Synthesis of Functionalized Diethyl(pyrrolidin-2-yl)phosphonate and Diethyl(5-oxopyrrolidin-2-yl)phosphonate

Abstract

Short and efficient syntheses of functionalized (pyrrolidin-2-yl)phosphonate and (5-oxopyrrolidin-2-yl)phosphonate have been developed. The synthetic strategy involved the diastereospecific 1,3-dipolar cycloaddition of N-benzyl-C-(diethoxyphosphoryl)nitrone to cis-1,4-dihydroxybut-2-ene and dimethyl maleate, respectively. O,O-Diethyl 3-carbamoyl-4-hydroxy(5-oxopyrrolidin-2-yl)phosphonate was obtained from O,O-diethyl 2-benzyl-4,5-dimethoxycarbonyl(isoxazolidin-3-yl)phosphonate by hydrogenation and subsequent treatment with ammonia, whereas transformation of O,O-diethyl 2-benzyl-4,5-dihydroxymethyl(isoxazolidin-3-yl)phosphonate into O,O-diethyl 3-aminomethyl-4-hydroxy(pyrrolidin-2-yl)phosphonate was accomplished by mesylation followed by hydrogenolysis to undergo intramolecular cyclization and the introduction of amino group via ammonolysis. Stereochemistry of the isoxazolidine cycloadducts, as well as the final functionalized (pyrrolidin-2-yl)- and (5-oxopyrrolidin-2-yl)phosphonates were established based on conformational analyses using vicinal H-H, H-P, and C-P couplings and supported by the observed diagnostic NOESY correlation signals.

Keywords: cycloaddition; isoxazolidines; phosphonates; substituted pyrrolidines.

Figure 1

Examples of pyrrolidine- and pyrrolidone-containing biologically active compounds.

Figure 2

Phosphoproline 15 and its functionalized analogues 16 and 17.

Scheme 1

Retrosynthesis of 18 and 19.

Scheme 2

Reaction and conditions: a. toluene, 60 °C (reaction time: 24 h for the synthesis of 20 and 96 h for the synthesis of 21).

Scheme 3

Reaction and conditions: a. toluene, 24 h, 60 °C, 74%.

Figure 3

The preferred conformation of 20 and the most important NOESY correlation for phosphonate 21 (blue arrows).

Scheme 4

Synthesis of γ-lactam 24. Reaction and conditions: a. H₂, Pd(OH)₂–C, MeOH, rt, 1.01 bar, 24 h, 75% or H₂, Pd(OH)₂–C, MeOH, rt, 15 bar, 5 h, 94%; b. aq. NH₃, MeOH, 17 h, 56%.

Figure 4

The preferred conformations of 18 and 24 with the most important NOESY correlations (blue arrow).

Scheme 5

Synthesis of functionalized proline analogues 28 and 30. Reaction and conditions: a. MsCl, Et₃N, CH₂Cl₂, 0 °C, 2h, 96%; b. H₂, Pd(OH)₂–C, MeOH, 1.01 bar, 22 h or H₂, Pd(OH)₂–C, MeOH, 15 bar, 6 h; c. K₂CO₃, CHCl₃, rt, 3 h, (38% and 70% in two steps: b and c); d. morpholine, neat, rt, 39 h, 33%; e. NaN₃, MeOH, 60 °C, 96 h, 43%; f. H₂, Pd(OH)₂–C, Boc₂O, EtOH, rt, 35 h, 69%.