Dioxolane-to-bridged acetal-to-spiroketal via ring-closing metathesis and rearrangement: A novel route to 1,7-dioxaspiro[5.5]undecanes

Article abstract of DOI:10.1021/ol0172368

(Equation Presented) 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 C₂ symmetric diene diol 3 wit

Full text of DOI:10.1021/ol0172368

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
burke@chem.wisc.edu
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,
C. J.; Heathcock, C. H. J. Org. Chem. 1999, 64, 8267-8274.
(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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Lett. 1993, 34, 3247-3250. (e) Horita, K.; Hachiya, S.; Ogihara, K.;
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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)
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10.1021/ol0172368 CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/15/2002

Scheme 1. Synthesis of Bicyclic Acetal 1
steric bias of the bicyclic acetal. We envisioned bicyclic
acetal 1 as a common intermediate in the strategy to obtain
1,7-dioxaspiro[5.5]undecanes 6 as illustrated in Figure 1.
65a in hexane gave triene 2 in modest yield, which could be
increased to 71% upon one recycle of the recovered starting
material. Intramolecular C-C bond formation/desymmetri-
zation of pseudo-C2-symmetric triene 2 via RCM with
Grubbs’ catalyst 11 afforded the 6,8-dioxabicyclo[3.2.1]-
octane 1 in excellent yield.
Several olefin functionalizations were performed that
exploited the rigid conformation of 1 (Scheme 2). Only one
Scheme 2. Functionalization of 1
Figure 1. Desymmetrization/spiroketalization strategy.
Bicyclic acetal 1 was synthesized in six steps from known
aldehyde 76 (Scheme 1). This aldehyde was subjected to
Lewis acid promoted thioketalization with 1,3-propanedithiol
to produce 8 in a quick and mild transformation.7 Dithiane
8 was alkylated with 1-bromo-3-chloropropane and depro-
tected with the hypervalent iodine species (CF3CO2)2IPh8 to
provide ketone 9, one partner for the intermolecular ketal-
ization. This ketalization was accomplished by combining
C2 symmetric diene diol 3,9 CSA, and 9 in refluxing toluene
with azeotropic removal of water to produce 10 in excellent
yield. Subjection of 10 to elimination with KOtBu/18-crown-
468
Org. Lett., Vol. 4, No. 3, 2002

Table 1. Spiroketalization Data
a 3 M HF in CH3CN. b 3% v/v HCl in MeOH. c Complex mixture of 21 and other uncharacterized products due to competitive deacetylation.
side of the ring olefin was accessible to Sharpless asymmetric
dihydroxylation while the (DHQ)2AQN10 ligand was em-
ployed to control the stereochemistry of dihydroxylation on
the terminal double bond. The reaction was rather sluggish
and took 2 days to convert 46% to the tetraol 12 and 48%
to the diol 13. Resubmission of 13 to the reaction conditions
resulted in 66% conversion to 12. Acetylation of 12
proceeded nearly quantitatively to yield the tetraacetate 14.
Epoxidation of 1 with dimethyldioxirane (DMDO)11 occurred
regio- and stereoselectively to give 15. This epoxide was
resistant to opening with vinyl Grignard, vinyl cuprate, and
hydride (Red-Al) nucleophiles. The sole product from the
attempted opening of epoxide 15 with vinyl Grignard was
the unexpected bromohydrin 16. This transformation was also
performed with MgBr2‚Et2O, but only 47% of the bromo-
hydrin 16 was isolated. Catalytic hydrogenation of 1 gave
the saturated bicyclic acetal 17.
deprotection of the primary alcohol to give intermediate i
(Scheme 3). Protonation promotes ring opening to the
Scheme 3. Spiroketalization
Acid-catalyzed spiroketalization of the functionalized 6,8-
dioxabicyclo[3.2.1]octanes was envisioned to occur via
(5) (a) Burke, S. D.; Mu¨ller, N.; Beaudry, C. M. Org. Lett. 1999, 1,
1827-1829. (b) Burke, S. D.; Voight, E. A. Org. Lett. 2001, 3, 237-240.
(c) Voight, E. A.; Rein, C.; Burke, S. D. Tetrahedron Lett. 2001, 42, 8747-
8749.
(6) Murphy, J. A.; Rasheed, F.; Roome, S. J.; Scott, K. A.; Lewis, N. J.
Chem. Soc., Perkin Trans. 1 1998, 2331-2339.
oxacarbenium ion ii, which has all three substituents in
pseudoaxial positions; a ring flip to iii places the substituents
in pseudoequatorial positions. Axial attack of the primary
alcohol on the oxacarbenium ion occurs in structure iii,
leading to a chair-chair conformation for spiroketal iV. In
this structure both ring oxygens are in axial positions, fully
maximizing the anomeric effect.1
(7) Park, J. H.; Kim, S. Chem. Lett. 1989, 629-632.
(8) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287-290.
(9) Burke, S. D.; Sametz, G. M. Org. Lett. 1999, 1, 71-74.
(10) Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996,
35, 448-451.
(11) Prepared as described in: Adam, W.; Bialas, J.; Hadjiarapoglou,
L. Chem. Ber. 1991, 124, 2377.
Org. Lett., Vol. 4, No. 3, 2002
469

