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.

1. Introduction

Pyrrolidine is an important fragment of many natural products [1,2,3,4] that can be exemplified by complex structures of swainsonin [5], monocotaline [6], lasiocarpine [7], and senecionine [8]. Pyrrolidine and pyrrolidinone moieties are also present in small biologically active molecules. For example, L-proline 1 and its hydoxylated analogue 2 (Figure 1) are the essential components of collagen, accounting for 30% of its composition and playing key roles in the stability of the collagen [9,10].

On the other hand, pyroglutamic acid 3 (Figure 1) is formed as a result of glutamate dehydration [11]. This is an intermediate substrate involved in the glutathione synthesis [12]. For decades, the basic structure of pyroglutamic acid has been modified and resulted in the syntheses of pharmacologically active compounds such as piracetam 4, oxiracetam 5, nebracetam 6, and its morpholine derivative 7 (Figure 1), which belong to “nootropic drugs” used in treatment of CNS diseases such as epilepsy and depression [13,14,15,16,17,18].

Hydroxylated pyrrolidine derivatives 8 and 9 (Figure 1) affected brain Glu levels and at the same time they did not exhibit brain and hepatic toxicity. The only disadvantage of these compounds is their inability to overcome the blood-brain interface [19]. Polyhydroxylated derivative of pyrrolidine 10, its enantiomer and 11 (Figure 1) have been obtained as inhibitors of α-glucosidases. Moreover, compound 11 demonstrates superior control of blood glucose levels [20]. On the other hand, antibiotic activity of several pyrrolidone-containing compounds has been observed, including compounds 12 and 13 [21] containing pyrrolidone ring incorporated in bicyclic system, as well as 14 (derivative of equisetin having additional methyl group at C3 in octahydronaphtalenyl moiety) acting on some multi-drug resistant bacteria [22] (Figure 1), and their resistance to β-lactamase have been recognized.

Over the decades, the importance of phosphonates in medicinal chemistry has been recognized [23,24,25]. Numerous phosphonates have been reported as analogues of biologically important compounds, including inhibitors of several enzymes, as well as antibacterial, antiviral, and fungicidal agents. Phosphonates have also been applied as mimetics of hydroxy- and amino acids in studies on their mode of action in biochemical transformations [26]. For this reason, phosphoproline 15 (Figure 2) [27] and its functionalized analogues received considerable attention and some of them have been successfully incorporated in biologically active systems such as analogues of dipeptides [28,29,30,31,32,33]. On the other hand, pyrrolidinone-containing phosphonate 16 (Figure 2), as a mixture of cyclic and non-cyclic form, has been recognized as inhibit NMCA β-lactamase. Moreover, a good activity of the cyclic form in the mixture of 16a and 16b tested against R39 D,D-peptidase has been proved [34].

Several years ago, stereoisomers of analogues of proline as respective diethyl phosphonates 17 (Figure 2) hydroxylated at C4 in pyrrolidine ring have been synthesized in our research group [35]. Herein the syntheses of phosphonates 18 and 19 containing pyrrolidine framework functionalized at C3 and C4 are described (Scheme 1). Since N-substituted C-phosphorylated nitrones [36] have been successfully applied in the synthesis of various (isoxazolidin-3-yl)phosphonates [36,37] we found them suitable also for the preparation of isoxazolidines 20 and 21, which could be then transformed into the designed compounds 18 and 19 or their functionalized analogues. While isoxazolidine cycloadducts obtained from allyl alcohol and C-phosphorylated nitrone have already been successfully transformed into compound 17 (Figure 2) having hydroxy group at C4 in pyrrolidine skeleton [35], the application of 1,4-dihydroxybut-2-ene in 1,3-dipolar cycloaddition would allow to synthesis pyrrolidine 19 functionalized in both C3 and C4 positions. On the other hand, rearrangement of isoxazolidine 20 to pyrrolidinone 18 would be possible following the strategy demonstrated for several examples of differently functionalized systems [38,39,40,41].

2. Results and Discussion

The nitrone 22 was synthesized and fully characterized previously [36]. Cycloaddition of nitrone 22 with dimethyl maleate was then performed and led to the formation of (isoxazolidin-3-yl)phosphonate 20 as a single diastereoisomer in 84% yield after chromatographic purification. Similarly, reaction of nitrone 22 with cis-1,4-dihydroxybut-2-ene gave diastereoisomeric cycloadduct 21 in 70% yield after column chromatography (Scheme 2). In both cases, formation of single diastereoisomeric product (20 or 21) was proved by the analyses of the ³¹P and ¹H NMR spectra of the crude product.

On the other hand, when maleic anhydride was used in the 1,3-dipolar cycloaddition with nitrone 22 isoxazolidine 23 was obtained exclusively in good yield (Scheme 3).

Since cis-alkenes were used for cycloadditions (Scheme 2 and Scheme 3), the cis relationship between HC4 and HC5 protons in 20 and 21, as well as in 23 can be arbitrarily assigned. To establish a relative configuration of (isoxazolidin-3-yl)phosphonate 18 the detailed conformational analysis was performed based on HCCP [42], HCCP [43,44], and CCCP [45,46] vicinal constants extracted from the ¹H and ¹³C-NMR spectra. The vicinal couplings (J(H-C3C4-H) = 8.0 Hz, J(H-C4C5-H) = 8.3 Hz, J(H-C4C3-P) = 16.0 Hz, J(P-CC-C5) = 8.0 Hz, and J(P-CC-CO) = 5.5 Hz) indicate the ₃E conformation of isoxazolidine ring. In this conformation the pseudoequatorially located diethoxyphosphoryl group at C3 is in trans relationship to both COOMe groups at C4 and C5 positions (Figure 3). On the other hand, to gather evidences for the spatial orientation of substituents in relation to the isoxazolidine moiety in (isoxazolidin-3-yl)phosphonate 21, NOESY experiment was performed. NOE diagnostic signals between HC4 and CH₂OP as well as between HC3 and C4-CH₂OH protons were noticed (Figure 3), which fully support the trans relationship between the HC3 and HC4 protons.

