A new synthesis of pentalenene using a novel tandem cyclisation involving ketene radical intermediates

Article abstract of DOI:10.1016/S0040-4039(99)02070-5

A new approach to the synthesis of the angular triquinane (±)- pentalenene, based on sequential 5-exo-trig and 5-exo-dig radical cyclisations involving ketene intermediates produced from an α,β- unsaturated acyl radical precursor, is described.

Full text of DOI:10.1016/S0040-4039(99)02070-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 403–405
A new synthesis of pentalenene using a novel tandem cyclisation
involving ketene radical intermediates
Nicole M. Harrington-Frost and Gerald Pattenden ∗
School of Chemistry, University of Nottingham, Nottingham NG7 2RD, UK
Received 12 October 1999; accepted 2 November 1999
Abstract
A new approach to the synthesis of the angular triquinane (±)-pentalenene, based on sequential 5-exo-trig
and 5-exo-dig radical cyclisations involving ketene intermediates produced from an α,β-unsaturated acyl radical
precursor, is described. © 2000 Published by Elsevier Science Ltd. All rights reserved.
The angular triquinane pentalenene 1 and its various oxygenated congeners are biologically im-
portant sesquiterpene antibiotics, whose synthesis1 and biosynthesis2 have aroused considerable at-
tention in recent years. Paramount among the synthetic approaches that have been developed to-
wards triquinanes, including pentalenene 1, are those based on tandem radical-mediated cyclisation
processes.3 In our recent studies with α,β-unsaturated acyl radical intermediates4 we have highlighted
the propensity for these species to react via their corresponding α-ketenyl radical counterparts, i.e.
R–CH_CH–·CO↔R–·CH–CH_C_O. In this letter we describe the development of this work leading
to a new and concise synthesis of (±)-pentalenene based on tandem cyclisation of ketene radical
intermediates derived from the α,β-unsaturated acyl radical intermediate 2 (Scheme 1).
Scheme 1.
Thus, following some precedent established by Davies and Doan,5 we first prepared the β,γ-
unsaturated ester 4 via deconjugative alkylation of the α,β-unsaturated ester 3 using lithium 2,2,6,6-
tetramethylpiperidinamide (LiTMP) and DMPU at −90°C followed by trapping the resulting enolate
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02070-5
tetl 15998

404
anion with the TBDMS ether of 3-iodo-1-propanol. In this manner, and at this carefully controlled tempe-
rature, we obtained almost exclusively the regioisomer 4, i.e. <5% of other cyclopentene regioisomers.6
Reduction of the ester 4 using DIBAL, followed by conversion of the resulting carbinol 5a into the
corresponding tosylate 5b, and a further reduction step, led to the TBS ether 6a (Scheme 2).
Scheme 2. Reagents: (i) LiTMP, DMPU, I(CH2)3OTBS, THF, −90°; (ii) DIBAL, toluene, −78°, 49% (two steps); (iii) TsCl,
DMAP, Et3N, CH2Cl2, 88%; (iv) LiEt3BH, THF, 97%; (v) AcOH/H2O/THF, 93%; (vi) (COCl)2, DMSO, CH2Cl2, Et3N, then
Ph3P:CHCO2Me, 80%; (vii) LiOH·H2O, THF/H2O, 98%; (viii) NPSP, n-Bu3P, CH2Cl2, −30°, 57%
After deprotection of 6a (to 6b), application of the Ireland one-pot Swern–Wittig procedure7 then
converted 6b into the E-α,β-unsaturated ester 7a in a satisfying 80% yield. Finally, saponification of
the ester 7a and treatment of the resulting carboxylic acid 7b with N-(phenylseleno)phthalimide (NPSP)
in the presence of n-Bu3P led to the key selenyl ester precursor 7c to the α,β-unsaturated acyl radical
intermediate 2.
When a solution of 7c in benzene was heated with Bu3SnH in the presence of catalytic AIBN, work
up and chromatography gave the α-methyl epimer of the tricyclic ketone 10 as the major product
(∼45%),6 together with small amounts of the corresponding β-methyl epimer of 10 (∼10%), and also
the aldehyde 7d resulting from competing in situ reduction of the ester starting material (∼25%). The
relative stereochemistry assigned to the triquinoid ketone 10 followed from inspection and comparison
Scheme 3.

405
of its NMR spectroscopic data with those in the literature.8 The tricyclic ketone 10 is produced from the
selenyl ester 7c by way of formation of the acyl radical 2 and 5-exo-trig radical cyclisation involving
the α-ketenyl radical counterpart 8 leading initially to the spiro-ketene radical intermediate 9. A 5-exo-
dig radical cyclisation into the ketene electrophore in 9 then leads to the enolate radical 11 which, on
quenching by H·, produces 10 (Scheme 3).
The synthesis of (±)-pentalenene 1 was completed following deprotonation and α-methylation of
10, using LDA and MeI, leading to 12, reduction of 12 to the corresponding carbinol 13, and finally
dehydration of 13 in hot benzene in the presence of PTSA (Scheme 4).
Scheme 4. Reagents: (i) LDA, THF, then MeI, 37%; (ii) NaBH4, MeOH, 52%; (iii) p-TsOH, benzene, ∆, 70%
The synthetic (±)-pentalenene displayed spectroscopic data which were identical to those reported in
the literature and from an earlier synthesis reported from our laboratory.9
Acknowledgements
We thank the Commonwealth Scholarship Commission for a scholarship to N.M.H.-F.
References
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6. All new compounds showed satisfactory spectroscopic data together with microanalytical and/or mass spectrometry data.
Selected spectroscopic data: Compound 10: νmax/cm−1 (film) 1737; δH (500 MHz) 0.97 (d, J 6.9, 3H, CH3CH), 0.99 (s, 3H,
CH3), 1.01 (s, 3H, CH3), 1.30–1.38 (m, 3H, 3×CHH), 1.63 (dd, J 7.0, 12.9, 1H, C(O)CHCHH), 1.72 (dd, J 12.9, 9.5, 1H,
C(O)CHCHH), 1.79–1.86 (m, 2H, 2×CHH), 1.86–1.95 (m, 1H, CH3CH), 2.07–2.14 (m, 2H, CHH and C(O)CHH), 2.40–2.47
(m, 2H, C(O)CH and CH2CHCH2), 2.78 (dd, J 18.6, 9.2, 1H, C(O)CHH); δC (500 MHz) 15.5 (CH3CH), 29.2 (CH3), 29.5
(CH3), 31.3 (CH2), 34.4 (CH2), 41.2 (quat. CMe2), 42.9 (CH), 44.6 (CH2), 45.8 (CH), 46.8 (CH2), 47.9 (CH2), 59.4 (CH),
62.7 (quat. C), 222.9 (C_O); m/z 206.1678 (M+ C14H22O requires M+, 206.1671).
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