Scalable Synthesis of Enantiomerically Pure Bicyclo[2.2.2]octadiene Ligands

Abstract

An operationally simple and scalable synthesis of enantiomerically pure bicyclo[2.2.2]octadiene (bod*) ligands relying on an organocatalytic one-pot Michael addition-aldol reaction with cheap 2-cyclohexenone and phenylacetaldehyde is presented. The crystalline bicyclic product 4a (6-hydroxy-5-phenylbicyclo[2.2.2]octan-2-one) is transformed into phenylbicyclo[2.2.2]oct-5-en-2-one 2, a versatile starting material for the 2-step synthesis of both symmetrical, such as Hayashi's Ph-bod* ligand, as well as novel unsymmetrical chiral dienes.

Iron Catalysis in Organic Synthesis

“…293 E-and Z-vinyl tosylates with an additional methoxycarbonyl group could be efficiently coupled with Grignard reagents to afford the corresponding E-and Z-trisubstituted α,β-unsaturated methyl esters with retention of configuration. 294 Two examples out of 30 are presented in Scheme 136.…”

A chiral bicyclo[2.2.2]octa-2,5-diene ligand substituted with the ferrocenyl group and its use for rhodium-catalyzed asymmetric 1,4-addition reactions

“…For comparison, this table also contains the results of reactions in the presence of other related chiral diene/rhodium complexes, which have been previously reported as effective catalysts for the asymmetric 1,4-addition. The higher enantioselectivity of Fc,Ph-bod than Ph-bod was also observed in the reaction of enone 3b with phenylboronic acids substituted with 4-methoxy 4o, 4-chloro 4p, and 4-methoxycarbonyl 4q groups (entries [13][14][15][16][17][18]. 1 Thus, the reaction of 2-cyclohexenone 3a with phenylboronic acid 4m (2 equiv.)…”

“…[10][11][12][13][14][15] Typically, they are asymmetric additions of organoboron reagents to unsaturated compounds, such as aldehydes, 10a imines, 11 β-alkoxyacrylates, 12 α,β-unsaturated sulfonyl compounds, 13 and enynamides. 17 In this article, we report on the synthesis of a novel diene obtained by introducing the ferrocenyl group onto the bod skeleton based on Abele's procedure, 16 and the diene ligand (Fc,Ph-bod) thus obtained which is substituted with ferrocenyl and phenyl groups is examined for its enantioselectivity in the rhodium-catalyzed asymmetric 1,4-addition of aryl-and alkenylboronic acids to α,β-unsaturated ketones. These chiral dienes have been examined as chiral ligands for the rhodiumcatalyzed asymmetric addition of arylboronic acids to enones and N-sulfonylimines.…”

Chemical Innovation through Ligand Total Synthesis

“…47 To overcome these drawbacks, an enantioselective approach based on a known organocatalytic transformation was implemented in kilogramscale (Scheme 2b). 48 The product was then further elaborated over three steps to yield (R,R)-Ph-bod* reducing the costs significantly and improving the product mass intensity (PMI, kg of product / kg of reagents) 49 dramatically.…”