Weinreb amides, acylation reagents

Deoxo-Fluor reagent is a versatile reagent for acyl fluoride generation and subsequent one-flask amide coupling. Georg and coworkers have explored the utility of this reagent for the one-flask conversion of acids to hydroxamic acids and Weinreb amides (Scheme 105) ". ... 

The first noncarbohydrate-based asymmetric synthesis of kedarosamine uses the A,0-protected D-threonine 166. It is first converted into the corresponding Weinreb amide via the acyl chloride. Subsequent coupling with the allyl Grignard reagent provides 167. The nonchelation controlled reduction of ketone 167 with NaBH4 is syn selective, whereas 1,2-chelation controlled reduction... 

The most popular method these days for the acylation of Grignard or organolithium reagents is the Weinreb amide (also discussed in chapter 8). Acylation of vinyl Grignard with the complex intermediate 60 was part of a synthesis of ( )-fumagillolB 62. 

Weinreb s amide) as acylating reagent Nahm, S Weinreb, S. M. Tetrahedron Lett., 1981,22, 3815-3818. 

Acyl fluorides. Carboxylic acids are readily transformed into acid fluorides by this reagent in the presence of i-Pr2NEt. Weinreb amides can be prepared henceforth. W-Protected chiral a-amino acids are derivatized without racemization. 

Reggelin and Brenig reported a different approach for the asymmetric synthesis on solid support (Scheme 1.6.38). An acylated Evans auxiliary was used as a soluble reagent for the transformation of polymer-supported aldehyde 81 into imide 82. The latter was converted into the Weinreb amide 83 which was - after protection of the hydroxyl group - submitted to DIBAH reduction to generate aldehyde 84. 

If, instead, one intends to use the keto group immediately after its introduction, one would rely on a related nucleophilic carbonylation of epoxides [89, 90, 91, 92]. The example given in Scheme 2.51 shows how an initially formed acylmorpholide can be readily converted into a ketone. Acyl-morpholides behave like Weinreb amides in the presence of organolithium reagents, making ketones (in this case a P-hydroxy-ketone) available [93]. 

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