title: Nitrenium ion azaspirocyclization-spirodienone cleavage: a new synthetic strategy for the stereocontrolled preparation of highly substituted lactams and N-hydroxy lactams.
abstract: [reaction: see text] Although 1,4-cyclohexadienes 2, obtained through the Birch reduction of arenes 1, have found widespread use as masked beta-oxo carbonyl synthons 3, the possibility that 2,5-cyclohexadienones 5 might also be employed to the same end has been overlooked despite their ready availability. As part of our ongoing investigation of the synthetic chemistry of nitrenium ions, we have developed a novel and efficient strategy for the stereoselective preparation of di- and trisubstituted azetidinone, pyrrolidinone, and piperidinone derivatives, which features the ozonolytic cleavage of azaspirocyclic 2,5-cyclohexadienones 12. For example, ozonolysis of spirodienone 12c in CH2Cl2 and reductive workup with dimethyl sulfide generated unstable beta-formyl ester 21, whereas cleavage in MeOH followed by reduction with thiourea led to hemiacetal 22. While both 21 and 22 partially decompose upon exposure to silica gel, they can be trapped in situ, with a variety of weakly basic nucleophiles, to usefully substituted products. The requisite spirodienone substrates are readily accessible through the nitrenium ion cyclization of alkyl omega-arylhydroxamates 10, which proceeds with moderate to high diastereoselectivity.
authors.affiliation: Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607, USA. wardropd@uic.edu
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Wardrop
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Burge
mesh_terms: D000577:Amides / Q000737:chemistry; D003500:Cyclization; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry; D013141:Spiro Compounds / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D000577:Amides; D007769:Lactams; D013141:Spiro Compounds