Enantioselective synthesis of (1S,3S,7R)-3-methyl-α-himachalene, the sex pheromone of the sandfly Lutzomyia longipalpis from Jacobina, Brazil

Article abstract of DOI:10.1016/S0040-4039(00)00831-5

(1S,3S,7R)-3-Methyl-α-himachalene, the sex pheromone of the male sandfly (Lutzomyia longipalpis) from Jacobina, Brazil, was synthesized enantioselectively by employing Evans' or Oppolzer's asymmetric methylation as the key step. The absolute configuration at the ring junction of this pheromone is opposite to that of the known (1R,7R)-α-himachalene of plant origin. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00831-5

Tetrahedron Letters 41 (2000) 5243±5247
Enantioselective synthesis of (1S,3S,7R)-3-methyl-a-
himachalene, the sex pheromone of the sand¯y Lutzomyia
longipalpis from Jacobina, Brazil
Kenji Mori,* Takuya Tashiro and Satoshi Sano
Department of Chemistry, Faculty of Science, Science University of Tokyo, Kagurazaka 1-3, Shinjuku-ku,
Tokyo, 162-8601, Japan
Received 24 April 2000; revised 15 May 2000; accepted 19 May 2000
Abstract
(1S,3S,7R)-3-Methyl-a-himachalene, the sex pheromone of the male sand¯y (Lutzomyia longipalpis) from
Jacobina, Brazil, was synthesized enantioselectively by employing Evans' or Oppolzer's asymmetric
methylation as the key step. The absolute con®guration at the ring junction of this pheromone is opposite to
that of the known (1R,7R)-a-himachalene of plant origin. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric synthesis; circular dichroism; Diels±Alder reaction; pheromones; terpenes and terpenoids.
The sand¯y Lutzomyia longipalpis is the vector of the protozoan parasite Leishmania chagasi,
the causative agent of visceral leishmaniasis in South and Central America.1 The structure and
absolute con®guration of the male-produced sex pheromone of L. longipalpis from Lapinha,
Brazil, was ®rmly established in 1999 as (S)-9-methylgermacrene-B (A, Scheme 1)2 by our synthesis
of (þ)-A3 as well as (S)-A4 and their comparison with the natural pheromone. As to the structure
and relative con®guration of the pheromone of the male L. longipalpis from Jacobina, Brazil, it
was shown to be (1RS,3RS,7SR)-3-methyl-a-himachalene (1)5 by our synthesis of (þ)-1.6 Its
absolute con®guration, however, remained unknown, although that of the parent sesquiterpene
a-himachalene (B) of plant origin had been known as 1R,7R since 1968.7 Our recent preparation
of the enantiomers of 1 enabled Pickett and his co-workers to assign 1S,3S,7R-con®guration to
the natural pheromone 1.8 It thus has become clear that the biosynthesis of 3-methyl-a-himachalene
(1) by L. longipalpis takes a steric course di€erent from that of (1R,7R)-a-himachalene (B) in
plants such as Himalayan deodar Cedrus deodara.9
We previously resolved (þ)-C (=18) by preparative HPLC on Chiralcel1 OD to give its enantio-
mers (ꢀ99% ee).8 Their CD spectral analysis coupled with MM3 calculation to deduce their most
stable conformation allowed us to assign their absolute con®guration on the basis of the octant
* Corresponding author. Fax: +81-3-3235-2214.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00831-5

5244
Scheme 1. Structure of 3-methyl-a-himachalene (1) and related compounds together with the retrosynthetic analysis
of 1.
rule:10 the ketone C with a positive Cotton e€ect at 296 nm was thought to be (1S,3S,7R)-C.
Applicability of the octant rule to such a cycloheptanone system, however, is uncertain. We
therefore decided to prepare optically active C by the intramolecular Diels±Alder reaction of
optically active D, which would be derived from (S)-acid E. The acid E would be obtainable by
asymmetric methylation of the corresponding 2-demethyl acid derivatives.
Scheme 2 summarizes our enantioselective synthesis of (1S,3S,7R)-1. The commercially available
diol 2 was converted to the known aldehyde 3.6 Chain-elongation of 3 by Wittig reaction yielded
4. Although catalytic hydrogenation of the double bond of 4 was unsuccessful, it could be
reduced with magnesium and methanol11 to give 5. Removal of the TBS protective group of 5
furnished 6, which was subjected to Swern oxidation to a€ord aldehyde 7. Ole®n formation by
Wittig reaction converted 7 to 8 after hydrolysis with methanolic potassium hydroxide. The E/Z
ratio of 8 was 98:2 as estimated by its GC analysis on TC-WAX1. Activation of acid 8 as mixed
anhydride 9 by treatment with pivaloyl chloride was followed by acylation with it of the Evans'
chiral auxiliary, (S)-4-benzyl-2-oxazolidinone,12 yielding 10.
Methylation of 10 with sodium hexamethyldisilazide (NaHMDS) and methyl iodide13 furnished
11. Removal of the chiral auxiliary14 gave carboxylic acid 12 ‰ꢀŠD22=+4.70 (c=1.02, CHCl3),
>99% ee by chiral GC on Chirasil-DEX1-CB, whose absolute con®guration must be S
according to the empirical rule generally accepted.13 To further support the assigned S con®g-
uration of (+)-12, an alternative method was employed for its preparation. Oppolzer's (1R,2S)-
(+)-camphorsultam15 was acylated with acyl chloride 13 derived from acid 8 to a€ord N-acyl
sultam 14. Methylation of 14 with n-butyllithium and methyl iodide16 gave 15, whose chiral
auxiliary was removed to furnish (+)-acid 12, ‰ꢀŠ2D2=+4.64 (c=1.08, CHCl3), >99% ee by chiral
GC on Chirasil-DEX1-CB. According to Oppolzer et al.,16 this acid should possess S absolute
con®guration. This result was in accord with the previous one by employing the Evans' method.
The ®nal and de®nitive proof of the S con®guration of (+)-12 is summarized in Scheme 3. The
commercially available (R)-19 was converted to 20 by the known method.17 Alkylation of methyl
isobutyrate with 20 gave 21, which was converted to (R)-25 ‰ꢀŠ2D2=+9.89 (c=1.14, CHCl3), in a
conventional manner via 22, 23, and 24. The alcohol 25 obtained by reduction of 11 with lithium
aluminum hydride was levorotatory, ‰ꢀŠ2D2=^9.31 (c=1.15, CHCl3), and therefore it was (S)-25.
Accordingly, the (+)-acid 12 must possess S con®guration.

