The catalytic dynamic resolution (CDR) of rac-2-lithio-N-Boc-piperidine using chiral ligand 8 or its diastereomer 9, in the presence of TMEDA has led to the highly enantioselective syntheses of either enantiomer of 2-substituted piperidines using a wide range of electrophiles. The CDR has been applied to the synthesis of R- or S-pipecolic acid derivatives, (+)-β-conhydrine, (S)-(+)-pelletierine, (S)-(−)-ropivacaine, and formal synthesis of (−)-lasubine II and (+)-cermizine C.

The kinetics of enantiomerization and dynamic thermodynamic resolution (DTR) of N-Boc-2-lithiopiperidine have been measured, revealing significant differences in enthalpy and entropy for these processes and a role for the achiral ligand TMEDA: the racemization and the DTR are catalytic and first order in [TMEDA], and this has implications for asymmetric synthesis with chiral organolithiums.

The highly enantioselective synthesis of 2-aryl-and 2-vinyl-piperidines has been accomplished through a catalytic dynamic resolution (CDR) of N-Boc-2-lithiopiperidine. The method has been applied to the synthesis of both enantiomers of the tobacco alkaloid anabasine.Optically active 2-aryl-and 2-vinyl-piperidines are found in a variety of natural products and some have useful pharmacological properties.1 -3 Previously, Dieter demonstrated that transmetalation of N-Boc-2-lithiopyrrolidine to its organocopper counterpart provides a convenient way to synthesize vinylated pyrrolidines.4 , 5 Using an asymmetric deprotonation methodology with the chiral base s-BuLi/(-)-sparteine6 , 7 to generate an enantioenriched organolithium, Dieter achieved enantioselective vinylations with er's up to 93:7. Later, Campos used the asymmetric deprotonation methodology and transmetalation to an organozinc species, followed by a palladium-mediated Negishi coupling with aryl bromides, to prepare N-Boc-2-arylpyrrolidines in good yields and ≥96:4 er's (Scheme 1).8 -11The remarkable chemical and configurational stability of the intermediate organozinc compound, even at 60 °C, and the high degree of tolerance for both electron rich and electron deficient aryl halides make this transformation very attractive.Previous attempts to synthesize enantioenriched 2-aryl-piperidines via Negishi coupling conditions have been less successful. O'Brien recently reported an asymmetric deprotonation of N-Boc-piperidine using s-BuLi and O'Brien's diamine12 (Figure 1), followed by trapping with 4-bromoveratrole, affording the arylated product in 33% yield and 82:18 er (S:R).11 Although the Coldham group successfully synthesized racemic members of this family via Negishi coupling,13 attempts to effect enantioselectivity by dynamic thermodynamic resolution (DTR) using stoichiometric amount of chiral ligand led to no arylation products.14 They reported two examples of enantioenriched 2-aryl-piperidines (er bgawley@uark.edu. Supporting Information Available Full experimental details and spectroscopic data. This information is available free of charge via the internet at http://pubs.acs.org. We recently reported the highly enantioselective synthesis of 2-substituted piperidines by catalytic dynamic resolution (CDR) of N-Boc-2-lithiopiperidine 1 using diastereomeric ligands (S,S)-2 and (S,R)-2 ( Figure 1).15 In our report, we utilized copper-mediated coupling to synthesize enantioenriched 2-allyl and 2-benzyl-piperidines (Scheme 2) via an organozinc reagent formed by transmetalation of the resolved N-Boc-2-lithiopiperidine. NIH Public AccessWe know (Scheme 2) that during transmetalation of lithium to zinc, then to copper, configurational stability is maintained. Based on Campos' results (Scheme 1), we hoped that during transmetalation from zinc to palladium, configurational integrity would be retained.Considering that we are able to resolve N-Boc-2-lithiopiperidine catalytically, we investigated a CDR in the Negishi arylations and vinylations. We herein e...

In diethyl ether, N-Boc-2-lithio-2-arylpiperidines have been found to be configurationally stable at −80 °C whereas N-Boc-2-lithio-2-arylpyrrolidines are configurationally stable at −60 °C. Several tertiary benzylic carbanions derived from enantioenriched 2-aryl heterocycles have been successfully alkylated or acylated with little to no loss of enantiopurity. The scope of the reactions has been explored. The enantiomerization dynamics of N-Boc-2-lithio-2-phenylpyrrolidine and N-Boc-2-lithio-2-phenylpiperidine have been studied in the presence of different solvents and achiral ligands.

The synthesis of functionalized azepanes was accomplished through the palladium-mediated cross-coupling of α-halo eneformamides with mostly unactivated nucleophiles under mild conditions. Alkenylations proceeded with excellent stereoselectivitiy. In most cases, high yields of the coupling products were obtained.