Synthetic studies of ingenol: Synthesis of in,out- tricyclo[7.4.1.01,5]tetradecan-14-one

Article abstract of DOI:10.1016/S0040-4039(00)00519-0

in,out-Tricyclo[7.4.1.0^1,5]tetradecan-14-one was synthesized from γ- butyrolactone in 12 steps using ring-closing olefin metathesis as the key step. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00519-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3927–3930
Synthetic studies of ingenol: synthesis of
in,out-tricyclo[7.4.1.01,5]tetradecan-14-one
Hideo Kigoshi,a,∗ Yuto Suzuki,b Kenta Aoki b and Daisuke Uemura b,∗
aResearch Center for Materials Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan
bDepartment of Chemistry, Graduate School of Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan
Received 1 March 2000; accepted 24 March 2000
Abstract
in,out-Tricyclo[7.4.1.01,5]tetradecan-14-one was synthesized from γ-butyrolactone in 12 steps using ring-closing
olefin metathesis as the key step. © 2000 Elsevier Science Ltd. All rights reserved.
Ingenol (1) is a diterpenoid isolated from Euphorbia ingens, possessing a bicyclo[4.4.1]undecane
skeleton with a highly strained inside-outside intrabridgehead stereochemistry.1 Many derivatives have
also been isolated.1 Ingenol and its derivatives interest organic chemists not only because of their
unique framework but also their biological activities, such as protein kinase C (PKC)-activating and
anti-HIV activities.2,3 Despite many synthetic studies,4 ingenol has not been synthesized and only a few
strategies for the construction of the unique in,out-bicyclo[4.4.1]undecane skeleton have been disclosed
by Winkler,5 Funk,6 Rigby,7 and Kuwajima.8
The strategies for the inside-outside intrabridgehead stereochemistry, such as the de Mayo reaction and
fragmentation,5 the Ireland–Claisen rearrangement for ring contraction,6 the 1,5-H sigmatropy to change
the intrabridgehead stereochemistry from out–out to in–out,7 and the tandem cyclization–rearrangement
reaction,8 have appeared, however, the direct cyclization to the in,out-bicyclo[4.4.1]undecane system has
not been reported. We describe herein the synthesis of in,out-tricyclo[7.4.1.01,5]tetradecan-14-one (2) by
direct cyclization using olefin metathesis.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00519-0
tetl 16798

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The key reaction of this synthesis was the ring-closing olefin metathesis with a Grubbs’ ruthenium
catalyst, RuCl2(_CHPh)(PCy3)2, which provides a new strategy for the synthesis of cyclic natural
products.9 In the ring-closing olefin metathesis, it is important that the two olefins being connected
to each other should be closely arranged. In the preliminary study, we found that ring-closing olefin
metathesis of trans-2,7-diallylcycloheptanone did not afford in,out-bicyclo[4.4.1]undecene but dimeric
compounds (Scheme 1). Thus, we chose olefin 3 as a key intermediate, in which the distance between
the two terminal olefins is closer, about 3.6 Å based on a molecular mechanics calculation,10 than that of
trans-2,7-diallylcycloheptanone.
Scheme 1. Ring-closing olefin metathesis of trans-2,7-diallylcycloheptanone
The synthesis of 2 is illustrated in Scheme 2.11 γ-Butyrolactone was reduced with DIBAL to give a
hemiacetal, the Wittig reaction of which afforded the unsaturated ester 4 (61%, two steps). Iodination
of the hydroxy group in 4 and subsequent reduction with DIBAL afforded the allylic alcohol 6. The
hydroxy group in 6 was protected to provide the THP ether 7 (71%, three steps). The alkylation reaction12
of cycloheptanone N,N-dimethylhydrazone with 7 (n-BuLi) followed by hydrolysis with silica gel13
gave the alkylated ketone 8 in 92% yield. Treatment of 8 with concentrated hydrochloric acid in 1,4-
dioxane readily afforded the allylic chloride 914 (94%), which was treated with t-BuOK in t-BuOH to
give the spiroketones 10a (28%) and 10b (43%).15,16 Allylation of 10a with KHMDS and allyl iodide
provided a 7:1 mixture of the allyl ketones 3 and 11 in 81% yield, which were separated by silica gel
column chromatography. We could not determine the stereochemistry of 3 and 11 by the spectroscopic
analysis, however, we predicted that the allylation of 10a should occur from the less hindered side of the
corresponding enolate, and the allyl ketone 3 should be predominantly obtained.
The ring-closing olefin metathesis of the allyl ketones 3 and 11 was investigated, respectively, and it
was proved that this reaction required a relatively higher temperature. The allyl ketone 3 reacted with
Grubbs’ ruthenium catalyst in boiling toluene to give the tricycloketone 12 in 20% yield, whereas the
ring-closing olefin metathesis of 11 gave the tricycloketone 13 in 76% yield. The tricycloketones 12
and 13 were catalytically hydrogenated to afford the previously reported compound 25c,17 (55%) and
compound 1418 (68%), respectively. Thus, the structures of 3 and 12 were confirmed.
In summary, we have synthesized in,out-tricyclo[7.4.1.01,5]tetradecan-14-one (2), the framework of
ingenol, in 12 steps from γ-butyrolactone using a Grubbs’ ring-closing metathesis. Application of this
strategy to the total synthesis of ingenols is currently underway in our laboratory.
Acknowledgements
We thank Mr Jun Yamamoto for his efforts on the preliminary study. This work was supported in part
by Grants-in-Aid for COE Research and Scientific Research from the Ministry of Education, Science,
Sports, and Culture, Japan.

