Expeditious Syntheses of (±)-allo-Sedamine and (±)-allo-Lobeline via a Combination of Aza-Sakurai-Hosomi and Hydroformylation Reactions

Abstract

The expeditious preparation of allo-sedamine and allo-lobeline via 1,3-diastereoselective aza-Sakurai-Hosomi reaction followed by hydroformylation is reported.

Key words

alkaloids - multicomponent reaction - diastereoselectivity - hydroformylation

References and Notes

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• For a review of the history, chemistry, and biology of Lobelia alkaloids, see:
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• 10b

  The structure of Biphephos is shown in Figure  [²] .

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6

Orientating experiments with different protecting groups on the alcohol were performed with TBS (5e/6e = 85:15), Bn (5e/6e = 75:25), Me (5e/6e = 70:30) using conditions from Table  [¹] , entry 1.

8

Typical Procedure for an Aza-Sakurai-Hosomi Reaction: In a dry flask under argon were introduced 4 (0.756 mmol) and R^²NH₂ (0.756 mmol) in anhydrous CH₂Cl₂ (4 mL, 0.2 M). The mixture was cooled to 0 ˚C by means of an ice bath. Allylsilane (0.765 mmol) was then added followed by a dropwise addition of a 1 M solution of BF₃˙OEt₂ in CH₂Cl₂ (0.756 mmol). The reaction was stirred for 1 h at 0 ˚C before addition of sat. NaHCO₃. The organic layer was extracted with CH₂Cl₂ (3 ×) and dried over Na₂SO₄. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography. Spectroscopic data for 6a: IR(film): 2952, 2928, 2856, 1696, 1508, 1250 cm^-¹. ^¹H NMR (200 MHz, CDCl₃): δ = 7.23-7.39 (m, 10 H), 5.70-5.80 (m, 1 H), 5.05-5.21 (m, 5 H), 4.82 (dd, J = 2.0, 9.1 Hz, 1 H), 3.80-3.91 (m, 1 H), 2.26-2.40 (m, 2 H), 1.93 (ddd, J = 2.9, 10.0, 13.8 Hz, 1 H), 1.68 (br d, J = 9.1 Hz, 1 H), 0.88 (s, 9 H), 0.05 (s, 3 H), -0.26 (s, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 155.9 (C), 145.0 (C), 136.9 (C), 134.5 (CH), 128.5 (CH), 128.3 (CH), 128.1 (CH), 128.0 (CH), 127.3 (CH), 125.9 (CH), 117.8 (CH₂), 72.7 (CH), 66.5 (CH₂), 48.4 (CH), 44.4 (CH₂), 39.7 (CH₂), 25.8 (Me), 18.1 (C), -4.5 (Me), -5.1 (Me). HRMS (ESI, positive, HCOOLi): m/z [M + Li] calcd for C₂₃H₃₉NO₃Si: 446.2698; found: 446.2690.

11

Typical Procedure for Hydroformylation: In a dry Schlenk glassware under argon were introduced Rh(CO)₂acac (1 mol%) and anhydrous degassed THF (1 mL). Biphephos (2 mol%) was added and CO evolution was observed. Subsequent addition of homoallylic amide (and PPTS) was performed. The mixture was transferred via a syringe in a dry stainless autoclave under argon. The glassware was rinsed with anhydrous degassed THF (3 ×) to reach a final concentration of 0.04 M. The autoclave was purged (3 ×) with H₂/CO (1:1) before setting the pressure at 5 bar. The autoclave was heated at 65 ˚C (internal temperature) by means of an oil bath. Once the reaction was finished, the autoclave was depressurized and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography. Spectroscopic data for 7: IR(film): 2951, 2927, 2854, 1703, 1651, 1324, 1089, 1060, 833 cm^-¹. ^¹H NMR (200 MHz, CDCl₃): δ = 7.15-7.36 (m, 10 H), 6.79 (br d, J = 8.2 Hz, 0.5 H, rotamers), 6.66 (br d, J = 8.2 Hz, 0.5 H, rotamers), 5.16 (s, 2 H), 4.94 (m, 0.5 H, rotamers), 4.81 (m, 1 H), 4.65 (m, 0.5 H, rotamers), 4.45 (m, 0.5 H, rotamers), 4.14 (m, 0.5 H, rotamers), 1.72-2.13 (m,
6 H), 0.87, 0.85 (s, 9 H, rotamers), 0.1 (s, 1.5 H, rotamers), -0.03 (s, 1.5 H, rotamers), -0.24, -0.26 (s, 3 H, rotamers). ^¹³C NMR (50 MHz, CDCl₃): δ = 153.2, 152.9 (rotamers, C), 145.3, 144.6 (rotamers, C), 136.5, 136.4 (rotamers, C), 128.6 (CH), 128.5 (CH), 128.2 (CH), 128.0 (CH), 127.3 (CH), 126.2, 126.1 (rotamers, CH), 124.3, 123.7 (rotamers, CH), 106.2 (CH), 73.8 (CH), 67.4 (CH₂), 49.1, 48.8 (rotamers, CH), 42.7 (CH₂), 26.0 (Me), 25.5, 24.7 (rotamers, CH₂), 18.2 (C), 17.8, 17.4 (rotamers, CH₂), -4.5, -4.8 (rotamers, Me). HRMS (ESI, positive, HCOOLi): m/z [M + Li] calcd for C₂₆H₃₇NO₃Si: 458.2698; found: 458.2685.