Convergent approach to pumiliotoxin alkaloids. Asymmetric total synthesis of (+)-pumiliotoxins A, B, and 225F.
A versatile convergent approach for preparing the pumiliotoxin alkaloids has been developed employing Pd(0)-catalyzed cross-coupling reactions between homoallylic organozincs and vinyl iodides. The (Z)-iodoalkylidene indolizidine 34, which served as a common key intermediate, was synthesized through highly stereoselective addition of the chiral silylallene 19 to (S)-acetylpyrrolidine followed by a palladium-catalyzed intramolecular carbonylation[bond]cyclization sequence. This synthetic process allowed the first total synthesis of (+)-pumiliotoxin 225F. The intermediate (Z)-iodoalkylidene indolizidine 34 obtained was converted to a homoallylzinc chloride derivative and subjected to homoallyl-vinyl cross-coupling with the (E)-vinyl iodide 42 using Pd(PPh(3))(4) catalyst to give the cross-coupled product 47 with a 1,5-diene side chain. Subsequent deprotection provided (+)-pumiliotoxin A. On the other hand, the (Z)-iodoalkylidene indolizidine 34 was transformed into the homoallyl-tert-butyl zinc derivative, which underwent palladium-catalyzed cross-coupling with the (E)-vinyl iodide 50 and subsequent deprotection to afford (+)-pumiliotoxin B.
Aoyagi
Sakae
S
School of Pharmacy, Tokyo University of Pharmacy and Life Science, Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Hirashima
Shintaro
S
Saito
Kosuke
K
Kibayashi
Chihiro
C
D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D000664:Amphibian Venoms / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D001001:Anura; D007202:Indicators and Reagents; D007212:Indolizines; D008968:Molecular Conformation; D015394:Molecular Structure; D010880:Piperidines; D013329:Structure-Activity Relationship
D000470:Alkaloids; D000664:Amphibian Venoms; D007202:Indicators and Reagents; D007212:Indolizines; D010880:Piperidines; C031598:pumiliotoxin B; C035482:pumiliotoxin A