Next, transformation of (isoxazolidin-3-yl)phosphonate 20 into (5-oxopyrrolidin-2-yl)phosphonate 24 was performed (Scheme 4). Hydrogenation of the N–O bond together with the removal of benzyl group in isoxazolidine 20 released the free amino group, which subsequently became involved in spontaneous intramolecular cyclization to γ-lactam to produce phosphonate 18 in good yield (75%). When hydrogenation was carried out at a pressure of 15 bar, reaction time was significantly shortened (24 h vs. 5 h); moreover, the application of this procedure allowed to isolate compound 16 in higher yield (94%). Since configurations of all stereogenic centers in isoxazolidine ring (namely at C3, C4, and C5) remain unchanged during this transformation, relative configuration of γ-lactam ring (at C2, C3, and C4, respectively) in 18 can be established unambiguously. 3-Methoxycarbonyl-(5-oxopyrrolidin-2-yl)phosphonate 18 was then successfully transformed into 3-carbamoyl derivative 24 via ammonolysis (56%).

In order to support the already established relative stereochemistry of (5-oxopyrrolidin-2-yl)phosphonates 18 and 24, conformational analyses were undertaken. Based on the vicinal couplings found in ¹H and ¹³C-NMR spectra of 18 (J(H-C3C4-H) = 8.8 Hz, J(H-C2C3-H) = 8.8 Hz, J(H-C3C2-P) = 17.6 Hz, J(P-CC-C4) = 7.8 Hz and J(P-CN-CO) = 7.8 Hz) and 24 (J(H-C3C4-H) = 9.1 Hz, J(H-C2C3-H) = 9.0 Hz, J(H-C3C2-P) = 18.0 Hz, J(P-CC-C4) = 8.7 Hz and J(P-CN-CO) = 7.9 Hz), the preferred ³E conformation of oxopyrrolidine ring was established in both phosphonates 18 and 24. In this conformation all substituents at C2, C3, and C4, namely OH, COR, and P(O)(OEt)₂ groups are located equatorially, consequently hydrogen atoms occupy axial positions (Figure 4). Moreover, when NOESY experiments were performed for both phosphonates 18 and 24, NOE diagnostic signals between HC4 and HC2 protons were noticed, which fully support their cis orientations.

On the other hand, (isoxazolidin-3-yl)phosphonate 21 was found to be a good substrate for the synthesis of functionalized phosphoproline derivative (Scheme 5). Phosphonate 21 was first mesylated to produce O,O-dimesyl derivative 25, which was then subjected to hydrogenolysis to accomplish cleavage of N–O bond followed by removal of benzyl group together with intramolecular cyclization to form pyrrolidine ring in compound 26 [35]. The resulted crude ammonium mesylate 26 was then neutralized with potassium carbonate in chloroform to give functionalized phosphoproline analogue 27 (38% yield in two steps). Again, when hydrogenation was carried out at 15 bar pressure, the reaction time required for transformation of (isoxazolidin-3-yl)phosphonate 25 into ammonium mesylate 26 was significantly shortened (22 h vs. 6 h), and after neutralization with potassium carbonate phosphoproline analogue 27 was obtained efficiently (70% yield in two steps). Finally, compound 27 was reacted with morpholine to give 28 in 33% yield. Alternatively, mesyl group in 27 was changed to amino function by treatment with sodium azide followed by hydrogenolysis in the presence of Boc₂O to produce phosphonate 30 (Scheme 5).

3. Materials and Methods

3.1. General Information

¹H-NMR spectra were taken in CDCl₃, C₆D₆ or CD₃OD on a Bruker Avance III (600 MHz, Bruker Instruments, Karlsruhe, Germany). For spectra recorded in CDCl₃ and C₆D₆ TMS was used as an internal standard; chemical shifts δ are given in ppm with respect to TMS and coupling constants J in Hz. ¹³C-NMR and ³¹P-NMR spectra were recorded in a ¹H-decoupled mode for CDCl₃, C₆D₆ or CD₃OD solutions on the Bruker Avance III (600 MHz) spectrometer at 151 and 243 MHz, respectively. IR spectral data were measured on a Bruker Alpha-T FT-IR spectrometer (Bruker Optik GmbH, Ettlingen, Germany). Melting points were determined on a Boetius apparatus and are uncorrected. Elemental analyses were performed by the Microanalytical Laboratory of the Faculty of Pharmacy (Medical University of Lodz) on a Perkin Elmer PE 2400 CHNS analyzer (Perkin-Elmer Corp., Norwalk, CT, USA), and their results were found to be in good agreement (±0.3%) with the calculated values. Experiments at 15 bar pressure were carried out in a Büchi pressure reactor (Büchi AG, Uster, Switzerland).

The following adsorbents were used: column chromatography, Merck silica gel 60 (70–230 mesh), analytical TLC, Merck TLC plastic sheets silica gel 60 F₂₅₄. TLC plates were developed in chloroform-methanol solvent systems. Visualization of spots was affected with iodine vapors. All solvents were purified by methods described in the literature.

¹H-, ¹³C- and ³¹P-NMR spectra of all new synthesized compounds are provided in Supplementary Materials.

3.2. General Procedure for the Synthesis of Isoxazolidines 20, 21 and 23

A solution of nitrone 22 (2.0 mmol) and alkene (2.2 mmol) in toluene (4 mL) were stirred at 60 °C for 24 to 96 h (until the disappearance of the nitrone). The reaction mixture was concentrated in vacuo. The crude product was purified by silica gel column.

