Search

Studying the relationship between catalyst conformational dynamics and selectivity in an asymmetric reaction is a challenge. In this study, cyclic peptides were computationally designed to stabilize different ground state conformations of a highly effective, flexible tetrapeptide catalyst for the atroposelective bromination of N-aryl quinazolinones. Through a combination of computational and experimental techniques, we have determined that dynamic movement of the lead catalyst plays a crucial role in achieving high enantioselectivity in the reaction of study. This approach may also serve as a valuable method for investigating the mechanism of other peptide-catalyzed transformations.

The catalytic, enantioselective N-oxidation of substituted pyridines is described. The approach is predicated on a biomolecule-inspired catalytic cycle wherein high levels of asymmetric induction are provided by aspartic-acid-containing peptides as the aspartyl side chain shuttles between free acid and peracid forms. Desymmetrizations of bis(pyridine) substrates bearing a remote pro-stereogenic center substituted with a group capable of hydrogen bonding to the catalyst are demonstrated. Our approach presents a new entry into chiral pyridine frameworks in a heterocycle-rich molecular environment. Representative functionalizations of the enantioenriched pyridine N-oxides further document the utility of this approach. Demonstration of the asymmetric N-oxidation in two venerable drug-like scaffolds, Loratadine and Varenicline, show the likely generality of the method for highly variable and distinct chiral environments, while also revealing that the approach is applicable to both pyridines and 1,4-pyrazines.

Commercially available tin amine protocol (SnAP) reagents provide a simple approach to the synthesis of a wide variety of saturated N-heterocycles from aldehydes. In this report, we disclose that the copper(II) promoter and hexafluoroisopropanol can be replaced by photocatalytic conditions using Ir[dF(CF3)ppy]2(dtbbpy)PF6 in CH3CN. Continuous flow photochemical conditions provide a clean, scalable approach to valuable products including morpholines, piperazines, thiomorpholines, diazepanes, and oxazepanes from aldehyde starting materials.

SnAP (Sn (tin) amine protocol) hydrazine reagents and aldehydes undergo oxidative, copper mediated coupling to form substituted 1,4,5-oxadiazepanes and 1,2,5-triazepanes. Unlike all prior reactions involving SnAP reagents, the SnAP hydrazine reagents undergo a molecular oxygen-assisted oxidative cyclization. The air- and moisture tolerant transformation accommodates a broad range of groups including electron-rich, electron-poor aromatic, heteroaromatic, and aliphatic aldehydes and is amenable to gram scale synthesis. These unusual, chiral heterocycles have unexpectedly large optical rotations, which may find use in optical materials. This article is protected by copyright. All rights reserved.

Redox neutral photocatalytic transformations often require careful pairing of the substrates and photoredox catalysts in order to achieve a catalytic cycle. This can limit the range of viable transformations, as we recently observed in attempting to extend the scope of the photocatalytic synthesis of N-heterocycles using silicon amine protocol (SLAP) reagents to include starting materials that require higher oxidation potentials. We now report that the inclusion of Lewis acids in photocatalytic reactions of organosilanes allows access to a distinct reaction pathway featuring an Ir(III)*/Ir(IV) couple instead of the previously employed Ir(III)*/Ir(II) pathway, enabling the transformation of aromatic and aliphatic aldehydes to thiomorpholines and thiazepanes. The role of the Lewis acid in accepting an electron—either directly or via coordination to an imine—can be extended to other classes of photocatalysts and transformations, including oxidative cyclizations. The combination of light induced reactions and Lewis acids therefore promises access to new pathways and transformations that are not viable using the photocatalysts alone., The presence of Lewis acids enabled the photocatalystic synthesis of thiomorpholines and thiazepanes. Mechanistic investigations additionally led to new conditions for the synthesis of morpholines and the oxidative cyclization of alkenes.

