# The regiospecific synthesis and reactivity of 2-hydroxybenzocyclobutenones.

 Title: The regiospecific synthesis and reactivity of 2-hydroxybenzocyclobutenones. Author: Lear, Yvonne. Abstract: Part I. A novel preparation of regiospecifically substituted 2-hydroxy-benzocyclobutenones is presented. The sequence involved conversion of ortho-bromobenzaldehydes via their cyanohydrins into TBS protected mandelate esters and subsequent cyclization by a halogen metal exchange reaction. Deprotection afforded 2-hydroxybenzocyclobutenones. Overall yield for the sequence was approximately 50%, and was improved by converting the ethyl esters into Weinreb amides prior to halogen metal exchange. Addition of aryl Grignard reagents to the 2-hydroxybenzocyclobutenones followed by oxidation and thermolysis yielded the target anthraquinones. The difficulties associated with the oxidation reaction are discussed since the best results were obtained using DMSO/SO$\sb3$-pyridine complex with a maximum yield of 50% for the compound with no substituents on the aromatic ring; yields were lower for substituted compounds. Alkylidene and bis-alkylidene benzocyclobutenones were synthesized by reacting the hydroxybenzocyclobutenones with Wittig type reagents. Reaction of 2-hydroxybenzocyclobutenone with Lawesson's reagent resulted in the formation of a ring expanded dithiolactone. Part II. The synthesis of a series of podophyllotoxin derivatives is presented. The first type result from nucleophilic substitution of the 4-hydroxy group under Lewis acid conditions using trimethylsilylcyanide or allyltrimethylsilane as the nucleophiles. The resulting 4-allyl-4-deoxypodophyllotoxin was reacted under hydroboration conditions to yield the 4-(hydroxypropyl) derivative, oxidation gave the corresponding carboxylic acid. These were demethylated to give the required free hydroxy group. The second type result from addition of organolithium reagents to podophyllotoxone or its 4$\sp\prime$-demethyl analogue. A tertiary alcohol of this type with a phenylethyl substituent in the C4 position was prepared. The most active of these compounds in vitro was the hydroxypropyl derivative which was chosen for in vivo study. In vivo testing showed the compound to be inactive. Part III. Conjugates of alpha-terthienyl and bovine serum albumin were prepared using both reductive amination techniques and the mixed anhydride process. The biological and photochemical characterization of these conjugates is presented. The bioassays showed the conjugates to be very toxic to yeast and brine shrimp while the photochemical studies showed the conjugates were highly fluorescent and produced sufficient singlet oxygen to cause significant cell damage. However, the lower quantum yield as compared to the free $\alpha$-T indicated a possibility of causing damage to the protein as well, thus altering its conformation. The mixed anhydride process was also used to prepare conjugates of $\alpha$-T with a mouse antibody and with the human antibody MRK 16 which is specific to p-glycoprotein. Date: 1997 URI: http://hdl.handle.net/10393/4430

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