Stereoselective total synthesis of (−)-nupharamine utilizing an α-chlorosulfide and a sulfinimine for C–C bond formation

Abstract

An efficient stereoselective synthesis of the nuphar alkaloid, (−)-nupharamine, is reported. The key features include the Lewis acid catalyzed reaction of an α-chlorosulfide with a silyl ketene acetal for C–C bond formation, creation of the stereocenter at C2 by a diastereoselective reaction of allyl indium with a sulfinimine and reductive amination for the introduction of the C6 stereocenter of the piperidine ring.

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Introduction

Nuphar alkaloids comprise the family of sesquiterpenoid and triterpenoid alkaloids possessing piperidine, indolizidine and quinolizidine ring systems that are isolated from aquatic plants of the genus Nuphar (Nymphaeaceae).¹ Nupharamine (1), was isolated from the Japanese water lily, Nuphar japonica,² found in Japan and Korea. It has been used as a diuretic and for the treatment of stomach ache.³ Other members of the family have been shown to possess antibiotic,^4a antifungal,^4b potent immunosuppressive,^4c central paralytic effects,^5a,b,c and antitumor activities.^5d,e The structural motif common to nuphar alkaloids is the trisubstituted piperidine ring with a methyl group at C-3 and a 3-furyl substituent at the C-6 position. Nuphar alkaloids have been targets for asymmetric synthesis due to their significant biological properties. The total synthesis of nupharamine 1 (Fig. 1) has been reported by several groups, utilizing a Diels–Alder strategy,⁶ an intramolecular aza-Wittig reaction,⁷ a cross-metathesis/reductive amination reaction,⁸ an intramolecular Mannich reaction⁹ and allenic hydroxylamine cyclisation¹⁰ as key steps.

Fig. 1 Nuphar alkaloid, nupharamine.

Results and discussion

Herein, we describe the stereoselective synthesis of (−)-nupharamine 1 by employing a Lewis acid catalyzed reaction of an α-chlorosulfide with a silyl ketene acetal, diastereoselective allylation of a t-butyl sulfinimine for C–N bond construction and reductive amination as key steps. The retrosynthetic analysis is depicted in Scheme 1. Nupharamine was visualized to be obtained by reductive amination of an amino ketone obtained from sulfinamide 2 which can be obtained by an allylation followed by cross-metathesis from sulfinimine 3. Compound 3 was envisaged to be obtained from β-keto sulfide 4 which in turn can be traced to sulfide 5 and silyl enol ether 6.

Scheme 1 Retrosynthetic analysis of nupharamine.

The synthesis began with the Michael addition of thiophenol 7 to methyl methacrylate 8 to furnish racemic ester 9. LAH reduction furnished alcohol 10, enzymatic resolution of which using vinyl acetate and Amano lipase furnished optically pure sulfide 11 (45% yield, 99% ee).¹¹ The protection of 11 under standard conditions using TBDPS-Cl afforded the silyl ether 5. The treatment of sulfide 5 with N-chlorosuccinimide furnished α-chlorosulfide 12^12,13 which without isolation was reacted with silyl ketene acetal 6, prepared from the corresponding ketone,¹⁴ in the presence of catalytic amounts of ZnBr₂ to yield keto sulfide 4,¹⁵ as an inseparable mixture of diastereomers in a 2 : 1 ratio. The thiophenyl residue in 4 was chemoselectively hydrogenolyzed using RANEY®-Ni pre-treated with acetone¹⁶ to furnish compound 13, Scheme 2.

Scheme 2 Synthesis of compound 13.

The keto group in 13 was protected as its ketal using ethylene glycol¹⁷ in the presence of catalytic amounts of p-toluenesulfonic acid to afford 14. Deprotection of the silyl ether in 14 using TBAF furnished the alcohol 15, which on oxidation using DMP¹⁸ yielded the aldehyde 16. Treatment of 16 with (R)-N-tert-butanesulfinamide¹⁹ in the presence of Ti(OEt)₄ furnished sulfinimine 3. Attempted reactions of 3 with prenyl lithium²⁰ expecting to obtain homoallylic amine derivative 2 did not bear fruit and the terminal alkene 18 was obtained exclusively.²¹

Exploring an alternative route, the three component allylation was attempted using aldehyde 16, sulfinamide 17 and allyl indium, generated in situ, as the reacting partners.²² The reaction proceeded cleanly to yield homoallyl amine derivative 19 selectively. The reaction outcome can be rationalized by invoking transition state I, wherein the allyl indium attacks the sulfinimine from the less hindered face by chelating to the oxygen atom. The trisubstituted alkene 2 was prepared via intermolecular olefin cross-metathesis²³ between olefin 19 and 2-methyl-2-butene using the second generation Hoveyda–Grubbs’ catalyst (HG-II, 1.5 mol%) under solvent-free reaction conditions at 40 °C. Compound 2 on treatment with 4 N HCl²⁴ in dioxane resulted in the concurrent hydration of the trisubstituted olefin, deprotection of the sulfinamide and 1,3-dioxolane groups to yield the amine·HCl, which on neutralization, followed by reduction using NaBH₄ in MeOH produced nupharamine 1 as the sole product⁷ in 70% yield. The hydride delivery to the imine from the face opposite to the bulky C-2 substituent as depicted in transition state II would explain the formation of 1, Scheme 3. The spectroscopic data and optical rotation of nupharamine 1 were in good agreement with those reported in the literature,⁸ {[α]²⁵_D = −37.5 (c 0.7, CHCl₃), lit.⁸ [α]²²_D = −38.7 (c 0.75, CHCl₃)}.