Dimethyl 2-benzyl-3-(diethoxyphosphoryl)isoxazolidine-4,5-dicarboxylate (20). Compound 20 was prepared from nitrone 22 (2.00 mmol, 0.542 g) and dimethyl maleate (2.20 mmol, 0.276 mL) and purified by column chromatography on a silica gel column with hexane-ethyl acetate (3:2, v/v) and crystallization (chloroform-hexane). Yield: 84% (0.697 g) as a white solid; m.p. = 75–78 °C. IR (KBr, cm⁻¹): ν_max= 2989, 2953, 2908, 1765, 1738, 1442, 1315, 1269, 1221, 1171, 1057, 1026, 984, 743, 707. ¹H NMR (600 MHz, CDCl₃): δ = 7.45–7.42 (m, 2H, H_Ar), 7.34–7.31 (m, 2H, H_Ar), 7.29–7.27 (m, 1H, H_Ar), 4.70 (d, ³J_H5–H4 = 8.3 Hz, 1H, HC5), 4.52 (d, ²J_Ha–Hb=14.0 Hz, 1H, H_aH_bCPh), 4.28–4.16 (m, 5H, 2 × CH₂OP, H_aH_bCPh), 3.95 (ddd, ³J_H4–P = 16.3 Hz, ³J_H4–H5 = 8.3 Hz,³J_H4–H3 = 8,0 Hz, 1H, HC4), 3.80 (dd, ³J_H3–H4 = 8.0 Hz, ²J_H3–P = 2.8 Hz, 1H, HC3), 3.73 (s, 3H, CH₃O), 3.71 (s, 3H, CH₃O), 1.35 (t, ³J = 7.0 Hz, 3H, CH₃CH₂OP), 1.31 (t, ³J= 7.0 Hz, 3H, CH₃CH₂OP). ¹³C NMR (151 MHz, CDCl₃): δ = 169.29 (d, ³J_PCCC = 5.5 Hz, C(O)C4), 168.88 (C(O)C5), 137.16, 129.10, 128.26, 127.41, 77.39 (d, ³J_PCCC = 8.0 Hz, C5), 63.96 (d, ¹J_PC = 169.6 Hz, C3) 63.93 (d, ³J = 6.5 Hz, CH₂N), 62.90 (d, ²J = 5.7 Hz, COP), 62.88 (d, ²J = 5.7 Hz, COP), 53.45 (CH₃O), 52.76 (CH₃O), 52.47 (C4), 16.54 (d, ³J = 5.8 Hz, CCOP), 16.35 (d, ³J = 5.7 Hz, CCOP). ³¹P NMR (243 MHz, CDCl₃): δ = 19.14. Analysis Calculated for C₁₈H₂₆NO₈P: C, 52.05; H, 6.31; N, 3.37; Found: C, 52.05; H, 6.31; N, 3.36.

Diethyl 2-benzyl-4,5-dihydroxy-isoxazolidinyl-3-phosphonate (21). Compound 21 was prepared from nitrone 22 (2.00 mmol, 0.542 g) and cis-2-butene-1,4-diol (2.20 mmol, 0.194 mL) and purified by column chromatography on a silica gel column with chloroform-methanol (50:1, v/v). Yield: 70% (0.502 g) as a yellowish oil. IR (film, cm⁻¹): ν_max= 3385, 3064, 3032, 1497, 1229, 1050, 1025, 973, 740, 573. ¹H NMR (600 MHz, CDCl₃): δ = 7.40–7.38 (m, 2H, H_Ar), 7.35–7.30 (m, 2H, H_Ar), 7.30–7.26 (m, 1H, H_Ar), 4.55 (d, ²J_HA-HB = 14.5 Hz, 1H, H_AH_BCPh), 4.32–4.20 (m, 4H, 2 × CH₂OP), 4.13 (ddd, ³J_H5–H4 = 9.7 Hz, ³J_H5–Ha = 5.9 Hz, ³J_H5–Hb = 3.5 Hz, 1H, HC5), 3.89 (d, ²J_HA–HB = 14.5 Hz, 1H, H_AH_BCPh), 3.86 (dd, ²J_Ha–Hb = 12.5 Hz, ³J_Ha–H5 = 5.9 Hz, 1H, H_aH_bC-C5), 3.76 (dd, ²J_Ha–Hb = 12.5 Hz, ³J_Hb–H5 = 3.5 Hz, 1H, H_aH_bC-C5), 3.78–3.74 (m, 2H, CH₂-C4), 3.10–3.00 (m, 2H, HC4, HC3), 1.38 (t, ³J = 7.2 Hz, 3H, CH₃CH₂OP), 1.36 (t, ³J= 7.2 Hz, 3H, CH₃CH₂OP). ¹H NMR (600 MHz, C₆D₆): δ = 7.54–7.51 (m, 2H, H_Ar), 7.24–7.21 (m, 2H, H_Ar), 7.14–7.10 (m, 1H, H_Ar), 4.54 (d, ²J_HA–HB = 14.4 Hz, 1H, H_AH_BCPh), 4.28 (dt, ³J_H5–H4 = 6.8 Hz, ³J_H5–Ha = 6.8 Hz, ³J_H5–Hb = 4.2 Hz, 1H, HC5), 4.08–3.94 (m, 4H, 2 × CH₂OP), 3.89 (d, ²J_HA–HB = 14.4 Hz, 1H, H_AH_BCPh), 3.89 (dd, ²J_Ha–Hb = 12.0 Hz, ³J_Ha–H5 = 6.8 Hz, 1H, H_aH_bC-C5), 3.87 (dd, ²J_Ha–Hb = 11.4 Hz, ³J_Ha–H4 = 7.9 Hz, 1H, H_aH_bC-C4), 3.79 (dd, ²J_Ha–Hb = 12.0 Hz, ³J_Hb–H5 = 4.2 Hz, 1H, H_aH_bC-C5), 3.76 (dd, ²J_Ha–Hb = 11.4 Hz, ³J_Hb–H4 = 4.0 Hz, 1H, H_aH_bC-C4), 3.20 (ddddd, ³J_H4–P = 18.7 Hz, ³J_H4–Ha = 7.9 Hz, ³J_H4–H5 = 6.8 Hz, ³J_H4–H3 = 6.8 Hz, ³J_H4–Hb = 4.0 Hz, 1H, HC4), 3.07 (dd, ³J_H3–H4 = 6.8 Hz, ²J_H3–P = 1.1 Hz, 1H, HC3), 1.06 (t, ³J = 7.0 Hz, 3H, CH₃CH₂OP), 1.04 (t, ³J = 7.0 Hz, 3H, CH₃CH₂OP). ¹³C NMR (151 MHz, C₆D₆): δ = 137.94, 129.02, 128.13, 127.99, 127.11, 79.53 (d, ³J_PCCC = 7.4 Hz, C5), 63.38 (d, ¹J_PC = 169.5 Hz, C3), 63.13 (d, ²J = 6.6 Hz, COP), 62.75 (d, ²J = 6.6 Hz, COP), 62.66 (d, ³J = 3.4 Hz, CH₂N), 60.59 (d, ³J = 7.5 Hz, CH₂C4), 59.33 (CH₂C5), 49.72 (C4), 16.19 (d, ³J = 5.7 Hz, CCOP), 16.13 (d, ³J = 5.7 Hz, CCOP). ³¹P NMR (243 MHz, CDCl₃): δ = 22.05 ppm. ³¹P NMR (243 MHz, C₆D₆): δ = 22.94. Analysis Calculated for C₁₆H₂₆NO₆P: C, 53.48; H, 7.29; N, 3.90. Found: C, 53.25; H, 7.16; N, 4.20.

