Asymmetric Electrophilic a-Amidoalkylation- la ’ A new Camphorimide Derived ChiraI Auxiliary for the Asymmetric Synthesis with N-Acyliminium Ions- Preparation of Aracemig 2-Substituted Piperidines.

Abstract: Compound 5 is a new a-amidoalkylation reagent for the asymmetric synthesis of 2-substi-tuted piperidines. Its chiial auxiliary 3 is derived from camphoric acid and designed for an asymmetric induction mechanism featuring pmcomplexation as the decisive step for stereodifferentiation. Reagent 5 can smoothly be alkylated with various organometallic reagents after its activation by HCl-addition which presumably results in u-chloroamide 6. Organozinc and organoaluminum compounds appear to give the best results with the highest diastereoselectivities b ing 97.8n.2 for the ethylation (7&a). 87.7/12.3 for the methylation (7b/Sb). %.5/3.5 for the butylation (7c/lk) and 90.4B.6 for the pheny-lation (7dD3d) of 5. From the a-amidoalkylation products 7a-d the corresponding optically active 2-substituted piperidinium chlorides!)a-d can be obtained by removal of the chii auxiliary which removal may be accomplished either through reduction with LiAlIQ or by hydrolysis with KOH. The preparation of 2-substituted piperidines in optically active form is an intensively studied object. This is at least in part due to the fact that this type of structure is common to several piperidine alkaloids and that such compounds may also serve as building blocks for the synthesis of mom complex alkaloids3 Among the methods currently available for the asymmetric synthesis of 2-substituted piperidines the most intriguing with regard to simplicity and flexibility, are those which allow the introduction of the 2-substituent i