Abstract. The range and utility of DABAL-Me 3 couplings of methyl esters and free carboxylic acids with primary and secondary amines under a variety of conditions (reflux, sealed tube, microwave) has been compared for a significant range of coupling partners of relevance to the preparation of amides of interest in pharmaceutical chemistry. Commercial microwave reactors promote the fastest couplings and allow the use of significantly sterically hindered amines (primary and secondary) and carboxylic acids derivatives. The influence of microwave energy on the reaction system was shown to be typically related to thermal effects (over-pressuring and superheating).

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A practical asymmetric 1,2-addition of functionalised arylzinc halides to aromatic and aliphatic aldehydes is described by the use of aminoalcohol catalysis in the presence of AlMe(3). The process is simple to carry out, uses only commercially available reagents/ligands and provides moderate to good (80-96 % ee) enantioselectivities for a wide range of substrates. Either commercial ArZnX reagents or those prepared in situ from low cost aryl bromides can be used. In the latter case electrophilic functional groups are tolerated (CO(2)Et, CN). The reaction relies on rapid exchange between ArZnX and AlMe(3) to generate mixed organometallic species that lead to the formation of a key intermediate that is distinctly different from the classic "anti" transition states of Noyori. NMR monitoring and related experiments have been used to probe the validity of the proposed selective transition state.

Acetylation of histones and additional nuclear proteins is a key mechanism in the regulation of gene expression. Aberrant acetylation has been linked to a wide range of diseases including cancer, inflammation, and neurodevelopmental disorders. Histone acetylation is introduced by histone acetyltransferases complexes (HATs), where substrate specificity is dramatically enhanced by scaffolding proteins that activate and target them to specific chromatin sites. A protein of interest with both epigenetic acetyl reader and scaffolding function is the protein Bromodomain and PHD finger-containing protein 1 (BRPF1). The Protein contains domains of two plant homeodomain (PHD) fingers separated by a zinc knuckle (PZP domain), a bromodomain, and a proline-tryptophan-tryptophan-proline (PWWP) Tudor domain. Native BRPF1 complexes can contain either MOZ/MORF or HBO1 as the catalytic MYST-family acetyltransferase subunit and the stable complex with Moz-Tif2 is known to lead to the development of human acute myeloid leukemia (AML). Given this, we chose to pursue the development of BRPF1 degraders to probe cancer disease biology especially in AML, where new therapies are required to overcome several unmet needs such as less-toxic treatments and relapsed/refractory disease paradigms. Here we present the design and synthesis of a range of BRPF1 degraders in highly desirable physicochemical space utilizing in-silico modeling. The prepared degraders which utilize multiple E3 ligases were then screened against cell lines harboring Mixed-lineage leukemia (MLL) translocations specifically the THP-1 cell line. In addition to this, we investigated the ability of the compounds to effectively degrade the target and suitability of our degraders for potential in-vivo exposure through a panel of routine ADMET assays. Citation Format: Daniel Joseph Glynn, Rosie Crampton, Thomas Pesnot, Andrew Scott, Anne-Chloe Nassoy, Ralph Kirk, Daniele Narducci, Gary Nelson, Lynette Ongiri, Habiba Begum, Vincent Rao, Matilda Bingham, Rhoanne McPherson, Darryl Turner. The development of BRPF1 degraders as a potential treatment for acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 419.

On DABAL-Me 3 Promoted Formation of Amides. -Range and utility of couplings of methyl esters and free carboxylic acids with primary and secondary amines in the presence of DABAL-Me3, an adduct of trimethylaluminum and DABCO, are studied. Commercial microwave reactors promote the fastest couplings and allow the use of even significantly sterically hindered amines. Stereogenic centers in the amine remain without racemization while α-stereocenters in aminoacids are usually extensively racemized. -(DUBOIS, N.; GLYNN, D.; MCINALLY, T.; RHODES, B.; WOODWARD*, S.; IRVINE, D. J.; DODDS, C.; Tetrahedron 69 (2013) 46, 9890-9897, http://dx.