2-Benzyl-3-(diethoxyphosphoryl)isoxazolidine-4,5-dicarboxylic acid (23). Compound 23 was prepared from nitrone 22 (2.00 mmol, 0.542 g) and maleic anhydride (2.20 mmol, 0.146 mL) and purified by column chromatography on a silica gel column with chloroform-methanol (10:1, v/v). Yield: 74% (0.573 g) as a yellowish oil. IR (film, cm⁻¹): ν_max= 3040, 2984, 2925, 1738, 1494 1206, 1045, 1020. ¹H NMR (600 MHz, CDCl₃): δ = 7.40–7.38 (m, 2H, H_Ar), 7.32–7.28 (m, 2H, H_Ar), 7.25–7.20 (m, 1H, H_Ar), 6.50–6.10 (br s, 2H, 2 × OH), 4.76 (d, ³J_H5–H4 = 8.3 Hz, 1H, HC5), 4.41 (d, ²J_Ha–Hb=14.0 Hz, 1H, H_aH_bCPh), 4.23 (d, ²J_Ha–Hb=14.0 Hz, 1H, H_aH_bCPh), 4.25–4.15 (m, 4H, 2 × CH₂OP), 4.02 (ddd, ³J_H4–P = 16.3 Hz, ³J_H4–H5 = 8.3 Hz,³J_H4–H3 = 8,0 Hz, 1H, HC4), 3.89 (dd, ³J_H3–H4 = 8.0 Hz, ²J_H3–P = 3.1 Hz, 1H, HC3), 1.33 (t, ³J = 7.1 Hz, 3H, CH₃CH₂OP), 1.31 (t, ³J= 7.1 Hz, 3H, CH₃CH₂OP). ¹³C NMR (151 MHz, CDCl₃): δ = 172.48 (C=O), 171.97 (C=O), 137.11, 129.10, 128.28, 127.42, 77.78 (br s, C5), 64.29 (d, ²J = 6.6 Hz, COP), 64.11 (d, ¹J_PC = 170.8 Hz, C3), 64.00 (d, ²J = 6.4 Hz, COP), 62.74 (br s, CH₂N), 53.43 (C4), 16.42 (d, ³J = 5.6 Hz, CCOP), 16.31 (d, ³J = 5.6 Hz, CCOP). ³¹P NMR (243 MHz, CDCl₃): δ = 19.85 ppm. Analysis Calculated for C₁₆H₂₂NO₈P: C, 49.62; H, 5.73; N, 3.62. Found: C, 49.90; H, 5.52; N, 3.86.

3.3. Preparation of γ-Lactam 18

Procedure A: A solution of isoxazolidine 20 (0.045 g, 0.108 mmol) in methanol (1 mL) was kept under an atmospheric pressure of hydrogen over 20% Pd(OH)₂–C (1.4 mg) at room temperature for 24 h. The suspension was filtered through a layer of Celite. The solution was concentrated, and the residue was chromatographed on silica gel column with chloroform-methanol (100:1, v/v) to give pure γ-lactam 18 (0.024 g, 0.081 mmol, 75%).

Procedure B: A solution of isoxazolidine 20 (0.208 g, 0.50 mmol) in methanol (5 mL) was kept in a pressure reactor under 15 bar pressure of hydrogen over 20% Pd(OH)₂-C (6.5 mg) at room temperature for 5 h. The suspension was filtered through a layer of Celite. The solution was concentrated, and the residue was chromatographed on a silica gel column with chloroform-methanol (100:1, v/v) to give pure γ-lactam 18 (0.138 g, 94%).

Methyl 2-(diethoxyphosphoryl)-4-hydroxy-5-oxopyrrolidine-3-carboxylate (18). White solid; m.p. = 120–124 °C. IR (KBr, cm⁻¹): ν_max= 3298, 3189, 3126, 2989, 2957, 2925, 2796, 1741, 1713, 1441, 1374, 1248, 1170, 1049, 1010, 862, 753. ¹H NMR (600 MHz, CDCl₃): δ = 7.15 (brs, 1H, NH), 4.54 (d, ³J_H3–OH = 7.6 Hz, 1H, OH), 4.46 (dd, ³J_H3–H4 = 8.8 Hz, ³J_H3–OH = 7.6 Hz, 1H, HC4), 4.25–4.14 (m, 4H, 2 × CH₂OP), 4.07 (dd, ³J_H2–H3 = 8.8 Hz, ²J_H2–P = 3.2 Hz, 1H, HC2), 3.79 (s, 3H, CH₃O), 3.40 (dt, ³J_H3–P = 17.6 Hz, ³J_H4–H3 = 8.8 Hz, ³J_H3–H2 = 8.8 Hz, 1H, HC3), 1.35 (t, ³J = 7.0 Hz, 3H, CH₃CH₂OP), 1.32 (t, ³J= 7.0 Hz, 3H, CH₃CH₂OP). ¹³C NMR (151 MHz, CDCl₃): δ = 174.94 (d, ³J_PCNC = 7.8 Hz, C5), 171.35 (d, ³J_PCCC = 2.3 Hz, C(O)CH₃), 72.89 (d, ³J_PCCC = 7.8 Hz, C4), 63.77 (d, ²J = 7.1 Hz, COP), 63.66 (d, ²J = 7.1 Hz, COP), 52.82 (CH₃O), 49.72 (d, ²J_CCP = 4.3 Hz, C3), 48.65 (d, ¹J_CP = 167.1 Hz, CP), 16.41 (d, J = 6.0 Hz, CCOP), 16.36 (d, J = 6.0 Hz, CCOP). ³¹P NMR (243 MHz, CDCl₃) δ = 20.63. Analysis Calculated for C₁₀H₁₈NO₇P: C, 40.68; H, 6.15; N, 4.74. Found: C, 40.88; H, 6.23; N, 4.91.

