Asymmetric synthesis of avenaciolide via cascade palladium catalysed cyclisation-carbonylation of bromodienes

Article abstract of DOI:10.1039/b403183k

An asymmetric synthesis of the secondary metabolite avenaciolide has been achieved utilising a diastereoselective palladium catalysed cyclisation- carbonylation of bromodienes.

Full text of DOI:10.1039/b403183k

Asymmetric synthesis of avenaciolide via cascade palladium catalysed
cyclisation–carbonylation of bromodienes†
Varinder K. Aggarwal,* Paul W. Davies and Andreas T. Schmidt
School of Chemistry, Bristol University, Cantock’s Close, Bristol, UK BS8 1TS.
E-mail: v.aggarwal@bristol.ac.uk; Fax: +44 (0)117 929 8611; Tel: +44 (0)117 954 6315
Received (in Cambridge, UK) 3rd March 2004, Accepted 1st April 2004
First published as an Advance Article on the web 27th April 2004
An asymmetric synthesis of the secondary metabolite avenacio-
lide has been achieved utilising a diastereoselective palladium
catalysed cyclisation–carbonylation of bromodienes.
addition it would allow us to explore the diastereoselectivity of the
key cyclisation–carbonylation step.
Palladium catalysed cascade reactions provide versatile methods to
rapidly build up complexity from relatively simple substrates.1
Recently we showed that 2-bromo-1,6-dienes can be converted into
cyclic g,d-unsaturated carboxylic esters through a palladium
catalysed cyclisation–carbonylation cascade process in the pres-
ence of carbon monoxide (Scheme 1).2 We also developed a similar
process for the conversion of enynes to cyclic g,d-unsaturated
carboxylic acids, using an excess of acetic acid.3
Scheme 2 Retrosynthetic analysis of avenaciolide 1.
Our synthesis began with Sharpless epoxidation10 of allylic
alcohol 7 followed by conversion to allylic alcohol 8 using the
protocol developed by Ibuka et al.11 The alcohol 8 was formed in
high enantioselectivity (90% ee). Alternative approaches starting
from nonanal and using asymmetric addition of divinyl zinc12 or
zinc catalysed addition of 2-methyl-3-butyn-2-ol13 with N-methy-
lephedrine as chiral ligand gave both lower enantioselectivities and
lower yields.
Etherification of 8 with 2,3-dibromopropene under a variety of
permutations of the standard conditions (addition of the dibromide
to a suspension of NaH in the presence of the alcohol) resulted in a
mixture of starting material, product 6 and enyne 9. However, by
premixing the dibromide and sodium hydride in the absence of any
solvent and adding the alcohol to this mixture, good yields of 6
were obtained. After 6 d the desired ether 6 was obtained in 93%
yield (Scheme 3).
Scheme 1 Cyclisation–carbonylation of 2-bromo-1,6-dienes.
These functionalised carbocycles and heterocycles are poten-
tially useful intermediates in natural product synthesis.4 We now
report a new asymmetric synthesis of avenaciolide 1 utilising our
palladium catalysed cyclisation–carbonylation of bromodienes as
the key step.
Avenaciolide is a secondary metabolite, isolated from Aspergil-
lus fermentation broths.5 It was found to exhibit antifungal and
weak antibacterial properties. Furthermore it was found to inhibit
glutamate transport in rat liver mitochondria.6 The biological
activity coupled with its interesting structure (bis-fused g-lactone
core with three contiguous chiral centres) has stimulated consider-
able synthetic activity in avenaciolide resulting in numerous
syntheses.7 One particularly elegant total synthesis utilised an
intramolecular alkoxycarbonylation of tungsten–p-allyl complexes
in the key step.8
Our retrosynthetic analysis of avenaciolide 1 is outlined in
Scheme 2. As in previous syntheses,9 the first disconnection is
removal of the methylene group to afford the known bislactone 2.
Change in oxidation state of one of the lactones provides the cyclic
ether 3, which can be disconnected to the alcohol 4, and thus alkene
5. The g,d-unsaturated carboxylic ester 5 can be formed from the
chiral bisallyl ether 6 using our methodology. This would represent
the first application of our methodology to a chiral system, and in
Scheme 3 Reagents and conditions: i, TBHP, (2)-DET, Ti(OiPr)4, DCM,
210 °C, 86%; ii, TsCl, DMAP, NEt3, 92%; iii, KI, then PPh3, I2 (cat.), 55%;
iv, 2,3-dibromopropene, NaH, then 8, 6 d, rt, 93%.
For the cyclisation–carbonylation reaction, we first used the
conditions developed in the previous investigations.2 Although the
cyclised product 5 was the major product, significant quantities of
the linear ester 10 were also formed (Table 1, entry 1). Using
triphenylphosphine instead of trifurylphosphine gave a higher yield
of the cyclic ester 5, which increased further with increased loading
of the palladium catalyst (entries 2 and 3). At the same time the
diastereoselectivity of the cyclisation increased up to a 10 : 1 ratio
for the desired diastereomer.
† Electronic supplementary information (ESI) available: experimental. See
http://www.rsc.org/suppdata/cc/b4/b403183k/
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C h e m . C o m m u n . , 2 0 0 4 , 1 2 3 2 – 1 2 3 3
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

