Asymmetric Synthesis of AntimalarialAlkaloids (+)-Febrifugine and (+)-Isofebrifugine

Abstract

Diastereoselective α-amidoalkylation of N,O-acetal,derivated from controlled regio and diastereoselective reductionof (S)-N-(4-methoxybenzyl)-3-silyloxyglutarimideprovided two dia­stereomeric 6-allyl-5-silyloxy-2-piperidinonesin 76:24 selectivity. The transformation of the major diastereomerinto a known advanced intermediate allowed the synthesis of (+)-febrifugineand (+)-isofebrifugine.

Key words

piperidines - alkaloids - allylations - N,O-acetal - asymmetric synthesis

References

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1

β-Dichroine and α-dichroineare two names once been proposed to two of three isomeric alkaloidsisolated from Dichroa febrifuga Lour.,which were correlated with febrifugine and isofebrifugine respectively,see ref. [2b] [3b]

23

To a cooled (-78 °C)solution of 22 (348 mg, 0.85 mmol) in anhydCH₂Cl₂ (10 mL) was added dropwise allyltrimethyl-silane(0.270 mL, 1.71 mmol). After being stirred for 5 min, a solutionof TiCl₄ (0.14 mL, 1.283 mmol) in anhyd CH₂Cl₂ (2mL) was added over a period of 40 min. The mixture was stirred for4 h at the same temperature and then allowed to warm to r.t. andstirred for 10 h. After which, a sat. aq NaHCO₃ (1 mL)and brine (2 mL) were slowly added. The organic layer was separatedand the aq phase was extracted with CH₂Cl₂ (2 × 2mL). The combined organic layers were dried over anhyd Na₂SO₄ andconcentrated. The crude was purified by chromatography on silicagel (EtOAc/PE) to give pure (5S,6S)-8 (86 mg),pure (5S, 6R)-23 (38 mg), and a mixture of un-separated(5S,6S)-8 and (5S,6R)-23 (191 mg) ina combined yield of 95%. Major diastereomer (5S,6S)-8: colorless oil. [α]_D ²⁰ +56.5(c 1.0, CHCl₃). IR(neat): ν_max = 3075,2952, 2929, 1642,1513, 1463, 1248, 1175 cm^-1. ¹H NMR(500 MHz, CDCl₃): δ = 7.08 (m, 2 H,Ar-H), 6.83 (m, 2 H, Ar-H), 5.87 (m, 1 H, CH=), 5.40 (d, J = 14.6 Hz,1 H, NCH₂), 5.13 (m, 1 H, =CH₂),5.09 (m, 1 H, =CH₂), 3.94-3.88 (m,1 H, H-5), 3.91 (s, 3 H, OCH₃), 3.88 (d, J = 14.6 Hz,1 H, NCH₂), 3.23 (vrt. dt, J = 6.6,4.7 Hz, 1 H, H-6), 2.63 (m, 2 H, =CCH₂) 2.50(ddd, J = 8.0,8.8, 17.0 Hz, 1 H, H-3), 2.27 (ddd, J = 7.4,8.2, 17.0 Hz, 1 H, H-3), 1.94 (m, 1 H, H-4), 1.81 (m, 1 H, H-4),0.9 (s, 9 H, t-Bu), 0.18 (s, 3 H, SiCH₃), 0.08(s, 3 H, Si-CH₃) ppm. ¹³CNMR (125 MHz, CDCl₃): δ = 169.39 (C=O),158.99 (Ar), 136.11 (CH=), 129.44 (Ar), 129.37 (2 C, Ar),117.44 (=CH₂), 114.01 (2 C, Ar), 68.38 (C-6),59.39 (C-5), 55.32 (OCH₃), 48.23 (N-CH₂),33.62 (=CH-CH₂), 28.96 (C-3), 25.77 (C-4), 25.68(3C, t-Bu), 17.97 (SiCMe₃), -4.90(Si-CH₃), -5.13 (SiCH₃) ppm. MS (ESI): m/z (%) = 390(100) [M + H⁺],412 (11) [M + Na⁺].HRMS calcd for [C₂₂H₃₅NO₃Si + H]⁺:390.2464. Found: 390.2463. (5S,6R)-Minor diastereomer 23:colorless oil. [α]_D ²⁰ -51.4(c 1.0, CHCl₃). ¹HNMR (500 MHz, CDCl₃): δ = 7.09 (m,2 H, Ar-H), 6.80 (m, 2 H, Ar-H), 5.67 (m, 1 H, CH=), 5.44(d, J = 14.9Hz, 1 H, NCH₂), 5.12 (m, 1 H, =CH₂),5.09 (m, 1 H, =CH₂), 3.95 (m, 1 H, H-5), 3.78(s, 3 H, OCH₃), 3.77 (d, J = 14.9Hz, 1 H, NCH₂), 3.21 (vrt. ddt, J = 9.8,3.4, 2.0 Hz, 1 H, H-6), 2.70 (ddd, J = 7.2,12.3, 18.5 Hz, 1 H, H-3), 2.52 (m, 1 H, =CCH₂),2.37 (ddd. J = 1.4,6.5, 18.5 Hz, 1 H, H-3), 2.09 (m, 1 H, =CCH₂),2.01 (m, 1 H, H-4), 1.74 (m, 1 H, H-4), 0.8 (s, 9 H, t-Bu), 0.08 (s, 3 H, SiCH₃),0.05 (s, 3 H, SiCH₃) ppm. ¹³CNMR (125 MHz, CDCl₃): δ = 169.68 (C=O),158.79 (Ar), 133.85 (CH=), 129.24 (Ar), 129.20 (2 C, Ar),118.32 (=CH₂), 113.94 (2 C, Ar), 65.78 (C-6),61.86 (C-5), 55.30 (OCH₃), 46.60 (NCH₂), 36.65(=CHCH₂), 26.89 (C-3), 25.68 (3 C, t-BuC), 24.17 (C-4), 17.92 (SiCMe₃), -4.94(2 C, SiCH₃) ppm. MS (ESI): m/z (%) = 390.1(100) [M + H⁺], 412.2(19) [M + Na⁺]. HRMScalcd for [C₂₂H₃₅NO₃Si + H]⁺:390.2464. Found: 390.2463.

