Enantioselective total synthesis of (+)-galbulinvia organocatalytic domino Michael–Michael–aldol condensation

Abstract

A concise and practical enantioselective synthesis of (+)-galbulin has been achieved using organocatalytic domino Michael-Michael-aldol condensation and organocatalytic kinetic resolution as the key steps.

Recent Progress in Organocatalytic Asymmetric Domino Transformations

“…[102] In 2012, Hong andc o-workersd evelopedatotal synthetic route towards (+ +)-galbulin (243)o nt he basis of an organocatalytic asymmetric domino Michael/Michael/aldol condensation reactiona ssociated with kinetic resolution as the key feature.T he corresponding domino reactiono ft he racemic keto aldehyde (AE)-241 and the a,b-unsaturated aldehyde 42a in the presence of diphenylprolinol silyl ether( S)-45 as the chiral catalyst provided the adduct 242 as as ingle enantiomer of the desired diastereomer. Only (S)-241 took part in the reactiona si tp rovided the sterically favorable transition state, [103] while (R)-241 remained unreacted in the reactionp ot. Compound 242 was further convertedt ot he desired natural product (+ +)-galbulin (243) via additional synthetic transformations (Scheme 63).…”

“…Compound 242 was further convertedt ot he desired natural product (+ +)-galbulin (243) via additional synthetic transformations (Scheme 63). [103] Li, Wang, andc o-workers synthesizedd ihydronaphthalenes andd ihydroisoquinolines 245 by using an organocatalytic enantioselective domino Michael/aldol Scheme 59. Synthesis of enantioenriched 3-hydroxycyclohexanones via an organocatalyzed domino Michael/aldol reaction.…”

Concise Synthesis of (+)-β- and γ-Apopicropodophyllins, and Dehydrodesoxypodophyllotoxin

“…Lignans are a class of secondary metabolites in various plants, and most of them have demonstrated interesting biological properties [ 1 , 2 ], thus attracting the attention of the synthetic chemists [ 3 , 4 ]. Some of 2,7′-cyclolignans such as 7,8,8′,7′-tetrahydronaphthalene (THN), 7′,8′-dihydronaphthalene (DHN) and 7′-arylnaphthalene types are exemplified in Scheme 1 a. Hong and co-workers used organocatalytic domino Michael–Michael–aldol reactions to construct THN skeleton of galbulin and realized its first enantioselective synthesis [ 5 ]. Barker and co-workers completed the first asymmetric synthesis of (−)-cyclogalgravin based on a key construction of C2–C7′ bond from in situ generated quinoid intermediate [ 6 ].…”

Organocatalysis in Total Synthesis

“…Other interesting example is the synthesis of (+)-galbulin via an organocatalytic domino Michael-Michael-aldol condensation schematically represented in Scheme XII.4 [61].…”