Insect Pheromone Synthesis in Brazil : an Overview

Nesta revisão estão descritas as sínteses de feromônios de insetos desenvolvidas e publicadas por grupos de pesquisa brasileiros, e tem por objetivo apresentar o estado da arte desta área de pesquisa no país e fornecer uma informação rápida sobre as moléculas já sintetizadas e metodologias empregadas. As sínteses estão apresentadas em ordem cronológica, exceto quando se trata de diferentes metodologias para a mesma molécula.


Introduction
The ever-increasing use of conventional pesticides leads to resistant pests, severely alters natural ecology, damages the environment and, ultimately, affects the economy adversely.The number of insect and other species developing resistance to pesticides is growing steadily, forcing chemical companies to develop novel pesticide formulas.In response to the problems caused by the increased use of conventional pesticides, the concept of integrated pest management (IPM) was developed.IPM combines chemical, biological and agrotechnical approaches to achieve pest control at a reasonable cost while minimizing damage to the environment.The first step in IPM is effective monitoring by the use of pheromones. 1 Pheromones are substances which occur in Nature and are used for chemical communication between animals.The term pheromone (from the Greek pherein = to transfer and hormon = to excite), coined by Karlson and Luscher, 2 is a substance which is secreted by an individual and received by a second individual of the same species, in which it releases a specific reaction, for example, a specific behaviour or a development process.The main ways of exploiting pheromones in pest control are: monitoring, mating disruption and mass trapping. 3Such pheromone applications provide significant cost reduction and environmental benefits to the farmer, to the consumer and to the society.
The first chemical identification of a pheromone took place in the late 1950s, after almost two decades of work by a team led by Butenandt. 4The team chose to study the domesticated silk moth, Bombyx mori, which could be reared in the enormous numbers needed.The silk moth pheromone was identified as (10E,12Z)-hexadecadien-1-ol (1), bombykol.This first sex pheromone identified was achiral, but in the late 1960s a number of chiral pheromones were discovered such as (+)-exo-brevicomin 2, the pheromone of the western pine beetle, Dendroctonus brevicomis 5 and (Z)-(-)-14-methylhexadec-8-en-1-ol (3), the sex attractant of female dermestid beetle, Trogoderma inclusum 6 (Figure 1).
An understanding of the relationship between structure and biological effect requires that the absolute configurations of the naturally occurring chiral pheromones are determined.It is now well established that pheromones are not always enantiomerically pure.Therefore, their enantiomeric composition must be determined in detail. 7ifficulties are often encountered in stereochemical studies of pheromones, because they are usually obtained in small quantities.Thus, organic synthesis plays an essential role on the pheromone chemistry, as it provides material for rigorous determination of the (absolute) configuration of the molecules and for carrying out extensive biological tests.The synthesis of compound 3 described in 1973 by Mori was the first successful identification of the absolute configuration of an insect pheromone by its enantioselective synthesis. 8,9][12][13][14][15][16][17] Rapid progress has been made in research on insect pheromones in Brazil during the last decade, including the identification, synthesis, biosynthesis and field evaluation of the bioactive compounds and continuing attempts are expected in the coming years. 18The growth of the field in Brazil naturally led to the organization of national meetings in the area.In December, 1999 the first Brazilian Meeting on Chemical Ecology (I EBEQ) was held at the Chemistry Department of Universidade Federal do Paraná and nowadays the community looks forward the fifth issue of the meeting, scheduled for October, 2007.As a consequence of the large diffusion of research results presented at I EBEQ, a special issue of the Journal of the Brazilian Chemical Society (2000,11(6)) was dedicated to Chemical Ecology.This issue features contributions from research groups from Brazil and abroad and provides an overview of the area in the late 1990s.
In this review, we summarize insect pheromone synthesis research in Brazil.The aim is to present the state of the art of this area in the country, and also to serve as an overview of the already synthesized molecules and employed methodology.The syntheses are presented in chronological order, except when they refer to different approaches for the same molecule.
Two other approaches to the synthesis of (-)-6 were also reported by Pilli and co-workers.In the first 31  homochiral lactone B in 6 steps, a known 32 precursor of (-)-6 (Scheme 4).In the second method, 33 a short preparation of enantiomerically enriched (80% e.e.) (-)-6 was developed in 8 steps and 13% overall yield, from methyl (R)-3-hydroxypentanoate readily prepared by baker´s yeast reduction of methyl 3-oxopentanoate in the presence of allyl alcohol as enzyme inhibitor (Scheme 5).
Pilli and Riatto 43 described later an asymmetric synthesis of (+)-sitophilure (8).The synthesis was carried out in 12 steps, in 18% overall yield and 82% enantiomeric excess, with the enzymatic reduction of methyl 3-oxopentanoate with S. cerevisiae in the presence of ethyl chloroacetate being used to generate the key chiral synthon (Scheme 8).