The N-heterocyclic carbene and hydroxamic acid cocatalyzed kinetic resolution of cyclic amines generates enantioenriched amines and amides with selectivity factors up to 127. In this report, a quantum mechanical study of the reaction mechanism indicates that the selectivity-determining aminolysis step occurs via a novel concerted pathway in which the hydroxamic acid plays a key role in directing proton transfer from the incoming amine. This modality was found to be general in amide bond formation from a number of activated esters including those generated from HOBt and HOAt, reagents that are broadly used in peptide coupling. For the kinetic resolution, the proposed model accurately predicts the faster reacting enantiomer. A breakdown of the steric and electronic control elements shows that a gearing effect in the transition state is responsible for the observed selectivity.

The kinetic resolution of N-heterocycles with chiral acylating agents reveals a previously unrecognized stereoelectronic effect in amine acylation. Combined with a new achiral hydroxamate, this effect makes possible the resolution of various N-heterocycles by using easily prepared reagents. A transition-state model to rationalize the stereochemical outcome of this kinetic resolution is also proposed.

Silicon amine protocol (SLAP) reagents for photocatalytic cross-coupling with aldehydes and ketones to form N-unprotected piperazines have been developed. This blue light promoted process tolerates a wide range of heteroaromatic, aromatic, and aliphatic aldehydes and structurally and stereochemically complex SLAP reagents. It provides a tin-free alternative to SnAP (tin amine protocol) reagents for the synthesis of substituted piperazines.

An eight-step synthesis of the tetracyclic pyridocarbazole alkaloid ellipticine (= 5,11-dimethyl-6H-pyrido[4,3-b]carbazole; 1a) in an overall yield of 13% is reported, starting from 4,7-dimethyl-1H-indene. Key steps were iodination, Suzuki coupling, reductive cyclization, DDQ oxidation, and heterocyclization under loss of H2O.

A novel chiral acyl hydroxamate reagent is developed and its application to the kinetic resolution of N-heterocycles is demonstrated.

[1346681-70-6] [1346681-72-8] C11H11NO3 (MW 205.21) InChI = 1S/C11H11NO3/c13-10-6-15-9-5-7-3-1-2-4-8(7)11(9)12(10)14/h1-4,9,11,14H,5-6H2/t9-,11+/m0/s1 InChIKey = RTMHYIADHDEGTI-GXSJLCMTSA-N (enantioselective amidation catalyst for kinetic resolution of N-heterocycles1) Physical Data: colorless needle (recrystallized from MeOH); compound decomposes at temperatures above 210 °C; −42.7 (c 0.5, EtOAc). Solubility: soluble in THF and DMSO; partially soluble in CH2Cl2, EtOAc, and MeOH. Preparative Methods: the chiral hydroxamic acid can be prepared from (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol (eq 1).1 This lactam (4,4a,9,9a-tetrahydro-1-oxa-4-aza-fluoren-3-one) is activated by N,O-bis(trimethylsilyl)acetamide, followed by oxidation with oxodiperoxymolybdenum(pyridine)(hexamethylphosphorictriamide) (MoO5·Py·HMPA, MoOPH)2 to afford the desired hydroxamic acid 1. (1) Purification: column chromatography (silica gel, 100% EtOAc) and recrystallization (MeOH). Handling, Storage, and Precautions: air and moisture stable; can be stored at room temperature in a desiccator with drying agent. Toxicity data is not available.

Scope, reactivity, and selectivity of the chiral hydroxamic acid-catalyzed kinetic resolution of chiral amines are improved compared to the original conditions by a improved catalyst structure and a more environmentally friendly reaction protocol.

The catalytic resolution of racemic cyclic amines has been achieved by an enantioselective amidation reaction featuring an achiral N-heterocyclic carbene catalyst and a new chiral hydroxamic acid cocatalyst working in concert. The reactions proceed at room temperature, do not generate nonvolatile byproducts, and provide enantioenriched amines by aqueous extraction.

The scope, reactivity, and selectivity of the chiral hydroxamic acid-catalyzed kinetic resolution of chiral amines are improved by a new catalyst structure and a more environmentally friendly reaction protocol. In addition to increasing selectivity across all substrates, these conditions make possible the resolution of N-heterocycles containing lactams or other basic functional groups that can inhibit the catalyst.