An easy route to optically active 1-substituted-1-pyridyl-methylamines by diastereoselective reduction of enantiopure N-tert-butanesulfinyl ketimines

The reduction of enantiopure N-tert-butanesulfinyl ketimines derived from pyridyl ketones afforded the related N-tert-butanesulfinyl amines with high yields and diastereoselectivities.     

Highly diastereoselective synthesis of α-trifluoromethylated α-propargylamines by acetylide addition to chiral CF3-substituted N-tert-butanesulfinyl ketimines

A convenient and practical method for the preparation of enantiomerically pure α-trifluoromethylated α-propargylamines is described. A range of enantiopure α-trifluoromethylated α-propargyl sulfinamides were obtained by the addition of lithium acetylides generated in situ with n-BuLi and terminal alkynes to diverse chiral CF₃-substituted (S)-N-tert-butanesulfinyl ketimines in moderate to excellent yields (56–97%) and with uniformly excellent diastereoselectivities (>99:1) by using Ti(OⁱPr)₄ as the catalyst and THF as the polar solvent. Enantiomerically pure α-trifluoromethylated α,α-dibranched propargyl amines were then readily obtained in excellent yields (87–97%) by acidic cleavage of the tert-butanesulfinyl group.     

One-pot asymmetric synthesis of α-trifluoromethylated amines from α-trifluoromethyl ketones

Diastereoselective reduction of (Rs)-N-tert-butanesulfinyl α-trifluoromethyl ketimines formed in situ from the corresponding α-trifluoromethyl ketones and N-tert-butanesulfinamide has been achieved, and either diastereomer of N-tert-butanesulfinyl α-trifluoromethyl amines was obtained in good yields with excellent diastereoselectivities (up to 99:1 dr) using NaBH₄ and L-Selectride as the reductants, respectively.     

Synthesis of chiral isoindolinones via asymmetric propargylation/lactamization cascade

A Zn-mediated propargylation/lactamization cascade reaction with chiral 2-formylbenzoate derived N-tert-butanesulfinyl imines was realized, which provided a practical and efficient method for the synthesis of chiral isoindolinones. High diastereoselectivities (up to 97:3 dr) and good reaction yields were observed for most examined cases.     

Nickel-catalyzed organozinc-induced unexpected 1,3-migration of tert-butyl from sulfur to carbon in N-tert-butanesulfinyl iminoacetates

The nickel-catalyzed reaction for an unexpected 1,3-migration of tert-butyl from sulfur to carbon, upon treatment of functionalized N-tert-butanesulfinyl iminoacetate in the presence of organozinc reagent, was developed. The generality has been explored by considering the flexibility in the structure of each reactive component, organozinc halide and N-tert-butanesulfinyl iminoacetate.     

Regio- and diastereoselective Reformatsky reaction of chiral fluoroalkyl α,β-unsaturated N-tert-butanesulfinyl ketimines: Efficient asymmetric synthesis of β-fluoroalkyl β-vinyl β-amino esters

Highly regio- and diastereoselective Reformatsky reaction of stable, chiral fluoroalkyl α,β-unsaturated N-tert-butanesulfinyl ketimines was developed, which provided an efficient method for the asymmetric synthesis of structurally diverse β-tetrasubstituted β-fluoroalkyl β-vinyl β-amino esters in good yields and with excellent diastereoselectivities (dr up to 96:4).     

Highly diastereoselective reactions of 2-lithiated indoles with chiral N-tert-butanesulfinyl aldimines for the synthesis of chiral (2-indolyl) methanamine derivatives

Nucleophilic addition reactions of 2-lithiated N-phenylsulfonylindoles with (R)-N-tert-butanesulfinyl aldimines provided chiral (2-indolyl) methanamine derivatives in moderate to good yields (up to 100%) with excellent diastereoselectivities (>99:1), in which no additional Lewis acids were required.     

A practical asymmetric synthesis of ortho-substituted 4-pyrazolyl-2-ethylamines

A reliable three-step synthesis of ortho-substituted 4-pyrazolyl-2-ethylamines starting from a pyrazole methyl ketone and N-tert-butanesulfinylamine is described. Strongly dehydrating conditions were required to form the N-tert-butanesulfinyl ketimines, but these intermediates were stable to aqueous work-up and chromatography. Reduction of N-tert-butanesulfinyl ketimines with L-selectride®, or Super-hydride®, in THF afforded excellent yields and diastereoselectivities of the sulfinamides, which were converted into chiral amines with methanolic HCl. The 4-pyrazolyl-2-ethylamines from these investigations are attractive building blocks for medicinal chemists, as they exhibit low molecular weight, and low calculated octanol-water partition coefficient (c Log P values), while disrupting planarity with three-dimensional character. For example, the amine products were utilized in structure-activity studies of the human transient receptor potential vanilloid 1 (TRPV1/VR1).     

A practical diastereoselective synthesis of β-hydroxy-β-trifluoromethyl imines

The asymmetric carbon-carbon bond formation reaction affording chiral β-hydroxy-β-trifluoromethyl imines is reported involving the nucleophilic addition of sulfinimine anions derived from chiral N-(tert-butanesulfinyl) ketimines to trifluoromethyl ketones. The reaction tolerates a wide range of nucleophiles, giving the condensation products in good to excellent total yields with good diastereoselectivities (up to 85:15 dr).     

