Enolates of amides

The Michael addition of lithium enolates of amides, which have preferentially the Z geometry, under kinetically controlled conditions to a,/i-unsaturated esters provides a highly... 

Most of the information on simple a-arylation reactions on the enolates of amides comes from a single study by Rossi and Alonso.128 They showed that with acetamide itself no arylation reactions took place, presumably on account of ionization of the N—H rather than the C—H bond and the observation that the... 

A concise and practical synthesis of HIV-1 protease inhibitor 2 was developed by Askin and coworkers, using the rigid tricyclic aminoindanol acetonide as a chiral platform.11 The diastereo-selective alkylation of (Z)-lithium enolate of amide 48 with amino epoxide 49 gave intermediate 50 in >90% yield and >98% de (Scheme 24.9). Lithium carbamate salt of 49 presumably activated the epoxide toward electrophilic epoxide opening, and alkylation of the (Z)-enolate occurred from the less hindered (3-face. The amino alcohol was deprotected by treatment with camphorsulfonic acid and gave 2 in good yield. 

The low reactivity of glycine enolate with unactivated alkyl halides to form a-amino acids could be overcome by stabilizing the nucleophile using m-aminoindanol-derived hippuric acid 53. This key substrate was readily prepared from commercially available azalactone 54 by a one-pot operation (85% yield, 2 steps). The lithium enolate of amide acetonide 53 with a wide range of alkyl halides proceeded in moderate yields (>60%) and excellent diastereoselectivities (>95% de). Assuming that lithium halide would facilitate the dissociation of the amide enolate from the aggregated state and thus enhance its reactivity, 4 equivalents of lithium chloride were used as additive and resulted in a 25% increase in yield (Scheme 24.11). Reactions with secondary halides... 

The reactive conformation of the possible rota-mers (rotation around the OC-CC bond) has to be unambiguous. Of the two possible planar conformations, which allow conjugation with the 7r-systems, the -c/.v-orientation of C = 0/ C = Cp is favored based on steric reasons (O < NR2, analogously to the well-known fact that ( -enolates of amides are more stable than ( )-enolates). 

Asymmetric alkylation of amides. The enolates of amides (2) obtained by acylation of ( + )- or ( —)-l are alkylated consistently with >95% de. The stereoselectivity is independent of the base, solvent, or temperature. The products are converted without racemization into the corresponding acids by dcmethylation (BCl,) followed by acid-catalyzed hydrolysis. 

Oppolzer developed this chemistry into an asymmetric synthesis of a-amino acids 110 using enolates of amides 107 derived from his chiral sultam 109. The hydroxylamines 108 are isolated in perfect diastereomeric purity which translates into high ees in the final products14 110. 

The lithium enolate of amide (226) shows reasonable diastereofacial selectivity in its reactions with several aldehydes (equation 127 Table 26). The hydroxymethyl group is important, as N-acetylphen-ethylamine has almost no diastereofacial preference. ... 

Similarly, selectivity was observed in Weinreb s efforts toward the synthesis of the microbial immunosuppressive agent FR901483.24 In this case, axial addition was favored by reaction of the lithium enolate of amide 35 with racemic 1 to produce 36. An interesting reversal of stereoselectivity was observed when, on slight alteration of the synthetic sequence, the Boc-protected amide was subjected to similar conditions. For reasons not fully understood, equatorial alcohol 37 was produced in a 53% yield, the structure of which was confirmed by X-ray crystal analysis. 

P-Hydroxy amides. Cerium(III) enolates of amides show better reactivities than the Li enolates toward ketones and aldehydes. Reaction with camphor gives >94% yield of the aldol. 

Inter- and intramolecular arylations of amides have been described [68]. Use of zinc enolates of amides affords high yields in some cases (Eq. 23) [69]. In the... 

Scheme 4.82 Pd-catalyzed cross-coupling of zinc enolates of amides with a7l bromides [260].

Intramolecular variants of the reaction were reported for the enolates of amides and aldehydes through the corresponding in situ generated enolates. The palladium-catalyzed conversion of ort/zo-bromoaniline-derived amides 157 into oxindoles 160 was first studied by Hartwig and Lee who noticed that... 

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