Synthesis of Pheromones: Highlights from 2002-2004
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Current Organic Chemistry, 2009, 13, 299-338 299 Synthesis of Pheromones: Highlights from 2002-2004 P. H. G. Zarbin1,*, J. A. F. P. Villar1, I. Marchi1, J. Bergmann2 and A. R. M. Oliveira1 1Departamento de Química, Universidade Federal do Paraná, CP 19081, 81531-990, Curitiba-PR, Brazil 2Instituto de Química, Pontificia Universidad Católica de Valparaíso, Avenida Brasil 2950, Valparaíso, Chile Abstract: This review summarizes the synthesis of pheromones published in the triennium 2002-2004. The syntheses of a total of 66 pheromone compounds (65 from insects, 1 from a crustacean species), belonging to 9 different structural cate- gories, are presented in schemes. New methodologies, but also well-known reactions have been employed to achieve the (in many cases stereoselective) synthesis of the compounds. 1. INTRODUCTION The chemical structures of pheromones identified so far are diverse and their complexity ranges from simple n- Since its very beginnings in the mid 19th century, or- alkanes to highly complex molecules bearing (multiple) cy- ganic chemistry has made advances unimaginable to the clic substructures, double or triple bonds, heteroatoms, early pioneers of the field. Among the experimental key and/or (multiple) stereogenic centers. In many cases, only techniques contributing to these advances are chromatogra- one stereoisomer or a defined mixture of stereoisomers is phy, which made possible the separation of complex mix- biologically active, while the unnatural isomers or a different tures, and spectroscopic (UV, IR, NMR) and mass spectro- ratio of isomers may be inactive or even inhibit the response metric methods, giving organic chemists powerful tools for to the natural compounds. Against this background, methods the structure determination of organic compounds. This, in are required which lead in high yields and with high stereo- turn, stimulated research in organic synthesis, as products selectivity to the desired compounds. Pheromone syntheses and by-products of reactions could be easily isolated and published over the last few decades have been reviewed re- characterized. As once stated by Meinwald, “Organic chem- peatedly. The most comprehensive reviews are probably istry blossomed into a self-contained, inward-looking sci- those written by Mori in 1981 and 1992 [2, 3]. Other ac- ence, bringing order and understanding to the synthesis and counts, relating pheromone synthesis to specific topics [4-6] reactions of millions of compounds” [1]. This order and un- and a partial, nevertheless impressive update [7] were pub- derstanding allowed the development of countless reactions lished by the same author. Most recently, and reflecting a of carbon-carbon bond formation or modification of func- growing branch in organic synthesis, the application of bio- tional groups, applicable to all classes of organic molecules, catalysis to the synthesis of pheromones has been reviewed which would later eventually be modified or improved, e.g. [8]. in terms of scope, yields, reaction conditions, or stereo- chemical selectivities. Research in chemical communication In this article, we review the syntheses of pheromones has been profiting from these decade-lasting and ongoing published in the triennium 2002-2004. The aim is to provide efforts, as the synthesis of pheromones is of great importance a comprehensive overview of the syntheses, and we sin- in the process of identifying these chemical messengers. cerely apologize to the authors of those articles which may Moreover, a sort of mutualism has been evolving, as many have escaped our attention. The presentation of the syntheses new synthetic methods have been developped with the ex- is done according to the compound class of the respective plicit aim to improve the synthetic route towards a phero- target compound, adopting the style established by Mori [3]. mone. 2. SYNTHESIS OF ALKANES AS PHEROMONES Pheromones are compounds which are produced and lib- erated by an individual, provocing a behavioural or physio- 2.1. 