ABSTRACT
Rhodium-catalyzed enantioselective synthesis of 1-phenoxycyclopropane-1-carbaldehydes by intermolecular cyclopropanation of terminal alkenes followed by imine hydrolysis is described. This methodology utilizes 4-aryloxy-1-sulfonyl-1,2,3-triazoles as the carbene precursors and the chiral dirhodium(II) tetracarboxylates Rh2(S-NTTL)4 or Rh2(S-DPCP)4 as the catalysts. These reactions are considered to proceed via rhodium-stabilized donor/acceptor carbene intermediates, and these studies demonstrate that a heteroatom donor group is compatible with an enantioselective transformation.
Subject(s)
Rhodium , Oxygen , Stereoisomerism , Molecular Structure , Triazoles , CatalysisABSTRACT
SETD2, a lysine N-methyltransferase, is a histone methyltransferase that plays an important role in various cellular processes and was identified as a target of interest in multiple myeloma that features a t(4,14) translocation. We recently reported the discovery of a novel small-molecule SETD2 inhibitor tool compound that is suitable for preclinical studies. Herein we describe the conformational-design-driven evolution of the advanced chemistry lead, which resulted in compounds appropriate for clinical evaluation. Further optimization of this chemical series led to the discovery of EZM0414, which is a potent, selective, and orally bioavailable inhibitor of SETD2 with good pharmacokinetic properties and robust pharmacodynamic activity in a mouse xenograft model.
ABSTRACT
SET domain-containing protein 2 (SETD2), a histone methyltransferase, has been identified as a target of interest in certain hematological malignancies, including multiple myeloma. This account details the discovery of EPZ-719, a novel and potent SETD2 inhibitor with a high selectivity over other histone methyltransferases. A screening campaign of the Epizyme proprietary histone methyltransferase-biased library identified potential leads based on a 2-amidoindole core. Structure-based drug design (SBDD) and drug metabolism/pharmacokinetics (DMPK) optimization resulted in EPZ-719, an attractive tool compound for the interrogation of SETD2 biology that enables in vivo target validation studies.
ABSTRACT
A remarkable aspect of enzyme evolution is the portability of catalytic mechanisms for fundamentally different chemical reactions. For example, aspartyl proteases, which contain two active site carboxylic acid groups, catalyze the hydrolysis of amide bonds, while glycosyltransferases (and glycosyl hydrolases), which often also contain two active site carboxylates, have evolved to form (or break) glycosidic bonds. However, neither catalyst exhibits cross-reactivity in the intracellular environment. The large, macromolecular architectures of these biocatalysts tailor their active sites to their precise, divergent functions. The analogous portability of a small-molecule catalyst for truly orthogonal chemical reactivity is rare. Herein, we report aspartic acid containing peptides that can be directed to different sectors of a substrate for which the danger of cross-reactivity looms large. A transiently formed aspartyl peracid catalyst can participate either as an electrophilic oxidant to catalyze alkene epoxidation or as a nucleophilic oxidant to mediate the Baeyer-Villiger oxidation (BVO) of ketones. We show in this study that an appended peptide sequence can dictate the mode of reactivity for this conserved catalytic functional group within a substrate that has the potential to undergo both alkene epoxidation and BVO; in both cases the additional aspects of chemical selectivity (regio- and stereoselectivity) are high. This sequence-dependent tuning of a common catalytic moiety for functional group selective reactions constitutes a biomimetic strategy that may impact late-stage diversification of complex polyfunctional molecules.
ABSTRACT
The enantioselective intermolecular sp(3) C-H functionalization at the allylic and benzylic positions was achieved using rhodium-catalyzed reactions with 4-phenyl-N-(methanesulfonyl)-1,2,3-triazole. The optimum dirhodium tetracarboxylate catalyst for these reactions was Rh2(S-NTTL)4. The rhodium-bound α-imino carbene intermediates preferentially reacted with tertiary over primary C-H bonds in good yields and moderate levels of enantioselectivity (66-82% ee). This work demonstrates that N-sulfonyltriazoles can be applied to the effective C-H functionalization at sp(3) C-H bonds of substrates containing additional functionality.
Subject(s)
Benzene Derivatives/chemical synthesis , Sulfinic Acids/chemistry , Triazoles/chemistry , Catalysis , Molecular Structure , Rhodium/chemistry , StereoisomerismABSTRACT
An effective method for aminoacylation of indoles and pyrroles has been achieved. The transformation involves a multicomponent one-pot cascade reaction between indoles or pyrroles, ynol ethers, and sulfonyl azides, creating four different bonds regioselectively through N-sulfonyltriazole intermediates. The oxo-tryptamines and oxo-pyrroloethanamines are generated in moderate to high yields under mild reaction conditions.
ABSTRACT
Metal-stabilized carbenes derived from diazo compounds have become broadly useful reactive intermediates for organic synthesis. This tutorial review will describe the recent advances in using N-sulfonyl-1,2,3-triazoles as precursors for the formation of metal-bound imino carbene intermediates. These intermediates undergo a variety of synthetically useful transformations, which include transannulation reactions to generate new heterocycles, cyclopropanation and subsequent ring expansions, ylide formation with subsequent rearrangements, and C-H functionalization. Furthermore, many of these transformations can be conducted with high levels of enantioselectivity by use of chiral rhodium(II) catalysts.
ABSTRACT
Catalytic enantioselective methods for the generation of cyclopropanes has been of longstanding pharmaceutical interest. Chiral dirhodium(II) catalysts prove to be an effective means for the generation of diverse cyclopropane libraries. Rh2(R-DOSP)4 is generaally the most effective catalyst for asymmetric intermolecular cyclopropanation of methyl aryldiazoacetates with styrene. Rh2(S-PTAD)4 provides high levels of enantioinduction with ortho-substituted aryldiazoacetates. The less-established Rh2(R-BNP)4 plays a complementary role to Rh2(R-DOSP)4 and Rh2(S-PTAD)4 in catalyzing highly enantioselective cyclopropanation of 3- methoxy-substituted aryldiazoacetates. Substitution on the styrene has only moderate influence on the asymmetric induction of the cyclopropanation.
ABSTRACT
A highly effective synthesis of 2,3-fused pyrroles from cyclic ketones has been achieved. The transformation includes a rhodium-catalyzed reaction of 4-alkenyl-1-sulfonyl-1,2,3-triazoles featuring an unusual 4π electrocyclization. The methodology was further extended to the synthesis of indoles using a one-pot reaction starting from 1-ethynylcyclohexenes.
Subject(s)
Indoles/chemical synthesis , Ketones/chemistry , Pyrroles/chemical synthesis , Catalysis , Cyclization , Indoles/chemistry , Pyrroles/chemistry , Rhodium/chemistry , Triazoles/chemistryABSTRACT
Warming of 4-phthalimido-N-mesyl-1,2,3-triazole in the presence of alkenes followed by silica gel induced hydrolysis results in a highly diastereoselective and catalyst-free entry to N-phthalimidocyclopropanecarboxaldehydes.