Synthetic study of presilphiperfolan-8-ol: Construction of the tricyclo[5.3.1.04,11]undecane framework utilizing intramolecular aldol condensation and mcmurry coupling

Article abstract of DOI:10.1246/cl.130394

The tricyclo[5.3.1.04,11]undecane framework of presilphiperfolan- 8-ol, tricyclic sesquiterpene alcohol was constructed by intramolecular aldol condensation and the McMurry coupling from two types of diketone compounds, which were obtained from (+)-pulegone through a five-step process. This synthetic route does not require the use of any protective groups.

Full text of DOI:10.1246/cl.130394

doi:10.1246/cl.130394
Published on the web June 5, 2013
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Synthetic Study of Presilphiperfolan-8-ol: Construction of the Tricyclo[5.3.1.04,11]undecane
Framework Utilizing Intramolecular Aldol Condensation and McMurry Coupling
Toyoharu Kobayashi, Hidenori Shiroi, Hideki Abe, and Hisanaka Ito*
School of Life Sciences, Tokyo University of Pharmacy and Life Sciences,
1432-1 Horinouchi, Hachioji, Tokyo 192-0392
(Received April 25, 2013; CL-130394; E-mail: itohisa@toyaku.ac.jp)
The tricyclo[5.3.1.04,11]undecane framework of presilphi-
perfolan-8-ol, tricyclic sesquiterpene alcohol was constructed by
intramolecular aldol condensation and the McMurry coupling
from two types of diketone compounds, which were obtained
from (+)-pulegone through a five-step process. This synthetic
route does not require the use of any protective groups.
H
H
H
H
OH
2
presilphiperfolan-8-ol (1)
tricyclo[5.3.1.04,11]-
undecane framework
Figure 1. Structure of presilphiperfolan-8-ol (1).
Presilphiperfolan-8-ol (1) (Figure 1), a tricyclic sesquiter-
pene alcohol, was isolated from the California coastal succulent
Eriophyllum staechadifolium and from Flourensia heterolepis
by Bohlmann and co-workers in 1981.1 The relative config-
uration of the stereogenic centers and the absolute configuration
of 1 were determined by Coates and co-workers in 1996.2
Presilphiperfolan-8-ol (1) and other presilphiperfolanols3 are
well known as prebotrydials and considered important biosyn-
thetic precursors to diverse sesquiterpenoids.1,2,4,5 The main
structural feature of presilphiperfolan-8-ol (1) is the tricyclo-
[5.3.1.04,11]undecane framework, including a strained trans-
fused bicyclo[3.3.0]octane moiety. This unprecedented structure
and the central biosynthetic role of 1 are of interest to organic
chemists. One group has succeeded in the enzymatic formation5
of presilphiperfolan-8-ol (1), but no total synthesis or synthetic
study of 1 has been reported. In addition, reports of the
asymmetric synthesis of the tricyclo[5.3.1.04,11]undecane frame-
work are very limited.6 Therefore, developing a concise route to
the tricyclo[5.3.1.04,11]undecane framework in an optically pure
form is needed before the total synthesis of presilphiperfolan-8-
ol (1) can be accomplished. This report describes the concise
synthesis of the tricyclo[5.3.1.04,11]undecane framework 2 via
two paths: intramolecular aldol condensation and the McMurry
coupling.
O
O
Intramolecular
aldol condensation
O
H
H
H
H
H
H
2
3
4
O
O
O
RCM
H
H
(+)-pulegone (7)
5
6
Figure 2. Synthetic strategy toward tricyclo[5.3.1.04,11]unde-
cane framework 2.
TMS
O
O
1.
TiCl4, CH2Cl2
2
2. KOH, MeOH
65% (2 steps)
(+)-pulegone (7)
8
dr = 4:1 (C2 position)
nOe
This synthetic strategy for tricyclo[5.3.1.04,11]undecane
framework 2 is outlined in Figure 2. The tricyclic compound 2
could be constructed by intramolecular aldol condensation of
diketone 4 followed by reduction of the carbonyl group of
resulting enone 3. Diketone 4 would be obtained from 5 via the
regioselective hydroboration-oxidation and oxidation of the
resulting alcohol. Bicyclic compound 5 would be synthesized by
ring-closing metathesis (RCM) from diene 6, which could be
derived from (+)-pulegone (7) using two types of allylation.
The synthesis of diketone 4, the precursor for intramolecular
aldol condensation, is shown in Scheme 1.7 The 1,4-addition
reaction of allylsilane to pulegone (7) followed by the isomer-
ization provided the compound 8 in 65% yield with 4:1
diastereoselectivity over two steps.8 Treatment of 8 with LDA
and allyl bromide gave the diene 6 in 75% yield with separable
stereoisomers in 5:1 ratio.9 The RCM10 of the diene 6 with a
second-generation Grubbs catalyst in CH2Cl2 under reflux
conditions for 2 h gave the bicyclic compound 5 in 83% yield.
O
Br
H
H
, LDA
Grubbs 2nd (0.05 equiv)
CH2Cl2 (0.005 M)
83%
6
2
THF
75%
dr = 5:1 (C6 position)
6
O
•
1.
BH3 THF, THF
O
then
•
O
O
O
NaBO3 4H2O
+
H
H
H
H
H
H
2. DMP, CH2Cl2
4 : 34%, 9 : 23%
4
9
5
•
BH3 THF, THF
then
PCC
4 : 41%, 9 : 28%
Scheme 1. Synthesis of diketone 4.
Chem. Lett. 2013, 42, 975-976
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