3.4. Ammonolysis of 18

To a solution of γ-lactam 18 (0.030 g, 0.10 mmol) in methanol (0.5 mL), aqueous NH₃, (25%, 0.4 mL) was added. The homogenous mixture was stirred at room temperature for 17 h. Solvents were removed in vacuo, and the residue was evaporated with anhydrous methanol (3 × 5 mL), chloroform (3 × 5 mL) and chromatographed on silica gel with chloroform-methanol (10:1, v/v) to give pure 24 (0.016 g, 60%).

2-(diethoxyphosphoryl)-4-hydroxy-5-oxopyrrolidine-3-carboxamide (24). White solid; m.p. = 133–135 °C. IR (KBr, cm⁻¹): ν_max= 3300, 3199, 2986, 1711, 1679, 1231, 1045, 1020. ¹H NMR (600 MHz, CD₃OD): δ = 4.40 (d, ³J_H3-H4 = 9.0 Hz, 1H, HC4), 4.25–4.20 (m, 4H, 2 × CH₂OP), 4.08 (dd, ³J_H2–H3 = 9.0 Hz, ²J_H2–P = 2.0 Hz, 1H, HC2), 3.18 (dt, ³J_H3–P = 18.0 Hz, ³J_H4–H3 = 9.0 Hz, ³J_H3–H2 = 9.0 Hz, 1H, HC3), 1.38 (t, ³J = 7.0 Hz, 6H, 2 × CH₃CH₂OP). ¹³C NMR (151 MHz, CD₃OD): δ = 177.19 (d, ³J_PCNC = 7.9 Hz, C5), 174.65 (C(O)NH₂), 74.11 (d, ³J_PCCC = 8.7 Hz, C4), 64.91 (d, ²J = 6.7 Hz, COP), 64.82 (d, ²J = 6.7 Hz, COP), 51.83 (d, ²J_CCP = 4.3 Hz, C3), 49.51 (d, ¹J_CP = 167.4 Hz, CP), 16.74 (d, J = 5.6 Hz, CCOP), 16.67 (d, J = 5.4 Hz, CCOP). ³¹P NMR (243 MHz, CD₃OD) δ = 21.25. Analysis Calculated for C₉H₁₇N₂O₆P: C, 38.58; H, 6.12; N, 10.00. Found: C, 38.29; H, 6.33; N, 9.92.

3.5. Mesylation of (Isoxazolidin-3-yl)Phosphonate 21

To a solution of isoxazolidine 21 (0.188 g, 0.523 mmol) in methylene chloride (6 mL) triethylamine (1.569 mmol, 0.219 mL) and mesyl chloride (1.569 mmol, 0.122 mL) were added at 0°C. The reaction mixture was stirred at this temperature for 2 h. The residue was washed with water (3 × 3 mL) and dried over MgSO₄. The solution was concentrated, and the residue was chromatographed on silica gel column with chloroform to give pure dimesylate 25 (0.250 g, 96%).

Diethyl 2-benzyl-4,5-(dimesyloxymethyl)-3-phosphonate (25). Colourless oil. IR (film, cm⁻¹): ν_max= 3030, 2986, 2934, 1358, 1243, 1177, 1051, 1023, 964, 812, 754, 628. ¹H NMR (600 MHz, CDCl₃): δ = 7.39–7.33 (m, 4H, H_Ar), 7.31–7.28 (m, 1H, H_Ar), 4.59 (d, ²J_Ha–Hb= 14.3 Hz, 1H, H_AH_BCPh), 4.46 (dd, ²J_Ha–Hb = 11.6 Hz, ³J_Ha–H4 = 3.9 Hz, 1H, H_aH_bC-C4), 4.40 (dd, ²J_Ha–Hb = 11.6 Hz, ³J_Ha–H4 = 6.8 Hz, 1H, H_aH_bC-C4), 4.33–4.21 (m, 7H, 2 × CH₂OP, HC5, H_aH_bC-C5), 3.88 (d, ²J_HA–HB=14.3 Hz, 1H, H_AH_BCPh), 3.27 (ddddd, ³J_H4–P = 17.3 Hz, ³J_H4–Ha = 6.8 Hz, ³J_H4–H5 = 8.9 Hz, ³J_H4–H3 = 6.6 Hz, ³J_H4–Hb = 3.9 Hz, 1H, HC4), 3.04 (s, 3H, CH₃), 2.97 (dd, ³J_H3–H4 = 6.6 Hz, ²J_H3–P = 3.1 Hz, 1H, HC3), 2.89 (s, 3H, CH₃), 1.41 (t, ³J = 7.1 Hz, 3H, CH₃CH₂OP), 1.39 (t, ³J= 7.1 Hz, 3H, CH₃CH₂OP). ¹³C NMR (151 MHz, CDCl₃): δ = 136.22, 129.30, 128.29, 127.65, 75.93 (d, ³J_PCCC = 7.6 Hz, C5), 66.55 (CH₂-C4), (65.86 (d, ³J = 8.0 Hz, CH₂-C4), 64.01 (d, ²J = 6.6 Hz, COP), 63.40 (d, ¹J_PC = 170.7 Hz, C3), 62.95 (d, ²J = 6.6 Hz, COP), 62.36 (d, ³J = 3.2 Hz, CH₂N), 46.63 (d, ²J = 2.0 Hz, C4), 37.65 (CH₃S), 37.57 (CH₃S), 16.64 (d, ³J = 5.5 Hz, CCOP), 16.48 (d, ³J = 5.5 Hz, CCOP). ³¹P NMR (243 MHz, CDCl₃): δ = 19.73. Analysis Calculated for C₁₈H₃₀NO₁₀PS₂: C, 41.94; H, 5.87; N, 2.72. Found C, 42.05; H, 5.93; N, 3.01.

