Total Synthesis of the Sex Pheromone of Clania variegata Snellen and Its Stereoisomers.

The paulownia bagworm, Clania variegata Snell, is an economically important pest of agriculture and forests. The sex pheromone of this pest and its stereoisomers were synthesized, and two of the stereoisomers were prepared for the first time. Our strategy was efficient and mainly included the ring-opening reaction of (S)-2-methyloxirane, the coupling of chiral sulfonate, the oxidative cleavage of olefin, and Yamaguchi esterification. Moreover, the overall yields of our synthesis were 23-29%, with eight steps in the longest route.

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.

Asymmetric Synthesis of Three Alkenyl Epoxides: Crafting the Sex Pheromones of the Elm Spanworm and the Painted Apple Moth.

A concise synthesis of the sex pheromones of elm spanworm as well as painted apple moth has been achieved. The key steps were the alkylation of acetylide ion, Sharpless asymmetric epoxidation and Brown's P2-Ni reduction. This approach provided the sex pheromone of the elm spanworm (1) in 31% total yield and those of the painted apple moth (2, 3) in 26% and 32% total yields. The ee values of three final products were up to 99%. The synthesized pheromones hold promising potential for use in the management and control of these pests.

Total synthesis of four stereoisomers of methyl 4,8,12-trimethylpentadecanoate, a major component of the sex pheromone of the stink bug Edessa meditabunda.

The male-produced sex pheromone of the stink bug Edessa meditabunda was previously identified as a mixture of the esters methyl 4,8,12-trimethylpentadecanoate (1) and methyl 4,8,12-trimethyltetradecanoate (2), produced in a ratio of 92 : 8, respectively. Bioassays showed that the synthetic major compound alone is sufficient to elicit a response from females, and that it is as attractive as the natural extract. Here we present a stereoselective synthesis of four stereoisomers of methyl 4,8,12-trimethylpentadecanoate. The synthetic route was based on the connection of three chiral building blocks. High stereoisomeric purity was achieved by using commercially available compounds with defined stereochemistry, (R) and (S)-citronellol and methyl (S)-3-hydroxy-2-methylpropionate. Different stereoisomers were synthesized by swapping the sequence in which the building blocks were inserted into the synthetic route. The key steps in the synthesis were coupling reactions using the Fouquet-Schlosser variant of the Grignard reaction. Although the absolute configuration of the natural product remained elusive due to chromatographic inseparability of the stereoisomers, the syntheses gave access to both enantiomers of the biosynthetically most likely stereoisomer syn,syn-1, while all other stereoisomers can be efficiently synthesized by our straightforward approach.

Female-Produced Sex Pheromone of Tetrastichus planipennisi, a Parasitoid Introduced for Biological Control of the Invasive Emerald Ash Borer, Agrilus planipennis.

The Asian eulophid wasp Tetrastichus planipennisi is being released in North America as a biocontrol agent for the emerald ash borer (Agrilus planipennis), a very destructive invasive buprestid beetle that is devastating ash trees (Fraxinus spp.). We identified, synthesized, and tested a female-produced sex pheromone for the wasp. The key component eliciting behavioral responses from male wasps in flight tunnel bioassays was identified as (6S,10S)-(2E,4E,8E)-4,6,8,10-tetramethyltrideca-2,4,8-triene. Female specificity was demonstrated by gas chromatographic (GC) comparison of male and female volatile emissions and whole body extracts. The identification was aided by coupled gas chromatography/mass spectrometry analysis, microchemical reactions, NMR, GC analyses with a chiral stationary phase column, and matching GC retention times and mass spectra with those of synthetic standards. The tetramethyl-triene hydrocarbon was synthesized as a mixture of two enantiomeric pairs of diastereomers, and as the pure insect-produced stereoisomer. In flight-tunnel bioassays, males responded to both the natural pheromone and the chiral synthetic material by upwind flight and landing on the source. In contrast, the mixture of four stereoisomers was not attractive, indicating that one or more of the "unnatural" stereoisomers antagonized attraction. Field trials, using yellow pan traps baited with natural pheromone, captured significantly more male wasps than control traps over a four week trial. The identified pheromone could increase the efficiency and specificity of the current detection methods for Tetrastichus planipennisi and aid in the determination of parasitoid establishment at release sites.

