Imines stereoselective reductions

The intramolecular version of this heterocyclization was applied to a short synthesis of diazasteroids (Scheme 12). Thus, imines 46 were converted in one-pot into [ 1,2-a]pyrrolopyrimidines 47 when treated with LDA, nitrile, and acid (40-95% yield) the stereoselective reduction of 47 to octahydroderivatives 48 was effected in 70-92% yield with NaBH4/ MeOH at 60°C (89S230 91MI5). Compound 48 (R1 = R2 = Ph) was successively allylated to 49 (94% yield) and cyclized in the presence of triflu-oromethanesulfonic acid to afford a 86 14 mixture of diastereoisomers (C-5 epimers) in 86% yield, from which major component 50 was separated by column chromatography [90TL(31 )2189]. 

The conjugate addition of iV-sulfinyl metalloeneamines to enones gave 19, which is converted in a facile manner to the corresponding piperidine in good diastereoselectivity after sequential stereoselective reduction, N-deprotection, cyclization, and imine reduction (Equation 35) <2005JOC7342>. 

Stereoselective reduction of cyclohexylimines. Imines of alkyl-substituted cyclohexyl ketones are reduced by this borohydride stereoselectively (>90%) to axial secondary amines. Axial primary cyclohexylamines are prepared conveniently by reduction of the imine derived from/ ,/) -dimethoxybenzhydrylamine and sub.scquent cleavage with formic acid (equation 1). 

The alkaloid (+)-pinidine81 (4) is obtained as a single a s-stereoisomer in a one-pot transformation of the chiral methyl sulfide 3 via oxidative amination, rearrangement, intramolecular imine formation and stereoselective reduction. 

The enantiospecific synthesis of natural and unnatural a-amino acids has been reviewed. Some of the most successful approaches involve the stereoselective hydrogenation of chiral dehydroamino acid derivatives. Many of these transformations are equivalent to the stereoselective reductive amination of a-keto acids (eq 2). For example, catalytic reduction of the imines of a-keto acids with chiral a-methylbenzylamine gives a-substituted a-amino acids with 12-80% ee (eq 3). ... 

Preparative Methods (i) preparation of racemic DPEN and its optical resolution Reaction of benzil and cyclohexanone in the presence of ammonium acetate and acetic acid at reflux temperature gives a cyclic bis-imine (1) (eq 1). Stereoselective reduction of the bis-imine with lithium in THF-liquid ammonia at —78 °C followed by addition of ethanol, then hydrolysis with hydrochloric acid and neutralization with sodium hydroxide produces the racemic diamine (2). Recrystallization of the l-tartaric acid salt from a 1 1 water-ethanol mixture followed by neutralization with sodium hydroxide, recrystallization from hexane results in (5,5)-DPEN (3) as colorless crystals. 

Cyclic imines will not be dealt with in this review as the conversion is often simply achieved. Mention will be made to the stereoselective reduction involved in the preparation of Solenopsin A and B (131), two naturally occurring piperidine alkaloids isolated from the venom of the fire ant. The desired trans isomer 131 was obtained with > 95% selectivity, using LAH (7 equiv) and trimethylaluminum (7 equiv) in THF. This selectivity could be reversed by using LAH (7 equiv) and NaOMe (14 equiv). °... 

Nitrogen containing heterocycles can he reduced by NaBH3CN under acidic conditions. Two recent examples involved the stereoselective reduction of pyrazines to piperazines (eq 43) and pyrazinones to piperazinones (eq 44). The effectiveness of the ongoing use of sodium cyanoborohydride in reduction of cyclic imine derivatives was demonstrated by these reactions. In both cases only a single diastereomer of product was detected and isolated. 

The second one involves highly stereoselective reduction of the 7-imino compound (88) with sodium cyanoborohydride under acidic condition at pH 3 in methanol, giving the 7P-isomer as the sole product in 90% yield [36]. The unique stereochemical outcome can be rationalized as follows. In an acid medium, sodium cyanoborohydride may produce a molecular complex of hydrogen cyanide and borane, HCN BH3, and this species reacts with either 7-methoxy amine (77) or 7-imine (88) to form (89) or (90), respectively. The methoxy-amine complex (89) may be converted into the imine-borane complex (90), which undergoes reduction with intramolecular hydride reduction either directly via (91) or more probably via a six-membered transition state (92). 

