Iminosugar-Phosphines as Organocatalysts in the [3 + 2] Cycloaddition of Allenoates and N-Tosylimines

Abstract

Iminosugar derivatives containing a pyrrolidine-phosphine moiety were prepared from carbohydrates and used as catalysts in the [3 + 2] cycloaddition reaction between alkyl allenoates and electron-deficient imines. The corresponding 1,2,3,5-tetrasubstituted pyrrolines were obtained in good yields and diastereoselectivities but with moderate enantiocontrol. The stereochemical outcome of the reaction depends on the substituent at the nitrogen atom and hydroxyl groups, the configuration of the stereogenic centers and the distance between the diphenylphosphine group and the pyrrolidine skeleton of the catalyst. The preparation of both enantiomers of the catalyst allowed the corresponding enantiomeric pyrrolines to be obtained with similar yields, diastereo- and enantioselectivities.

1. Introduction

Chirality is an essential characteristic for a large number of industrial and biological compounds such as agrochemicals, drugs or natural products. Over the past few decades, enantioselective catalysis has become the main approach for the asymmetric synthesis of chiral molecules [1]. In this field, chiral tertiary phosphines play a significant role and have been widely used as organocatalysts or ligands in many types of catalytic asymmetric reactions [2,3]. The catalytic activity of tertiary phosphines is due to the free lone pair of electrons on the phosphorus atom, which enables them to be more nucleophilic than their corresponding amine analogues. A wide variety of nucleophilic phosphine-catalyzed annulation reactions has been established as powerful tools for the synthesis of carbo- and heterocycles from readily simple building blocks [4]. In particular, the phosphine-catalyzed [3 + 2] annulation reactions of allenoates and electron-deficient imines is one of the most attractive methods for the synthesis of substituted pyrrolines [5]. In 1998, Lu and co-workers reported the pioneering development of phosphine-catalyzed [3 + 2] cycloadditions of 2,3-butadienoates and electron-deficient imines to afford 2-substituted-3-pyrrolines [6]. Kwon and co-workers [7] extended the reaction to γ-substituted allenoates affording 2,5-disubstituted-3-pyrrolines with high diastereoselectivities. Since then, this reaction has been investigated by several research groups in order to develop an asymmetric variant using chiral catalysts, such as the readily available phosphines with axial and planar chirality [8,9,10], rhenium-based phosphines [11], phosphinothiourea derivatives [12,13], dipeptide-based phosphines [14] or planar [2.2]paracyclophane-based phosphine-phenol [15], among others [16]. Recently, a diversity of axially chiral phosphines has been prepared and preliminarily applied to several asymmetric transformations [17,18]. It is noteworthy that the first phosphine-catalyzed asymmetric synthesis of 2,5-disubstituted pyrrolines using γ-substituted allenoates was reported by Kwon and co-workers [19]. Two new diastereoisomeric rigid chiral [2.2.1]bicyclophosphines were developed as organocatalysts for this reaction. Both phosphines behaved as pseudoenantiomers and yielded the corresponding enantiomeric pyrrolines with good yields and excellent enantioselectivities. In addition, these authors have recently reported [20] the use of the natural terpenoid carvone as the starting material for the synthesis of novel P-stereogenic chiral phosphines. These organocatalysts have been used in the asymmetric synthesis of a library of pyrrolines with high yields and enantioselectivities, including the biologically active compound (R)-efsevin.

Although carbohydrates are inexpensive and readily available compounds, relatively abundant in enantiomerically pure form and easily modulated with well-established carbohydrate chemistry, their use as starting materials for the synthesis of organocatalysts remains scarce [21]. We have recently reported [22,23] the synthesis of a novel class of pyrrolidine-based phosphine/phosphinite/aminophosphite ligands from readily available sugars. These compounds were used in the enantioselective Pd-allylic substitution and Ir-catalyzed hydrogenation reactions of minimally functionalized olefins, obtaining excellent enantioselectivities. Herein, we disclose the synthesis of iminosugar derivatives containing a pyrrolidine-phosphine moiety from commercial carbohydrates. These compounds have been used as catalysts in the [3 + 2] cycloaddition between alkyl allenoates and electron-deficient imines, affording 2,5-disubstituted-3-pyrrolines with good yields and diastereoselectivities but with moderate enantioselectivities (Scheme 1). The possibility of using the phosphine catalyst in both enantiomeric forms has allowed the corresponding enantiomeric 3-pyrrolines to be obtained with similar yields, diastereo- and enantioselectivities.

2. Results and Discussion

2.1. Synthesis of Pyrrolidine-Based Phosphine Organocatalysts

The new organocatalysts were easily prepared from available and inexpensive carbohydrates, such as L-arabinose, D-ribose and D-mannose. Starting from L-arabinose (Scheme 2), the organocatalysts 1 and 2 were obtained. Their synthesis started from the previously reported N-Boc-pyrrolidine 3 [24]. Reduction of 3 with LiBH₄ gave the N-Boc protected alcohol 4. Standard tosylation of 4 afforded the cyclic carbamate 5, as previously described for ent-5 [25]. Nucleophilic ring opening of 5 by treatment with KPPh₂ in THF at reflux gave the amino-phosphine catalyst 1 (δ_P = −23.2 ppm). Reaction with methoxycarbonyl chloride gave the corresponding carbamate which, after reduction with LiAlH₄ in THF at reflux, afforded the N-methyl derivative 2 in 74% yield (two steps).

Starting from D-ribose (Scheme 3), pyrrolidine phosphine 7, which presents a shorter phosphine alkyl chain, was prepared following the procedure reported by us [23] that implies the ring opening of the cyclic carbamate 6 by reaction with KPPh₂ in THF. N-methyl derivative 9 [22] was prepared by reaction of 7 with methoxycarbonyl chloride affording 8 and subsequent reduction with LiAlH₄ in THF at reflux. The reductive amination of 7 with butanal and benzaldehyde afforded N-butyl- and N-benzyl-pyrrolidine derivatives 10 and 11, respectively. Standard acylation of 7 using benzoyl and pivaloyl chloride afforded the pyrrolidine derivatives 12 and 13, respectively, in excellent yields. Finally, the reaction of 7 with 3,5-bistrifluoromethylisothiocyanate gave the thiourea-phosphine derivative 14 [23] in moderate yield.

Moreover, pyrrolidine 16 bearing a less rigid backbone skeleton compared with pyrrolidine 9, was prepared from 15 [23] by reaction with KPPh₂ in THF at reflux followed by treatment with methoxycarbonyl chloride and final reduction with LiAlH₄ in THF at reflux (Scheme 4).

Finally, starting from D-mannose (Scheme 5), the N-Boc protected pyrrolidine-phosphine 17 [23], with a 2,3-cis configuration in the pyrrolidine backbone, was prepared. Then, reduction with LiAlH₄ in THF at reflux afforded the N-methyl derivative 18 in good overall yield.

2.2. Pyrrolidine-Phosphines as Organocatalysts in [3 + 2] Cycloadditions between Alkyl Allenoates and Electron-Deficient Imines

The library of pyrrolidine-based phosphine organocatalysts was evaluated in the [3 + 2] cycloadditions between alkyl allenoates and electron-deficient imines. Preliminary experiments were carried out following Kwon’s procedure [19]. Thus, model substrates N-tosylimine 19a [26] and ethyl allenoate 20a [27] were made to react in benzene at room temperature with 20 mol% of organocatalyst (Scheme 6). We first tested the reactivity of catalysts 1, 2, 7 and 9 which differ in the distance between the diphenylphosphine group and the pyrrolidine backbone (1, 2 vs. 7, 9) and the substitution at the nitrogen atom of the pyrrolidine moiety (1, 7 vs. 2, 9) (

Table 1. Preliminary screening for the model reaction ¹.

