A total synthesis of (±)-1-desoxyhypnophilin: Using ring closing metathesis for the construction of cyclic enones

Article abstract of DOI:10.1016/S0040-4039(00)01595-1

The paper describes the first total synthesis of (±)-1-desoxyhypnophilin, a linear triquinane isolated from the East African mushroom Lentinus crinitus which displays promising antimicrobial activity. The key strategic feature is a new cyclopentannulation method for appending cycloalkenones onto ketones involving sequential use of a ring closing metathesis reaction with a tertiary allylic alcohol and a PCC induced oxidative rearrangement. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01595-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8985–8987
A total synthesis of ( )-1-desoxyhypnophilin: using ring
closing metathesis for the construction of cyclic enones
David C. Harrowven,a,* Matthew C. Lucasa and Peter D. Howesb
aDepartment of Chemistry, The University, Southampton S017 1BJ, UK
bMedicinal Chemistry 2, GlaxoWellcome Medicines Research Centre, Gunnels Wood Road, Stevenage,
Herts SG1 2NY, UK
Received 10 August 2000; revised 4 September 2000; accepted 14 September 2000
Abstract
The paper describes the first total synthesis of ( )-1-desoxyhypnophilin, a linear triquinane isolated
from the East African mushroom Lentinus crinitus which displays promising antimicrobial activity. The
key strategic feature is a new cyclopentannulation method for appending cycloalkenones onto ketones
involving sequential use of a ring closing metathesis reaction with a tertiary allylic alcohol and a PCC
induced oxidative rearrangement. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: terpenes and terpenoids; natural products; ring closing metathesis; cyclisations; triquinanes.
Identified in 1994 as a constituent of the East African mushroom Lentinus crinitus, 1-desoxy-
hypnophilin 2 has been shown to exhibit promising antimicrobial activity.1 Closely related to
hypnophilin 3 and coriolin 4, these naturally occurring oxygenated triquinanes are presumed to
be derived in Nature from a common precursor, diene 1.1–3 While numerous syntheses of
hypnophilin and coriolin have been reported, many utilising ingenious cyclopentannulation
strategies,4 diene 1 and 1-desoxyhypnophilin 2 have yet to succumb to total synthesis.
The route we envisioned for the synthesis of 1-desoxyhypnophilin involved a four-step
annulation strategy for the synthesis of cyclic enones (Scheme 1). Thus, allylation of bicyclic
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01595-1

8986
ketone 5 was followed by treatment of the resulting enone 7 with vinylmagnesium chloride/
cerium(III) chloride complex to give diene 8. A ring closing metathesis using Grubbs’ catalyst
then gave 9.5 Though exposure of 9 to PCC failed to provide tricyclic enone 6,6 we were
sufficiently encouraged to embark on the target synthesis using the known ketone 10 as a
convenient starting point.7
Scheme 1.
Firstly the ketone 10 was enolised and methylated to give 11, which in turn was enolised and
allylated to provide 13.8 A cerium(III) chloride promoted addition of vinylmagnesium chloride
to the ketone then provided diene 14 which underwent ring closure to 15 when exposed to
Grubbs’ catalyst.8 Oxidation with pyridinium chlorochromate to enone 16 and methyleneation
according to the procedure of Greene then gave diene 1.9 Finally, selective epoxidation with
hydrogen peroxide provided ( )-1-desoxyhypnophilin 2 (Scheme 2): our synthetic sample
exhibiting spectral characteristics identical to those reported previously.1
Scheme 2. Reagents and conditions: (a) LDA, THF–HMPA, −90°C, 2 h then MeI, −90°C, 6 h, 84%; (b) Et3N, DMF,
TMSCl, D, 24 h, 74%; (c) MeLi, THF–HMPA, −78°C, 15 min then allyl bromide, −78°C, 3 h, 90%; (d) vinylMgBr,
,
CeCl3, THF, 0°C, 15 h, 70%; (e) (PCy3)2Cl2RuꢀCHPh, CH2Cl2, reflux, 3 h, 88%; (f) PCC, 4 A MS, CH2Cl2, rt, 18
h, 60%; (g) HCO2Me, LiHMDS, THF, −78°C, 1 h then CH2O, aq. acetone, K2CO3, rt, 18 h, 42% [+ 19% 16]; (h)
H2O2, NaHCO3, aq. THF, 4°C, 15 h, 73% [+ 20% 1]
In conclusion, we have achieved the first total synthesis of ( )-1-desoxyhypnophilin 2 and
developed a useful annulation protocol for the synthesis of cyclic enones. We are presently
exploring the scope of the annulation sequence for the synthesis of other polycycles and
exploring further its use in target oriented synthesis.

8987
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