Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, March 5, 2018
Douglass F. Taber
University of Delaware

The Ma Synthesis of Lungshengenin D

Lungshengenin D (3) was isolated from the Chinese flowering plant Isodon lungshengensis, long used in traditional medicine for the treatment of hepatitis. Dawei Ma of the Shangai Institute of Organic Chemistry envisioned (J. Am. Chem. Soc. 2017, 139, 2932. DOI: 10.1021/jacs.7b00140) a convergent route to 3, by which 1 would be prepared in enantiomerically-pure form, then cyclized to 2.

The preparation of the left-hand fragment of 1 began with commercial 2,4,4-trimethylcyclohexenone 4. Enantioselective Itsuno-Corey reduction gave the alcohol 5, that was protected with the carbamoyl chloride 6 to deliver the carbamate 7.

The authors used the Stork-Danheiser strategy to prepare 13, the right-hand half of 1. Alkylation of 8 with 9 followed by rearrangement following the Stoltz protocol led to 10 as a 13:1 mixture of enantiomers. Through the algebra of convergent assembly, only 13 derived from the major enantiomer (illustrated) would combine with 7 to give 1.

To prepare for that coupling, 10 was reduced and hydrolyzed to give 11, that was oxidatively cyclized to 12. Addition of metalated 7 to the derived aldehyde 8 then delivered 1. The anticipated cyclization led to 2 as the expected (from intramolecular bond formation) cis-fused diastereomer, an inconsequential mixture of acetates.

Deprotection and oxidation of 2 led to the diketone, that was equilibrated to the more stable trans-fused diastereomer 14. Selective enol ether formation followed by oxidation gave the enone, that was deprotected to give the triketone 15. Selective α-oxygenation led via the intermediate alcohol to the cyclic ether 16. Selective reduction followed by mesylation, reduction and reoxidation enabled removal of the unneeded carbonyl, leading to 17. Nucleophilic epoxidation followed by reduction and selective acetylation then completed the synthesis of lungshengenin D (3).

Two-phase workup can often be made more efficient by adding salt to the aqueous phase. Alan M. Hyde of Merck Process reported (Org. Process Res. Dev. 2017, 21, 1355. DOI: 10.1021/acs.oprd.7b00197) a detailed study, informed by the Hofmeister series, of optimal strategies for such salting out.

D. F. Taber, Org. Chem. Highlights 2018, March 5.