Mechanistic Investigations of the Pd‐Catalyzed Hydrogenolysis of Ketene Heterodimer β‐Lactones

Abstract

Catalytic hydrogenolysis of the Z‐isomer of a series of aryl‐substituted ketene heterodimer β‐lactones facilitated access to deoxypropionate derivatives with a dr ranging from 54:46 to 86:14, favoring the anti‐isomer, and with excellent transfer of chirality (91 → 99 % ee for 13 examples). Although X = 4‐F was determined to provide optimal diastereoselectivity (dr 86:14), a non‐linear relationship between diastereoselectivity and aryl substituent σ values was found. For cases where a para‐ or ortho‐EWG was present on the aryl ring of the ketene heterodimer, formation of significant amounts of β‐lactone (20–44 %) as by‐product was observed. The results of a number of control reactions point to anti‐β‐elimination and an anti‐selective hydrogenation of an E‐isomer olefin intermediate being key steps in the reaction mechanism. The synthetic potential of the deoxypropionate derivative products was demonstrated by oxidative conversion into a 1,5‐difunctionalized deoxypropionate motif.

Addition of heteroatom nucleophiles to ketene dimers

“…During our initial studies we investigated the reaction of Weinreb amine with a variety of ketene heterodimers to access synthetically useful enantioenriched Weinreb amides. 19,20,27 The reaction conditions chosen, 1-2 equiv Weinreb amine and ca. 5-10 mol% 2-pyridone, were originally introduced by Calter's group for the synthesis of dipropionate synthons.…”

“…[17][18][19][20] We had also investigated addition of H-and C-centered nucleophiles to ketene dimers, as well as more recently hydrogenation/hydrogenolysis of ketene heterodimers. [21][22][23][24][25][26] Herein, we describe our studies investigating the reaction of heteroatom nucleophiles with ketene dimers, with an emphasis on a discussion of scope and diastereoselectivity wherever applicable. During this study we focused on the reaction of nitrogen-centered nucleophiles (Weinreb amine, lithiated Weinreb amide, and an amino acid derivative), and oxygen-centered nucleophiles (metal alkoxides).…”

Asymmetric synthesis of enantioenriched α-allyl esters through Pd(BINAPHANE)-catalysed allylation of disubstituted ketenes

“…A range of ketenes (seven in all) such as methylphenylketene, ethylphenylketene, i-butylphenylketene, methyl-i-propylketene, diphenylketene and alkylarylketenes bearing electron donating groups on the aryl ring performed well from a reactivity standpoint, albeit with quite varying effects on enantioselectivity (3–80% ee). 13,14 An ortho -donating group, in particular, was found to be detrimental to enantioselectivity, with an ee of 14% ( versus 70% ee for no ortho -substituent, Table 3 entry 13 vs . entry 5) being obtained, and this was ascribed to the increase in steric bulk associated with the ortho -substituent leading to a mixture of enolate isomers from reversible addition of ArO − to the ketene.…”