Synthesis of the Sex Pheromone of the Oleander Scale ( Aspidiotus nerii).

A total synthesis of the oleander scale [ Aspidiotus nerii (Bouche)] sex pheromone, the unique sesquiterpenoid containing a cyclobutane moiety of this class of compounds, has been developed. In order to implement this sex pheromone as a new environmentally friendly tool to manage this pest, a more cost-effective, multigram synthesis was required. This new synthetic route, having a Blaise reaction, iron-catalyzed carbon-carbon coupling, and [2 + 2] photocycloaddition reactions as key steps, provides a general access to 4-alkyl lactones as well as a robust access to the target sex pheromone. Starting from readily available compounds as 3-hydroxypropanenitrile, ethyl bromoacetate, and 2-acetyl butyrolactone, the synthetic sequence afforded the A. nerii sex pheromone with minimum intermediate purification and good overall yield in nine linear steps.

Facile and Efficient Syntheses of (11Z,13Z)-Hexadecadienal and Its Derivatives: Key Sex Pheromone and Attractant Components of Notodontidae.

Syntheses of (11Z,13Z)-hexadecadienal (1), (11Z,13Z)-hexadecadienol (2), (11Z,13Z)-hexadecadien-1-yl acetate (3), and (Z)-13-hexadecen-11-ynal (4) from commercially available starting material 10-bromo-1-decanol are reported. These (Z,Z)-dienes and conjugated en-yne moieties are common in sex pheromone and attractant components for many Notodontide insect pests. The synthetic scheme, using the C10 + C3 + C3 strategy, was mainly based on three key steps: alkylation of lithium alkyne under a low temperature, cis-Wittig olefination of the aldehyde with propylidentriphenylphosphorane, and hydroboration-protonolysis of alkyne. This synthetic route provided (11Z,13Z)-hexadecadienal (1) in a 23.0% total yield via an eight-step sequence, alcohol (2) in a 21.9% total yield, acetate (3) in a 21.4% total yield, and (Z)-13-hexadecen-11-ynal (4) in a 34.7% total yield. This simple strategy provides a new way to achieve syntheses of the key sex pheromones of Notodontide insect pests.

Aggregation Pheromone of the Bearded Weevil, Rhinostomus barbirostris (Coleoptera: Curculionidae): Identification, Synthesis, Absolute Configuration and Bioactivity.

The bearded weevil, Rhinostomus barbirostris (Coleoptera: Curculionidae: Dryophthorinae), attacks coconut trees, oil palms and other species of Arecaceae. Besides direct damage, R. barbirostris may be a vector of diseases in coconut and oil palms, such as stem bleeding (resinosis) and red ring disease. Currently, the only method to control this weevil is by visual observation of damage and removal of infected plants. Semiochemical-based trapping could improve the effectiveness of monitoring and management of R. barbirostris. In comparisons of volatiles released by R. barbirostris males and females by gas chromatography (GC) two male-specific compounds were observed. GC-mass spectrometry (MS) and GC-Fourier transform-infrared (FTIR) analyses of the natural compounds suggested these were diastereoisomers of 5-hydroxy-4-methylheptan-3-one, also known as sitophilure, a pheromone component of other dryophthorine species. Synthesis of the mixture of all four stereoisomers of sitophilure was performed in two steps, and the chemical structures were confirmed by comparing GC retention times and MS and FTIR spectra of natural and synthetic compounds. The absolute configurations of the two male-specific compounds were elucidated by enantioselective GC; the major component was the (4S,5R)-isomer, and the minor component (4S,5S)-sitophilure. In analyses by GC-electroantennography (EAG) the antennae of male and female R. barbirostris only responded to the (4S,5R)-isomer of the synthetic sitophilure. The stereoisomeric mixture of sitophilure was attractive to both sexes of R. barbirostris in laboratory experiments in the presence of sugar cane volatiles, and a similar result was obtained in a preliminary field trapping test.

