Sulfamate Acetamides as Self-Immolative Electrophiles for Covalent Ligand-Directed Release Chemistry.

Electrophiles for covalent inhibitors that are suitable for in vivo administration are rare. While acrylamides are prevalent in FDA-approved covalent drugs, chloroacetamides are considered too reactive for such purposes. We report sulfamate-based electrophiles that maintain chloroacetamide-like geometry with tunable reactivity. In the context of the BTK inhibitor ibrutinib, sulfamate analogues showed low reactivity with comparable potency in protein labeling, in vitro, and cellular kinase activity assays and were effective in a mouse model of CLL. In a second example, we converted a chloroacetamide Pin1 inhibitor to a potent and selective sulfamate acetamide with improved buffer stability. Finally, we show that sulfamate acetamides can be used for covalent ligand-directed release (CoLDR) chemistry, both for the generation of "turn-on" probes as well as for traceless ligand-directed site-specific labeling of proteins. Taken together, this chemistry represents a promising addition to the list of electrophiles suitable for in vivo covalent targeting.

Design and application of intramolecular vinylogous Michael reaction for the construction of 2-alkenyl indoles.

A base-mediated transformation based on a designed intramolecular vinylogous Michael addition (intra-VMA) is presented to access 3-substituted 2-alkenyl indole derivatives. The reaction represents the first example of the intra-VMA for the construction of indoles. A one-pot N-allylation of ortho-tosylamidocinnamates/congeners with γ-bromocrotonates followed by intra-VMA has been described to provide access to a diverse range of 2-alkenyl indole derivatives in reasonable to high yields. The synthetic value of the developed intra-VMA has been demonstrated by gram-scale synthesis of a representative indole derivative and also by the formal synthesis of MK-7246: a Merck's clinical CRTH2 antagonist.

Tandem Copper-Catalyzed Regioselective N-Arylation-Aza-Michael Addition: Synthesis of Tetracyclic 5H-Benzothiazolo[3,2-a]quinazoline Derivatives.

A copper-catalyzed tandem process integrating regioselective N-arylation, followed by aza-Michael addition, is disclosed using 2-aminobenzothiazoles and ortho-halo cinnamic acid congeners. This process generated diverse tetracyclic 5H-benzothiazolo[3,2-a]quinazoline derivatives in moderate to good yields. The present tandem reaction appears to proceed through concomitant ring opening of 2-aminobenzothiazole and S-arylation to give the ortho-cyanamide-substituted diaryl thioether intermediate. The thus generated intermediate likely undergoes an unprecedented Truce-Smiles-type rearrangement involving S- to N-aryl migration, followed by reformation of the thiazole ring and intramolecular aza-Michael addition to furnish the title products.

N-Heterocyclic carbene (NHC)-catalyzed tandem imine umpolung-aza-Michael addition-oxidation of ß-carboline cyclic imines.

Herein we describe an NHC-catalyzed umpolung of ß-carboline-based cyclic imines for their conversion to the corresponding N-substituted cyclic amides. The key to the success of this transformation appears to be that NHC upon reaction with the imine concomitantly goes through the generation of an aza-Breslow intermediate and aza-Michael addition followed by oxidation with molecular oxygen to deliver the N-substituted amide products. The developed method has enabled the synthesis of various biologically relevant ß-carboline-1-one derivatives in good yields.

One-Pot Allylation-Intramolecular Vinylogous Michael Addition-Isomerization Cascade of o-Hydroxycinnamates and Congeners: Synthesis of Substituted Benzofuran Derivatives.

A unique intramolecular vinylogous Michael addition leading to the synthesis of heterocycles has been disclosed. Base-promoted one-pot sequential O-allylation of o-hydroxy-cinnamates or -cinnamonitrile or -chalcones with γ-bromocrotonates followed by an intramolecular conjugate addition of vinylogous Michael donors resulted in the formation of highly substituted benzofuran derivatives in good to excellent yields. The intramolecular event followed by two [1,3]-H shifts leading to aromatization appears to be the key to the success of this unprecedented transformation.

Tandem Aza Michael Addition-Vinylogous Nitroaldol Condensation: Construction of Highly Substituted N-Fused 3-Nitropyrazolopyridines.

A base-mediated tandem aza-Michael addition-vinylogous nitroaldol condensation has been described between 3,5-dialkyl 4-nitropyrazoles and alkynyl ketones/aldehydes. This transition metal-free atom economical transformation occurred via C-N and C═C bond formations in one step with the elimination of water. The construction of a variety of highly substituted N-fused 3-nitropyrazolopyridine derivatives has been demonstrated with good yields. Good to excellent regioselectivities have been achieved with unsymmetrically substituted 4-nitropyrazoles.

N-Heterocyclic carbene (NHC)-catalysed atom economical construction of 2,3-disubstituted indoles.

A novel organocatalytic approach, harnessing the unique reactivities of N-heterocyclic carbenes (NHCs), has been revealed for the construction of indoles. The NHC-catalysed atom economical synthesis of a wide range of 2-substituted indole-3-acetic acid derivatives is displayed. Strategic application of the developed method was demonstrated for a short synthesis of a cyclin-dependent kinase (CDK) inhibitor: paullone.