3.6. The Synthesis of (Pyrrolidin-2-yl)Phosphonate 24 from Dimesylate 25

Procedure A: A solution of dimesylate 25 (0.20 g, 0.39 mmol) in methanol (2.5 mL) was kept under atmospheric pressure of hydrogen over 20% Pd(OH)₂-C (3.9 mg) at room temperature for 22 h. The reaction progress was controlled by TLC. The suspension was filtered through a layer of Celite. The solution was concentrated to give ammonium mesylate (26), which was then dissolved in chloroform (4 mL) and anhydrous potassium carbonate (0.108 g, 0.78 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. Then anhydrous MgSO₄ was added, and the suspension was filtered through a layer of Celite. The solution was concentrated, and the residue was chromatographed on silica gel column with chloroform-methanol (100:1, v/v) to give pure 27 (0.049 g, 38%).

Procedure B: A solution of dimesylate 25 (0.236 g, 0.46 mmol) in methanol (5 mL) was kept in a pressure reactor under 15 bar pressure of hydrogen over 20% Pd(OH)₂-C (10 mg) at room temperature for 6 h. The suspension was filtered through a layer of Celite. The solution was concentrated to give ammonium mesylate (26), which was then dissolved in chloroform (10 mL) and anhydrous potassium carbonate (0.127 g, 0.92 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. Then anhydrous MgSO₄ was added, and the suspension was filtered through a layer of Celite. The solution was concentrated, and the residue was chromatographed on silica gel column with chloroform-methanol (100:1, v/v) to give pure 27 (0.106 g, 70%).

Diethyl 4-hydroxy-3-mesyloxymethyl(pyrrolidin-2-yl)-phosphonate (27). Colorless oil. IR (film, cm⁻¹): ν_max= 3386, 2986, 2875, 1644, 1352, 1222, 1174, 1025, 970, 818. ¹H NMR (600 MHz, CDCl₃): δ = 4.31 (dd, J = 10.2 Hz, J = 5.6 Hz, 1H, HCH-C3), 4.25–4.15 (m, 6H, HC4, HCH-C3, 2 × CH₂OP), 3.26 (dd, ²J_H2–P = 7.9 Hz, ³J_H2–H3 = 5.8 Hz, 1H, HC2), 3.17 (dd, ²J_Ha–Hb = 11.5 Hz, ³J_H5–H = 5.3 Hz, 1H, HHC5), 3.10 (dd, ²J_Ha–Hb = 11.4 Hz, ³J_H5–H = 3.0 Hz, 1H, HHC5), 3.06 (s, 3H, CH₃S), 2.65 (ddddd, ³J_H3–P = 18.5 Hz, ³J_H3–H2 = 5.8 Hz, ³J_H3–H4 = 5.8 Hz, ³J_H3–H = 5.6 Hz, ³J_H3–H = 2.7 Hz, 1H, HC3), 1.36 (t, ³J = 7.1 Hz, 3H, CH₃CH₂OP), 1.35 (t, ³J = 7.1 Hz, 3H, CH₃CH₂OP). ¹H NMR (600 MHz, CD₃OD): δ = 4.45 (dd, J = 10.3 Hz, J = 4.3 Hz, 1H, CH₂-C3), 4.35 (dd, J = 10.3 Hz, J = 5.2 Hz, 1H, CH₂-C3), 4.27–4.20 (m, 4H, 2 × CH₂OP), 4.18 (ddd, J = 5.9 Hz, J = 5.8 Hz, J = 5.7 Hz, 1H, HC4), 3.30 (dd, ²J_H2–P = 8.9 Hz, ³J_H2–H3 = 8.8 Hz, 1H, HC2), 3.15 (s, 3H, CH₃S), 3.06 (dd, ²J_Ha–Hb = 11.5 Hz, ³J_H5–H = 8.9 Hz, 1H, HHC5), 2.86 (ddd, ²J_Ha–Hb = 11.5 Hz, ³J_H5–H = 5.7 Hz, ³J_H5–CN–H = 1.1 Hz, 1H, HHC5), 2.47 (ddddd, ³J_H3–P = 18.0 Hz, ³J_H3–H2 = 8.8 Hz, ³J_H3–H4 = 5.8 Hz, ³J_H3–H = 5.2 Hz, ³J_H3–H = 4.3 Hz, 1H, HC3), 1.39 (t, ³J = 7.1 Hz, 3H, CH₃CH₂OP), 1.38 (t, ³J = 7.1 Hz, 3H, CH₃CH₂OP). ¹³C NMR (151 MHz, CD₃OD): δ = 74.65 (d, ³J_PCCC = 7.9 Hz, C4), 69.44 (d, ³J_PCCC = 2.6 Hz, COMs), 64.48 (d, J = 7.1 Hz, COP), 64.21 (d, J = 7.2 Hz, COP), 55.35 (d, ¹J_PC = 167.5 Hz, C2), 55.09 (d, ³J_PCNC = 8.9 Hz, C5), 50.19 (C3), 37.13 (CH₃S), 16.80 (d, J = 5.6 Hz, POCC), 16.80 (d, J = 5.7 Hz, POCC). ³¹P NMR (243 MHz, CDCl₃): δ = 26.33. Analysis Calculated for C₁₀H₂₂NO₇PS: C, 36.25; H, 6.69; N, 4.23. Found: C, 36.46; H, 6.96; N, 4.20.

3.7. Synthesis of (Pyrrolidin-2-yl)Phosphonate 28

(Pyrrolidin-2-yl)-phosphonate 27 (0.040 g, 0.12 mmol) with morpholine (1.5 mL) was kept at room temperature for 39 h. After that chloroform (15 mL) was added. The solution was washed with water (2 × 10 mL), dried over MgSO₄ and concentrated. The residue was chromatographed on silica gel column with chloroform-methanol (100:1, 50:1, v/v) to give pure 28 (0.014, 33%).