Scheme 3 Synthesis of nupharamine.

Conclusions

The α-chlorosulfide prepared from sulfide 5 has been employed in the reaction with silyl ketene acetal for C–C bond formation. The t-butyl sulfinamide auxiliary has been employed for the stereoselective creation of the C-2 stereogenic center by reaction with allyl indium. A reductive amination reaction has been utilized to create the C-6 stereocenter. The synthetic route disclosed can be readily adapted to prepare other members of nuphar alkaloids.

Experimental

General information

All materials were used as received from a commercial supplier without further purification. All anhydrous reactions were performed using oven-dried or flame dried glassware. Tetrahydrofuran (THF) was distilled over Na/Ph₂CO under a nitrogen atmosphere. Dichloromethane (CH₂Cl₂), and triethylamine (TEA) were dried over CaH₂ and distilled prior to use. All reactions were monitored by using E. Merck analytical thin layer chromatography (TLC) plates and analyzed with 254 nm UV light and/or anisaldehyde–sulfuric acid or potassium permanganate or PMA treatment. Silica gel for column chromatography was purchased from Acme (Silica Gel 60–120, 100–200 mesh). All ¹H and ¹³C NMR spectra were recorded in CDCl₃ using Gemini 200, Avance 300, Inova 400, and Inova 500 spectrometers. Chemical shifts (δ) are reported in parts per million (ppm) relative to residual CHCl₃ as an internal reference (1H: δ 7.26 ppm, 13C: δ 77.00 ppm). Coupling constants (J) are reported in Hertz (Hz). Peak multiplicity is indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet) and m (multiplet). Mass spectra were recorded using a Waters mass spectrometer. HPLC spectra were recorded using a Waters 2998 spectrometer. High resolution mass spectra (HRMS) were recorded using an Applied Bio-Sciences HRMS spectrometer and a Thermo LTQ-Orbitrap mass spectrometer. All IR-spectra were recorded using a Nexus 870-FT-IR Thermo Nicolet spectrometer.

Methyl 2-methyl-3-(phenylthio)propanoate (9). To a stirred solution of freshly distilled methyl methacrylate 8 (20 g, 200 mmol, 1 eq.) in benzene (400 mL) at rt was added DBU (3 mL, 20 mmol, 0.1 eq.) followed by dropwise addition of thiophenol 7 (22.4 mL, 220 mmol, 1.1 eq.) over a period of 15 min. The resulting solution was then stirred at rt for 5 h. The reaction was quenched by the addition of 0.5 N HCl (40 mL) and the mixture was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with 1 N NaOH (50 mL) and brine (100 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The resulting compound was purified by silica gel column chromatography using hexanes–EtOAc (98 : 2, v/v) as the eluent to afford compound 9 (37.8 g, 180 mmol) in 90% yield as an oil. TLC R_f = 0.4 (5% EtOAc–hexanes). IR (neat): 2948, 1736, 1581, 1437, 1210, 1165, 742, 692 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 7.32–7.30 (d, J = 6.8 Hz, 2H), 7.25 (t, J = 6.8 Hz, 2H), 7.16 (t, J = 6.8 Hz, 1H), 3.64 (s, 3H), 3.23 (dd, J = 12.8, 6.7 Hz, 1H), 2.87 (dd, J = 12.8, 7.5 Hz, 1H), 2.70–2.59 (m, 1H), 1.26 (d, J = 6.7 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 174.8, 135.6, 129.8, 128.7, 126.2, 51.5, 39.4, 37.2, 16.5. MS (ESI): 233 [M + Na]⁺. HRMS (ESI): m/z calcd for C₁₁H₁₄O₂NaS 233.0612, found 233.0602.

2-Methyl-3-(phenylthio)propan-1-ol (10). To a suspension of LAH (6.0 g, 158 mmol, 1 eq.) in anhydrous THF (150 mL) cooled at 0 °C was added a solution of compound 9 (33.1 g, 158 mmol, 1 eq.) in anhydrous THF (60 mL) dropwise over a period of 30 min. The reaction mixture was stirred for an additional 30 min at 0 °C and allowed to warm to rt and stirred for 2 h. The reaction mixture was diluted with ether (200 mL) and quenched with ice pieces. The reaction mixture was stirred at room temperature for 1 h, the resulting reaction mixture was filtered through a pad of Celite, and the filter cake was washed with EtOAc (3 × 200 mL) and MeOH (100 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the crude product. Purification of the crude residue by silica gel column chromatography using hexanes–EtOAc (8 : 2, v/v) as the eluent afforded racemic alcohol 10 (22.9 g, 126 mmol) in 80% yield as a colorless liquid. TLC R_f = 0.12 (20% EtOAc–hexanes). IR (neat): 3390, 2959, 2876, 1583, 1478, 1030, 739, 691 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 7.35 (t J = 6.7 Hz, 2H), 7.28 (t, J = 6.7 Hz, 2H), 7.17 (t, J = 6.7 Hz, 1H), 3.64 (dd, J = 10.5, 5.2 Hz, 1H), 3.59 (dd, J = 10.5, 6.0 Hz, 1H), 3.07 (dd, J = 12.8, 6.7 Hz, 1H), 2.84 (dd, J = 12.8, 6.7 Hz, 1H), 2.00–1.91 (m, 1H), 1.63 (bs, 1H), 1.04 (d, J = 6.7 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 136.6, 128.7, 125.6, 66.4, 37.1, 35.3, 16.3. MS (ESI) 205 [M + Na]⁺. HRMS (ESI): m/z calcd for C₁₀H₁₄ONaS 205.0663, found 205.0669.

