Total synthesis of phenanthroindolizidine alkaloids via asymmetric deprotonation of N-Boc-pyrrolidine

Abstract

A concise and efficient enantioselective strategy to synthesize two typical phenanthroindolizidine alkaloids, 14-hydroxyantofine and antofine, was developed, featuring an asymmetric deprotonation/diastereoselective carbonyl addition sequence during which the formation of a chiral C-13a center and connection of pyrrolidine and phenanthrene moieties were achieved efficiently in one step. The absolute configuration of the C-13a stereocenter can be delicately controlled by using different enantiomers of sparteine, both of which are commercially available.

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Introduction

Phenanthroindolizidine alkaloids, isolated mainly from Tylophora, Cynanchun, Pergularia, and some genera of the Asclepiadaceas family, have attracted continuous attention from both the synthetic and pharmaceutical communities owing to their unique structural features and low natural abundance, as well as their noteworthy biological activities since the first isolation of (R)-tylophorine [(−)-1b] (Fig. 1) in 1935.¹

Fig. 1 Representative phenanthroindolizidine alkaloids and (+)-sparteine (L).

In the past few decades, a number of impressive enantioselective synthetic routes for phenanthroindolizidine alkaloids have been reported.^1c,2 As these alkaloids possess a stereogenic center at the α position of the nitrogen atom, the chiron approach starting with optical α-amino acids or their derivatives has been widely used.^{1c,2b,d,e,h,i,k} In addition, a few other remarkable strategies have also been employed in recent years, including the chiral auxiliary procedure,^2j,3 asymmetric transition-metal-catalyzed intramolecular carboamination,^2c,f enantioselective phase-transfer alkylation,^2a and proline-catalyzed asymmetric α-aminoxylation of an aldehyde,^2g etc. Although a sustainable source of these alkaloids for bioactivity studies can be provided by the approaches mentioned above, a more efficient synthetic strategy is still desirable.

Asymmetric deprotonation of N-Boc-pyrrolidine using s-BuLi/(+)-sparteine, which gives a configurationally preferred carbanion, followed by nucleophilic substitution/addition was an attractive approach developed by Beak et al. for the direct functionalization of pyrrolidine (Scheme 1).⁴ Although detailed mechanistic studies have been done for this elegant and creative methodology,⁵ only a few successful applications in the total synthesis of natural products and chiral drug molecules have been reported, most of which used sinuous approaches to realize the asymmetric functionalization.^4d,e,6 To showcase the efficiency and convenience of this methodology, we wish herein to report a concise synthesis of (+)-14-hydroxyantofine (2) and (+)-antofine (1a), both of which are enantiomers of these alkaloids in nature (Fig. 1).

Scheme 1 Asymmetric deprotonation of N-Boc-pyrrolidine using s-BuLi/(+)-sparteine (L).

Results and discussion

Retrosynthetically, (+)-antofine (1a) and (+)-14-hydroxyantofine (2) were envisioned to be accessible via Pictet–Spengler cyclization of compounds 5 (Table 1) and 7a/7b (Scheme 3), respectively. Key intermediate 5 could be obtained by S_N2 substitution of chiral 2-lithio-N-Boc-pyrrolidine (3) to 4a or 4b (Table 1), and 7a/7b by a nucleophilic carbonyl addition of 3 to phenanthryl aldehyde 6 (Table 1). The starting materials 4a,^7a 4b (ref. 2i) and 6 (ref. 7b) were readily available by using an efficient and practical FeCl₃-mediated oxidative coupling method for constructing a polymethoxy-phenanthrene moiety developed by our group.⁸

Table 1 Synthesis of (+)-antofine (1a) by alkylation of N-Boc-pyrrolidine

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Initially, alkylation of N-Boc-pyrrolidine with bromide 4b was put into practice, as shown in Table 1. To explore the reactivity, tetramethylethylenediamine (TMEDA) was first employed as a ligand. Deprotonation of N-Boc-pyrrolidine with s-BuLi/TMEDA gave (±)-2-lithio-N-Boc-pyrrolidine, then bromide 4b was added. Gratifyingly, the desired coupled product (±)-5 was obtained in a moderate yield. It is worth noting that a main by-product 5a was isolated in a 22% yield, which was believed to be produced from lithium–bromide exchange⁹ of 4b with 2-lithio-N-Boc-pyrrolidine and subsequent dimerization. To decrease the lithium–halogen exchange, 4b was replaced by chloride 4a, which showed that 4a could give better results (Table 1, entry 1).

