After obtaining siloxyfuran 5, we next investigated a
key intramolecular C-glycosylation for the synthesis of
oxabicyclo[3.2.1]octene 4 (Scheme 3). Upon treatment of
siloxyfuran 5 with a Lewis acid such as SnCl4, TiCl4, or
BF3•OEt2 in CH2Cl2, a complex mixture of products was
obtained. After extensive examination, we determined that
TMSOTf and 2,4,6-collidine in CH2Cl2 at ꢀ20 °C was the
optimal condition for the intramolecular C-glycosylation
to give desired oxabicyclo[3.2.1]octene 4 in 83% yield as a
single product. The structure of 4 was unambiguously con-
firmed by X-ray crystallographic analysis.15
Scheme 4. Total Synthesis of Polygalolide A (1)
Scheme 3. Synthesis of Oxabicyclo[3.2.1]octene 4 and Proposed
Mechanism for the Intramolecular C-Glycosylation
The high stereoselectivity of the intramolecular C-gly-
cosylation, as predicted (Scheme 3), is dictated by the effect
of the siloxy substituent at the C-3 position. Under the
reaction conditions, siloxyfuran 5 would give an oxocar-
benium cation intermediate, which has two possible tran-
sition states (TS-1 and TS-2) in a cyclization step. Con-
sidering allylic 1,3-strain, the C-glycosylation proceeds
through the more stable TS-2 with minimum steric hin-
drance between the two TBS groups to yield product 4
exclusively.
(8) (a) Ichikawa, Y.; Isobe, M.; Konobe, M.; Goto, T. Carbohydr.
Res. 1987, 171, 193–199. (b) Saeeng, R.; Sirion, U.; Sahakitpichan, P.;
Isobe, M. Tetrahedron Lett. 2003, 44, 6211–6215. (c) Isobe,M.;Phoosaha,
W.; Saeeng, R.; Kira, K.; Yenjai, C. Org. Lett. 2003, 5, 4883–4885.
(d) Saeeng, R.; Isobe, M. Org. Lett. 2005, 7, 1585–1588. (e) Saeeng, R.;
Isobe, M. Chem. Lett. 2006, 35, 552–557.
(9) (a) Tanaka, S.; Tsukiyama, T.; Isobe, M. Tetrahedron Lett. 1993, 34,
5757–5760. (b) Tanaka, S.; Isobe, M. Tetrahedron 1994, 50, 5633–5644.
(c) Hamajima, A.; Isobe, M. Angew. Chem., Int. Ed. 2009, 48, 2941–2945.
(10) (a) Reetz, M. T. Angew. Chem., Int. Ed. 1984, 23, 556–569.
(b) Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191–1223.
(11) (a) Koviach, J. L.; Chappell, M. D.; Halcomb, R. L. J. Org.
Chem. 2001, 66, 2318–2326. (b) Bolitt, V.; Mioskowski, C. J. Org. Chem.
1990, 55, 5812–5813.
Next, oxabicyclo[3.2.1]octene 4 was transformed into
tetracyclic lactone 3, as shown in Scheme 4. Hydrolysis of 4
with LiOH gave a hemiacetal, and partial hydrogenation
of the desilylated acetylenic moiety with Lindlar’s catalyst
and subsequent reduction with Et3SiH and BF3•OEt2
˚
in the presence of MS-4 A afforded spirolactone 14. At
this stage, oxygen functionality at the C-3 position was
removed using the BartonꢀMcCombie deoxygenation
protocol.16 Deprotection of the TBS group was followed
(12) Boukouvalas, J.; Marion, O. Synlett 2006, 1511–1514.
(13) Although the stereochemistry of the generated alcohol at the C-3
position was not determined at this stage, the configuration was finally
confirmed to be S by X-ray crystallographic analysis of oxabicyclo-
[3.2.1]octene 4.
(14) (a) Vedejs, E.; Diver, S. T. J. Am. Chem. Soc. 1993, 115, 3358–
3359. (b) Vedejs, E.; Bennett, N. S.; Conn, L. M.; Diver, S. T.; Gingras,
M.; Lin, S.; Oliver, P. A.; Peterson, M. J. J. Org. Chem. 1993, 58, 7286–
7288.
(15) CCDC 836367 (4) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
data_request/cif.
(16) (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 1574–1585. (b) Barton, D. H. R.; Crich, D.; Lobberding,
A.; Zard, S. Z. Tetrahedron 1986, 42, 2329–2338.
6534
Org. Lett., Vol. 13, No. 24, 2011