Table 1 Palladium catalysed cyclisation–carbonylation of 6
The formal synthesis of avenaciolide was then completed by
oxidising 3 under Sharpless’ conditions16 to afford the bislactone 2.
Although the lactone 2 was obtained in only 29% yield, 28% of the
starting material was recovered. Addition of further quantities of
the ruthenium catalyst did not improve the yield and other oxidants
(pyridinium dichromate,17 manganese salen complexes18 and
cobalt(III) complexes19) were not effective.
In conclusion we have developed a new asymmetric formal
synthesis of avenaciolide starting from simple, inexpensive materi-
als utilising our cyclisation–carbonylation methodology. We were
able to show that this palladium catalysed reaction is not only
highly efficient for the construction of rings which do not have a
high propensity for cyclisation, but also that the process is highly
diastereoselective. The heterocyclic g,d-unsaturated carboxylic
esters can easily be converted to lactones and bislactones.20
The authors thank AstraZeneca plc for support of a studentship
(PD), EPSRC and Professor Phil Parsons for useful discussions.
Yields (%)a
Entry
Conc. [Pd]
Phosphine
5
10
drb
1
2
3
5 mol%
2 mol%
5 mol%
P(2-furyl)3
PPh3
PPh3
51
56
61
19
18
7
4 : 1
8 : 1
10 : 1
Reagents and conditions: PdCl2(PPh3)2, ratio phosphine : [Pd] = 4
: 1, MeOH/MeCN/H2O (1/2/0.1), 2 atm. CO, 24 h, 85 °C.a Isolated
yields of esters purified by column chromatography. b Determined
by 1H NMR.
Notes and references
1 R. Grigg and V. Sridharan, J. Organomet. Chem., 1999, 576, 65.
2 V. K. Aggarwal, P. W. Davies and W. O. Moss, Chem. Commun., 2002,
972.
3 V. K. Aggarwal, M. Butters and P. W. Davies, Chem. Commun., 2003,
1046.
4 T. Hudlicky, G. Sinai-Zingde, M. G. Natchus, B. C. Ranu and P.
Papadopolous, Tetrahedron, 1987, 43, 5685.
The high diastereoselectivity can be explained by the preferred
conformation of the transition state 12, assuming that both the octyl
group and the ligated palladium prefer a pseudo equatorial position
(Scheme 4). A similar model was proposed by Negishi for the
cyclisation of iododienes.14
5 D. Brookes, B. K. Tidd and W. B. Turner, J. Chem. Soc., 1963, 5385; J.
J. Ellis, F. H. Stodola, R. F. Vesonder and C. A. Glass, Nature (London),
1964, 203, 1382; D. Brookes, S. Sternhell, B. K. Tidd and W. B. Turner,
Aust. J. Chem., 1965, 18, 373.
6 J. Meyer and D. M. Vigras, Biochem. Biophys. Acta, 1973, 325, 375; J.
D. McGivan and J. B. Chappell, Biochem. J., 1970, 116, 37P.
7 For a review see V. S. Martin, C. M. Rodriguez and T. Martin, Org.
Prep. Proc. Int., 1998, 30, 291; for more recent publications see E.
