ORGANIC
LETTERS
2002
Vol. 4, No. 3
467-470
Dioxolane-to-Bridged
Acetal-to-Spiroketal via Ring-Closing
Metathesis and Rearrangement: A
Novel Route to 1,7-
Dioxaspiro[5.5]undecanes
Valerie A. Keller, Joseph R. Martinelli, Eric R. Strieter, and Steven D. Burke*
Department of Chemistry, UniVersity of Wisconsin-Madison, 1101 UniVersity AVenue,
Madison, Wisconsin 53706-1396
Received December 15, 2001
ABSTRACT
Several examples of 1,7-dioxaspiro[5.5]undecane spiroketal systems have been synthesized from the common bicyclic intermediate 1 via
acid-catalyzed rearrangement. Intermolecular ketalization of C symmetric diene diol 3 with ketone 9 and then desymmetrization by ring-
2
closing metathesis rapidly constructs bicyclic acetal 1. The locked conformation and steric bias of 1 allow stereoselective functionalization of
one or both double bonds before spiroketalization.
Spiroketals occur widely among natural products of biologi-
cal and pharmaceutical interest, including marine toxins,
insect pheromones, antibiotics, and anticancer agents.1 Recent
synthetic and therapeutic interest in spiroketal-containing
natural products such as the halichondrins2 and the spong-
istatins3 underscores the need for efficient, versatile, and
stereoselective methods of spiroketal synthesis.
Traditional routes to spiroketals typically involve construc-
tion of an acyclic keto-diol via intermolecular C-C bond
formation followed by an intramolecular dehydrative ketal-
ization. An appealing alternative is illustrated in this paper
that employs an intermolecular ketalization to converge
subunits, followed by an intramolecular C-C bond forma-
tion/desymmetrization through ring-closing metathesis (RCM).4
Bicyclic acetal formation via this ketalization/RCM se-
quence has been developed for the synthesis of (+)-exo- and
endo-brevicomin5a and the sialic acids KDN and Neu5Ac.5b,c
The rigid 6,8-dioxabicyclo[3.2.1]octanes formed in these
routes allow stereoselective functionalization of the six
membered ring as a result of the locked conformation and
(3) (a) Evans, D. A.; Trotter, B. W.; Coleman, P. J.; Coˆte´, B.; Dias, L.
C.; Rajapakse, H. A.; Tyler, A. N. Tetrahedron 1999, 55, 8671-8726. (b)
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, 187-192. (c) Hayward,
M. M.; Roth, R. M.; Duffy, K. J.; Dalko, P. J.; Stevens, J. G.; Kishi, Y.
Angew. Chem., Int. Ed. Engl. 1998, 37, 192-196. (d) Paterson, I.; Chen,
D. Y.-K.; Coster, M. J.; Acen˜a, 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, 4055-4060. (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, 191-195. (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.;
Sobukawa, M. Angew. Chem., Int. Ed. 2001, 40, 196-199. (g) Crimmins,
M. T.; Katz, J. D. Org. Lett. 2000, 2, 957-960. (h) Claffey, M. M.; Hayes,
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(1) Perron, F.; Albizati, K. F. Chem. ReV. 1989, 89, 1617-1661.
(2) (a) Burke, S. D.; Austad, B. C.; Hart, A. C. J. Org. Chem. 1998, 63,
6770-6771. (b) Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.;
Jung, S. H.; Kishi, Y.; Matelich, M. C.; Scola, P. M.; Spero, D. M.; Yoon,
S. K. J. Am. Chem. Soc. 1992, 114, 3162-3164. (c) Horita, K.; Sakurai,
Y.; Nagasawa, M.; Maeno, K.; Hachiya, S.; Yonemitsu, O. Synlett 1994,
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(4) For recent reviews, see: (a) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000,
39, 3012-3043. (b) Schrock, R. R. Tetrahedron 1999, 55, 8141-8153. (c)
Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450. (d) Armstrong,
S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371-388. (e) Schuster, M.;
Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2037-2056.
10.1021/ol0172368 CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/15/2002