ORGANIC
LETTERS
2012
Vol. 14, No. 1
146–149
Radical Cyclization Cascades of
Unsaturated Meldrum’s Acid Derivatives
Brice Sautier,† Sarah E. Lyons,† Michael R. Webb,‡ and David J. Procter*,†
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL,
U.K., and Medicines Research Centre, GlaxoSmithKline, Gunnels Wood Road,
Stevenage, Herts, SG1 2NY, U.K.
Received October 31, 2011
ABSTRACT
Unsaturated, differentially substituted Meldrum’s acid derivatives undergo cascade cyclizations upon ester reduction with SmI2ÀH2O. The
cascade cyclizations proceed in good yield and with high diastereocontrol and convert simple, achiral starting materials to complex molecular
architectures, bearing up to four stereocenters, in a single operation. The cascades are triggered by the generation and trapping of unusual
radical-anions formed by electron transfer to the ester carbonyl.
Electron-transfer to the carbonyl groups of unactivated
esters forms the basis of classical organic transformations
such as the acyloin condensation1 and the BouveaultÀ
Blanc reduction.2 Prior to our recent studies,3 the possibi-
lity of exploiting the radical-anions formed by electron
transfer to the ester carbonyl group in additions to alkenes
had received little attention.4 Here we report radical
cascade reactions of unsaturated Meldrum’s acid deriva-
tives that allow complex carbocyclic motifs to be assem-
bled in a single operation. The cyclization cascade is tri-
ggered by the generation and trapping of unusual radical
anions formed from the ester carbonyl by electron transfer
from SmI2ÀH2O.5
We recently reported the first reductions of lactones
and Meldrum’s acid derivatives by SmI2 using H2O as
an activating cosolvent6 (e.g., Scheme 1, eq 1).3aÀc We
have since shown that unactivated acyclic aliphatic esters
can be reduced using SmI2ÀH2OÀNEt3.7 Furthermore,
we have shown for the first time that the unusual radical-
anions formed by electron transfer to the ester carbonyl
group can be exploited in additions to alkenes (e.g.,
Scheme 1, eq 2).3bÀe
† University of Manchester.
‡ GlaxoSmithKline.
€
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ꢀ
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r
10.1021/ol2029367
Published on Web 11/30/2011
2011 American Chemical Society