Amphidinolide B: Total Synthesis, Structural Investigation, and Biological Evaluation

Abstract

The total synthesis of amphidinolide B1 and the proposed structure of amphidinolide B2 has been accomplished. Key aspects of this work include the development of a practical, non-transition metal mediated method for the construction of the C13-C15 diene, the identification of α-chelation and dipole minimization models for diastereoselective methyl ketone aldol reactions, the discovery of a spontaneous Horner-Wadsworth-Emmons macrocyclization strategy and the development of a novel late stage method for construction of an allylic epoxide moiety. The originally proposed structure for amphidinolide B2 and diastereomers thereof display potent anti-tumor activities with IC50 values ranging from 3.3 nM to 94.5 nM against human solid and blood tumor cells. Of the different stereoisomers, the proposed structure of amphidinolide B2 is over 12-fold more potent than the C8,9-epimer and C18-epimer in human DU145 prostate cancer cells. These data suggest that the epoxide stereochemistry is a significant factor for anticancer activity.

Further studies on cation clock reactions in glycosylation: observation of a configuration specific intramolecular sulfenyl transfer and isolation and characterization of a tricyclic acetal

“…Sequential saponification and alkylation with iodomethylallylsilane 14 followed by controlled oxidation of thioglycoside 17 with m CPBA led to sulfoxide 6 , as a 5:3 mixture of the S R and S S isomers in 61 % yield.…”

Functionalisation of Macroheterocycles with Preserving and Changing Their Sizes

“…The first one consisted in stereoselective (dr 10:1) reduction with cathehol borane into allyl alcohol (70) involved in the stereoselective Sharpless epoxidation. In the presence of diisopropyltartrate, dr-selectivity of the latter reaction is 10:1, [54] and in its absence, it is drastically decreased to 1.5:1.…”

“…This process has been carried out in stereselective synthesis [54][55][56] of amphidinolide B (66) that is a representative of a family of amphidinolides that are isolated from dinoflagellates Amphidinium sp. and show anticancer activity.…”

Experimental and Computational Studies Unraveling the Peculiarity of Enolizable Oxoesters in the Organocatalyzed Mannich-Type Addition to Cyclic N-Acyl Iminium Ions

“…Notwithstanding the increasing importance of organocatalysis in modern synthetic organic chemistry and the large variety of reactions described, the use of oxoesters in organocatalyzed reactions has not been considered to a large extent. For Alkyl 5-oxopentanoates have also been frequently used in Horner-Wadsworth-Emmons (HEW)-olefinations to give a variety of biologically active natural products [2][3][4][5][6][7][8][9]. Notwithstanding the increasing importance of organocatalysis in modern synthetic organic chemistry and the large variety of reactions described, the use of oxoesters in organocatalyzed reactions has not been considered to a large extent.…”