First Total Synthesis of (±)-Melinonine-E and (±)-Strychnoxanthine Using a Radical Cyclization Process as the Core Ring-Forming Step

Abstract

The first total synthesis of (±)-melinonine-E and (±)-strychnoxanthine is described. The key common step for the synthesis of both alkaloids is the elaboration of the 2-azabicyclo[3.3.1]nonane nucleus (D and E rings) by a radical carbocyclization, using an α-carbamoyldichloromethyl radical as a donor. The closure of the C ring by a Bischler−Napieralski cyclization, followed by an epimerization process to gain the axial nitrile 20, and appropriate reduction transformations afforded pentacyclic alcohol 23. This alcohol was converted into either (±)-melinonine-E (1) or (±)-strychnoxanthine (2) by means of a palladium black dehydrogenation of the C ring or a SeO2 oxidation of the corresponding acetate 25, respectively.

Enantioselective Syntheses of Heteroyohimbine Natural Products: A Unified Approach through Cooperative Catalysis

“…Zuschriften functionality.T his final transformation was accomplished through ap alladium black mediated dehydrogenation [3,31] to obtain the corresponding b-carbolinium salts (Scheme 3).…”

“…This structural motif is rare among natural products [2] and is especially unusual in total synthesis,w ith the only examples being strychnoxanthine (3)and melinonine-E (4). [3] Alstonine has recently been identified as the major component of aplant-based treatment used in Nigeria by traditional healers to treat psychotic disorders. [4] However,the scarcity and lack of purity from natural sources,a sw ell as the uncertainty regarding its exact mechanism of action, illustrates the need for an asymmetric synthesis to enable further study.T he related trans diastereomer,s erpentine,e xhibits anticancer [5] and antimalarial [6] properties and there have been limited efforts at elucidating its mechanism of action.…”

Translocation versus cyclisation in radicals derived from N-3-alkenyl trichloroacetamides

“…Trichloroacetyl chloride (0.49 mL, 4.38 mmol) in CH 2 Cl 2 (1.5 mL) was added and the resulting mixture was heated at reflux 50 for 24 h. The reaction mixture was concentrated, and the resulting residue was dissolved in CH 2 Cl 2 , washed with 1 N aqueous HCl, and saturated aqueous Na 2 CO 3 . The organic layer was dried, concentrated, and purified by chromatography (10% EtOAc-hexane) to give 6 (643 mg, To a solution of p-toluenesulfonic acid monohydrate (6 mg, 0.032 mmol) in isopropenyl acetate (1.5 mL) warmed at reflux temperature was added a solution of aldehyde 8 (103 mg, 0.32 mmol) in isopropenyl acetate (3 mL) and the mixture was 105 stirred for 24 h. To the cooled reaction mixture was added Et 2 O (10 mL) and the solution was washed with 5% aqueous NaHCO 3 …”

“…atom transfer mediated by CuCl 1 or Grubbs' ruthenium metathesis catalysts, 2 and the hydride reductive method 3 ). Their usefulness in radical cyclisations leading to 6-membered rings can be attributed to the 20 stability of the formed N-(3-alkenyl)carbamoyldichloromethyl radicals, which reduces the occurrence of the disruptive 1,5-hydrogen shift.…”

An unusual reactivity of BBr3: Accessing tetrahydroisoquinoline units from N-phenethylimides

“…7a Hence the in situ generated intermediate II , N -acyliminium ion, was reduced with NaBH 4 /CH 3 OH instead of quenching with water in a one pot fashion to deliver the tricyclic lactam, pyrroloisoquinolinone 8a in 88% yield. 12 Similarly, the imide 5c gave 8c in 69% yield along with demethylated products. Glutarimides 5b and 5d gave the cyclized tricyclic lactams, tetrahydroisoquinoline core 8b and 8d , present in the α-glucosidase inhibitors schulzeine-A/B/C, 13 in 89% and 71% yields respectively.…”