Benzyl amine asymmetric reductive amination

The strategy for the asymmetric reductive acylation of ketones was extended to ketoximes (Scheme 9). The asymmetric reactions of ketoximes were performed with CALB and Pd/C in the presence of hydrogen, diisopropylethylamine, and ethyl acetate in toluene at 60° C for 5 days (Table 20) In comparison to the direct DKR of amines, the yields of chiral amides increased significantly. Diisopropylethylamine was responsible for the increase in yields. However, the major factor would be the slow generation of amines, which maintains the amine concentration low enough to suppress side reactions including the reductive aminafion. Disappointingly, this process is limited to benzylic amines. Additionally, low turnover frequencies also need to be overcome. 

The asymmetric reduction of azomethines C6H5(R)C = NCf,H5 (R = CH3, Et, Pr, i-Pr) with a lithium aluminum hydride-3-0-benzyl-l,2-0-cyclohexylidene-a-D-glucofuranose complex gives optically active secondary amines C6H5(R)C HNHC6H5 (R = CH3, Et, Pr, / Pr) with S configuration in 75-80% yield, with 23.6% cc in the case of R = CH32 ... 

Pli2P(=0)-assisted asymmetric deprotonation of benzylic amines using BuLi/(—)-sparteine allows the synthesis of a series of phos-phinamides with good to excellent enantioinduction (eq 43). The cleavage of these derivatives to the corresponding amines is effected by cone HCl in THF or under reductive conditions, for example, L1A1H4 in THF. ... 

An asymmetric approach to differentially substituted cw-1,2-diamino cyclohexanes also utilized the Curtius rearrangement. The chiral diamine products are components of biologically active small molecules and useful as conformationally restricted peptide-like scaffolds. y Amino acid 54 was prepared in enantiomerically pure form using asymmetric reductive amination and converted to phthaloyl-protected y -amino acyl azide 56. Curtius rearrangement, followed by addition of benzyl alcohol and further heating provided chiral c/5-1,2-diamine 57 with orthogonal A-protection. 

At almost the same time, MacMillan and coworkers found that the reductive amination starting from aldehyde, amine, and Hantzsch ester 39 also proceeded smoothly by means of 1 in the presence of 5 A MS to afford benzylic amines 43 with 83-97% ee (Scheme 11.11) [22]. They proved that dialkyl ketones as well as alkyl aryl ketones were suitable substrates even methyl ethyl ketone was reduc-tively aminated with 83% ee. They also reported the asymmetric reduction of pyruvic-acid-derived cyclic imino ester 44. In this reaction, the structure of 44 exhibited a remarkable correlation to MM3 calculations in terms of both hydrogen bond orientation and specific architectural elements that dictate iminium enan-tiofacial discrimination. 

SCHEME 39.35. Asymmetric reductive amination using chiral benzyl amine as auxiliary. 

An early approach to the formation of chiral amines by nonenzymatic asymmetric synthesis was the reduction of prochiral ketoximes and their O-tetrahydropyranyl and O-methyl derivatives with lithium aluminum hydride-3-0-benzyl-1,2-0,0-cyclohexylidene-a-D-glucofuranose complex (16)33 in ether and prochiral ketoximes... 

Chiral addition of allyl metals to imines is one of the useful approaches toward the synthesis of homoallylic amines. These amines can be readily converted to a variety of biologically important molecules such as a-, / -, and y-amino acids. Itsuno and co-workers utilized the allylborane 174 derived from diisopropyl tartrate and cr-pinene for the enantioselective allylboration of imines. The corresponding iV-aluminoimines 173 are readily available from the nitriles via partial reduction using diisobutylaluminium hydride (DIBAL-H) <1999JOM103>. Recently, iV-benzyl-imines 176 have also been utilized for the asymmetric allylboration with allylpinacol boronate 177 in the presence of chiral phosphines as the chiral auxiliaries to obtain homoallylic A -benzylamines 178 in high yield and selectivity (Scheme 29) <2006JA7687>. 

The reported asymmetric synthesis of (—)-(R)-sitagliptin was completed in seven steps from commercially available starting materials. Acid-catalyzed hydrolysis of P-dalkylamino ferfbutyl ester 23c, coupling with the triazolopyrazine building block to amide, reduction of amide to tert amine and hydrogenolysis of the N-benzyl and N-phenylethyl unit, afforded (—)-(R)-sitagliptin in 43 % overall yield and 42 % e.e. 

Asymmetric Total Synthesis of ( )-Deoxoproso-phylline Zhu and Jourdant reported on an asymmetric total synthesis of (—)-deoxoprosophylline 157 starting from chiral L-Af,Af-dibenzyl serine and methyl aceto-acetate by exploiting a highly diastereoselective intramolecular reductive amination. The compound 155 underwent chemoselective iV-debenzylation followed by reductive amination to afford O-benzyl deoxoprosophyl-line 156. After this step, a simple 0-debenzylation... 

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