After investigating the reactivity of N-Boc-pyrrolidine, it was found that the asymmetric version was affected by the use of chiral ligand (+)-sparteine (Table 1, entries 3 and 4). Although great effort was made to optimize the reaction conditions, unfortunately, the desired product 5 could only be obtained in moderate enantiomeric excess and low yields. The reason for the lower yield was proposed to be the steric effect when the relatively bulky ligand was introduced. The subsequent Pictet–Spengler cyclization proved to be effective, giving antofine (1a) in a high yield (91%) and moderate ee (60%).

It was thought that the notable lithium–halogen exchange⁹ during the alkylation should be responsible for the unsatisfying yield and ee. To explore the mechanism, 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) was introduced into the reaction system (Table 1, entry 5).¹⁰ Product 5 was gained in a lower yield (23%) but a slightly raised ee (58%). Meanwhile, radical trapping product 4c (Table 1) was isolated in an 18% yield, which suggested a free radical process, as shown in Scheme 2. Besides being generated by direct S_N2 substitution of chiral 3 with 4b, 5 could also be produced by free radical coupling after the single electron transfer (SET) process between 3 and 4b, during which the racemization of chiral 3 and dimerization of free radical intermediate 4r were unavoidable. We declare that this SET mechanism is at least a minor pathway but there must exist a lithium–halogen exchange pathway not involving SET.^9,11

Scheme 2 Proposed mechanism of lithium–halogen exchange between 3 and 4b.

To avoid lithium–halogen exchange, a second strategy—carbonyl addition of 3 to 6—was explored (Scheme 3). To our delight, treatment of N-Boc-pyrrolidine with s-BuLi/(+)-sparteine in diethyl ether gave chiral 3, which underwent reaction with phenanthryl aldehyde 6 to give the enantiomerically enriched, diastereomeric intermediates 7a and 7b in 26% and 61% yields, respectively. Then diastereoisomers 7a and 7b were subjected to Pictet–Spengler cyclization conditions separately. Interestingly, both isomers gave the same cyclization product 2 in moderate yields (58%, 54%) and high ee (97%, 96%), and the other diastereomeric product was not detected. It is believed that racemization at the C-14 stereocenter occurred under the harsh acidic Pictet–Spengler cyclization conditions, so only one configurationally preferred product was obtained. The NMR data of synthesized product 2 were identical to those reported in literature.¹² However, the specific rotation of compound 2 was opposite to the natural product, thus we confirmed that the absolute configuration of 2 was (13aS, 14S). After dehydroxylation, 1a was obtained in a 96% yield and 98% ee.

Scheme 3 Synthesis of (+)-14-hydroxyantofine (2) and (+)-antofine (1a) by carbonyl addition of N-Boc-pyrrolidine.

Conclusions

In conclusion, a concise strategy to synthesize two typical phenanthroindolizidine alkaloids, antofine (1a) and 14-hydroxyantofine (2), has been explored, featuring asymmetric deprotonation of the N-Boc-pyrrolidine followed by reaction with carbon electrophiles. For the alkylation of compound 3 with 4, a notable lithium–halogen exchange was observed, which should account for the unsatisfying yield and ee. For the carbonyl addition of 3 to 6, a gratifying result was obtained. Product 2 was gained in a 47% total yield and 96–97% ee from 6 in two steps, then after undergoing one more step 1a could be obtained in a 96% yield and 98% ee.

Experimental section

General information

The melting points were determined using an X-4 binocular microscope melting-point apparatus and were uncorrected. ¹H NMR spectra were obtained using a Bruker AV 400 spectrometer. Chemical shifts (δ) were given in parts per million (ppm) and were measured downfield from internal tetramethylsilane. ¹³C NMR spectra were recorded using a Bruker AV 400 instrument (100 MHz) and CDCl₃ as the solvent. Chemical shifts (δ) were reported in parts per million. High-resolution mass spectra were obtained using an FT-ICR MS spectrometer (Ionspec, 7.0 T). Optical rotations were measured using an Autopol IV auto digital polarimeter (Rudolph Research Analytical). All anhydrous solvents were dried and purified by standard techniques just before use. All reagents were purchased from commercial suppliers without further purification. Reactions were monitored by thin layer chromatography on plates (GF254) using UV light as a visualizing agent. (+)-Sparteine was purchased from Aladdin Industrial Corporation. If not noted otherwise, flash column chromatography used silica gel (200–300 mesh).

