Highly Diastereoselective Construction of Carbon- Heteroatom Quaternary Stereogenic Centers in the Synthesis of Analogs of Bioactive Compounds: From Monofluorinated Epoxyalkylphosphonates to α-Fluoro-, ß-, or γ-Amino Alcohol Derivatives of Alkylphosphonates.

The synthesis of the stable surrogates of an important amino acid (R)-4-amino-3-hydroxybutyric acid (GABOB) such as substituted hydroxy aminophosphonic acids bearing a quaternary stereogenic center is presented. Highly diastereoselective formations of fluorinated spiroepoxy alkylphosphonate or related tertiary carbon-containing oxiranes from ß-keto phosphonates possessing methyl, phenyl, or cyclohexenyl substituents, are reported. Stereoselective acid-promoted epoxide opening by bromide or azide followed by reduction/protection afforded tertiary bromides or N-Boc derivatives of ß-amino-γ-hydroxy alkylphosphonates in most cases, while the reactions of oxiranes with different amines yielded their ß-hydroxy-γ-amino regioisomers. Surprisingly, during the synthesis of amino phosphonic acids, we observe that the acid-induced rearrangement proceeded in a high diastereospecific manner, leading finally to substituted ß-hydroxy-γ-aminoalkylphosphonic acids.

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 ß-fluoropiperidine-α-phosphonates formed, while the reaction of protected N-benzyl serinols gave fluorinated oxazolidines. Moreover, application of PyFluor gave sulfonate derivatives.

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.