Asymmetric Total Synthesis of (+)-Waihoensene

Abstract

The asymmetric total synthesis of (+)-waihoensene, which has a cis-fused [6,5,5,5] tetracyclic core bearing an angular triquinane, a cis-fused six-membered ring, and four contiguous quaternary carbon atoms, was achieved through a sequence of chemical reactions in a stereochemically well-defined manner. The total synthesis features the following: (1) Cu-catalyzed asymmetric conjugated 1,4-addition; (2) diastereoselective Conia-ene type reaction; (3) diastereoselective intramolecular Pauson− Khand reaction; (4) Ni-catalyzed diastereoselective conjugated 1,4-addition; and (5) radical-initiated intramolecular hydrogen atom transfer (HAT). Control experiments and density functional theory calculations support the proposed HAT process.

Contiguous Quaternary Carbons: A Selection of Total Syntheses

“…The groups of Yang and Snyder made use of both a Conia-ene reaction to install the bicyclic system with two quaternary centers in place and a Pauson–Khand reaction to assemble the tetracyclic core, setting another quaternary center [ 5 , 6 ].…”

“…In 2020, the first asymmetric synthesis of (+)-waihoensene ( 23 ) was completed by Yang and coworkers in 15 steps and 3.8% overall yield [ 5 ]. Here, well-considered transformations like a Conia-ene-type reaction, a Pauson–Khand reaction, and an intramolecular hydrogen atom transfer (HAT) were employed as key steps on route to (+)-waihoensene ( 23 ).…”

“…Starting from vinylogous ester 35 , a sequence containing Stork–Danheiser transposition, asymmetric conjugate addition, Sakurai allylation and Ohira–Bestmann homologation provided diyne 40 in only six steps as the precursor for the Conia-ene reaction [ 5 ] ( Scheme 8 ).…”

“…To generate the only remaining all-carbon quaternary stereocenter, a Ni-catalyzed diastereoselective conjugate addition using Ni(acac) 2 and Me 2 Zn was employed. Next, a Wittig reaction of mono-ketal 42 and subsequent treatment with hydrochloric acid gave tetracycle 43 with all four all-carbon quaternary centers in place [ 5 ] ( Scheme 9 ).…”

“…Waihoensene ( 23 ) was successfully synthesized by Lee and coworkers in 2017 [ 4 ]. Three years later, syntheses of waihoensene ( 23 ) by the groups of Yang and Snyder followed [ 5 , 6 ]. Finally, a total synthesis of musabalbisiane A, mentioned in Hanessian and Overman’s review, is still not published [ 1 ].…”