(S)-2-Methyl-3-(phenylthio)propan-1-ol (11). To a stirred solution of (±) alcohol 10 (18.2 g, 100 mmol, 1 eq.) in anhydrous chloroform cooled at 0 °C were added vinyl acetate (34.4 g, 400 mmol, 4 eq.) and Pseudomonas fluorescens Amano Lipase (PFL) (1.1 g). The resulting solution was then stirred at 0 °C for 5 h when HPLC using a chiral column revealed the absence of (R)-11. (HPLC: ee = 99.0%, Chiralpak IC column, mobile phase: hexane/isopropanol 98/02, flow rate: 1 mL min⁻¹, temperature = 25 °C, detection: UV 220 nm, retention time (S)-isomer = 21.67 min, (R)-isomer 19.88 min). The resulting reaction mixture was filtered through a pad of Celite, dried over Na₂SO₄, filtered and concentrated under reduced pressure to yield the crude product. Purification of the crude residue by column chromatography using hexanes–EtOAc (8 : 2, v/v) as the eluent afforded alcohol 11 (8.19 g, 45 mmol) in 45% yield as a colorless liquid. [α]²⁵_D = +11.5 (c 1.0, CH₂Cl₂).

(S)-tert-Butyl(2-methyl-3-(phenylthio)propoxy)diphenylsilane (5). To a stirred solution of alcohol 11 (7.64 g, 42 mmol, 1 eq.) in anhydrous dichloromethane (100 mL) cooled at 0 °C were added imidazole (6.28 g, 92.4 mmol, 2.2 eq.) and TBDPS-Cl (12.70 g, 46.2 mmol, 1.1 eq.). The reaction mixture was stirred for 1 h before being diluted with dichloromethane (50 mL), washed with water (100 mL) and brine (50 mL) and dried over Na₂SO₄. The organic layer was evaporated under reduced pressure to afford the crude compound, which was purified by column chromatography on silica gel using hexanes–EtOAc (9.5 : 0.5, v/v) as the eluent to afford compound 5 (16.7 g, 40 mmol) in 95% yield as a yellow oil. TLC R_f = 0.42 (5% EtOAc–hexanes). [α]²⁵_D = +18.5 (c 1.0, CHCl₃). IR (neat): 2957, 2930, 2858, 1472, 1109, 1084, 738, 700, 503 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 7.65–7.59 (m, 4H), 7.38–7.24 (m, 8H), 7.20 (t, J = 7.5 Hz, 2H), 7.09 (t, J = 7.5 Hz, 1H), 3.63 (dd, J = 9.8, 4.5 Hz, 1H), 3.52 (dd, J = 9.8, 6.7 Hz, 1H), 3.21 (dd, J = 12.8, 6.0 Hz, 1H), 2.66 (dd, J = 12.8, 7.5 Hz, 1H), 2.01–1.86 (m, 1H), 1.06 (s, 9H), 1.09 (d, J = 6.7 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 137.2, 135.5, 133.5, 129.5, 128.7, 128.5, 127.6, 125.3, 67.4, 36.9, 35.7, 26.8, 19.2, 16.2. MS (ESI): 443 [M + Na]⁺. HRMS (ESI): m/z calcd for C₂₆H₃₂ONaSSi 443.1835, found 443.1846.

