An aldol-based ‘build/couple/pair’ (B/C/P) strategy was applied to generate a collection of stereochemically and skeletally diverse small molecules. In the build phase, a series of asymmetric syn- and anti- aldol reactions were performed to produce four stereoisomers of a Boc protected γ-amino acid. In addition both stereoisomers of O-PMB-protected alaninol were generated to provide a chiral amine coupling partner. In the couple step, eight stereoisomeric amides were synthesized by coupling the chiral acid and amine building blocks. The amides were subsequently reduced to generate the corresponding secondary amines. In the pair phase, three different reactions were employed to enable intramolecular ring-forming processes, namely: nucleophilic aromatic substitution (SNAr), Huisgen [3+2] cycloaddition and ring-closing metathesis (RCM). Despite some stereochemical dependencies, the ring-forming reactions were optimized to proceed with good to excellent yields providing a variety of skeletons ranging in size from 8- to 14-membered rings. Scaffolds resulting from the RCM pairing reaction were diversified on solid-phase to yield a 14,400-membered library of macrolactams. Screening of this library led to the discovery of a novel class of histone deacetylase inhibitors, which display mixed enzyme inhibition and led to increased levels of acetylation in a primary mouse neuron culture. The development of stereo-structure/activity relationships (SSAR) was made possible by screening all 16 stereoisomers of the macrolactams produced through the aldol-based B/C/P strategy.

The synthesis and diversification of a densely functionalized azetidine ring system to gain access to a wide variety of fused, bridged and spirocyclic ring systems is described. The in vitro physicochemical and pharmacokinetic properties of representative library members are measured in order to evaluate the use of these scaffolds for the generation of lead-like molecules to be used in targeting the central nervous system. The solid-phase synthesis of 1976-membered library of a spirocyclic azetidines is also described.

A regioselective intramolecular Huisgen cycloaddition was performed on various azido alkyne substrates giving rise to macrocyclic triazole rings. Using catalyst control, a common intermediate has been converted to two structurally unique macrocycles with either a 1,5-or a 1,4-triazole resulting in an n or n + 1 ring size. This is the first example of an intramolecular ruthenium-catalyzed Huisgen cycloaddition.The preparation and screening of small molecules constitutes a powerful strategy for the discovery of biological probes and pharmaceutical agents. 1-3 Diversity of structure within a particular compound collection is key to the discovery of hits over a wide range of biological areas. It has recently been shown that even large screening collections that lack diversity are insufficient to provide lead compounds against a range of antibacterial targets. 4 A current strategy for achieving diverse compound collections through diversity-oriented synthesis (DOS) focuses on the use of functional group pairing. 5,6 By using scaffolds with multiple functional group "handles" and joining them in a pairwise, intramolecular, and chemoselective fashion both skeletal diversity and rigidity are achieved. A complementary approach for generating structural diversity is known as "reagent-based" diversification. 7 This strategy involves the preparation of a singular scaffold that, when subjected to different reaction conditions, selectively yields different products. 1,8 To further develop this strategy, robust methodologies that allow for reagent-based differentiation must be developed.The Huisgen 1,3-dipolar cycloaddition is a widely utilized reaction in DOS. 9,10 This `click' reaction results from the ligation of azides and alkynes to give a triazole moiety. This reaction has been shown to be effective in the formation of a variety of macrocyclic rings. 11 A key point of interest for us was the regioselectivity of the cycloaddition. We surmised that a reagentbased diversity approach could be applied to generate both possible regioisomers from a common substrate as shown in Scheme 1. While many advances have been made in the formation of 1,4-triazoles using copper (I) catalysis, 9 the formation of 1,5-triazole rings using ruthenium (II) catalysis has only recently been reported and has been demonstrated in an intermolecular fashion and in a much more limited scope. 10,12 *E-mail: lisa@broad.mit.edu. Supporting Information Available Experimental procedures, compound characterization data and X-ray crystallographic information files. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public Access Author ManuscriptOrg Lett. Author manuscript; available in PMC 2010 June 4. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptWith this in mind, we sought to expand the existing Huisgen methodology to make macrocyclic triazole rings regioselectively. This method is ideally suited to the preparation of smallmolecule libraries, because one compound can be converted int...