Asymmetric spiroacetalization catalysed by confined Brønsted acids.

Acetals are molecular substructures that contain two oxygen-carbon single bonds at the same carbon atom, and are used in cells to construct carbohydrates and numerous other molecules. A distinctive subgroup are spiroacetals, acetals joining two rings, which occur in a broad range of biologically active compounds, including small insect pheromones and more complex macrocycles. Despite numerous methods for the catalytic asymmetric formation of other commonly occurring stereocentres, there are few approaches that exclusively target the chiral acetal centre and none for spiroacetals. Here we report the design and synthesis of confined Brønsted acids based on a C(2)-symmetric imidodiphosphoric acid motif, enabling a catalytic enantioselective spiroacetalization reaction. These rationally constructed Brønsted acids possess an extremely sterically demanding chiral microenvironment, with a single catalytically relevant and geometrically constrained bifunctional active site. Our catalyst design is expected to be of broad utility in catalytic asymmetric reactions involving small and structurally or functionally unbiased substrates.

Synthesis of the Sex Pheromone of the Tea Tussock Moth Based on a Resource Chemistry Strategy.

Synthesis of the sex pheromone of the tea tussock moth in 33% overall yield over 10 steps was achieved. Moreover, the chiral pool concept was applied in the asymmetric synthesis. The synthesis used a chemical available on a large-scale from recycling of wastewater from the steroid industry. The carbon skeleton was constructed using the C4+C5+C8 strategy. Based on this strategy, the original chiral center was totally retained.

Female Sex Pheromone of the Cone Moth, Dioryctria mendacella: Investigation of Synergism between Type I and Type II Pheromone Components.

Polyunsaturated hydrocarbons (Type II pheromone components) have been reported to be synergists for unsaturated acetates, alcohols or aldehydes (Type I components) in the sex pheromones of several species of Lepidoptera. However, there is some debate over whether the active components are the hydrocarbons themselves or more volatile degradation products. Extracts of pheromone glands of adult females of the cone moth, Dioryctria mendacella (Lepidoptera: Pyralidae), contain (Z,E)-9,11-tetradecadienyl acetate (ZE9,11-14:Ac) and at least ten times as much (Z,Z,Z,Z,Z)-3,6,9,12,15-pentacosapentaene (ZZZZZ3,6,9,12,15-25:H). The former elicits a strong electroantennogram response from males while no response could be recorded to the latter. In field trapping tests, both compounds were individually unattractive to male D. mendacella moths, but blends of the two compounds containing at least a 10:1 ratio of ZZZZZ3,6,9,12,15-25:H : ZE9,11-14:Ac were highly attractive. The relatively involatile hydrocarbon was shown to be released from the dispensers used and no significant degradation could be detected. Furthermore, blends of ZE9,11-14:Ac and analogs of ZZZZZ3,6,9,12,15-25:H with fewer carbons and/or double bonds that might be expected to produce similar degradation products to ZZZZZ3,6,9,12,15-25:H were unattractive. This indicated a specific response to the hydrocarbon itself, further substantiated by the observation that related hydrocarbons did not interfere with the activity of ZZZZZ3,6,9,12,15-25:H. Thus a three-step conversion of fish oil was used to produce a blend of unsaturated hydrocarbons containing ZZZZZ3,6,9,12,15-25:H as the major component, albeit only 30% of the total, and a blend of this material with ZE9,11-14:Ac was as attractive to male D. mendacella moths as blends with an equivalent amount of the purified material. This mixture of unsaturated hydrocarbons is much cheaper to produce than the pure pentaene, and may be useful in lures for other species using these compounds. Dioryctria mendacella is a major constraint to production of edible pine kernels throughout the Mediterranean region. Pheromone traps will provide a means to improve monitoring of seasonal flight patterns and changes in population abundance of this pest.