Entry	Cat	Yield (%) 2	ee (%) 3	cis/trans 4
1	1	77	rac.	92:8
2	2	84	27	95:5
3	7	62	rac.	92:8
4	9	80	50	94:6

¹ Reaction conditions: 19a (1 equiv), 20a (1.2 equiv) and Cat (20 mol%) were stirred in benzene (0.6 mL) at rt for 9 h. ² Yield of isolated product. ³ Determined by HPLC. ⁴ Determined by ¹H NMR of the reaction crude.

). In all cases the cis-2,5-substituted-3-pyrrolines were obtained with good yields and excellent diastereomeric ratio (dr).

The enantioselectivity depended on the substitution at the nitrogen atom of the pyrrolidine as the corresponding racemic 3-pyrroline was obtained with catalysts 1 and 7 while moderate enantiomeric excesses (ees) were observed with N-methyl pyrrolidines 2 and 9 (entries 2 and 4). Furthermore, it was observed that the stereochemical outcome of the reaction depends on the length of the phosphine alkyl chain (entries 2 and 4). The highest enantioselectivity was achieved with organocatalyst 9 (entry 4). The absolute configuration was assigned by comparison with data previously reported [19].

As a moderate enantioselectivity was observed, we envisaged an optimization of the reaction conditions. The results are summarized in

Table 2. Optimization screening for the model reaction ¹.

Entry	x mol%	Solvent	T	t (h)	Yield (%) 2	ee (%) 3	cis/trans 4
1	20	Benzene	rt	7	80	50	94:6
2	20	Toluene	rt	7	88	55	94:6
3	20	Toluene 5	rt	7	67	53	93:7
4	20	CH2Cl2	rt	7	47	45	81:19
5	20	MeCN	rt	7	46	27	77:23
6	20	1,2-DCB	rt	7	51	46	87:13
7	20	THF	rt	7	80	50	93:7
8	20	THF:EtOH 10:1	rt	7	85	53	89:11
9	20	THF:EtOH 5:1	rt	7	72	53	87:13
10	20	Et2O	rt	7	84	59	93:7
11	10	Et2O	rt	24	63	59	95:5
12	40	Et2O	rt	2	95	58	95:5

¹ Reaction at 0.154 mmol scale. ² Yield of isolated product. ³ Determined by HPLC. ⁴ Determined by ¹H NMR of the reaction crude. ⁵ 20 mol% of H₂O and 5 mol% of Et₃N were used as additive. 1,2-DCB = 1,2-diclorobenzene.

. We noticed that the solvent had a slight influence on the yield and on the enantio- and diastereoselectivity of the reaction (entries 1–10). The best results were obtained using benzene, toluene or ethereal solvents (entries 1, 2, 7, 10–12) whereas CH₂Cl₂, MeCN and 1,2-dichlorobenzene led to a decrease in yield, ees and drs (entries 4, 5 and 6). The addition of H₂O and Et₃N as additives resulted in a reduction of yield (entry 3) and the use of mixtures THF:EtOH resulted in a decrease in diastereoselectivity (entries 8, 9). Et₂O was identified as the best solvent, affording the desired product 21a in 84% yield, 59% ee and excellent 93:7 dr (entry 10). Moreover, the amount of catalyst could be reduced to 10 mol% without affecting enantioselectivity, but a longer reaction time was needed with a significant reduction of yield (entry 11). Instead, a higher catalyst load (40 mol%) speeded up the reaction and increased the yield. However, no improvement in the enantioselectivity was observed (entry 12).

To further improve the enantioselectivity, we studied the reaction with pyrrolidine phosphines 8–14 that present different substituents at the nitrogen atom. Moreover, the influence of the pyrrolidine backbone rigidity and the configuration of carbons bearing the isopropylidenedioxy group in the catalyst (compounds 16–18) were also studied. Model [3 + 2] cycloaddition reaction using the optimized reaction conditions was used in these studies (

Table 3. Screening of organocatalysts ¹.

Entry	Cat	T	t (h)	Yield (%) 2	ee (%) 3	cis/trans 4
1	8	rt	7	90	52	93:7
2	9	rt	7	84	59	93:7
3	10	rt	7	74	56	95:5
4	11	rt	7	88	55	94:6
5	12	rt	7	82	31	95:5
6	13	rt	7	58	33	90:10
7	14	rt	7	74	rac.	95:5
8	16	rt	7	quant.	−30	97:3
9	17	rt	7	96	12	94:6
10	18	rt	7	80	−11	97:3
11	9	0 °C	30	89	64	96:4
12	9	−30 °C	160	63	67	91:9

¹ Reaction at 0.154 mmol scale. ² Yield of isolated product. ³ Determined by HPLC. ⁴ Determined by ¹H NMR of the reaction crude.

). Similar yield, enantio- and diastereoselectivities were observed for derivatives 9–11 bearing alkyl substituents at the pyrrolidinic nitrogen (entries 2–4). The best results were obtained for R = Me (9) (entry 2, 84% yield, 59% ee and 93:7 dr). The ees dropped to 31 and 33% with N-acyl catalysts 12 and 13, respectively (entries 5 and 6). The presence of a bulky ^tBu group at the nitrogen atom (13) led to lower yield (58%). The use of thiourea derivative 14 was also studied, affording the 3-pyrroline with good yield and excellent diastereoselectivity (74% and 95:5 dr) but with a complete loss of enantioselectivity (entry 7). The results with catalyst 16 which bears benzyl groups instead of the isopropylidine group indicated that the enantioselectivity is very sensitive to the rigidity of the pyrrolidine moiety, affording 21a with an excellent yield and dr (97:3) but a poorer enantiomeric excess (30%, entry 8). Surprisingly, 3-pyrroline ent-21a was obtained as major product in this case. A significant decrease of enantioselectivity was also observed for 2,3-cis derivatives 17 and 18 (12 and 11% ee, respectively, entries 9 and 10), which present different configurations at C-3 and C-4 of the pyrrolidine backbone compared to 8–14.

It was also found that in these 2,3-trans-3,4-cis-N-substituted catalysts, the substituent at the nitrogen atom of the pyrrolidine controlled the type of enantioselectivity, obtaining one or another enantiomer in each case (entry 9 vs. entry 10). A study of the influence of the temperature in the model reaction with the most promising catalyst 9 (entries 2, 11 and 12) was then performed. A marked decrease of the reaction rate, yields and dr was observed at –30 °C (entries 2 vs. 11–12). The best general results were obtained at 0 °C (entry 11) without a significative difference in the ee obtained at –30 °C (64 and 67% ee, respectively).

We next moved to explore the scope of the reaction using different alkyl allenoates and electron-deficient imines (Scheme 7). In general, [3 + 2] cycloadditions between a variety of alkyl allenoates (20a–c) and electron-deficient imines (19a–d) afforded the corresponding 3-pyrrolines 21a–f in good-to-high yields and diastereoselectivities. When employing the allenoates 20a,c and N-tosylimine 19a, the reactions proceeded with higher enantioselectivities (63 and 59% ee, respectively) than when using the unsubstituted allenoate 20b (30% ee). Arylimines bearing electron-donating or electron-withdrawing groups (OMe, 19b and Cl, 19c) were suitable substrates, furnishing similar yield, enantio- and diastereoselectivities than for imine 19a. However, the enantioselectivity significantly decreased upon using the p-NO₂-arylimine 19d (34% ee). The assignment of the absolute configuration of 3-pyrrolines 21a–c was carried out by comparison with literature [19], while the absolute configuration of 3-pyrrolines 21d–f was assumed to be the same as that of 21a.

