Total synthesis of (+/-)-jiadifenin and studies directed to understanding its SAR: probing mechanistic and stereochemical issues in palladium-mediated allylation of enolate-like structures.
The total synthesis of jiadifenin has been accomplished. The synthesis allows us to build an SAR profile which suggests that the jiadifenin skeleton may be less desirable from the standpoint of nominating a potential drug than that of its prerearrangement precursor. The key steps of the jiadifenin problem involve the construction of two 1,3-related quaternary carbons. The paper describes how the stereochemistry was managed in this context. The issue was studied in considerable detail at the level of a then new allyl transfer reaction arising from a palladium-mediated transfer process of an allyl carbonate. By use of externally deuterated diallyl carbonate, we could probe, for the first time, the stereochemical relationship between the inter- and intramolecular versions of this process. The existence of concurrent inter- and intramolecular allylation reactions was demonstrated by deuteration experiments. While in the particular case at hand, we find very little difference in stereochemical outcome as one partitions between the inter- and intramolecular pathways, the techniques employed are applicable to other systems.
Carcache
David A
DA
Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10021, USA.
Cho
Young Shin
YS
Hua
Zihao
Z
Tian
Yuan
Y
Li
Yue-Ming
YM
Danishefsky
Samuel J
SJ
D000498:Allyl Compounds / Q000737:chemistry*; D010165:Palladium / Q000737:chemistry; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000498:Allyl Compounds; D012717:Sesquiterpenes; C457979:jiadifenin; D010165:Palladium