Tandem Inter [4 + 2]/Intra [3 + 2] Cycloadditions. 17. The Spiro Mode. Efficient and Highly Selective Synthesis of Azapropellanes

Scott E. Denmark, Donald S. Middleton

Research output: Contribution to journalArticle

Abstract

A new variant of the tandem inter [4 + 2]/intra [3 + 2] nitroalkene cycloaddition has been developed. Intermolecular [4 + 2] cycloaddition of a 2-nitroalkene (bearing an unsaturated ester moiety, the dipolarophile) with a vinyl ether produces a cyclic nitronate substituted at C(3) wherein the only stereogenic center is the anomeric carbon C(6). Since the dipolarophile is attached to a tether extending from the C(3) of the nitronate (α-carbon of the nitroalkene), the intramolecular [3 + 2] cycloaddition affords a spiro tricyclic nitroso acetal. The cycloaddition proceeds smoothly for three- and four-atom tethers to afford five- and six-membered rings. Both E- and Z-unsaturated esters serve well as dipolarophiles, but the E-isomers react more selectively. Hydrogenolysis of the nitroso acetals affords the spiro tricyclic α-hydroxy lactams in good yield. Remarkably high levels of asymmetric induction are observed with the use of a chiral vinyl ether derived from (1R,2S)-2- phenylcyclohexanol. The origin of asymmetric induction is a combination of the established face selectivity of the enol ether and the preference for a distal fold of the tether away from the substituent on the anomeric carbon. The scope and limitations of this transformation and an analysis of the origin of stereoselectivity are provided.

Original languageEnglish (US)
Pages (from-to)1604-1618
Number of pages15
JournalJournal of Organic Chemistry
Volume63
Issue number5
DOIs
StatePublished - Mar 6 1998

ASJC Scopus subject areas

  • Organic Chemistry

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