Diastereoselective synthesis of the C(17)-C(28) fragment (the C-D spiroketal unit) of spongistatin 1 (altohyrtin A) via a kinetically controlled iodo-spiroketalization reaction.

Article abstract of DOI:10.1021/ol0266875

[reaction: see text] A convergent and stereocontrolled synthesis of spiroketal 15 corresponding to the C-D fragment of spongistatin 1 has been accomplished by a sequence utilizing a kinetically controlled intramolecular iodo-spiroketalization of glycal 2,

Full text of DOI:10.1021/ol0266875

ORGANIC
LETTERS
2002
Vol. 4, No. 21
3719-3722
Diastereoselective Synthesis of the
C(17)−C(28) Fragment (The C−D
Spiroketal Unit) of Spongistatin 1
(Altohyrtin A) via a Kinetically
Controlled Iodo-Spiroketalization
Reaction
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 and stereocontrolled synthesis of spiroketal 15 corresponding to the C−D fragment of spongistatin 1 has been accomplished
by a sequence utilizing a kinetically controlled intramolecular iodo-spiroketalization of glycal 2, which in turn was synthesized via a ring-
closing metathesis reaction.
The spongipyran macrolides are a class of marine natural
products that were independently isolated and characterized
by Pettit,1-3 Kitagawa,4,5 and Fusetani6 in 1993. The extra-
ordinary cytotoxicity of this class of compounds toward
neoplastic cell lines and the very small amounts available
from natural sources have stimulated numerous studies on
the synthesis of these compounds.7,8 Thus far, total syntheses
of two members of this class have been reported.9-13 We
have previously published a synthesis of the E-F bispyran
unit,14 and we now report a synthesis of the C-D spiroketal
fragment of spongistatin 1. Our intention was to construct
(7) For a comprehensive list of references to synthetic approaches to
the spongistatins, see ref 13 and the references therein.
(8) Paterson, I.; Coster, M. J. Tetrahedron Lett. 2002, 43, 3285.
(9) Evans, D. A.; Trotter, B. W.; Coleman, P. J.; Cote, B.; Dias, L. C.;
Rajapakse, H. A.; Tyler, A. N. Tetrahedron 1999, 55, 8671.
(10) 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, 192.
(11) 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.
(12) 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.; 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.
(2) Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. L.; Boyd, M. R. J.
Chem. Soc., Chem. Commun. 1993, 1166.
(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.
(13) Crimmins, M. T.; Katz, J. D.; Washburn, D. G.; Allwein, S. P.;
McAtee, L. C. J. Am. Chem. Soc. 2002, 124, 5661.
(14) Micalizio, G. C.; Pinchuk, A. N.; Roush, W. R. J. Org. Chem. 2000,
65, 8730.
10.1021/ol0266875 CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/17/2002

