Total synthesis of neodolastane diterpenes trichoaurantianolides C and D.

The first total synthesis of trichoaurantianolides C and D is described. An enantiocontrolled pathway leads to rapid construction of the tricyclic carbon skeleton and establishes the trans-dimethyl geometry of the quaternary bridgehead carbons via a reductive cyclization. Application of the π-allyl Stille cross-coupling leads to a nonracemic allylic alcohol as a prerequisite for the introduction of asymmetry in the cycloheptane system. Two strategies have been examined for elaboration of the unsaturated tetrahydrofuranyl ring from a common tricyclic intermediate. These efforts reveal a number of unanticipated issues of reactivity and significant stereochemical requirements for a novel acyloin rearrangement as well as the elimination and cyclodehydration of chiral α-hydroxy ketones. Key reactions leading to completion of the synthesis include the stereoselective addition of isopropenyllithium TMEDA complex and a facile chemoselective oxidation with selenium dioxide.

Investigation into the functional impact of the vancomycin C-ring aryl chloride.

A vancomycin aglycon analogue that possesses a reduced C-ring and an intact E-ring chloride was prepared and its antimicrobial activity towards Staphylococcus aureus and binding affinity to model cell wall ligands were established. Comparison of the derivative with a series of vancomycin aglycon analogues that possess and lack the chloro substituents on the aryl C- and E-rings defines the impact and further refines the role the C-ring chloride plays in promoting both target binding affinity and binding selectivity for d-Ala-d-Ala and its impact on antimicrobial activity.

Probing the role of the vancomycin e-ring aryl chloride: selective divergent synthesis and evaluation of alternatively substituted E-ring analogues.

The selective functionalization of vancomycin aglycon derivatives through conversion of the E-ring aryl chloride to a reactive boronic acid and its use in the synthesis of a systematic series of vancomycin E-ring analogues are described. The series was used to examine the E-ring chloride impact in binding d-Ala-d-Ala and on antimicrobial activity. In contrast to the reduced activity of the unsubstituted E-ring derivatives, hydrophobic and relatively nonpolar substituents approach or match the chloro-substituted vancomycin and were insensitive to the electronic character of the substituent (e.g., Cl vs CN/OMe), whereas highly polar substituents fail to provide the enhancements. Moreover, the active permethylated vancomycin aglycon derivatives exhibit VanB VRE antimicrobial activity at levels that approach (typically within 2-fold) their activity against sensitive bacteria. The robust borylation reaction also enabled the functionalization of a minimally protected vancomycin aglycon (N-Boc-vancomycin aglycon) and provides a direct method for the preparation of previously inaccessible analogues.