Published on Web 11/15/2006
A General Strategy for Synthesis of Both (6Z)- and
(6E)-Cladiellin Diterpenes: Total Syntheses of
(-)-Cladiella-6,11-dien-3-ol, (+)-Polyanthellin A,
(-)-Cladiell-11-ene-3,6,7-triol, and (-)-Deacetoxyalcyonin
Acetate
Hyoungsu Kim, Hyunjoo Lee, Jayoung Kim, Sanghee Kim, and Deukjoon Kim*
Contribution from the Research Institute of Pharmaceutical Sciences, College of Pharmacy,
Seoul National UniVersity, San 56-1, Shinrim-Dong, Kwanak-Ku, Seoul 151-742, Korea
Received August 9, 2006; E-mail: deukjoon@snu.ac.kr
Abstract: The first total synthesis of an (E)-cladiellin diterpene, (-)-cladiella-6,11-diene-3-ol (1), was
accomplished featuring an intramolecular amide enolate alkylation-intramolecular Diels-Alder strategy.
In addition, a highly stereo-, regio-, and chemoselective synthetic strategy for other members of the cladiellin
diterpenes such as (+)-polyanthellin A (2), (-)-cladiell-11-ene-3,6,7-triol (3), and (-)-deacetoxyalcyonin
acetate (4) was developed utilizing the synthetic (E)-cladiellin 1 as a common intermediate by taking
advantage of the unique chemical properties of its C(6)-(E)-oxatricyclic skeleton.
Introduction
our intramolecular amide enolate alkylation (IAEA) methodol-
ogy,4 total synthesis of the more challenging and hitherto
The cladiellin diterpenes, the most abundant class of 2,11-
cyclized cembranoid natural products, have been isolated from
marine invertebrates.1 These medium-sized oxatricyclic marine
natural products possess a nine-membered ring, and both C(6)-
(E)- and (Z)-isomers are found in nature. Owing to their
fascinating molecular architecture and diverse biological activity,
the 2,11-cyclized cembranoids have attracted considerable
attention from the synthetic community over the past decade,
leading to the total synthesis of several members of this family2
along with a number of approaches to their synthesis.3 However,
total synthesis of the cembrane-derived diterpenes with a (6E)-
oxonene unit has not been realized to date. With the notion that
both the (6Z)- and (6E)-oxonene cores could be constructed by
inaccessible (6E)-cladiellins was undertaken. In this article, we
report an asymmetric total synthesis of (-)-cladiella-6,11-dien-
3-ol (1),5 which constitutes the first total synthesis of an (E)-
cladiellin diterpene. Furthermore, the synthetic (E)-cladiellin 1
could be transformed into other members of the cladiellin
diterpenes such as (+)-polyanthellin (2),6 (-)-cladiell-11-ene-
3,6,7-triol (3),7 and (-)-deacetoxyalcyonin acetate (4)8 in a
highly stereo-, regio-, and chemoselective fashion by taking
advantage of the unique chemical properties of its (6E)-
oxatricyclic skeleton (vide infra).
Results and Discussion
As shown in Scheme 1, we envisaged that (-)-cladiella-6,-
11-dien-3-ol (1) could be elaborated from key oxatricycle 5,
which in turn could be prepared by an intramolecular Diels-
Alder (IMDA) reaction of tetraene 6. We further envisioned
that 2,9-cis-disubstitued (E)-oxonene 7 could be secured through
an intramolecular amide enolate alkylation of chloro amide 8.
Our preliminary studies suggested that the secondary nature of
C(3) and the syn relative stereochemistry of C(2) and C(3) in
key internal alkylation substrate 8 are vital for efficient
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10.1021/ja065782w CCC: $33.50 © 2006 American Chemical Society
J. AM. CHEM. SOC. 2006, 128, 15851-15855
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