Sharpless disparlure

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

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. 

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 ... 

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... 

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 first commercial application of Sharpless technology was in the synthesis of (+)-disparlure (Figure 17), which is operated by Upjohn in a multi-10 kg scale. 

Rossiter BE, Katsuki T, Sharpless KB (1981) Asymmetric epoxidation provides shortest routes to four chiral epoxy alcohols which are key intermediates in syntheses of methymycin, erythromycin, leukotriene C-1 and disparlure. J Am Chem Soc 103 464-465... 

This methodology [94TL3601] was used to construct the optically active erythro-diol 8, which was then stereospecifically converted to (+)- disparlure (9), the sex attractant pheromone of the female gypsy moth. This transformation represents a formal asymmetric epoxidation across a nonfunctionalized olefin, not a direct option with traditional Sharpless asymmetric epoxidation technology. This clever variation using initial Sharpless dihydroxylation (applicable to nonfunctionalized olefins) and subsequent epoxide formation is starting to be recognized as a useful indirect method for asymmetric epoxidation. 

Besides the more common reactions such as hydrogenation, isomerization, alkylation, and the Diels-Alder reaction. Sharpless epoxidation and dihydroxylation by asymmetrical catalysis are rapidly emerging as reactions with immense industrial potential. Table 9.7 lists some important syntheses based on asymmetric catalysis. These include processes for the pharmaceutical drugs (S)-naproxen, (S)-ibuprofen, (,S)-propranolol, L-dopa, and cilastatin, a fragrance chemical, L-menthol, and an insecticide (/ )-disparlure. Deltamethrin, an insecticide, is another very good example of industrial asymmetric synthesis. The total synthetic scheme is also given for each product. In general, the asymmetric step is the key step in the total synthesis, but this is not always so, as in the production of ibuprofen. Many of the processes listed in the table are in industrial production. 

More than a laboratory synthesis. Sharpless epoxidation has been adapted to the large-scale preparation of (+)-disparlure, a sex pheromone used to control gypsy moth infestations, and of (/ )-glycidol, an intermediate in the synthesis of cardiac drugs known as beta-blockers. 

From a historical perspective, the Monsanto process for the preparation of (l.)-DOPA in 1974 laid the foundation stone for industrial enantioselective catalysis. Since then it has been joined by a number of other asymmetric methods, such as enantioselective Sharpless epoxidation (glycidol (ARCO) and disparlure (Baker)), and cyclopropanation (cilastatin (Merck, Sumitomo) and pyre-throids (Sumitomo)). Nevertheless, besides the enantioselective hydrogenation of an imine for the production of (S)-metolachlor(a herbicide from Syngenta), the Takasago process for the production of (-)-menthol remains since 1984 as the largest worldwide industrial application of homogeneous asymmetric catalysis. [124]... 

Q In case of the enantio-selective epoxidation of allyl alcohol to glycidol, the Sharpless procedure, as conducted by ARCO, has to compete with an enzymatic resolution process from DAISO however, for the preparation of disparlure the Sharpless epoxidation proves unsurpassed. 

At the same time, Kenji Mori published a similar route to (+)-disparlure. [195] Since disparlure may virtually be buUt up from the other end, for the Sharpless epoxidation diethyl (L)-tartrate is used instead of the (D)-enantiomer. Byrecrys-taUisation of the 3,5-dinitrobenzoate, the desired enantiomer of the intermediate can be enriched. EnantiomericaUy pure (+)-disparlure is finally obtained by chain extension with lithium dinonylcuprate. 

Disparlure (J. T. Baker Co.)- The first commercial application of the very powerful Sharpless epoxidation technology has reportedly been an intermediate for disparlure (an insect pheromone) by J. T. Baker Co., probably on a very small scale of a few kilograms per year (62). On this scale the rather low temperature and relatively high catalyst loading of Ti/diisopropyl tartrate (dipt) are not prob-... 

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