Synthesis of Pheromones

Pheromone science is one of the new fields of science, whose development in the late 20th century was remarkable. Once chemists knew that the communications among a variety of organisms depend on chemical substances termed pheromones, they isolated, identified and synthesized hundreds of pheromones to use them practically for pest control. In this 21st century, practical application of pheromone science in bioindustries is being actively pursued all over the world. My synthetic works have been focused on this branch of science for almost 40 years. This chapter summarizes my works in pheromone science. 

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Construction of the carbon frameworks by using the activating property of the nitro group followed by denitration provides a useful tool for the preparation of various naniral products as shovm in Schemes 3 5-3 7 For example, fZ -jasmone and dihydrojasmone, constinients of the essential oilof jasmone flowers, have been prepared as shown in Scheme 3 5 Schemes 3 6 and 3 7 present a synthesis of pheromones via denitration of ct-nitro ketones " ... 

The addition of the lithium azaenolate of the SAMP hydrazone of propanal to methyl (E)-2-butenoate to furnish the (S,S,S)-adduct in 58% yield with > 96% ee and de is illustrative for the efficiency of this asymmetric Michael addition10°. Only the anti-isomer (an / adduct) is found. This methodology was used in the synthesis of pheromones of the small forest and red wood ant200. 

F. Sato developed titanium (Il)-based c/s-reduction of alkynes as shown in Scheme 5 [14], and the method was applied to the synthesis of pheromones by Kitching (Scheme 6) [15]. This titanium (Il)-based reaction gives pure (Z)-alkenes. Kitching summarized the contemporary methods for the synthesis of skipped polyynes and their reduction to skipped polyenes [15]. 

Mori K (2000) Chemoenzymatic synthesis of pheromones, terpenes, and other bioregulators. In Patel RN (ed) Stereoselective biocatalysis. Marcel Dekker, New York, p 59... 

Evidence for de novo synthesis of pheromone components was obtained by showing that labeled acetate and mevalonate were incorporated into ipsdienol by male Ips pini [103,104]. Similarly, labeled acetate and other labeled intermediates were shown to be incorporated into frontalin in a number of Dendroctonus species [105]. Possible precursors to frontalin include 6-methyl-6-hep-ten-2-one, which was incorporated into frontalin by D. ruffipennis [106]. The precursor 6-methyl-6-hepten-2-one also was shown to be converted to bre-vicomin in the bark beetle, Dendroctonus ponderosae [107]. In addition, the expression patterns of HMG-CoA reductase and HMG-CoA synthase are tightly correlated with frontalin production in Dendroctonus jeffreyi [108, 109]. A geranyl diphosphate synthase cDNA from I. pini was also isolated, functionally expressed, and modeled [110]. These data indicate that the de novo isoprenoid biosynthetic pathway is present in bark beetles. A variety of other monoterpene alcohols such as myrcenol, pityol, and sulcitol are probably synthesized through similar pathways [111]... 

Some observed side-products (87 or 90) can be suppressed, for example by the use of modified catalysts (Pd(dba)2/4—6equiv. PPh3 instead of Pd(PPh3)4 in Eq. 14.10). Additional model studies demonstrated the utility of a-allenyl acetates and phosphates by the successful synthesis of pheromone (R)-94 [47] and of enzyme inhibitor 95 [48] (Scheme 14.20). 

Fig. 6 Reaction scheme for the synthesis of pheromone components of male Dinoderus bifoveolatus 116 and 117...

Studies on isolation from adrenal cortex and the synthesis of cortisone (in 28 steps), an anti-arthritic hormone, was accomplished in the 1940s by Woodward and others. Cortisone was used as an important military medicine during World War II. Carl Djerassi from Stanford University directed the research at the Syntex Laboratories, which led to the synthesis of the first oral contraceptive pill for women. Koji Mori is very active in the field of the synthesis of pheromones. 

The synthesis of pheromones remains an important cornerstone of pheromone research and development. The initial synthesis of an insect pheromone serves not only to confirm the structural identification, but also provides authentic material for either laboratory or field bioassay. Oftentimes, larger quantities of the pheromones are desired for the development of monitoring and pest control methods. The scale up of the synthesis of complex pheromone compounds is often a major bottleneck in the practical application of pheromones. Also, the unusual structure of some pheromone compounds beckons synthetic chemists to apply new methodology in order to show off their methods. 

