Novel Methods for N- and O–Atom Transfer to Small Molecules

by

David Fisher

Nitrogen and oxygen are ubiquitous in natural products, pharmaceuticals, polymers, and

dyes. As a result, the development of new methods for C–N and C–O bond formation is a major

focus for synthetic organic chemists. Several new strategies for the installation of N- and O atoms

in organic molecules are described herein.

4-Hydroxycyclopentenones are important building blocks for the synthesis of

prostaglandins and other biologically active molecules and natural products. In 1976, Giovanni

Piancatelli discovered that 2-furylcarbinols could be converted to trans-4-

hydroxycyclopentenones via an acid-catalyzed cascade reaction involving a thermal 4π

viii

electrocyclization. This process is known today as the Piancatelli rearrangement and remains

among the most efficient methods for the synthesis of 4-hydroxycyclopentenones. Despite the

significance of this approach, it can be limited by high catalyst loadings, harsh reaction

conditions, and unavoidable isomerization to the thermodynamic product. We have developed a

general, mild, dysprosium (III) trifluoromethanesulfonate-catalyzed rearrangement that provides

exclusive access to either 4-hydroxycyclopentenone isomer.

Nitrosoarenes typically serve as 2π synthons in transformations such as the aldol, DielsAlder,

and ene reactions. Despite being efficient spin trapping agents, arylnitrosos have not been

utilized in single electron transfer processes as a tool in organic synthesis. In polymer chemistry,

alkyl radical additions with nitroso compounds are used in a process known as radical trapassisted

atom transfer radical coupling (RTA-ATRC) to stitch together polymer chains for the

synthesis of alkoxyamine-linked diblock copolymers. We have developed this concept as a

synthetic tool in small molecule organic chemistry.

Recently, we reported a mild, catalytic method for the synthesis of hindered a-amino

carbonyl compounds utilizing radical additions with in situ-generated nitroso compounds. The

process is redox neutral, uses catalytic CuCl2 to simultaneously generate the reactive

intermediates, occurs at room temperature and has a high degree of functional group

compatibility. Additionally, a three component coupling reaction for the synthesis of hindered

anilines was developed by merging radical chemistry with nitroso compounds. This process

utilizes commercially available starting materials and forms two C–N bonds in one pot. Finally,

an intramolecular approach for the synthesis of amino alcohols is reported. This strategy

provides spatial control over the N– and O–atom transfer event in the reaction with bis-alkyl

halides.