Diethyl (4-hydroxy-3-(piperidin-1-ylmeylyl)pyrrolidin-2-yl)phosphonate (28). Colourless oil. IR (film, cm⁻¹): ν_max= 3442, 2960, 2930, 2859, 2815, 1646, 1446, 1222, 1049, 1027. ¹H NMR (600 MHz, CDCl₃): δ = 4.30–4.15 (m, 4H, 2 × CH₂OP), 4.08–4.05 (br m, 1H, HC4), 3.75–3.70 (br m, 4H), 3.37 (dd, ²J_H2–P = 5.4 Hz, ³J_H2–H3 = 5.4 Hz, 1H, HC2), 3.27 (dd, ²J_Ha–Hb = 10.9 Hz, ³J_H5–H = 5.6 Hz, 1H, HHC5), 3.03 (dd, ²J_Ha–Hb = 10.9 Hz, ³J_H5–H = 4.5 Hz, 1H, HHC5), 2.60–2.45 (m, 7H, HC3, 3 × CH₂-C3), 1.38 (t, ³J = 7.1 Hz, 3H, CH₃CH₂OP), 1.36 (t, ³J = 7.1 Hz, 3H, CH₃CH₂OP). ¹³C NMR (151 MHz, CDCl₃): δ = 77.16 (d, ³J_PCCC = 5.4 Hz, C4), 66.69 (CH₂-O-CH₂), 61.11 (d, ³J_PCCC = 8.8 Hz, CH₂N), 63.12 (d, J = 7.4 Hz, COP), 62.37 (d, J = 7.5 Hz, COP), 55.64 (d, ¹J_PC = 166.1 Hz, C2), 53.75 (2 × CH₂N), 53.60 (d, ³J_PCNC = 6.6 Hz, C5), 45.40 (C3), 16.62 (d, J = 5.5 Hz, POCC), 16.54 (d, J = 5.9 Hz, POCC). ³¹P NMR (243 MHz, CDCl₃): δ = 28.04. Analysis Calculated for C₁₃H₂₇N₂O₅P: C, 48.44; H, 8.44; N, 8.69. Found: C, 48.27; H, 8.48; N, 8.93.

3.8. Synthesis of azide 29

To a solution of mesylate 27 (0.100 g, 0.30 mmol) in methanol (2 mL) sodium azide was added (0.060 g, 0.90 mmol). The reaction mixture was stirred at 60°C for 96 h. The solvent was removed and the reside was chromatographed on silica gel column with chloroform-methanol (100:1, 50:1, v/v) to give pure azide 29 (0.036 g, 43%).

Diethyl (3-(azidomethyl)-4-hydroxypyrrolidin-2-yl)phosphonate (29). Colourless oil. IR (film, cm⁻¹): ν_max= 3355, 2985, 2933, 2872, 2103, 1648, 1445, 1354, 1225, 1175, 1026, 970. ¹H NMR (600 MHz, CDCl₃): δ = 4.26–4.13 (m, 4H, 2 × CH₂OP), 4.11 (ddd, ³J_H4–H5 = 5.2 Hz, ³J_H4–H5 = 2.5 Hz, ³J_H4–H3 = 2.5 Hz, 1H, HC4), 3.45 (ddd, ²J_H–H = 12.2 Hz, ²J_H–H3 = 6.7 Hz, ⁴J_H–P = 0.9 Hz, 1H, HCHN₃), 3.40 (dd, ²J_H–H = 12.2 Hz, ²J_H–H3 = 6.7 Hz, 1H, HCHN₃), 3.23 (dd, ²J_H2–P = 7.2 Hz, ³J_H2–H3 = 4.8 Hz, 1H, HC2), 3.17 (dd, ²J_Ha–Hb = 11.3 Hz, ³J_H5–H4 = 5.2 Hz, 1H, HHC5), 3.07 (dd, ²J_Ha–Hb = 11.3 Hz, ³J_H5–H4 = 2.5 Hz, 1H, HHC5), 2.50 (ddddd, ³J_H3–P = 14.8 Hz, ³J_H3–H = 6.7 Hz, ³J_H3–H = 6.7 Hz, ³J_H3–H2 = 4.8 Hz, ³J_H3–H4 = 2.5 Hz, 1H, HC3), 1.36 (t, ³J = 7.1 Hz, 6H, 2 × CH₃CH₂OP). ¹³C NMR (151 MHz, CDCl₃): δ = 75.36 (d, ³J_PCCC = 5.5 Hz, C4), 63.36 (d, J = 6.9 Hz, COP), 62.74 (d, J = 7.0 Hz, COP), 55.94 (d, ¹J_PC = 164.1 Hz, C2), 54.87 (d, ³J_PCNC = 8.6 Hz, C5), 52.48 (d, ³J_PCCC = 10.5 Hz, CH₂N₃), 49.35 (C3), 16.57 (d, J = 5.5 Hz, POCC), 16.53 (d, J = 5.5 Hz, POCC). ³¹P NMR (243 MHz, CDCl₃): δ = 27.42. Analysis Calculated for C₉H₁₉N₄O₄P: C, 38.85; H, 6.88; N, 20.14. Found: C, 39.03; H, 6.94; N, 20.11.

3.9. Synthesis of (Pyrrolidin-2-yl)Phosphonate 30

A solution of azide 29 (0.036 g, 0.13 mmol) Boc₂O (0.125 g, 0.572 mmol) in ethanol (0.5 mL) was kept under atmospheric pressure of hydrogen over 20% Pd(OH)₂-C (1.7 mg) at room temperature for 35 h. The suspension was filtered through a layer of Celite. The solution was concentrated, and the residue was chromatographed on silica gel column with chloroform-methanol (100:1, 50:1, v/v) to give pure 27 (0.050 g, 69%).

