The origin of greater than 200:1 enantioselectivity in a catalytic Diels-Alder reaction as revealed by physical and chemical studies

Stereocontrolled Preparation of Fully Substituted Cyclopentanes: Relevance to Total Synthesis

“…This step proceeds by enolization followed by intramolecular oxirane ring-opening and finally dehydrative ring-contraction to provide the enone/ester 35 in good yield. Subsequent α-alkylation affords the ketone 39 that bears a 1,5-diene system susceptible to equilibration via a [3,3]-sigmatropic rearrangement (39Ǟ40) as first described by Woodward. [13] This process provides a latent chloride functionality at C7 of norbornene 40 in the form of a ketone thereby rendering relatively simple Diels-Alder adducts such as 34 useful as synthons for the preparation of complex cyclopentanes.…”

“…A recent refinement of Corey's prostanoid-related methodologies (Scheme 1) [3] features a catalytic enantioselective Diels-Alder reaction between 5-alkyl cyclopentadiene 10 and 2-bromoacrolein. The bracketed transition-state pathway [3c,3d] relies on the ability of π-electron-rich indole to stabilize the O-coordinated dienophile in an s-cis conformation to bias the enantiofacial selectivity of the cycloaddition.…”

“…Gin and co-workers have employed a long known [3,3]sigmatropic rearrangement (vida infra) of bridged tricyclodecadienes (e.g. 39, Scheme 5) [12] in order to obtain a C7-functionalized norbornene intermediate suitable for elaboration to the chlorocyclopentane core of 4.…”

“…Chen has developed a Mn(OAc) 3 -promoted oxidative radical heterobicyclization of β-keto esters tethered to unsaturated N-heterocyclic ring systems (Scheme 7). [14] When 49 is treated with Mn III in warm acetic acid the resulting enolate undergoes single electron oxidation to an electrophilic α-radical [15] that cyclizes by a 5-exo/6-endo pathway to generate 50 and 51 in a cascade bicyclization reaction.…”

“…[1] Utilizing a bicyclo[2.2.1]heptane approach ( Figure 1, B) to forge the oxygenated five-membered carbocyclic framework, stereocontrolled total syntheses of prostoglandins E 2 and F 2α (1) were accomplished [2] and subsequently rendered catalytic and enantioselective. [3] The Corey route intersects with a relatively uncommon chiral synthon: a fully substituted cyclopentane 8 bearing all of the requisite functionality for elaboration to 1. This work remains particularly relevant as five-membered carbocyclic cores bearing stereopentads of comparable molecular complexity are found in a subset of the highly sought after pyrrole-imidazole family of marine alkaloids (e.g.…”