate from that work. The ability to utilize
(8) Evans, D. A.; Trotter, B. W.; Coleman, P. J.; Cote, B.; Dias, L. C.;
Rajapakse, H. A.; Tyler, A. N. Tetrahedron 1999, 55, 8671.
(9) Hayward, M. M.; Roth, R. M.; Duffy, K. J.; Dalko, P. I.; Stevens,
K. L.; Guo, J. S.; Kishi, Y. Angew. Chem., Int. Ed. 1998, 37, 196.
(10) 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.
(11) Smith, A. B.; Lin, Q. Y.; Doughty, V. A.; Zhuang, L. H.; McBriar,
M. D.; Kerns, J. K.; Brook, C. S.; Murase, N.; Nakayama, K. Angew. Chem.,
Int. Ed. 2001, 40, 196.
(1) Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. L.; Boyd, M. R. J.
Chem. Soc., Chem. Commun. 1993, 1166.
(2) 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) 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.
(4) Kobayashi, M.; Aoki, S.; Sakai, H.; Kihara, N.; Sasaki, T.; Kitagawa,
I. Chem. Pharm. Bull. 1993, 41, 989.
(5) Kobayashi, M.; Aoki, S.; Sakai, H.; Kawazoe, K.; Kihara, N.; Sasaki,
T.; Kitagawa, I. Tetrahedron Lett. 1993, 34, 2795.
(6) Fusetani, N.; Shimoda, K.; Matsunaga, S. J. Am. Chem. Soc. 1993,
115, 3977.
(12) Crimmins, M. T.; Katz, J. D.; Washburn, D. G.; Allwein, S. P.;
McAtee, L. C. J. Am. Chem. Soc. 2002, 124, 5661.
(13) Micalizio, G. C.; Pinchuk, A. N.; Roush, W. R. J. Org. Chem. 2000,
65, 8730.
(7) See ref 14 and references therein.
(14) Holson, E. B.; Roush, W. R. Org. Lett. 2002, 4, 3719.
10.1021/ol026688x CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/17/2002

common intermediates of such complex structures is critical
in efforts to synthesize sufficient quantities of the natural
product for more detailed biological evaluation. To maximize
efficiency, bifurcation along the synthetic pathway should
occur at as late a stage as possible.
Upon examination of the two spiroketal units in spong-
istatin 1, we realized the opportunity that exists for accessing
both units by using the same precursor for the A and D rings
(Figure 1). Disconnection of the spiroketal centers leads to
Figure 2. Retrosynthetic Analysis of the A-B Spiroketal.
2). Ketone 7 could in turn be derived from alcohol 8 or its
C(9) epimer. Although the stereochemistry at C(9) of 8 is
arbitrary, we chose to target the configuration shown in 8 to
minimize 1,3-diaxial interactions during cyclization leading
to the spiroketal. There are two possible bond disconnections
that could be made to utilize our intramolecular iodo-
spiroketalization strategy.14 Based on similar glycal sub-
structures identified earlier (see 3 and 6), disconnection of
the B ring leads to 9, which contains the structural features
common to both the A and D rings of the spongistatin
spiroketals. Glycal 9 may be derived from 4 by inversion of
configuration at C(9) and C(11). Glycal 4 is derived from
ester 10 via an olefination-ring-closing metathesis se-
quence.14 Ester 10, in turn, is derived from alcohol 11 and
carboxylic acid 12, the preparation of which was described
in our synthesis of the C-D spiroketal.14
Initially, we explored the Mitsonobu reaction (PPh3,
DEAD, p-nitrobenzoic acid20) to effect the double inversion
of 4, but only mixtures of monoacetylated (monoinverted)
products were obtained. Consequently, we chose to adopt a
two-step procedure for this key transformation (Scheme 1).
