A chemoenzymatic and enantioselective route to the tricyclic frameworks associated with the protoilludane and marasmane classes of sesquiterpene

Article abstract of DOI:10.1071/CH04131

The enantiomerically pure cis-1,2-dihydrocatechol 3, which is obtained in quantity by microbial dihydroxylation of toluene, has been converted over ten steps, including an initial Diels-Alder cycloaddition reaction, into the tricyclic ketone 12. Direct irradiation of a benzene solution of the latter compound affords a mixture of compounds 13 and 14 which embody the tricyclic frameworks of the sesquiterpene natural products tsugicoline A (1) and isovelleral (2), respectively.

Full text of DOI:10.1071/CH04131

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Aust. J. Chem. 2004, 57, 895–897
A Chemoenzymatic and Enantioselective Route to the
Tricyclic Frameworks Associated with the Protoilludane
and Marasmane Classes of Sesquiterpene
Martin G. BanwellA,B and Gwion J. HarfootA
A Research School of Chemistry, Institute of Advanced Studies, Australian National University,
Canberra ACT 0200, Australia.
B Author to whom correspondence should be addressed (e-mail: mgb@rsc.anu.edu.au).
The enantiomerically pure cis-1,2-dihydrocatechol 3, which is obtained in quantity by microbial dihydroxylation of
toluene, has been converted over ten steps, including an initial Diels–Alder cycloaddition reaction, into the tricyclic
ketone 12. Direct irradiation of a benzene solution of the latter compound affords a mixture of compounds 13 and
14 which embody the tricyclic frameworks of the sesquiterpene natural products tsugicoline A (1) and isovelleral
(2), respectively.
Manuscript received: 13 May 2004.
Final version: 30 June 2004.
Tsugicoline A (1, Scheme 1) is a representative member of
the ꢀ6-protoilludane class of sesquiterpene natural product.
The compound was first isolated, by an Italian group, from
the fungus Laurilia tsugicola (Echinodontium tsugicola) in
1995.[1] While it is inactive against bacteria and fungi, tsugi-
coline A does inhibit the germination of the cress Lepidium
sativum, a property which may be attributed to the pres-
ence of the strained enone moiety. The structurally related
isovelleral (2), which belongs to the marasmane class of
sesquiterpenes, was isolated from Basidiomycetes species
belonging to the genus Lactarius[2] and displays antibacte-
rial as well as antifeedant properties,[3] the latter feature likely
important in the chemical defence mechanisms of the produc-
ing organisms.[4] In contrast to the situation with congener 1,
dialdehyde 2 has been the subject of several successful total
synthesis studies.[5] Through such work it has been shown
that the antimicrobial and cytotoxic activities of isovelleral
and its non-natural enantiomer are comparable but the natu-
ral product is approximately ten times more mutagenic in an
Ames test. Both enantiomers have the same affinity for the
vanilloid receptor but significantly different affinities for the
dopamine D1 receptor.[6]
As part of an ongoing program to exploit various fer-
mentation products as starting materials in total synthesis,[7]
we have recently described the conversion of the cis-1,2-
dihydrocatechol 3 into both the triquinane-type sesquiterpene
(–)-hirsutene[8] and the cyperene-type sesquiterpene (–)-
patchoulenone.[9] Compound 3 is available in bulk quantities
and enantiomerically pure form through microbial dihydr-
oxylation of toluene using a genetically engineered form of
Escherichia coli [JM109 (pDTG601)] that over-expresses the
enzyme toluene dioxygenase (TDO).[10] As an extension of
work in this area, we now outline simple protocols for the
conversion of metabolite 3 into the tricyclic frameworks asso-
ciated with tsugicoline A (1) and isovelleral (2). Since the
enantiomeric form of compound 3 is also known,[11] then
the work described here also provides access to the tricyclic
frameworks associated with the non-natural enantiomers of
compounds 1 and 2.
HO
H
H
7
OHC
HO
9
11
6
3
1
OHC
H
O
H
4
OH
The crucial elements of the present work are shown in
Scheme 2 and the early stages are identical to those associ-
ated with our recently disclosed synthesis of (–)-hirsutene,[8]
but they are repeated here for the sake of completeness.
Thus, diene 3 engages in a high-pressure (19 kbar)-promoted
reaction with cyclopenten-2-one (4) to give the syn-adduct
5 (70%) as the major product of reaction. Protection of
the cis-diol within this adduct as the corresponding ace-
tonide 6 (98%) was carried out under standard conditions
1
2
HO
HO
3
Scheme 1.
© CSIRO 2004
10.1071/CH04131
0004-9425/04/090895

