Construction of vicinal quaternary carbon atoms by Ireland ester Claisen rearrangement: Total synthesis of (±)-herbertenolide, (±)-herberteneacetal, (±)-herbertene-1,14-diol and (±)-herbertene-1,15-diol

Article abstract of DOI:10.1016/j.tetlet.2005.05.065

Efficient total syntheses of the herbertane sesquiterpene title compounds have been accomplished employing an Ireland ester Claisen rearrangement and ring-closing metathesis reaction sequence based strategy for the construction of two stereogenic vicinal quaternary carbon atoms on a cyclopentane.

Full text of DOI:10.1016/j.tetlet.2005.05.065

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4879–4881
Construction of vicinal quaternary carbon atoms by Ireland
ester Claisen rearrangement: total synthesis of
( )-herbertenolide, ( )-herberteneacetal,
( )-herbertene-1,14-diol and ( )-herbertene-1,15-diol
A. Srikrishna* and B. Vasantha Lakshmi
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
Received 10 April 2005; revised 10 May 2005; accepted 16 May 2005
Available online 6 June 2005
Abstract—Efficient total syntheses of the herbertane sesquiterpene title compounds have been accomplished employing an Ireland
ester Claisen rearrangement and ring-closing metathesis reaction sequence based strategy for the construction of two stereogenic
vicinal quaternary carbon atoms on a cyclopentane.
Ó 2005 Elsevier Ltd. All rights reserved.
Herbertanes 1 are a small group of sesquiterpenes,
X
which are considered as chemical markers for the liver-
worts belonging to the genus Herbertus.1 Herbetenolide
2 was first isolated and characterized by the research
group of Matsuo from the liverwort Herberta adunca,
the extract of which has been shown to exhibit remark-
able growth suppression of some plant pathogenic fun-
gi.2 In 2000,1 Asakawa and co-workers reported a
number of herbertanes, for example, 3–6, carrying oxy-
gen functionality not only in the aromatic portion of the
molecule but more unusually on the methyl groups (C-
13–C-15) attached to the cyclopentane ring in addition
to herbertenolide 2. The phenolic herbertanes, for exam-
ple, 1b–d and 2–6 have been shown to possess interesting
biological properties such as growth inhibiting and
antilipid peroxidation activities.2,3
OH
15
7
O
Y
3
X
1
14
9
Z
OH
5
1a-e
4
13
2. X=O
R
Herbertene-1,13-diol
3. X=H,OH
OH
R
X
Y
Z
OH
OH
OH
a. Me
H
H
H
b. Me OH H
H
OH
H
c. Me
d. Me OH OH
e.CHO OH
H
H
H
H
6
5
Herbertene-1,15-diol
Herbertene-1,14-diol
mation of a carbon–oxygen into a carbon–carbon bond
with predictable stereochemistry; easy creation of a ste-
reogenic quaternary carbon atom and the assembly of
complex, highly functionalized structures.
The Ireland ester Claisen rearrangement (the silyl ketene
acetal variant of the Claisen rearrangement, Eq. 1)4 is a
highly useful reaction in organic synthesis. There are
several reasons for the popularity of this reaction, viz.
the ability to use only stoichiometric combinations of
the allyl alcohol and the acid components; the relatively
low temperature of the pericyclic process; the transfor-
O
O
COOH
O
OTMS
R"
ð1Þ
R"
R'
R
R"
R
R'
R
R'
The presence of a sterically crowded 1-aryl-1,2,2-tri-
methylcyclopentane, the difficulty associated with the
construction of vicinal quaternary carbon atoms on a
cyclopentane ring and the novel biological properties
associated with the phenolic herbertanes made the
herbertenoids important synthetic targets of current
Keywords: Ireland–Claisen rearrangement; RCM reaction; Herber-
tanes; Vicinal quaternary carbon atoms.
*
Corresponding author. Tel.: +91 80 22932215; fax: +91 80
23600683; e-mail: ask@orgchem.iisc.ernet.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.065

