Application of the lithiation-borylation reaction to the rapid and enantioselective synthesis of the bisabolane family of sesquiterpenes

Article abstract of DOI:10.1039/c2cc32176a

The expedient enantioselective synthesis of 5 bisabolane sesquiterpenes has been achieved using a common, one-pot lithiation-borylation reaction of secondary benzylic carbamates and either protodeboronation or oxidation to give the natural products in few

Full text of DOI:10.1039/c2cc32176a

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Chemical Communications
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Volume 48 | Number 74 | 25 September 2012 | Pages 9197–9320
ISSN 1359-7345
COMMUNICATION
Varinder K. Aggarwal et al.
Application of the lithiation–borylation reaction to the rapid and enantioselective synthesis
of the bisabolane family of sesquiterpenes

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COMMUNICATION
Application of the lithiation–borylation reaction to the rapid and
enantioselective synthesis of the bisabolane family of sesquiterpenesw
Varinder K. Aggarwal,* Liam T. Ball, Simon Carobene, Rickki L. Connelly,
Matthew J. Hesse, Benjamin M. Partridge, Philippe Roth, Stephen P. Thomas and
Matthew P. Webster
Received 25th March 2012, Accepted 4th May 2012
DOI: 10.1039/c2cc32176a
The expedient enantioselective synthesis of 5 bisabolane sesqui-
terpenes has been achieved using a common, one-pot lithiation–
borylation reaction of secondary benzylic carbamates and either
protodeboronation or oxidation to give the natural products in
fewer than 5 steps, with high yield and >94 : 6 er.
increases the appeal of such a synthetic strategy as both
antipodes of the enantioenriched carbamates 7 are readily
accessible in high er by asymmetric reduction of the corre-
sponding ketones 9, using Noyori’s transfer hydrogenation
procedure,7 and subsequent carbamoylation. Although seemingly
lacking in complexity, the bisabolanes pose a significant test for
the lithiation–borylation reaction. The benzylic stereocenter is
prone to racemisation on treatment with base or, possibly, during
The bisabolane family of sesquiterpenes (Fig. 1, 1–5) exhibit a
wide range of biological activity and have been used in
traditional medicine.1 Isolated from sources as diverse as marine
coral and sunflowers, they feature a functionalised aromatic ring
bearing a tertiary or quaternary benzylic stereocentre.2 The
parent sesquiterpene, a-curcumene 1 has been isolated in both
enantiomeric forms.2c Oxidation of a-curcumene at either the
aromatic ring or benzylic carbon gives gossonorol 2, curcuphenol
3, curcuhydroquinone 4 and curcuquinone 5. Although relatively
simple at first glance, the benzylic stereocenter is synthetically
challenging3 and various members of the bisabolane family have
been targets around which the effectiveness of asymmetric
methodologies have been benchmarked.4
The lithiation–borylation reaction has emerged as a powerful
tool for the construction of complex molecular frameworks
bearing secondary, tertiary and, even, quaternary stereocenters.5
Having recently developed a one-pot, highly stereocontrolled
lithiation–borylation and protodeboronation sequence6 we were
keen to explore the use of this transformation in enantioselective
natural product synthesis. The bisabolane sesquiterpenes were
identified as both suitable and challenging targets.
Key to our retrosynthetic analysis was the use of a lithiation–
borylation reaction between the appropriate enantioenriched
O-carbamates 7 and boronic ester 8 to give boronic esters 6.
These boronic esters would then give access to a series of
bisabolane sesquiterpenes either directly (protodeboronation
or oxidation) or with relative synthetic ease (e.g. demethylation,
followed by oxidation) (Fig. 1). The ready availability of
secondary alcohols from which carbamate 7 is derived,
School of Chemistry, University of Bristol, Bristol BS8 1TS, UK.
E-mail: V.Aggarwal@Bristol.ac.uk; Fax: +44 (0)117 925 1295;
Tel: +44 (0)117 954 6315
w Electronic supplementary information (ESI) available: Full experi-
mental and characterisation data is provided. See DOI: 10.1039/
c2cc32176a
Fig. 1 Retrosynthetic analysis of the bisabolane sesquiterpenes using
a common lithiation–borylation strategy.
c
9230 Chem. Commun., 2012, 48, 9230–9232
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protodeboronation or oxidation of the boronic esters 6, and
the functionalised aromatic ring could prevent both chemoselective
lithiation and, when bearing electron-donating groups, could
participate in the expulsion of the carbamate group.
Lithiation–borylation reaction of carbamates 7b and 7c
with boronic ester 8 gave, after MgBr2–MeOH promoted
1,2-metallate rearrangement, boronic esters 6b and 6c, which
were treated directly with TBAFÁ3H2O to give the O-methyl
protected natural products 10b and 10c. In the case of the
dimethoxy substituted carbamate 7c no loss of carbamate er