Total Synthesis, Stereochemical Assignment, and Field-Testing of the Sex Pheromone of the Strepsipteran Xenos peckii.

The sex pheromone of the endoparasitoid insect Xenos peckii (Strepsiptera: Xenidae) was recently identified as (7E,11E)-3,5,9,11-tetramethyl-7,11-tridecadienal. Herein we report the asymmetric synthesis of three candidate stereostructures for this pheromone using a synthetic strategy that relies on an sp(3) -sp(2) Suzuki-Miyaura coupling to construct the correctly configured C7-alkene function. Comparison of (1) H NMR spectra derived from the candidate stereostructures to that of the natural sex pheromone indicated a relative configuration of (3R*,5S*,9R*). Chiral gas chromatographic (GC) analyses of these compounds supported an assignment of (3R,5S,9R) for the natural product. Furthermore, in a 16-replicate field experiment, traps baited with the synthetic (3R,5S,9R)-enantiomer alone or in combination with the (3S,5R,9S)-enantiomer captured 23 and 18 X. peckii males, respectively (mean±SE: 1.4±0.33 and 1.1±0.39), whereas traps baited with the synthetic (3S,5R,9S)-enantiomer or a solvent control yielded no captures of males. These strong field trapping data, in combination with spectroscopic and chiral GC data, unambiguously demonstrate that (3R,5S,9R,7E,11E)-3,5,9,11-tetramethyl-7,11-tridecadienal is the X. peckii sex pheromone.

Mating Disruption of a Carpenter Moth, Cossus insularis (Lepidoptera: Cossidae) in Apple Orchards with Synthetic Sex Pheromone, and Registration of the Pheromone as an Agrochemical.

Mating disruption of the carpenter moth, Cossus insularis (Staudinger) (Lepidoptera: Cossidae), with a synthetic version of its sex pheromone, a mixture of (E)-3-tetradecenyl acetate and (Z)-3-tetradecenyl acetate, was tested for three successive years in apple (Malus domestica Borkh.) orchards. Pheromone trap catches, percentage mating of tethered females and females enclosed with males in a mating cage, and tree damage were measured in both the pheromone-treated and untreated control orchards. The attraction of male moths to pheromone traps at heights of 1.5, 3, and 5 m was strongly disrupted when the pheromone dispensers were placed at 1.5 m height. Mating of tethered females placed at 1 m was completely inhibited, and the mating of tethered females at a height of 3 m was significantly reduced by the treatment in comparison to matings in an untreated control orchard. Similarly, mating of pairs of moths enclosed in mating cages was significantly reduced by the synthetic pheromone treatment in comparison to controls. The percentage of damaged trees in the pheromone-treated orchard also decreased significantly over the course of the experiment. These results suggest that mating disruption with the synthetic sex pheromone appears promising for reducing damage caused by C. insularis in apple orchards in Japan, and a commercial mating disruption product has been developed and registered.

Sex and Aggregation-Sex Pheromones of Cerambycid Beetles: Basic Science and Practical Applications.

Research since 2004 has shown that the use of volatile attractants and pheromones is widespread in the large beetle family Cerambycidae, with pheromones now identified from more than 100 species, and likely pheromones for many more. The pheromones identified to date from species in the subfamilies Cerambycinae, Spondylidinae, and Lamiinae are all male-produced aggregation-sex pheromones that attract both sexes, whereas all known examples for species in the subfamilies Prioninae and Lepturinae are female-produced sex pheromones that attract only males. Here, we summarize the chemistry of the known pheromones, and the optimal methods for their collection, analysis, and synthesis. Attraction of cerambycids to host plant volatiles, interactions between their pheromones and host plant volatiles, and the implications of pheromone chemistry for invasion biology are discussed. We also describe optimized traps, lures, and operational parameters for practical applications of the pheromones in detection, sampling, and management of cerambycids.

