Homer-Emmons coupling

Among other reactions which have proved to be useful for the synthesis of targeted libraries are the Wittig and the closely related Homer-Emmons couplings. These powerful reactions can be carried out with either polymer-bound aldehydes/ketones or polymer-bound ylides. 

Horita, K, Nagasawa, M., Hachiya, S., Sakurai, Y, Yamazaki, T, UenishL J., and Yonemitsu, O. (1997) Synthetic studies of halichondrin B, an antitumor polyether macrolide isolated from a marine sponge. 8. Synthesis of the lactone part (C1-C36) via Homer-Emmons coupling between C1-C15 and C16-C36 fragments and Yamaguchi lactonization. Tetrahedron Lett., 38, 8965-8968. 

Other approaches to direct C2Q couplings have been reported (9,30—35). Based on their knowledge of sulfone chemistry, Rhc ne-Poulenc has patented many syntheses of P-carotene which use this olefination chemistry (36—41). Homer-Emmons chemistry has also been employed for this purpose (42). The synthetic approaches to the carotenoids have been reviewed (43). 

With respect to the coupling reactions of stannylthiazoles with aryl halides, the union of 4-chlorobromobenzene and 2-tributylstannylthiazole constructed arylthiazole 53 [37]. The Stille reaction of 3-bromobenzylphosphonate (54) and 2-tributylstannylthiazole led to heterobiaryl phosphonate 55, which may be utilized as a substrate in a Wadsworth-Homer-Emmons reaction or a bioisosteric analog of a carboxylic acid [38], The phosphonate did not interfere with the reaction. In addition, the coupling of 5-bromo-2,2-dimethoxy-l,3-indandione (56) and 2-tributylstannylbenzothiazole resulted in adduct 57, which was then hydrolyzed to 5-(2 -benzothiazolyl)ninhydrin [39]. 

One method for preparing imidazolylstannanes is direct metalation followed by treatment with RjSnCl [21]. l-Methyl-2-tributylstannylimidazole, derived in such manner, was coupled with 3-bromobenzylphosphonate (26) to furnish heterobiaryl phosphonate 27 [22], Under the same reaction conditions, 4-bromobenzylphosphonate led to the adduct in 69% yield, whereas only 24% yield was obtained for 2-bromobenzylphosphonate. The low yield encountered for the ortho derivative may be attributed to the steric factors to which the Stille reaction has been reported to be sensitive [23]. Heterobiaryl phosphonates such as 27 are not only substrates for the Wadsworth-Homer-Emmons reaction, but also bioisosteric analogs of the carboxylic acid group. 

For a review, see Jarosz, S, Synthesis of higher carbon sugars via coupling of simple monosaccharides — Wittig, Homer-Emmons, and related methods, J. Carbohydr. Chem., 20, 93-107, 2001. 

Regioselective reduction of the C-1 carboxylate of dimethyl (R)-malate (203) with BMS-NaBH4 followed by protection of the diol with either triethylsilyl groups or an acetonide furnishes 978. Condensation of the ester group with the anion of dimethyl methylphosphonate produces j -ketophosphonate 979 in high yield. Coupling of 979 with (2 S)-3-hydroxy-2-methylpropionate-derived aldehyde 980 under Homer—Emmons conditions affords 981, which contains the basic skeletal requirements for the C-16 to C-26 subunit (982) of hali-chondrin B (Scheme 144) [213]. 

Phosphonates. In a Homer-Emmons-based synthesis of di- and trisubstituted (Z)-Q(, -unsaturated esters, the strongly dissociated base system of potassium bis(trimethylsilyl)amide/18-Crown-6 was used to prepare the desired phosphonate anions. This base system, coupled with highly electrophilic bis(trifluoro-ethyl)phosphono esters, gave phosphonate anions which, when allowed to react with aldehydes, gave excellent selectivity for the (Z)-Q , -unsaturated esters (eq 15). ... 

Many solid-phase syntheses that involve the extension of ir-conjugated systems are known in the literature. Heck, Stille, Suzuki, Homer-Emmons, Wittig, and other metal-induced coupling reactions were all demonstrated to work on solid supports, some at relatively high yields [154—156]. Table 7.2 summarizes some of these reactions with respect to conditions and yields many other examples may be found in the literature. 

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. 

Yet another type of cyclization was observed for o-bromostilbenes, which actually competes with the second coupling step of o-dibromobenzene with styrene when only 1 equiv of styrene is used. o-Bromostilbene and substituted analogs, prepared from o-bromobenzaldehydes by Wittig-Homer-Emmons oleflnations, undergo efficient... 

The synthesis of the nucleophilic coupling component 52 started with the reduction of 3-bromo-2-methylbenzenecarboxylic acid, and followed with a Homer-Wads worth-Emmons reaction of the corresponding aldehyde, and a 1,2-reduction of... 

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