When using catalyst ent-9 [28], these reactions proceeded with similar yields, diastereo- and enantioselectivities, obtaining the corresponding enantiomeric 3-pyrrolines ent-(21a–f) (Scheme 8 and Supplementary Materials).

Although moderate enantioselectivities were observed in these reactions, the possibility of generating both 3-pyrroline enantiomers using enantiomeric pyrrolidine phosphines as catalysts is an undoubted advantage. A theoretical study to explain the enantioselection of these reactions is underway in our laboratory.

3. Materials and Methods

3.1. General Methods

Optical rotations were measured in a 1.0 cm or 1.0 dm tube with a Jasco P-2000 spectropolarimeter (Tokyo, Japan). Infrared spectra were recorded with a Jasco FTIR-410 spectrophotometer (Tokyo, Japan). ¹H, ¹³C and ³¹P NMR spectra were recorded with Bruker AMX300 (Billerica, MA, USA), AV300 and AV500 spectrometers (Billerica, MA, USA) for solutions in CDCl₃, C₆D₆, and DMSO-d₆ at room temperature, except when indicated. Chemical shifts are relative to that of SiMe₄ (¹H and ¹³C) as an internal standard or H₃PO₄ (³¹P) as an external standard. δ values are given in ppm and J in hertz (Hz). J are assigned and not repeated. All the assignments were confirmed by COSY and HSQC experiments. High resolution mass spectra were recorded on a Thermo Scientific Q-Exactive spectrometer (Waltham, MA, USA). NMR and mass spectra were registered in CITIUS (University of Seville). TLC was performed on silica gel 60 F254 (Merck), with detection by UV light, charring with p-anisaldehyde, vanillin, ninhydrin, or Pancaldi reagent [(NH₄)₆MoO₄, Ce(SO₄)₂, H₂SO₄, H₂O]. Silica gel 60 (Merck, 40−60 and 63−200 μm) was used for preparative chromatography. THF was distilled over Na/benzophenone ketyl; CH₂Cl₂ was distilled from CaH₂. The enantio- and diastereomeric ratios of the products were determined by chiral stationary phase HPLC (Daicel Chiralpak IA, IC, ID IF columns, Osaka, Japan).

