An Aldol-Based Build/Couple/Pair Strategy for the Synthesis of Medium- and Large-Sized Rings: Discovery of Macrocyclic Histone Deacetylase Inhibitors

Abstract

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.

Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications

“…Synthesis of triazole macrocycles using RuAAC as the macrocyclization step 156 The same group then utilized this method in a large diversity-oriented synthesis (DOS) library in their search for new macrocyclic histone deacetylase inhibitors (HDACs), 157 using a three phase DOS strategy called build/couple/pair (B/C/P), a method described in more detail in section 5.7. 158 In the pair phase, different macrocyclic structures of a linear intermediate were subjected to different reactions, including RuAAC, to generate a total of 48 macrocyclic scaffolds ranging from 8-to 14-membered ring systems.…”

“…Macrocyclization by RuAAC affording 12-membered triazole macrocycles 157 Zhang et al studied two different strategies for making triazole macrocycles in their synthesis of macrocyclic vancomycin mimics. [160][161] Macrocyclization by RuAAC was successful but with some difficulty for the smallest ring 77 (n=1), due to rigidity of the corresponding linear azidoalkyne 78 (n=1), giving rise to both dimer and trimer by-products (Scheme 37).…”

De novo branching cascades for structural and functional diversity in small molecules

“…1). The proposed reaction mechanisms for the de novo cascades I, II and IV leading to the formation of azepinones 11, isoxazolidines (12) or allyl indoles (13, Fig. 4a), respectively, are supported by various reported cycloaddition reactions between N-phenyl nitrones and allenes [30][31][32] .…”

“…Consequently, new synthetic challenges have emerged aiming at divergent access to structurally distinct and complex scaffolds [9][10][11] . Different approaches have been developed to incorporate structural diversity to a compound collection, for instance, in the build-couple-pair strategies 12,13 , folding 14 and branching pathways [15][16][17] , structural variations either in the building blocks or the reacting partners of common substrates derive the formation of new scaffolds. Synthesis of natural product scaffold-based [18][19][20][21] compound libraries either employs accessible complex natural products or their derivatives for generating new and complex scaffold structures or build up compound libraries around privileged scaffolds 1,22 .…”

Diversity-oriented synthesis of macrocyclic peptidomimetics

“…The synthesis of 1,5-triazole containing macrocycles via 1,3-dipolar cycloadditions (61) is much less common, and in the very limited number of examples that use α-azido acid containing substrates, the yields of the isolated products are typically very low (47). A method where the formation of the macrocycle proceeded with good regioselectivity (1,5-triazole over 1,4-triazole) and moderate yields has been recently described, but there were no stereogenic centers adjacent to the azide present in the substrates (62,63). We faced the challenge of performing the same reaction with chiral α-azido acids, desiring both high yields and no epimerization of the chiral center adjacent to the azide.…”