(S)-5-(tert-Butyldiphenylsilyloxy)-1-(furan-3-yl)-4-methyl-3-(R,S)(phenylthio)pentan-1-one (4). To a solution of compound 5 (4.20 g, 10 mmol, 1 eq.) in anhydrous dichloromethane (50 mL) was added the solution of N-chlorosuccinimide (1.5 g, 11 mmol, 1.1 eq.) in dichloromethane (50 mL) at ambient temperature and the mixture was stirred for 15 min. Another flame-dry rb flask was charged with the solution of freshly prepared silyl ketene acetal 6 (4.28 g, 20 mmol, 2 eq.) in dichloromethane (10 mL) followed by the addition of the above-generated chlorosulfide through cannula and ZnBr₂ (1.5 mL, 1.5 mmol, 1.5 M in THF, 0.15 eq.). The mixture was stirred at rt for 30 min. The reaction was quenched by the addition of H₂O (15 mL). The layers were separated and the aq. layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to furnish the crude product, which was purified by column chromatography on silica gel using hexanes–EtOAc (9.5 : 0.5, v/v) as the eluent to afford sulfide 4 (3.43 g, 6.5 mmol) as an inseparable mixture of diastereomers in 65% yield as a gummy liquid. TLC R_f = 0.3 (5% EtOAc–hexanes). IR (neat): 3448, 2959, 2930, 2857, 1725, 1467, 1375, 1259, 1111, 1038, 803, 703, 506 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 7.9 (s, 1H), 7.8 (s, 1H), 7.75 (s, 1H), 7.65 (s, 1H), 7.63–7.44 (m, 8H), 7.39–7.19 (m, 12H), 7.19–7.0 (m, 10H), 6.66 (s, 1H), 6.59 (s, 1H), 3.72–3.65 (m, 4H), 3.55–3.47 (m, 2H), 3.04 (dd, J = 15.8, 6.9 Hz, 1H), 2.91 (dd, J = 15.8, 7.9 Hz, 1H), 2.88 (dd, J = 12.8, 6.9 Hz, 1H), 2.82 (dd, J = 12.8, 5.8 Hz, 1H), 2.10–2.04 (m, 1H), 2.03–1.95 (m, 1H), 0.97 (d, J = 8.8 Hz, 3H), 0.93 (s, 9H), 0.86 (d, J = 6.9 Hz, 3H), 0.83 (s, 9H).¹³C NMR (75 MHz, CDCl₃): δ 192.6, 192.2, 147.4, 147.3, 143.8, 143.7, 135.5, 135.3, 134.7, 133.5, 130.0, 129.7, 129.5, 129.4, 129.3, 129.1, 128.7, 128.5, 127.5, 127.4, 125.7, 125.3, 108.5, 108.3, 67.3, 66.5, 46.0, 44.4, 37.2, 37.0, 35.7, 35.4, 26.8, 26.6, 19.2, 19.0, 16.3, 16.2. MS (ESI): 551 [M + Na]⁺. HRMS (ESI): m/z calcd for C₃₂H₃₆O₃NaSSi 551.2047, found 551.2048.

(R)-5-(tert-Butyldiphenylsilyloxy)-1-(furan-3-yl)-4-methylpentan-1-one (13). A suspension of RANEY®-nickel (10 g) in acetone (20 mL) was stirred for 30 min at rt. Acetone was removed and the residue was washed with THF (2 × 20 mL).The solution of compound 4 (10.4 g, 20 mmol, 1 eq.) in anhydrous THF (30 mL) was added to the suspension of RANEY®-nickel in THF (20 mL) and the reaction mixture was stirred at rt for 3 h. The RANEY®-nickel was removed by filtration through a Celite plug and the filter cake was washed with EtOAc (2 × 60 mL). The combined filtrates were washed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the crude product which was purified by silica gel column chromatography by using hexanes–EtOAc (9.5 : 0.5, v/v) as the eluent to afford compound 13 (6.3 g, 15 mmol) in 75% yield as a yellow liquid. TLC R_f = 0.2 (5% EtOAc–hexanes). [α]²⁵_D = −3.5 (c 1.0, CHCl₃). IR (neat): 2932, 2860, 1677, 1468, 1389, 1154, 1107, 749, 701, 503 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 7.93 (s, 1H), 7.68–7.63 (m, 4H), 7.46–7.33 (m, 7H), 6.74 (d, J = 1.5 Hz, 1H), 3.53 (dd, J = 10.5, 6.1 Hz, 1H), 3.49 (dd, J = 10.5, 5.2 Hz, 1H), 2.70 (t, J = 6.7 Hz, 2H), 1.92–1.79 (m, 1H), 1.78–1.66 (m, 1H), 1.65–1.51 (m, 1H), 1.05 (s, 9H), 0.95 (d, J = 6.7 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 194.7, 146.8, 143.9, 135.6, 133.8, 129.6, 127.6, 108.8, 68.4, 38.1, 35.3, 27.7, 27.0, 19.4, 17.0. MS (ESI): 443 [M + Na]⁺. HRMS (ESI): m/z calcd for C₂₆H₃₂O₃NaSi 443.2013, found 443.2018.

(R)-tert-Butyl(4-(2-(furan-3-yl)-1,3-dioxolan-2-yl)-2-methylbutoxy)diphenylsilane (14). To a stirred solution of compound 13 (6.3 g, 15 mmol, 1 eq.) in benzene (60 mL) cooled at 0 °C, ethylene glycol (3.1 mL) and p-toluenesulfonic acid (0.28 g, 1.5 mmol, 0.1 eq.) were added. The resulting mixture was stirred at reflux (Dean–Stark system containing benzene in the trap) for 10 h. An aq. saturated solution of NaHCO₃ (5 mL) was added. The layers were separated and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using hexanes–EtOAc (9 : 1, v/v) as the eluent to afford compound 14 (5.42 g, 11.7 mmol) in 78% yield as an oil. TLC R_f = 0.32 (5% EtOAc–hexanes). [α]²⁵_D = +4.1 (c 1.0, CHCl₃). IR (neat): 2930, 1459, 1395, 1215, 1163, 1104, 767, 702, 606 cm⁻¹. ¹H NMR (200 MHz, CDCl₃): δ 7.68–7.61 (m, 5H), 7.44–7.33 (m, 7H), 6.30 (s, 1H), 4.02–3.94 (m, 2H), 3.90–3.83 (m, 2H), 3.48 (dd, J = 10.1, 5.8 Hz, 1H), 3.41 (dd, J = 10.1, 6.7 Hz, 1H), 1.98–1.78 (m, 2H), 1.70–1.48 (m, 2H), 1.26–1.13 (m, 1H), 1.02 (s, 9H), 0.91 (d, J = 6.7 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 143.1, 139.9, 135.5, 134.0, 129.6, 129.4, 127.5, 108.7, 107.8, 68.7, 64.6, 37.0, 35.7, 26.9, 26.8, 19.2, 16.7. MS (ESI): 465 [M + H]⁺. HRMS (ESI): m/z calcd for C₂₈H₃₇O₄Si 465.2456, found 465.2465.

