Lithium amino borohydride

Lithium amino borohydride (LiBH3NR2) is powerful and selective reagent with reactivity comparable to LiAlH4. It reduces aldehydes, ketones, esters and amides to alcohols. But sterically hindered lithium amino borohydrides convert amides to amines. 

The reduction of a-hydroxynitriles to yield vicinal amino alcohols is conveniently accomplished with complex metal hydrides for example, lithium aluminum hydride or sodium borohydride [69]. However, it is still worth noting that a two-step chemo-enzymatic synthesis of (R)-2-amino-l-(2-furyl)ethanol for laboratory production was developed followed by successful up-scaling to kilogram scale using NaBH4/CF3COOH as reductant [70],... 

Nonmetallic systems (Chapter 11) are efficient for catalytic reduction and are complementary to the metallic catalytic methods. For example lithium aluminium hydride, sodium borohydride and borane-tetrahydrofuran have been modified with enantiomerically pure ligands161. Among those catalysts, the chirally modified boron complexes have received increased interest. Several ligands, such as amino alcohols[7], phosphino alcohols18 91 and hydroxysulfoximines[10], com-plexed with the borane, have been found to be selective reducing agents. 

Consequently, by choosing proper conditions, especially the ratios of the carbonyl compound to the amino compound, very good yields of the desired amines can be obtained [322, 953]. In catalytic hydrogenations alkylation of amines was also achieved by alcohols under the conditions when they may be dehydrogenated to the carbonyl compounds [803]. The reaction of aldehydes and ketones with ammonia and amines in the presence of hydrogen is carried out on catalysts platinum oxide [957], nickel [803, 958] or Raney nickel [956, 959,960]. Yields range from low (23-35%) to very high (93%). An alternative route is the use of complex borohydrides sodium borohydride [954], lithium cyanoborohydride [955] and sodium cyanoborohydride [103] in aqueous-alcoholic solutions of pH 5-8. 

Conversion of the keto ketoxime 1 to the exo-exo-amino alcohol 2 has been accomplished by hydrogenation over Adams catalyst and by reduction with lithium aluminum hydride. Amino alcohol 2 has also been prepared from 1 by a two-stage process in which selective reduction of the ketone is carried out with sodium borohydride, and the resultant hydroxy oxime is reduced with lithium aluminum hydride or by hydrogenation over Adams catalyst. ... 

The COOH-terminal amino acid of a peptide or protein may be analyzed by either chemical or enzymatic methods. The chemical methods are similar to the procedures for NH2-terminal analysis. COOH-terminal amino acids are identified by hydrazinolysis or are reduced to amino alcohols by lithium borohydride. The modified amino acids are released by acid hydrolysis and identified by chromatography. Both of these chemical methods are difficult, and clear-cut results are not readily obtained. The method of choice is peptide hydrolysis catalyzed by carboxypeptidases A and B. These two enzymes catalyze the hydrolysis of amide bonds at the COOH-terminal end of a peptide (Equation E2.3), since carboxypeptidase action requires the presence of a free a-carboxyl group in the substrate. 

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. 

The tetrahydro-derivatives of the oxazole and isoxazole system are unstable. As a consequence, only acyclic products have been reported from the reductions with complex metal hydrides. 2,5-Diphenyl-oxazole (119) gave 2-benzylamino-l-phenylethanol (120),141 and 3,5-diphenyl-2-isoxazoline (121) was converted to 3-amino-l,3-diphenylpropanol (122)142 on reduction with lithium aluminum hydride. 3-Phenylbenzisoxazole was resistant to reduction with lithium aluminum hydride and sodium borohydride,143 but benz-oxazole (123), benzoxazol-2-one (124), and benzoxazol-2-thione (125) have been reported 141 to yield 2-methylaminophenol (126) on reduction with lithium aluminum hydride. 

A closer consideration of the methods as yet applied for COOH-terminal amino acid determination in gelatin and collagen shows that they would not differentiate between a-, and 7-peptide linkages. It is, however, possible that modifications of the lithium borohydride and the hydrazinolysis methods could be used for a quantitative study of /3-aspartyl and 7-glutamyl residues in proteins and especially in collagen and gelatin. 

Lithium borohydride is very widely used for the specific cleavage of ester linkages. It is generally thought not to reduce free carboxyl groups or amide groups. On this basis it was introduced into protein chemistry as a reagent to be used in the determination of COOH-terminal amino acids (Chibnall and Rees, 1951). 

Fig. 9. Use of lithium borohydride to study COOH-terminal amino acids.

Blumenfeld and Gallop (1962b) have used lithium borohydride reduction, with subsequent chromatographic separation of the amino alcohols produced, to identify the carboxyl donor of the ester links previously found by Gallop et al. (1959) using hydroxylamine and hydrazine. The peaks obtained on the chromatogram for the two products in question, namely homoserine and /3-amino-7-hydroxybutyric acid, are very small, but nonetheless seem to establish that a- and /3-carboxyl groups of aspartic acid participate in the hydroxylamine-sensitive links. 

Hydroxymethylpyrazines may be prepared by reduction of carboxylic acid derivatives. Thus reduction of 2-amino-3-methoxycarbonylpyrazine with lithium aluminum hydride in tetrahydrofuran gave 2-amino-3-hydroxymethylpyrazine (1074, 1075) the imide from 23-dicarboxypyrazine (20) with sodium borohydride in tetrahydrofuran gave 2-carbamoyl-3-hydroxymethylpyrazine (21), and the methylcarbamoyl analogue was prepared similarly (1076). 

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