5,9-Dimethylpentadecane (1) logical response in another individual of the same species. The coffee leaf miner, Leucoptera coffeella, is an eco- As pheromones are usually produced in minute amounts, nomically important pest of coffee trees in Brazil. It has been thus preventing crystallographic or extensive NMR experi- demonstrated by Francke and co-workers [9] that the main ments, their independent synthesis is required to confirm the component of the female-produced sex pheromone of this identification and to establish the absolute configuration in species is 5,9-dimethylpentadecane (1), however, the stereo- case of chiral compounds. Furthermore, chemical synthesis chemistry of the natural pheromone remains unknown. of pheromones provides the amounts necessary for the evaluation of their biological activity in the laboratory or in Moreira and Corrêa [10] described an enantioselective the field. synthesis of three stereoisomers of 1, from commercial isopulegol and synthetic neo-isopulegol [11, 12] (Scheme 1). Zarbin et al. [13] described a straightforward synthesis of *Address correspondence to this author at the Departamento de Química, racemic 1 employing an unsymmetrical double Wittig olefi- Universidade Federal do Paraná, CP 19081, 81531-990, Curitiba-PR, Brazil; Tel: +55 41 33613174; Fax: +55 41 33613186; nation as the key reaction to build the carbon skeleton of the E-mail: [email protected] 1385-2728/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd. 300 Current Organic Chemistry, 2009, Vol. 13, No. 4 Zarbin et al. 1) B2H6 1) NaH, BnBr, THF, 83% OH O 2) H2O2, NaOH, OH 2) PCC, CH2Cl2, 93% H O THF, 0 °C, 84% H 3) m-CPBA/NaHCO , 75% OH 3 (-)- isopulegol OBn 1) MeOH, H+(cat), 93% OTs 2) TsCl, Py, 72% n-BuMgBr, Li2CuCl4 3) LiAIH , THF 4 THF, -78 oC, 90% 4) TsCl, Py, 93% OBn OBn 1) H2, Pd/C, MeOH, 73% n-PrMgBr, Li CuCl 2 4 2) MsCl, Py, CH2Cl2, 91% o THF, -78 C, 90% OMs (5S,9S) - 1 n-BuMgBr, From (+)-neoisopulegol Li2CuCl4 similarly OTs OBn (5R,9S) - 1 OBn EtMgBr, Li2CuCl4 OBn Scheme 1. (5S,9R) - 1 2.1 equiv PPh3, DMF, 92% Br Br BrPh3P PPh3Br 1) 1.1 equiv n-BuLi, - 90 oC 2) 1 equiv 2-octanone, - 90 oC to rt. 3) 1.1 equiv n-BuLi, -90 oC 4) 1 equiv 2-hexanone, -90 oC to rt., 64% H , Pd/C, 2 hexane, 93% 1 54% overall yield Scheme 2. molecule. The bis-phosphonium salt obtained from 1,3- 2.2. (S)-9-Methylnonadecane (2) and meso-13,23- dibromopropane and triphenylphosphine, was reacted con- dimethylpentatriacontane (3) secutively with the ketones 2-octanone and 2-hexanone, af- (S)-9-Methylnonadecane (2) is a sex pheromone compo- fording the asymmetric diene, which was readily hydrogen- ated over Pd/C, furnishing 1 in 54% overall yield (Scheme nent of the cotton leafworm Alabama argillacea [14], and meso-13,23-dimethylpentatriacontane (3), is the sex phero- 2). Synthetic 1 showed high biological activity when tested mone of the tse tse fly Glossina pallidipes [14]. in field experiments. Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 4 301 H O O H H Ref. [16] CBr4, PPh3, CH2Cl2, 78% H H H H H HO Br O OH O 1) m-CPBA, MgSO4, CH2Cl2 1) NaOEt, NaBH4, EtOH, 77% 2) PTSA, EtOH, 59% overall 2) H2, Pd/C, EtOAc, 83% H Br O 1) PCC, CH2Cl2, 78% HO + - O 2) [C7H15PPh3] I , n-BuLi, o THF, -78 C, 98% A 1) DIBAL-H, toluene, -78oC, 86% O ( )8 ( )6 + - 2) [C2H5PPh3] I , n-BuLi, THF, O o -78 C, 92% 3) H2, Pd/C, EtOAc, 95% 2 1) PCC, CH2Cl2, 78% A ( )7 O + - 2) [C9H19PPh3] I , n-BuLi, THF, -78oC, 89% 3) DIBAL-H, toluene, -78 oC, 80% B 1) TBDPSCl, imidazole, DMAP, DMF, 81% 1) TBAF, THF, 94% A TBDPSO ( ) ( ) o 3 4 2) DIBAL-H, toluene, -78 C, 80% 2) I2, PPh3, imidazole, CH3CN, + - o 3) [C6H13PPh3] I , n-BuLi, Et2O, 0 C to rt. 87% o THF, -78 C, 89% 3) PPh3, toluene, reflux, 80% o 1) n-BuLi, THF, B, -78 C IPh3P ( )4 2) H2, Pd/C, 99% ( )10 ( )10 3 Scheme 3. Lamers et al. [15] reported the synthesis of these two [20] described the synthesis of a mixture of all isomers of 4 pheromones starting from the readily available (+)- in 6 steps, starting from hepta-1,6-diene. Pure (R,R)-4 was aromadendrene via the chiral intermediate A [16] (Scheme synthesized by hydrolytic kinetic resolution of the bisepox- 3). ide obtained from hepta-1,6-diene using 1.4 % equiv. of [(R,R)-(salen)Co(III)(OAc)]-Z complex (Fig. 1), followed by 2.3. 7,11-Dimethylheptadecane (4) a Grignard reaction and methylation (Scheme 4). The hydrocarbons 7-methylheptadecane and 7,11- dimethylheptadecane (4) have been identified as constituents 3. SYNTHESIS OF ALKENES AS PHEROMONES of the female-produced sex pheromone of the spring hem- 3.1. (6Z,9Z)-Heneicosa-6,9-diene (5), (3Z,6Z,9Z)- lock looper (Lambdina athasaria) and the pitch pine looper heneicosa-3,6,9-triene (6), and heneicosane (7) (L. pellucidaria) [17, 18]. Subsequently, bioassays con- firmed that (S)-7-methylheptadecane and meso-4, that is (6Z,9Z)-Heneicosa-6,9-diene (5), (3Z,6Z,9Z)-heneicosa- (7S,11R), are the bioactive stereoisomers [19]. Chow et al. 3,6,9-triene (6), and heneicosane (7), have been identified as 302 Current Organic Chemistry, 2009, Vol. 13, No. 4 Zarbin et al. 1) n-C5H11MgBr, CuI, O O OO m-CPBA, CH2Cl2 Et2O ( ) 5 ( )5 2) Jones Reagent. 1) MeMgI, Et2O ( )4 H2, Pd/C ( )5 ( )5 ( )5 2) DMSO racemic and meso-4 OH OOO OH + OO1) (R,R)-Z, H2O OH OH + HO OH 1) n-C5H11MgBr, CuI OMs OMs OO Me2CuLi, ( )5 ( )5 ( )5 ( ) 2) MsCl, Et3N 5 Et2O (R,R)-4 Scheme 4. H H H H N H2O N N H2O N Co Co tBu O O tBu tBu O O tBu OAc OAc tBu tBu tBu tBu (R,R)-Z (S,S)-Z Fig.