Enantioselective Construction of α‐Quaternary Cyclobutanones by Catalytic Asymmetric Allylic Alkylation

Abstract

No Strain, No Gain! The first transition metal-catalyzed enantioselective α-alkylation of cyclobutanones is reported. This method employs palladium catalysis and an electron deficient PHOX type ligand to afford all–carbon α-quaternary cyclobutanones in good to excellent yields and enantioselectivities.

Advances in Stereoconvergent Catalysis from 2005 to 2015: Transition-Metal-Mediated Stereoablative Reactions, Dynamic Kinetic Resolutions, and Dynamic Kinetic Asymmetric Transformations

“…Since their development of an enantioselective allylic alkylation, the Stoltz group has increased the scope of this transformation substantially to include, 1,3-dioxan-5-one- ( 9 ), 21 β-thiocyclohexenone-( 10 ), 22,23 3-ketal- ( 11 ), 24 β-alkoxy-cycloheptenone- ( 12 ), 25,26 5-alkyl- and 5-alkoxy- ( 13 ), β-aminocyclohexenone- ( 14 ), 1-alkoxypiperidine-2,6-dione- ( 15 ), dihydropyridin-4(1 H )-one- ( 16 ), 27 cyclobutanone- ( 17 ), 28 valerolactam and 2-piperazinone- ( 18 ), 29 2-aminomethylcyclohexanone- ( 19 ), 30 4-oxazolidinone- ( 20 ), morpholin-3-one- ( 21 ), 1,2-oxazepan-3-one- ( 22 ), 31 and cyclopentanone-based ( 23 ) 32 allyl β-ketoesters (Figure 2). Notably, the use of oxygen- and nitrogen-based heterocycles allows for the facile synthesis of quaternary stereocenter-bearing polyketide and pharmaceutical-type fragments in a straightforward manner.…”

Enantioselective Synthesis of α‐Secondary and α‐Tertiary Piperazin‐2‐ones and Piperazines by Catalytic Asymmetric Allylic Alkylation

“…[21] Morpholin-3-ones were also identified as viable substrates under the same conditions, generating an α-tertiary stereo center. [22] We sought to extend this catalyst system to enantio selectively generate α-tertiary piperazin-2-ones ( 6 ), which, upon subsequent reduction, would generate chiral tertiary piperazines ( 7 ).…”

“…Taking into consideration our prior results, in which N -benzoyl protected lactams reacted with high enantioselectivities in the decarboxylative asymmetric allylic alkylation, [21e] we began our studies with the 1,4-bisbenzoylated piperazin-2-one 8a (Table 1). When utilizing Pd 2 (pmdba) 3 [tris(4,4’-methoxydibenzylideneacetone) dipalladium (0)] at 5 mol % catalyst loading and the ( S )-(CF 3 ) 3 - t -BuPHOX ligand at 12.5 mol % loading in a 0.014 M solution of toluene, the bis- N -benzoylated α-allylated product 9a (Table 1) was formed in high yield but modest ee.…”

“…Considering that benzoylated compounds provided the best results in the lactam case, [21e] we examined additional acyl protecting groups (Table 1). The para -fluoro benzoyl and para -methoxybenzoyl compounds 9d and 9e were obtained in nearly identical ee and just slightly lower yields, demonstrating that substantial electronic changes of the N (1)-substituent do not have a strong influence on the reaction efficiency or selectivity.…”

“…The 1,4-diazepan-2-one 9o was formed with only moderate enantiomeric excess, a result that suggests that the reaction is sensitive to ring size, contrary to the lactam examples. [21e] …”