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A. Srikrishna, B. V. Lakshmi / Tetrahedron Letters 46 (2005) 4879–4881
interest.5–8 Recently, Garcia-Garibay and co-workers
reported6a the total synthesis of herbertenolide 2
employing a solid state photochemical decarbonylation
as the key step for the generation of the vicinal quater-
nary carbon atoms; whilst Monti and co-workers have
reported6b their strategy to herbertene-1,14-diol 5.7,8
Recently,5a we have developed a Claisen rearrange-
ment-RCM based strategy for the synthesis of herber-
tene-1,13-diol 4. Herein, we report an efficient
methodology for the total synthesis of herbertenolide
2, herberteneacetal 3, herbertene-1,14-diol 5 and herber-
tene-1,15-diol 6 employing a combination of the Ireland
ester Claisen rearrangement and ring-closing metathesis
(RCM) reactions for the generation of vicinal quater-
nary carbon atoms on a cyclopentane moiety.
O
P
EtO
EtO
COOEt
1)
R
O
NaH, THF, rt, 12 h, 85%
MeO
2) LiAlH4, Et2O
-70 ºC, 2 h, 97%
MeO
12 R = COOEt
10 R = CH2OH
11
1) CH3CH2C(OEt)3,
EtCOOH, 180 ºC,
16 h, 85%
OH
OH
O
2) 5% NaOH, H2O-MeOH
reflux, 2 h, 95%
13
DCC, DMAP
O
10 + 13
CH2Cl2, rt, 6 h
O
95%
MeO
It was conceived (Scheme 1) that the Ireland ester Clai-
sen rearrangement of ester 7 would provide a mixture
of stereoisomeric dienes 8. RCM reaction of the dienes
8 followed by functional group modifications would
lead to herbertenolide 2 and epiherbertenolide 9, which
could be transformed into herbertene-1,15-diol 6 and
herbertene-1,14-diol 5, respectively.
7
a) LDA, THF, -70 ºC; TMSCl,
NEt3, 0.5 h; rt, 5 h; reflux 2 h;
b) aq. HCl, 0.5 h;
N
N
77%
Cl
Ru
c) CH2N2, Et2O, 0 ºC, 0.5 h
Ph
14Cl
PCy3
10 mol% 14
CH2Cl2, rt, 3 h
The synthetic sequence is depicted in Schemes 2 and 3.
The cinnamyl alcohol 10 required for the generation of
ester 7 was prepared from acetophenone 11, which was
obtained by Friedel CraftÕs acylation of p-anisyl methyl
ether. Thus, Horner–Wadsworth–Emmons reaction of
acetophenone 11 with triethyl phosphonoacetate and so-
dium hydride in THF furnished cinnamate 12, which on
low temperature reduction with lithium aluminum hy-
dride (LAH) in ether generated the cinnamyl alcohol
10, in >82% overall yield.9 The acid component of ester
7, 2-methylpent-4-enoic acid 13, was obtained by ortho-
ester Claisen rearrangement of allyl alcohol with triethyl
orthopropionate followed by hydrolysis of the resultant
ester.10 A dicyclohexylcarbodiimide (DCC) mediated
reaction was chosen to couple acid 13 with cinnamyl
alcohol 10. Thus, reaction of acid 13 with DCC, N,N-
dimethylaminopyridine (DMAP) and alcohol 10 in
methylene chloride at room temperature furnished ester
7 in 95% yield, whose structure was established from its
spectral data. After exploring various reaction condi-
tions, it was found that generation of the TMS enol
ether of ester 7 with LDA, trimethylsilyl chloride and
triethylamine in THF at ꢀ70 °C followed by refluxing
the reaction mixture for 2 h resulted in the Ireland ester
98%
COOMe
COOMe
H2, 10% Pd/C,
EtOH, 4 h
MeO
MeO
15
8
100%
+
COOMe
COOMe
MeO
16a
MeO
( 2 : 3 )
16b
Scheme 2.
HO
BBr3, CH2Cl2
0 ºC, 2 h
ref. 8a
16b
16a
OH
O
O
98%
9
5
HO
BBr3, CH2Cl2
0 ºC, 2 h
LAH, Et2O,
0 ºC, 2 h
98%
95%
OH
O
O
6
2
iBu2AlH
98%
THF, -70 ºC, 2 h
+ 6
3,5,6
O
OH
3
COOMe
RCM
O
2,9
O
MeO
Scheme 3.
Ireland-
Claisen
Claisen rearrangement. Hydrolysis of the reaction mix-
ture with dilute hydrochloric acid followed by esterifica-
tion with ethereal diazomethane furnished a 3:2 epimeric
mixture of esters 8 in 77% yield,11 whose gross structures
were deduced from their spectral data. Formation of
the two isomers, obviously, was a consequence of the
O
O
COOMe
MeO
MeO
7
8
Scheme 1.

