Disparlure epoxidation

The method has been applied in asymmetric and regioselective syntheses of several natural compounds. Two simple examples are the commercial syntheses of the gipsy moth hydrophobic sex attractant, disparlure (RE. Rossiter, 1981, 1985) and < mono-epoxidation of a diene in a leukotriene B4 synthesis (L.S. Mills, 1983). 

Functional group transformations of epoxides rank among the fundamental reactions of organic chemistry and epoxides are commonplace natural products The female gypsy moth for example attracts the male by emittmg an epoxide known as disparlure On detechng the presence of this pheromone the male follows the scent to its ongm and mates with the female... 

Many naturally occurring substances are epoxides You have seen two examples of such compounds already m disparlure the sex attractant of the gypsy moth (Section 6 18) and m the carcinogenic epoxydiol formed from benzo[a]pyrene (Section 118) In most cases epoxides are biosynthesized by the enzyme catalyzed transfer of one of the oxy gen atoms of an O2 molecule to an alkene Because only one of the atoms of O2 is trans ferred to the substrate the enzymes that catalyze such transfers are classified as monooxy genases A biological reducing agent usually the coenzyme NADH (Section 15 11) is required as well... 

Scheme 4. The Sharpless asymmetric epoxidation in the J.T. Baker Company s commercial synthesis of (7/ ,8S)-disparlure (15).

When n-BuLi is used instead of t-BuLi, the byproduct after desulfinylation (n-BuS(O)Ph) possesses an acidic proton, which is abstracted by the metalated epoxide. Hence, overall, a stereoselective protodesulfmylation is achieved. This can be used for the asymmetric synthesis of epoxides, such as that of (-)-disparlure from enantiopure sulfoxide 222 (Scheme 5.53) [78]. 

Of course, (+)-disparlure is only one of the many natural products that contain either an epoxide or an aziridine. Important and intriguing biologically active compounds such as the mitomycins, azinomycins, and epothilones also bear these functional groups. 

This is the first example of a reaction for which the presence of a chelating ligand was observed to facilitate rather than retard metal-catalysed epoxidation (Gao et al., 1987). It was found that the use of molecular sieves greatly improves this process by removing minute amounts of water present in the reaction medium. Water was found to deactivate the catalyst. All these developments led to an improved catalytic version that allows a five-fold increased substrate concentration relative to the stoichiometric method. Sensitive water-soluble, optically active glycidols can be prepared in an efficient manner by an in situ derivatisation. This epoxidation method appears to be competitive with enzyme-catalysed processes and was applied in 1981 for the commercial production of the gypsy moth pheromone, (-1-) disparlure, used for insect control (Eqn. (25)). 

R,8S)-(+)-Disparlure (12) is the female sex pheromone of the gypsy moth (Lymantria dispar). Advent of Sharpless asymmetric dihydroxylation (AD) allowed several new syntheses of 12 possible. Sharpless synthesized 12 as shown in Scheme 17 [27]. Scheme 18 summarizes Ko s synthesis of 12 employing AD-mix-a [28]. He extended the carbon chain of A by Payne rearrangement followed by alkylation of an alkynide anion with the resulting epoxide to give B. Keinan developed another AD-based synthesis of 12 as shown in Scheme 19 [29]. Mit-sunobu inversion of A to give B was the key step, and the diol C could be purified by recrystallization. 

A study using the gypsy moth, Lymantria dispar, illustrates the overall pathways involved in production of epoxide pheromone components (Fig. 3) [77]. This insect uses disparlure, Me2,epo7-18 H, as a pheromone component. In-... 

It should be added that many other groups have contributed to the predevelopments of these inventions and also to later developments. All four reactions find wide application in organic synthesis. The Sharpless epoxidation of allylic alcohols finds industrial application in Arco s synthesis of glycidol, the epoxidation product of allyl alcohol, and Upjohn s synthesis of disparlure (Figure 14.4), a sex pheromone for the gypsy moth. The synthesis of disparlure starts with a Ci3 allylic alcohol in which, after asymmetric epoxidation, the alcohol is replaced by the other carbon chain. Perhaps today the Jacobsen method can be used directly on a suitable Ci9 alkene, although the steric differences between both ends of the molecules are extremely small ... 

Scheme 14. Resolution of a czs-2,3-disubstituted epoxide and synthesis of (+)-disparlure...

The epoxide disparlure has been isolated as the gypsy moth sex attractant. These pheromones are in experimental use for control of these pests. 

This transformation has been applied to several chiral production processes, the first being the synthesis of a pheromone (Disparlure) intermediate (S) albeit with low turnover numbers and only 91 % ee. Another industrial product is the epoxide of allyl alcohol as developed by PPG-Sipsy, to give a process where catalyst loading was decreased by molecular sieve addition and the safety factors involving peroxide contamination were overcome. These examples are shown in Figure 1.46. 