was observed and only a 2% erosion in er was observed in
the case of the mono-methoxy substituted analogue 7b.
The synthesis of (R)-(À)-curcuphenol 3 was completed by
demethylation of 10b to give (R)-(À)-curcuphenol 3 in just 4
steps from the commercially available ketone, 11% overall
yield and excellent er (96 : 4).
In order to test the viability of our retrosynthetic analysis we
initially applied the lithiation–borylation and protodeborona-
tion sequence to the enantioselective syntheses of (S)-(+)-a-
curcumene 1 and (R)-(+)-gossonorol 2, by oxidation, from a
single enantioenriched carbamate 7a (Scheme 1). Here a
common boronic ester 6a would give both natural products
by either protodeboronation or oxidation, respectively. Thus,
Noyori reduction of 9a followed by carbamoylation gave
carbamate 7a6a which was treated with s-BuLi and reacted
with boronic ester 8. Subsequent addition of MgBr2–MeOH
and warming triggered 1,2-metallate rearrangement, leading to
boronic ester 6a which was not isolated. This boronic ester was
either treated with TBAFÁ3H2O to give the protodeboronated
product (S)-(+)-a-curcumene 1, or oxidised with basic H2O2 to
give (R)-(+)-gossonorol 2. In both cases the natural products
were isolated in 85% yield and excellent er, showing near-
perfect retention of er from the carbamate 7a. Our three-step
syntheses of a-curcumene 1 and gossonorol 2 are, to the best of
our knowledge, the shortest highly enantioselective syntheses of
these natural products.
Although the preparation of protodeboronation product
10c represented formal syntheses of both (R)-(À)-curcuhydro-
quinone
4
and (R)-(À)-curcuquinone 5, we chose to
complete the syntheses. Thus CAN-mediated oxidation of
the dimethoxy-protected natural product 10c gave (R)-(À)-
curcuhydroquinone 5 in 4 steps and moderate yield, but
excellent er (94 : 6). Reduction of the quinone 5 with ethanolic
NaBH4 gave (R)-(À)-curcuhydroquinone 4 in 5 linear steps
and excellent er (94 : 6).
Scheme 1 Enantioselective synthesis of (S)-(+)-a-curcumene 1 and
(R)-(+)-gossonorol 2. (a) Noyori’s (R,R)-catalyst, NEt3, HCO2H. (b) CbCl,
NaH, THF, reflux. (c) (i) s-BuLi, À78 1C, Et2O, (ii) 8, MgBr2 (2 M in
MeOH), À78 1C to reflux. (d) TBAFÁ3H2O. (e) H2O2, NaOH, H2O.
Scheme 2 Enantioselective synthesis of (R)-(À)-curcuphenol 3 (R)-(À)-
curcuhydroquinone
4
and (R)-(À)-curcuquinone 5. (a) Noyori’s
(S,S)-catalyst, NEt3, HCO2H. (b) CbCl, NaH, THF, reflux. (c) (i) s-BuLi,
À78 1C, Et2O. (ii) 8, MgBr2 (2 M in MeOH), À78 1C to reflux.
(iii) TBAFÁ3H2O. (d) EtSH, NaH, DMF, 120 1C (e) CAN, H2O,
MeCN, rt. (f) NaBH4, EtOH, rt.
With our synthetic strategy validated, we turned our atten-
tion to the three phenolic sesquiterpenes (R)-(À)-curcuphenol 3,
(R)-(À)-curcuhydroquinone 4 and (R)-(À)-curcuquinone 5
(Scheme 2). These substrates posed additional synthetic
challenges as the aryl-methoxy groups could be expected to
direct ortho-lithiation on the aromatic ring or, following
a-oxy-lithiation, give a lithium-carbenoid by expulsion of the
carbamate group. All three syntheses began with asymmetric
transfer-hydrogenation of ketones 9b and 9c using Noyori’s
(S,S)-catalyst7 to give, after carbamoylation, the carbamates 7b
and 7c in 98 : 2 er and 96 : 4 er, respectively. Although
reduction of dimethoxy-substituted ketone 9c proved to be
slow, good yield (92% brsm) and excellent er (96 : 4) was
nevertheless achieved with increased catalyst loading and longer
reaction time.
In summary, we have completed the expedient enantio-
selective synthesis of 5 sesquiterpenes in excellent er using
a common lithiation–borylation strategy. In the case of
(S)-(+)-a-curcumene and (R)-(+)-gossonorol the syntheses
were completed in single one-pot, two-step reactions giving
the products in 85% yield in both cases, from the known
carbamate 7a. The syntheses of (R)-(À)-curcuphenol, (R)-(À)-
curcuquinone and (R)-(À)-curcuhydroquinone demonstrated
the successful application of the lithiation–borylation proto-
deboronation sequence to more functionalised targets. Once
again, these sesquiterpenes were prepared in very high er in
fewer than 5 linear steps.
c
This journal is The Royal Society of Chemistry 2012
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We thank the EPSRC National Mass Spectrometry Service
for providing high-resolution mass spectra. VKA thanks the
Royal Society for a Wolfson Research Merit Award and
EPSRC for a Senior Research Fellowship. L.T.B., S.C., and
M.J.H. thank the Bristol Chemical Synthesis Doctoral Training
Centre, funded by EPSRC (EP/G036764/1), AstraZeneca,
GlaxoSmithKline, Novartis, Pfizer, Syngenta and the Univer-
sity of Bristol, for the provision of a PhD studentship. We
thank Inochem-Frontier Scientific for generous donation of
organoboron reagents.
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c
9232 Chem. Commun., 2012, 48, 9230–9232
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