176756-69-7

Upstream product

• 169137-91-1 [(Z)-2-((R)-Toluene-4-sulfinyl)-1-trifluoromethyl-vinyl]-carbamic acid benzyl ester 
• 197704-06-6 Trifluoro-acetic acid (R)-2-[(E)-benzyloxycarbonylimino]-3,3,3-trifluoro-1-p-tolylsulfanyl-propyl ester 

Downstream Products

• 188566-32-7 [(S)-2,2,2-Trifluoro-1-((S)-hydroxy-phenyl-methyl)-ethyl]-carbamic acid benzyl ester 
• 219953-77-2 ((1S,2R)-2-Hydroxy-1-trifluoromethyl-pent-4-enyl)-carbamic acid benzyl ester 
• 188566-37-2 [(R)-2,2,2-Trifluoro-1-((S)-hydroxy-phenyl-methyl)-1-p-tolylsulfanyl-ethyl]-carbamic acid benzyl ester 
• 188566-30-5 ((1R,2S)-2-Hydroxy-1-p-tolylsulfanyl-1-trifluoromethyl-propyl)-carbamic acid benzyl ester 

Relevant academic research and scientific papers

CR-trifluoro- and difluoropyruvaldehyde AT,S-ketals: Chiral synthetic equivalents of β-trifluoro and β-difluoro α-amino aldehydes

A new, efficient, and stereoselective two-step approach to stereochemically defined chiral nonracemic γ-tri- and γ-difluoro β-amino alcohols (70% to >95% ee) is described, using tri- and difluoropyruvaldehyde W,S-ketals (R)-la,b as starting materials. Addition of Grignard reagents to (R)-l occurs with moderate to excellent anfi-stereocontrol, depending on the nature of the organomagnesium halides, providing the β-p-tolylthio β-benzyloxycarbonylamino secondary carbinols 5. The stereochemical outcome of these reactions can be rationalized by means of a chelated Cram's cyclic model, where the NCbz group is the chelating ligand and the p-tolylthio residue acts as the stereocontrolling "large" group. Reductive displacement of the 2-p-tolylthio substituent of 5 efficiently takes places by means of the NaBH4pyridine system, probably via the corresponding intermediate transient imines 13, providing sulfur-free γ-tri- and γ-difluorinated β-amino alcohols 7 with high levels of anii-stereoselectivity. A considerable shift toward syra-stereoselectivity was obtained performing the reaction on the corresponding phenylacetates 8. Cleavage and reduction of the NHCbz moiety of 7 provided tri- and difluoro analogues of, respectively, norephedrine (11) and ephedrine (12).

Preparation of (R)-Fluoropyruvaldehyde N,S-Ketals by Highly Stereospecific Tandem Pummerer Rearrangement/1,2-p-Tolylthio Group Migration of (R)-α-(Fluoroalkyl)-β-sulfinylenamines

Fluoropyruvaldehyde N,S-ketals (R)-2 have been prepared in good yields (up to 88%) and ee (up to 79%) from α-(fluoroalkyl)-β-sulfinylenamines (R)-(Z)-1, through a new self-immolative tandem sequential process, consisting of a Pummerer reaction, promoted by trifluoroacetic anhydride, followed by a 1,2-migration of the p-tolylthio group, triggered by addition of silica gel or aqueous base. Each transfer of stereogenic center, from sulfur to the α-carbon and then to the β-carbon, occurs with an average degree of enantioselectivity up to 94:6. Cis geometry between the sulfinyl and the amino groups of the starting enamine (R)-1 is necessary for achieving high level of stereocontrol, since neighboring group participation by the N-Cbz amino group prevents the sulfinyl center from racemization promoted by trifluoroacetic anhydride. NMR studies have shown that imines 3 are intermediate products of the Pummerer rearrangement, which are stable in the reaction environment.

Synthesis of N-Cbz-fluoropyrruvaldehyde N,S-ketals: Construction of highly stereoselective and high yielding synthetic reactions using multivariate modelling and design

The synthesis of (R)-fluoropyruvaldehyde-N,S-ketals via a tandem self-immolative Pummerer-type rearrangement of enantiopure (R)-α-fluoroalkyl-β-sulfinylenamines has been studied using statistical experimental design and multivariate modelling. By this study a procedure has been established which simultaneously gives excellent enantioselectivity and synthetically useful yields. The improvement of the ee of the trifluoro derivative was from 69% to 82%. The optimised procedure has been scaled up (10 fold) and extended to the corresponding difluoro and chlorodifluoro derivatives, with similarly good results. The chemometric analysis, along with a crossover experiment, strongly supports the hypothesis of a strictly intramolecular process, according to the previously proposed mechanism.

Highly stereoselective tandem Pummerer reaction/α-hydroxy imine rearrangement of e.P. β-sulfinylenamines

The highly stereoselective tandem Pummerer reaction/α-hydroxy imine rearrangement of E.P. α-fluoroalkyl-β-sulfinylenamines affording chiral non-racemic fluoropyruvaldehydes N,S-ketals is described.