Procedure A: racemic deprotonation of N-Boc-pyrrolidine and subsequent functionalization (Table 1, entries 1 and 2)

To a solution of TMEDA (278 mg, 2.4 mmol, 1.2 equiv.) and N-Boc-pyrrolidine (344 mg, 2.0 mmol, 1.0 equiv.) in Et₂O (60 mL) at −78 °C was added s-BuLi (2.2 mL, 1.0 M in hexane, 1.1 equiv.). The reaction mixture was stirred for 4 h at −78 °C, and then a suspension of electrophile 4 or 6 (1.0 mmol, 0.5 equiv.) in Et₂O (10 mL) was added. The mixture was stirred for 4–6 h at −78 °C, then allowed to warm slowly to 0 °C in 3 h. Workup consisted of the addition of water (20 mL), extraction of the aqueous layer with Et₂O (2 × 10 mL), extraction of the combined Et₂O extracts with 5% phosphoric acid (2 × 10 mL) and brine (2 × 10 mL), drying over anhydrous magnesium sulfate, filtration, and concentration in vacuo.

Procedure B: asymmetric deprotonation of N-Boc-pyrrolidine and subsequent functionalization (Table 1, entries 3–5)

To a solution of (+)-sparteine (563 mg, 2.4 mmol, 1.2 equiv.) and N-Boc-pyrrolidine (344 mg, 2.0 mmol, 1.0 equiv.) in Et₂O (60 mL) at −78 °C was added s-BuLi (2.2 mL, 1.0 M in hexane, 1.1 equiv.). The following operation was in accordance with procedure A.

Preparation of racemic 5 and 5a from 4a or 4b (Table 1, entries 1 and 2)

Taking 4a as an example (Table 1, entry 1), lithiation of N-Boc-pyrrolidine was carried out according to procedure A, then a suspension of 4a (317 mg, 1.0 mmol) in Et₂O (10 mL) was added. Purification by flash chromatography with 1/6 (v/v) EtOAc–hexane, followed by recrystallization from 1.0 mL methanol gave racemic 5 (280 mg, 62%) as a white solid; m.p. 150–152 °C (ref. 2b: 99–101 °C). ¹H NMR (400 MHz, CDCl₃) δ = 8.33 (s, 1H, Ar-H), 7.91 (s, 1H, Ar-H), 7.85 (d, J = 2.0 Hz, 1H, Ar-H), 7.73 (d, J = 8.8 Hz, 1H, Ar-H), 7.39 (s, 1H, Ar-H), 7.17 (dd, J = 8.8, 2.0 Hz, 1H, Ar-H), 4.26 (m, 1H, N-CH, 2-H), 4.22 (s, 3H, OMe), 4.12 (s, 3H, OMe), 4.02 (s, 3H, OMe), 3.92 (m, 1H, Ar-CH₂), 3.49 (m, 1H, Ar-CH₂), 3.32 (m, 1H, N-CH₂, 5-H), 2.59 (m, 1H, N-CH₂, 5-H), 2.02 (m, 1H, 3-H), 1.84 (m, 2H, 3-H, 4-H), 1.67 (m, 1H, 4-H), 1.51 (s, 9H, CH₃) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 157.8, 154.7, 149.8, 148.7, 131.1, 130.6, 129.5, 127.3, 126.0, 125.7, 124.5, 115.2, 106.8, 103.9, 103.4, 78.9, 57.2, 56.7, 56.0, 55.6, 46.8, 38.6, 29.0, 28.6, 23.5 ppm. Filtering the insoluble solid out of the organic/aqueous phase during the workup procedure gave 5a (45 mg, 16%) as an off-white solid; m.p. 265–270 °C. ¹H NMR (400 MHz, CDCl₃) δ = 7.95 (s, 2H, Ar-H), 7.87 (d, J = 2.4 Hz, 2H, Ar-H), 7.74 (d, J = 8.8 Hz, 2H, Ar-H), 7.58 (s, 2H, Ar-H), 7.37 (s, 2H, Ar-H), 7.20 (dd, J = 8.7, 2.4 Hz, 2H, Ar-H), 4.12 (s, 6H, OMe), 4.04 (s, 6H, OMe), 3.87 (s, 6H, OMe), 3.57 (s, 4H, Ar-CH₂) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 157.9, 149.3, 148.7, 133.1, 130.3, 129.6, 126.8, 126.2, 124.8, 124.1, 115.5, 104.7, 104.7, 103.9, 56.0, 55.8, 55.6, 33.8 ppm. HRMS (ESI): calcd for C₃₆H₃₅O₆ [M + H]⁺ 563.2428, found 563.2423.