(R)-4-(2-(Furan-3-yl)-1,3-dioxolan-2yl)-2-methylbutan-1-ol (15). To a solution of compound 14 (5.42 g, 11.7 mmol, 1 eq.) in anhydrous THF (45 mL) cooled at 0 °C was added TBAF (11.7 mL, 1.0 M in THF, 1 eq.). The reaction mixture was stirred at ambient temperature for 5 h and then concentrated in vacuo. The residue was purified by silica gel column chromatography using hexanes–EtOAc (8 : 2, v/v) as the eluent to afford the alcohol 15 (2.37 g, 10.5 mmol) in 90% yield as an oil. TLC R_f = 0.1 (20% EtOAc–hexanes). [α]²⁵_D = −11.7 (c 2.0, CHCl₃). IR (neat): 3421, 2954, 2883, 1663, 1465, 1187, 1044, 874, 800, 602 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 7.38 (s, 1H), 7.36 (s, 1H), 6.32 (s, 1H), 4.01–3.96 (m, 2H), 3.92–3.87 (m, 2H), 3.48 (dd, J = 10.5, 5.6 Hz, 1H), 3.42 (dd, J = 10.5, 6.1 Hz, 1H), 2.01–1.95 (m, 1H), 1.91–1.85 (m, 1H), 1.66–1.59 (m, 1H), 1.54–1.47 (m, 1H), 1.26–1.19 (m, 1H), 0.90 (d, J = 6.7 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 143.1, 139.8, 127.6, 108.6, 107.7, 67.6, 64.5 36.8, 35.5, 26.6, 16.5. MS (ESI): 249 [M + Na]⁺. HRMS (ESI): m/z calcd for C₁₂H₁₈NaO₄ 249.1097, found 249.1113.

(R)-4-(2-(Furan-3-yl)-1,3-dioxolan-2yl)-2-methylbutanal (16). To a stirred solution of alcohol 15 (1.13 g, 5 mmol, 1 eq.) in anhydrous dichloromethane (20 mL) was added solid NaHCO₃ (2.0 g, 25 mmol, 5 eq.) followed by the Dess–Martin periodinane (2.5 g, 6.0 mmol, 1.2 eq.). After stirring for 30 min, the reaction mixture was filtered through a pad of Celite. The filtrate was washed with aq. saturated Na₂S₂O₃ (20 mL), saturated aqueous NaHCO₃ (20 mL) and brine (20 mL) and dried over Na₂SO₄. The solution was filtered and concentrated under reduced pressure to provide the aldehyde 16 (0.9 g, 4 mmol) in 80% yield as a clear colorless oil which was used without further purification. TLC R_f = 0.21 (20% EtOAc–hexanes). [α]²⁵_D = −13.5 (c 1.0, CHCl₃). IR (neat): 2930, 1720, 1664, 1459, 1389, 1156, 1108, 756, 602 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 9.59 (d, J = 1.5 Hz, 1H). 7.39 (s, 1H), 7.37 (s, 1H), 6.32 (s, 1H), 4.01–3.97 (m, 2H), 3.92–3.87 (m, 2H), 2.37–2.32 (m, 1H), 1.97–1.88 (m, 2H), 1.85–1.78 (m, 1H), 1.50–1.43 (m, 1H), 1.08 (d, J = 6.7 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 203.9, 143.1, 139.6, 127.2, 108.3, 107.1, 64.4, 45.6, 36.4, 24.1, 13.1. MS (ESI): 279 [M + Na]⁺. HRMS (ESI): m/z calcd for C₁₃H₂₀O₅Na 279.1200, found 279.1203. Note: the mass is for the hemiacetal formed by dissolving the aldehyde in methanol.

