Diastereoselective reductive amination

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). 

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)-... 

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-... 

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]. 

Diastereoselective Reductive Amination Using Chiral Auxiliaries... 

SCHEME 39.40. Direct diastereoselective reductive amination of (3-hydroxy ketones to synthesize 1,3-iyw-amino alcohols. 

Chiral Pool Strategy via Diastereoselective Reductive Amination... 

An efficient enantioselective total synthesis of (—) -cis-clavidpitic acid was reported by Park and coworkers (Scheme 12.3) [103]. The asymmetric phase-transfer catalytic alkylation of 65a with 68 was employed as the key step, producing the urmatural oi-amino acid derivative 69 for the introduction of the 5S chirality. Starting from a glycine derivative 65a, Maruoka and coworkers successfully developed a strategy for the asymmetric synthesis of cyclic amino acids having a piperidine or azepane core structure by the combination of a phase-transfer catalytic asymmetric alkylation and a subsequent diastereoselective reductive amination. This approach allows the... 

Rather than preforming the a-amino ketimines to be reduced, it is often advantageous to form in situ the more reactive iminium ions from a-aminoketones and primary amines or ammonium salts in the presence of the reducing agent, e.g., sodium cyanoborohydride. Use of this procedure (reductive amination) with the enantiopure a-aminoketone 214 and benzylamine allowed the preparation of the syn diamines 215 with high yields and (almost) complete diastereoselectivities [100] (Scheme 32). Then, the primary diamines 216 were obtained by routine N-debenzylation. Similarly, the diamine 217 was prepared using ammonium acetate. In... 

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-... 

Researchers have found that the reduction of a variety of aziridine esters yields the corresponding aziridine aldehyde which dimerizes diastereoselectively <06JA14772>. The reduction of 112 with excess DIBAL yields the dimer 113, which is in equilibrium with the monomer 114. This molecule reacts as the monomer and both reduction to 115 or reductive amination to 117 proceed in quantitative yields. In a very interesting reaction, treatment of 113 with /V-benzyl tryptamine provides the pentacyclic 116 in excellent yield. 

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... 

Additionally, 1,2-dihydroxyethylene dipeptide analogues without the C-terminal carboxylic acid have been used to obtain aspartyl proteases inhibitors.[641 These efforts include stereoselective alkylation of imines, one-pot reductive amination of epoxy ketones, ring opening of epoxides with sodium azide, diastereoselective dihydroxylation of allylic amines, and enzymatic resolution and stereocontrolled intramolecular amidation. 

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. 

An inspection of the stereochemistry at C-2 for the iminosugars revealed that the reductive amination with Pd/C was highly diastereoselective. Interestingly, as already stated [15, 18, 20, 34], we found that the hydrogen was added to the face opposite to the C-4 hydroxyl group, regardless of the relative stereochemistry of the other substituents. Hence, the stereochemistry observed at C-2 was controlled exclusively by the configuration at C-4. An exception was found for the reductive amination of compound 7. In this case, there was no face selectivity and a circa 1 1 diastereomeric mixture was obtained. 

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). - ... 

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