3.2. Synthesis of Phosphine Catalysts

• (2S,3R,4S)-N-terc-Butyloxycarbonyl-2-hydroxyethyl-3,4-O-isopropylidene pyrrolidine-3,4-diol (4). To a solution of 3 [24] (1.74 g, 5.27 mmol) in anh. THF (22 mL) cooled at 0 °C, LiBH₄ (9.3 mL, 2 M in THF, 18.5 mmol) was added dropwise under Ar. The reaction mixture was stirred at room temperature for 4 d and then cooled at 0 °C. Then, a saturated aqueous solution of NaHCO₃ (30 mL) was added slowly and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried with Na₂SO₄, filtered and evaporated. The resulting residue was purified by chromatography column on silica gel (Et₂O:cyclohexane, 1:2→2:1), to give 4 (1.28 g, 4.44 mmol, 84%) as a white solid. [α]_D²³ + 33.9 (c 0.80, CH₂Cl₂). IR (ν cm⁻¹) 3431 (OH), 2981, 2935, 1662 (C=O), 1403, 1242, 1160, 859. ¹H NMR (300 MHz, DMSO-d₆, 363 K, δ ppm, J Hz) δ 4.73–4.66 (m, 2H, H-3, H-4), 3.98 (t, 1H, J_OH,2′ = 5.4, OH), 3.88–3.81 (m, 1H, H-2), 3.72–3.62 (m, 1H, H-5a), 3.55–3.45 (m, 2H, H-2′), 3.18–3.13 (m, 1H, H-5b), 2.03–1.92 (m, 1H, H-1′a), 1.87–1.78 (m, 1H, H-1′b), 1.44 (s, 3H, -C(CH₃)₂), 1.42 (s, 9H, -C(CH₃)₃), 1.30 (s, H, -C(CH₃)₂). ¹³C NMR (75.4 MHz, DMSO-d₆, 363 K, δ ppm) δ 153.4 (C=O), 111.2 (-C(CH₃)₂), 79.3 (C-3 or C-4), 78.4 (-C(CH₃)₃), 76.6 (C-3 or C-4), 58.1 (C-2′), 56.4 (C-2), 50.1 (C-5), 32.1 (C-1′), 27.7 (-C(CH₃)₃), 26.0 (-C(CH₃)₂), 24.7 (-C(CH₃)₂). HRMS (ESI) m/z found 310.1621, calc. for C₁₄H₂₅NO₅Na [M + Na]⁺: 310.1625.
• (7S,8R,8aS)-7,8-O-Isopropylidene-pentahydropyrrolo [1,2-c]-oxazol-4-ona-7,8-diol (5). To a solution of 4 (816 mg, 2.84 mmol) in dry pyridine (15 mL) at 0 °C, TsCl (1.4 g, 7.1 mmol) was slowly added. After stirring at room temperature for 4 h, the mixture was heated at 50 °C for 4.5 h. The solvent was then removed, and the resulting residue was purified by chromatography column on silica gel (EtOAc), to give 5 (441 mg, 2.07 mmol, 73%) as a white solid. [α]_D²⁰ – 48.0 (c 0.72, CH₂Cl₂). IR (ν cm⁻¹) 2982, 2937, 1664 (C=O), 1399, 1160, 1091, 858. ¹H NMR (300 MHz, CDCl₃, δ ppm, J Hz) δ 4.74–4.70 (m, 1H, H-7), 4.62 (dd, 1H, J = 6.0, J = 4.5, H-8), 4.35 (ddd, 1H, J_2a,2b = 10.8, J = 4.2, J = 2.7, H-2a), 4.22–4.15 (m, 1H, H-2b), 4.14 (d, 1H, J_6a,6b = 13.2, H-6a), 3.57–3.51 (m, 1H, H-8a), 3.21 (dd, 1H, J_6b,7 = 4.8, H-6b), 2.31–2.17 (m, 1H, H-1a), 2.03–1.94 (m, 1H, H-1b), 1.42 (s, 3H, -C(CH₃)₂), 1.30 (s, 3H, -C(CH₃)₂). ¹³C NMR (75.4 MHz, CDCl₃, δ ppm) δ 153.1 (C=O), 112.4 (-C(CH₃)₂), 80.8 (C-8), 78.6 (C-7), 65.8 (C-2), 58.8 (C-8a), 52.2 (C-6), 26.5 (-C(CH₃)₂)), 24.8 (-C(CH₃)₂)), 22.0 (C-1). HRMS (ESI) m/z found 236.0894, calc. for C₁₀H₁₅NO₄Na [M + Na]⁺: 236.0893.
• (2S,3R,4S)-2-Diphenylphosphinoethyl-3,4-O-isopropylidene-pyrrolidine-3,4-diol (1). To a solution of 5 (192 mg, 0.90 mmol) in anh. THF (9.5 mL) at 0 °C was slowly added KPPh₂ (0.5 M in THF, 2.2 mL, 1.1 mmol) under Ar. The mixture was heated at reflux for 1.5 h and then warmed to room temperature IRA-120H⁺ was added, and the resulting mixture was filtered through Celite and washed with CH₂Cl₂. The solvent was evaporated, and the residue was purified by chromatography column on silica gel (CH₂Cl₂:acetone, 5:1, 1% Et₃N) to give 1 (221 mg, 0.623 mmol, 69%) as a colourless oil. [α]_D²³ + 66.2 (c 1.0, CH₂Cl₂). IR (ν cm⁻¹) 3320 (NH), 2982, 2924, 1662, 1276, 1042, 695. ¹H NMR (500 MHz, CDCl₃, δ ppm, J Hz) δ 7.49–7.45 (m, 2H, H-arom.), 7.43–7.39 (m, 2H, H-arom.), 7.34–7.29 (m, 6H, H-arom.), 4.65 (dd, 1H, J_4,3 = 5.5, J_4,5b = 4.0, H-4), 4.51 (dd, 1H, J_3,2 = 4.0, H-3), 3.04 (d, 1H, J_5a,5b = 13.5, H-5a), 2.72–2.69 (m, 1H, H-2), 2.57 (dd, 1H, H-5b), 2.29–2.23 (m, 1H, H-2′a), 2.19–2.13 (m, 1H, H-2′b), 1.79–1.72 (m, 3H, H-1′, NH), 1.40 (s, 3H, -C(CH₃)₂), 1.30 (s, 3H, -C(CH₃)₂). ¹³C NMR (125 MHz, CDCl₃, δ ppm, J Hz) δ 139.1 (d, J_C,P = 12.6, C_arom-P), 138.3 (d, J_C,P = 12.6, C_arom-P), 133.1 (d, J_C,P = 18.5, C-arom.), 132.7 (d, J_C,P = 18.1, C-arom.), 128.7 (C-arom.), 128.6–128.5 (m, C-arom.), 110.5 (-C(CH₃)₂), 82.3, 81.6 (C-3, C-4), 65.1 (d, J_C,P = 13.4, C-2), 53.1 (C-5), 25.9 (-C(CH₃)₂), 25.6 (d, J_C,P = 11.4, C-2′), 25.2 (d, J_C,P = 16.8, C-1′), 24.1 (-C(CH₃)₂). ³¹P NMR (121.5 MHz, CDCl₃, δ ppm) δ 15.8 (s). HRMS (ESI) m/z found 356.1762, calc. for C₂₁H₂₇NO₂P [M + H]⁺: 356.1774.
• (2S,3R,4S)-N-Methyl-2-diphenylphosphinoethyl-3,4-O-isopropylidene-pyrrolidine-3,4-diol (2). To a solution of 1 (80 mg, 0.23 mmol) in anh. CH₂Cl₂ (1.0 mL) at 0 °C was successively added Et₃N (34 µL, 0.25 mmol) and ClCO₂CH₃ (20 µL, 0.25 mmol). The mixture was stirred at 0 °C for 2 h. Then, HCl 0.1 M (5 mL) was added and the aqueous layer was extracted three times with CH₂Cl₂. The combined organic layers were washed with a saturated aqueous solution of NaHCO₃, dried with Na₂SO₄, filtered and evaporated. The resulting crude was dissolved in anh. THF (1.5 mL) and added to a suspension of LiAlH₄ (25 mg, 0.66 mmol) in anh. THF (0.5 mL) at 0 °C. The mixture was heated at reflux for 2.5 h and then cooled at 0 °C. Et₂O and a saturated aqueous solution of Na₂SO₄ were successively added and the mixture was filtered through Celite and washed with CH₂Cl₂. The solvent was evaporated and the residue was purified by chromatography column on silica