Convergent Approach to Pumiliotoxin Alkaloids. Asymmetric Total Synthesis of (+)-Pumiliotoxins A, B, and 225F

• Published in: Journal of organic chemistry Vol. 67; no. 16; pp. 5517 - 5526
• Main Authors: Aoyagi, Sakae, Hirashima, Shintaro, Saito, Kosuke, Kibayashi, Chihiro
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.08.2002; Amer Chemical Soc
• Subjects: Alkaloids - chemical synthesis; Alkaloids - chemistry; Amphibian Venoms - chemical synthesis; Amphibian Venoms - chemistry; Animals; Anura; Chemistry; Chemistry, Organic; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Indicators and Reagents; Indolizines; Molecular Conformation; Molecular Structure; Organic chemistry; Physical Sciences; Piperidines; Preparations and properties; Science & Technology; Structure-Activity Relationship; ORGANOZINC REAGENTS; L-PROLINE; ENANTIOSELECTIVE TOTAL SYNTHESIS; CROSS-COUPLING REACTION; FORMAL SYNTHESIS; PALLADIUM-CATALYZED AMIDATION; INDOLIZIDINE ALKALOIDS; IMINIUM ION; STEREOCONTROLLED SYNTHESIS; REGIOCONTROLLED SYNTHESIS; Zinc Organic compounds; Enantiomer(+); Transition element complexes; Angular nitrogen heterocycle; Proline; Alcohol; Zerovalent metal; Palladium complex; Iodine Organic compounds; Pyrrolidine derivatives; Alkaloid; Asymmetric synthesis; Vinylic compound; Cross reaction; Bicyclic compound; Chemical synthesis; Indolizine derivatives; Catalytic reaction; Organic silane; Dienic compound; Total synthesis; Chemical coupling; Carbonylation; Cyclization; Platinoid Complexes; Allenic compound; Homoallylic compound; Ethylenic compound
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo0200466

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−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(PPh3)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.