Synthesis of cyclic hemiketals and spiroketals from dioxanorbornanes

Article abstract of DOI:10.1021/ol048578r

(Chemical Equation Presented) A new method for the synthesis of substituted pyranone hemiketals from dioxanorbornanes via Sml₂ is described. Also reported is a synthesis of spiro[4.5]ketals from analogous intermediates via acid-promoted deprote

Full text of DOI:10.1021/ol048578r

ORGANIC
LETTERS
2004
Vol. 6, No. 21
3735-3737
Synthesis of Cyclic Hemiketals and
Spiroketals from Dioxanorbornanes
Jeffrey D. Winkler* and Peter J. Mikochik
Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
winkler@sas.upenn.edu
Received July 22, 2004
ABSTRACT
A new method for the synthesis of substituted pyranone hemiketals from dioxanorbornanes via SmI2 is described. Also reported is a synthesis
of spiro[4.5]ketals from analogous intermediates via acid-promoted deprotection/ketalization.
Cyclic hemiketals such as 1 (Scheme 1) are ubiquitous
components in naturally occurring compounds.1,2 Elegant
studies by Padwa3 and others4 have established that dipolar
cycloaddition of carbonyl ylids with carbonyl compounds
leads to the formation of the dioxanorbornanone nucleus 2,
as outlined in Scheme 1. We now demonstrate a novel
approach to the generation of pyranone hemiketal 1 that
underscores the utility of dioxanorbornanones 2 in the
construction of oxygenated ring systems.
The construction of dipole 3 (R ) n-C6H13) is outlined in
Scheme 2. Dimethylation of benzyl 3-ketononanoate (NaH,
MeI) led to the formation of 5 in 84% yield. The diazoketone
6 could be prepared in a one-pot reaction sequence, via (1)
hydrogenolysis of 5 to generate the unstable â-ketoacid, (2)
formation of the corresponding mixed anhydride with methyl
chloroformate and triethylamine, and (3) reaction of the
derived mixed anhydride with diazomethane to give diazo-
diketone 6 in 69% yield from 5. Reaction of 6 with
pivaldehyde in the presence of 5 mol % Rh2(OAc)4 gave 7
in excellent yield. The assignment of the exo orientation of
the tert-butyl group on the dioxanorbornanone ring system
(1) Norcross, R. D.; Paterson, I. Chem. ReV. 1995, 95, 2041-2114.
(2) Pettit, G. R.; Gao, F.; Herald, D. L.; Blumberg, P. M.; Lewin, N. E.;
Nieman, R. A. J. Am. Chem. Soc. 1991, 113, 6693-6695.
(3) (a) Padwa, A.; Fryxell, G. E.; Zhi, L. J. Am. Chem. Soc. 1990, 112,
3100-3109. (b) Padwa, A.; Chinn, R. L.; Hornbuckle, S. F.; Zhang, Z.
J. J. Org. Chem. 1991, 56, 3271-3278. (c) Padwa, A.; Chinn, R.
L.; Hornbuckle, S. F.; Zhang, Z. J. Tetrahedron Lett. 1989, 30, 301-
304.
Scheme 1
(4) (a) Muthusamy, S.; Babu, S. A.; Nethaji, M. Tetrahedron 2003, 59,
8117-8127. (b) Muthusamy, S.; Babu, S. A.; Gunanathan, C.; Ganguly,
B.; Suresh, E.; Dastidar, P. J. Org. Chem. 2002, 67, 8019-8033. (c) Nair,
V.; Sheela, K. C.; Sethumadhavan, D.; Dhanya, R.; Rath, N. P. Tetrahedron
2002, 58, 4171-4177. (d) Muthusamy, S.; Babu, S. A.; Gunathan, C.
Tetrahedron Lett. 2002, 43, 3931-3934. (e) Muthusamy, S.; Babu, S. A.;
Gunathan, C.; Suresh, E.; Dastidar, P.; Jasra, R. V. Tetrahedron 2001, 57,
7009-7019. (f) Nair, V.; Sheela, K. C.; Sethumadhavan, D.; Bindu, S.;
Rath, N. P.; Eigendorf, G. K. Synlett 2001, 272-274. (g) Muthusamy, S.;
Babu, S. A.; Gunanathan, C. Tetrahedron Lett. 2000, 41, 8839-8842. (h)
Pirrung, M. C. Kaliappan, K. P. Org. Lett. 2000, 3, 353-355.
10.1021/ol048578r CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/22/2004

