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.

[Bis‐(trifluoroacetoxy)iodo]benzene‐Mediated Oxidative Direct Amination C–N Bond Formation: Synthesis of 1H‐Indazoles

“…Organoiodine (III) reagents have been widely used for the synthesis of various five‐membered, six‐membered, and seven‐membered N ‐containing spiro and fused heterocycles, including indoles , 1,4‐diazepines , 1,2,4‐triazolo[1,5‐ a ]pyridines , pyrazole , oxazoles , indazoles , and pyrrolidinones , via an intramolecular nitrenium ion azaspirocyclization reaction . Combining with our recent research on the synthesis of N ‐containing heterocycles from readily available acyclic amine precursors , we made efforts to realize an intramolecular cyclization of 1 to 2 by means of hypervalent iodine‐mediated oxidative direct C–N bond formation (Table ).…”

SN2′ Alkylation of Chiral Allylic Cyanohydrin O‐Phosphates with Organocuprates

“…General Procedure for the Synthesis of the Enantioenriched Aldehydes 7 by Ozonolysis of Compounds 3a: 23 A stream of oxygen and ozone was passed at –78 °C through a solution of product 3a (0.25 mmol) in dichloromethane (3 mL) for 30 min. The blue solution was the purged with a stream of argon for 10 min, thiourea (0.3 mmol, 34 mg) was added, and the resulting solution was allowed to warm to room temperature overnight.…”

Synthesis and reactivity of spiro-fused β-lactams

“…In another report, the cleavage of the cyclohexadienone ring spiro-fused to 2-azetidinones 86 has been realised through a series of reactions starting with ozonolysis, forming methyl N-alkoxy 4-hydroxymethyl-2-oxoazetidine-4-carboxylates 186 (Scheme 70). 48 The removal of the mesyloxy group from the pyrrolidine ring of spiroazetidinones 48 through elimination in a basic medium has been deployed to create a carbon-carbon double bond, resulting in a pyrroline ring system (Scheme 71). 30 Thus, treatment of N-Cbz-protected compounds 48a and 48b with potassium carbonate led to the formation of enantiomeric products 187a and 188, respectively.…”