Preparation of (+)-5 and 5a from 4a or 4b (Table 1, entries 3 and 4)

Taking 4a as an example (Table 1, entry 4), lithiation of N-Boc-pyrrolidine was carried out according to procedure B and then a suspension of 4a (317 mg, 1.0 mmol) in Et₂O (10 mL) was added. Purification by flash chromatography with 1/6 (v/v) EtOAc–hexane, followed by recrystallization from 1.0 mL methanol gave (+)-5 (150 mg, 33%) as a white solid. Chiral HPLC analysis (Chiralcel AD-H column, i-PrOH : hexane = 10 : 90, 1.0 mL min⁻¹) showed that the product had an enantiomeric excess of 62%. Filtering the insoluble solid out of the organic/aqueous phase during the workup procedure gave 5a (31 mg, 11%) as an off-white solid. Other data were identical to those of racemic 5 and 5a in procedure A.

Preparation of (+)-5, 4c, and 5a from 4b (Table 1, entry 5)

Lithiation of N-Boc-pyrrolidine according to procedure B was carried out, then a suspension of 4b (361 mg, 1.0 mmol, 0.5 equiv.) and TEMPO (624 mg, 4.0 mmol, 2.0 equiv) in Et₂O (10 mL) was added. Purification by flash chromatography with 1/10 (v/v) EtOAc–hexane gave (+)-5 (106 mg, 23%) as a white solid [chiral HPLC analysis (Chiralcel AD-H column, i-PrOH : hexane = 10 : 90, 1.0 mL min⁻¹) showed that the product had an enantiomeric excess of 58%]; and 4c (80 mg, 18%) as a white solid; m.p. 138–139 °C. ¹H NMR (400 MHz, CDCl₃) δ = 7.93 (s, 1H, Ar-H), 7.86 (d, J = 2.4 Hz, 1H, Ar-H), 7.81 (d, J = 8.8 Hz, 1H, Ar-H), 7.66 (s, 1H, Ar-H), 7.50 (s, 1H, Ar-H), 7.20 (dd, J = 8.8, 2.4 Hz, 1H, Ar-H), 5.24 (s, 2H, Ar-CH₂), 4.12 (s, 3H, OMe), 4.07 (s, 3H, OMe), 4.03 (s, 3H, OMe), 1.59–1.52 (m, 6H, CH₂), 1.37 (s, 6H, CH₃), 1.18 (s, 6H, CH₃) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 158.3, 149.3, 148.7, 131.0, 130.3, 129.2, 126.4, 125.8, 125.0, 124.6, 115.4, 105.4, 103.9, 103.6, 78.4, 56.1, 56.0, 55.6, 39.4, 32.9, 20.5, 17.0 ppm. HRMS (ESI): calcd for C₂₇H₃₆NO₄ [M + H]⁺ 438.2639, found 438.2635. Filtering the insoluble solid out of the organic/aqueous phase during the workup procedure gave 5a (34 mg, 12%) as an off-white solid. Other data were identical to those of racemic 5 and 5a in procedure A.