A Sea Lamprey (Petromyzon marinus) Sex Pheromone Mixture Increases Trap Catch Relative to a Single Synthesized Component in Specific Environments.

Spermiating male sea lamprey (Petromyzon marinus) release a sex pheromone, of which a component, 7α, 12α, 24-trihydoxy-3-one-5α-cholan-24-sulfate (3kPZS), has been identified and shown to induce long distance preference responses in ovulated females. However, other pheromone components exist, and when 3kPZS alone was used to control invasive sea lamprey populations in the Laurentian Great Lakes, trap catch increase was significant, but gains were generally marginal. We hypothesized that free-ranging sea lamprey populations discriminate between a partial and complete pheromone while migrating to spawning grounds and searching for mates at spawning grounds. As a means to test our hypothesis, and to test two possible uses of sex pheromones for sea lamprey control, we asked whether the full sex pheromone mixture released by males (spermiating male washings; SMW) is more effective than 3kPZS in capturing animals in traditional traps (1) en route to spawning grounds and (2) at spawning grounds. At locations where traps target sea lampreys en route to spawning grounds, SMW-baited traps captured significantly more sea lampreys than paired 3kPZS-baited traps (~10% increase). At spawning grounds, no difference in trap catch was observed between 3kPZS and SMW-baited traps. The lack of an observed difference at spawning grounds may be attributed to increased pheromone competition and possible involvement of other sensory modalities to locate mates. Because fishes often rely on multiple and sometimes redundant sensory modalities for critical life history events, the addition of sex pheromones to traditionally used traps is not likely to work in all circumstances. In the case of the sea lamprey, sex pheromone application may increase catch when applied to specifically designed traps deployed in streams with low adult density and limited spawning habitat.

(2S,4E)-2-Hydroxy-4-octen-3-one, a Male-Produced Attractant Pheromone of the Cerambycid Beetle Tylonotus bimaculatus.

We report the identification of a novel pheromone structure from males of the cerambycid beetle Tylonotus bimaculatus Haldeman (Cerambycinae: Hesperophanini), a species native to eastern North America. Volatiles collected from adult males contained (2S,4E)-2-hydroxyoct-4-en-3-one (71%), (3R,4E)-3-hydroxyoct-4-en-2-one (15%), (E)-4-octen-2,3-dione (13%), and 2,3-octanedione (1.5%). Four independent field bioassays with synthetic compounds confirmed that adults of both sexes were attracted by the racemate of the major component, (E)-2-hydroxyoct-4-en-3-one. No other cerambycid species were attracted in significant numbers. Attraction of both sexes is consistent with the male-produced pheromones of many other species in the subfamily Cerambycinae, but T. bimaculatus is unusual in having a pheromone chemistry that is so far unique among species in that subfamily.

Female sex pheromones of two Japanese saturniid species, Rhodinia fugax and Loepa sakaei: identification, synthesis, and field evaluation.

While 11 species in the family Saturniidae are found in Japan, no sex pheromones of the native species had been investigated previously. We collected larvae of Rhodinia fugax in Nagano and Tottori Prefecture, and of Loepa sakaei in Okinawa Prefecture, and extracted sex pheromones of these two species from virgin female moths. In gas chromatography-electroantennogram detection (GC-EAD) analyses, male antennae of each species responded to one component in the respective pheromone extracts of conspecific females. Chemical analyses of the extracts by GC/mass spectrometry revealed that the EAD-active compounds of R. fugax and L. sakaei were a hexadecadienal and a tetradecadienyl acetate, respectively. The two species belong to the subfamily Saturniinae, and the mass spectra of both were similar to that of the 6,11-hexadecadienyl acetate identified from Antheraea polyphemus, classified in the same subfamily, suggesting the same 6,11-dienyl structure for the C16 aldehyde and a 4,9-dienyl structure for the C14 acetate. Based on this assumption, four geometrical isomers of each dienyl compound were stereoselectively synthesized via acetylene intermediates, compared to the natural products, and tested in the field. Male catches confirmed the pheromone structures of the two Japanese saturniid species as (6E,11Z)-6,11-hexadecadienal for R. fugax and (4E,9Z)-4,9-tetradecadienyl acetate for L. sakaei. The compounds have a characteristic 1,6-dienyl motif common to the pheromones of Saturniinae species.