5245
Scheme 2. Synthesis of (+)-3-methyl-a-himachalene (1). Reagents: (a) Ph3PˆCHCO2Et, C6H6, re¯ux (89%). (b) Mg,
+
MeOH (77%). (c) HF aq., MeCN (93%). (d) (COCl)2, DMSO, CH2Cl2, then Et3N (83%). (e) CH2ˆC(Me)CH2PPh3 Cl^,
t-BuOK, THF; KOH, MeOH (83% two steps). (f) PivCl, Et3N, CH2Cl2. (g) (S)-4-Benzyl-2-oxazolidinone, n-BuLi, THF
(78% two steps). (h) NaHMDS, MeI, THF (70%). (i) LiOH, H2O2, THF±H2O (4:1) (92%). (j) (COCl)2, Et3N, CH2Cl2
(75%). (k) (1R,2S)-(+)-2,10-Camphorsultam, NaH, toluene (88%). (l) n-BuLi, MeI, THF±HMPA (81%). (m) LiOH,
.
H2O2, THF±H2O (63%). (n) EDC, MeO(Me)NH HCl, i-Pr2NEt, DMAP, CH2Cl2 (80%). (o) CH2ˆCHMgBr, THF.
(p) LiClO4, (+)-CSA, Et2O±THF (83% two steps). (q) Tebbe reagent [Cp2Ti(Cl)CH2AlMe2], toluene±THF (quant.).
Conversion of (S)-12 to the pheromone (1S,3S,7R)-1 followed the route previously employed
for the synthesis of (þ)-1.6 The (S)-acid 12 yielded the corresponding N-methoxy-N-methylamide
16 [18% overall yield based on 3 (10 steps)] by treatment with N,O-dimethylhydroxylamine
hydrochloride under the Weinreb conditions.18 Treatment of 16 with vinylmagnesium bromide
furnished 17. Because our attempts to achieve asymmetric Diels±Alder reaction of 17 by means of
chiral Lewis acid catalysis were all fruitless, 17 was cyclized under the Grieco conditions19 in the
presence of lithium perchlorate and (+)-camphor-10-sulfonic acid in diethyl ether and THF to give
18 as a 55.1:44.9 mixture of the rings A/B cis- and trans-adducts. Precise GC analysis on Chirasil-
DEX1-CB of the mixture revealed its composition as shown in the bottom part of Scheme 2.

5246
Scheme 3. Synthesis of (R)-25. Reagents: (a) MeCH(Me)CO2Me, LDA, THF (93%). (b) DIBAL-H, CH2Cl2 (88%).
(c) Dess±Martin Periodinane, CH2Cl2 (78%). (d) CH2ˆC(Me)CH2PPh3+Cl^, t-BuOK, THF (69%). (e) TBAF, THF
(81%). (f) LiAlH4, THF (82%)
Disappointingly, the desired 18 was the second minor product. Fortunately, however, the S con-
®guration at C-3 was almost perfectly retained (vide infra). Further puri®cation of the stereo-
isomeric mixture of 18 by MPLC a€orded pure (1S,3S,7R)-18 ‰ꢀŠ2D2=+166 (c=0.32, CHCl3), ca.
99% ee as checked by GC on Chirasil-DEX1-CB. This (1S,3S,7R)-ketone 18 exhibited a strong
positive Cotton e€ect [lmax=297 nm, D"=+1.55 (c=0.032 M in hexane)] in accordance with our
earlier resolution and CD studies on 18.8 Finally, methylenation of (1S,3S,7R)-18 with Tebbe
reagent20,21 a€orded (1S,3S,7R)-3-methyl-ꢀ-himachalene (1) ‰ꢀŠD21=+181 (c=0.32, CHCl3), ca.
99% ee as determined by chiral GC on Chirasil-DEX1-CB. The spectral data [IR, MS, 1H NMR
(500 MHz) and 13C NMR (126 MHz)] of (1S,3S,7R)-1 were identical with those reported for (þ)-1.
The overall yield of (1S,3S,7R)-1 was 12% based on 12 (four steps) or 2.7% based on 3 (13 steps).
It should be added that the naturally occurring (1R,7R)-a-himachalene (B) was reported to be
levorotatory: ‰ꢀŠ2D5=^192.3 (CHCl3).9
In conclusion, the enantioselective synthesis of (1S,3S,7R)-(+)-3-methyl-a-himachalene (1)22
was achieved to give highly enantiomerically pure 1, although there is still room for improvement
in the eciency of the overall process.
Acknowledgements
We thank Professor J. A. Pickett (IACR-Rothamsted, U.K.) for his cooperation. We
acknowledge the ®nancial support of this work by a Grant-in-Aid for Scienti®c Research (No.
11480165), Japanese Ministry of Education, Science, Sports, and Culture.
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