Approaches to the neurotrophically active natural product 11-O-debenzoyltashironin: A chemoenzymatic total synthesis of the structurally related sesquiterpene khusiol

Article abstract of DOI:10.1002/asia.201100913

Soothes your nerves: The enantiomerically enriched cis-1,2-dihydrocatechol 4 has been converted, over 16 steps including one involving an intramolecular Diels-Alder reaction, into the sesquiterpenoid natural product khusiol (3), which is structurally related to the neurite outgrowth-promoting natural product 11-O-debenzoyltashironin (1).

Full text of DOI:10.1002/asia.201100913

COMMUNICATION
DOI: 10.1002/asia.201100913
Approaches to the Neurotrophically Active Natural Product 11-O-
Debenzoyltashironin: A Chemoenzymatic Total Synthesis of the Structurally
Related Sesquiterpene Khusiol
Mukesh K. Sharma, Martin G. Banwell,* Anthony C. Willis, and A. David Rae[a]
The sesquiterpenoid natural product 11-O-debenzoylta-
shironin (1, Scheme 1) and the corresponding benzoate ester
tashironin (2) have been isolated from the pericaps of the
eastern Asian plant Illicium merrillianum.[1] The structures
of these compounds were determined using NMR spectro-
scopic techniques, and the former was shown to induce neu-
Scheme 1. Structures of compounds 1–4. Bz=benzoyl.
rite outgrowth in fetal rat cortical neurons at concentrations
as low as 0.1 mm.[1] As such and because of its compact and
highly substituted tetracyclic structure, 11-O-debenzoylta-
shironin has attracted some attention as a synthetic target.[2]
In 2006 Danishefsky and co-workers reported the first and
thus far only total synthesis of (Æ)-1,[3] and two years later
they described a modification of their elegant transannular
Diels–Alder approach to the preparation of enantiomeri-
cally enriched variants of the intermediates associated with
the original synthesis.[4] Starting in 2007 Mehta and Maity
have reported a series of impressive studies[5] on the con-
struction, in racemic form, of the tetracyclic core of com-
pounds 1 and 2. This work, which employs a tandem oxida-
present work was the cis-1,2-dihydrocatechol 4, which is
readily obtained in approximately 80% ee through the enzy-
matic cis dihydroxylation of p-iodotoluene.[8]
The assembly of the tricyclic core of khusiol (Scheme 2)
followed a pathway established during a recently completed
model study.[9] Thus, the readily derived acetonide derivative
5[9,10] of diol 4 was converted, by metalation/trans-metalation
protocols,[11] into the corresponding cuprate, which was
treated with the dienone 6,[9,12] thereby producing, through a
selective conjugate addition process, the a,b-unsaturated
ketone 7 (60%).[9] While compound 7 failed to engage in an
IMDA reaction upon heating, one of the epimeric alcohols
(8),[9] obtained by sodium borohydride mediated reduction
of this enone, underwent the desired cycloaddition reaction
on heating in mesitylene,[13] thereby producing the epimeri-
cally pure tricyclic alcohol 9[9] (71% yield based on recov-
ered S-8) that incorporates the two contiguous quaternary
carbon centers associated with target 3.
Compound 9, the assigned structure of which is supported
by single-crystal X-ray analyses of the corresponding 3,5-di-
nitrobenzoate[9] and ketone (see the Supporting Information
for details of the X-ray analysis of the latter),[14] is presuma-
bly formed preferentially in the IMDA reaction because at
the transition state for this process the hydroxy group asso-
ciated with substrate R-8 resides on the exo-face of the de-
veloping cis-perhydroindene substructure.
The next phase of the synthesis involved establishing a
protocol for introducing the C3 methyl group. To these
ends, compound 9 was oxidized to the corresponding ketone
(99%) using a mixture of pyridinium dichromate (PDC)
and acetic acid. The resulting reaction mixture was subject-
ed to hydrogenation, thus affording the saturated system 10
(99%). Treatment of this compound with TMSOTf in the
presence of triethylamine resulted in the formation of the
kinetically favored silyl enol ether that was subjected to oxi-
dation using a combination of IBX and MPO in DMSO.[15]
tive dearomatization
—
intramolecular Diels–Alder
(IMDA) reaction — ring-closing metathesis (RCM) se-
quence, has recently culminated in a total synthesis of (Æ)-
11-O-methyldebenzoyltashironin. No further work in the
area has been described to date, and the lack of any report-
ed structure–activity relationship studies is probably a re-
flection of the lengthy nature of the existing approaches to
compound 1 and its congeners. In an effort to address this
matter as well as the need to obtain the nonracemic forms
of compound 1 and its congeners, we have begun exploring
chemoenzymatic approaches to the tricyclic carbon frame-
work of 11-O-benzoyltashironin. In this connection we now
report the first enantioselective total synthesis of the sesqui-
terpenoid khusiol (3),[6,7] a system that embodies the same
3,6,7,7-tetramethyloctahydro-3a,6a-ethanoindene framework
encountered in compound 1 although possessing the oppo-
site stereochemistry at C3. The starting material used in the
[a] M. K. Sharma, Prof. M. G. Banwell, Dr. A. C. Willis, Prof. A. D. Rae
Research School of Chemistry, Institute of Advanced Studies
The Australian National University
Canberra ACT 0200 (Australia)
Fax : (+61)2-6125-8114
E-mail: mgb@rsc.anu.edu.au
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100913.
676
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Chem. Asian J. 2012, 7, 676 – 679