gel (EtOAc:cyclohexane, 1:2) to give 2 (60 mg, 0.16 mmol, 74%, 2 steps) as a colourless oil. [α]_D²³ + 154.5 (c 0.56, CH₂Cl₂). IR (ν cm⁻¹) 2935, 2774, 1432, 1150, 1077, 695. ¹H NMR (300 MHz, CDCl₃, δ ppm, J Hz) δ 7.55–7.50 (m, 2H, H-arom.), 7.43–7.38 (m, 2H, H-arom.), 7.34–7.29 (m, 6H, H-arom.), 4.63–4.56 (m, 2H, H-4, H-3), 3.15 (d, 1H, J_5a,5b = 11.1, H-5a), 2.42–2.37 (m, 1H, H-1a’), 2.15 (s, 3H, N-CH₃), 2.04 (dd, 1H, J_5b,4 = 3.9, H-5b), 2.00–1.90 (m, 2H, H-2, H-1′b), 1.87–1.63 (m, 2H, H-2′a, H-2′b), 1.45 (s, 3H, -C(CH₃)₂), 1.32 (s, 3H, -C(CH₃)₂). ¹³C NMR (75.4 MHz, CDCl₃, δ ppm, J Hz) δ 139.7 (d, J_C,P = 12.7, C_arom-P), 137.9 (d, J_C,P = 12.7, C_arom-P), 133.3 (d, J_C,P = 18.7, C-arom.), 132.5 (d, J_C,P = 17.8, C-arom.), 128.8 (C-arom.), 128.5–128.4 (m, C-arom.), 110.8 (-C(CH₃)₂), 80.6 (C-3 or C-4), 78.0 (C-3 or C-4), 71.2 (d, J_C,P = 14.3, C-2), 62.2 (C-5), 40.5 (N-CH₃), 26.1 (-C(CH₃)₂), 24.9 (-C(CH₃)₂), 24.3(d, J_C,P = 10.9, C-1′), 24.0 (d, J_C,P = 16.0, C-2′). ³¹P NMR (121.5 MHz, CDCl₃, δ ppm) δ 15.0 (s). HRMS (ESI) m/z found 370.1932, calc. for C₂₂H₂₉NO₂P [M + H]⁺: 370.1930.
• (2S,3R,4S)-N-Methoxycarbonyl-2-diphenylphosphinomethyl-3,4-O-isopropylidene-pyrrolidine-3,4-diol (8). To a solution of 7 [22] (330 mg, 0.970 mmol) in anh. CH₂Cl₂ (5.0 mL) at 0 °C, was successively added Et₃N (0.15 mL, 1.1 mmol) and ClCO₂CH₃ (84 µL, 1.1 mmol). The mixture was stirred at 0 °C for 2.5 h. Then, HCl (0.1 M) was added and the aqueous layer was extracted three times with CH₂Cl₂. The combined organic layers were washed with a saturated aqueous solution of NaHCO₃, dried with Na₂SO₄, filtered and evaporated. The resulting residue was purified by chromatography column on silica gel (EtOAc:cyclohexane, 1.4) to give 8 (273 mg, 0.680 mmol, 70%) as a colourless oil. [α]_D²⁵ + 77.6 (c 0.71, CH₂Cl₂). IR (ν cm⁻¹) 2988, 2940, 1699 (C=O), 1446, 1081, 695. ¹H NMR (300 MHz, CDCl₃, δ ppm, J Hz) δ 7.63–7.58 (m, 2H, H-arom), 7.46–7.28 (m, 8H, H-arom.), 4.79 (ap.t, 1H, J_3,4 = J_3,2 = 6.0, H-3), 4.72–4.67 (m, 1H, H-4), 4.00–3.91 (m, 1H, H-2), 3.80–3.74 (m, 1H, H-5a), 3.61 (s, 3H, OCH₃), 3.40 (dd, 1H, J_5b,5a = 12.3, J_5b,4 = 4.5, H-5b), 2.99–2.91 (m, 1H, H-1a’), 2.45–2.37 (m, 1H, H-1b’), 1.49 (s, 3H, -C(CH₃)₂), 1.35 (s, 3H, -C(CH₃)₂). ¹³C NMR (75.4 MHz, CDCl₃, δ ppm, J Hz) δ 155.7 (C=O), 139.5 (d, J_C,P = 12.6, C_arom-P), 138.2 (d, J_C,P = 13.3, C_arom-P), 133.3 (d, J_C,P = 19.7, C-arom.), 132.7 (d, J_C,P = 18.6, C-arom.), 128.9 (C-arom.), 128.6 (d, J_C,P = 6.8, C-arom.), 128.5 (C-arom.), 128.4 (d, J_C,P = 6.9, C-arom.), 113.0 (-C(CH₃)₂, 80.1 (d, J_C,P = 2.3, C-3), 77.8 (C-4), 58.3 (d, J_C,P = 23.4, C-2), 52.4 (-OCH₃),51.1 (C-5), 28.6 (d, J_C,P = 11.4, C-1′), 26.9 (-C(CH₃)₂), 25.4(-C(CH₃)₂). ³¹P NMR (121.5 MHz, CDCl₃, δ ppm) δ 20.7 (s). HRMS (ESI) m/z found 400.1662, calc. for C₂₂H₂₇NO₄P [M + H]⁺: 400.1672.
• (2S,3R,4S)-N-Butyl-2-diphenylphosfinomethyl-3,4-O-isopropylidene-pyrrolidine-3,4-diol (10). A solution of butanal (35 µL, 0.38 mmol) in 2,2,2-trifluoroethanol (0.8 mL) was heated at 35 °C for 5 min. Then, 7 [22] (64 mg, 0.19 mmol) was added and the reaction mixture was heated at 35 °C for 1 h. NaBH₄ (15 mg, 0.38 mmol) was added and then the mixture was stirred for 1 h. The mixture was filtered through Celite and washed with CH₂Cl₂. The solvent was evaporated, and the residue was purified by chromatography column on silica gel (Et₂O:cyclohexane, 1:5) to give 10 (49 mg, 0.12 mmol, 66%) as a colourless oil. [α]_D²² + 152.2 (c 0.65, CH₂Cl₂). IR (ν cm⁻¹) 2952, 2930, 1028, 694. ¹H NMR (300 MHz, CDCl₃, δ ppm, J Hz) δ 7.55–7.49 (m, 2H, H-arom.), 7.47–7.40 (m, 2H, H-arom.), 7.37–7.28 (m, 6H, H-arom.), 4.62 (dd, 1H, J_3,4 = 6.3, J_3,2 = 4.5, H-3), 4.56 (dd, 1H, J_4,5b = 4.5, H-4), 3.19 (d, 1H, J_5a,5b = 11.1, H-5a), 2.86–2.77 (m, 1H, N-CH₂), 2.51–2.43 (m, 1H, H-1′a), 2.38 (dt, 1H, J_1′b,1′a = 13.3, J_1′b,2 = J_1′b,P = 3.3, H-1′b), 1.98–1.86 (m, 2H, H-5b, H-2), 1.81–1.73 (m, 1H, N-CH₂), 1.52 (s, 3H, -C(CH₃)₂), 1.44–1.24 (m, 7H, -C(CH₃)₂, -CH₂CH₂CH₂CH₃), 0.89 (t, 3H, ³J_H,H = 7.0, -CH₃). ¹³C NMR (75.4 MHz, CDCl₃, δ ppm, J Hz) δ 139.6 (d, J_C,P = 12.2, C_arom-P), 138.7 (d, J_C,P = 13.6, C_arom-P), 133.4 (d, J_C,P = 19.8, C-arom.), 132.4 (d, J_C,P = 17.7, C-arom.), 129.0 (C-arom.), 128.6 (d, J_C,P = 7.1, C-arom.), 128.3 (d, J_C,P = 8.3, C-arom.), 128.3 (C-arom.), 111.1 (-C(CH₃)₂), 80.8 (d, J_C,P =3.8, C-3), 78.0 (C-4), 66.0 (d, J_C,P = 19.8, C-2), 59.4 (C-5), 52.8 (-NCH₂), 29.9 (-NCH₂CH₂), 26.4 (-C(CH₃)₂), 26.0 (d, J_C,P = 12.4, C-1′), 25.6 (-C(CH₃)₂), 20.8 (-NCH₂CH₂CH₂), 14.1 (-CH₃). ³¹P NMR (121.5 MHz, CDCl₃, δ ppm) δ 21.4 (s). HRMS (ESI) m/z found 398.2243, calc. for C₂₄H₃₃NO₂P [M + H]⁺: 398.2243.
