Chemoenzymatic total synthesis of the sesquiterpene (2)-patchoulenone
Martin Banwell*† and Malcolm McLeod
Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 0200, Australia
Monochiral cis-1,2-dihydrocatechol 2, obtained by microbial
oxidation of toluene, has been converted, via intermediate 3,
into the cyperene-type sesquiterpene 1.
The 1,4,9,9-tetramethyl-2,4,5,6,7,8-hexahydro-3H-3a,7-me-
thanoazulene framework associated with the cyperene-type
sesquiterpenes has been the subject of a number of synthetic
studies5 and the title compound itself has been synthesised by
Hikino et al6 who used (+)-camphor as the starting material.
The racemic modification of patchoulenone has also been
prepared via the Lewis acid catalysed addition of a diazo ketone
to a tethered olefin.7 We now report a quite distinct and
chemoenzymatic total synthesis of (2)-patchoulenone which
employs the monochiral cis-1,2-dihydrocatechol 2, obtained by
microbial oxidation of toluene, as starting material.8
(2)-Patchoulenone 1 is a prominent member of the cyperene
class of sesquiterpenes and was first isolated in 1964 from
Cyperus rotundus Linné (Cyperaceae), a plant common in
Sudan, India, China, Thailand and Japan.1,2 The compound has
OH
OH
In connection with synthetic approaches to taxoids, we have
recently described9 the conversion of compound 2 into the
bicyclo[5.3.1]undecenone 3. As has been observed in a closely
related system,10 the carbon–carbon double-bond and carbonyl
group within compound 3 are in close proximity. As a
consequence the molecule readily engages in a tin(II) chloride
catalysed intramolecular Prins reaction (Scheme 1) to give the
tricyclic isomer 4 {97%, [a]D 232 (c 2.0)‡}. Hydrogenation of
compound 4 using H2 at 60 psi and with palladium on carbon as
catalyst provided a ca. 3:1 mixture of the saturated cis-diol 6§
{59%, mp 209–211 °C (sealed tube), [a]D 221.4 (c 0.6)} and its
C4-epimer {21%, mp 207–209 °C (sealed tube), [a]D +37.2 (c
0.7)} which could be separated from one another by flash
chromatography. An alternative route to the pivotal compound
6 involved subjecting compound 3 to reductive cyclisation
using samarium(II) iodide11 and a chromatographically separa-
ble mixture of 5 {39%, mp 53–54 °C, [a]D +17.9 (c 0.9)} and
the D4(10)-isomer {54%, [a]D +65 (c 0.4)} of compound 4 was
produced. Hydrogenolysis of compound 5 could be achieved
under standard conditions and the resulting diol 6 (95%) was
oxidised to the acyloin 7 {91%, [a]D 20.2 (c 1.0)} using the
Swern reagent. Dehydration of compound 7 to the enone 8
{68%, [a]D 2150 (c 0.5)} could be effected using thionyl
chloride in pyridine at 40 °C. This latter compound was
subjected to reaction with the Gilman reagent derived from
H
O
O
OBn
1
2
3
also been identified as a constituent of, inter alia, the root bark
of Uvaria narum Wall. (Annonaceae)3 and Piptostigma fugax.4
Despite a number of the source plants being used in traditional
medicines, only a modest amount is known about the biological
properties of (2)-patchoulenone. Thus, compound 1 shows2 in
vitro activity (EC50 1.08 3 1024
) against the malarial parasite
M
Plasmodium falciparum, strong anti-fungal activity against
Rhizoctonia solani and Saprolegnia asterophora,4 and sig-
nificant toxicity in a brine shrimp bioassay.4
10
4
i
ii
HO
4
OBn
4
3
methyllithium and copper( ) bromide–dimethyl sulfide (DMS)
I
HO
complex12 and the ensuing enolate anion trapped with trime-
thylsilyl chloride to give the unstable silyl enol ether 9, which
was obtained as a single diastereoisomer. Dehydrogenation of
compound 9 with DDQ/2,6-lutidine13 then gave (2)-patch-
oulenone 1 {77% from 8, mp 50–51 °C (lit.,1 52.5 °C), [a]D
HO
iv
iii
6
HO
OBn
v
1
2101 (c 0.4) [lit.,1 297.1 (c 8.0)]}, the H and 13C NMR
5
spectral data for which matched those reported2 for the natural
product.
We thank the Institute of Advanced Studies for financial
support including the provision of a Postdoctoral Fellowship to
M. M. Drs G. Whited and L. Kwart of Genencor International
Inc. (Palo Alto) are thanked for providing generous supplies of
the cis-1,2-dihydrocatechol 2.
viii
vii
vi
1
HO
OSiMe3
O
O
9
8
7
Scheme 1 Reagents and conditions: i, SnCl2 (0.25 equiv.), CHCl3, 18 °C, 1
h; ii, H2 (60 psi), 10% Pd/C, MeOH, 18 °C, 48 h; iii, SmI2 (1.6 equiv.),
HMPA, THF, 0 °C, 0.25 h; iv, H2 (1 atm), 10% Pd/C, THF, 18 °C, 0.75 h;
v, (COCl)2 (3.0 equiv.), DMSO (5.0 equiv.), CH2Cl2, 278 °C, 0.25 h, then
6, 0.25 h then Et3N (6.0 equiv.) 278 to 0 °C, 0.25 h; vi, SOCl2, pyridine, 40
°C, 1 h; vii, MeLi (10 equiv.), CuBr·DMS (5.0 equiv.), THF, 240 °C, 0.5
h, then 8, Me3SiCl (10 equiv.), HMPA, 278 °C, 0.5 h; viii, DDQ (4.0
equiv.), 2,6-lutidine (6.5 equiv.), CH2Cl2, 18 °C, 0.1 h
Notes and References
† E-mail: mgb@rsc.anu.edu.au
‡ All optical rotations were determined in chloroform solution at 20 °C
§ All new and stable compounds had spectroscopic data (IR, NMR, mass
spectrum) consistent with the assigned structure. Satisfactory combustion
and/or high resolution mass spectral analytical data were obtained for new
compounds and/or suitable derivatives.
Chem. Commun., 1998
1851
Banwell, Martin