896
M. G. Banwell and G. J. Harfoot
R
R
2,2-dimethoxypropane
LiAlH4
99%
p-TsOH
19 kbar
70%
H
H
O
H
O
O
OH
HO
O
O
3
ϩ
H
H
H
O
OH
98%
O
4
5
6
7
8
R ϭ H
R ϭ Me
LiHMDS, MeI
100%
Barton–McCombie
deoxygenation
76–82%
4-NHAc-TEMPO
H
R
H
H
H3Oϩ
95%
HO
O
p-TsOH
H
H
H
OH
O
O
91%
H
MEM-Cl,
Hünig’s base
91%
100%
hn,
benzene
11 R ϭ OH
12 R ϭ OMEM
10
9
H
H
H
H
H
ϩ
ϩ
H
O
H
H
H
OMEM
15
O
MEMO
OMEM
13
14
hn, benzene
55%
Scheme 2.
and thus enabled geminal dimethylation adjacent (α) to the
carbonyl group. This was achieved using LiHMDS (lithium
hexamethyldisilazide)/MeI and thereby afforded target 7
in quantitative yield. The now redundant ketone carbonyl
group was removed by initial reduction of compound 7
to the corresponding alcohol 8 (99% of a 9 : 1 mixture
of epimers) followed by Barton–McCombie reduction of
the derived xanthate esters with Bun3SnH, thereby afford-
ing acetonide 9 (76–82%). Acetal cleavage within the last
compound proved rather difficult but could be achieved
upon prolonged exposure of a THF solution of the sub-
strate to acetic acid in water, thus affording diol 10 in 95%
yield at 44% conversion. Selective oxidation of the hydroxyl
group remote from the bridgehead methyl group within com-
pound 10 was carried out using the sterically demanding
oxoammonium salt derived from p-TsOH-promoted dispro-
portionation of 4-acetamido-TEMPO (TEMPO = 2,2,6,6-
tetramethylpiperidinyl-1-oxy) and, in this manner, the acyloin
11 was obtained in 91% yield at 96% conversion. Com-
pound 11 proved to be a rather sensitive material. It is
prone to oligomerization, a process that can be stopped
through its conversion into the corresponding MEM (2-
methoxyethoxymethyl) ether 12 (91%) using MEM-Cl in the
presence of Hünig’s base.
13 (80% at 20% conversion), 14 (10% at 20% conversion of
a 7 : 3 mixture of epimers), and the previously observed[8]
triquinane 15 (10% at 20% conversion) was obtained. The
structures of compounds 13 and 14 follow from comprehen-
sive spectroscopic studies, including NOE experiments, of
each of them.The tricyclic compound 13 is presumed to arise
through a 1,3-acyl migration process,[12] while congener 14
is the product of a decarbonylation reaction that could occur
directly from substrate 12 and/or after conversion of this last
compound into isomer 13. Certainly, resubjection of cyclo-
butanone 13 to the original photolysis reaction affords a 7 : 3
mixture of the epimeric forms of cyclopropane 14 (55%).
The reaction sequence outlined above would seem to offer
very good prospects for achieving a total synthesis of tsugi-
colineA (1). For example, compound 13 reacts (Scheme 3) in
a diastereofacially selective manner with dimethyldioxirane
(DMDO)[13] to give the epoxide 16 (53%), the stereochem-
istry of which follows from NOESY experiments that reveal
interactions between H6 and H8 but not H7 and H9. Treat-
ment of compound 16 with LiHMDS affords the allylic
alcohol 17 (55%) although the major product of reaction,
at least when a large excess of base is used, is the fascinating
‘hetero-dimer’ 18 (49%). Compound 18 is presumed to arise
through initial addition of the conjugate base of alcohol 17 to
the cyclobutanone carbonyl of compound 16. The hydroxyl
group of the resulting hemiacetal, or its conjugate base, then
engages in an intramolecular Michael addition reaction with
the pendant enone residue to give the observed acetal 18.
Presumably formation of this dimer could be suppressed
In the pivotal step of the reaction sequence leading to the
carbocyclic frameworks associated with compounds 1 and 2,
a benzene solution of ketone 12 was subject to direct irradi-
ation with a high-pressure mercury lamp and in this manner
a chromatographically separable mixture of photoproducts

Route to the Frameworks Associated with Protoilludane and Marasmane
897
O
H
for continued encouragement and the provision of generous
quantities of cis-1,2-dihydrocatechol 3. G.J.H. is the grateful
recipient of an APA and various supplementary scholar-
ships that have supported him during the course of his Ph.D.
studies.
8
7
9
DMDO
53%
6
13
H
H
O
OMEM
16
References
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LiHMDS
O
H
H
HO
H
H
H
O
H
7
ϩ
H
O
O
OMEM
4
H
OMEM
MEMO
O
17
18
Scheme 3.
throughinsitutrappingoftheproductofepoxideringopening
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Exploiting the results detailed above in a total synthesis of
tsugicoline A (1) requires, among other things, the develop-
ment of methods for introducing the C7 hydroxymethyl group
and inverting stereochemistry at C4 within a compound such
as 17 or a precursor such as acyloin 11. Attempts to effect the
latter conversion on compound 11 using Mitsunobu protocols
have been unsuccessful thus far. While chemical methods for
introduction of the hydroxymethyl group could probably be
devised, a more attractive approach would involve incorpo-
rating such a moiety from the beginning of the synthesis. In
particular, it might be anticipated[11] that dihydroxylation of
m-methylbenzyl alcohol (or some equivalent thereof) using
TDO in a whole-cell biotransformation would deliver the cis-
1,2-dihydrocatechol 19 (Scheme 4) which could be carried
forward, in the manner described in Schemes 2 and 3, to
give the C7-hydroxymethylated equivalent of compound 17.
Obviously, metabolite 19 would also be highly relevant to the
development of a synthesis of isovelleral. Studies aimed at
generating compound 19 by fermentation are now underway
in these laboratories and will be reported upon in due course.
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HO
(a) T. Hudlicky, D. Gonzalez, D. T. Gibson, Aldrichim. Acta
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OH
HO
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Singh in 1993:
19
Scheme 4.
Acknowledgements
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We thank Dr Gregg Whited (Genencor International Inc.,
PaloAlto, CA) and Professor T. Hudlicky (Brock University)