Uncovering the Most Kinetically Influential Reaction Pathway Driving the Generation of HCN from Oxyma/DIC Adduct: A Theoretical Study.

The combination of ethyl (hydroxyimino)cyanoacetate (Oxyma) and diisopropylcarbodiimide (DIC) has demonstrated superior performance in amino acid activation for peptide synthesis. However, it was recently reported that Oxyma and DIC could react to generate undesired hydrogen cyanide (HCN) at 20 °C, raising safety concerns for the practical use of this activation strategy. To help minimize the risks, there is a need for a comprehensive investigation of the mechanism and kinetics of the generation of HCN. Here we show the results of the first systematic computational study of the underpinning mechanism, including comparisons with experimental data. Two pathways for the decomposition of the Oxyma/DIC adduct are derived to account for the generation of HCN and its accompanying cyclic product. These two mechanisms differ in the electrophilic carbon atom attacked by the nucleophilic sp2-nitrogen in the cyclization step and in the cyclic product generated. On the basis of computed "observed" activation energies, ΔG obs ⧧, the mechanism that proceeds via the attack of the sp2-nitrogen at the oxime carbon is identified as the most kinetically favorable one, a conclusion that is supported by closer agreement between predicted and experimental 13C NMR data. These results can provide a theoretical basis to develop a design strategy for suppressing HCN generation when using Oxyma/DIC for amino acid activation.

Continuous Platform to Generate Nitroalkanes On-Demand (in situ) using Peracetic Acid-Mediated Oxidation in a PFA Pipes-in-Series Reactor.

The synthetic utility of the aza-Henry reaction can be diminished on scale by potential hazards associated with the use of peracid to prepare nitroalkane substrates, and the nitroalkanes themselves. In response, a continuous and scalable chemistry platform to prepare aliphatic nitroalkanes on-demand is reported, using the oxidation of oximes with peracetic acid and direct reaction of the nitroalkane intermediate in an aza-Henry reaction. A uniquely designed pipes-in-series plug flow tube reactor addresses a range of process challenges including stability and safe handling of peroxides and nitroalkanes. The subsequent continuous extraction generates a solution of purified nitroalkane which can be directly used in the following enantioselective aza-Henry chemistry to furnish valuable chiral diamine precursors in high selectivity, thus, completely avoiding isolation of potentially unsafe low molecular weight nitroalkane intermediate. A continuous campaign (16 h) established that these conditions were effective in processing 100 g of the oxime and furnishing 1.4 L of nitroalkane solution.

Development of an Intermittent-Flow Enantioselective Aza-Henry Reaction Using an Arylnitromethane and Homogeneous Brønsted Acid-Base Catalyst with Recycle.

A stereoselective aza-Henry reaction between an arylnitromethane and Boc-protected aryl aldimine using a homogeneous Brønsted acid-base catalyst was translated from batch format to an automated intermittent-flow process. This work demonstrates the advantages of a novel intermittent-flow setup with product crystallization and slow reagent addition which is not amenable to the standard continuous equipment: plug flow tube reactor (PFR) or continuous stirred tank reactor (CSTR). A significant benefit of this strategy was the integration of an organocatalytic enantioselective reaction with straightforward product separation, including recycle of the catalyst, resulting in increased intensity of the process by maintaining high catalyst concentration in the reactor. A continuous campaign confirmed that these conditions could effectively provide high throughput of material using an automated system while maintaining high selectivity, thereby addressing nitroalkane safety and minimizing catalyst usage.

(S)-N-{3-[1-cyclopropyl-1-(2,4-difluoro-phenyl)-ethyl]-1H-indol-7-yl}-methanesulfonamide: a potent, nonsteroidal, functional antagonist of the mineralocorticoid receptor.

A novel, potent series of indole analogs were recently developed as MR antagonists, culminating in 14. This compound represents the first MR antagonist in this class of molecules, exhibiting picomolar binding affinity and in vivo blood pressure lowering at pharmaceutically relevant doses.

Preparation of novel aza-1,7-annulated indoles and their conversion to potent indolocarbazole kinase inhibitors.

The synthesis of novel aza-1,7-annulated indoles was achieved and these were converted to indolocarbazoles that proved to be potent kinase inhibitors. These compounds were also evaluated in a human colon carcinoma cell line and proved to be good antiproliferative agents.

1,7-annulated indolocarbazoles as cyclin-dependent kinase inhibitors.

The synthesis and kinase inhibitory activity of a series of novel 1,7-annulated indolocarbazoles 6 and 16 is described. These compounds exhibited potent inhibitory activity against cyclin-dependent kinase 4 and good antiproliferative activity in a human colon carcinoma cell line.

Synthetic approaches to indolo[6,7-a]pyrrolo[3,4-c]carbazoles: potent cyclin D1/CDK4 inhibitors.

Synthesis of indolo[6,7-a]pyrrolo[3,4-c]carbazoles 1, a new class of cyclin D1/CDK4 inhibitors, by oxidation of the corresponding aryl indolylmaleimides 2, will be described. Two approaches to the synthesis of 2 were identified that required new methods for the synthesis of 7-substituted indole acetamides 3 and N-methyl (indol-7-yl)oxoacetates 6. The chemistry developed enabled introduction of functionality (-OR, NR(2)) at C(12) and N(13) facilitating structure-activity relationship (SAR) evaluation of this indolocarbazole platform.

Synthesis of aryl- and heteroaryl[a]pyrrolo[3,4-c]carbazoles.

Synthesis of aryl- and hetero[a]pyrrolo[3,4-c]carbazoles by photochemical oxidation and Heck cyclization are described. Photochemical oxidation of 2-naphthyl indolyl maleimide affords two different carbazole regioisomers, depending on the reaction conditions. The regiochemistry of the cyclization can be controlled using the Heck reaction.

Novel, potent and selective cyclin D1/CDK4 inhibitors: indolo[6,7-a]pyrrolo[3,4-c]carbazoles.

The synthesis and CDK inhibitory properties of a series of indolo[6,7-a]pyrrolo[3,4-c]carbazoles is reported. In addition to their potent CDK activity, the compounds display antiproliferative activity against two human cancer cell lines. These inhibitors also effect strong G1 arrest in these cell lines and inhibit Rb phosphorylation at Ser780 consistent with inhibition of cyclin D1/CDK4.

Osmium-Promoted Electrophilic Substitution of Anisoles: A Versatile New Method for the Incorporation of Carbon Substituents.

A structurally and electronically diverse set of anisoles are dihapto-coordinated to the pi-base pentaammineosmium(II) and treated with a variety of carbon electrophiles (e.g. Michael acceptors, acetals). After deprotonation of a 4H-anisolium intermediate with a tertiary amine base, C(4)-substituted anisole complexes are isolated. The functionalized arenes are removed from the metal center either by mild heating or treatment with an oxidant (e.g. AgOTf, DDQ, CAN). The resulting substituted anisoles are isolated with yields ranging from 55-95%.