The preparation of optically active beta-aminovinyl sulfoxides and a study of the heteroatom -substituted sulfoxide -directed lactonization.

Abstract

Previous discoveries in our laboratory led to the establishment of a new process for the synthesis of optically active active $\gamma$-butyrolactones. This process, known as the vinyl sulfoxide lactonization, utilizes a stereoselective and enantioselective addition of a haloketene to an optically active vinyl sulfoxide. This thesis describes the generalization of the vinyl sulfoxide lactonization to prepare $\beta$-amido vinyl sulfoxides and $\beta$-amido-$\gamma$-butyrolactones. New methodology for the synthesis of optically active $\beta$-amido vinyl sulfoxides has been developed. The synthetic sequence involves, (1) the base catalyzed condensation of an optically active aryl alkyl sulfoxide with dimethylformamide or methyl formate, (2) reaction of the resulting lithium enolate with benzylamine hydrochloride, and, (3) protection of the enamino nitrogen atom with a variety of acyl halides after deprotection with n-butyllithium. In this manner, a series of optically active $\beta$-amido vinyl sulfoxides was prepared that included: (E)-t-butyl-N-benzyl-N-(2-((R))-p-toluenesulfinyl)propenyl) carbamate, (E)-benzyl-N-benzyl-N-(2-((R)-p-toluenesulfinyl)propenyl) carbamate, and (E)-benzyl-N-benzyl-N-(2-((R)-p-toluenesulfinyl)-2-phenylethenyl) carbamate. These $\beta$-amido vinyl sulfoxides were converted to the corresponding $\beta$-amido-$\gamma$-butyrolactones upon treatment with dichloroketene or chlorocyanoketene. Dichloroketene was generated in situ from trichloroacetyl chloride and a zinc-copper couple at temperatures from $-$40$\sp\circ$C to $-$20$\sp\circ$C. Chlorocyanoketene was thermally generated in refluxing toluene from 4-azido-3-chloro-5-methoxy-2(5)-furanone. A variety of N-protected $\beta$-amino-$\gamma$-butyrolactones was obtained in good yields (50-80%) after dechlorination with aluminum amalgam in wet tetrahydrofuran. An attempt at an intramolecular displacement of the arylthio group of the $\beta$-amido-$\gamma$-arylthio-$\gamma$-butyrolactone is described. The requisite $\beta$-amido vinyl sulfoxides, (E)-t-butyl-N-(3,4-dimethoxy)benzyl-N-(2-((R)-p-toluenesulfinyl)ethenyl) carbamate and (E)benzyl-N-(3,4-dimethoxy)benzyl-N-(2-((R)-p-toluenesulfinyl)ethenyl) carbamate, were prepared and converted to the corresponding $\gamma$-butyrolatones. Attempted cyclizations of the two $\gamma$-butyrolactones with electrophilic reagents such as tributylstannyl triflate and cuprous triflate were unsuccessful in producing the tetrahydroisoquinoline ring system.