Total Synthesis of (+)-α-Onocerin in Four Steps via Four-Component Coupling and Tetracyclization Steps

Abstract

A remarkably short (four steps, 31% overall yield) enantioselective synthesis of the structurally unique C2-symmetric tetracyclic triterpene (+)-alpha-onocerin (1) has been developed. The brevity of this mechanism depends on the assembly of four fragments (two molecules of a chiral epoxy ketone and two molecules of vinyllithium) to generate the chiral bis-epoxide 4 in one step, and on the efficient formation of all four carbocyclic rings in one step by cation-olefin tetracyclization. New and general methodology for the conversion of vinyl tert-butyldimethylsilyl ethers to vinyl triflates with retention of E or Z olefinic geometry also was utilized in the synthesis of 1. A short enantioselective synthesis of a non-C2-symmetric diastereomer of 1 is also described which uses the new methodology.

Functionalization and Rearrangement of Spirocyclohexadienyl Oxindoles: Experimental and Theoretical Investigations

“…The siloxycyclohexadienes 5 c and 5 d were then transformed into the desired nonsubstituted dienes 7 a and 7 b using a two-step sequence (Scheme 4). Compounds 5 c and 5 d were first converted, by treatment with PhNTf 2 , into the corresponding triflates, [11] which were not isolated but directly transformed into the desired dienes through a palladium-mediated hydrogenation. [12] Compounds 7 a and 7 b were isolated in satisfying 87 and 81 % overall yields, respectively.…”

Multicomponent Reactions in the Total Synthesis of Natural Products

“…Using a similar process, (þ)-a-onocerin 54, a known acetylcholinesterase inhibitor [32], was assembled by Corey and co-workers in only four steps starting from advanced acyclic intermediate 56 (Scheme 12.10) [33].…”

“…The Lewis acid-catalyzed cationic p-tetracylization of 60 and treatment with TBAF delivered the desired compound 54 in 31% overall yield and a small amount of its epimeric analogue 55. The latter compound can also be efficiently assembled using a three-component reaction as outlined in Scheme 12.11 [33]. The dilithio derivative of 1,4-bisphenylsufonylbutane 61 was formed prior to the introduction of homochiral acylsilane 56 into the reaction mixture.…”

“…Synthesis of epi-a-onocerin using a threecomponent nucleophilic addition/Brook rearrangement/ elimination on acylsilanes, by Corey and co-workers [33]. ii.…”

Construction of Bridged Polycyclic Systems by Polyene Cyclization

“…It was anticipated that introductiono fa ne ster functionality as the R 1 substituent would suppress the generation of ap ositive charge a to the electronwithdrawing substituent, leading to the preferentialf ormation of bridged compound 2.Since the ester group lowers the electron density of the p-bond, we decided to use substrate 1 with aT MS group at the allylic position (R 2 = TMS) aiming not only to enhancet he nucleophilicity of the p-bond, but also to stabilizet he positive charge on the b-carbona tom in intermediate 4. [11,12] However,i tr emains uncertainw hether conformational constraints imposed by the six-membered ring woulda llow intermediate 3 to adoptarequired conformation for cyclizationt oo ccur.…”