Scheme 2
Scheme 3
Scheme 4. Subjection of 13 to the same reaction conditions
employed for the formation of 6 (Scheme 2) led to the
formation of dipole precursor 14. Reaction of 14 with
pivaldehyde in the presence of Rh2(OAc)4 led to the synthesis
of 15 in excellent yield. Treatment of 15 with 3% methanolic
HCl led to the exclusive formation of 17. The stereoselec-
tivity of the cyclization of 15 can be attributed to the addition
of the hydroxybutyl group anti to the C-5 carbinol substituent
in the oxonium ion intermediate 16. The stereochemistry
of 17 was confirmed by reduction to the corresponding
R-alcohol 18, the structure and stereochemistry of which was
established by X-ray crystallographic analysis.
We have demonstrated that dioxanorbornanone cyclo-
adducts can be selectively transformed into pyranone hemi-
ketals and furanone-based spiroketals, respectively. The
application of this methodology to the synthesis of oxygen-
ated ring systems is currently underway in our laboratory,
and our results will be reported in due course.
was based on extensive precedent for related transformations4
and could be confirmed by 1H NMR analysis, which revealed
an absence of coupling between Ha and Hb in 7, a result that
is consistent only with exo-cycloadduct 7.
Exposure of 7 to samarium diiodide (in the presence of
samarium metal) in MeOH/THF (1:6) at -90 °C led to the
predominant formation of 9, which corresponds to the
opening of the desired hemiketal ring, along with hemiketal
8 (ca. 4:1). Exposure of the mixture of 8 and 9 resulting
from the SmI2 reduction of 7 to TsOH in MeOH gave 10 as
the sole product in 56% yield over the two steps (reduction
and ketalization). The exclusive formation of 10 is consistent
with the anomeric effect,5 i.e., axial orientation of the
methoxy group and equatorial orientation of the tert-butyl
Scheme 4
1
substituent in 10, and was confirmed by H NMR analysis,
in which the cis relative stereochemistry of the methoxy and
the methine shown in 10 was established by NOESY.
We have also examined acidic hydrolysis of the dioxan-
orbornanone cycloadduct 7. Reaction of 7 with TsOH in
methanol leads to the quantitative formation of 12. The
stereoselective addition of methanol anti to the C-5 carbinol
substituent in oxonium ion 11 proceeds in the same sense
as that observed by Veyrie`res in a closely related system.6,7
We reasoned that intramolecular addition of an alcohol
moiety to the oxonium ion intermediate 11 derived from 7
would lead to an efficient synthesis of spirocyclic ketals.8
The preparation of the key intermediate 15 is shown in
(5) Beaulieu, N.; Dickinson, R. A.; Deslongchamps, P. Can. J. Chem.
1980, 58, 2531-2536.
(6) (a) Jaouen, V.; Je´gou, A.; Leme´e, L.; Veyrie`res, A. Tetrahedron 1999,
55, 9245-9260. (b) Goursaud, F.; Peyrane, F.; Veyrie`res, A. Tetrahedron
2002, 58, 3629-3637.
3736
Org. Lett., Vol. 6, No. 21, 2004

Acknowledgment. We would like to thank the National
Institutes of Health and GlaxoSmithKline for their generous
support of this program.
Supporting Information Available: Spectroscopic data
and experimental procedures for the preparation of 5-18
and X-ray data for 18. This material is available free of
charge via the Internet at http://pubs.acs.org.
(7) For the addition of carbon nucleophiles 5-substituted tetrahydrofuran-
based oxonium ions, see: (a) Tomooka, K.; Matsuzawa, K.; Suzuki, K.;
Tsuchihashi, G. Tetrahedron Lett. 1987, 28, 6339-6342. (b) Schmitt, A.;
Reissig, H. Synlett 1990, 40-42. (c) Shaw, J. T.; Woerpel, K. A.
Tetrahedron 1999, 55, 8747-8756. (d) Pilli, R. A.; Riatto, V. B.
Tetrahedron: Asymmetry 2000, 11, 3675-3686.
OL048578R
(8) For the synthesis of spirocyclic ketals via intramolecular capture of
a tetrahydropyrilium ion, see: Keller, V. A.; Martinelli, J. R.; Strieter, E.
R.; Burke, S. D. Org. Lett. 2002, 4, 467-470.
Org. Lett., Vol. 6, No. 21, 2004
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