Catalytic Carbonylations in Total Synthesis and Chemistry and Biology of Aryl Isonitriles

Dexter C Davis, Purdue University

Abstract

As a useful and abundant one-carbon building block, carbon monoxide has found extensive use in the synthesis of complex molecules owing to its high reactivity under transition metal catalysis and the ease of incorporation of carbonyl functionality. Herein will be discussed a novel application of carbon monoxide towards the synthesis of oxaspirolactones, a structural motif frequently found in natural products of diverse structure and biological activity. This reaction was developed following the exploration of the reactivity of hydroxycyclopropanols under palladium catalysis and carbon monoxide atmosphere. A cascade sequence of metal-assisted beta-carbon elimination to form a metal homoenolate followed by hemiketal formation, carbon monoxide insertion and lactonization forms the oxaspirolactone products. The synthetic scope and efficiency of the reaction was explored and the method was applied in the expedient total syntheses of two natural products, α-levantanolide and α-levantenolide. Efficient synthetic routes towards three sesquiterpenoid oxaspirolactone natural products, abiespiroside A and beshanzuenones C and D, were developed. The key oxaspirolactone moiety was installed by a stereoselective hydroalkoxycarbonylation followed by a Reformatsky-type addition of a bromomethyl acrylate. Using this route, a common precursor to all three natural products was accessed on the gram scale in only 9 steps from (+)-carvone. This precursor was converted to abiespiroside A by a β-selective glycosidation/saponification sequence, and to beshanzuenone C and D by selenium dioxide-mediated oxidations. Novel synthetic methodologies for the synthesis of substituted phenanthridines and oxindoles utilizing tandem cyclizations of β-keto radicals were developed. Cyclopropanols readily undergo single-electron oxidation and ring opening to give β-keto radicals which underwent cyclization with biaryl isonitriles and acrylamides followed by homolytic aromatic substitution to give ketoalkylated phenanthridines and oxindoles. The reactions were found to proceed under mild conditions tolerating a wide range of functional groups using cheap and commercially available manganese salts as single-electron oxidants. Concomitant installation of ketone functionality provides a handle for further functionalization of these important and biologically relevant scaffolds. Methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA) have emerged as a global health concern. A new class of compounds featuring an aryl isonitrile moiety has been discovered that exhibits potent inhibitory activity against several clinically-relevant MRSA and VRSA isolates. Structure-activity relationship studies have been conducted to identify the aryl isonitrile group as the key functional group responsible for the observed antibacterial activity. The most potent antibacterial aryl isonitrile analogs (MIC 2 μM) did not show any toxicity against mammalian cells up to a concentration of 64 μM.

Degree

Ph.D.

Advisors

Dai, Purdue University.

Subject Area

Chemistry|Organic chemistry

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