The [1,4]-Wittig rearrangement is potentially useful not only for the carbon-carbon bond formation but also for enolate formation. However, synthetic applications have been rather limited, because of the low yields and restricted range of substrates. Schlosser s group have developed a practical approach to aldehydes based on a [1,4]-rearrangement/ enolate trapping sequence. In contrast, standard aqueous workup gave poor yield of aldehyde. This protocol was employed as the key step in a synthesis of pheromone (102) from 99 via 100 and 101 (equation 56f. ... 

A highly selective method for the preparation of optically active 3-substituted or 3, y-disubstituted-S-keto esters and related compounds is based on asymmetric Michael additions of chiral hydrazones (156), derived from (5)-l-amino-2-methoxymethylpyrrolidine (SAMP) or its enantiomer (RAMP), to unsaturated esters (154).167-172 Overall, a carbonyl compound (153) is converted to the Michael adduct (155) as outlined in Scheme 55. The actual asymmetric 1,4-addition of the lithiated hydrazone affords the adduct (157) with virtually complete diastereoselection in a variety of cases (Table 3). Some of the products were used for the synthesis of pheromones,169 others were converted to 8-lactones.170 The Michael acceptor (158) also reacts selectively with SAMP hydrazones.171 Tetrahydroquinolindiones of type (159) are prepared from cyclic 1,3-diketones via SAMP derivatives like (160), as indicated in Scheme 56.172... 

The addition of diorganozinc reagents to a-alkoxyaldehydes furnishes selectively protected 1,2-diols.19 Applications toward the synthesis of pheromones like (-)-exo- and (-)-endo-brevicomin 2 and 3 exploits the catalytic nature of the stereochemical induction, e.g. the newly formed chiral centre depends only on the configuration of the chiral catalyst 1. 

The (S)-(+)-y-butyrolactone-Y-carboxylic acid is a useful Intermediate for the synthesis of pheromones,4 natural lignans,5 and other derivatives.6 In the same manner, but starting with D-glutamic acid, the (R)-(-)-lactone acid may be prepared. Lactonization occurs with full retention of configuration at the chiral center.8 9 Recently, authors have described an efficient method which allows the formation of derivatives of the (R)-(-)-lactone from the more available (S)-(+) counterpart.10... 

Synthesis of Pheromones from the Products of Acyloin-Type Condensation... 

Those who have followed the pheromone field know that there have been great strides forward in virtually every aspect of pheromone technology, especially in the past decade. Aside from the biological aspects of the problem, which are not directly addressed here, substantial progress has been made in isolation, identification, analysis and synthesis of pheromones, and—most important and recently—in actual applications of insect pheromones to solve difficult pest-control problems. 

Since the synthesis of pheromones has been extensively reviewed,2-8 corresponding aspects will not be the subject of this chapter. 

ABSTRACT This work describes various aspects of the concept, classification, identification, biosynthesis, chemistry and biological properties of pheromones. In addition, the available evidence relating to the vomeronasal organ (VNO), human pheromones and their possible role in human behavior is summarized. The latest works on the synthesis of pheromones with relevant activities are also included. 

Over the past four decades, insect pheromones have gained considerable interest as alternatives to conventional insecticides and become a significant part of natural product chemistry. General strategies and methods employed in synthesising insect pheromones constitute a collection almost as broad as the entire scope of organic synthesis. A number of timely reviews on the synthesis of pheromones have been... 

Aspects of pheromone synthesis have been reviewed [46h, 46i, 47, 145,146], including the enantioselective synthesis of pheromones. Enantioselective synthesis of a chiral and non-racemic pheromone can be executed by one of the following three methods [46h] ... 

There are three methods available for the enantioselective synthesis of pheromones (1) derivation from enantiopure natural products, (2) enantiomer separation (optical resolution), and (3) chemical or biochemical asymmetric synthesis. Practitioners of enantioselective synthesis must be familiar with the analytical methods for the determination of enantiomeric purity of an optically active compound. These basic methods will be explained briefly in this section, and discussed in depth through examples in the later sections of this chapter. 

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