Asymmetric synthesis of spiro 2-pyrrolidin-5-ones, 2-piperidin-6-ones and 1-isoindolin-3-ones. Part 2: N-Acyliminium ion cyclisations with an internal alkene nucleophile

Scaffold Diversity from N-Acyliminium Ions

“…Vernon and co-workers reported the asymmetric synthesis of spiro-2-pyrrolidin-5-ones/-2-piperidin-6-ones 214 and 215 and spiro-1-isoindolin-3-ones 221 and 222 from oxylactams. , Bicyclic oxylactam pyrrolidines and piperidines 213 were synthesized from ( R )-phenylglycinol-derived NAIs through cyclization with tethered arene nucleophiles, giving mixtures of diastereoisomeric products with dr ratios of approximately 3:1 . Other types of bicyclic oxylactams derived from N -(2-hydroxy-1­( R )-phenylethyl)-succinimide and tricyclic oxylactam obtained from phthalimide were cyclized to give spirocyclohexane­[1,2′]-pyrrolidin-5′-ones 216 and 217 and spirocyclohexane­[1,1′]­isoindolin-3′-ones 218 and 219 , but this method could not be extended to the corresponding spirocyclopentane compound (Scheme ).…”

Spirocyclic systems derived from pyroglutamic acid

“…26 We report here an extension of this concept, suitable for access to enantiopure spirocyclic lactamlactam and lactam-lactone systems; some of this work has been reported in preliminary form 31 and very similar synthetic work has recently been published. 32 Various approaches for the rapid asymmetric synthesis of spiro-2-pyrrolidin-5-ones have recently been reported, [33][34][35] including by a-diazocarbonyl insertion chemistry, 36 Pd-catalyzed intramolecular amidations 37 and iodocarbocyclisations, 38 and lactone-lactam spirocyclic systems as mimics of lycoperdic acid have recently been reported. 39 We used as our starting point the bicyclic lactam system 2b, readily prepared from ethyl pyroglutamate 1a in three steps using literature methodology; 40 for the acylation of lactam 2a to ethoxycarbonyl derivative 2b, it was found that ethyl chloroformate gave a substantially better yield (90%) than the literature approach using diethyl carbonate.…”

A Novel Asymmetric Azaspirocyclisation Using a Morita-Baylis-Hillman-Type Reaction

“…The first two steps are adapted from a known preparation of aminal 13. 8 The adaptation (reversing the order of the first two steps) 9 not only made purification of 13 much easier on the scale required, but also led to a more reproducible and less capricious process in our hands. Cross metathesis with acrolein gave the azaspirocycle precursors 9.…”