Amines diastereoselective reductive

The Leuckart-Wallach reaction is the oldest method of reductive amination of carbonyl compounds. It makes use of formamide, formic acid or ammonium formate at high temperature. The final product is a formamide derivative, which can be converted to an amine by reduction or hydrolysis. The method has been applied to the preparation of 1,2-diamines with a norbornane framework, which are interesting rigid analogues of 1,2-diaminocyclohexanes. As a matter of fact, starting from N-acetyl-2-oxo-l-norbornylamine 222, the diamide 223 was obtained with excellent diastereoselectivity and then converted to the M-methyl-N -ethyl derivative 224 by reduction with borane [ 104] (Scheme 34). On the other hand, when the reac-... 

The initial synthetic route employed by the medicinal chemistry group is straightforward a moderately diastereoselective reductive amination between ethyl-2-oxo-4-phenylbutyrate (13) and alanyl-proline (14) generated a 1.6 1 mixture of diastereomers favoring the desired (5,5,5)-enantiomer (Scheme 10.2). Fractional recrystallization afforded enalapril as the maleate salt (Harris et al., 1983 Wyvratt et al., 1984). Although requiring only one synthetic step, the diastereoselectivity of the process is poor, reducing the overall yield. 

The Merck process group subsequently published a more detailed route amenable towards multikilogram scales (Blacklock et al., 1988). This synthesis begins with treatment of alanine with phosgene to produce A-carboxyanhydride (NCA) 16 (Scheme 10.3). Under basic aqueous conditions this anhydride is coupled with proline to produce, upon acidic work-up, the dipeptide alanyl-proline (14). Enalapril is then prepared in one synthetic step by a diastereoselective reductive amination between ethyl-2— oxo-4-phenylbutyrate (13) and 14. This reaction was the subject of extensive optimization, and it was found that the highest diastereoselectivity was obtained by hydrogenation over Raney nickel in the presence of acetic acid (25%), KF (4.0 equiv.), and 3 A molecular sieves (17 1 dr). Enalapril is then isolated in diastereomerically pure form as its maleate salt (Huffman and Reider, 1999 Huffman et al., 2000). 

The original racemic patents described the use of resolution to give a chiral oxirane, such as 25, as an intermediate or the use of a chiral auxiliary (20) to produce the salmeterol enantiomers. Alkylation of chiral amine 20 with 2-benzyloxy-5-(2-bromo-acetyl)-benzoic acid methyl ester, followed by diastereoselective reduction of the ketone with lithium borohydride furnished intermediate 21 after chromatographic separation of the diasteromers. Removal of the benzyl group and the chiral auxiliary was... 

Sertraline is the active pharmaceutical ingredient (API) in Pfizer s antidepressant Zoloft [25]. The developed commercial process employs an SMB chromatographic resolution of tetralone (Scheme 13.10) in >99% ee followed by diastereoselective reductive amination to give 95% sertraline (cis-isomer) and 5% trans-isomer the (4R)-tetralone can be racemized with an alkoxide base [8]. Asymmetric processes to sertraline have been described [26]. Our studies started with the original patented process involving palladium-catalyzed reductive amination of a tetralone to give a mixture of 80% racemic-cis and 20% racemic-trans diastereomers [27]. The cis-diastereomer can be purified by selective crystallization from toluene followed by diastereomeric crystallization of the (lS,4S)-enantiomer using (R)-... 

In other reports, /i-cyclodcxtrins have been used to induce asymmetry in borohydride reduction of ketones,166 a diastereoselective reduction has been controlled167 by a real lyltricarbonyl iron lactone tether , a phosphinamide has been combined with a dioxaborolidine unit as an activated, directed catalyst for ketone reduction,168 reductive amination using benzylamine-cyanoborohydride converts 3-hydroxy ketones into syn-1,3-amino alcohols,169 l-(3,4-dimethoxyphenyl)-2-(2-methoxyphenoxy)propan-l-one has been reduced diastereoselectively,170 and production of chiral alcohols via (i) Itsuno-Corey and Brown procedures171 and (ii) lithium aluminium hydride modified by chiral nucleophiles172 has been reviewed. 

Stereospecific Reductive Amination of Carbonyl Compounds. Catalytic or chemical reduction of chiral imines derived from (1) often proceeds with high diastereoselectivity. Reductive removal of the a-methylbenzyl group yields chiral primary amines (eq 18 and 19). - ... 

