A synthetic strategy for accessing a collection of structurally complex, “unnatural” compounds is presented. Key reactions in the 7-step synthetic sequence are an aza-variant of the Norrish-Yang cyclization and an insertion of carbene into a benzene ring (Buchner ring expansion). Critical advance in defining a new way of making azetidinols, relies on concealing the lone pair by protonation with a strong tosic acid. This obviates the need to introduce a protecting group for nitrogen (and remove it subsequently). Tosylate salts of several piperidines substituted with acetophenone derivatives were used in the first complexity-generating reaction. Interestingly, morpholine derivatives were photochemically inert; neither cyclization nor fragmentation was observed. Why this is so was revealed through X-ray diffraction of the starting salts: in morpholine derivatives tosylate anion is positioned parallel and proximal to the carbonyl group which undergoes π*&lt;-n excitation with light. We hypothesize that this arrangement is efficiently quenching the excited state through energy transfer to a neighboring π-system of the tosylate. The geometry of tosylate in piperidine derivatives is perpendicular and away from the carbonyl. Products of aza-yang cyclization are formed as single diastereomers and contain tertiary alcohol which we used for attachment of additional components. While the esterification of sterically congested, tertiary alcohols represents a challenge, we identified conditions under which we efficiently coupled various phenylacetic acids with the azetidinols. Converting activated methylene in these aryl acetate esters to diazo compounds and photochemical expulsion of N<sub>2</sub> led to the insertion of a carbene into the proximal phenyl ring. Electrocyclic opening of the cyclopropyl diene leads to cyclohepatriene ring. Two diastereomers are possible in the carbene addition step, and we obtained both in a 2:1 ratio. The compounds thus prepared contain 7-, 6-, 5-, and 4-membered rings, and 3 stereocenters, and lactone, azetidine, and cycloheptatriene functional moieties. These structural features are appealing for further biological experimentation with these compounds.

Collection of cycloheptatriene containing azetidine lactones obtained through a sequential application of a newly developed aza-yang cyclization and Buchner ring expansion

ACS Spring 2022

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