Employing a remote conformational bias, inhibition of gamma-butyrolactone formation, and a sodium template to enhance macrocyclization in carbene addition reactions

Ring closure via dirhodium(II) catalyzed diazo decomposition of diazoacetates is an efficient method of asymmetric macrocycle formation, affording up to 28-membered rings without the high dilution requirement of many other macrocyclization methods. To overcome reaction pathways that compete with macrocyclization, such as gamma-butyrolactone formation via C--H insertion, and to enhance control of the stereocenters formed in carbene addition reactions, remote conformational bias of a diazoacetate, inhibition of gamma-butyrolactone formation, and template directed macrocycle formation, were each independently investigated.;The influence of a remote conformational bias in a diazoacetate on diastereoselectivity in carbene addition reactions was evaluated using diazoacetates prepared from threitol 2,3-diprotected as a 1,4-dioxane (1) or a 1,3-dioxolane. Diazo decomposition of A with chiral dirhodium(II) and copper(I) catalysts afforded diastereoisomer ratios as high as 99:1 and match/mismatch interactions between substrate and catalyst, while diazo decomposition of 1,3-dioxolane derived diazoacetates afforded no greater than 90:10 diastereoselectivity, and no match/mismatch relationship was found when using dirhodium(II) carboxamidate catalysts, though one is believed to exist when using a chiral copper(I)/ 2. Results indicate that the influence of a remote conformational bias on diastereoselectivity is the dihedral angle from the template.*;In a separate study, effective inhibition of competitive gamma-butyrolactone formation was accomplished by using a 1,2-benzenedimethanol linker, allowing the formation of up to 28-membered macrocycles via carbene addition to an allyl ether C=C bond with good yields. Catalysts such as Rh2(MEOX) 4 and Rh2(DOSP)4, which have been ineffective in macrocycle formation, can catalyze diazo decomposition of these diazoacetates to afford macrocycles in greater than 50% yield. The elimination of gamma-butyrolactone formation allows a greater number of dirhodium(II) catalysts to be used for macrocycle formation.;The influence of a sodium ion from NaBPh4 and of copper(I) as a template on diazo decomposition reaction selectivity was evaluated using substrates that link a diazoacetate to an allyl ether through penta(ethylene glycol). Sodium ion inhibits oxonium ylide formation and modifies diastereoselectivity in copper(I) catalyzed reactions to afford cyclopropanes in a ratio of 80:20 (Z:E) versus a 57:43 ratio without the template.;*Please refer to dissertation for diagrams.