Bioinspired Diversification Approach Toward the Total Synthesis of Lycodine-Type Alkaloids

Abstract

Nitrogen heterocycles (azacycles) are common structural motifs in numerous pharmaceuticals, agrochemicals, and natural products. Many powerful methods have been developed and continue to be advanced for the selective installation and modification of nitrogen heterocycles through C-H functionalization and C-C cleavage approaches, revealing new strategies for the synthesis of targets containing these structural entities. Here, we report the first total syntheses of the lycodine-type Lycopodium alkaloids casuarinine H, lycoplatyrine B, lycoplatyrine A, and lycopladine F as well as the total synthesis of 8,15-dihydrohuperzine A through bioinspired late-stage diversification of a readily accessible common precursor, N-desmethyl-β-obscurine. Key steps in the syntheses include oxidative C-C bond cleavage of a piperidine ring in the core structure of the obscurine intermediate and site-selective C-H borylation of a pyridine nucleus to enable cross-coupling reactions.

Figure 1

Bioinspired plans for the synthesis of lycodine alkaloids.

Scheme 1. Synthesis of the Bicyclo[3.3.1]nonane Core in N-Desmethyl-α-obscurine through Formal (3 + 3)-Cycloaddition

Reagents and conditions: (a) NaOEt, EtOH, 21 °C, then acrylonitrile, 0 to 21 °C, then TsOH, 145 °C (38%, > 13 g scale); (b) Zn(NO₃)₂·6H₂O, acetone oxime, H₂O, 90 °C, then vacuum, 120 °C (46%, > 2 g scale); (c) aq. H₂O₂, LiOH·H₂O, MeOH, H₂O, 21 °C (90%, 30 g scale); (d) PhSH, Na, THF, 21 °C, then 19, 85 °C; (e) NaBO₃·H₂O, AcOH, 40 °C (65%, 2 steps, > 17 g scale); (f) DBU, ⁱPrOH, 0 °C, then acrylonitrile, 0 to 40 °C (60%, > 7 g scale); (g) ethylene glycol, p-TsOH, HC(OEt)₃, 75 °C (97%); (h) LiAlH₄, Et₂O, 0 °C (84%, > 2 g scale); (i) aq. HClO₄, 1,4-dioxane, 105 °C; (j) Boc₂O, Et₃N, THF, 60 °C (54%, 2 steps); (k) Pb(OAc)₄, CHCl₃, 21 °C (90%); (l) Tf₂O, pyridine, CH₂Cl₂, −78 to 21 °C (78%).

Scheme 2. Synthesis of C-Ring Cleaved Lycodine Alkaloids from Protected β-Obscurine.

Reagents and conditions: (a) RuO₂·H₂O, NaIO₄, H₂O, 21 °C, then 24, ^tBuOH, 60 °C (86%); (b) aq. 1 M LiOH, THF, 30 °C; (c) MeI, Ag₂CO₃, CHCl₃, 75 °C (86%, 2 steps); (d) aq. 1 M LiOH, THF, 65 °C (97%); (e) PdBr₂, DPE-Phos, Piv₂O, Et₃N, DMPU, 130 °C (65%); (f) TMSI, CHCl₃, 65 °C (89%); (g) Sm, aq. 3 M HCl, 0 to 21 °C (84%); (h) Pd(dba)₂, P(^tBu)₃, ⁱPrCOCl, toluene, 90 °C (81%); (i) TMSI, CHCl₃, 65 °C (41%).

Scheme 3. Couplings of a Site-Selectively Functionalized Lycodine Congener in the Syntheses of C2-Substituted Alkaloids

Reagents and Conditions: (a) HCO₂NH₄, Pd(OAc)₂, dppf, Et₃N, DMF, 60 °C (99%); (b) B₂ pin₂, [Ir(COD)(OMe)]₂, dtbbpy, THF, 80 °C; (c) CuBr₂, MeOH, H₂O, 80 °C (74%, 2 steps); (d) RuPhos Pd G4, Cs₂CO₃, toluene, 70 °C [(2′S)-33: 65%, (2′R)-33: 65%, 33 as epimeric mixture at C2′ with rac-32: 72%]; (e) NaOH, MeOH, 1,4-dioxane, 70 °C (f) aq. 6 M HCl, 70 °C [(2′S)-8: 90%, (2′R)-8: 68%; 2 steps]; (g) ^sBuLi, (+)- or (−)-sparteine, MTBE, −78 °C, then ZnCl₂, THF, −78 to 21 °C, then 31, Pd(OAc)₂, ^tBu₃PHBF₄, MTBE, 60 °C [(2′S)-36: 55%, (2′R)-36: 88%]; (h) aq. 6 M HCl, 21 °C [(2′S)-14: quantitative, (2′R)-14: 70%]; (i) 31, NiCl₂-glyme, dtbbpy, Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆, Cs₂CO₃, DMF, 450 nm LED, 21 °C (84%); (j) PhOH, TMSCl, CH₂Cl₂, 21 °C; (k) 500 psi H₂, Pd/C, CF₃CO₂H, MeOH, 21 °C (71%, 2 steps).