Reductive aminations, ester

The zwitterion (6) can react with protic solvents to produce a variety of products. Reaction with water yields a transient hydroperoxy alcohol (10) that can dehydrate to a carboxyUc acid or spHt out H2O2 to form a carbonyl compound (aldehyde or ketone, R2CO). In alcohoHc media, the product is an isolable hydroperoxy ether (11) that can be hydrolyzed or reduced (with (CH O) or (CH2)2S) to a carbonyl compound. Reductive amination of (11) over Raney nickel produces amides and amines (64). Reaction of the zwitterion with a carboxyUc acid to form a hydroperoxy ester (12) is commercially important because it can be oxidized to other acids, RCOOH and R COOH. Reaction of zwitterion with HCN produces a-hydroxy nitriles that can be hydrolyzed to a-hydroxy carboxyUc acids. Carboxylates are obtained with H2O2/OH (65). The zwitterion can be reduced during the course of the reaction by tetracyanoethylene to produce its epoxide (66). 

Esters of diphenylacetic acids with derivatives of ethanol-amine show mainly the antispasmodic component of the atropine complex of biologic activities. As such they find use in treatment of the resolution of various spastic conditions such as, for example, gastrointestinal spasms. The prototype in this series, adiphenine (47), is obtained by treatment of diphenyl acetyl chloride with diethylaminoethanol. A somewhat more complex basic side chain is accessible by an interesting rearrangement. Reductive amination of furfural (42) results in reduction of the heterocyclic ring as well and formation of the aminomethyltetrahydro-furan (43). Treatment of this ether with hydrogen bromide in acetic acid leads to the hydroxypiperidine (45), possibly by the intermediacy of a carbonium ion such as 44. Acylation of the alcohol with diphenylacetyl chloride gives piperidolate (46). ... 

Some workers avoid delay. Pai)adium-on-carbon was used effectively for the reductive amination of ethyl 2-oxo-4-phenyl butanoate with L-alanyl-L-proline in a synthesis of the antihyperlensive, enalapril maleate. SchifTs base formation and reduction were carried out in a single step as Schiff bases of a-amino acids and esters are known to be susceptible to racemization. To a solution of 4,54 g ethyl 2-oxO 4-phenylbutanoate and 1.86 g L-alanyl-L-proline was added 16 g 4A molecular sieve and 1.0 g 10% Pd-on-C The mixture was hydrogenated for 15 hr at room temperature and 40 psig H2. Excess a-keto ester was required as reduction to the a-hydroxy ester was a serious side reaction. The yield was 77% with a diastereomeric ratio of 62 38 (SSS RSS)((55). 

The N-substituted aminoacids required could be prepared by microwave-assisted reductive amination of aminoacid methyl esters with aldehydes, and although in the Westman report soluble NaBH(OAc)3 was used to perform this step, other reports have shown how this transformation can be performed in using polymer-supported borohydrides (such as polymer-supported cyanoborohydride) under microwave irradiation [90]. An additional point of diversity could be inserted by use of a palladium-catalyzed reaction if suitably substituted aldehydes had been used. Again, these transformations might eventually be accomplished using supported palladium catalysts under microwave irradiation, as reported by several groups [91-93]. 

Sodium triacetoxyborohydride is an alternative to NaBH3CN for reductive amination. This reagent can be used with a wide variety of aldehydes or ketones with primary and secondary amines, including aniline derivatives.93 This reagent has been used successfully to alkylate amino acid esters.94... 

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. 

Santagada and coworkers have disclosed a reductive amination method for the generation of a reduced peptide bond by reaction of a protected amino acid aldehyde with an N-deprotected amino ester using sodium cyanoborohydride as reducing agent [296]. 

This chapter aims to provide an overview of the current state of the art in homogeneous catalytic hydrogenation of C=0 and C=N bonds. Diastereoselec-tive or enantioselective processes are discussed elsewhere. The chapter is divided into sections detailing the hydrogenation of aldehydes, the hydrogenation of ketones, domino-hydroformylation-reduction, reductive amination, domino hydroformylation-reductive amination, and ester, acid and anhydride hydrogenation. 

The numerous synthetic approaches relied principally on the formation of a 5-substituted proline ester by reductive amination followed by cyclization of the lactam ring. 

Methyl 2,3-epoxypropanoate can be prepared by reaction of potassium glycidate with dimethyl sulfate and one equivalent of benzyltriethylammonium chloride in methylene chloride at room temperature (65% yield).14 The reactions of this ester with organolithium or organomagnesium reagents at low temperature afford optically pure epoxy ketones14 that may be transformed via reductive amination to anti amino epoxides.15... 

