Homer-Wads worth-Emmons reaction

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... 

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. 

Example 9.8 This is an example of the creative use of a chiral building block from nature in the synthesis of (+)-sertraline (15,46 )-TM 9.3. Asymmetric synthesis starts from D-glyceraldehyde available by oxidative splitting of maimose or ascorbic acid [23]. Protected as acetal 17, this aldehyde is coupled to -alkene 19 with phosphonate 18, a reagent in the Homer-Wads worth-Emmons reaction (Scheme 9.13). 

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

An important application of the Reformatsky reaction is the conversion of P-hydroxy esters to a, P-unsaturated esters. Acid-catalyzed dehydration usually leads to a mixture of a, P- and P, y-unsaturated esters. However, conversion of the initially formed p-hydroxy esters to their corresponding acetates by treatment with acetyl chloride, followed by base-catalyzed dehydration with NaOEt, produces conjugated esters in high purity. This sequence of reactions provides an alternative route to the Homer-Wads worth-Emmons olefmation of ketones (see Chapter 8). 

An alternative route allowed the generation of the C5 chiral center by hetero-Michael addition on cx,p-unsaturated Weinreb amide 54, which in turn could derived from aldehyde 52 through crotyltitanation and homologation (Scheme 12). Thus, crotyltitanation reaction of aldehyde 52 with (/f)-4 cleanly led to the syn-anti homoallylic alcohol 53. a, i-Unsaturated Weinreb amide 54 was obtained through a classical two-step sequence involving a Homer-Wads worth-Emmons olefination. Then, reaction of 54 with benzaldehyde mediated by potassium bis(trimethylsilyl)amide (KHMDS) afforded benzyli-dene 55 in 79% yield with an excellent diastereoselectivity (dr >95 5). After reduction to aldehyde 56, the last C1-C7 subunit was obtained in 32.7% overall yield for eight steps. 

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