Synthesis and field evaluation of stereoisomers and analogues of 5-methylheptadecan-7-ol, an unusual sex pheromone component of the lichen moth, Miltochrista calamina.

Females of the lichen moth, Miltochrista calamina (Arctiidae, Lithosiinae), were previously shown to produce 5-methylheptadecan-7-ol (1) as a sex pheromone. In field tests, males were attracted only by the (5R,7R)-isomer of the four stereoisomers that were prepared by separation from two mixtures of diastereoisomers. A new route to (5R,7R)-1 starting from (S)-propylene oxide was developed utilizing the SN2 reaction of an optically active secondary tosylate and the Jacobsen hydrolytic kinetic resolution of an epoxide intermediate as key steps. Enantioselective HPLC analysis of the product and the antipode synthesized from (R)-propylene oxide confirmed their high enantiomeric excess (> 99 %). Using this stereospecific synthesis, six analogues with the same configuration as (5R,7R)-1 but with different alkyl chain(s) connected to the stereogenic centers were prepared in order to obtain GC/MS data and to examine the ability of M. calamina males to discriminate between them. The mass spectra of the synthetic analogues revealed characteristic fragment ions derived by cleavage around the methyl group in addition to that at the hydroxyl group. In field trapping tests, five out of the six compounds were attractive to male M. calamina moths, indicating that the males distinguished the configurations of methyl and hydroxyl groups but were less able to perceive differences in the lengths of the two alkyl chains in the pheromone.

Identification, synthesis, and behavioral activity of 5,11-dimethylpentacosane, a novel sex pheromone component of the greater wax moth, Galleria mellonella (L.).

The greater wax moth, Galleria mellonella (L.), is a serious and widespread pest of the honeybee, Apis mellifera L. In contrast to most moths, for which long-range mate finding is mediated by female-produced sex pheromones, G. mellonella males attract conspecific females over long distances by emitting large amounts of a characteristic scent in combination with bursts of ultrasonic calls. The male scent for this species was previously identified as a blend of nonanal and undecanal. When these compounds were bioassayed, characteristic short-range sexual behavior, including wing fanning, was triggered in conspecific females, but the aldehyde blend failed to elicit attraction over longer distances. We identified, via analysis and synthesis, a third male-specific compound, 5,11-dimethylpentacosane. We show that it acts as a behavioral synergist to the aldehydes. In wind tunnel experiments, very few female moths responded to the aldehyde blend or to 5,11-dimethylpentacosane tested separately, but consistently showed orientation and source contact when a combination of all three compounds was applied. The level of attraction to the three-component mixture was still lower than that to male extract, indicating that the composition of compounds in the synthetic blend is suboptimal, or that additional pheromone components of G. mellonella are yet to be identified. The identification of 5,11-dimethylpentacosane is an important step for the development of an efficient long-range attractant that will be integrated with other environmentally safe strategies to reduce damage to beehives caused by wax moths.

Enantiospecific synthesis and filed evaluation of four stereoisomers of 10,14-dimethyloctadec-1-ene, a sex pheromone component secreted by female moths of the apple leafminer.

All four stereoisomers of 10,14-dimethyloctadec-1-ene, a sex pheromone component of the apple leafminer (Lyonetia prunifoliella: Lepidoptera), were synthesized starting from (R)- and (S)-propylene oxide by applying stereospecific inversion of chiral secondary tosylates as a key step. Field evaluation showed that male moths of the Japanese population were selectively attracted by the (10S,14S)-isomer and that the activity was not inhibited by the enantiomer.