A. Srikrishna, B. V. Lakshmi / Tetrahedron Letters 4 (2005) 4879–4881
4881
generation of the E- and Z-TMS enol ethers. Since the
Acknowledgements
generation of two isomers in this reaction is advanta-
geous in the present context, no attempt was made to
explore the reaction conditions for the generation of
one isomer exclusively.
We thank Professor Asakawa for providing copies of
the NMR spectra of herbertenolide, herbertenediols
and herberteneacetal, and the CSIR, New Delhi, for
the award of a research fellowship to BVL.
Since the RCM reaction of one of the isomers was found
to be very slow with GrubbsÕ first generation catalyst
[Cl2Ru(PCy3)2@CHPh], the reaction was carried out
with GrubbsÕ second-generation catalyst 14. Treatment
of the diene esters 8 with 10 mol % 14 in methylene chlo-
ride for 3 h at room temperature cleanly furnished an
epimeric mixture of the cyclopentene carboxylates 15,
in near quantitative yield.11 Hydrogenation of the cyclo-
pentene moiety in the epimeric mixture of esters 15 in
ethanol using 10% palladium on carbon as the catalyst
at one atmospheric pressure of hydrogen quantitatively
furnished esters 16a and 16b, which were separated by
column chromatography on silica gel impregnated with
silver nitrate. The stereostructures of esters 16a and 16b
were established from their spectral data, in particular,
Supplementary data
Spectral data for all important compounds are reported
in this manuscript. Supplementary data associated with
this article can be found, in the online version at
doi:10.1016/j.tetlet.2005.05.065.
References and notes
1. Irita, H.; Hashimoto, T.; Fukuyama, Y.; Asakawa, Y.
Phytochemistry 2000, 55, 247.
2. Matsuo, A.; Yuki, S.; Nakayama, M. J. Chem. Soc.,
Perkin Trans. 1 1986, 701.
3. Fukuyama, Y.; Kiriyama, Y.; Kodama, M. Tetrahedron
Lett. 1996, 37, 1261; Fukuyama, Y.; Asakawa, Y. J.
Chem. Soc., Perkin Trans. 1 1991, 2737.
1
on the basis of the H NMR signals due to the methyl
group at C-1 and the ester methyl group (shielding is
observed for the methyl which is syn to the aryl group,
a characteristic feature in herbertanes and cuparanes).
4. Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94,
5897; Ireland, R. E.; Wipf, P.; Armstrong, J. D. J. Org.
Chem. 1991, 56, 650; Gilbert, J. C.; Yin, J.; Fakhreddine,
F. H.; Karpinski, M. L. Tetrahedron 2004, 60, 51.
5. (a) Srikrishna, A.; Lakshmi, B. V. Synlett 2005, 1173; (b)
Boxall, R. J.; Ferris, L.; Grainger, R. S. Synlett 2004,
2379; (c) Srikrishna, A.; Rao, M. S. Eur. J. Org.
Chem. 2004, 499; (d) Srikrishna, A.; Babu, N. C.; Rao,
M. S. Tetrahedron 2004, 60, 2125, and references cited
therein.
6. (a) Ng, D.; Yang, Z.; Garcia-Garibay, M. A. Org. Lett.
2004, 6, 645; (b) Acherar, S.; Audran, G.; Fotiadu, F.;
Monti, H. Eur. J. Org. Chem. 2004, 5092.
7. For the two earlier syntheses of herbertenolide, see: (a)
Eicher, T.; Servet, F.; Speicher, A. Synthesis 1996, 863; (b)
Fukuyama, Y.; Yuasa, H.; Tonoi, Y.; Harada, K.; Wada,
M.; Asakawa, Y.; Hashimoto, T. Tetrahedron 2001, 57,
9299.
Reaction of ester 16a with boron tribromide directly fur-
nished herbertenolide 2, in 98% yield (Scheme 3), which
exhibited spectral data identical to those of the natural
product.2,7 Similarly, ester 16b furnished epiherberteno-
lide 9, in 98% yield, on reaction with boron tribromide,
whose reduction to herbertene-1,14-diol 5, by LAH in
quantitative yield, has already been reported.8a Reduc-
tion of herbertenolide 2 with LAH furnished herber-
tene-1,15-diol 6 in 95% yield,1 whereas, reduction of
herbertenolide 2 with diisobutylaluminum hydride in
THF furnished a mixture of herberteneacetal 3 and her-
bertene-1,15-diol 6 in 98% yield, which were separated
by column chromatography on silica gel. Herberteneac-
etal 3 and herbertene-1,15-diol 6 exhibited 1H NMR
spectral data identical to those of the natural products.1
8. To the best of our knowledge there is no report on the
synthesis of herberteneacetal. For earlier syntheses of
herbertene-1,14-diol, see: (a) Fukuyama, Y.; Matsumoto,
K.; Tonoi, Y.; Yokoyama, R.; Takahashi, H.; Minami,
H.; Okazaki, H.; Mitsumoto, Y. Tetrahedron 2001, 57,
7127; (b) Srikrishna, A.; Rao, M. S. Tetrahedron Lett.
2002, 43, 151; (c) Paul, T.; Pal, A.; Gupta, P. D.;
Mukherjee, D. Tetrahedron Lett. 2003, 44, 737.
9. Srikrishna, A.; Rao, M. S. Synlett 2002, 340.
10. Gunther, H. J.; Guntrum, E.; Jager, V. Liebigs Ann. Der.
Chem. 1984, 15.
11. Even though it was possible to separate the isomers by
careful chromatography, this was found to be much easier
at a later stage, reactions were thus carried out with the
mixture. However, for characterization purposes, separa-
tion was carried out on a small sample.
In conclusion, we have developed an Ireland ester Cla-
isen rearrangement and RCM reaction sequence based
methodology for the efficient construction of the two
vicinal quaternary carbon atoms present in herbertanes.
The high efficiency of the sequence compensated the
generation of two isomers in the key step. It is worth
noting that introduction of a C-1 methyl group at a later
stage of the sequence, that is, after the synthesis of the 2-
aryl-2-methylcyclopentanecarboxylate, generates exclu-
sively the cis isomer 16b,8b,6b which will lead to epiher-
bertenolide 9 only. In the present strategy, herbertene-
1,15-diol 6 and herbertene-1,14-diol 5 (in a 2:3 ratio)
were obtained in 55% overall combined yield, starting
from the easily available acetophenone 11.