Studies on the terpenoids and related alicyclic compounds. XXXV. Studies directed toward a total synthesis of ingenol esters: Synthesis of the C/D-ring moiety of ingenol esters from (+)-3-carene via tin(IV) chloride-promoted intramolecular directed Aldol reaction.

Abstract

Listen

Translate article

(+)-(1S, 5R, 7R)-5, 8, 8-Trimethylbicyclo [5. 1. 0] octan-3-one (2), which comprises the C/D-ring moiety of ingenol esters (1) and is an important chiral synthon for a total synthesis of ingenol esters from easily available (+)-3-carene (3), was synthesized. Intramolecular alkylation of 5b with a strong base under kinetic control gave only the undesired five-membered ketone (6). The intramolecular directed aldol reaction of a mixture of the silyl enol ethers, (9) and (10), easily derived from (+)-3 in good overall yield, was achieved in the presence of tin (IV) chloride to afford 11, 12, and 13 in 66, 9, and 6% yields, respectively. β-Elimination of the methoxy group of 11 gave an enone (14), which was methylated with lithium dimethylcuprate to afford the title compound (2) in good yield ; The configuration of the C-5 methyl group of 2 was deduced from the fact that catalytic hydrogenation of the enone (16), derived from 14 via 15, gave 2. Finally the stereochemistry of 2 was unambiguously determined by the chemical correlation of 18a, derived from 15, with 24b, derived from the known compound 19.