Preparation of 1a from (+)-5

(+)-5 (45 mg, 0.1 mmol, 62% ee) provided by the above procedure (Table 1, entry 4) was dissolved in ethanol (2 mL). Conc. HCl (0.5 mL, 36–38%) and formaldehyde solution (0.5 mL, 37%) were then added and the reaction mixture was heated under reflux for 12 h under an Ar atmosphere. After removing most of the ethanol, aqueous NaOH (1.0 M, 10 mL) was added and the mixture was extracted with CH₂Cl₂ (3 × 10 mL), and the combined organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Purification of the residue by flash chromatography with 20/1 (v/v) CH₂Cl₂–CH₃OH gave 1a (33 mg, 91%) as a white solid; m.p. 215–217 °C (ref. 2h: 209–211 °C). Chiral HPLC analysis (Chiralcel AD-H column, i-PrOH : hexane = 50 : 50, 1.0 mL min⁻¹) showed that the product had an enantiomeric excess of 60%. ¹H NMR (400 MHz, CDCl₃) δ = 7.92 (s, 1H, Ar-H), 7.91 (d, J = 2.4 Hz, 1H, Ar-H), 7.83 (d, J = 9.2 Hz, 1H, Ar-H), 7.32 (s, 1H, Ar-H), 7.21 (dd, J = 9.2, 2.4 Hz, 1H, Ar-H), 4.71 (d, J = 14.8 Hz, 1H, 9-H), 4.11 (s, 3H, OMe), 4.07 (s, 3H, OMe), 4.02 (s, 3H, OMe), 3.71 (d, J = 14.8 Hz, 1H, 9-H), 3.44–3.50 (m, 1H, 13a-H), 3.40–3.33 (m, 1H, 14-H), 2.85–2.96 (m, 1H, 14-H), 2.42–2.50 (m, 2H, 11-H), 2.19–2.26 (m, 1H, 13-H), 2.00–2.06 (m, 1H, 13-H), 1.89–1.94 (m, 1H, 12-H), 1.75–1.79 (m, 1H, 12-H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 157.4, 149.4, 148.3, 130.2, 127.1, 126.8, 125.6, 124.3, 124.2, 123.5, 114.9, 104.7, 104.0, 103.8, 60.2, 56.0, 55.9, 55.5, 55.1, 53.9, 33.8, 31.3, 21.6 ppm.

Preparation of 7a/7b from 6

Lithiation of N-Boc-pyrrolidine was carried out according to procedure B, then a suspension of 6 (296 mg, 1.0 mmol) in Et₂O (10 mL) was added. Purification by flash chromatography with 1/4 (v/v) EtOAc–hexane gave the minor diastereomer 7a (122 mg, 26%) as a white solid; m.p.195–197 °C. ¹H NMR (400 MHz, CDCl₃) δ = 8.14 (s, 1H, Ar-H), 7.88–7.75 (m, 4H, Ar-H), 7.18 (dd, J = 8.8, 2.0 Hz, 1H, Ar-H), 6.11 (s, 1H, Ar-CH), 4.28–4.35 (m, 1H, N-CH, 2-H), 4.18 (s, 3H, OMe), 4.08 (s, 3H, OMe), 4.01 (s, 3H, OMe), 3.40–3.48 (m, 2H, N-CH₂, 5-H), 2.43–2.47 (m, 1H, 3-H), 2.07–2.15 (m, 1H, 3-H), 1.93–2.02 (m, 1H, 4-H), 1.64–1.72 (m, 1H, 3-H), 1.53 (s, 9H, CH₃) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 158.0, 155.5, 149.6, 148.5, 133.0, 130.6, 130.3, 125.7, 125.3, 124.3, 121.5, 115.2, 105.6, 103.8, 103.3, 79.4, 70.2, 61.6, 56.7, 55.9, 55.6, 48.1, 28.6, 25.0, 24.1 ppm; HRMS (ESI): calcd for C₂₇H₃₃NNaO₆ [M + Na]⁺ 490.2200, found 490.2197; and the major diastereomer 7b (286 mg, 61%) as a white foamy solid; m.p. 93–95 °C; ¹H NMR (400 MHz, CDCl₃) δ = 7.97 (brs, 1H, Ar-H), 7.90 (s, 1H, Ar-H), 7.82 (s, 1H, Ar-H), 7.75 (d, J = 8.8 Hz, 1H, Ar-H), 7.63 (brs, 1H, Ar-H), 7.17 (dd, J = 8.8, 2.0 Hz, 1H, Ar-H), 6.21 (brs, 1H, OH), 5.09 (brs, 1H, Ar-CH), 4.63 (brs, 1H, N-CH, 2-H), 4.10 (s, 3H, OMe), 4.08 (s, 3H, OMe), 3.99 (s, 3H, OMe), 3.42–3.50 (m, 2H, N-CH₂, 5-H), 1.79–1.91 (m, 1H, 3-H), 1.66–1.76 (m, 1H, 3-H), 1.54 (s, 9H, CH₃), 1.37–1.47 (m, 2H, 4-H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 158.6, 158.3, 149.0, 148.6, 133.0, 131.0, 130.3, 126.0, 125.6, 125.2, 115.5, 106.0, 103.7, 103.7, 80.9, 63.6, 56.0, 55.9, 55.5, 47.8, 29.0, 28.5, 24.1 ppm; HRMS (ESI): calcd for C₂₇H₃₃NNaO₆ [M + Na]⁺ 490.2200, found 490.2196.