The attachment of the strongly electronegative phosphinyl (P—O) group to an imine, usually via reaction of an oxime with a chlorophosphine, also gives highly electrophilic imines which are reduced by NaBFWTHF and various modified borohydride and LAH derivatives " under mild conditions. The product A-phosphinylamines are protected forms of primary amines since removal of the phosphorus substituent is accomplished under mild acidic conditions. Entries 12 and 13 (Table 16) present representative reductions and illustrate (entry 13) that highly diastereoselective reductions of cyclic systems to axial amine derivatives are accomplished with LiBHBu s. Enantioselective reductions of A-diphenylphosphinyl imines to optically active amine derivatives have also been reported (Chapter 1,7, this volume). ... 

Another example is shown in Scheme 9.45, in which arylsulfinylmethyl lithium couples with polyfluoroalkylimidoyl chlorides 197. Diastereoselective reduction of imine 198 to amine 199 followed by nonoxidative desulfinylative hydroxylation and oxidation of hydroxymethyl group provides trifluoro- and difluoroalanines 202 (see Scheme 9.45) [72]. The same protocol is applicable for the synthesis of 3,3-difluorocyclic amino acids 208 (see Scheme 9.46) [72, 73]. The borohydride reduction of sulfinylimine 204 proceeds with almost complete diastereoselectivity (>98% de). The conventional chemical modifi-... 

Racemic compounds containing a carbonyl function can serve as good models for the study of diastereoselective reductive aminations using achiral amines as educts. Intermediates in these reactions ate imines. The related racemic amines are obtained with relatively low diastereose-lectivity11-14. 

Synthesis involving sugar chemistry continues to take advantage of the mildness and selectivity of sodium cyanoborohydride as well, demonstrated in the synthesis of glucuronides (eq 33). A large portion of recent articles featuring NaBHsCN have reported stereoselective chemistry, such as in the report of diastereoselective reductive amination of 3-hydroxy ketones (eq 34). In some cases, essentially complete control of diastere-oselectivity could be obtained. In another example, where a galac-... 

Primary chloride removal was also slower than N—O bond cleavage. Thus, the newly formed amine from the highly diastereoselective reduction of oxazole 65 was able to further react with the chloro electrophile producing the pyrrole in an overall 96% yield (Scheme 24). ... 

Historically, the biocatalytic acyloin condensation was first observed by Liebig in 1913 during studies on baker s yeast [1460]. A few years later, Neuberg and Hirsch reported the formation of 3-hydroxy-3-phenylpropan-2-one (phenyl acetyl carbinol, PAC) from benzaldehyde by fermenting baker s yeast [1461]. Without knowledge on the actual enzyme(s) involved, this biotransformation assumed early industrial importance when it was shown that the acyloin thus obtained could be converted into (-)-ephedrine by diastereoselective reductive amination, a process which is still utilized in almost unchanged form at a capacity of 120 t/year [1462, 1463] (Scheme 2.199). Subsequent studies revealed that this yeast-based protocol can be extended to a broad range of aldehydes [1464, 1465]. 

Another of the arylalanines, L-tryptophan, was used at the same laboratories [81] for the synthesis of novel benzazepines (56) as dual inhibitors of ACE and thromboxane synthase (Scheme 5.25). Ozonolysis of 7V-acetyl l-tryptophan to effect scission of the indole ring followed by 7V-protection gave the 4-keto acid (57) as a cyclization precursor. Downstream transformations included diastereoselective reduction of the ketone functionality and reductive alkylation of the amine substituent with ethyl 2-oxo-4-phenyl-butanoate. 

Masson and Zhu et al. applied a calcium phosphate catalyst in asymmetric amination reactions of enamides (Tables 11 and 12) [50] for reviews of asymmetric amination reactions, see [51-58]. The amination products were easily converted to 2-hydrazinoketones and 1,2-diamines by hydrolysis or diastereoselective reduction. 

S.4.2.4 Routes Employing Late-Stage N/C-6 Bond Formation Perhaps unsurprisingly, most of the reported syntheses of the lasubines fall into this category. However, only two of them led to lasubine I (1341). Yamazaki, Aoyagi, and coworkers converted the (S)-amine 1378 in several steps into the Weinreb amide 1379, which reacted with allylmagnesium bromide followed by diastereoselective reduction of the resulting ketone... 

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