Enantioselective synthesis of the bicyclo[4.3.0]nonane ring system of the pinguisane-type sesquiterpenoids via a Br?nsted acid promoted transannular enol alkylation

Article abstract of DOI:10.1016/j.tetlet.2005.12.084

The bicyclo[4.3.0]nonane ring system of the pinguisane-type sesquiterpenoid natural products, including the vicinal quaternary stereocentres, has been synthesised as a single enantiomer via a novel Br?nsted acid promoted transannular alkylation of an enol

Full text of DOI:10.1016/j.tetlet.2005.12.084

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1453–1455
Enantioselective synthesis of the bicyclo[4.3.0]nonane ring system
of the pinguisane-type sesquiterpenoids via a Brønsted acid
promoted transannular enol alkylation
Paul A. Clarke,* Richard J. G. Black and Alexander J. Blakeꢀ
School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
Received 21 November 2005; accepted 14 December 2005
Abstract—The bicyclo[4.3.0]nonane ring system of the pinguisane-type sesquiterpenoid natural products, including the vicinal qua-
ternary stereocentres, has been synthesised as a single enantiomer via a novel Brønsted acid promoted transannular alkylation of an
enol with an unactivated alkene.
Ó 2006 Elsevier Ltd. All rights reserved.
A wide range of sesquiterpenes possessing the bicyclo-
[4.3.0]nonane ring system have been isolated from liver-
worts (Fig. 1),1 and some of these compounds have been
shown to have anticancer,2 antimicrobial3 and antifee-
dant activities.4 The key structural features of this class
of natural product is the dense array of stereogenic cen-
tres around the bicyclo[4.3.0]nonane system, particu-
larly the presence of two vicinal quaternary stereogenic
carbons at the 6, 5 ring junction. This array of stereo-
genicity and the presence of the two quaternary centres
has made the synthesis of this class of natural product a
significant challenge.
To date there have been far general strategies, which
have been used to construct the ring systems present in
these natural products, including annulation of a pre-
existing cyclohexanone unit,5 intramolecular Diels–
Alder cyclisations,6 cycloisomerisations7 and cationic
cyclisations.8 However, these strategies require a large
number of chemical steps in order to set up the bicyclo-
[4.3.0]nonane ring system and to install the vicinal
quaternary centres. To our knowledge, only the annula-
tion strategy has provided an enantioselective route to
this class of molecule.5e,f
We had an interest in the use of transannular cyclisation
reactions for the construction of bicyclic ring systems
and were interested in developing such a strategy for
the synthesis of the bicyclo[4.3.0]nonane unit replete
with the vicinal quaternary stereocentres and functional-
ity, which would allow for the conversion of the cyclisa-
tion product into one or more of the pinguisane-type
sesquiterpenes. Additionally, we wished for this route
to provide a single enantiomer of the bicyclo[4.3.0]nonane
unit. As we had some experience of transannular cyclisa-
tions across nine-membered rings we opted to break
retrosynthetically the carbon–carbon bond common to
both the five- and six-membered rings, thus revealing a
cyclononene ring 2 as a bicyclo[4.3.0]nonane precursor
(Fig. 2). We were attracted to a system such as 2 as it
was reminiscent of the nine-membered ring 3 we had
prepared in our synthesis of the DEF-rings of hexa-
cyclinic acid and FR182877. In order to assess the feasibil-
ity of this transannulation strategy for the construction
MeO
O
O
O
HO
O
O
O
pinguisenol
norpinguisanolide
acutifolone A
Figure 1.
Keywords: Pinguisane sesquiterpenoids; Transannular cyclisations;
Enol alkylation; Brønsted acid; Vicinal quaternary centres.
*
Corresponding author at present address: Department of Chemistry,
University of York, Heslington, York YO10 5DD, UK. Tel.: +44
01904 432614; e-mail: pac507@york.ac.uk
ꢀ Corresponding author for information concerning crystallographic
data.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.084

