Dynamic Kinetic Resolution and Desymmetrization Processes: A Straightforward Methodology for the Enantioselective Synthesis of Piperidines

Abstract

A straightforward procedure for the synthesis of enantiopure polysubstituted piperidines is reported. It involves the direct generation of chiral non-racemic oxazolo[3,2-a]piperidone lactams that already incorporate carbon substituents on the heterocyclic ring and the subsequent removal of the chiral auxiliary. The key step is a cyclocondensation reaction of (R)-phenylglycinol or other amino alcohols with racemic or prochiral delta-oxo (di)acid derivatives in highly stereoselective processes involving dynamic kinetic resolution and/or desymmetrization of diastereotopic or enantiotopic ester groups.

Towards a total synthesis of the manadomanzamine alkaloids: the first asymmetric construction of the pentacyclic indole core

“…4a,d,g,e The use of racemic multi-functional aldehyde substrates in stereoselective condensation reactions has been much explored by Bosch and Amat. 6 In our hands, the condensation of racemic cis/trans-2 with (S)-tryptophanol under Dean-Stark conditions in toluene for 24 hours gave a 1:1 mixture of two readily separable diastereoisomers 5a,b in 69% overall yield (Scheme 3). Presumably the dynamic kinetic resolution that is well known for such substrates under cyclocondensation conditions occurs here to give the preferred trans orientation in 2.…”

“…Presumably the dynamic kinetic resolution that is well known for such substrates under cyclocondensation conditions occurs here to give the preferred trans orientation in 2. 6 The relative stereochemistry of 5a was determined by n.O.e studies on the isolated compound 7 and that of isomer 5b by X-ray crystallographic analysis. Whereas diastereoisomer 5a has the correct relative and absolute stereochemistry at what will become the C-10 and C-24 positions of the manadomanzamine natural products, isomers such as 5b may prove useful in future analogue generation studies.…”

“…The preferred aminal conformations 6a,b allow a favoured trans-decalin-like arrangement of the reactive intermediate, with an all-equatorial substituent pattern, 6 prior to irreversible lactamization, with the H-atom at the aminal carbon centre preferred in an axial arrangement, leading only to minimal diaxial interactions in these conformations. With individual asymmetric building blocks 5a and 5b in hand, we turned our attention to the proposed N-acyliminium cyclization step.…”

Enantio‐ and Diastereoconvergent Cyclocondensation Reactions: Synthesis of Enantiopure cis‐Decahydroquinolines

“…The desired stereoselectivity in these enantio-and diastereoconvergent processes is ensured by dynamic kinetic resolution of the racemic substrate [1] and /or by differentiation of diastereotopic or enantiotopic ligands. [2] In this context, some years ago we reported [3] enantioselective dynamic kinetic resolution and desymmetrization processes by cyclocondensation of chiral aminoalcohols with racemic and prochiral -oxoacid derivatives, ultimately leading to enantiopure polysubstituted piperidines. [4] With the aim of exploring the synthetic potential of this methodology in the assembly of more complex enantiopure heterocyclic scaffolds, we planned to study cyclocondensation reactions of (R)-phenylglycinol with cyclohexanone-based -keto diesters 1.…”

Enantioselective formal synthesis of ent-rhynchophylline and ent-isorhynchophylline

“…As outlined in Scheme 1, the synthesis of rhynchophyllines 5 from the spiroindoline 4 would involve the following transformations: i) removal of the hydroxymethyl group, ii) stereoselective introduction of the C-20 ethyl substituent to obtain the required trans C 15 -C 20 stereochemistry, iii) oxidation of the indoline moiety to the oxindole functionality, iv) chemoselective 10 reduction of the lactam carbonyl, and finally, v) introduction of the C-16 methoxyvinyl appendage. The removal of the hydroxymethyl substituent, which has acted as an element of stereocontrol during the spirocyclization step, was accomplished by oxidation to a carboxylic acid, 15 followed by a radical reductive decarbonylation via a selenoester 13 to give the tetracyclic lactam 5 (Scheme 2).…”