ORGANIC
LETTERS
2012
Vol. 14, No. 14
3720–3723
Formal Synthesis of Merrilactone A Using
a Domino Cyanide 1,4-AdditionꢀAldol
Cyclization
Naim Nazef,§ Robert D. M. Davies,‡ and Michael F. Greaney*,†
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, U.K.,
School of Chemistry, University of Edinburgh, Joseph Black Building, King’s Buildings,
West Mains Road, Edinburgh EH9 3JJ, U.K., and AstraZeneca, Mereside, Alderley Park,
Macclesfield, Cheshire SK10 4TG, U.K.
Received June 7, 2012
ABSTRACT
A formal synthesis of merrilactone A has been completed using a domino 1,4-additionꢀaldol process as the key step. Both iodo- and cyano-1,
4-additionꢀaldol cyclizations were productive in forming the highly hindered C1ꢀC9 bond linking vic-quaternary and tertiary stereocenters.
The latter method was used to complete a formal total synthesis of the natural product.
The neurotrophic sesquiterpene merrilactone A, 1, was
isolated by Fukuyama in 2000 from the pericarps of
Illicium merrilianium.1 The highly congested terpenoid
structure, featuring five contiguous, fully substituted
carbon centers, has inspired total syntheses from the groups
of Danishefsky,2 Inoue and Hirama,3 Mehta,4 Frontier,5
ourselves,6 and Zhai.7,8 In each case, creative strategies were
necessary to achieve stereocontrolled CꢀC bond formation
in such a sterically hindered architecture, with the cyclo-
pentane C-ring, containing four fully substituted carbons
plus a secondary stereocenter, being a particular challenge.
Our first synthesis used a reductive epoxide cyclization of
the highly functionalized cyclopentane 3 as the key step
(Scheme 1). Treatment of 3 with Ti(III) affords the bicycle 4
having the complete carbon skeleton of merrilactone A.
Two orthogonal functionalization sequences then afforded
merrilactone A, 1, or the related sesquiterpene anislactone
A, 2. We now wish to report a second synthesis of the
merrilactone A structure, based on a domino conjugate
§ University of Edinburgh.
‡ AstraZeneca.
† University of Manchester.
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r
10.1021/ol301513h
Published on Web 07/09/2012
2012 American Chemical Society