Preparation of 2 from 7a

To a solution of 7a (94 mg, 0.2 mmol) in ethanol (5 mL) was added conc. HCl (0.5 mL, 36–38%), the reaction mixture was heated under reflux for 1 h, then formaldehyde solution (2.0 mL, 37%) was added, and the reaction mixture was heated under reflux for 56 h under an Ar atmosphere. After removing most of the ethanol, aqueous NaOH (1.0 M, 10 mL) was added and the mixture was extracted with CH₂Cl₂ (3 × 10 mL), and the combined organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Purification of the residue by flash chromatography with 20/1 (v/v) CH₂Cl₂–CH₃OH gave 2 (44 mg, 58%) as a light-yellow solid; m.p. 221–223 °C. [α]²⁶_D = +197.4 (c 0.23, CHCl₃); {ref. 12: m.p. 237–239 °C, [α]¹¹_D = −217.1 (c 0.23, CHCl₃)}; chiral HPLC analysis (Phenomenex Lux Cellulose-1 column, i-PrOH : CH₃CN (0.1% Et₃N) = 5 : 95, 1.0 mL min⁻¹) showed that the product had an enantiomeric excess of 97%. ¹H NMR (400 MHz, CDCl₃) δ = 7.86 (s, 1H, Ar-H), 7.84 (s, 1H, Ar-H), 7.72 (d, J = 2.0 Hz, 1H, Ar-H), 7.03 (d, J = 9.2 Hz, 1H, Ar-H), 6.85 (dd, J = 9.2, 2.0 Hz, 1H, Ar-H), 4.94 (s, 1H, 14-H), 4.79 (brs, 1H, OH), 4.15 (s, 3H, OMe), 4.11 (s, 3H, OMe), 4.02 (s, 3H, OMe), 3.55 (d, J = 15.6 Hz, 1H, 9-H), 3.16–3.20 (d, J = 15.6 Hz, 1H, 9-H), 3.13–3.16 (m, 1H, 11-H), 2.35–2.42 (m, 2H, 13a-H, 12-H), 2.17–2.25 (m, 1H, 11-H), 2.07–1.95 (m, 1H, 12-H), 1.95–1.85 (m, 2H, 13-H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 157.7, 149.4, 148.3, 130.5, 127.7, 127.2, 126.8, 124.2, 123.7, 122.8, 114.6, 105.2, 104.0, 103.3, 65.4, 64.8, 56.1, 55.9, 55.4, 55.3, 53.4, 24.0, 21.6 ppm.

Preparation of 2 from 7b

To a solution of compound 7b (219 mg, 0.47 mmol) in ethanol (12 mL) was added conc. HCl (1.0 mL, 36–38%), the reaction mixture was heated under reflux for 1 h, then formaldehyde solution (4.0 mL, 37%) was added and the reaction mixture was heated under reflux for 60 h under an Ar atmosphere. Workup was similar to the above procedure and purification by flash chromatography gave 2 (95 mg, 54%) as a light-yellow solid. [α]²⁶_D = +191.6 (c 0.23, CHCl₃); chiral HPLC analysis (Phenomenex Lux Cellulose-1 column, i-PrOH : CH₃CN (0.1% Et₃N) = 5 : 95, 1.0 mL min⁻¹) showed that the product had an enantiomeric excess of 96%. Other data were identical to those above.

