An Unexpected Michael–Aldol–Smiles Rearrangement Sequence for the Synthesis of Versatile Optically Active Bicyclic Structures by Using Asymmetric Organocatalysis

Abstract

A facile and simple organocatalytic procedure to generate optically active 6-alkyl- and 6-aryl-substituted bicyclo[2.2.2]oct-5-en-2-ones is presented. The reaction is catalysed by a 9-amino-9-deoxyepiquinine trifluoroacetic acid salt, which activates alpha,beta-unsaturated cyclic ketones for the 1,4-addition of beta-keto benzothiazoyl sulfones in a stereoselective fashion. Subsequent intramolecular aldol reaction and Smiles rearrangement gives rise to important optically active bicycles, which are a common motif in natural products, ligands in asymmetric catalysis and substrates for Cope rearrangements, photochemical reactions, radical cyclisations and metathesis. Different bicyclic structures were obtained by utilisation of various cyclic enones or by performing ring-expanding reactions. Furthermore, two possible mechanistic pathways are outlined and discussed.

Smiles Rearrangements

“…[45][46][47] Indeed, the organocatalytic conjugate addition of -keto BT-sulfones 59 to cycloalkenone provides valuable diketosulfones 60 for further transformations. [45][46][47] Indeed, the organocatalytic conjugate addition of -keto BT-sulfones 59 to cycloalkenone provides valuable diketosulfones 60 for further transformations.…”

Recent Advances in Organocatalytic Methods for Asymmetric CC Bond Formation

“…successfully deployed β‐ketosulfones in combination with a cinchona derived catalyst 31 . The corresponding reaction products are useful precursors for a series of important building blocks 61…”

“…The corresponding reaction products are useful precursors for a series of important building blocks. [61] Ruano et al described additions of b-arylnitriles and unsaturated aldehydes catalyzed by a chiral pyrrolidine ent-63. By subsequent reduction and hydrolysis the corresponding d-lactones are formed in good yields and moderate to very good enantioselectivity.…”

Asymmetric Organocatalytic Reactions of α,β-Unsaturated Cyclic Ketones

“…For instance, Jørgensen and co-workers introduced benzothiazolyl-β-ketosulfones (41) as valuable starting material for the asymmetric synthesis of these compounds, using 9-amino-9-deoxyepiquinine TFA salt (42) as the catalyst in the first stage of the reaction [57]. In fact, they can be easily converted into enantioenriched alkenyl (44), alkynyl (45), and ketone derivatives (46) [57] as well as 6-substituted bicyclo[2.2.2]oct-5-en-2-ones (47) (Scheme 12) [58].…”