EMPLOYING A REMOTE CONFORMATIONAL BIAS, INHIBITION OF GAMMA-BUTYROLACTONE FORMATION, AND A SODIUM TEMPLATE TO ENHANCE MACROCYCLIZATION IN CARBENE ADDITION REACTIONS

Loading...
Thumbnail Image

Files

umi-umd-2403.pdf (2.04 MB)
No. of downloads: 1686

Publication or External Link

Date

2005-09-19

Citation

DRUM DOI

Abstract

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.

Notes

Rights