A New Asymmetric Synthesis of ( S )-14-Methyl-1-Octadecene,the Sex Pheromone of the Peach Leafminer Moth

Abstract

An asymmetric synthesis of 14-methyl-1-octadecene, the sex pheromone of the peach leafminer moth, has been efficiently achieved. A key chiral intermediate, (R)−4-(benzyloxy)−3-methylbutanal, which has been developed as the resource chemical, can be obtained in large quantities from the steroid industry. 1,11-Undecanediol is selectively masked, and then converted into a phosphonium salt derivative, thereby effectively constructing a carbon skeleton. The target molecule is synthesized in 8 linear steps, with a 42% yield. The key characteristic of our synthesis lies in its chiral-pool strategy.

Recently, there has been a sharp conflict between intense agricultural production and environmental issues. We all have to face the harmful environmental effects from traditional agricultural production. ¹ Therefore, there is an urgent demand for the development of a “green” production mode, such as low-dosage sex pheromones to control pests without the negative side effects. The peach leafminer moth (Lyonetia clerkella) is one of the most destructive pests in East Asia, and also feeds on pear, plum, and apple. ² It induces defoliation when the leaves are infested with only a few larvae. This has led a high demand for the use of sex pheromones to control its population by disrupting its mating process. Regarding chirality, the purity of the different enantiomers will change biological activity dramatically, but the provision of enantio-pure pheromones at low cost is still an unmet need in the industry.

Sugie et al. first isolated (S)−14-methyl-1-octadecene (1) (Figure 1) as the sex pheromone of the peach leafminer moth, ² and the synthesis of the racemic form of 1 was then achieved by a couple of teams. ^{3 -5} It was revealed that the S-isomer was active through lure experiments on peach leafminer moths, while the R-isomer was almost inactive. ⁶ Recently, Ando disclosed an informal synthesis of (±)−1, employing Schlosser’s copper-catalyzed Grignard reaction. ⁷ As for the asymmetric synthesis of 1, Mori used methylated paracyclonic acid obtained from microbial transformation as a chiral center; Reyes used (S, S)-(+)-pseudoephedrine to induce the chiral methyl. ⁸ Using the expensive chiral starting material (R)−4-menthenone, ⁹ Kharisov reported the asymmetric synthesis of (S)−1. However, a more economical synthesis of 1 is still needed, with a view to utilizing this kind of chemical to interfere with the mating process of the peach leafminer moth. ¹⁰

Figure 1

Chemical structure of the sex pheromone of the peach leafminer moth.

Our research group is committed to discovering a new method for the synthesis of the sex pheromone of the peach leafminer moth. ¹¹ We are interested in using more economical, effective, and natural chemical substances to synthesize the sex pheromone. After oxidative degradation of the green and environmentally friendly diosgenin Figure 2, a steroidal sapogenin obtained from Dioscorea zingiberensis (Dioscorea oppositifolia), ¹² (5R)−3-hydroxy-5-methyltetrahydro-2H-pyran-2-one, is obtained as a by-product. ¹³ In this article, we report our new synthetic method for (S)−1 through the chiral pool strategy. ¹⁴

Figure 2

Dioscorea oppositifolia and the resource chemicals.

The retrosynthetic analysis of 1 is shown in Figure 3. The molecule was disassembled into a C3 subunit, a chiral synthon C5 subunit, and a C11 moiety. The C5 subunit is one of the derivatives of the arsenal of resource chemicals. ^{15 -17} The C3 and C11moiety could be provided by phosphonium salt formation.

Figure 3

Retrosynthetic analysis of 1.