976
produced the desired tricyclic compound 2 in 27% yield (67%
based on recovered starting materials). In addition, the intra-
molecular McMurry coupling of 9 proceeded successfully using
O
O
H
H
14
TiCl3/LiAlH4 to afford the compound 2 in 68% yield.
In summary, a concise route to the tricyclo[5.3.1.04,11]un-
decane framework of presilphiperfolan-8-ol (1) was developed,
utilizing the intramolecular aldol condensation and McMurry
coupling as key reactions. This synthetic route does not require
the use of any protective groups. Further investigation with the
goal of total synthsis of presilphiperfolan-8-ol (1) is currently
being pursued.
4
O
O
H
H
9
This work was supported financially by the Platform for
Drug Discovery, Informatic, and Structural Life Science from
the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
Figure 3. ORTEP drawings of 4 and 9.
O
O
O
t-BuOK
References and Notes
t-BuOH
H
H
1
2
3
F. Bohlmann, C. Zdero, J. Jakupovic, H. Robinson, R. M.
King, Phytochemistry 1981, 20, 2239.
R. M. Coates, Z. Ho, M. Klobus, S. R. Wilson, J. Am. Chem.
Soc. 1996, 118, 9249.
H
H
99%
4
3
TFA, NaBH4
a) S. Melching, W. A. König, Phytochemistry 1999, 51, 517.
b) S. C. Pinto, G. G. Leitão, H. R. Bizzo, N. Martinez, E.
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Jakupovic, Phytochemistry 1996, 41, 837.
CH2Cl2/CH3CN/AcOH
27%
(67% brsm)
O
O
TiCl3, LiAlH4
H
H
THF
68%
H
H
2
9
4
C. Pinedo, C.-M. Wang, J.-M. Pradier, B. Dalmais, M.
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Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
Scheme 2. Synthesis of tricycle[5.3.1.04,11]undecane frame-
work 2.
5
6
7
Next, the regioselective hydroboration-oxidation of 5 followed
by oxidation of the resulting alcohol was attempted. Using
BH3¢THF/NaBO3¢4H2O and the Dess-Martin oxidation, the
desired diketone 4 was obtained in 34% yield, along with
regioisomer 9 in 23% yield. Using PCC as an oxidant11 after
hydroboration of 5 produced diketones 4 and 9 in 41 and 28%
yield, respectively. The structures of 4 and 9 were unambigu-
ously confirmed by single-crystal X-ray crystallography12
(Figure 3). An attempt was made to use bulkier boran reagents
(e.g., 9-BBN and catecholborane) to improve the regioselectivity
of hydroboration of 5, but the reactions did not proceed and
diketone 4 was not obtained.
Due to the poor regioselectivity of the hydroboration of 5,
diketones 4 and 9 were available. Therefore, the tricyclo-
[5.3.1.04,11]undecane framework 2 could be constructed from
diketones 4 and 9: compound 2 could be obtained directly by the
intramolecular McMurry coupling of diketone 9.
The synthesis of tricyclic compound 2 is shown in
Scheme 2. The key intramolecular aldol reaction of 4 with t-
BuOK in t-BuOH at room temperature proceeded successfully to
provide the tricyclic compound 3 in 99% yield. Conversion of
the carbonyl group of 3 to a methylene group in 2 was successful
using Gribble’s method.13 Thus, treatment of compound 3 with
excess NaBH4 and TFA in CH2Cl2, CH3CN, and AcOH
8
9
R. B. Miles, C. E. Davis, R. M. Coates, J. Org. Chem. 2006,
71, 1493.
The C-6 configuration was determined by the nOe correla-
tion between H-6 proton and H-2 proton.
10 For recent review of the application for ring-closing meta-
thesis to total synthesis of natural products, see: K. C.
Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem., Int. Ed.
2005, 44, 4490.
11 H. C. Brown, S. U. Kulkarni, C. C. Rao, Synthesis 1980,
151.
12 Crystallographic data of compounds 4 and 9 have been
deposited with Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC-932539 and CCDC-
932540, respectively.
13 G. W. Gribble, R. M. Leese, B. E. Evans, Synthesis 1977,
172.
14 A. L. Baumstark, C. J. McCloskey, K. E. Witt, J. Org. Chem.
1978, 43, 3609.
Chem. Lett. 2013, 42, 975-976
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/