Preparation of 1a from 2

Two parts of 2 (44 + 95 mg, 0.367 mmol) prepared from 7a and 7b were gathered and dissolved in trifluoroacetic acid (4 mL), then triethylsilane (0.36 g, 3.1 mmol) was added, and the resulting mixture was stirred at room temperature for 12 h in the dark. The solvent was made basic with aqueous NaOH (2.0 M, 40 mL) and extracted with CH₂Cl₂ (3 × 20 mL), and the combined organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Purification of the residue by flash chromatography using basic alumina (200–300 mesh) with 40/1 (v/v) CH₂Cl₂–CH₃OH gave 1a (127 mg, 96%) as a white solid. Chiral HPLC analysis (Chiralcel AD-H column, i-PrOH : hexane = 50 : 50, 1.0 mL min⁻¹) showed that the product had an enantiomeric excess of 98%. [α]²⁵_D = +80.9 (c 0.45, CHCl₃); {ref. 2h: [α]²⁰_D = +85 (c 2.0, CHCl₃); 99% ee}; other data were identical to those of 1a prepared from 5.

Acknowledgements

This work was supported by the National Key Project for Basic Research (2010CB126106), the National Natural Science Foundation of China (21132003, 21121002, 21372131, 21002053), Tianjin Natural Science Foundation (11JCZDJC20500), and the Specialized Research Fund for the Doctoral Program of Higher Education (20130031110017).

