Stereocontrolled synthesis of vicinally functionalized piperidines by nucleophilic β-addition of alkyllithiums to α-aryl substituted piperidine enecarbamates

Abstract

Substituted piperidines are emerging as important medicinally-active structural motifs. Here, we report highly stereoselective carbolithiation reactions of α-aryl piperidine enecarbamates that offer direct access to vicinally-substituted piperidine compounds. We have also demonstrated that the carbanion intermediates can be trapped with a carbon electrophile

One-shot access to α,β-difunctionalized azepenes and dehydropiperidines by reductive cross-coupling of α-selenonyl-β-selenyl enamides with organic bromides

“…Of note, the deprotonating base, temperature, and reaction time are key adjustable parameters for mitigating deformylation (where applicable), α′-, allylic-, aryl-, or reductive-lithiation. As noted earlier, in our previous vicinal difunctionalization strategy, 67 we were not able to achieve β-arylation nor α-alkylation of dehydropiperidines. 9 The importance of the α-selenonyl group in this reaction manifold is highlighted by the observation that α-carbo-functionalized enecarbamates such as 2a/b/d (see Scheme 2) fail to react under the specified conditions.…”

Regio- and stereoselective intermolecular carbolithiation reactions

“…The rst example of highly diastereoselective carbolithiations, followed by protonation, of a-arylated dehydro-piperidine enecarbamates 120 with alkyllithium nucleophiles was also described (Scheme 41). 57 This umpolung-type synthetic sequence can lead to the diastereoselective synthesis of piperidine derivatives bearing vicinal (C2, C3) substituents, providing a method to obtain difunctionalized piperidines, useful precursors for the synthesis of compounds of medicinal and biological importance. The carbolithiation process is highly diastereoselective, with the C-2 aryl and the C-3 alkyl groups in anti position.…”

Trapping of carbolithiation-derived tertiary benzylic α-lithio piperidines with carbon electrophiles: Controlling the formation of α-amino quaternary and vicinal stereocenters

“…2B). 33 In that report, it was noted that incipient attempts at methylating the benzylic organolithium generated from enecarbamate 3a were quite promising (see 5a, Fig. 2C).…”

“…32 Additionally, we and Sarpong have revealed that the addition of organolithium nucleophiles to the β-position of α-arylated piperidine enecarbamates such as 3 followed by protonation of the resulting intermediate tertiary organolithium, is possible, under additive-free conditions (see 4, Fig. 33 In that report, it was noted that incipient attempts at methylating the benzylic organolithium generated from enecarbamate 3a were quite promising (see 5a, Fig. 33 In that report, it was noted that incipient attempts at methylating the benzylic organolithium generated from enecarbamate 3a were quite promising (see 5a, Fig.…”

“…2B), 33 a few setbacks were encountered. 33 Enecarbamates bearing stereoelectronically diverse aryl substituents, including π-deficient heteroaryl motifs (e.g., 3i) are tolerated in this transformation. Thus, prior to examining the scope of carbolithiation/ trapping of aryl enecarbamates with carbon electrophiles, it was of interest to seek ways to side-step the previously encountered shortcomings.…”