cis-2-Isopropenyl-1-methylcyclobutaneethanol (14) (Grandisol)
Grandisol ( 14) is the major component of the maleproduced pheromone of the cotton boll weevil, Anthonomus grandis. 19The alcohol and its corresponding aldehyde, grandisal, were also found in the pheromonal secretion of several other beetles. 57The potential use of this pheromone in traps for monitoring crop infestation in integrated pest management prompted research groups world wide to search for an efficient preparation of the more active (+)-enantiomer.
Monteiro and Stefani 61 described a stereoselective synthesis of (±)-grandisol (14)   16) In 1994, Aldrich and co-workers identified methyl 2,6,10-trimethyldodecanoate (15) and methyl 2,6,10trimethyltridecanoate (16) as components of the maleproduced sex pheromones of the stink bugs, Euschistus heros and Euschistus obscurus. 62,63The same compounds were later found in headspace volatiles from Brazilian male bug, Piezodorus guildinii, but the biological roles of these compounds in the species have not been delineated. 64,65A stereospecific synthesis of the eight stereoisomers of 16 was developed by Mori and Murata, 66 but the absolute configuration of this insect-produced compound was never reported.

1-Hydroxy-5-nonanone (17)
The hydroxy-ketone 17 was identified as a minor component of the rectal glandular extract and volatile emission of males of the fruit fly Bactrocera cacuminatus. 71erreira and Zarbin 72 described an expeditious synthesis of

3,5,6-Trimethyltetrahydropyran-2H-one (24)
Brown and Moore 85 reported the identification of δ-lactone 24 in the extract of male heads of Calomyrmex sp.ants, that was presumed to function as a sex pheromone.Pilli et al. 86 described the synthesis of four racemates of lactone 24.The anti-hydroxy ester A was produced through the stereoselective aldol condensation of the E-lithium enolate derived from 2,6-di-tert-butyl-4-methylphenyl propionate and acetaldehyde.Coumpoud A was converted into tosylate B, which was employed as commom intermediate in two different routes of the synthesis of δ-lactones 24a and 24b (Scheme 22).Similarly, a mixture of δ-lactones 24c and 24d was prepared starting with the stereoselective aldol condensation of acetaldehyde and the lithium enolate of the syn-selective silyloxyketone C (Scheme 23).Based on the comparison of mass spectra and gas chromatographic properties of lactones 24a-24d with those reported in the literature for the natural product, 85 the relative configuration was assigned as (3SR,5RS,6SR)-24.
In order to establish the importance of the stereochemistry on the biological activity of this compound, Zarbin et al. 107 described a new and highly enantioselective approach to the synthesis of natural (S)-30, starting from the easily available D-mannitol, in a route that employed the known (R)-glyceraldehyde acetonide as key intermediate.The GC analysis of an acetyl derivative of the final product, using a chiral stationary phase column, revealed an enantiomeric excess higher than 99.5% (Scheme 31).9][110] Santangelo et al. 111 reported the syntheses of all four possible isomers of 31 employing one starting material, 9-decen-1-ol, via divergent synthetic routes (17-26% overall yield) (Scheme 32).

5,9-Dimethylpentadecane (34)
The coffee leaf miner, Leucoptera coffeella, is an economically important pest of coffee trees in Brazil.It has been demonstrated by Francke and co-workers 117 that the main component of the female-produced sex pheromone of this species is 5,9-dimethylpentadecane (34), however, the stereochemistry of the natural pheromone remains unknown.
(E)-11-Hexadecen-1-ol (44) and (E)-11-hexadecenyl acetate (45) have been recently described by Zarbin et al. 138 as components of the sex pheromone of Lonomia obliqua, one of the most important urban insects in Brazil due to the urticanting spines in the larval stage.This moth has become of great importance in medicine because of the danger it represents. 139Compounds 44 and 45 were synthesized employing alkyne chemistry (23 -30% overall yield) (Scheme 43).

Conclusions and Perspectives
In conclusion, in the last 20 years projects involving Chemical Ecology and more specifically synthesis of insect pheromones have considerably grown in Brazil  (Figure 2).Several research groups are also working in isolation and identification of pheromones of Brazilian insect pests, which will certainly contribute for the development of the area in the near future.Control of insects using pheromones is a multidisciplinary approach and requires efforts on many facets.Nowadays, there is a greater demand to produce environmentally sound and chemical residue-free agricultural products, and the initial doubt and obstacles against using pheromones for pest management have been overcome in recent decades. 140n Brazil, the research and the development of this area is still concentrating in the Academia.The challenge today for the accurate monitoring and/or control of insects using pheromone is the production in large scale of the pheromone components and the development of proper dispenser system, which would decrease the price of the blends and stimulate their use in the field.This would be a prerequisite to be able to defeat the army of insects in the next decade.

Figure 2 .
Figure 2. Number of syntheses of insect pheromones developed and published by Brazilian research groups in the last two decades the oxazolidinone A was straightforwardly converted to the

Scheme 6.
in 19% overall yield, starting with a simple cyclobutyl derivative to which the methyl group and the 1,2-cis disposed side chains were appended through a remote alkylation protocol (Scheme 14).

Scheme 25.
as a minor pheromone component of the common wasp, Paravespula vulgaris.Zarbin et al.
in 65% overall yield, employing an organocuprate generated by tellurium/lithium exchange in the key step (Scheme 41).