• (2S,3R,4S)-N-Benzyl-2-diphenylphosphinomethyl-3,4-O-isopropylidene-pyrrolidine-3,4-diol (11). To a solution of 7 [22] (66 mg, 0.19 mmol) in anh. 1,2-dichloroethane (2 mL) were successively added benzaldehyde (40 µL, 0.39 mmol) and NaBH(OAc)₃ (87 mg, 0.41 mmol). The mixture was stirred at room temperature for 3 h, and then a saturated aqueous solution of NaHCO₃ (5 mL) was added. The aqueous layer was extracted three times with CH₂Cl₂. The combined organic layers were dried with Na₂SO₄, filtered, and evaporated. The residue was purified by chromatography column on silica gel (Et₂O:cyclohexane, 1.5) to give 11 (48 mg, 0.11 mmol, 58%) as a colourless oil. [α]_D²² + 115.2 (c 1.0, CH₂Cl₂). IR (ν cm⁻¹) 2985, 1433, 1028, 695. ¹H NMR (300 MHz, CDCl₃, δ ppm, J Hz) δ 7.45–7.32 (m, 4H, H-arom.), 7.29–7.19 (m, 6H, H-arom.), 7.18–7.10 (m, 5H, H-arom.), 4.59 (dd, 1H, J_3,4 = 6.3, J_3,2 = 4.8, H-3), 4.43 (dd, 1H, J_4,5b = 4.5, H-4), 3.96 (d, 1H, ²J_H,H = 13.8, -CH₂Ph), 2.96–2.88 (m, 2H, H-5a, -CH₂Ph), 2.48–2.32 (m, 2H, H-1′a, H-1′b), 2,04–1.96 (m, 1H, H-2), 1.82 (dd, 1H, J_5b,5a = 11.1, H-5b), 1.47 (s, 3H, -C(CH₃)₂), 1.23 (s, 3H, -C(CH₃)₂). ¹³C NMR (75.4 MHz, CDCl₃, δ ppm, J Hz) δ 139.3 (d, J_C,P = 12.0, C_arom-P), 138.8 (d, J_C,P = 13.8, C_arom-P), 133.6 (d, J_C,P = 20.1, C-arom.), 132.4 (d, J_C,P = 17.8, C-arom.), 129.2 (C-arom.), 128.7–128.3 (m, C-arom.), 126.9 (C-arom.), 111.3 (-C(CH₃)₂), 80.9 (d, J_C,P = 3.7, C-3), 77.9 (C-4), 65.2 (d, J_C,P = 22.4, C-2), 59.3 (C-5), 56.6 (-CH₂Ph), 26.6 (-C(CH₃)₂), 26.4 (d, J_C,P = 12.4, C-1′), 25.8 (-C(CH₃)₂). ³¹P NMR (121.5 MHz, CDCl₃, δ ppm) δ 21.7 (s). HRMS (ESI) m/z found 432.2092, calc. for C₂₇H₃₁NO₂P [M + H]⁺: 432.2087.
• (2S,3R,4S)-N-Benzoyl-2-diphenylphosphinomethyl-3,4-O-isopropylidene-pyrrolidine-3,4-diol (12). To a solution of 7 [22] (88 mg, 0.26 mmol) in anh. CH₂Cl₂ (2 mL) cooled at 0 °C, was successively added Et₃N (72 µL, 0.52 mmol) and benzoyl chloride (40 µL, 0.34 mmol). The mixture was stirred at room temperature for 2.5 h. Then, a saturated aqueous solution of NH₄Cl was added and the aqueous layer was extracted with CH₂Cl₂. The combined organic layers were washed with brine, dried with Na₂SO₄, filtered and evaporated. The resulting residue was purified by chromatography column on silica gel (EtOAc:cyclohexane, 1.4→1:2) to give 12 (113 mg, 0.250 mmol, 98%) as a colourless oil. [α]_D²⁶ + 75.1 (c 0.77, CH₂Cl₂). IR (ν cm⁻¹) 2993, 2927, 1631 (C=O), 1078, 695. ¹H NMR (300 MHz, CDCl₃, δ ppm, J Hz) δ 7.67–7.63 (m, 2H, H-arom), 7.52–7.26 (m, 13H, H-arom.), 4.83 (ap.t, 1H, J_3,4 = J_3,2 = 6.0, H-3), 4.62 (q, 1H, J_4,5b = J_4,5a = 6.3, H-4), 4.57–4.48 (m, 1H, H-2), 3.70 (dd, 1H, J_5a,5b = 11.7, H-5a), 3.57 (dd, 1H, H-5b), 3.03–2.91 (m, 1H, H-1a’), 2.51 (dd, 1H, J_1b’,1a’ = 13.2, J_1b’,2 = 10.2, H-1b’), 1.55 (s, 3H, -C(CH₃)₂), 1.35 (s, 3H, -C(CH₃)₂). ¹³C NMR (75.4 MHz, CDCl₃, δ ppm, J Hz) δ 170.1 (C=O), 139.5 (d, J_C,P = 12.4, C_arom-P), 137.8 (d, J_C,P = 11.6, C_arom-P), 136.2 (C-arom.), 133.2 (d, J_C,P = 19.5, C-arom.), 132.8 (d, J_C,P = 18.9, C-arom.), 130.6 (C-arom.), 128.9–128.4 (m, C-arom.), 128.4 (C-arom.), 127.8 (C-arom.), 113.3 (-C(CH₃)₂), 79.6 (d, J_C,P = 2.8, C-3), 78.0 (C-4), 57.7 (d, J_C,P = 22.0, C-2), 54.1 (C-5), 28.1 (d, J_C,P = 14.3, C-1′), 27.4 (-C(CH₃)₂), 25.6 (-C(CH₃)₂). ³¹P NMR (121.5 MHz, CDCl₃, δ ppm) δ 20.8 (s). HRMS (ESI) m/z found 446.1867, calc. for C₂₇H₂₉NO₃P [M + H]⁺: 446.1880.
• (2S,3R,4S)-N-Pivaloyl-2-diphenylphosphinomethyl-3,4-O-isopropylidene-pyrrolidine-3,4-diol (13). To a solution of 7 [22] (104 mg, 0.300 mmol) in anh. CH₂Cl₂ (2.5 mL) cooled at 0 °C, was successively added Et₃N (85 µL, 0.61 mmol) and pivaloyl chloride (50 µL, 0.39 mmol). The mixture was stirred at room temperature for 2 h. Then, a saturated aqueous solution of NH₄Cl was added and the aqueous layer was extracted with CH₂Cl₂. The combined organic layers were washed with brine, dried with Na₂SO₄, filtered and evaporated. The resulting residue was purified by chromatography column on silica gel (EtOAc:cyclohexane, 1:5) to give 13 (121 mg, 0.290 mmol, 94%) as a colourless oil. [α]_D²⁶ + 50.1 (c 0.79, CH₂Cl₂). IR (ν cm⁻¹) 2988, 2929, 1625 (C=O), 1079, 696. ¹H NMR (300 MHz, CDCl₃, δ ppm, J Hz) δ 7.69–7.63 (m, 2H, H-arom), 7.46–7.27 (m, 8H, H-arom.), 4.72 (ap.t, 1H, J_3,4 = J_3,2 = 6.0, H-3), 4.63 (q, 1H, J_4,5b = J_4,5a = 6.6, H-4), 4.48–4.39 (m, 1H, H-2), 4.05 (ddd, 1H, J_5a,5b = 11.1, J = 0.9, H-5a), 3.45 (dd, 1H, H-5b), 2.89 (dt, 1H, J_1a’,1b’ = 13.5, J_1a’,2 = J_1a’,P = 4.5, H-1a’), 2.37 (dd, 1H, J_1b’,2 = 10.2, H-1b’), 1.49 (s, 3H, -C(CH₃)₂), 1.34 (s, 3H, -C(CH₃)₂), 1.18 (s, 9H, -C(CH₃)₃). ¹³C NMR (75.4 MHz, CDCl₃, δ ppm, J Hz) δ 177.0 (C=O), 140.0 (d, J_C,P = 12.4, C_arom-P), 138.3 (d, J_C,P = 13.9, C_arom-P),133.1 (d, J_C,P = 19.1, C-arom.), 132.9 (d, J_C,P = 19.0, C-arom.), 128.7 (d, J_C,P = 6.6, C-arom.), 128.6 (C-arom.), 128.4 (C-arom.), 128.3 (d, J_C,P = 6.9, C-arom.), 113.2 (-C(CH₃)₂, 78.5 (d, J_C,P =2.3, C-3), 78.3 (C-4), 58.7 (d, J_C,P = 21.9, C-2), 52.3 (C-5), 39.2 (-C(CH₃)₃), 27.8 (C-1′, -C(CH₃)₃), 27.4 (-C(CH₃)₂), 25.7 (-C(CH₃)₂). ³¹P NMR (121.5 MHz, CDCl₃, δ ppm) δ 19.3 (s). HRMS (ESI) m/z found 426.2181, calc. for C₂₅H₃₃NO₃P [M + H]⁺: 426.2193.
