Diastereoselective cyanation

Strecker-type reaction of TMS cyanide with chiral sulfinimines gives diastereoselective cyanations at the imine carbon, at —78 °C in DMF, using simple metal-free Lewis base catalysts such as tetraalkylammonium carboxylates.73... 

A second-generation process ronte was developed that improves upon the initial process route (Scheme 6). - - In this simplified process approach, the molecular symmetry of the starting caronic anhydride was maintained to the latest stage possible. Caronic anhydride (30) was initially converted directly to imide 40 by heating with either ammonium hydroxide or formamide with DMAP under Dean-Stark conditions. In an alternative two-step protocol, heating of 30 with benzyl amine produced an intermediate benzyl imide, which was deprotected to 40 under catalytic hydrogenation conditions. Reduction of imide 40 with lithium aluminum hydride afforded 41, which was desymmetrized under oxidative conditions to produce racemic imine 42. Diastereoselective cyanation favored trans-43, which underwent methanolysis under Pinner conditions. Finally, classical resolution by crystallization with D-DTTA afforded 24 as the D-DTTA salt with >95% ee. 

Diastereoselective Cyanation Electrochemical cyanation of L-proline derivative proceeded to afford 5-cis substituted product in excellent diastereoselectivity (Scheme 7) [8],... 

This multi-step scheme illustrates the synthetic efforts that have been invested in the construction of homochiral biaryl 15 without loss of enantiomeric purity. It covers many significant modem synthetic reactions diastereoselective cyanation, of the carbonyl group in (-i-)-9 in step i, promoted by a fi-orientation of the carbonyl oxygen to the orffio-substituent as the result of a stereoelectronic effect [52] oxidative removal of the Cr(CO)3 group in 13 (step vi) and stereoselective azidation with inversion of the configuration (step vii). For more details, the interested reader should consult the cited literature. 

For this class of reactions, only a few examples which proceed with reasonable diastereoselectivity are known. Allylation of a-methoxycarbamate 1, easily obtained as a 1 1 mixture of isomers by anodic oxidation of protected threonine, produces an 83 17 mixture of enantiomers on treatment with trimethyl(2-propcnyl)silanel03. Cyanation with trimcthylsilyl cyanide proceeds less stereoselectively (67 33 93 % yield). 

Sn(OTf)2 can function as a catalyst for aldol reactions, allylations, and cyanations asymmetric versions of these reactions have also been reported. Diastereoselective and enantioselective aldol reactions of aldehydes with silyl enol ethers using Sn(OTf)2 and a chiral amine have been reported (Scheme SO) 338 33 5 A proposed active complex is shown in the scheme. Catalytic asymmetric aldol reactions using Sn(OTf)2, a chiral diamine, and tin(II) oxide have been developed.340 Tin(II) oxide is assumed to prevent achiral reaction pathway by weakening the Lewis acidity of Me3SiOTf, which is formed during the reaction. 

Extension of this reaction toward a one-pot asymmetric Mannich-hydrocyanation reaction sequence was also reported by the Barbas group [29]. In this one-pot two-step process proline-catalyzed asymmetric Mannich reaction of unmodified aldehydes with the a-imino glyoxylate was performed first, then diastereoselective in situ cyanation. The resulting /i-cyanohydroxymethyl a-amino acids were obtained with high enantioselectivity (93-99% ee) [29]. Another one-pot two-step reaction developed by Barbas et al. is the Mannich-allylation reaction in which the proline-catalyzed Mannich reaction is combined with an indium-promoted allylation [30], This one-pot synthesis was conducted in aqueous media and is the first example of a direct organocatalytic Mannich reaction in aqueous media [28, 30]. 

Likewise, imine 118 was transformd into 120, a mimic of a conformationally rigid glutamic acid, via cyanide 119 (see Scheme 9.25) [50]. 1-Phenyl-1,1-difluoroacetaldehyde imine 121 was also used as a precursor of 3,3-difluorophenylalanine 123 via cyanide 122, but no diastereoselectivity was observed in the cyanation step (see Scheme 9.26) [51]. 

Substituted 2-oxazolidones 165 are useful chiral auxiliaries for diastereoselective functionalization at the a-carbon of their amide carbonyl group. The a-fluoroaldehydes 166 were prepared by a series of reactions electrophilic fluorination of the corresponding oxazolidinone sodium enolates with AMluorobenzenesulfonimine reductive removal of the auxiliary with LiBH4 and Dess-Martin oxidation. The aldehydes are so unstable for isolation that they are converted with (R)-/ -toluenesulfinamide to /7-toluenesul(inimines 167, which are isol-able and satisfactorily enantio-enriched. Chiral sulfinimine-mediated diastereoselective Strecker cyanation with aluminum cyanide provided cyanides 168 in excellent diastereose-lectivity, which were finally derived to 3-fluoroamino acids 169 (see Scheme 9.37) [63]. 

---