Asymmetric epoxidation is a key step in a synthesis of (+ )-disparlure (I), the sex utlructunt of the gypsy moth, as outlined in equation (I). ... 

This catalytic epoxidation method has been applied to the synthesis of a variety of natural products, particularly polyhydioxylated compounds, including carbohydrates (54) and macrolides. In addition, this reaction has been used for commercial synthesis of disparlure, a gypsy moth pheromone [J. T. Baker Co. (55) and the Shanghai Institute for Organic Chemistry (56)], and more importantly, glycidol, a versatile intermediate for synthesis of /3-blockers and other functionalized chiral molecules (Arco Co.) (Scheme 23) (57). 

Sharpless epoxidation of (E)-(l,2-dialkyl)vinylsilanols 13, prepared from hydrolysis of ( )-( 1,2-dialkyl )vinyldimethylbutoxysilanes 12, gave silylepoxides 14, which were treated with Et4NF in MeCN to afford epoxides 15 in 62-70% overall yield and 44-70% ee (Scheme 6AA.6).7 The overall transformation can be considered as asymmetric epoxidation of simple internal alkenes. This approach was applied to the synthesis of a naturally occurring insect sex pheromone (+)-disparlure.7... 

Disparlure can be prepared by epoxidation of the corresponding alkene. Cis alkenes yield cis epoxides upon epoxidation. d.v-2-Mcthyl-7-octadcccnc is therefore the alkene chosen to prepare disparlure by epoxidation. 

Many insect pheromones are derivatives of simple alkenes. Disparlure 56, an attractant for the gypsy moth, is an epoxide derived by stereospecific epoxidation from the Z-alkene 57. As neither substituent is anion-stabilising, a simple Wittig should give the right geometry. 

Kasang G. and Schneider D. (1974) Biosynthesis of the sex pheromone disparlure by olefin-epoxide conversion. Naturwissenschaften 61, 130-131. 

Prestwich G. D., Graham S. M. and Konig W. A. (1989) Enantioselective opening of (+)-and (-)-disparlure by epoxide hydrase in gypsy moth antennae. J. Chem. Soc. Commun., 575-577. 

Females of the lymantriid, Porthetria dispar, the gypsy moth, liberate cls-7,8-epoxy-2-methyloctadecane (disparlure) as a sex pheromone (78). The probable precursor of the epoxide, (Z)-2-methyl-7-octadecene, is present in the gland in large quantities, and it has been demonstrated that the olefin is epoxidized in vivo (79). Disparlure is rapidly adsorbed on the male antennae and quickly converted to two more polar metabolites (80), probably as a consequence of hydrolysis of the epoxide group. 

Sharpless also found that this reaction works witlronly a catalytic amount of titanium-tartrate complex, because the reaction products can be displaced from the metal centre by more of the two reagents. The catalytic version of the asymmetric epoxidation is well suited to industrial exploitation, and the American Company J. T. Baker employs it to make synthetic disparlure, the pheromone of... 

The sex attractant pheromone of the gypsy moth [Lymantrla dispar (L.)] is disparlure (cis-7,8-epoxy-2-methyloctadecane). The natural attractant is the (+) enantiomer it is a powerful attractant for male moths and is used throughout the United States as a bait in traps to detect infestations. A convenient and economic synthesis, recently reported, involves oxidation of an inactive unsaturated precursor with an optically active complex to yield an epoxide of high enantiomeric purity. 

Disparlure, Ci9H3gO, contains one degree of unsaturation, which the H NMR absorption at 2.8 5 identifies as an epoxide ring. 

Another biologically important epoxide is disparlure (4), the pheromone of the gypsy moth. This economically important insect epoxidizes a straight-chain alkene to produce just one enantiomer. The epoxide is required to be displayed as a single enantiomer to be attractive59. 

Disparlure, the sex pheromone of the female gypsy moth and the epoxide that opened Chapter 12, is synthesized by a stepwise reaction sequence that uses an epoxidation reaction as the final step. 

Step [1] The cis epoxide in disparlure is prepared from a cis alkene A by epoxidation. 

Part [3] The cis alkene A is epoxidized to disparlure using a peroxyacid such as mCPBA. 

Epoxidation of the cis alkene A from two different sides of the double bond affords two cis epoxides in the last step—a racemic mixture of two enantiomers. Thus, half of the product is the desired pheromone disparlure, but the other half is its biologically inactive enantiomer. Separating the desired from the undesired enantiomer is difficult and expensive, because both compounds have identical physical properties. A reaction that affords a chiral epoxide from an achiral precursor without forming a racemic mixture is discussed in Section 12.15. 

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