Alcázar, M. Kassou, I. Matheu and S. Castillón, Eur. J. Org. Chem.,
2000, 2285 and references therein.
Scheme 4 Model for the diastereoselectivity of the cyclisation.
Attempts to utilise enyne 9 in the related cyclisation suffered
from low yields due to the sensitivity of the allylic ether towards
acid.
8 M.-J. Chen, K. Narkuman and R.-S. Liu, J. Org. Chem., 1999, 64,
8311.
Ozonolysis of 5 afforded the ketone 14.4 This ketone was treated
with DBU in refluxing THF giving exclusively the thermodynam-
ically favoured trans-diastereomer. During this process some ester
hydrolysis occurred, but both the ketone 14 and its corresponding
free carboxylic acid underwent a diastereoselective reduction with
L-selectride in good yield giving the cyclic lactone 3 after acidic
work-up (Scheme 5). Studies by Loza et al. on the stereochemical
aspects of the reductions of 2,3-disubstituted cyclopentenones have
already shown that the attack of L-selectride at low temperatures
occurs trans to the substituent in the 2-position.15
9 W. L. Parker and F. Johnson, J. Org. Chem., 1973, 38, 2489.
10 R. M. Hanson and K. B. Sharpless, J. Org. Chem., 1986, 51, 1922.
11 N. Fujii, H. Habashita, M. Akaji, K. Nakai, T. Ibuka, M. Fujiwara, H.
Tamamura and Y. Yamamoto, J. Chem. Soc., Perkin Trans. 1, 1996,
865.
12 W. Oppolzer and R. N. Radinov, Tetrahedron Lett., 1988, 29, 5645.
13 D. Boyall, F. Lopez, H. Sasaki, D. Frantz and E. M. Carreira, Org. Lett.,
2000, 2, 4233.
14 E. I. Negishi and C. Copéret, Org. Lett., 1999, 1, 165.
15 E. Loza, D. Lola, J. Freimanis, I. Turovskis, S. Rozˆıte, R. Bokaldere and
O. Sahartova, Tetrahedron, 1988, 44, 1207.
16 P. H. J. Carlsen, T. Katsuki, V. S. Martin and K. B. Sharpless, J. Org.
Chem., 1981, 46, 3936.
17 E. J. Corey and G. Schmidt, Tetrahedron Lett., 1979, 399.
18 A. Miyafuji and T. Katsuki, Tetrahedron, 1998, 54, 10339.
19 E. Hata, T. Takai and T. Mukaiyama, Chem. Lett., 1993, 1513.
20 The heterocyclic ester 5 can representatively be easily oxidised to the
highly substituted lactone 15, further demonstrating the use of such
methodology to form biologically relevant molecules in a rapid and
efficient manner (Scheme 6).
Scheme 5 Reagents and conditions: i, O3, DCM, 278 °C, then Me2S, 278
°C to rt; ii, DBU (1 equiv.), THF, 3 h, reflux, 69% (over two steps); iii, L-
selectride (1.2 equiv.), THF, 278 °C, 70%; iv, RuCl3 (5 mol%), NaIO4 (4.1
equiv.), CCl4/MeCN/H2O (2 : 2 : 3), 29% (40% based on recovery).
Scheme 6 Reagents and conditions: i, py·CrO3, DCM, 1 h, reflux, 64%.
C h e m . C o m m u n . , 2 0 0 4 , 1 2 3 2 – 1 2 3 3
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