Synthesis of a C(8)-C(18) segment of the larger fragment of lb using the same basic strategy is depicted in Scheme 25. Here, hydroxy ketone 176 was subjected to syn-selective (dr of crude product=90 10) reductive amination [42] with sodium cyanoborohydride and benzylamine followed by tetrahydro-oxazine formation using aqueous formaldehyde. The resulting heterocycle 182 was then converted to unsaturated ester 184 by successive desilylation, oxidation, and entirely (Z)-selective Horner-Wadsworth-Emmons olefination. Re-... 

The spacer arm length between the hapten and the carrier is in the range of 6 to 8 A, which should eliminate any steric interference with carrier side chains. According to the protocol described by Schultz the haptens were coupled to BSA and KLH via A-(3-dimethylaminopropyl)-A -ethylcarbodiimide or the N-hydroxysuccinimide ester at pH 5.5 in water. Other coupling strategies include substitution with diazonium salts and reductive amination. The ratio of hapten-carrier range between 8 and 15 haptens per carrier. 

In the enzymatic part of the process, a one-pot conversion was achieved by using Candida lipase (Lip) to hydrolyze the ester and then LeuDH to catalyze the reductive amination (with or without N labeling). In this case, the coenzyme recycling was accomplished by adding FDH and formate. The same group used a similar enzymatic strategy to prepare labeled L-threonine and L-allothreonine starting from the a-keto methyl ester. ... 

Reductive amination of carbonyl compounds, 59, 1 71, 1 Reductive cyanation, 57, 3 Redutive desulfonylation, 72, 2 Reductive desulfurization of thiol esters,... 

The MacMillan laboratory has produced an interesting study on the reductive amination of a broad scope of aromatic and aliphatic methyl ketones catalyzed by ent-lk, utilizing Hantzsch ester as a hydride source (Scheme 5.26) [48]. Apphcation of corresponding ethyl ketones gave very low conversions. Computational studies indicated that while catalyst association with methyl ketones exposes the C=N Si face to hydride addition, substrates with larger alkyl groups are forced to adopt conformations where both enantiofaces of the iminium ir... 

Cyanogen bromide method A,A -Carbonyl diimidazole method Divinylsulfone method Epoxy (bisoxirane) method Ethyldimethylaminopropyl carbodiimide method Eluoromethylpyridinium toluenesulfonate method A-hydroxysuccinimide ester method Schiff base (reductive amination) method Tresyl chloride/tosyl chloride method Sulfhydryls Azalactone method (for azalactone supports)... 

Several syntheses of muraghtazar (3) have appeared in patents (Cheng et al.) and journals (Devasthale et al., 2005) (Scheme 8.3). Alkylation of 4-hydroxybenzaldehyde with the phenyloxazolemesylate 23, prepared readily from commercially available alcohol 22, yielded aldehyde 24, which was treated with glycine methyl ester under reductive amination conditions to provide secondary amine 25 in excellent yield. Reaction of amine 25 with 4-methoxyphenyl chloroformate followed by hydrolysis of the methyl ester afforded 3 in 94% yield. 

The synthesis of valsartan (2) by Novartis/Ciba-Geigy chemists is highlighted in Scheme 9.5. Biphenylbenzyl bromide 18 is converted to biphenyl acetate 19 in the presence of sodium acetate in acetic acid. Hydrolysis of 19 followed by Swern oxidation delivered the biphenyl aldehyde 20, which underwent reductive amination with (L)-valine methyl ester (21) to give biphenyl amino acid 22. Acylation of 22 with penta-noyl chloride (23) afforded biphenyl nitrile 24, which is reacted with tributyltin azide to form the tetrazole followed by ester hydrolysis and acidihcation to provide valsartan (2). [See Biihlmayer et al. (1994, 1995).]... 

The two main resin linkers developed so far are shown in Scheme 18, i.e. tris(alk-oxy)benzylamide- 412 and 4-alkoxybenzylamide-type linkers)341 the former being TFA labile and thus fully compatible with Fmoc/tBu and the latter strongly acid labile and correspondingly compatible with Boc/Bzl chemistry. As shown in the case of the tris(alk-oxy)benzaldehyde handle such handles may be introduced into the C-terminal amino acid ester by reductive amination, and after suitable N -protection coupled to amino-functionalized resins (see Scheme 18). Alternatively, the tris(alkoxy)benzaldehyde-functionalized resin, BAL resin, (see Scheme 14) is used to link the C-terminal amino acid ester by reductive amination. To overcome the difficult acylation of the V -arylamino acid ester derivative on resin (best results with 10 equivalent symmetrical anhydrides), synthesis in solution of the C-terminal dipeptide building block containing the amide handle followed by its attachment to the resin has been proposed)341 ... 

---