1,3-allylic strain as a strategic diversification element for constructing libraries of substituted 2-arylpiperidines.

Screening approaches to probe molecules for drug discovery require access to high-quality, small-molecule libraries. One contemporary challenge in providing such access is the construction of libraries that maximize the coverage of chemical (functional group), stereochemical, and spatial diversity in a given chemotype. Although the problem of functional group diversity has been addressed since the earliest days of combinatorial chemistry and parallel synthesis, the incorporation of stereochemical diversity and, more broadly, shape diversity has required the development of new strategies. These include the use of spatially diverse scaffolds or the pre-construction of stereochemically diverse building blocks that are then combined to afford final products (“build-couple-pair” is an example of this). Herein we describe a conformational switching approach toward shape-diverse piperidine libraries in which the presence or absence of 1,3-allylic strain (A strain) is leveraged to enhance both 1) scaffold diversity by regiodivergent opening of epoxide intermediates and 2) the conformational space of the final library through the simple expedient of changing the nature of nitrogen substitution. The concept is illustrated in Scheme 1 for a series of substituted 2-arylpiperidines. For a given epoxide isomer, the conformation of the piperidine ring will depend on whether the N1 atom is sp hybridized (Ar preferring an equatorial position because of the minimization of 1,3-diaxial interactions) or sp (Ar preferring axial position because of A strain in the equatorial isomer). Nucleophilic addition to the epoxide would then take place according to the F rst–Plattner principle (trans-diaxial opening), leading to two constitutional isomers from this epoxide intermediate (2,4versus 2,5cis Ar/Nu relationships). Stereochemical diversity would then follow by applying the same principles to the alternative epoxide diastereomer, affording the analogous 2,4and 2,5trans isomers. Once prepared—and likely following the downstream introduction of functional group diversity—the compounds in the library could then be substituted at N by a different set of alkyl or acyl substituents, thus leading to a doubling of the library members through conformational diversity. We chose to demonstrate this approach by preparing a library based on the triazole-containing piperidines shown in Scheme 2 (selected because the arylpiperidine chemotype appears in a number of bioactive compounds and is therefore a desirable library scaffold for broad screening). To a first approximation, the expected conformations in one such library are shown (four isomers bearing two different N groups), thus demonstrating the range of conformational and configurational space covered by these compounds. To demonstrate the value of 1,3-allylic strain in scaffold preparation, we first carried out the stereochemically and constitutionally differentiated scaffold syntheses shown in Scheme 3. Four 2-aryl-1,2,3,6-tetrahydropyridines were constructed from substituted benzaldehydes in two steps by bisallylation/N-acylation and subsequent ring-closing metathesis. The N-acylated derivatives underwent highly stereoselective epoxidation reactions, presumably because the top faces as drawn were blocked by the aromatic groups in the most stable conformations. By using m-CPBA or methylScheme 1. Use of A strain to control constitutional (2,4vs. 2,5-Ar/ Nu relationship), stereochemical (cis vs. trans), and conformational diversity in piperidine libraries. Functional group diversity arises from variations in Ar, Nu, and R.