Regioselective Fluorination of α‐Hydroxy‐β‐aminophosphonates by Using PyFluor

Abstract

We report a simple protocol for the synthesis of α‐fluoro‐β‐aminophosphonates by the regioselective fluorination of α‐hydroxy‐β‐aminophosphonates under mild conditions. The fluorination reactions were mediated by the PyFluor reagent and occurred with the retention of configuration. The main products of this reaction were a series of α‐fluoro‐β‐aminophosphonates, which can be used as precursors in the preparation of medicinally important compounds (e.g., dipeptide analogues).

Efficient synthesis of dipeptide analogues of α-fluorinated β-aminophosphonates

“…The crude products were isolated using column chromatography (chloroform → chloroform/methanol 100:0.5 v/v). The NMR spectroscopic data for amino alcohols 5 were in good agreement with our previous research [30,31,48].…”

“…The mechanism of the PyFluor-mediated deoxyfluorination of the α-hydroxy-β-aminophosphonates 5 was previously proposed. Based on spectroscopic studies ( 19 F, 1 H-HOESY, 1 H, 1 H-NOESY, as well as J-couplings) a relative configuration of N,N-dibenzyl-protected α-fluoro-β-aminophosphonates 11 was established as (1R,2S), but we failed to crystallize these compounds [31]. That is why the removal of the benzyl protecting group from fluorides 11 and the transfer of the free amines 13 into the salts 14 was applied.…”

“…Our previous studies have shown that the regioselectivity of the nucleophilic fluorination of amino alcohols can be controlled depending on the fluorinating reagent used [30,31]. This work presents the optimization of nucleophilic fluorination conditions.…”

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

“…Moreover, remaining diastereoisomer 3b stayed intact in the reaction mixture, while reaction at a higher temperature (45 C, 0.75 h) led to decomposition of starting materials. These results are contrary to the reaction of b-amino-a-hydroxyalkylphosphonates with PyFluor where mainly a-uoroalkylphosphonates were formed,17 although the amount of the second regioisomer in our case was higher compared to the analogous reaction of 3a,b with DAST.Taking into account the neighbouring groups participation in deoxyuorination of a-hydroxyphosphonate proline derivatives, we have decided to investigate similar reaction on serine derivatives having N-Cbz, N-Boc, and N-Bn protecting groups.Thus, the reaction with DAST [À78 C (3 h) / RT (16 h)] carried on 15a,b or 16a,b [99 : 1 d.r., (4S,1 0 R, : 4R,1 0 S)] gave two type of products: bicyclic 17 and aziridines 18 with yields 32% and 17% (or 17 and 19 with yields 40% and 56%, respectively) (Scheme 7). Similarly, to the formation of 6a,b, bicyclic oxazolidine-2-one 17 arose by the attack of carbamate C]O electron pair (from Cbz or Boc) on leaving group (-OSF 2 N(Et) 2 ) coming from the reaction of an alcohol moiety with DAST (Scheme 7).…”

“…On the other hand, the reactions of 1a,b or 2a,b (with a different ratio of stereoisomers) carried out with Deoxo-uor (RT, 24 h) gave the same products 4-7, 9-10 with a parallel ratio to reaction with DAST. Moreover, the reactions of 1a,b (3 17 On the base of the results described for prolinols 1-2a,b we next examined the uorination of diastereoisomeric mixture of 3a,b having benzyl as N-protecting group ( Table 2).…”