Formal enantioselective total synthesis of bisdehydroneostemoninine

Abstract

A formal enantioselective total synthesis of bisdehydroneostemoninine employing L-glutamic acid as the chiral pool is described. The key features of the synthesis include regioselective and enantioselective opening the chiral epoxide with dimethylsulfonium methylide and tandem Friedel–Crafts cyclization followed by lactonization to form the 5-7-5 tricyclic core of the target stemona alkaloids. The synthetic route provides opportunities to explore the biological behavior of enantiopure bisdehydroneostemoninine.

Keywords:

• Natural product
• stemona alkaloids
• bisdehydroneostemoninine
• total synthesis

Disclosure statement

The authors declare no conflict of interest.

Scheme 3. The synthesis of intermediate (19). Reagents and conditions: (a) NaH, THF, 0 °C, 0.5 h, then TBSCl, 3 h, 54%. (b) Me₃SI, LHMDS, THF, –10 °C, room temperature, 2 h, 89%. (c) TIPSOTf, Et₃N, 0 °C, 1 h, 93%. (d) PPTS, THF, rt, 12 h and then TsCl, Et₃N, 4-DMAP, THF, rt, 12 h, 45%. (e) NaH, DMF, 2 h, and then TBAF, overnight, 93%. (f) Grubbs (2nd) (5%), methyl acrylate, DCM, 40 °C, 24 h, 92%. (g) BF₃ ether, DCM, 0 °C to rt, overnight, 57%.

Scheme 2. The synthesis of intermediate (13). Reagents and conditions: (a) HBr, KBr, NaNO₂, −15 °C to rt, 3 h. (b) BH₃ Me₂S, THF, MeOH, rt, 10 h, two steps: 60%. (c) NaH, THF, 0 °C, 0.5 h, then TsCl, py, 1 h, 52%. (d) Me₃SI, LHMDS, THF, –10 °C.

Scheme 1. The attempt to synthesize compound 8.

Table 1. Conversion of enone 4 to the allylic alcohol 5.

Additional information

Funding

This work was financially supported by Key R&D Program of Shanxi Province (No. 201803D421059) and Science and Technology Innovation Project of Shanxi Province (No. 2016115).