Functionalized dioxabicyclo[3.2.1]octanes 14 and 16, fully
saturated 17, and the original bridged bicyclic acetal 1 were
subjected to both HF and HCl conditions for deprotection/
spiroketalization (Table 1). Reaction times were faster with
HF than HCl, a result of the TBDPS protecting group being
more labile under the former conditions. Spiroketalization
of the four substrates proceeded without complications except
for 14 where an inseparable mixture of 21 and other
unidentified products was obtained upon treatment with HCl
in methanol. Deacetylation is competitive with silyl depro-
tection under these conditions, revealing the secondary
alcohols, which can trap the oxacarbenium ion.
1H NMR and crystallographic data for spiroketals 19-21
confirm their stereochemistry as that depicted in iV (Scheme
3). NOE studies of spiroketals 1912 and 21 showed the
enhancements illustrated in Figure 2. A crystal structure of
Figure 3. Crystal structure of 20.
of this new route to spiroketals in target- and diversity-
oriented synthesis13 are underway.
Acknowledgment. We thank the NIH [grant CA 74394]
(S.D.B.) for generous support of this research. The NSF
(CHE-8813550 and CHE-9629688) and NIH (1 S 10
RR04981-01) are acknowledged for their generous support
of the NMR facilities of the University of Wisconsin-
Madison Department of Chemistry. We thank the Hilldale
Foundation and Pfizer Summer Undergraduate Research
Foundation (J.R.M.) for its support. We thank Robert Clark
for obtaining the crystal structure of 20. We also thank
William D. Thomas for his helpful conversations on the
preparation of DMDO.
Figure 2. NOE enhancements.
bromohydrin spiroketal 20 (Figure 3) confirms this stereo-
chemical outcome, with both ring oxygens in axial positions.
In conclusion, we have shown that 1 can be used as a
general substrate that can be selectively functionalized to
produce a variety of spiroketal precursors. Acid-catalyzed
ketal isomerization proceeds well with these substrates,
resulting in only one spiroketal diastereomer. Applications
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 1, 2, 7-10, and
12-21 and crystallographic data for compound 20. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0172368
(12) Unsaturated spiroketal 18 was subjected to catalytic hydrogenation
and the spectra of the resulting product were identical to those of 19,
confirming its structure.
(13) (a) Hall, D. G.; Manku, S.; Wang, F. J. Comb. Chem. 2001, 3, 125-
150. (b) Schreiber, S. L. Science 2000, 287, 1964-1969.
470
Org. Lett., Vol. 4, No. 3, 2002