Dynamic thermodynamic and dynamic kinetic resolution of 2-lithiopyrrolidines.

Dynamic resolution has been studied as a method for the asymmetric synthesis of 2-substituted pyrrolidines. Highly enantioselective electrophilic substitutions of racemic 2-lithiopyrrolidines in the presence of a chiral ligand have been achieved. The organolithium compounds were prepared by tin-lithium exchange from the corresponding tributylstannanes and n-butyllithium or by deprotonation of N-(tert-butyloxycarbonyl)pyrrolidine with sec-butyllithium. A range of N-substituents and chiral ligands were investigated for the dynamic resolution. Electrophilic quench of the resolved diastereomeric 2-lithiopyrrolidine-chiral ligand complexes provided the enantiomerically enriched 2-substituted pyrrolidines. With N-alkyl derivatives, the resolution occurs conveniently at (or just below) room temperature and either enantiomer of the product can be formed by appropriate choice of the chiral ligand. The asymmetric induction occurs as a result of a thermodynamic preference for one of the diastereomeric complexes. The minor complex was found to have a faster rate of reaction with the electrophile. The use of N-allylic derivatives provides a means to prepare the N-unsubstituted pyrrolidine products. Best results were obtained with the N-2,3-dimethylbut-2-enyl derivative, and this N-substituent could be cleaved using 1-chloroethyl chloroformate. With N-Boc-2-lithiopyrrolidine, the enantioselectivity arises by a kinetic resolution and high levels of asymmetric induction in the presence of excess n-butyllithium can be obtained. Dynamic kinetic resolution of the N-Boc derivative is limited in the scope of electrophile that can be used.

Dynamic kinetic resolution of N-Boc-2-lithiopyrrolidine.

Asymmetric substitution of the organolithium derived either from N-Boc-2-tributylstannylpyrrolidine by tin-lithium exchange or from N-Boc-pyrrolidine by deprotonation occurs in the presence of a commercially available chiral diamine ligand with high levels of enantioselectivity by a dynamic kinetic resolution pathway.

Model studies toward the synthesis of kirkine.

In model studies towards the synthesis of kirkine, the carbon skeleton was constructed using a radical cascade reaction. Two different approaches towards the synthesis have been examined as well as the regioselectivity of the radical cyclisation.

Barrier to enantiomerization of unstabilized, chelated, and dipole-stabilized 2-lithiopyrrolidines.

Kinetics experiments have been used to establish the free energy, enthalpy, and entropy of activation for the enantiomerization of three structural classes of 2-lithiopyrrolidines. We find that alpha-aminoorganolithiums chelated by a N-methoxyethyl or N-Boc group have a barrier to enantiomerization (DeltaG++) 2-3 kcal/mol lower than that of unstabilized alpha-aminoorganolithiums at 273 K. Density functional calculations were performed to clarify possible ground state and transition structures and to identify possible pathways for inversion of these chiral organolithium species.

A new, unexpected synthesis of 1,3-dithietanones.

Treatment of a geminal pivaloxy xanthate, prepared by an intermolecular radical addition of a xanthate to vinyl pivalate, gives a 1,3-dithietanone, a little known class of compounds.