• (2S,3R,4S)-N-Methyl-3,4-di-O-benzyl-2-diphenylphosphinomethyl-pyrrolidine-3,4-diol (16). To a solution of 15 [23] (58 mg, 0.26 mmol) in anh. THF (1.5 mL) at 0 °C was slowly added KPPh₂ (0.5 M in THF, 0.52 mL, 0.26 mmol) under Ar. The mixture was heated at reflux for 2 h and then warmed to room temperature IRA-120H⁺ was added, and the resulting mixture was filtered through Celite and washed with CH₂Cl₂. The solvent was evaporated and the residue was purified by chromatography column on silica gel (CH₂Cl₂, 1% Et₃N) to give the corresponding diphenylphosphinomethyl-pyrrolidine (49 mg, 0.10 mmol, 60%). To a solution of this compound (49 mg, 0.10 mmol) in anh. CH₂Cl₂ (0.5 mL) at 0 °C, was successively added Et₃N (16 µL, 0.11 mmol) and ClCO₂CH₃ (9.0 µL, 0.11 mmol). The mixture was stirred at 0 °C for 4.5 h. Then, HCl (0.1 M) was added and the aqueous layer was extracted with CH₂Cl₂. The combined organic layers were washed with a saturated aqueous solution of NaHCO₃, dried with Na₂SO₄, filtered and evaporated. The resulting crude was dissolved in anh. THF (1.0 mL) and added to a suspension of LiAlH₄ (12 mg, 0.29 mmol) in anh. THF (0.5 mL) at 0 °C. The mixture was heated at reflux for 2 h and then cooled at 0 °C. Et₂O and a saturated aqueous solution of Na₂SO₄ were successively added and the mixture was filtered through Celite and washed with CH₂Cl₂. The solvent was evaporated and the residue was purified by chromatography column on silica gel (EtOAc:cyclohexane, 1:2) to give 16 (33 mg, 0.070 mmol, 64%, 2 steps) as a colourless oil. [α]_D²⁶ + 86.5 (c 0.73, CH₂Cl₂). IR (ν cm⁻¹) 2916, 2851, 1026, 736, 688. ¹H NMR (500 MHz, C₆D₆, δ ppm, J Hz) δ 7.59–7.56 (m, 2H, H-arom.), 7.46–7.43 (m, 4H, H-arom.), 7.32–7.31 (m, 2H, H-arom.), 7.18–7.00 (m, 12H, H-arom.), 4.86 (d, 1H, ²J_H,H = 11.5, -CH₂Ph(a)), 4.56 (d, 1H, -CH₂Ph(a)), 4.39 (s, 2H, -CH₂Ph(b)), 3.98 (t.a, 1H, J_3,4 = J_3,2 = 5.0, H-3), 3.74–3.71 (m, 1H, H-4), 3.26 (dd, 1H, J_5a,5b = 10.0, J_5a,4 = 4.5, H-5a), 2.85–2.81 (m, 1H, H-1′a), 2.63–2.56 (m, 2H, H-2, H-1′b), 2.23 (dd, 1H, J_5b,4 = 6.5, H-5b), 2.21 (s, 3H, N-CH₃). ¹³C NMR (125.7 MHz, C₆D₆, δ ppm, J Hz) δ 140.8 (d, J_C,P = 14.0, C_arom-P), 140.2 (d, J_C,P = 14.8, C_arom-P), 139.7 (C-arom.), 139.5 (C-arom.), 133.6 (d, J_C,P = 19.4, C-arom.), 133.1 (d, J_C,P = 18.0, C-arom.), 128.7–127.6 (m, C-arom.), 80.3 (d, J_C,P = 5.6, C-3), 78.8 (C-4), 73.6 (-CH₂Ph(a)), 71.9 (-CH₂Ph(b)), 65.5(d, J_C,P = 19.3, C-2), 58.4 (C-5), 42.0 (N-CH₃), 28.9 (d, J_C,P = 12.9, C-1′). ³¹P NMR (121.5 MHz, CDCl₃, δ ppm) δ 20.4 (s). HRMS (ESI) m/z found 496.2384, calc. for C₃₂H₃₅NO₂P [M + H]⁺: 496.2400.
• (2S,3S,4R)-N-Methyl-2-diphenylphosphinomethyl-3,4-O-isopropylidene-pyrrolidine-3,4-diol (18). To a suspension of LiAlH₄ (30 mg, 0.79 mmol) in anh. THF (1.6 mL) at 0 °C was added a solution of 17 [23] (70 mg, 0.16 mmol) in anh. THF (1.6 mL). The mixture was heated at reflux for 2.5 h under Ar and then cooled at 0 °C. Et₂O and a saturated aqueous solution of Na₂SO₄ were successively added and the mixture was filtered through Celite and washed with CH₂Cl₂. The solvent was evaporated and the residue was purified by chromatography column on silica gel (EtOAc:cyclohexane, 1:3) to give 18 (47 mg, 0.13 mmol, 84%) as a pale yellow oil. [α]_D²⁷ + 56.8 (c 1.32, CH₂Cl₂). IR (ν cm⁻¹) 2985, 2932, 1206, 1055, 694. ¹H NMR (300 MHz, CDCl₃, δ ppm, J Hz) δ 7.52–7.43 (m, 4H, H-arom.), 7.34–7.30 (m, 6H, H-arom.), 4.64–4.60 (m, 1H, H-4), 4.49 (dd, 1H, J = 6.9, J = 4.2, H-3), 3.22 (dd, 1H, J_5a,5b = 10.2, J_5a,4 = 6.3, H-5a), 2.58–2.44 (m, 3H, H-1′a, H-2, H-5b), 2.24 (s, 3H, N-CH₃), 2.07–1.99 (m, 1H, H-1′b), 1.44 (s, 3H, -C(CH₃)₂), 1.28 (s, 3H, -C(CH₃)₂). ¹³C NMR (75.4 MHz, CDCl₃, δ ppm, J Hz) δ 139.1–137.7 (m, C-arom.), 133.3 (d, J_C,P = 19.4, C-arom.), 132.9 (d, J_C,P = 18.9, C-arom.), 129.0 (C-arom.), 128.8 (C-arom.), 128.6 (d, J_C,P = 7.0, C-arom.), 128.5 (d, J_C,P = 6.7, C-arom.), 113.3 (-C(CH₃)₂), 85.4 (d, J_C,P = 6.5, C-3), 77.9 (C-4), 68.6–68.4 (m, C-2), 61.2 (C-5), 40.0 (N-CH₃), 29.4 (d, J_C,P = 14.8, C-1′), 27.2 (-C(CH₃)₂), 25.1 (-C(CH₃)₂). ³¹P NMR (121.5 MHz, CDCl₃, δ ppm) δ 24.3 (s). HRMS (ESI) m/z found 356.1756, calc. for C₂₁H₂₇NO₂P [M + H]⁺: 356.1774.
• (2R,3S,4R)-N-Methyl-2-diphenylphosphinomethyl-3,4-O-isopropylidene-pyrrolidine-3,4-diol (ent-9). To a solution of ent-7 (391 mg, 1.15 mmol) in anh. CH₂Cl₂ (5.5 mL) at 0 °C, was successively added Et₃N (175 µL, 1.26 mmol) and ClCO₂CH₃ (100 µL, 1.26 mmol). The mixture was stirred at 0 °C for 4.5 h. Then, HCl (0.1 M) was added and the aqueous layer was extracted three times with CH₂Cl₂. The combined organic layers were washed with a saturated aqueous solution of NaHCO₃, dried with Na₂SO₄, filtered and evaporated. The resulting residue was purified by chromatography column on silica gel (EtOAc:cyclohexane, 1:4) to give the corresponding N-methoxycarbonyl pyrrolidine (326 mg, 0.820 mmol, 74%, 2 steps). A solution of this compound (311 mg, 0.790 mmol) was dissolved in anhydrous THF (6.0 mL) and added to a suspension of LiAlH₄ (90 mg, 2.4 mmol) in anh. THF (2.0 mL) at 0 °C. The mixture was heated at reflux for 1 h and then cooled at 0 °C. Et₂O and a saturated aqueous solution of Na₂SO₄ were successively added and the mixture was filtered through Celite and washed with CH₂Cl₂. The solvent was evaporated and the residue was purified by chromatography column on silica gel (EtOAc:cyclohexane, 1:2→1:1) to give ent-9 (257 mg, 0.720 mmol, 92%) as a colourless oil. NMR and IR data are in accordance with those of its enantiomer 9 [18]. [α]_D²⁷ – 163.3 (c 1.23, CH₂Cl₂). HRMS (ESI) m/z found 356.1759, calc. for C₂₁H₂₇NO₂P [M + H]⁺: 356.1774.

