Enantioselective Total Synthesis of (+)-Tricycloclavulone

Article abstract of DOI:10.1021/ja049750p

The first total synthesis of (+)-tricycloclavulone having a unique tricyclo[5,3,0,0^1,4]decane skeleton and six chiral centers was achieved in a highly stereoselective manner. It includes a catalytic enantioselective [2+2]-cycloaddition reaction using novel chiral copper catalyst, extremely effecting an intramolecular ester transfer reaction, and asymmetric reduction of the carbonyl group on the α-chain using Noyori's chiral ruthenium catalyst. Copyright

Full text of DOI:10.1021/ja049750p

Published on Web 03/18/2004
Enantioselective Total Synthesis of (+)-Tricycloclavulone
Hisanaka Ito,* Mineki Hasegawa, Yosuke Takenaka, Tatsuya Kobayashi, and Kazuo Iguchi*
School of Life Science, Tokyo UniVersity of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji,
Tokyo 192-0392, Japan
Received January 15, 2004; E-mail: itohisa@ls.toyaku.ac.jp; onocerin@ls.toyaku.ac.jp
Scheme 1. Synthetic Plan of Tricycloclavulone (1)
Marine natural products have received much attention for their
attractive structural features and biological activities.1 Since the
isolation of clavulone I, about 40 related marine prostanoids were
isolated from Okinawan soft coral ClaVularia Viridis.2 Many of
these compounds have antiproliferative activities in human cancer
cell lines. Tricycloclavulone (1), which has a tricyclo[5.3.0.01,4]-
decane skeleton, was recently isolated as an abnormal marine
prostanoid from C. Viridis by our group.3 Although its planar
structure and the relative stereochemistry of the chiral centers on
the tricyclic core in 1 were determined by spectroscopic analysis,
the stereochemistry of the carbon bearing the acetoxy group on
the R-chain as well as the absolute stereochemistry have not yet
been examined. In addition, tricycloclavulone (1), possessing a
highly functionalized and strictly fixed 5,5,4-ring system, is a quite
attractive synthetic target for organic chemists. The diverse
structural features of 1 in conjunction with its potential for biological
activity have stimulated our considerable interest. We report herein
the first enantioselective total synthesis of (+)-tricycloclavulone
(1).4
Scheme 2. Enantioselective [2+2]-Cycloaddition Reaction
Our strategy for the total synthesis of tricycloclavulone (1) as
an optically active form focused on the use of an enantioselective
[2+2]-cycloaddition reaction catalyzed by a novel catalyst and
sequential addition of an ω-chain and an R-chain to establish the
stereogenic centers on the C-ring with complete control of the
stereochemistry through an intramolecular ester transfer reaction
(Scheme 1). The strictly fixed tricyclic system would efficiently
work to shield the concave face of the C-ring. Therefore, the
introduction of both side chains could be carried out on the convex
face in a highly diastereoselective manner. From a retrosynthetic
perspective, we envisioned the construction of the tricyclic ring
system at an early stage for the total synthesis.
An efficient synthesis of the tricyclic system4 was developed by
starting from 2-methoxycarbonyl-2-cyclopenten-1-one (6)5 and
phenylthioacetylene (7)6 via a chiral Lewis acid-catalyzed enantio-
selective [2+2]-cycloaddition reaction (Scheme 2).7 Our initial
effort for developing an enantioselective [2+2]-cycloaddition by
using known chiral catalysts (Ti-TADDOL,8 Cu-BOX9) gave
unsatisfactory results. Therefore, we examined the development of
an efficient catalytic system for the reaction of 6 with 7. As shown
in Scheme 2, a novel catalyst prepared from simple chiral
bis-pyridine ligand 8 and copper salt accelerated the reaction of 6
with 7 and gave bicyclic intermediate 510 with 73% ee in 67% yield.
The synthesis of the tricyclic core was improved over that of
our reported procedure4 by the use of second generation Grubbs
catalyst (Scheme 3). The bicyclic compound 5 was converted to 9
by five steps. The construction of the tricyclic ring system from 9
using first generation Grubbs catalyst11 was examined under several
conditions, but the desired compound was not obtained because of
the steric hindrance around both vinyl groups on compound 9. Thus,
the ring-closing metathesis of desilylated compound of 9 proceeded
to give a tricyclic compound in 94% yield.4 On the other hand,