Scheme 2. Assembly of the khusiol framework. HMPA=hexamethyl-
phosphoramide, BHT=butylhydroxytoluene, PDC=pyridinium dichro-
mate, IBX=2-iodoxybenzoic acid, MPO=4-methoxypyridine-N-oxide,
TMSOTf=trimethylsilyl trifluoromethanesulfonate.
Scheme 3. Completion of the synthesis of khusiol (3). AIBN=azobisiso-
butyronitrile, TEMPO=(2,2,6,6-tetramethylpiperidin-1-yl)oxyl, p-
TsOH=p-toluenesulfonic acid, DMAP=4-(N,N-dimethylamino)pyridine.
By such means enone 11 was obtained in 74% yield (from
10).
The completion of the synthesis of target 3 (Scheme 3) in-
volved conjugate addition of the organocopper species gen-
erated in situ from methyl magnesium bromide and
CuBr·SMe2 to enone 11. As a result, the C3-methylated
product 12 (85%) was obtained, the structure of which was
determined by extensive 2D NMR spectroscopic studies.
Treatment of compound 12 with NaBH4 afforded a 4:1 mix-
ture of the epimeric alcohols 13 (88% combined yield) that
was converted (as a mixture) into the corresponding mixture
of xanthate esters 14 (90%) under standard conditions. Sub-
jection of these esters to the Barton–McCombie reduction
protocol[16] using nBu3SnH in the presence of AIBN then
gave the deoxygenated compound 15 in 72% yield (from
14). Acid-promoted hydrolysis of the acetonide unit within
compound 15 was effected with acetic acid in water and the
diol 16 (50% or 80% based on recovered 15) so-formed
was subjected to a Bobbitt-type oxidation using the oxam-
monium salt derived from the reaction of 4-(AcNH)TEM-
PO and p-TsOH.[17] In this way the acyloin 17 (60%) was
formed in a remarkably selective manner. Compound 17
was converted into the corresponding benzoate 18 (88%)
under standard conditions and the latter treated with sama-
rium diiodide in THF/methanol,[18] thereby affording ketone
19[19] in 80% yield. Following a procedure defined by Shank-
er and Subba Rao,[7] compound 19 was subjected to a dis-
solving metal reduction using Li in liquid ammonia and am-
monium chloride as a proton source. In this way a chroma-
tographically separable mixture of compound 3 (67%, ca.
85% ee) and its C5-epimer (5%) was obtained. The NMR
and mass spectral data obtained for the former product
were in complete accord with the assigned structure and
matched those recorded in the literature for the racemic[7] as
well as the enantiomerically pure modifications[6] of com-
pound 3. Final confirmation of the structure of our sample
of khusiol followed from a single-crystal X-ray analysis of
the derived 3,5-dinitrobenzoate.[20] Details are provided in
the Supporting Information.
A method for establishing the R configuration at C3 in
the 3,6,7,7-tetramethyloctahydro-3a,6a-ethanoindene frame-
work, as required in developing a synthesis of the title com-
pound 1, is shown in Scheme 4. Thus, the cuprate derived
from iododiene 5 was added to the trimethylated dienone
20,[21] and the resulting approximately 2:1 mixture of the
epimeric forms of compound 21 (74%) was treated with
Chem. Asian J. 2012, 7, 676 – 679
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677