To improve upon the selectivity of the ketimine reduction process further, the hydrosilylation of a range of substrates derived from (/ )- -phenylethylamine were examined [37]. Optimization of the reaction conditions allowed obtaining complete diastereoselective reduction of a wide range of acetophenone-derived ketimines as well as a-imino esters, demonstrating the cooperative effect of catalyst and the (/ )-methyl benzyl residue at the imine nitrogen. In this context, we reported also a low cost protocol for a highly stereoselective reduction of ketimines bearing a very cheap and removable chiral auxiliary, promoted by an achiral inexpensive Lewis base, such as DMF [38]. 

In 2006, Enders and Vrettou [32] reported a concise total synthesis of (-l-)-poly-oxamic acid (82) through an organocatalytic Mannich reaction (Scheme 17.12). Asymmetric Mannich reaction of ketone 79 and Boc-protected imine 80 using L-proline 24 afforded the adduct 81 in 85% yield as a mixture of diastereomers with 92% ee (>98 2 dr). A stereoselective reduction of 81 using L-selectride, followed by ozonolysis and subsequent acid deprotection completed the total synthesis of (-l-)-polyoxamic acid (82). 

Synthetic highlights A variety of pathways have been taken in the synthetic approach to sertraline. These include stereoselective reduction of ketones and imines under kinetic and thermodynamic control, using diastereoselective or enan-tioselective catalysts and reagents, desymmetrization of oxabenzonorbomadiene followed by the Suzuki coupling of arylboronic acids and vinyl halides and Pd-Catayzed (Tsuji-Trost) coupling of arylboronic acids and allylic esters. For the production of sertraline, the simulated moving bed (SMB), a cost-effective technology, has been introduced. 

Stereoselective Reduction of Ketones and Imines Under Kinetic... 

The industrial method is developed based on the preparation of ketimine TM 9.3b followed by reduction. It should be observed that ketone TM 9.3a and imine TM 9.3b are racemic compounds. By non-stereoselective reduction of imine to methylamine, diastereomeric 1,4-dr and, A-trans racemates are formed. 

Secondary Amines.—The reduction of imines to the corresponding secondary amines can be effected by various methodologies. New additions are the sodium triacyloxyborohydrides (easily obtainable from sodium borohydride and AT-acyl derivatives of optically active amino-acids), which are used for the asymmetric reduction of cyclic imines. Also now available is a highly stereoselective reduction of N-benzylimines derived from substituted cyclohexanones, with alkali-metal borohydrides, in particular L-selectride. A fiuther addition is the first report of the reduction of aldimines by hydrogen transfer from propan-2-ol,... 

A rare case of enzyme catalyzing imine reduction reaction (see also Section 13.4.4) is the stereoselective reduction of dihydrofolic acid to (6S)-tetrahydrofolic acid by dihydrofolate reductase (DHFR) at the expense of NADPH. This biocatalytic step was employed in the synthesis of (S)-leucovorin [(6S)-5-formyl-5,6,7,8-tetrahydro-folate], a drug used in cancer chemotherapy. DHFR produced by E. coli was combined with a GDH/glucose cofactor recycling system and yielded (6S)-tetrahy-drofolic acid, which upon formylation furnished L-leucovorin with >99.5% de (Figure 13.31) [37-39]. 

Iwasaki F, Onomura O, Mishima K, Kanematsu T, Maki T, Matsumura Y. First chemo- and stereoselective reduction of imines using trichlorosilane activated with /V-formylpyrroli-dine derivatives. Tetrahedron Lett. 2001 42 2525-2527. 

Scheme 4. Stereoselective reduction of p-sulfinyl imines, and elaboration into both enantiomers of 3,3,3-trifluoroalanine.

---