3.3. Enantioselective Phosphine-Catalyzed [3 + 2] Cycloaddition between Allenoates and Electron-Deficient Imines

• General procedure: To a solution of the imine 19 (1.0 equiv, 0.154 mmol) and phosphine 9 or ent-9 (0.2 equiv, 0.03 mmol, 11 mg) in Et₂O (0.6 mL) cooled at 0 °C or in toluene (0.6 mL) at r.t. the allenoate 20 (1.2 equiv, 0.185 mmol) was added dropwise in Et₂O or toluene (0.6 mL). The reaction mixture was stirred for the specified time at specific temperature. Then, the solvent was concentrated and the resulting residue was purified by chromatography column on silica gel to give pure 21 or ent-21. Enantiomeric ratios were determined by HPLC analysis. Diastereomeric ratios were determined by analysis of ¹H NMR reaction crudes. Racemic samples were prepared with PPh₃ o PBu₃ (20 mol%) in toluene at room temperature following this general procedure.
• (2R,5S) Ethyl 2-phenyl-5-methyl-1-tosyl-2,5-dihydro-1H-pyrrole-3-carboxylate (21a). Reaction of imine 19a [26] (40 mg, 0.15 mmol), 9 (11 mg, 0.03 mmol) and allenoate 20a [27] (24 mg, 0.19 mmol) in Et₂O (1.2 mL) for 30 h at 0 °C and chromatography column (toluene:acetone, 60:1), afforded 21a (53 mg, 0.14 mmol, 89%, 63% ee, dr 96:4 cis/trans) as a pale yellow oil. NMR and IR data are in accordance with literature [7] [α]_D²⁶ – 110.8 [c 1.0, CHCl₃, 63% ee (2R,5S)]. Lit. [19]. [α]_D²⁰ – 18.0 [c 1.0, CHCl₃, 4% ee (2R,5S)]. The enantiomeric ratios were determined by HPLC using a Chiralpak ID column [n-hexanes/iPrOH (70:30)]; flow rate 1.0 mL/min, λ = 210 nm, T = 30 °C; t_R ((2S,5R), minor) = 15.3 min, t_R ((2R,5S), mayor) = 24.0 min.
• (2R)-Ethyl 2-phenyl-1-tosyl-2,5-dihydro-1H-pyrrole-3-carboxylate (21b). Reaction of imine 19a (40 mg, 0.15 mmol), 9 (11 mg, 0.03 mmol) and allenoate 20b [29] (21 mg, 0.19 mmol) in Et₂O (1.2 mL) for 38 h at 0 °C and chromatography column (EtOAc:cyclohexane, 1:5), afforded 21b (45 mg, 0.12 mmol, 79%, 30% ee (2R)) as a colourless oil. NMR and IR data are in accordance with literature [29]. [α]_D²⁴ – 63.0 [c 1.0, CHCl₃, 30% ee (2R)]. Lit. [19]. [α]_D²⁰ + 147.4 [c 1.0, CHCl₃, 72% ee (2S)]. The enantiomeric ratios were determined by HPLC using a Chiralpak IC column [n-hexanes/iPrOH (50:50)]; flow rate 1.0 mL/min, λ = 210 nm, T = 30 °C; t_R (2S, minor) = 15.2 min, t_R (2R, mayor) = 22.1 min.
• (2R,5R) Ethyl 5-(terc-butyl)-2-phenyl-1-tosyl-2,5-dihydro-1H-pyrrole-3-carboxylate (21c). Reaction of imine 19a (40 mg, 0.15 mmol), 9 (11 mg, 0.03 mmol) and allenoate 20c [29] (31 mg, 0.19 mmol) in toluene (1.2 mL) for 48 h at room temperature and chromatography column (EtOAc:cyclohexane, 1:8), afforded 21c (66 mg, 0.15 mmol, quant., dr 100:0 cis/trans, 59% ee (2R,5R)) as a pale yellow oil. NMR and IR data are in accordance with literature [7]. [α]_D²³ – 70.8 [c 1.0, CHCl₃, 59% ee (2R,5R)]. Lit. [19]. [α]_D²⁰ – 84.5 [c 1.0, CHCl₃, 73% ee (2R,5R)]. The enantiomeric ratios were determined by HPLC using a Chiralpak IA column [n-hexanes/iPrOH (80:20)]; flow rate 1.0 mL/min, λ = 210 nm, T = 30 °C; t_R ((2S,5S), minor) = 5.0 min, t_R ((2R,5R), mayor) = 6.1 min.
• (2R,5S) Ethyl 5-methyl-2-(4-methoxyphenyl)-1-tosyl-2,5-dihydro-1H-pyrrole-3-carboxylate (21d). Reaction of imine 19b [30] (45 mg, 0.15 mmol), 9 (11 mg, 0.03 mmol) and allenoate 20a (24 mg, 0.19 mmol) in Et₂O (1.2 mL) for 44 h at 0 °C and chromatography column (toluene:acetone, 50:1), afforded 21d (40 mg, 0.10 mmol, 62%, dr 94:6 cis/trans, 57% ee (2R,5S)) as a pale yellow oil. NMR and IR data are in accordance with literature [31]. [α]_D²³ – 116.1 [c 1.0, CHCl₃, 57% ee (2R,5S)]. The enantiomeric ratios were determined by HPLC using a Chiralpak IF column [n-hexanes/iPrOH (70:30)]; flow rate 1.0 mL/min, λ = 210 nm, T = 30 °C; t_R ((2S,5R), minor) = 16.4 min, t_R ((2R,5S), mayor) = 20.8 min.
• (2R,5S) Ethyl 2-(4-chlorophenyl)-5-methyl-1-tosyl-2,5-dihydro-1H-pyrrole-3-carboxylate (21e). Reaction of imine 19c [30] (46 mg, 0.15 mmol), 9 (11 mg, 0.03 mmol) and allenoate 20a (24 mg, 0.19 mmol) in Et₂O (1.2 mL) for 38 h at 0 °C and chromatography column (toluene:acetone, 50:1), afforded 21e (57 mg, 0.14 mmol, 88%, dr 95:5 cis/trans, 62% ee (2R,5S)) as a colourless oil. NMR and IR data are in accordance with literature [31]. [α]_D²³ – 124.0 [c 1.0, CHCl₃, 62% ee (2R,5S)]. The enantiomeric ratios were determined by HPLC using a Chiralpak IC column [n-hexanes/iPrOH (90:10)]; flow rate 1.0 mL/min, λ = 210 nm, T = 30 °C; t_R ((2S,5R), minor) = 30.3 min, t_R ((2R,5S), mayor) = 41.5 min.
• (2R,5S) Ethyl 5-methyl-2-(4-nitrophenyl)-1-tosyl-2,5-dihydro-1H-pyrrole-3-carboxylate (21f). Reaction of imine 19d [30] (47 mg, 0.15 mmol), 9 (11 mg, 0.03 mmol) and allenoate 20a (24 mg, 0.19 mmol) in Et₂O (1.2 mL) for 16 h at 0 °C and chromatography column (toluene:acetone, 50:1), afforded 21f (42 mg, 0.10 mmol, 64%, dr 84:16 cis/trans, 34% ee (2R,5S)) as a colourless oil. NMR and IR data are in accordance with literature [31] [α]_D²³ – 82.5 [c 1.0, CHCl₃, 34% ee (2R,5S)]. The enantiomeric ratios were determined by HPLC using a Chiralpak IC column [n-hexanes/iPrOH (70:30)]; flow rate 1.0 mL/min, λ = 210 nm, T = 30 °C; t_R ((2S,5R), minor) = 25.3 min, t_R ((2R,5S), major) = 31.5 min.