second generation Grubbs catalyst11 was employed, and the reaction
of 9 proceeded to give a tricyclic compound in satisfactory yield.
To achieve the total synthesis of 1, the development of an
efficient constructive method for the side chains was very important.
Our efforts for the stereoselective introduction of both side chains
to the tricyclic core are shown in Scheme 3. For the protection of
the R,â-unsaturated ketone moiety on the A-ring, the carbonyl group
on the A-ring was stereoselectively converted to a hydroxyl group
with DIBAL-H12 to give 12 (diastereomeric ratio was 3.8:1).
Although other reducing agents were also examined, undesired 1,4-
reduction on the A-ring and/or the reduction of the vinyl sulfone
moiety proceeded. Stereoselective introduction of the ω-chain was
easily achieved by treatment of 12 with n-butyllithium in 92% yield.
This result encouraged us to construct both side chains in a one-
pot reaction. Therefore, the capture of the anion on the carbon
bearing the sulfone, which was generated after the 1,4-addition of
n-butyllithium, was examined. When the capture of the anion
intermolecularly by using some electrophilic reagents (aldehydes
or acid halides) was examined, only hydroxymethylation by using
formaldehyde proceeded, albeit in unsatisfactory yield. So, we
planned to incorporate a carbon electrophile into the hydroxyl group
on the A-ring for the introduction of the R-chain by an intra-
molecular ester transfer reaction.13 Methoxycarbonylation of the
9
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J. AM. CHEM. SOC. 2004, 126, 4520-4521
10.1021/ja049750p CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Total Synthesis of (+)-Tricycloclavulone
Acknowledgment. We thank the Uehara Memorial Foundation
for financial support.
sterically hindered hydroxyl group was achieved by employing
methylmagnesium bromide as a base followed by addition of methyl
chloroformate to afford 4 in 80% yield. The stereoselective 1,4-
addition of the ω-chain by dibutylcopper lithium followed by the
intramolecular ester transfer reaction succeeded to give compound
13 as a single stereoisomer in 83% yield. Stereoselective preparation
of 3 was achieved through deprotection of the TES group and
subsequent intramolecular lactonization followed by treatment of
SmI2 for the reductive desulfonylation.14 Recrystallization of
compound 3 was examined to increase the optical purity, and twice
recrystallization gave compound 3 as an almost optically pure form
(99% ee). Elongation of the R-chain was achieved as follows. The
lactone was reduced with LiAlH4 to give a diol. Oxidation of the
diol was successful by employing Swern oxidation to afford a keto
aldehyde in 74% yield. The Wittig-Horner-Emmons reaction of
keto aldehyde with 5-(dimethoxyphosphoryl)-4-oxopentanoic acid
methyl ester (14)15 gave compound 2 in 72% yield. Enantioselective
reduction of the carbonyl group on the R-chain of 2 with chiral
ruthenium catalyst 15 developed by Noyori et al.16 proceeded to
give 16 in a highly diastereoselective manner (11:1, major isomer
had the same stereochemistry as natural product 1). The absolute
configuration of the hydroxyl group on the R-chain was determined
by the Kusumi-Kakisawa method.17 Acetylation of 16, desilylation,
followed by acetylation completed the enantioselective total
synthesis of (+)-tricycloclavulone (1). The spectral data (1H, 13C,
and Ms) and [R]D value of synthetic tricycloclavulone were identical
to those of natural 1.3
Supporting Information Available: Experimental procedures and
characterization data for all new products (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
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In conclusion, the first enantioselective total synthesis and
determination of the complete stereochemistry of (+)-tricyclocla-
vulone were achieved through an enantioselective [2+2]-cycload-
dition reaction with a novel catalyst, ring-closing olefin metathesis,
sequential addition of an R- and an ω-chain through a stereocon-
trolled intramolecular ester transfer reaction, and enantioselective
reduction of the carbonyl group with a chiral ruthenium catalyst.
The results of the biological assay of 1 and the details of the
catalytic enantioselective [2+2]-cycloaddition reaction will be
reported in due course.
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