New route to the synthesis of the illudane skeleton by Michael-Michael- elimination reaction

Article abstract of DOI:10.1016/S0040-4039(00)00974-6

A new route to the synthesis of an optically active illudane skeleton from (R)-(-)-pantolactone (4) is established. The tricyclic ring system was constructed by Michael-Michael-elimination reaction of the enolate of (3S,5R)-3-(tert-butyldimethylsilyloxy)-

Full text of DOI:10.1016/S0040-4039(00)00974-6

Tetrahedron Letters 41 (2000) 5923±5926
New route to the synthesis of the illudane skeleton by
Michael±Michael-elimination reaction
Kazuo Tokuzaki, Yasuhiro Kanemitu, Takehiko Yoshimitsu and Hiroto Nagaoka*
Meiji Pharmaceutical University, Noshio, Kiyose, Tokyo 204-8588, Japan
Received 8 May 2000; revised 8 June 2000; accepted 9 June 2000
Abstract
A new route to the synthesis of an optically active illudane skeleton from (R)-(^)-pantolactone (4) is
established. The tricyclic ring system was constructed by Michael±Michael-elimination reaction of the
enolate of (3S,5R)-3-(tert-butyldimethylsilyloxy)-5-methoxymethyloxy-1-propionylcyclopentene (10) with
ethyl cyclopropylidenacetate (3). # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: Michael reactions; terpenes and terpenoids; antitumor compounds.
Illudin M (1) and illudin S (2), produced by the bioluminescent mushroom Omphalous illuens
(synonymous with Lampteromyces japonicus), are highly toxic sesquiterpenes, each possessing a
rare tricyclic ring system (illudane skeleton).1 Selective toxicity toward tumor cells of illudins and
certain derivatives of illudins has been reported.2 Their unique structural features and biological
signi®cance have attracted much interest in synthetic studies on these products.3 This paper
describes a new synthetic route to the illudane skeleton having most of the functionalities
necessary for producing illudins from (R)-(^)-pantolactone (4). The concept for constructing the
tricyclic ring system was based on Michael±Michael-elimination reaction of the enolate of i
having a leaving group at C-5 with ethyl cyclopropylideneacetate (3),4 to give enone iii via enolate
ii, as shown in Fig. 1.
Figure 1.
* Corresponding author. Fax: +00-81-424-95-8796; e-mail: nagaoka@my-pharm.ac.jp
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00974-6

5924
Enone 10 corresponding to i was synthesized via Michael±aldol reaction of cyano aldehyde 6
obtained from hemiacetal 55 through the Wittig reaction and Swern oxidation. Reaction of 6 with
^
+ 6
.
Oshima's reagent (PhS AlMe3 Li ) in THF proceeded stereoselectively to a€ord cyclopentanol
77 (93%) with a trace amount of its diastereomer, and treatment of 7 with potassium tert-
butoxide gave 8 (Scheme 1). The Baylis±Hillman reaction of 6 with DABCO8 for the direct
formation of 8 failed to proceed. Transformation of the cyano group in 8 into a propionyl group
was carried out by reaction with ethyl lithium to give 9, whose secondary hydroxy group at C-5
was activated as a methoxymethyl ether to form 10.9
Scheme 1. Reagents and conditions: (a) Ph3PˆCHCN, CH2ClCH2Cl, 70ꢀC, 8 h; (b) (COCl)2, DMSO, CH2Cl2, ^78 to
ꢀ
ꢀ
^
+
ꢀ
.
^45 C, 1 h, then Et3N, 0 C, 20 min (two steps, 82%); (c) PhS AlMe3 Li , THF, 0±22 C, 8 h, 7 (93%), stereoisomer of 7
(trace); (d) t-BuOK, THF, 24ꢀC, 1 h, 79%; (e) EtLi, THF, ^20ꢀC, 30 min, then NH4Cl aq, 24ꢀC, 10 h, 77%; (f)
MOMCl, i-Pr2NEt, CH2Cl2, 22ꢀC, 88%; (g) LHMDS, THF±HMPA then 3, ^78 to 0ꢀC; (h) TMSOTf, Et3N, CH2Cl2,
rt, 1 h, 90%; (i) DIBAH, CH2Cl2, ±78ꢀC, quant.; (j) VO(acac)2, TBHP, CH2Cl2, rt, 12 h, 63% (14: 31%; 15: 32%); (k)
TBAF, THF, rt, 1 h, quant.
Reaction of the kinetic enolate generated from 10 with LHMDS with cyclopropylideneacetate
25
3 at ^78 to ^5ꢀC in a 3:2 mixture of THF and HMPA proceeded to produce enone 11,7 ‰ꢀŠ ^43.2
D
(c 0.84; CHCl3) in 31% yield, and its stereoisomer 127 (10%) with tandem Michael reaction and
elimination of the methoxymethyloxy group. On the other hand, attempts to e€ect the reaction of
the enolate of 18 bearing a 5b-methoxymethyloxy group, prepared from 8,10 with 3 to produce 20
met with failure. However, the enolate of 17 was found to react with 3 to give 197 in 25% yield,
and this product could be converted to enone 20 by mesylation of the hydroxy group and

5925
successive DBU treatment (Scheme 2). Stereoselectivity in the reaction of 17 with 3 may be
explained based on transition state C leading to 19, as shown in Fig. 3. In this state, a,b-unsaturated
ester 3 approaches the dienolate of 17 from the less hindered side with coordination between the
lithium cation in the enolate of 17 and carbonyl oxygen of 3. Reaction of 10 with 3 appeared to
proceed via transition state B (Fig. 2). In this case, transition state A corresponding to C (Fig. 3)
would be disfavored owing to steric repulsion between the ethoxycarbonyl group in 3 and the 5a-
methoxymethyloxy group of 10.
Scheme 2.
Figure 2.
Figure 3.
Stereoselective introduction of the b-hydroxy group at C-7 was achieved by the neighboring
e€ect of the 3b-hydroxymethyl group in 13, which was converted from 11 by formation of the
corresponding silyl enol ether followed by DIBAH reduction. The double bond of the enol ether
was readily oxidized with tert-butyl hydroperoxide in the presence of a catalytic amount of
VO(acac)2 to give a mixture of keto alcohol 14 and acetal 15,11 both of which were subsequently
25
D
converted to triol 16, ‰ꢀŠ +40.8 (c 0.5; CHCl3), by removal of the silyl group in quantitative
yield.
In conclusion, suitably functionalized illudane skeleton 16 was synthesized in optically active
form from hemiacetal 5 in 11 steps via Michael±Michael-elimination reaction of 10 with 3 as the
crucial step. The total synthesis of 1 using 16 is presently being attempted at this laboratory.

5926
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