Amides stereoselective reduction

Stereoselective reduction of chiral 2-furoic amides has been studied in detail and used as a key step in the synthesis of (+)-nemorensic acid <00JCS(P1)3724> <00CC465>. 

Stereoselective reduction of -keto amides.1 a-Methyl-p-keto amides are reduced by this silane in combination with tris(diethylamino)sulfonium difluorotri-methylsilicate (10, 452-453) in DMPU to the anti-alcohol, but are reduced by this silane in TFA to the syn-alcohol. 

In preparation for the eventual removal of the undesired oxygen function at C-10 of 313 via a Birch reduction, the phenol 313 was phosphorylated with diethyl phosphorochloridate in the presence of triethylamine to give 314, which underwent stereoselective reduction with sodium borohydride with concomitant N-deacylation to deliver the amino alcohol 315. N-Methylation of 315 by the Eschweiler-Clarke protocol using formaldehyde and formic acid followed by ammonolysis of the ester group and acetylation of the C-2 hydroxyl function afforded 316. Dehydration of the amide moiety in 316 with phosphorus oxychloride and subsequent reaction of the resulting amino nitrile 317 with LiAlH4 furnished 318, which underwent reduction with sodium in liquid ammonia to provide unnatural (+)-galanthamine. 

Stereoselective reduction of -keto amides. a-Alkyl-3-keto amides (1) are reduced with high iyn-selectivity by ZnCBH ) or by the combination of NaBH, and ZnfClO ) (equation I). 

Stereoselective reduction of chiral 2-alkyl-3-keto amides. The chiral propionamide (1) derived from tran.t-2,5-bis(methoxymethoxymethyl)pyrrolidine undergoes stereoselective acylation of the enolate in the presence of ZnCh to give 2-alkyl-3-oxo amides (2). These products undergo reduction with zinc borohydride to give syn-2-alkyl-3-hydroxy amides (3). 

Stereoselective reduction of a-alkyl-3-keto acid derivatives represents an attractive alternative to stereoselective aldol condensation. Complementary methods for pr uction of either diastereoisomer of a-alkyl-3-hydroxy amides from the corresponding a-alkyl-3-keto amides (53) have been developed. Zinc borohydride in ether at -78 C gave the syn isomer (54) with excellent selectivity ( 7 3) in high yield via a chelated transition state. A Felkin transition state with the amide in the perpendicular position accounted for reduction with potassium triethylborohydride in ether at 0 C to give the stereochemi-cally pure anti diastereoisomer (55). The combination of these methods with asymmetric acylation provided an effective solution to the asymmetric aldol problem (Scheme 6). In contrast, the reduction of a-methyl-3-keto esters with zinc borohydride was highly syn selective when the ketone was aromatic or a,3-unsaturated, but less reliable in aliphatic cases. Hydrosilylation also provided complete dia-stereocontrol (Scheme 7). The fluoride-mediated reaction was anti selective ( 8 2) while reduction in trifluoroacetic acid favored production of the syn isomer (>98 2). No loss of optical purity was observed under these mild conditions. 

A large amount of activity on 1,4-benzodiazepine derivatives was reported in 2004. Tetrahydro-l,4-benzazepin-2-one derivatives are of interest as P-turn peptidomimetics and their solid-phase synthesis was reported by Kim et al. <04JC0207>. The diasteroselective synthesis of two enantiopure tetrahydro-l,4-benzodiazepin-5-ones was also achieved based on intramolecular azide cycloaddition and subsequent stereoselective reduction of the 1,4-benzodiazepinone products <04TA687>. A different approach to tetrahydro-1,4-benzodiazepin-5-ones 80 involves the 1,2-thiazine 1-oxides 77 as key intermediates. These intermediates were then converted to the nitroaryl amides 78 (R , R, R = H or Me) which could be cyclised to 80 after hydrogenation of the nitro group via the intermediates 79 <04T3349>. 

P-Hydroxy esters and -amides. /3-Keto esters and amides undergo reduction with good stereoselectivity. Thus the 2-methyl derivatives give predominantly the erythro products, which is opposite to the results of a BU4NBH4 reduction. 

Preparation of the A-ring unit (Scheme 11) started with ethyl L-malate, which was converted into the enone 37 through the Weinreb amide derived from the ester 36. Stereoselective reduction [41] of 37 produced the syn... 

The application of proUne methylester as an auxihary in the stereoselective reduction of a-keto amides is such an example [29]. This process is interesting because of the opportunity to obtain mandeUc acid derivatives in both optically pure forms from one single proUne enantiomer. 

Industrial Synthetic Improvements. One significant modification of the Stembach process is the result of work by Sumitomo chemists in 1975, in which the optical resolution—reduction sequence is replaced with a more efficient asymmetric conversion of the meso-cyc. 02Lcid (13) to the optically pure i7-lactone (17) (Fig. 3) (25). The cycloacid is reacted with the optically active dihydroxyamine [2964-48-9] (23) to quantitatively yield the chiral imide [85317-83-5] (24). Diastereoselective reduction of the pro-R-carbonyl using sodium borohydride affords the optically pure hydroxyamide [85317-84-6] (25) after recrystaUization. Acid hydrolysis of the amide then yields the desired i7-lactone (17). A similar approach uses chiral alcohols to form diastereomic half-esters stereoselectivity. These are reduced and direedy converted to i7-lactone (26). In both approaches, the desired diastereomeric half-amide or half-ester is formed in excess, thus avoiding the cosdy resolution step required in the Stembach synthesis. 

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