Enones Homer-Emmons reaction

Canevet, J.C., and Sharrard, E, Synthesis of cyclic enones and dienic acids by Wittig-Homer-Emmons reaction. Tetrahedron Lett., 23, 181, 1982. 

The sulfone-alkylation method of Julia (1968) was a significant advance in retinoid total synthesis and has potential utility for labeled s)mthesis work. But the most useful reactions that have been adapted for the preparation of labeled retinoids are the well-developed procedures for the Wittig (Pommer, 1960) and the Homer-Emmons reactions (Bautagy and Thomas, 1974). These reactions are for synthesis of unsaturated and trans- and cw-a,p-enone compounds from the condensation of aldehydes and ketones with phosphoranes and with phos-phonoacetates, phosphonoacetonitrile, and oxophosphonates. These reactions suggest profitable application to the synthesis of retinoids, including labeled materials. 

The same strategy has been used to prepare trans bicyclic enones. The protected C5 phosphonylated aldehyde is obtained in 84% yield by a CuBr SMe2-mediated Michael addition of the Grignard reagent derived from 4-chlorobutyraldehyde diethyl acetal to a 5-phosphonylated 2,3-dihydro-4-pyridone in THF. Subsequent room-temperature hydrolysis of the acetal using aqueous oxalic acid in THF affords a near-quantitative yield of the crude aldehyde, which undergoes an intramolecular Homer-Wadsworth-Emmons reaction under treatment with Et3N/LiCl in THF at room temperature (89%). ... 

A mild base such as diisopropylethylamine or DBU can be used for the Homer-Wads worth-Emmons reaction in the presence of a complexing agent such as lithium chloride. These conditions are useful for sensitive substrates, such as chiral compounds with an enolizable stereocentre. For example, the enone 66 is formed in high optical purity under these conditions (2.81), whereas use of the base potassium tert-butoxide gives the product as a racemic mixture. 

Muscone (40) is a sex pheromone of the musk deer and a chemical component of cosmetics. A 12-member library of racemic muscone analogs was synthesized by Nicolaou et al.," who anployed a cyclorelease method on solid support to form the macrocycle scaffold (Figure 11.17). A phosphonate-functionalized resin loaded on encoded SMART microreactors 36 was coupled to olelinic esters 35 to form the p-ketophosphonates 37. Sorting and cross olefin metathesis of 37 with two alkenols followed by oxidation with Dess-Martin reagent gave aldehydes 38. An intramolecular ketophosphonate-aldehyde condensation (Homer-Emmons-Wadsworth reaction) of 38 caused smooth cyclorelease of macrocyclic enones 39. Parallel solution-phase chemistry completed the sequence. 

The formation of flve-membered cyclic imines through a Staudinger/intramolecular aza-Wittig reaction can also be performed by solid-phase synthesis and has been applied for the first synthesis of lanopylin Bi (108). The total synthesis, which takes only four steps, starts with a phase-transfer alkylation of diethyl 2-oxopropylphosphonate 105 with a 2-iodoethyl azide, affording the azido phosphonate 106, which undergoes a phase-transfer Homer-Emmons Wittig reaction with heptadecanal to provide the azido enone 107. An intramolecular aza-Wittig reaction of the enone 107 with polymer-supported triphenylphosphine in toluene completed the first total synthesis of lanopylin Bi (108) in 76% yield (Scheme 15.22). 

Aldehyde 123 was then reacted in a stereoselective Homer-Wadsworth-Emmons reaction with the sodium salt of phosphonate 124 to produce enone 125 (Scheme 3.31). Chemo- and stereoselective rednction of enone 125 with zinc borohydride provided secondary alcohol 126 as a 1 1 mixture of C-15 epimers, which could be separated by chromatography. Next, solvolysis of the acetate in 126 with basic methanol was followed by protection of the two alcohols with dihydropyran in the presence of a catalytic amount of para-toluenesulfonic acid. Reduction with DIBAL-H then provided lactol 127. Wittig reaction of 127 with the nonsta-bilized ylide 128 and snbsequent deprotection produced ( )-prostaglandin F (113). 

Step 2 Intramolecular Homer-Wads worth-Emmons (HWE) reaction furnishes the cyclic enone G. 

The addition of highly basic NaOt-Bu to chiral aluminium(m) lithium(i) bis(binaphtholate) 70 was also effective, and the enantioselective Michael reaction of cyclic enones with Homer-Wadswoth-Emmons reagents, such as 71, proceeded at room temperature (Scheme 2.41). Complex 70 itself did not promote the reaction even at 50 °C. 

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