Treatment of diol 4 with methanesulfonyl chloride and Et3N
in CH2Cl2 provided the bismesylate, which was used directly
in the subsequent reaction. Displacement of the mesylates
with cesium acetate21-23 in toluene at 80 °C for 24 h provided
Figure 1. Identification of a Common Intermediate for the A-B
and C-D Spiroketals.
similarly substituted glycal precursors such as 3 and 6. The
divergence between the spiroketal precursors lies at the two
hydroxyl centers (e.g., C(11) and C(9) in 3, and C(19) and
C(21) in 6) on the appended alkyl side chain. To utilize 4,
an intermediate from our C-D spiroketal synthesis, as an
intermediate in the synthesis of the A-B spiroketal, inversion
of the stereochemistry at C(11) and installation of the tertiary
alcohol at C(9) would be needed.
On the basis of previous work in construction of the A-B
spiroketal,15-19 we planned to install the C(9) tertiary alcohol
via methyl Grignard addition to a ketone such as 7 (Figure
(15) Evans, D. A.; Coleman, P. J.; Dias, L. C. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2738.
(16) Paterson, I.; Oballa, R. M. Tetrahedron Lett. 1997, 38, 8241.
(17) Paquette, L. A.; Zuev, D. Tetrahedron Lett. 1997, 38, 5115.
(18) Crimmins, M. T.; Washburn, D. G. Tetrahedron Lett. 1998, 39, 7487.
(19) Claffey, M. M.; Hayes, C. J.; Heathcock, C. H. J. Org. Chem. 1999,
64, 8267.
(20) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
(21) Kruizinga, W. H.; Strijtveen, B.; Kellogg, R. M. J. Org. Chem. 1981,
46, 4321.
(22) Huffman, J. W.; Desai, R. C. Synth. Commun. 1983, 13, 553.
(23) Torisawa, Y.; Okabe, H.; Ikegami, S. Chem. Lett. 1984, 1555.
3724
Org. Lett., Vol. 4, No. 21, 2002

Scheme 1. Synthesis of the A-B Spiroketal Core
Scheme 2. Completion of the A-B Spiroketal
the bisacetate 13 in 70% yield over two steps. Deprotection
of the acetates under basic conditions (K2CO3, MeOH)
provided the diol 9 in 88% yield.
nane25 afforded the ketone 7 in almost quantitative yield
(99%). Finally, addition of MeMgBr to ketone 7 provided
the A-B spiroketal 15 as a single isomer (73%). The
configuration of 15 was confirmed on the basis of several
1H NMR NOE enhancements (Figure 4).12
The stage was now set for application of the intramolecular
iodo-spiroketalization reaction, this time targeting spiroketal
14 possessing two stabilizing anomeric effects. Treatment
of diol 9 with NIS in CH2Cl2 at -78 °C provided the
spiroketal 14 as a single isomer (84%). Diagnostic 1H NMR
NOE enhancements were observed between H(11)-H(9) and
H(11)-H(3) in 14 (Figure 3). These 1H NMR NOE experi-
Figure 4. Diagnostic NOEs for A-B Spiroketal 15.
In summary, we have achieved a highly convergent,
stereocontrolled synthesis of the A-B spiroketal fragment
15 of spongistatin 1. This synthesis proceeds in seven steps
from a late-stage intermediate 4 from our synthesis of the
C-D spiroketal. Further studies directed toward the comple-
tion of the C(1)-C(28) fragment of spongistatin 1 will be
reported in due course.
Figure 3. Diagnostic NOEs for 14.
ments confirmed the stereochemistry of 14 and also estab-
lished that we had indeed inverted both of the hydroxyl
centers in the conversion of 4 to 13. Additional enhancements
were observed between H(6)-H(5) and H(6)-H(8)ax that
helped to confirm the stereochemistry of 14.
Acknowledgment. We thank the NIH (GM 38436) for
support of this research. We also thank Dr. Glenn Micalizio
for helpful discussions.
Final elaboration of 14 to the A-B spiroketal 15 began
with the reductive dehalogenation of 14 with tributyltin
hydride and triethylborane,24 which provided 8 (92%)
(Scheme 2). Oxidation of 8 with the Dess Martin periodi-
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 7-9 and 13-15
and stereochemical assignments for 14 and 15. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL026688X
(24) Miura, K.; Ichinose, Y.; Nozaki, K.; Fugami, K.; Oshima, K.;
Utimoto, K. Bull. Chem. Soc. Jpn. 1989, 62, 143.
(25) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
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