Enabling, Decagram-Scale Synthesis of Macrocyclic MCL-1 Inhibitor ABBV-467.

ABBV-467 is a highly potent and selective MCL-1 inhibitor that was advanced to a phase I clinical trial for the treatment of multiple myeloma. Due to its large size and structural complexity, ABBV-467 is a challenging synthetic target. Herein, we describe the synthesis of ABBV-467 on a decagram scale, which enabled preclinical characterization. The strategy is convergent and stereoselective, featuring a hindered biaryl cross coupling, enantioselective hydrogenation, and conformationally preorganized macrocyclization by C-O bond formation as key steps.

Kinetic characterization of the inhibition of protein tyrosine phosphatase-1B by Vanadyl (VO2+) chelates.

Protein tyrosine phosphatases (PTPases) are a prominent focus of drug design studies because of their roles in homeostasis and disorders of metabolism. These studies have met with little success because (1) virtually all inhibitors hitherto exhibit only competitive behavior and (2) a consensus sequence H/V-C-X5-R-S/T characterizes the active sites of PTPases, leading to low specificity of active site directed inhibitors. With protein tyrosine phosphatase-1B (PTP1B) identifed as the target enzyme of the vanadyl (VO2+) chelate bis(acetylacetonato)oxidovanadium(IV) [VO(acac)2] in 3T3-L1 adipocytes [Ou et al. J Biol Inorg Chem 10: 874-886, 2005], we compared the inhibition of PTP1B by VO(acac)2 with other VO2+-chelates, namely, bis(2-ethyl-maltolato)oxidovanadium(IV) [VO(Et-malto)2] and bis(3-hydroxy-2-methyl-4(1H)pyridinonato)oxidovanadium(IV) [VO(mpp)2] under steady-state conditions, using the soluble portion of the recombinant human enzyme (residues 1-321). Our results differed from those of previous investigations because we compared inhibition in the presence of the nonspecific substrate p-nitrophenylphosphate and the phosphotyrosine-containing undecapeptide DADEpYLIPQQG mimicking residues 988-998 of the epidermal growth factor receptor, a relevant, natural substrate. While VO(Et-malto)2 acts only as a noncompetitive inhibitor in the presence of either subtrate, VO(acac)2 exhibits classical uncompetitive inhibition in the presence of DADEpYLIPQQG but only apparent competitive inhibition with p-nitrophenylphosphate as substrate. Because uncompetitive inhibitors are more potent pharmacologically than competitive inhibitors, structural characterization of the site of uncompetitive binding of VO(acac)2 may provide a new direction for design of inhibitors for therapeutic purposes. Our results suggest also that the true behavior of other inhibitors may have been masked when assayed with only p-nitrophenylphosphate as substrate.

Addition of Trifluoroborates to Oxetanyl N,O-Acetals: Entry into Spiro and Fused Saturated Heterocycles.

N,O-Acetals derived from 3-oxetanone and 1,2-amino alcohols undergo addition reactions with alkynyl-, allyl-, allenyl-, and vinylpotassium trifluoroborates. The resulting products undergo cyclization by orthogonal activation of the oxetane and the alkyne to give a diverse set of spiro and fused heterocycles.

Stereodivergent approach to the avermectins based on "super silyl" directed aldol reactions.

A stereodivergent approach to the spiroketal fragment of the avermectins is described. The strategy utilizes a sequence of three aldol reactions directed by the tris(trimethylsilyl)silyl "super silyl" group. Central to this strategy is that each aldol reaction can be controlled to allow access to either diastereomer in high stereoselectivity, thereby affording 16 stereoisomers along the same linear skeleton. The aldol products can be transformed into spiroketals, including an advanced intermediate in the total synthesis of avermectin A1a.