tert-butyl 3-{[(tert-butoxycarbonyl)amino]methyl}-2-(diethoxyphosphoryl)-4-hydroxypyrrolidine-1-carboxylate (30). Colorless oil. IR (film, cm⁻¹): ν_max= 3312, 2980, 2933, 1743, 1703, 1519, 1279, 1254, 1165, 1028. ¹H NMR (600 MHz, CDCl₃): δ = 5.40–5.00 (br s, 1H, OH), 4.80–4.72 (br m, 1H, HC4), 4.25–4.15 (br m, 5H, 2 × CH₂OP and HCHN), 4.10–4.00 (br m, 1H, HCHN), 3.48–3.40 (br m, 1H, HCH5), 3.28–3.20 (br m, 2H, HC2 and HCHC5), 2.85–2.70 (m, 1H, HC3), 1.50 (s, 9H, (CH₃)₃C), 1.48 (s, 9H, (CH₃)₃C), 1.46 (br s, 9H, (CH₃)₃C), 1.35 (t, J = 7.0 Hz, 6H, 2 × CH₃CH₂OP). ¹³C NMR (151 MHz, CDCl₃): δ = 165.12 (C=O), 153.75 (C=O), 152.98 (C=O), 82.86 (C(CH₃)₃), 80.78 (C(CH₃)₃), 79.37 (C(CH₃)₃), 76.01 (very broad s, C4, 60%) and 75.13 (very broad s, C4, 40%), 62.83 (d, J = 7.2 Hz, CH₂OP), 62.53 (br d, J ~ 7 Hz, CH₂OP), 55.76 (very broad d, J ~ 167 Hz, C2, 40%) and 54.75 (very broad d, J ~ 164 Hz, C2, 60%), 50.47 (very broad s, C5, 60%) and 50.11 (very broad s, C5, 40%), 47.00 (very broad s, CH₂N, 40%) and 45.45 (very broad s, CH₂N, 60%), 42.46 (C3, 60%) and 41.93 (C3, 40%), 28.37, 28.26, 27.71, 16.48 (d, J = 5.7 Hz, POCC), 16.43 (very broad s, POCC). ³¹P NMR (243 MHz, CDCl₃): δ = 24.06. Analysis Calculated for C₂₄H₄₅N₂O₁₀P: C, 52.16; H, 8.21; N, 5.07. Found: C, 52.32; H, 8.14; N, 5.02.

4. Conclusions

The 1,3-dipolar cycloadditions of N-benzyl-C-(diethoxyphosphoryl)nitrone 22 with dimethyl maleate and cis-1,4-dihydroxybut-2-ene, as well as maleic anhydride proceeded diastereospecifically to give cycloadducts 20, 21 and 23, respectively. Isoxazolidine 20 was smoothly hydrogenated to substituted (5-oxopyrrolidin-2-yl)phosphonate 18 and subsequently transformed into derivative 24 by exchanging of COOMe at C3 into amido function. For transformation of isoxazolidine 21 into functionalized derivative of (pyrrolidin-2-yl)phosphonate 28, reaction sequence consisted of a standard mesylation of both hydroxy groups, a hydrogenolytic cleavage of the N–O bond, removal of benzyl group followed by spontaneous formation of the pyrrolidine ring by intramolecular S_N2 reaction and finally exchanging the other mesyloxy group to amino function. Since 3-methoxycarbonyl-(5-oxopyrrolidin-2-yl)phosphonate 18 and 3-mesyloxymethyl(pyrrolidin-2-yl)phosphonate 27 contain reactive groups, i.e., COOMe at C3 in 18 and MsO at C3 in 27, studies on their further functionalization based on their reactions with other nucleophiles are underway in our laboratory. The presented methodology could also be adopted for the synthesis of other stereoisomeric isoxazolidines via application of respective trans-alkenes in 1,3-dipolar cycloaddition to C-phosphorylated nitron 22. Moreover, the syntheses elaborated herein pave the way for new enantiomerically pure functionalized phosphonate analogues of prolines, substituted glutamic acid by application of the N-chiral C-phosphorylated nitrones.

Supplementary Materials

Figure S1: ¹H NMR Spectrum for 20 in CDCl₃, Figure S2: ¹³C NMR Spectrum for 20 in CDCl₃, Figure S3: ³¹P NMR Spectrum for 20 in CDCl₃, Figure S4: ¹H NMR Spectrum for 21 in CDCl₃, Figure S5: ¹H NMR Spectrum for 21 in C₆D₆, Figure S6: ¹³C NMR Spectrum for 21 in C₆D₆, Figure S7: ³¹P NMR Spectrum for 21 in CDCl₃, Figure S8: ³¹P NMR Spectrum for 21 in C₆D₆, Figure S9: ¹H NMR Spectrum for 23 in CDCl₃, Figure S10: ¹³C NMR Spectrum for 23 in CDCl₃, Figure S11: ³¹P NMR Spectrum for 23 in CDCl₃, Figure S12: ¹H NMR Spectrum for 18 in CDCl₃, Figure S13: ¹³C NMR Spectrum for 18 in CDCl₃, Figure S14: ³¹P NMR Spectrum for 18 in CDCl₃, Figure S15: ¹H NMR Spectrum for 24 in CD₃OD, Figure S16: ¹³C NMR Spectrum for 24 in CD₃OD, Figure S17: ³¹P NMR Spectrum for 24 in CD₃OD, Figure S18: ¹H NMR Spectrum for 25 in CDCl₃, Figure S19: ¹³C NMR Spectrum for 25 in CDCl₃, Figure S20: ³¹P NMR Spectrum for 25 in CDCl₃, Figure S21: ¹H NMR Spectrum for 27 in CDCl₃, Figure S22: ¹H NMR Spectrum for 27 in CD₃OD, Figure S23: ¹³C NMR Spectrum for 27 in CD₃OD, Figure S24: ³¹P NMR Spectrum for 27 in CDCl₃, Figure S25: ¹H NMR Spectrum for 28 in CDCl₃, Figure S26: ¹³C NMR Spectrum for 28 in CDCl₃, Figure S27: ³¹P NMR Spectrum for 28 in CDCl₃, Figure S28: ¹H NMR Spectrum for 29 in CDCl₃, Figure S29: ¹³C NMR Spectrum for 29 in CDCl₃, Figure S30: ³¹P NMR Spectrum for 29 in CDCl₃, Figure S31: ¹H NMR Spectrum for 30 in CDCl₃, Figure S32: ¹H NMR Spectrum for 30 in CDCl₃, Figure S33: ³¹P NMR Spectrum for 30 in CDCl₃.

Author Contributions

Conceptualization, I.E.G. and D.G.P.; methodology, I.R. and A.H.; synthesis, I.R. and A.H.; investigation, D.G.P., I.R., A.H. and I.E.G.; resources and project administration, D.G.P., I.R. and I.E.G.; writing—original draft preparation, I.E.G., I.R. and D.G.P.; writing—review and editing, I.E.G., I.R. and D.G.P.; supervision, I.E.G. and D.G.P.; funding acquisition, I.E.G. and D.G.P. All authors have read and agreed to the published version of the manuscript.

Funding

This work was funded by the Medical University of Lodz (internal fund 503/3-014-01/503-31-001).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data is contained within the article.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples are not available.

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Figures and Schemes

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%.