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Scheme 2. Reagents and conditions. (a) DIBAL, toluene, −78°C, 1 h, 95%; (b) Ph3P_CHCOOMe, benzene, 23°C, 1 h, 64%;
(c) I2, Ph3P, imidazole, toluene, 23°C, 1 h, 79%; (d) DIBAL, toluene, −78°C, 1 h; (e) DHP, p-TsOH, CH2Cl2, 23°C, 1 h, 90% in
two steps; (f) cycloheptanone N,N-dimethylhydrazone, n-BuLi, THF, 23°C, 2 h; (g) silica gel, CH2Cl2, 23°C, 19 h, 92% in two
steps; (h) conc. HCl, dioxane, 23°C, 5 h, 94%; (i) t-BuOK, t-BuOH, reflux, 3.5 h, 28% for 10a, 43% for 10b; (j) allyl iodide,
KHMDS, THF, 0°C, 3 h, 81% (3:11=7:1); (k) RuCl2(_CHPh)(PCy3)2, toluene, reflux, 20% for 12, 76% for 13; (l) H2, Pd/C,
EtOH, 23°C, 1 h, 55% for 2, 68% for 14
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10. The global minima were calculated in a Multiconformer conformational search using MacroModel (Version 6.0).

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11. All new compounds exhibited spectral (1H NMR, 13C NMR, IR, MS) and analytical (HRMS) data fully consistent with the
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15. Although the reaction conditions for the spirocyclization were investigated, such as t-BuONa/t-BuOH, t-BuOLi/t-BuOH,
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2.
1
17. Compound 2: IR (CHCl3) 2945, 2860, 1720, 1450, 1380 cm−1; H NMR (270 MHz, CDCl3) δ 2.88 (br tt, J=11.9, 2.0
Hz, 1 H), 2.04–0.86 (m, 21H); 13C NMR (100 MHz, CDCl3) δ 217.0, 63.5, 54.3, 50.3, 41.1, 36.2, 35.0, 30.8, 30.6, 30.54,
30.51, 30.48, 26.0, 25.2; EIMS m/z 206 (M+, 100), 188 (21).
18. Compound 14: IR (CHCl3) 2930, 2860, 1680, 1460, 1360 cm−1; 1H NMR (270 MHz, CDCl3) δ 2.73 (m, 1H), 2.19–2.12
(m, 2H), 1.95–1.17 (m, 19H); 13C NMR (67.8 MHz, CDCl3) δ 219.2, 63.4, 54.7, 43.3, 38.8, 35.0, 34.1, 34.0, 30.0, 28.7,
26.6, 26.3, 24.7, 20.9; EIMS m/z 206 (M+, 100), 188 (31); HREIMS calcd for C14H22O (M+) 206.1671, found 206.1643.