Enantioselective Syntheses of Rigidiusculamides A and B: Revision of the Relative Stereochemistry of Rigidiusculamide A

Abstract

The first enantioselective synthesis of cytotoxic natural products rigidiusculamides A (ent-21) and B (8) has been achieved by two synthetic routes. The first one is convergent based on the common intermediate 11, obtained through a high yielding SmI(2) -mediated Reformatsky-type reaction. A highly diastereoselective one-pot Dess-Martin periodinane-mediated bis-oxidation allowed the direct conversion of the diastereomeric mixture of 11 into rigidiusculamide B (8). Isolation of minor diastereomer 21, in combination with computational work, allowed us to suggest the structure of the natural rigidiusculamide A to be ent-21, as synthesized by the second route. Four diastereomers (7, ent-7, 22a, and 22b) and an enantiomer (21) of rigidiusculamide A (ent-21) have been synthesized. On the basis of literature precedents and computational work, a biosynthetic pathway for rigidiusculamides A and B was proposed to account for the opposite configuration at C-5 of those two congeners.

Naturally occurring tetramic acid products: isolation, structure elucidation and biological activity

“…198 The 3S, 4S, 5S conguration of 193 determined using Snatzke's dimolybdenum CD method was found to be incorrect and was later revised to 3S, 4S, 5R as informed by its total synthesis; the absolute stereochemistries of 194-196 are 3S, 4S, 5S. 198,199 consistent with an epimerization reaction that takes place aer the generation of rigidiusculamide A. Compounds 193 and 194 have been found to exert moderate cytotoxicity against HeLa and MCF-7 cell lines with IC 50 values ranging from 48.2-100.4 mg mL À1 , whereas, 195 and 196 are inactive against the same cell lines even up to concentrations of 120 mg mL À1 .…”

“…200 Additionally, 197 (in contrast to 198) was found to be a potent inhibitor of human telomerase displaying an IC 50 of 1.3 mM. 203 Fusarisetin A (199), possesses an unprecedented pentacyclic ring system, and was originally identied from a soil fungus Fusarium sp. FN080326 by application of a three-dimensional matrigel-induced acinar morphogenesis assay system in 2011.…”

Cross-Coupling Reactions Using Samarium(II) Iodide

“…Other applications of this class of SmI 2 -promoted cross-couplings have also been reported. In 2012, Huang reported the intermolecular SmI 2 -mediated Reformatsky reaction between ethyl 2-bromopropanoate and a chiral 2-amino aldehyde in the enantioselective synthesis of rigidiusculamide B (Scheme ) . The reaction proceeded in good yield to give a mixture of diastereoisomers, which were separated after cyclization to the γ-butyrolactam.…”

“…In 2012, Huang reported the intermolecular SmI 2 -mediated Reformatsky reaction between ethyl 2-bromopropanoate and a chiral 2-amino aldehyde in the enantioselective synthesis of rigidiusculamide B (Scheme 243). 513 The reaction proceeded in good yield to give a mixture of diastereoisomers, which were separated after cyclization to the γ-butyrolactam. In 2005, Quirion reported the intermolecular SmI 2 -mediated Reformatsky addition of ethyl bromodifluoroacetate to various sugar lactones in good yields and high diastereoselectivity in an approach to fluorinated CF 2 -glycosides (Scheme 244).…”

Total Synthesis of (−)-Sessilifoliamide J

“…As a continuation of a program directed toward the total synthesis of alkaloids, we have embarked recently on the total synthesis of sessilifoliamide J ( 1 ) . Our previous synthetic efforts have led to the synthesis of 9- epi -sessilifoliamide J along with sessilifoliamide J ( 1 ) as a minor diastereomer .…”