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In the investigation of a chemical reaction, researchers typically survey variables such as time, temperature, and stoichiometry to optimize yields. This Account demonstrates how control of these variables, often in nontraditional ways, can provide significant improvements in enantiomeric ratios for asymmetric reactions. Dynamic thermodynamic resolution (DTR) offers a convenient method for the resolution of enantiomeric products in the course of a reaction. This process depends on an essential requirement: the equilibration of the penultimate diastereomers must be subject to external control. As a general case, the reaction of A(R), A(S) with B under the influence of the chiral species, L*, gives resolved products C(R) and C(S). In the first step of dynamic resolution under thermodynamic control, the enantiomeric reactants A(R) and A(S) and L* form the diastereomers A(R)/L* and A(S)/L*. The equilibrium between A(R) and A(S) can be rapid, slow, or not operative, and L* can represent a ligand, an auxiliary, or a crystallization process that provides a chiral environment. Second, the populations of the diastereomers are controlled, usually by thermal equilibration. Finally, the reaction of the diastereomers with a reagent B provides the enantiomeric products C(R) and C(S). The control of the diastereomeric equilibrium distinguishes DTR from other resolution techniques. By contrast, physical resolutions separate thermodynamically stable, nonequilibrating diastereomers, and dynamic kinetic resolutions utilize kinetic control for reactions of rapidly equilibrating diastereomers. The dynamic thermodynamic resolutions discussed in this Account illustrate cases of significantly improved enantioselectivities using this technique. Although many of the well-recognized cases come from organolithium chemistry, the principles are general, and we also present cases facilitated by other chemistries. This approach has been used to control enantioselectivities in a number of different reactions, with improvements in enantiomeric ratios up to 99% from essentially racemic reactants.

A new and efficient preparation of pharmacologically and biologically important 2,5-disubstituted 6-azaindoles was achieved from cyclizations of aziridin-2-yl dipropargylic alcohols as adducts of two propargyl groups to ethyl 1-benzylaziridine-2-carboxylate. The sequential cyclizations include pyrrole formation and a novel base-catalyzed intramolecular acetylenic Schmidt reaction.

Sequences of α'-lithiations and electrophilic substitutions of Boc-pyrrolidines, Boc-piperidines, and Boc-hexahydroazepines that provide compounds which are substituted adjacent to nitrogen are reported, and the pathways of the reactions are discussed. By this methodology monosubstituted 2 and disubstituted 2,4, 2,6, and 2,5 Boc-piperidines are obtained as single or separable diastereoisomers consistent with equatorial lithiations and retentive electrophilic substitution in chair conformations

Enantiomerically pure (l)-tryptophanol (5) was synthesized from 4(R)-iodomethyl-2-oxazolidinone (2) and indolylmagnesium bromide in three steps (52% overall yield). Using this procedure, we also prepared various tryptophanols with substituent(s) on the indole ring. Furthermore, optically active 4(R)-iodomethyl-2-oxazolidinone was readily prepared from an enantiomerically pure aziridine-2(S)-methanol in high yield. [reaction: see text]

The α-lithiations and electrophilic substitutions of selected Boc piperidines provide single or separable diastereoisomeric 2-substituted, 2,4-disubstituted, and 2,4,6-trisubstituted Boc piperidines which are readily hydrolyzed to the substituted piperidines

Une alkylation entierement regiospecifique sur des bromures allyliques γ-silyles stereospecifiquement est effectuee avec une variete de nucleophiles anioniques