24

Major diastereomer (5S,6S)-24: whitesolid. Mp 67-68 °C. [α]_D ²⁰ -4.5(c 1.05, CHCl₃). IR(film): ν_max = 3222,1669 cm^-1. ¹H NMR(500 MHz, CDCl₃): δ = 5.73 (m, 1 H, =CH), 5.61(brs, 1 H, NH), 5.22 (m, 1 H, =CH₂), 5.19 (m,1 H, =CH₂), 4.0 (m, 1 H, H-5), 3.36 (ddd, J = 2.8, 3.6,9.7 Hz, 1 H, H-6, decoupling H-5, J = 3.6,9.7 Hz), 2.57 (ddd, 6.4, 12.1, 18.6 Hz, 1 H, H-3), 2.32 (m, 2 H, =CH-CH₂),2.20 (ddd, J = 9.0,9.8, 18.6 Hz, 1 H, H-3), 1.97 (m, 1 H, H-4), 1.84 (m, 1 H, H-4),0.90 (s, 9 H, t-Bu), 0.08 (s, 3 H, SiCH₃), 0.02(s, 3 H, SiCH₃) ppm. ¹³CNMR (125 MHz, CDCl₃): δ = 171.54 (C=O),133.63 (CH=), 119.54 (CH₂=), 65.96(C-5), 56.43 (C-6), 36.96 (C-4), 28.15 (CH₂-CH=),26.37 (C-3), 25.76 (3 C, t-Bu), 18.11(SiCMe₃), -4.39 (SiCH₃), -4.94 (SiCH₃)ppm. MS (ESI): m/z (%) = 270,(100) [M + H⁺], 292 (20) [M + Na⁺].HR-ESI-MS calcd for [C₁₄H₂₇NO₂Si + H]⁺: 270.1889.Found: 270.1907. Minor diastereomer (5S,6R)-25: whitesolid. Mp 67-68 °C. [α]_D ²⁰ +15.3(c 0.98, CHCl₃). IR(film): ν_max = 3190,1682 cm^-1. ¹H NMR(500 MHz, CDCl₃): δ = 5.74 (m, 1 H,CH=), 5.70 (m, 1 H, NH), 5.21 (dd, J = 0.8, 14.7 Hz, 1 H, =CH₂),5.18 (dd, J = 0.8,14.7 Hz, 1 H, =CH₂), 3.66 (ddd, J = 3.3,6.5, 9.3 Hz, 1 H, H-5, irradiation at H-6 gave dd, J = 3.3,9.3 Hz), 3.23 (ddd, J = 9.5, 6.5, 4.5 Hz,1 H, H-6), 2.53 (ddd, J = 5.8, 6.2, 17.8 Hz,1 H, H-3), 2.34 (ddd, J = 6.5, 9.4, 17.8 Hz,1 H, H-3), 2.12-1.92 (m, 1 H, CH₂CH=),1.84-1.78 (m, 2 H, H-4), 0.9 (s, 9 H, t-Bu),0.56 (s, 3 H, SiCH₃), 0.50 (s, 3 H, SiCH₃)ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 171.28(C=O), 133.41 (CH=), 119.67 (CH₂=),69.11 (C-5), 58.11 (C-6), 38.55 (C-4), 28.46 (C-3), 28.30 (CH₂-CH=),25.71 (3 C, t-Bu), 17.95 (SiCMe₃), -4.27(SiCH₃), -4.75 (SiCH₃) ppm. MS (ESI): m/z (%) = 270(100) [M + H⁺], 292(3) [M + Na⁺]. HR-ESI-MScalcd for [C₁₄H₂₇NO₂Si + H]⁺:270.1889. Found: 270.1890.

25

The ee was determined by HPLC analysisusing a Chiracel^® OJ-H column (0.46 cm × 25cm; column temperature: r.t.; eluent: hexane/isopropylalcohol = 37:3; flow rate = 1.0mL/min; wavelength: 240 and 260 nm, t _R = 11.50and 16.39 min).