Results and Discussion

As shown in Scheme 1, our synthesis started from (R)−4-(benzyloxy)−3-methylbutanal (10), which can be obtained from (5R)−3-hydroxy-5-methyltetrahydro-2H-pyran-2-one 11. At −78 °C, the tetrahydrofuran (THF) solution of compound 9 was deprotonated by addition of n-butyllithium (n-BuLi), and then a solution of 10 (in THF) was added and allowed to react for 1 hour. After a conventional quench, an olefin (8) with high Z selectivity (Z/E ≥ 49:1) ¹⁸ could be obtained. Palladium on carbon (Pd/C) catalyzed compound 8 could effectively hydrogenate to remove benzyl (Bn) and double bonds. After Dess-Martin oxidation, compound 7 was transformed into aldehyde 6 in a very good yield. After a new round of the Wittig reaction with propyl ylide, a Z/E mixture of 5 was obtained. In the presence of tetrabutylammonium fluoride (TBAF), compound 5 removed the triisopropylsilyl (TIPS) group to obtain the Z/E mixture 4.

Scheme 1

Synthetic pathway for (S)−1.

With compound 3 secured, (S)−1 could be obtained through a set of functional group transformations. Firstly, alcohol 3 was changed to a bromide 2; then, after reacting with the big sterically hindered base KOBu-t, the final olefin 1 was obtained in fairly good yield. The physicial characters were identical with previous reports. (S)−14-Methyloctadec-1-ene (1). $[\alpha {]}_{\mathrm{D}}^{25}$ = +1.17° (c 1.82, n-hexane). $[\alpha {]}_{\mathrm{D}}^{25}$ = +0.9° (c 1, CHCl₃), lit. ^{8 1}H NMR (500 MHz, CDCl₃) δ = 5.86 (ddt, J = 16.9, 10.2, 6.7, 1 hour, CH₂ = CH), 5.04 (dd, J = 17.1, 1.5, 1 hour, CH=CH₂), 4.98 (dd, J = 10.2, 0.9, 1 hour, CH=CH₂), 2.09 (q, J = 6.9, 2 hours, CH₂), 1.42‐1.12 (m, 27 hours), 0.94 (t, J = 6.8, 3 hours, CH₃), 0.89 (d, J = 6.6, 3 hours, CH₃). ¹³C NMR (125 MHz, CDCl₃) δ 139.28, 114.08, 37.14, 36.82, 33.85, 32.77, 30.06, 29.75, 29.71, 29.70, 29.65, 29.54, 29.37, 29.19, 28.99, 27.12, 23.07, 19.74, 14.17.

Reagents and conditions: a) n-BuLi, THF, compound 9, -78°C~rt, 84%; b) H2, MeOH, Pd/C, rt, 95%; c) DMP, DCM, 0°C~rt, 93%; d) n-BuLi, THF, triphenyl(propyl)phosphonium iodide, -78°C ~rt, 83%; e) TBAF, DCM, 0°C ~rt, 93%; f) H2, MeOH, Pt/C, rt, 95%; g) CBr4, PPh3, DCM, 0°C~rt, 91%; h) KOBu-t, THF, 85%.

Conclusions

In summary, we have built the C-C skeleton of the pheromone of the peach leafminer moth through the ‘C3 +C5+C11’ strategy. The asymmetric total synthesis of the sex pheromone of peachleaf miner moth, (S)−14-methyl-1-octadecene was achieved with Wittig coupling and hydrogenation as the key steps in 42% overall yield, starting with (R)−4-(benzyloxy)−3-methylbutanal 10. In this synthesis, the chiral center was completely derived from the natural product (5R)−3-hydroxy-5-methyltetrahydro-2H-pyran-2-one. Because there was no step in the synthesis process to cause the racemisation of the stereoisomeric center, 98% (S)−1 can be considered as its e.e. The chirality of the natural molecules was fully retained.

Supplemental Material

Online supplementary file 1 - Supplemental material for A New Asymmetric Synthesis of (S)-14-Methyl-1-Octadecene, the Sex Pheromone of the Peach Leafminer Moth

Supplemental material, Online supplementary file 1, for A New Asymmetric Synthesis of (S)-14-Methyl-1-Octadecene, the Sex Pheromone of the Peach Leafminer Moth by Guo-Guo He, Si-Fan Liu, Bao-Qi Rao, Hong-Jin Bai and Zhen-Ting Du in Natural Product Communications