Efficient preparation of Ellman’s imines from trifluoromethyl ketones promoted by zirconium(IV) tert-butoxide

An efficient synthesis of chiral N-tert-butanesulfinyl trifluoromethyl ketimines by using zirconium(IV) tert-butoxide is described. Compared to conventional titanium(IV) ethoxide, this protocol gave better result especially for sterically hindered ketones. In addition to the high reactivity, a high degree of enantiopurity of the N-tert-butanesulfinyl group is retained.     

An improved procedure for the diastereoselective addition of triorganozincates to N-(tert-butanesulfinyl)imines: use of catalytic dialkylzinc

The addition of triorganozincates to (R)-N-(tert-butanesulfinyl)benzaldimine has been performed with very good results by using a catalytic amount of Me₂Zn (0.15 equiv) to generate the organozincate. Yields and/or diastereoselectivities of the formed α-branched sulfinamides improve in comparison with the values obtained in the same reactions carried out with an excess of a previously formed triorganozincate. On the other hand, the transfer of the two alkyl groups of a dialkylzinc reagent to the imine has been achieved by using 0.5 equiv of dialkylzinc and 1.5 equiv of MeMgBr to generate the trialkylzincate. In both methods, good to excellent yields and diastereomeric ratios (up to 98:2) have been obtained.     

Asymmetric synthesis of phosphonotrifluoroalanine and its derivatives using N-tert-butanesulfinyl imine derived from fluoral

Addition of dialkyl phosphites to (S)-N-tert-butanesulfinyl imine derived from fluoral afforded, under mild conditions, the corresponding N-tert-butanesulfinyl α-aminophosphonates in moderate to high yields and diastereoselectivity. The major diastereomers of N-tert-butanesulfinyl α-aminophosphonates of (S_S,S) configuration were isolated, and after partial or complete deprotection, converted into enantiomerically pure phosphonotrifluoroalanine and its dialkyl esters.     

Concise and stereoselective synthesis of 2,5- and 2,4-disubstituted thiazole amino acid subunits for synthesizing thiazole-containing peptides

A concise, highly stereoselective synthesis of 2,4- and 2,5-disubstituted thiazole amino acids was developed. These are important building blocks for various biologically active thiazole-containing natural peptides and their regioisomeric analogues. The fundamental reactions are diastereoselective addition of (4- or 5-bromothiazol-2-yl)lithium to N-tert-butanesulfinyl imine with subsequent Pd-catalyzed phenoxycarbonylation.     

Asymmetric synthesis of dihydroquinazolinones via directed ortho metalation and addition to tert-butanesulfinyl imines

An asymmetric route to dihydroquinazolinones via the addition of ortho metalated substrates to tert-butanesulfinyl imines is reported. The scope of the nucleophile and electrophile components and the absolute stereochemical outcome are presented.     

Preparation of bisindolylalkanes from N-tert-butanesulfinyl aldimines

A series of bisindolylalkanes were synthesized by nucleophilic addition reactions of indole with N-tert-butanesulfinyl aldimines in good to excellent yields catalyzed by either iodine, potassium hydrogen sulfate and amberlyst.     

Diastereoselective Pd/In bimetallic inter-intramolecular (class 2) cascade reactions of allenyl-imines and aryl iodides

A new diastereoselective Pd/In bimetallic inter-intramolecular cascade reaction employing allenyl-sulfinimines and aryl iodides is described. The tert-butanesulfinyl chiral auxiliary affords chiral, highly substituted cis-pyrrolidines and piperidines.     

Stereoselective tribromomethylation of N-(tert-butanesulfinyl)imines with bromoform: practical synthesis of α-tribromomethyl amines

The unprecedented nucleophilic tribromomethylation of N-(tert-butanesulfinyl)imines with bromoform has been shown to be a highly stereoselective and practical method for the synthesis of enantiomerically pure α-tribromomethyl amines. THF has proven to be the best solvent in this addition reaction. By changing the reaction solvent from THF to DMF, 2,2-dibromoaziridines can also be synthesized directly from bromoform and N-(tert-butanesulfinyl)imines under similar reaction conditions.     

Asymmetric synthesis of 2-chloroaziridines via a diastereoselective nucleophilic dichloromethylation and N-alkylation in one pot

A diastereoselective nucleophilic dichloromethylation between the N-tert-butanesulfinyl imines and dichloromethyllithium was developed. A series of 2-chloroaziridines with excellent yields and dr values were obtained via this nucleophilic addition and N-alkylation in one pot. On the basis of X-ray crystallography experiment, the predicting model for this diastereoselective transformation was provided.     

Asymmetric aza-Diels-Alder reactions of an N-tert-butanesulfinyl α-imino ester

Diastereoselective aza-Diels-Alder (aza-DA) reactions of an N-tert-butanesulfinyl α-imino ester with different dienes including activated and non-activated dienes in the presence of BF₃·OEt₂ are described. Diastereoselectivities up to 99% were observed for acyclic unactivated dienes. The absolute configurations of two aza-DA products have been solved by X-ray analysis.     

Synthesis of β-disubstituted β-amino isoxazolyl ketones by addition of ketimines with isoxazolyl methyl ketone enolates

A series of β-disubstituted N-sulfinyl β-amino isoxazolyl ketones has been prepared by addition of tert-butanesulfinyl ketimines with the n-BuLi-generated enolates of isoxazolyl methyl ketones.