1454
P. A. Clarke et al. / Tetrahedron Letters 47 (2006) 1453–1455
O
O
O
OTBS
R
R
t-
BuO C
2
1
2
3
Figure 2.
S
OH
O
S
O
O
i
N
O
N
N
O
H
OAc
OAc
Bn
O
Bn
5
6
7
TBSO
OAc
O
TBSO
ii, iii
iv
OMe
H
Me
OR
9 R = H
10 R =Ac
8
v
O
t-BuO2C
TBSO
OR
O
O
OTBS
vi
vii
Ot-Bu
11
4
Scheme 1. Reagents and conditions: (i) TiCl4, (À)-sparteine, CH2Cl2, À78 to 0 °C, 78%; (ii) MeNHOMeÆHCl, Me3Al, THF, À20 °C; (iii) TBSCl,
imidazole, DMF, 71% (over two steps); (iv) DIBAL-H, THF, À78 °C, 48% (9) and 43% (10); (v) Ac2O, Et3N, CH2Cl2, NaHCO3, 0 °C to rt, 90%; (vi)
t
SnCl2, BuO2CCHN2, CH2Cl2, 89%; (vii) NaH, Pd(PPh3)4, dppe, THF, reflux, 47%.
of the bicyclo[4.3.0]nonane unit with the vicinal quater-
nary stereocentres we envisaged modifying our previous
route to construct cyclisation precursor 4 (Scheme 1).
While 4 does not contain all the elements necessary to
enable the elaboration of the transannular cyclisation
product into the natural products, it does provide us
with an opportunity to access the feasibility of our stra-
tegy using a molecule, which we had to hand as part of
our investigations on the hexacyclinic acid9,10 and
FR182877 structures.10,11
to provide 10 in a 90% yield. The b-ketoester 11 was
installed by treatment of 10 with tert-butyl diazoacetate
and SnCl2. Finally, closure of the nine-membered ring
was achieved by use of our previously reported condi-
tions.10 This furnished 4 in a disappointing, but ade-
quate, 47% yield.
In earlier studies we had shown that similar systems
underwent transannular cyclisations of the various oxy-
gen functionalities around the nine-membered ring, to
form either ether or lactone containing products.10 We
required that the enolisation occurs between C(1) and
C(2) so that transannulation may occur to form the
bicyclo[4.3.0]nonane system (Fig. 3), rather than
between C(9) and C(1), which would probably not lead
to any cyclisation product.
Our synthesis of 4 (Scheme 1) began by conducting an
‘Evans-like’ aldol reaction of oxazolidinethione 6 with
aldehyde 5 under conditions reported by Crimmins,12
which produced the all syn-aldol product 7 in 78% yield
as a single diastereomer. Weinreb amide formation and
silyl protection of the alcohol proceeded smoothly
and in 71% yield over the two steps. Reduction of the
Weinreb amide to the aldehyde was achieved by use of
DIBAL-H and furnished essentially a 1:1 mixture of
9 and 10. The free allylic alcohol in 9 was re-acylated
In order to prevent cyclisation via oxygen and enolisa-
tion between C(9) and C(1), we opted to form lactone
13 (Scheme 2), which was prepared in 71% yield by
HF deprotection of the silyl ether and removal of the
O
O
OH
t-BuO2C
1
t-BuO2C
9
2
transannulation
OTBS
6
12
4
Figure 3.

P. A. Clarke et al. / Tetrahedron Letters 47 (2006) 1453–1455
1455
O
O
O
t-
BuO C
2
i, ii
OTBS
O
4
13
Scheme 2. Reagents and conditions: (i) HF, MeCN; (ii) TFA, CH2Cl2,
71% (over two steps).
tert-butyl ester and in situ lactonisation with TFA. An
X-ray crystal structure of 13 revealed that the ketone
carbonyl and H(2) were appropriately aligned for enoli-
sation to occur (Fig. 4), if conditions could be found.
We were confident that enolisation would not occur
between C(9) and C(1) as that would necessitate the
formation of an anti-Bredt bridgehead double bond.
Figure 5. X-ray structure of compound 14.
carbon–carbon double bond. This extends the scope of
transannulation reactions in the synthesis of complex
and biologically active natural products. Work is on
going to apply this strategy to the synthesis of pinguise-
nol and acutifolone A, and these studies will be reported
in due course.
Acknowledgements
We thank the EPSRC and Pfizer for studentship funding
(R.J.G.B.) and AstraZeneca for an unrestricted research
award (P.A.C.).
References and notes
1. (a) Asakawa, Y. In Progress in the Chemistry of Organic
Natural Products; Herz, W., Kirby, G. W., Moore, R. E.,
Steglich, W., Tamm, Ch., Eds.; Springer: Wien, New York,
1995; Vol. 65, p 1; (b) Asakawa, Y.; Toyota, M.; Aratani,
T. Tetrahedron Lett. 1976, 40, 3619; (c) Hashimoto, T.;
Irita, H.; Tanaka, M.; Takaoka, S.; Asakawa, Y. Tetra-
hedron Lett. 1998, 39, 2977.
Figure 4. X-ray structure of lactone 13.
We rationalised that a Brønsted acid capable of promot-
ing enolisation as well as protonation of the double
bond on the other side of the ring would stand the best
chance of success. To this end we treated 13 with 15 eq.
of HBF4 in Et2O/AcOH, and we were delighted to
witness the clean formation of a new product, which
was identified by comprehensive NMR spectroscopy
and X-ray crystallography as the desired bicyclo-
[4.3.0]nonane ring system 14 (Scheme 3, Fig. 5). The
lactone was opened with NaOMe in MeOH to yield
the bicyclo[4.3.0]nonane core of the pinguisane-type
sesquiterpenoids complete with the vicinal quaternary
centres, as a single enantiomer.
2. Belkin, M.; Fitzgerald, D.; Felix, M. D. J. Natl. Cancer
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O
O
O
O
O
OH
O
i
ii
MeO C
2
O
13
14
15
Scheme 3. Reagents and conditions: (i) 54% HBF4 in Et2O, AcOH,
66%; (ii) NaOMe, MeOH, 70%.
10. Clarke, P. A.; Grist, M.; Ebden, M.; Wilson, C.; Blake, A.
J. Tetrahedron 2005, 61, 353.
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2004, 45, 927.
12. Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary,
K. J. Org. Chem. 2001, 66, 894.
In conclusion, we have developed a conceptually novel
asymmetric approach to the construction of the bicy-
clo[4.3.0]nonane ring systems of the pinguisane-type ses-
quiterpenoids, by use of a Brønsted acid promoted
transannular cyclisation of an enol onto an unactivated