(R,E)-N-((R)-4-(2-(Furan-3-yl)-1,3-dioxolan-2-yl)-2-methylbutylidene)-2-methylpropane-2-sulfinamide (3). To a stirred solution of aldehyde 16 (0.25 g, 1 mmol, 1 eq.) in anhydrous THF (5 mL) was added Ti(OEt)₄ (0.41 mL, 2 mmol, 2 eq.) under a N₂ atmosphere. Then, (R)-tert butanesulfinamide 17 (0.12 g, 1 mmol, 1 eq.) was added. The reaction solution was stirred at rt for 5 h. While rapidly stirring, the reaction was quenched by adding equal volumes of brine (5 mL) and EtOAc (5 mL). The mixture was diluted with EtOAc (10 mL) and stirred vigorously for 20 min. The resulting mixture was filtered through a pad of Celite, and the filter cake was washed with EtOAc (10 mL). The combined filtrates were washed with brine (10 mL), the combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The compound was purified by silica gel column chromatography using hexanes–EtOAc (8 : 2, v/v) as the eluent to furnish compound 3 (1.04 g, 3.2 mmol) in 80% yield as an oil. TLC R_f = 0.2 (20% EtOAc–hexanes). [α]²⁵_D = −177.5 (c 1.0, CHCl₃). IR (neat): 3138, 2958, 2868, 1623, 1502, 1462, 1365, 1193, 1074, 1023, 868, 687 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 7.93 (d, J = 5.2 Hz, 1H), 7.38–7.34 (m, 2H), 6.30 (s, 1H), 4.02–3.94 (m, 2H), 3.93–2.84 (m, 2H), 2.69–2.52 (m, 1H), 1.98–1.85 (m, 2H), 1.83–1.66 (m, 1H), 1.60–1.47 (m, 1H), 1.18 (s, 9H), 1.13 (d, J = 6.8 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 172.8, 143.2, 139.9, 127.6, 108.6, 107.4, 64.7, 56.4, 37.1, 29.7, 27.6, 22.4, 17.1. MS (ESI): 328 [M + H]⁺. HRMS (ESI): m/z calcd for C₁₆H₂₆O₄NS 328.1577, found 328.1576.

(R)-N-((4R,5R)-7-(2-(Furan-3-yl)-1,3-dioxolan-2-yl)-3,3,5-methylhept-1-en-4-yl)-2-methylpropane-2-sulfinamide (18). Lithium (0.2 g) was added in small pieces to a solution of 3-methylbut-2-enyl phenyl ether (0.34 g, 2 mmol, 4 eq.) in dry diethyl ether/dry THF (1 : 1 v/v, 5 mL) under nitrogen, followed by three drops of methanol. At the first appearance of a green coloration, the reaction mixture was cooled to 5 °C and stirred for a further 2 h. The now orange solution was transferred to a stirred solution of compound 3 (0.16 g, 0.5 mmol) in dry diethyl ether (4 mL) at −78 °C. The resulting mixture was stirred at the same temperature for 20 min, and the reaction was then quenched by the slow addition of methanol (15 mL). Diethyl ether (10 mL) and water (10 mL) were added, the phases were separated, and the aqueous phase was extracted with diethyl ether (2 × 10 mL). The combined extracts were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford the crude product, which was purified by column chromatography on silica gel using hexanes–EtOAc (8 : 2, v/v) as the eluent to furnish compound 18 (0.12 g, 0.36 mmol) in 72% yield as an oil. TLC R_f = 0.1 (20% EtOAc–hexanes). ¹H NMR (300 MHz, CDCl₃): δ 7.40–7.34 (m, 2H), 6.36 (s, 1H), 5.80 (dd, J = 17.3, 11.3 Hz, 1H), 5.0 (dd, J = 11.3, 1.5 Hz, 1H), 4.96 (dd, J = 17.3, 1.5 Hz, 1H), 4.0–3.96 (m, 2H), 3.90–3.86 (m, 2H), 3.34 (d, J = 9.0 Hz, 1H), 2.89 (d, J = 8.3 Hz, 1H), 2.02–1.95 (m, 1H), 1.97–1.82 (m, 1H), 1.76–1.64 (m, 2H), 1.56–1.43 (m, 1H), 1.25 (s, 9H), 1.02 (s, 3H), 0.09 (s, 3H), 0.84 (d, J = 6.7 Hz, 3H).

(R)-N-((4S,5R)-7-(2-(Furan-3-yl)-1,3-dioxolan-2-yl)-5-methylhept-1-en-4-yl)-2-methylpropane-2-sulfinamide (19). To a stirred solution of aldehyde 16 (0.9 g, 4 mmol, 1 eq.) in anhydrous THF (6 mL) were added (R)-N-tert-butanesulfinamide 17 (0.43 g, 3.6 mmol, 0.9 eq.), indium powder (0.52 g, 4.4 mmol, 1.1 eq.) and Ti(OEt)₄ (1.67 mL, 8 mmol, 2 eq.) at rt. The resulting reaction mixture was stirred for 1 h, after which time allyl bromide (0.48 mL, 5.45 mmol, 1.36 eq.) was added via a syringe over 2 min at rt. The mixture was heated to 60 °C for 5 h. After cooling to rt, the reaction mixture is carefully added to a mixture of ethyl acetate : brine (50 mL, 4 : 1 v/v) with stirring. The resulting white suspension was filtered through a short plug of Celite, and washed with ethyl acetate (20 mL). The combined filtrates were washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the crude product which was purified by column chromatography on silica gel using hexanes–EtOAc (7 : 3, v/v) to give the amine 20 (1.25 g, 3.4 mmol) in 85% yield as a yellow color oil. TLC R_f = 0.21 (30% EtOAc–hexanes). [α]²⁵_D = −7.9 (c 1.2, CHCl₃). IR (neat): 3448, 2931, 1626, 1389, 1218, 1048, 760, 703, 613 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 7.38–7.34 (m, 2H), 6.30 (s, 1H), 5.81–5.71 (m, 1H), 5.17–5.11 (m, 2H), 4.0–3.96 (m, 2H), 3.90–3.86 (m, 2H), 3.22–3.17 (m, 2H), 2.41–2.30 (m, 1H), 2.23–2.15 (m, 1H), 2.02–1.95 (m, 1H), 1.84–1.77 (m, 1H), 1.76–1.59 (m, 2H), 1.58–1.49 (m, 1H), 1.18 (s, 9H), 0.87 (d, J = 6.7 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 143.2, 139.9, 134.7, 127.6, 119.0, 108.6, 107.6, 64.6, 58.3, 55.7, 37.4, 36.0, 26.3, 24.2, 22.7, 14.8. MS (ESI): 370 [M + H]⁺. HRMS (ESI): m/z calcd for C₁₉H₃₂O₄NS 370.2047, found 370.2052.