this spiroketal fragment in a convergent and highly stereo-
controlled fashion with particular attention to the stereo-
chemistry at the C(23) spiroketal center.
The propensity for the axial addition of electrophilic
reagents and alcohols to activated glycals is well precedented
in intermolecular reactions in carbohydrate chemistry.21,22
Several groups have used this type of reaction in constructing
spiroketals.23-26 However, this strategy has not been applied
to the stereoselective synthesis of the intrinsically less stable
spiroketal isomer (the isomer that contains less than the
maximal number of stabilizing anomeric effects). In addition
to controlling the stereochemistry at the C(23) spiroketal
center, we hoped that introduction of a heteroatom adjacent
to the ketal linkage would provide enhanced stability of this
unit toward acid-catalyzed epimerization.27 Another feature
of our strategy is the formation of glycal 2 from the ester 4
via a Tebbe olefination-ring-closing metathesis (RCM)
sequence.28 Ester 4 would in turn be derived from two
components of roughly equal complexity, e.g., 5 and 6
(Figure 1).
On the basis of the work of several groups on the synthesis
of the C-D system,9,11-13,15-20 it was clear that highly
stereocontrolled installation of the C(23) spiroketal center
would require a kinetically controlled event. Other groups
have successfully established the stereochemistry at this site
under kinetic control;16,19,20 however, many approaches have
relied on equilibration of the C(23) stereocenter under a
variety of acidic conditions (Mg(O2CCF3)2,9 ZnCl2,18
Ca(ClO4)2/HClO4,12 CF3COOH,17 HF/pyridine,10 HCl11) tak-
ing advantage of an internal metal chelate or intramolecular
hydrogen bond that favors the naturally occurring C-D
spiroketal stereochemistry. These interactions compensate for
the absence of double anomeric stabilization of the C-D
spiroketal.
Synthesis of carboxylic acid 5 began with Noyori hydro-
genation29 of the readily available â-ketoester 7,30 which
provided the â-hydroxy ester in 81% yield and excellent
enantioselectivity (95% ee, determined by Mosher ester
analysis31,32) (Scheme 1). Homologation of the â-hydroxy
Our approach focused on the kinetic formation of the
correct C(23) stereochemistry via an intramolecular iodo-
spiroketalization reaction. A key intermediate in our synthesis
is glycal 2 (Figure 1). Activation of glycal 2 with NIS
Scheme 1. Synthesis of Carboxylic Acid 5
ester via Claisen condensation with the lithium enolate of
tert-butyl acetate provided the â-keto-δ-hydroxy ester 8
(15) Paquette, L. A.; Braun, A. Tetrahedron Lett. 1997, 38, 5119.
(16) Claffey, M. M.; Hayes, C. J.; Heathcock, C. H. J. Org. Chem. 1999,
64, 8267.
(17) Zemribo, R.; Mead, K. T. Tetrahedron Lett. 1998, 39, 3895.
(18) Terauchi, T.; Sato, I.; Tsukada, T.; Kanoh, N.; Nakata, M.
Tetrahedron Lett. 2000, 41, 2649.
(19) Crimmins, M. T.; Katz, J. D. Org. Lett. 2000, 2, 957.
(20) Paterson, I.; Wallace, D. J.; Gibson, K. R. Tetrahedron Lett. 1997,
38, 8911.
(21) Thiem, J.; Klaffke, W. In Top. Curr. Chem. 1990, 154, 285.
(22) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl.
1996, 35, 1380.
(23) Ley, S. V.; Lygo, B. Tetrahedron Lett. 1982, 23, 4625.
(24) Greck, C.; Grice, P.; Ley, S. V.; Wonnacott, A. Tetrahedron Lett.
1986, 27, 5277.
(25) Diezmartin, D.; Grice, P.; Kolb, H. C.; Ley, S. V.; Madin, A.
Tetrahedron Lett. 1990, 31, 3445.
(26) Uchiyama, M.; Oka, M.; Harai, S.; Ohta, A. Tetrahedron Lett. 2001,
42, 1931.
(27) Roush, W. R.; Sebesta, D. P.; James, R. A. Tetrahedron 1997, 53,
8837.
Figure 1. Retrosynthetic Analysis of the C-D Spiroketal.
(28) Nicolaou, K. C.; Postema, M. H. D.; Claiborne, C. F. J. Am. Chem.
Soc. 1996, 118, 1565.
(29) Kitamura, M.; Tokunaga, M.; Ohkuma, T.; Noyori, R. Tetrahedron
Lett. 1991, 32, 4163.
(30) Nakatsuka, M.; Ragan, J. A.; Sammakia, T.; Smith, D. B.; Uehling,
D. E.; Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 5583.
followed by intramolecular trans diaxial addition of the
δ-hydroxy group would provide the C(23) C-D spiroketal
center with the configuration found in the natural product.
3720
Org. Lett., Vol. 4, No. 21, 2002