M. G. Banwell et al.
COMMUNICATION
Acknowledgements
We thank the Australian Research Council and the Institute of Advanced
Studies at the ANU for generous financial support. M.K.S. is the grateful
recipient of an Australian Government Endeavour Postgraduate Award.
Keywords: asymmetric synthesis · cycloaddition · synthetic
methods · terpenoids
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Scheme 4. Assembly of the carbocyclic framework of 11-O-debenzoylta-
shironin. TBAF=tetra-n-butylammonium fluoride, TMSCl=trimethyl-
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[3] S. P. Cook, A. Polara, S. J. Danishefsky, J. Am. Chem. Soc. 2006, 128,
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yield. Heating this mixture in mesitylene at 1658C for 96 h
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[13] For related examples of the divergent behavior of enones and the
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[14] CCDC 795966 contains the supplementary crystallographic data for
the ketone derived from compound 9. These data can be obtained
free of charge from the Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
Figure 1. ORTEP derived from the single-crystal X-ray analysis of a mix-
ture of compounds ent-24 and 24 (compound 24 shown). Thermal ellip-
soids are drawn at the 30% probability level. H atoms are shown as
spheres of arbitrary radius.
[15] K. C. Nicolaou, T. Montagnon, P. S. Baran, Angew. Chem. 2002, 114,
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Chem. Asian J. 2012, 7, 676 – 679

Approaches to the Natural Product 11-O-Debenzoyltashironin
[17] For an example of
a
related oxidation see: a) M. G. Banwell,
[21] G. Vassilikogiannakis, M. Orfanopoulos, J. Org. Chem. 1999, 64,
3392.
K. A. B. Austin, A. C. Willis, Tetrahedron 2007, 63, 6388. This proto-
col is based on one first described by Ma and Bobbitt: b) Z. Ma,
J. M. Bobbitt, J. Org. Chem. 1991, 56, 6110.
[22] The crystal chosen for analysis contained a ca. 3:2 mixture of ent-24
and 24. This result arises from the starting material 4 containing ca.
10% of ent-4. The structure was solved and refined as an average
structure in space group P21212 with the two molecules occupying
general positions in the asymmetric unit. Molecule 1 was ordered,
but molecule 2 was 0.810(2):0.190 disordered. See the Supporting In-
formation for further details. CCDC 795967 contains the supplemen-
tary crystallographic data for the compound mixture ent-24/24.
These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
[18] For an example of a related reduction, see: D. J.-Y. D. Bon, M. G.
Banwell, A. C. Willis, Tetrahedron 2010, 66, 7807.
[19] The (À)- and (+)-forms of this ketone have been obtained by oxida-
tion of khusiol (see Ref. [6a]) and allo-cedrol (see Ref. [6b]), re-
spectively. Khusione (19) has also been isolated from Haitian vetiver
oil: P. Weyerstahl, H. Marschall, U. Splittgerber, D. Wolf, Flavour
Fragrance J. 2000, 15, 61.
[20] CCDC 808111 contains the supplementary crystallographic data for
the 3,5-dinitrobenzoate derived from compound 3. These data can
be obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Received: November 8, 2011
Published online: January 25, 2012
Chem. Asian J. 2012, 7, 676 – 679
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