Enantioselective Synthesis of the Active Sex Pheromone Components of the Female Lichen Moth, Lyclene dharma dharma, and Their Enantiomers

The Lichen moth, Lyclene dharma dharma (Arctiidae, Lithosiinae), plays a significant role in forest ecosystem dynamics. A concise and novel method to synthesize the active sex pheromone components, (S)-14-methyloctadecan-2-one ((S)-1), (S)-6-methyloctadecan-2-one ((S)-2), and their enantiomers has been developed. Key steps in the synthesis include the use of Evans’ chiral auxiliaries, Grignard cross-coupling reactions, hydroboration–oxidation, and Wacker oxidation. The synthesized sex pheromone components hold potential value for studies on communication mechanisms, species identification, and ecological management.

Molecules 2024, 29, 2918 2 of 14 2-one with a total yield of 10% in seven steps, using (S)-3-butyn-2-ol as a chiral starting material, with a copper-catalyzed coupling reaction of alkynyl 2-pyridyl sulfonate and an alkyl lithium reagent as the key reaction [7].The reported synthetic routes still have some shortcomings, such as difficult synthetic routes, expensive chiral starting materials, complex synthetic operations, and poor overall yields.To facilitate future applications of the active sex pheromone components in exploring the communication mechanisms of Lichen moths, species-specific studies and ecological management, and developing a concise and efficient synthetic method, are still in demand [8].Herein, we synthesized the active sex pheromone components of Lyclene dharma dharma (Arctiidae, Lithosiinae) and their enantiomers by an enantioselective synthesis strategy.Our methodology employed Evans' chiral auxiliaries, a Grignard cross-coupling reaction, hydroboration-oxidation and Wacker oxidation as key reactions, enabled straightforward synthesis, and yielded the target pheromone with high enantiomeric purity.

Retrosynthetic Analysis
The retrosynthetic analysis of (S)-14-methyloctadecan-2-one ((S)-1) is delineated in Scheme 1.The target sex pheromone (S)-1 could be synthesized via Wacker oxidation of alkyl chiral terminal alkene (S)-12.The coupling of but-3-en-1-ylmagnesium bromide 11 with the sulfonate ester of chiral primary alcohol (S)-10 yielded (S)-12.Chiral primary The synthesis of the active sex pheromone components (S)-1, (S)-2, and their enantiomers ((R)-1, (R)-2) was previously based on a chiral pool strategy.In 2009, Mori com-pleted the synthesis of sex pheromone components in Lyclene dharma dharma, the synthesis of (S)-1 with a total yield of 6% in 13 steps, (S)-2 with a total yield of 20% in 11 steps, using enantiomers of citronellal and methyl (S)-3-hydroxy-2-methylpropanoate as chiral starting materials, with olefin cross metathesis as the key reaction [5].They then employed the Wittig reaction, alkylation of alkynes, and acetoacetic ester synthesis to construct sex pheromone components in Lyclene dharma dharma from (S)-and (R)-citronellal; they synthesized (S)-1 with a total yield of 11% in 15 steps, (S)-2 with a total yield of 10% in 13 steps [6].In 2023, Kobayashi and colleagues reported the synthesis of (S)-14-methyloctadecan-2-one with a total yield of 10% in seven steps, using (S)-3-butyn-2-ol as a chiral starting material, with a copper-catalyzed coupling reaction of alkynyl 2-pyridyl sulfonate and an alkyl lithium reagent as the key reaction [7].The reported synthetic routes still have some shortcomings, such as difficult synthetic routes, expensive chiral starting materials, complex synthetic operations, and poor overall yields.To facilitate future applications of the active sex pheromone components in exploring the communication mechanisms of Lichen moths, species-specific studies and ecological management, and developing a concise and efficient synthetic method, are still in demand [8].Herein, we synthesized the active sex pheromone components of Lyclene dharma dharma (Arctiidae, Lithosiinae) and their enantiomers by an enantioselective synthesis strategy.Our methodology employed Evans' chiral auxiliaries, a Grignard cross-coupling reaction, hydroboration-oxidation and Wacker oxidation as key reactions, enabled straightforward synthesis, and yielded the target pheromone with high enantiomeric purity.
Scheme 4. Synthesis of the active sex pheromone component (S)-1 and its enantiomer.

Synthesis of Bioactive Components of Sex Pheromone 2
Following the successful synthesis of the key intermediate (S)-16, we aimed to synthesize the target pheromone (S)-2 and its enantiomer (R)-2, as shown in Scheme 6. Compound (S)-16 was converted into the activated sulfonate ester through reaction with p-Scheme 5. Synthesis of chiral primary alcohol (S)-and (R)-16.
Scheme 6. Synthesis of the active sex pheromone component (S)-2 and its enantiomer.

General Information
All reactions were conducted under an inert argon atmosphere within a Schlenk line system.Commercially available reagents were used as received, while solvents were distilled prior to use according to standard procedures. 1 HNMR spectra (500 MHz, TMS at δ 0.00 ppm or CDCl3 at δ 7.26 ppm) and 13 CNMR spectra (126 MHz, CDCl3 at δ 77.16 ppm Scheme 6. Synthesis of the active sex pheromone component (S)-2 and its enantiomer.

Conclusions
To summarize, a concise and novel method to synthesize the active sex pheromone components of L. dharma dharma ((S)-1 and (S)-2) and their enantiomers was developed.We successfully synthesized the target sex pheromone component (S)-1 in seven steps with a total yield of 29%, and the target sex pheromone component (S)-2 in five steps with a total yield of 23%, and their optical purities were both greater than 99%.Compared with reported synthetic strategies, our synthetic route has the advantages of cheap starting materials, short route, high overall synthesis yield, and excellent optical purity of the target compound.Our strategy centrally employed Evans' chiral auxiliary to construct the stereocenter, while the pheromone skeleton was built efficiently through Grignard cross-coupling reactions, hydroboration-oxidation, and Wacker oxidation.The synthetic sex pheromone components will advance the study of communication mechanisms in lichen moths, species identification, and supported ecological management.

Figure 1 .
Figure 1.The active sex pheromone components of L. dharma dharma and their enantiomers.

Figure 1 .
Figure 1.The active sex pheromone components of L. dharma dharma and their enantiomers.

Scheme 4 .
Scheme 4. Synthesis of the active sex pheromone component (S)-1 and its enantiomer.