References

1. (a) A. N. Ratnagiriswaran and K. Venkatachalam, Indian J. Med. Res, 1935, 22, 433–441; (b) E. Gellert, J. Nat. Prod., 1982, 45, 50–73; (c) Z. G. Li, Z. Jin and R. Q. Huang, Synthesis, 2001, 16, 2365–2378; (d) J. P. Michael, Nat. Prod. Rep., 2001, 18, 520–542; (e) D. S. Bhakuni, J. Indian Chem. Soc., 2002, 79, 203–210; (f) J. P. Michael, Nat. Prod. Rep., 2005, 22, 603–626; (g) A. G. Damu, P. K. Kuo, L. S. Shi, C. Y. Li, C. S. Kuoh, P. L. Wu and T. S. Wu, J. Nat. Prod., 2005, 68, 1071–1075; (h) A. Toribio, A. Bonfils, E. Delannay, E. Prost, D. Harakat, E. Henon, B. Richard, M. Litaudon, J. M. Nuzillard and J. H. Renault, Org. Lett., 2006, 8, 3825–3828; (i) S. R. Chemler, Curr. Bioact. Compd., 2009, 5, 2–19; (j) H. Y. Min, H. J. Chung, E. H. Kim, S. Kim, E. J. Park and S. K. Lee, Biochem. Pharmacol., 2010, 80, 1356–1364; (k) C. W. Yang, Z. Y. Lee, I. J. Kang, D. L. Barnard, J. T. Jan, D. Lin, C. W. Huang, T. K. Yeh, Y. S. Chao and S. J. Lee, Antiviral Res., 2010, 88, 160–168.
2. For recent selected examples, see: (a) S. Kim, J. Lee, T. Lee, H. G. Park and D. Kim, Org. Lett., 2003, 5, 2703–2706; (b) A. Fürstner and J. W. Kennedy, Chem. – Eur. J., 2006, 12, 7398–7410; (c) W. Zeng and S. R. Chemler, J. Org. Chem., 2008, 73, 6045–6047; (d) X. M. Yang, Q. Shi, K. F. Bastow and K. H. Lee, Org. Lett., 2010, 12, 1416–1419; (e) A. Stoye and T. Opatz, Org. Lett., 2010, 12, 2140–2141; (f) D. N. Mai and J. P. Wolfe, J. Am. Chem. Soc., 2010, 132, 12157–12159; (g) M. B. Cui, H. J. Song, A. Z. Feng, Z. W. Wang and Q. M. Wang, J. Org. Chem., 2010, 75, 7018–7021; (h) Z. W. Wang, Z. Li, K. L. Wang and Q. M. Wang, Eur. J. Org. Chem., 2010, 292–299; (i) B. Su, C. L. Cai and Q. M. Wang, J. Org. Chem., 2012, 77, 7981–7987; (j) B. Su, F. Z. Chen and Q. M. Wang, J. Org. Chem., 2013, 78, 2775–2779; (k) W. J. Ying and J. W. Herndon, Eur. J. Org. Chem., 2013, 3112–3122.
3. (a) M. Ihara, Y. Takino, M. Tomotake and K. Fukumoto, J. Chem. Soc., Perkin Trans. 1, 1990, 8, 2287–2292; (b) D. L. Comins, X. Chen and L. A. Morgan, J. Org. Chem., 1997, 62, 7435–7438; (c) H. Suzuki, S. Aoyagi and C. Kibayashi, J. Org. Chem., 1995, 60, 6114–6122; (d) D. David, L. Stéphane, C. Axel, D. Eric and G. Pierre, Eur. J. Org. Chem., 2010, 1943–1950.
4. (a) S. T. Kerrick and P. Beak, J. Am. Chem. Soc., 1991, 113, 9708–9710; (b) P. Beak, S. T. Kerrick, S. D. Wu and J. X. Chu, J. Am. Chem. Soc., 1994, 116, 3231–3239; (c) D. Hoppe, F. Hintze and P. Tebben, Angew. Chem., Int. Ed., 1990, 29, 1424–1425; (d) R. K. Dieter, C. M. Topping, K. R. Chandupatla and K. Lu, J. Am. Chem. Soc., 2001, 123, 5132–5133; (e) K. R. Campos, A. Klapars, J. H. Waldman, P. G. Dormer and C. Y. Chen, J. Am. Chem. Soc., 2006, 128, 3538–3539.
5. For reviews, see: (a) P. Beak, A. Basu, D. J. Gallagher, Y. S. Park and S. Thayumanavan, Acc. Chem. Res., 1996, 29, 552–560; (b) D. Hoppe and T. Hense, Angew. Chem., Int. Ed., 1997, 36, 2282–2316.
6. For examples: (a) R. T. Watson, V. K. Gore, K. R. Chandupatla, R. K. Dieter and J. P. Snyder, J. Org. Chem., 2004, 69, 6105–6114; (b) R. K. Dieter and N. Y. Chen, J. Org. Chem., 2006, 71, 5674–5678; (c) D. Stead, P. O'Brien and A. Sanderson, Org. Lett., 2008, 10, 1409–1412; (d) A. Klapars, K. R. Campos, J. H. Waldman, D. Zewge, P. G. Dormer and C. Y. Chen, J. Org. Chem., 2008, 73, 4986–4993; (e) J. L. Bilke, S. P. Moore, P. O'Brien and J. Gilday, Org. Lett., 2009, 11, 1935–1938 ; for an unsuccessful trial about alkylation of N-Boc-pyrrolidine, see: ; (f) S. Yamashita, N. Kurono, H. Senboku, M. Tokuda and K. Orito, Eur. J. Org. Chem., 2009, 1173–1180.
7. For the preparation of 4a, see: (a) T. R. Govindachari, I. S. Ragade and N. Viswanatha, J. Chem. Soc., 1962, 1357–1360 ; for 6: ; (b) M. L. Bremmer, N. A. Khatri and S. M. Weinreb, J. Org. Chem., 1983, 48, 3661–3666.
8. K. L. Wang, M. Y. Lü, Q. M. Wang and R. Q. Huang, Tetrahedron, 2008, 64, 7504–7510.
9. (a) W. F. Bailey and J. J. Patricia, J. Organomet. Chem., 1988, 352, 1–46; (b) D. Seyferth, Organometallics, 2006, 25, 2–24.
10. (a) W. K. Robbins and R. H. Eastman, J. Am. Chem. Soc., 1970, 92, 6077–6079; (b) V. W. Bowry and K. U. Ingold, J. Am. Chem. Soc., 1992, 114, 4992–4996; (c) M. J. Fernández, L. Gude and A. Lorente, Tetrahedron Lett., 2001, 42, 891–893.
11. P. Beak and D. J. Allen, J. Am. Chem. Soc., 1992, 114, 3420–3425 , and references cited therein.
12. Z. Rui, S. D. Fang, Y. Chen and S. X. Lü, Zhiwu Xuebao, 1991, 33, 870–875.

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Footnote

† Electronic supplementary information (ESI) available: ¹H and ¹³C NMR spectroscopic data for 5, 5a, 4c, 7a, 7b, 1a, and 2. HRMS (ESI) data for 5a, 4c, 7a, 7b, and 2. Chiral-HPLC chromatogram for 5, 2, 1a. See DOI: 10.1039/c3ra47465h

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