Stereoselective synthesis of 2-aminocyclobutanols via photocyclization of α-amido alkylaryl ketones:: Mechanistic implications for the Norrish/Yang reaction

A series of chiral N-acylated alpha-amino rho-methylbutyrophenone derivatives 1a-1h was synthesized from alpha-amino acids via a three-step procedure. These substrates were photolyzed in benzene and gave Norrish II and Norrish I cleavage products as well as the N-acylated 2-aminocyclobutanols that derive from gamma-hydrogen abstraction and 1,4-triplet biradical combination (Yang cyclization). The products were formed with characteristic Yang/cleavage ratios. The quantum yields for the photodecomposition of the N-acetyl-protected substrates 1 b,e,f were moderate (12-26%); the diastereoselectivities of the cyclobutanol formation were remarkably high for all substrates. High diastereospecificity was observed for the isoleucine derivatives (2S,3S)-1g and allo-(2S,3R)-1g; the Yang reaction dominated the photochemistry of allo-1g, whereas 1g gave preferentially Norrish II cleavage, The role of hydrogen bonding as one of the stereo-directing effects was demonstrated by comparison of the cyclization efficiency of the valine derivative 1e with 1h,i,j. Also, aromatic beta-keto esters gave the Yang cyclization products in low yields. The diastereoselectivity of the cyclobutanol formation was rationalized by a three-step mechanism where every step is connected with one distinct stereochemical induction mechanism: (a) diastereoselective hydrogen abstraction, (b) conformational equilibration of the 1,4-tetramethylene biradicals (as calculated by semiempiric methods) controlled by hydrogen bonding, and (c) diastereoselective biradical combination (versus cleavage) influenced by spin-orbit coupling controlled intersystem crossing geometries.