Magdalena Rapp

Tri- and tetrafluoropropionamides derived from chiral secondary amines – synthesis and the conformational studies

A convenient procedure for the preparation of tri- and tetrafluoropropionamides derived from R-(+)/S-(−)-N-methyl-1-phenylethylamine and cyclic pyrrolidine derivatives has been described. The X-ray analysis and the theoretical calculations have been used to study conformational analysis of obtained compounds. In contrast to single α-fluorine substituted amides, which preferred anti conformation around the F–C–CO bond, for tetrafluorinated amides the additional trifluoromethyl group forces the conformation of the F–C–CO bond as nearly syn.

Functionalization of α-hydroxyphosphonates as a convenient route to N-tosyl-α-aminophosphonates

Direct conversion of the α-hydroxyl group by para-toluenesulfonamide to yield α-(N-tosyl)aminophosphonates is reported. α-Aminophosphonates 23a,b–37a,b were obtained from the corresponding α-hydroxyphosphonates 6a,b–21a,b in the presence of K2CO3, via the retro-Abramov reaction of the appropriate aldehydes, 1–5. The subsequent formation of imines with simultaneous addition of diethyl phosphite provided access to the α-sulfonamide phosphonates 23a,b–37a,b with better diastereoselectivity than in the case of the Pudovik reaction. The mechanism for this transformation is proposed herein. When Cbz N-protected aziridine 9a,b and phenylalanine analogue 12a,b were exploited, intramolecular substitution was observed, leading to the corresponding epoxide 38 as the sole product, or oxazolidin-2-one 39 as a minor product. Analogous substitution was not observed in the case of proline 18a,b and serine 21a,b derivatives.

Application of DAST mediated reactions in transformations of α-hydroxyphosphonates derived from O-isopropylidene-protected carbohydrate derivatives

GRAPHICAL ABSTRACT ABSTRACT Various α-hydroxyphosphonates derived from O-isopropylidene glyceraldehyde, hexofuranose and pentofuranose have been prepared to test nucleophilic fluorination reactions. The substrates have been conveniently prepared in Pudovik reactions and the stereoselectivity, as well as the configuration of the obtained carbohydrates have been described. Reactions have been accomplished using DAST as the fluorinating reagent. Treatment of protected glycerol phosphonate with DAST gave unusual conversions leading to fosfomycin analogue possessing an oxirane ring. Subsequent reaction with diethylaminesulfur trifluoride (DAST) yielded β-ketophosphonate. By contrast, stereoselective deoxyfluorination of hydroxyphosphonates derived from an O-isopropylidene pentofuranose gave the major fluoride possessing D-glu configuration while the reaction with di-O-isopropylidenehexofuranose derivative, has not been successful presumably due to stereochemical properties of the substrate.

Pyrrolidine and oxazolidine ring transformations in proline and serine derivatives of α-hydroxyphosphonates induced by deoxyfluorinating reagents

Transformations of α-hydroxyphosphonates derived from proline or serine by treatment with different deoxyfluorinating reagents (DAST, Deoxofluor, PyFluor) are reported. Depending on the applied reagent, as well as the protecting group used (N-Cbz, N-Boc, N-Bn) different types of products are observed. The reaction of N-Cbz or N-Boc prolinols with DAST or Deoxofluor due to aziridinium intermediate participation gave fluorinated amino phosphonates such as piperidine and pyrrolidine derivatives and/or oxazolidine-2-ones. Similarly, the analogous reaction of N-Cbz or N-Boc protected serinol yielded oxazolidine-2-ones or its fluorinated analogues. As the second type of product formed by DAST-induced reaction of serine derivatives, aziridines were obtained. Only in the case of deoxyfluorination of N-benzyl prolinols were both diastereoisomers of β-fluoropiperidine-α-phosphonates formed, while the reaction of protected N-benzyl serinols gave fluorinated oxazolidines. Moreover, application of PyFluor gave sulfonate derivatives.

α,α-Difluoro-β-iminophosphonates, an alternative strategy towards the synthesis of α,α-difluoro-β-aminophosphonate derivatives

α,α-Difluoromethylenephosphonates are generally known as stable natural phosphate mimics with significantly improved biological activities. A number of α,α-difluoroalkylphosphonates have already been found to be important enzyme inhibitors. Herein, we report an alternative strategy towards the synthesis of α,α-difluoromethylene-β-aminophosphonate derivatives. A small library of N-substituted α,α-difluoro-β-aminophosphonates was designed and described via NMR study. The protocol began with the condensation of β-ketophosphonates with a series of primary amines. The key step of the synthesis is an electrophilic fluorination, mediated by Selectfluor®, of the mixture of β-enamino/β-iminophosphonates leading to α,α-difluoro-β-iminophosphonates followed by reduction. The title compounds may behave as convenient building blocks for further more advanced modification.