in 85% yield. Reduction of 8 with tetramethylammonium
triacetoxyborohydride33 provided the anti 1,3-diol 9 in 86%
yield and 8:1 diastereoselectivity; the stereochemistry of 9
was determined by conversion of the diol to the acetonide.34,35
At this juncture, we chose to delay the differentiation of the
two hydroxyl groups until the iodo-spiroketalization event.
Therefore, protection of the alcohols as TBS ethers (TBSCl,
Et3N, DMAP, CH2Cl2) followed by separation of the
diastereomers by column chromatography provided dia-
stereomerically pure ester 10. Finally, conversion of the tert-
butyl ester to the carboxylic acid via a two-step reduction
and oxidation sequence provided the acid 5 in excellent yield
(86% over two steps).
Scheme 3. Synthesis of Glycal 2
The synthesis of fragment 6 began with ester 11 (derived
from commercially available D-malic acid)36 (Scheme 2).
olefination and RCM reaction sequence28 using excess Tebbe
reagent41 (Cp2Ti(Cl)CH2AlMe2) in refluxing THF but did
not observe formation of the ring-closed product, and only
small amounts of the enol ether. Consequently, we adopted
a two-step sequence involving olefination followed by
RCM.42,43 Treatment of ester 4 with the Tebbe reagent
provided the enol ether 3 (75%), which underwent RCM
using Grubbs’s second generation ruthenium catalyst44 to
provide glycal 14 in 81% yield. Deprotection of the bis-
TBS ether 14 using TBAF then provided the dihydroxy
glycal 2, the substrate for the spiroketalization sequence.
After examining several electrophilic activating agents
(N-(phenylseleno)pthalimide, NBS, I(sym-collidine)2ClO4,
PhSeBr, PhSeCl, PhSCl, arylbis(arylthio)sulfonium salts45)
to effect the spiroketalization, the best yields and selectivities
were achieved by treating 2 with NIS in CH2Cl2 at -90 °C
(Scheme 4). This protocol provided the spiroketal 15 in 63%
yield with 8:1 diastereoselectivity.
Scheme 2. Synthesis of Alcohol 6
Formation of the Weinreb amide using the Merck protocol37
followed by addition of the cis-propenyl Grignard reagent
and zinc borohydride reduction38 of the resulting enone
provided alcohol 12 in good yield (56% over three steps)
and selectivity (14:1 dr); the stereochemistry of the new
hydroxyl center was determined by Mosher analysis.31,32
Protection of the secondary alcohol as the p-methoxybenzyl
(PMB) ether followed by acetonide deprotection (AcOH,
H2O, THF) provided diol 13 in 89% overall yield. Finally,
protection of the primary alcohol as a benzyl ether via the
stannylene acetal39 provided the fully differentiated alcohol
6 in 83% yield.
Scheme 4. Iodo-spiroketalization Sequence
Coupling of carboxylic acid 5 and alcohol 6 was effected
by using the Yamaguchi protocol,40 which provided ester 4
in 98% yield (Scheme 3). Initially, we attempted a one-pot
(31) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
(32) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092.
(33) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560.
(34) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31,
945.
(35) Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron Lett. 1990,
31, 7099.
(36) Saito, S.; Ishikawa, T.; Kuroda, A.; Koga, K.; Moriwake, T.
Tetrahedron 1992, 48, 4067.
The configuration of the major spiroketal isomer 15 was
confirmed via 1H NMR NOE experiments (Figure 2). Critical
(37) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling,
U. H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461.
(38) Oishi, T.; Nakata, T. Acc. Chem. Res. 1984, 17, 338.
(39) Nagashima, N.; Ohno, M. Chem. Pharm. Bull. 1991, 39, 1972.
(40) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(41) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc.
1978, 100, 3611.
(42) Postema, M. H. D.; Calimente, D. Tetrahedron Lett. 1999, 40, 4755.
(43) Rainer, J. D.; Cox, J. M.; Allwein, S. P. Tetrahedron Lett. 2001,
42, 179.
Org. Lett., Vol. 4, No. 21, 2002
3721

Treatment of 15 with KHMDS and MeI gave the methyl
ether 17, which was subjected to reductive dehalogenation
using tributyltin hydride and triethylborane46 to provide the
fully elaborated C-D spiroketal 18 in 59% yield over two
steps.
In summary, we have achieved a highly stereoselective
and convergent synthesis of the C-D spiroketal fragment
18 of spongistatin 1. Formation of the monoanomeric
spiroketal linkage at C(23) was accomplished under kineti-
cally controlled iodo-spiroketalization conditions, which
provided the desired configuration with good stereochemical
control. A second application of this methodology to the
synthesis of the A-B spiroketal is presented in the following
paper.
1
Figure 2. Diagnostic H NMR NOEs in 15 and 16.
among these are the H(24)-H(21)18,19 and H(24)-H(19)10,11
enhancements.
The configuration of the minor isomer 16 was also
assigned on the basis of several key 1H NMR NOE
enhancements (Figure 2). The chair conformation for the
C(19)-C(22) segment is defined by the NOE enhancement
between H(19)-H(21). The second ring, which adopts a
more boatlike conformation, is defined by H(24)-H(25) and
H(24)-H(22ax) NOE enhancements. The most telling NOEs
are between H(22)-H(27).
Acknowledgment. We thank the NIH (GM 38436) for
support of this research.
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 2-6, 8-10, and
12-18. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0266875
(44) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(45) Grewal, G.; Kaila, N.; Franck, R. W. J. Org. Chem. 1992, 57, 2084.
(46) Miura, K.; Ichinose, Y.; Nozaki, K.; Fugami, K.; Oshima, K.;
Utimoto, K. Bull. Chem. Soc. Jpn. 1989, 62, 143.
3722
Org. Lett., Vol. 4, No. 21, 2002