Total Synthesis of (+)-Cassaine Utilizing an Anionic Polycyclization Strategy

A stereoselective total synthesis of (+)-cassaine (<b>1</b>) via an anionic polycyclization methodology is described. Commercially available (+)-carvone (<b>5</b>), the only chiral source, was used to fix the entire stereochemistry of the natural product. Anionic polycyclization of a new substituted 2-(methoxycarbonyl)cyclohex-2-en-1-one (<b>4</b>) with known 1-phenylysulfinyl-3-penten-2-one (<b>3</b>) provided the versatile tricycle (<b>2</b>) with requisite stereochemistry. A sequence of functional group manipulations of tricycle (<b>2</b>) furnished the natural product <b>1</b>

Anionic Polycyclization Entry to Tricycles Related to Quassinoids and Terpenoids: A Stereocontrolled Total Synthesis of (+)-Cassaine

A full account of our anionic polycyclization approach to access highly functionalized tricycles related to quassinoids and terpenoids from several optically active bicyclic enone systems and Nazarov reagents is presented. (+)-Carvone is the only chiral source used to fix the entire stereochemistry of all of the tricycles, and the stereochemical outcome of this process was unambiguously determined by X-ray crystallographic analysis. The utility of this strategy was demonstrated by the stereocontrolled construction of advanced tricycles related to the highly potent anticancer natural product bruceantin, a member of quassinoid family, and the total synthesis of the cardioactive terpenoid (+)-cassaine, a nonsteroidal inhibitor of Na⁺-K⁺-ATPase

Total Synthesis of (+)-Cassaine Utilizing an Anionic Polycyclization Strategy

A stereoselective total synthesis of (+)-cassaine (<b>1</b>) via an anionic polycyclization methodology is described. Commercially available (+)-carvone (<b>5</b>), the only chiral source, was used to fix the entire stereochemistry of the natural product. Anionic polycyclization of a new substituted 2-(methoxycarbonyl)cyclohex-2-en-1-one (<b>4</b>) with known 1-phenylysulfinyl-3-penten-2-one (<b>3</b>) provided the versatile tricycle (<b>2</b>) with requisite stereochemistry. A sequence of functional group manipulations of tricycle (<b>2</b>) furnished the natural product <b>1</b>

Synthesis of the Antiproliferative Agent Hippuristanol and Its Analogues from Hydrocortisone via Hg(II)-Catalyzed Spiroketalization: Structure–Activity Relationship

An efficient synthesis of hippuristanol (<b>1</b>), a marine-derived highly potent antiproliferative steroidal natural product, and nine closely related analogues has been accomplished from the commercially available hydrocortisone utilizing Hg­(II)-catalyzed spiroketalization of 3-alkyne-1,7-diol motif as a key strategy. This practical synthetic sequence furnished <b>1</b> in 11% overall yield from hydrocortisone in 15 linear steps. Modifications to the parent molecule <b>1</b> encompassed changing the functional groups on rings A and E. Each analogue was screened for their effects on inhibition of cap-dependent translation, and the assay results were used to establish structure–activity relationships. These results suggest that the stereochemistry and all substituents of spiroketal portion (rings E and F) and C3-α and C11-β hydroxyl functional groups on rings A and C, respectively, are critical for the inhibitory activity of natural product <b>1</b>