(R)-N-((3R,4S)-1-(2-(Furan-3-yl)-1,3-dioxolan-2-yl)-3,7-dimethyl-oct-6-en-4-yl)-2-methylpropane-2-sulfinamide (2). 2-Methyl-2-butene (1.5 mL) was collected in a sealed tube, cooled at −78 °C, containing compound 19 (0.55 g, 1.5 mmol, 1 eq.) and Hoveyda–Grubbs-II catalyst (19.0 mg, 0.023 mmol, 0.015 eq.). The resulting reaction mixture was slowly warmed to rt and refluxed at 40 °C for 10 h. Excess 2-methyl-2-butene was evaporated and the residue was purified by column chromatography on silica gel using hexanes–EtOAc (7 : 3, v/v) to give the cross-metathesis product 2 (0.46 g, 1.1 mmol) in 78% yield as an oil. TLC R_f = 0.3 (30% EtOAc–hexanes). [α]²⁵_D = −21.5 (c 1.0, CHCl₃). IR (neat): 3448, 2922, 2852, 1713, 1461, 1214, 1122, 1028, 926, 748, 667 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 7.38–7.33 (m, 2H), 6.30 (s, 1H), 5.09 (t, J = 6.8 Hz, 1H), 4.02–3.98 (m, 2H), 3.92–3.88 (m, 2H), 3.16–3.08 (m, 2H), 2.26–2.12 (m, 2H), 2.03–1.92 (m, 1H), 1.84–1.41 (m, 4H), 1.72 (s, 3H), 1.63 (s, 3H), 1.18 (s, 9H), 0.87 (d, J = 6.4 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 143.2, 139.9, 135.4, 127.6, 120.1, 108.6, 107.7, 64.7, 59.3, 55.5, 37.5, 35.8, 30.1, 26.3, 25.9, 22.6, 18.0, 14.8. MS (ESI): 354 [M + H]⁺. HRMS (ESI): m/z calcd for C₁₉H₃₂O₃NS 354.2111, found 354.2112. Note: the mass is for the ketone resulting from the hydrolysis of the dioxolane.

4-((2S,3R,6S)-6-(Furan-3-yl)-3-methylpiperidin-2-yl)-2-methylbutane-2-ol (1). To a solution of compound 2 (0.15 g, 0.4 mmol, 1 eq.) in anhydrous MeOH (4 mL) cooled at 0 °C was added HCl in 1,4-dioxane (4 M, 0.5 mL, 2 mmol, 5 eq.). The reaction mixture was stirred for 4 h at 0 °C. The solvent and excess HCl were removed under reduced pressure. The residue was diluted with dichloromethane (5 mL) then washed with aq. saturated solution of Na₂CO₃ (5 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude residue was dissolved in anhydrous MeOH (4 mL) cooled at 0 °C and NaBH₄ (30 mg, 0.8 mmol, 2 eq.) was added and the mixture was stirred at the same temperature for 2 h. The solvent was removed under reduced pressure, and the reaction mixture was diluted with dichloromethane (5 mL) and water (2 mL). The layers were separated, and the aqueous layer was extracted with CH₂Cl₂ (2 × 5 mL). The combined organic layers were dried over NaSO₄, filtered and concentrated under reduced pressure. Purification on silica gel doped with Et₃N using dichloromethane–MeOH (95 : 5, v/v) afforded nupharamine (70 mg, 0.28 mmol) in 70% yield as an oil. TLC R_f = 0.3 (5% MeOH–dichloromethane). [α]²⁵_D = −37.5 (c 0.7, CHCl₃). {lit.⁸ [α]²²_D = −38.7 (c 0.75, CHCl₃)}. IR (neat): 3444, 3019, 2923, 2855, 1636, 1461, 1376, 1218, 1079, 769 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 7.36–7.33 (m, 2H), 6.42 (s, 1H), 3.62 (dd, J = 11.5, 2.2 Hz, 1H), 2.42–2.37 (m, 1H), 1.9–1.72 (m, 4H), 1.6–1.42 (m, 4H), 1.26–1.13 (m, 2H), 1.21 (s, 3H), 1.19 (s, 3H), 0.9 (d, J = 6.4 Hz, 3H). MS (ESI): 252 [M + H]⁺. HRMS (ESI): m/z calcd for C₁₅H₂₆O₂N 252.1958, found 252.1966.

