ORGANIC
LETTERS
2007
Vol. 9, No. 19
3857-3858
Hydroxyl-Directed Nitrile Oxide
Cycloaddition Reactions with Cyclic
Allylic Alcohols
Nina Becker and Erick M. Carreira*
Laboratorium fu¨r Organische Chemie, ETH Zurich, CH-8093 Zu¨rich, Switzerland
Received July 27, 2007
ABSTRACT
Diastereoselective cycloaddition reactions between a nitrile oxide and cyclic allylic alcohols are reported. The products isolated are densely
functionalized building blocks that are not otherwise easily accessed with existing methods and concepts previously established for the
construction of acyclic polyketides.
We have previously conducted an in-depth study on the
hydroxyl directed cycloaddition reaction of acyclic allylic
alcohols and nitrile oxides.1 This approach provides access
to a wide range of acyclic polyketide arrays. Herein we
document the cycloaddition reaction of cyclic allylic alco-
hols, which proceeds in useful yields and high levels of
diastereocontrol (eq 1). The isolated adducts provide access
to an unusual set of densely functionalized polyketide
building blocks.
cased in the context of complex molecule syntheses in our
group. By contrast the use of cyclic allylic alcohols lacks
relevant precedence, despite the fact that their utility would
considerably expand the scope of building blocks available.
The cycloaddition of cyclohex-2-enol was reported to give
a complex mixture of many products.2c Additionally, Kim
reported two examples of aromatic nitrile oxides reacting
with tertiary cyclic allylic alcohols;3 the reactions, however,
were slow (48 h).4 Moreover, it was far from clear whether
the cycloaddition reaction would be amenable to generaliza-
tion. Additionally, the implementation of the cycloaddition
would benefit from the use of aliphatic nitrile oxides, which
are more capricious and prone to dimerization than the
aromatic counterparts. Thus, we have focused on the use of
the nitrile oxide generated from 1 and a collection of cyclic
allylic alcohols (eq 1). As shown in Table 1, cycloadditions
can be effected with five-, seven-, or eight-membered cyclic
allylic alcohols displaying various substitution patterns. The
typical reaction conditions involve the use of 1.3 equiv of
nitrile oxide, 3.3 equiv of isopropyl alcohol, and 3.0 equiv
The use of acyclic allylic alcohols in diastereoselective
nitrile oxide cycloaddition reactions first described by
Kanemasa2 has been subsequently investigated and show-
(1) (a) Bode, J. W.; Fraefel, N.; Muri, D.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2001, 40, 2082. (b) Bode, J. W.; Carreira, E. M. J. Am. Chem. Soc.
2001, 123, 3611. (c) Bode, J. W.; Carreira, E. M. J. Org. Chem. 2001, 66,
6410. (d) Fader, L. D.; Carreira, E. M. Org. Lett. 2004, 6, 2485. (e) Muri,
D.; Lohse, N.; Carreira, E. M. Angew. Chem., Int. Ed. 2005, 44, 4036.
(2) (a) Kanemasa, S.; Kobayashi, S.; Nishiuchi, M.; Yamamoto, H.;
Wada, E. Tetrahedron Lett. 1991, 32, 6367. (b) Kanemasa, S.; Nishiuchi,
M.; Wada, E. Tetrahedron Lett. 1992, 33, 1357. (c) Kanemasa, S.; Nishiuchi,
M.; Kamimura, A.; Hori, K. J. Am. Chem. Soc. 1994, 116, 2324.
(3) Kim, H. R.; Song, J. H.; Rhie, S. Y.; Ryo, E. K. Synth. Commun.
1995, 25, 1801.
(4) (a) For diastereoselective nitrile oxide cycloadditions with 3-alkyl-
4-hydroxycyclopenten-2-ones, which proceed largely on the basis of sterics
differences, see: Adembri, G.; Giorgi, G.; Lampriello, R. L.; Paoli, M. L.;
Sega, A. J. Chem. Soc., Perkin Trans. 1 2000, 2649. (b) Basra, S. K.; Drew,
M. G. B.; Mann, J.; Kane, P. D. J. Chem. Soc., Perkin Trans 1 2000, 3592.
10.1021/ol7017032 CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/23/2007