Enantioselective Organocatalytic Four‐Atom Ring Expansion of Cyclobutanones: Synthesis of Benzazocinones

Abstract

An enantioselective Michael addition– four‐atom ring expansion cascade reaction involving cyclobutanones activated by a N‐aryl secondary amide group and ortho‐amino nitrostyrenes has been developed for the preparation of functionalized eight‐membered benzolactams using bifunctional aminocatalysts. Taking advantage of the secondary amide activating group, the eight‐membered cyclic products could be further rearranged into their six‐membered isomers having a glutarimide core under base catalysis conditions without erosion of optical purity, featuring an overall ring expansion– ring contraction strategy.

Innentitelbild: Enantioselective Organocatalytic Four‐Atom Ring Expansion of Cyclobutanones: Synthesis of Benzazocinones (Angew. Chem. 2/2019)

“…Initially,aseries of cyclobutanones 1 bearing different N-aryl secondary amide activating groups were examined. All of them reacted smoothly with the orthoamino nitrostyrene 2a to afford the desired benzazocinone products 3b-j and ent-3 k in fair to good yields along with high to excellent enantioselectivities.T he absolute configuration of product 3b was unambiguously determined to be (5S,6R)b yX -ray diffraction techniques (see the Supporting Information), [13] which is consistent with previous results. [10] In line with previous studies on organocatalytic Michael additions with secondary b-ketoamides, [10,14] substrates bearing aR 1 electron-withdrawing substituent systematically afforded better enantioselectivities,which was attributed to the higher acidity of the secondary amide N À Hp roton in these cases resulting in more compact and better-defined transition states in the Michael addition step.A sas cope limiting issue,t he analog of 1 having a N-tert-butyl group in place of the N-aryl substituent did not react with nitrostyrene 2a using catalyst OC1,w hile catalyst OC9 promoted only the corresponding Michael addition at as low rate without evidence for any fragmentation.…”

A Method of Calculating the Kamlet–Abboud–Taft Solvatochromic Parameters Using COSMO-RS

“…For this purpose, the kinetics of a Michael addition catalysed by potassium phosphate was measured in six solvents (Scheme 2). 1,4-Addition reactions are widely used in drug discovery and studied in the development of enantioselective catalysis [37]. It was found that the rate of the reaction favoured high β values and small solvent molar volumes (V M ) according to Equation (4).…”

A happy medium: the synthesis of medicinally important medium-sized rings via ring expansion

“…Most organocatalytic cascade reactions focus on the preparation of more energetically favourable 5-and 6-membered rings; however Coquerel et al devised an innovative enantioselective organocatalytic synthesis of benzazocinones 42 based on a Michael addition-4-atom ring expansion cascade from activated cyclobutanones 39 and ortho-amino nitrostyrene derivatives 40 (Scheme 4b). 19 Relief of ring strain means that even relatively stabilised anilide nucleophiles are sufficiently reactive to promote effective 4-to 8-membered ring expansion, via cyclobutanone intermediates of the form 41.…”