migration8 in allylic ethers. This way, allylic ethers 2, 3,
and 4 were converted into vinylic ethers 5, 6, and 7. Radical
cyclization reaction of 5, 6, and 7 proceeded efficiently to
produce the oxacyclic products 8, 9, and 10 (Scheme 2).9
Scheme 3. Total Synthesis of (+)-Monocerin
Scheme 2. Radical Cyclization of Vinylic Ethers
Radical cyclization of both E- and Z-isomers of 6 and 7
apparently produced only the “2,5- or 2,6-cis” products 9
and 10 exhibiting similar stereoselectivity encountered in the
reactions of stabilized vinylic ethers.7
The synthetic sequence for monocerin started with a stereo-
selective aldol reaction of the chiral imide 1110 and 3,4,5-
trimethoxybenzaldehyde, and subsequent reduction with lithium
borohydride produced the MOM-protected triol 12 in good
yield. Selective tosylation of the primary hydroxyl group,
O-alkylation with 1-bromo-2-butene, and phenylselenide sub-
stitution led to the allylic ether selenide 1311 (Scheme 3).
Double-bond migration was catalyzed by the Wilkinson
catalyst, and the product vinylic ether 14, which was obtained
as a ∼2:3 mixture of E- and Z-isomer, was treated with
tris(trimethylsilyl)silane in the presence of triethylborane. This
way, oxolane 15 was obtained in 74% yield from 13. Formation
of other stereoisomeric products was not noticed.
The MOM protecting group participated in the next reaction
as dioxatricycle 16 was obtained from 15 via treatment with
titanium(IV) chloride. Ruthenium-catalyzed oxidation12 of 16
led to lactone 17, which was converted into (+)-monocerin (1)13
upon partial demethylation2 with boron tribromide.14
The vinylic ether radical cyclization strategy described in
this communication provides a direct and stereoselective
route to (+)-monocerin. The scheme may be adapted for
synthesis of a large number of oxacyclic natural products,
which will be the focus of future studies.
(6) (a) Inoue, M.; Ishihara, Y.; Yamashita, S.; Hirama, M. Org. Lett.
2006, 8, 5801–5804. (b) Inoue, M.; Yamashita, S.; Ishihara, Y.; Hirama,
M. Org. Lett. 2006, 8, 5805–5808. (c) Inoue, M.; Saito, F.; Iwatsu, M.;
Ishihara, Y.; Hirama, M. Tetrahedron Lett. 2007, 48, 2171–2175.
(7) For a few recent examples, see: (a) Kwon, M. S.; Woo, S. K.; Na,
S. W.; Lee, E. Angew. Chem., Int. Ed. 2008, 47, 1733–1735. (b) Kim, W. H.;
Hong, S. K.; Lim, S. M.; Ju, M.-A.; Jung, S. K.; Kim, Y. W.; Jung, J. H.;
Kwon, M. S.; Lee, E. Tetrahedron 2007, 63, 9784–9801. For more examples
on vinyl ether radical cyclization, read the following review: (c) Lee, E. In
Radicals in Organic Synthesis, Vol. 2: Applications; Renaud, P., Sibi, M. P.,
Eds.; Wiley-VCH: Weinheim, 2001; pp 303-333.
Acknowledgment. This research was supported by a grant
from the Marine Biotechnology Program funded by the Ministry
of Land, Transport and Maritime Affairs, Republic of Korea,
and a grant from the Korea Research Foundation (MOEHRD)
(KRF-2005-070-C00073). Brain Korea 21 graduate fellowship
grants to Y.E.L. and H.K.K. are gratefully acknowledged.
(8) Corey, E. J.; Suggs, W. J. J. Org. Chem. 1973, 38, 3224.
(9) Lee, Y. E. Radical Cyclization Strategy for Oxacyclic Natural Product
Synthesis. M. S. Dissertation, Seoul National University, Seoul, Korea, 2002.
(10) Owen, R. M.; Roush, W. R. Org. Lett. 2005, 7, 3941–3944.
(11) Use of commercially available 1-bromo-2-butene led to the
formation of a mixture (E:Z ) ∼4:1) of the allylic ether 4.
(12) Martin, O. R.; Hendricks, C. A. V.; Deshpande, P. P.; Cutler, A. B.;
Kane, S. A.; Rao, S. P. Carbohydr. Res. 1990, 196, 41–58.
Supporting Information Available: Experimental proce-
dures and 1H NMR and 13C NMR spectra of the intermediates
and products. This material is available free of charge via the
(13) The synthetic sample exhibited identical spectroscopic properties
as reported for the natural sample.
(14) The overall yield of (+)-1 from 11 was 7.8% in 10 steps. In Mori
synthesis, (+)-1 was prepared from ethyl (S)-3-hydrxyhexanoate in 14 steps
in 6.6% overall yield. In Marsden synthesis, (()-1 was synthesized from
(()-1-hepten-4-ol in 8 steps in 6.5% overall yield.
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