Acknowledgements

S. Rajendar is thankful to CSIR for SRF fellowship. S.R. acknowledges funding from DST and CSIR, New Delhi as a part of XII five year plan programme under the title ORIGIN (CSC-108).

Notes and references

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2. Y. Arata and T. Ohashi, Yakugaku Zasshi, 1957, 77, 792.
3. T. Ohashi, Yakugaku Zasshi, 1959, 79, 729.
4. (a) J. T. Wrobel, in The Alkaloids, ed. R. H. F. Manske, Academic Press, New York, 1967, vol. 9, pp. 441–465; (b) J. Cybuski and J. T. Wrobel, in The Alkaloids, ed. A. Brossi, Academic Press, New York, 1989, vol. 35, pp. 215–257; (c) H. Matsuda, H. Shimoda and M. Yoshikawa, Bioorg. Med. Chem., 2001, 9, 1031.
5. (a) Y. Arata and T. Ohashi, Yakugaku Zasshi, 1957, 77, 236; (b) M. Kokate, I. Kawasaki, S. Matsutani, S. Kusumoto and T. Kaneko, Bull. Chem. Soc. Jpn., 1962, 35, 698; (c) C. F. Wong, E. Auer and R. T. Lalonde, J. Org. Chem., 1970, 35, 517; (d) H. Matsuda, T. Morikawa, M. Oda, Y. Asao and M. Yoshikawa, Bioorg. Med. Chem. Lett., 2003, 13, 4445; (e) H. Matsuda, K. Yoshida, K. Miyagawa, Y. Nemoto, Y. Asao and M. Yoshikawa, Bioorg. Med. Chem. Lett., 2006, 16, 1567.
6. (a) Y. Shishido and C. Kibayashi, Tetrahedron Lett., 1991, 32, 4325; (b) J. Barluenga, F. Aznar, C. Ribas and C. Valdes, J. Org. Chem., 1999, 64, 3736.
7. T. Honda, F. Ishikawa and S. Yamane, J. Chem. Soc., Chem. Commun., 1994, 499.
8. S. Blechert and J. Gebauer, Synlett, 2005, 2826.
9. F. A. Davis and M. Santhanaraman, J. Org. Chem., 2006, 71, 4222.
10. R. W. Bates and C. J. Lim, Synlett, 2010, 866.
11. P. Grisenti, P. Ferraboschi, A. Manzocchi and E. Santaniello, Tetrahedron, 1992, 18, 3827. The reaction progress was monitored by HPLC. The title compound had physical characteristics in excellent agreement with the known literature compound. S. Raghavan and S. Rajendar, Org. Biomol. Chem., 2015, 13, 5044 . For the preparation of the enantiomer of 11 see: R. Baker, M. J. O'Mahony and C. J. Swain, J. Chem. Soc., Perkin Trans. 1, 1987, 1623.
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13. S. Raghavan, V. Vinoth Kumar and L. Raju Chowhan, Synlett, 2010, 1807.
14. Compound 6 was obtained by a three step sequence (i) 3-furaldehyde was treated with methyl magnesium iodide to furnish the secondary alcohol; (ii) oxidation with IBX in DMSO yielded 3-acetylfuran; (iii) the silyl enol ether 6 was prepared from 3-acetylfuran and tert-butyldimethylchlorosilane under standard conditions in the presence of ZnCl₂/Et₃N in benzene; see: A. Benıtez, F. Ruth Herrera, M. Romero and F. X. Talamas, J. Org. Chem., 1996, 61, 1487.
15. The configuration of the newly created stereocenter of the major isomer was not established since it was to be destroyed subsequently.
16. S. A. Snyder and E. J. Corey, J. Am. Chem. Soc., 2006, 128, 740.
17. R. K. Boeckman, M. Ricodel, R. Ferreira, L. H. Mitchell, P. Shao, M. J. Neeb and Y. Fang, Tetrahedron, 2011, 67, 9787.
18. (a) D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155; (b) D. B. Dess and J. C. Martin, J. Am. Chem. Soc., 1991, 113, 7277.
19. D. J. Weix and J. A. Ellman, Org. Lett., 2003, 5, 1317.
20. Prenyl lithium was prepared by reductive cleavage of phenyl prenyl ether with lithium; see: A. J. Birch, J. E. T. Corrie and G. S. R. Subba Rao, Aust. J. Chem., 1970, 23, 1811.
21. The configuration at C2 was assigned based on the precedent.
22. J. C. Gonzalez-Gomez, M. Medjahdi, F. Foubelo and M. Yus, J. Org. Chem., 2010, 75, 6308.
23. A. K. Chatterjee, D. P. Sanders and R. H. Grubbs, Org. Lett., 2002, 4, 1939.
24. J. W. Evans and J. A. Ellman, J. Org. Chem., 2003, 68, 9948.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ob01750e

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