A New Route to Diastereomerically Pure Cyclopropanes Utilizing Stabilized Phosphorus Ylides and γ-Hydroxy Enones Derived from 1,2-Dioxines:  Mechanistic Investigations and Scope of Reaction

Abstract

A new chemical transformation for the construction of diversely functionalized cyclopropanes utilizing 1,2-dioxines and stabilized phosphorus ylides as the key precursors is presented. Through a series of mechanistic studies we have elucidated a clear understanding of the hitherto unknown complex relationship between 1, 2-dioxines 1a-e, and their isomeric cis/trans gamma-hydroxy enones (23 and 21a-e), cis/trans hemiacetals 24a-e, and beta-ketoepoxides (e.g., 26), and how these precursors can be utilized to construct diversely functionalized cyclopropanes. Furthermore, several new synthetically useful routes to these structural isomers are presented. Key features of the cyclopropanation include the ylide acting as a mild base inducing the ring opening of the 1,2-dioxines to their isomeric cis gamma-hydroxy enones 23a-e, followed by Michael addition of the ylide to the cis gamma-hydroxy enones 23a-e and attachment of the electrophilic phosphorus pole of the ylide to the hydroxyl moiety, affording the intermediate 1-2lambda(5)-oxaphospholanes 4 and setting up the observed cis stereochemistry between H1 and H3. Cyclization of the resultant enolate (30a or 30b), expulsion of triphenylphosphine oxide, and proton transfer from the reaction manifold affords the observed cyclopropanes in excellent diastereomeric excess. The utilization of Co(SALEN)(2) in a catalytic manner also allows for a dramatic acceleration of reaction rates when entering the reaction manifold from the 1,2-dioxines. While cyclopropanation is favored by the use of ester-stabilized ylides, the use of keto- or aldo-stabilized ylides results in a preference for 1,4-dicarbonyl formation through a competing Kornblum-De La Mare rearrangement of the intermediate hemiacetals. This finding can be attributed to subtle differences in ylide basicity/nucleophilicity. In addition, the use of doubly substituted ester ylides allows for the incorporation of another stereogenic center within the side chain. Finally, our studies have revealed that the isomeric trans gamma-hydroxy enones and the beta-keto epoxides are not involved in the cyclopropanation process; however, they do represent an alternative entry point into this reaction manifold.

Rearrangements of organic peroxides and related processes

“…Finally, the protonation of the tert -butoxide anion results in the formation of tert -butanol ( 228 ). As alternative bases Et 3 N [ 338 – 339 ], phosphorus ylides [ 340 ] and LiOH [ 341 – 342 ] can be used and the Kornblum–DeLaMare rearrangement proceeds also on SiO 2 [ 343 ].…”

Ligand-Free Iron-Catalyzed Carbon(sp2)–Carbon(sp2) Cross-Coupling of Alkenyllithium with Vinyl Halides

“…1-((1E,3E)-1,3-Pentadien-1-yl)-4-(trifluoromethyl)benzene (3ha). 28 Prepared according to the general procedure and purified by preparative thin-layer chromatography (cyclohexane). White waxlike solid (63% yield from 1h, 26.7 mg).…”

Organocatalytic Redox Isomerization of Electron-Deficient Allylic Alcohols: Synthesis of 1,4-Ketoaldehydes

“…Previously, few acid- and base-catalyzed redox isomerization of γ-hydroxy enones to 1,4-diketones have been reported . Taylor et al also observed formation of 1,4-diketones and 1,4-ketoaldehydes during the reaction of 1,2-dioxines and phosphorus ylide though lower yields (∼30%) were observed for 1,4-ketoaldehydes . Miles and co-workers disclosed DABCO catalyzed isomerization of 6-hydroxy-2 H -pyranones to 1,2,5-triketones .…”