Kinetic and thermodynamic control of axial chirality in biaryl-derived fused oxazolidine lactams exploiting a centre-axis relay of unit efficiency

Abstract

The condensation of a 2-substituted-2-aminoethanol with methyl 2'-formylbiphenyl-2-carboxylate produces only two of the four possible axially chiral 6,7-dihydrodibenz[c,e]oxazolo[3,2-a]azepin-9(4bH)-ones (fused oxazolidine lactams), with kinetically controlled diastereoisomer ratios of up to 96 : 4. Within each lactam product the central chirality of the oxazolidine-fused benzylic position C(4b) is relayed to the biaryl axis with unit efficiency, the mis-matching of these stereogenic elements being prohibited due to strain, as predicted by molecular mechanics calculations. Diastereoisomeric lactam pairs can be equilibrated by heating with acid, and under these thermodynamic conditions reversed diastereoisomer ratios of up to 26 : 74 are observed.

Enantioselective Route to 5-Methyl- and 5,7-Dimethyl-6,7-dihydro-5H-dibenz[c,e]azepine: Secondary Amines with Switchable Axial Chirality

“…Our route to (5 R )- 4 begins with the condensation of the biphenylcarboxylic acid 11 , prepared from diphenic anhydride in two steps by slight modifications of the published procedures, with ( R )-2-phenylglycinol 12 under the conditions developed by ourselves and, independently, Levacher’s group, which provides the oxazolidine lactam 13 diastereoselectively and in good yield (Scheme ). Lactams such as these are remarkably resistant to the formation of acyliminiums, and 13 proved stable to various reduction protocols that would normally involve such intermediates (Et 3 SiH/TFA, etc.).…”

Developments in Meyers’ Lactamization Methodology: En Route to Bi(hetero)aryl Structures with Defined Axial Chirality

“…A few years ago, the team of Wallace and our group developed independently a Meyers’ lactamization process leading to axially chiral 7,5-fused lactams 3 with high diastereomeric excesses from biaryl precursors 2 (Scheme ) . This alternative strategy allowed us to master in a one-step operation both the absolute configuration of the stereogenic center bearing the pseudoaxial R 1 substituent and the a R biaryl axis configuration derived thereof, central to axial chirality transfer in action indeed.…”

“…This alternative strategy allowed us to master in a one-step operation both the absolute configuration of the stereogenic center bearing the pseudoaxial R 1 substituent and the a R biaryl axis configuration derived thereof, central to axial chirality transfer in action indeed. Despite the promises of this approach to control an otherwise configurationally unstable biaryl axis, important bottlenecks remain: (1) limitation to R 1 = Me and few heterocyclic benzodiazepine derivatives probed besides biaryl compounds, and (2) better diastereoselectivities (>95% de) were usually obtained by means of keto-ester 2c instead of aldehyde ester 2a or keto-carboxylic acid 2b (82–86% de) starting materials, but several days of reaction were required to reach completion. , Herewith, we are pleased to report a novel development of this original methodology allowing the construction of dibenzo(di)azepine architectures flanked by various R 1 substituents requiring only few hours of reaction upon the use of a suited coacid and microwave irradiation.…”