A Selenourea-Thiourea Brønsted Acid Catalyst Facilitates Asymmetric Conjugate Additions of Amines to α,ß-Unsaturated Esters.

ß-Amino esters are obtained with high levels of enantioselectivity via the conjugate addition of cyclic amines to unactivated α,ß-unsaturated esters. A related strategy enables the kinetic resolution of racemic cyclic 2-arylamines, using benzyl acrylate as the resolving agent. Reactions are facilitated by an unprecedented selenourea-thiourea organocatalyst. As elucidated by DFT calculations and 13C kinetic isotope effect studies, the rate-limiting and enantiodetermining step of the reaction is the protonation of a zwitterionic intermediate by the catalyst. This represents a rare case in which a thiourea compound functions as an asymmetric Brønsted acid catalyst.

Catalytic Enantioselective Synthesis of Mariline†A and Related Isoindolinones through a Biomimetic Approach.

The catalytic enantioselective synthesis of isoindolinones was achieved through the condensation of 2-acyl-benzaldehydes and anilines. In the presence of 1 mol % of a chiral phosphoric acid catalyst, reactions reach completion within 10 min and provide products with up to 98 % ee. Anilines with an ortho t-butyl group form atropisomeric products, thereby enabling the simultaneous generation of axial and point chirality from two achiral substrates. This method was applied to the first synthesis of mariline A.

Computer-aided key step generation in alkaloid total synthesis.

Efficient chemical synthesis is critical to satisfying future demands for medicines, materials, and agrochemicals. Retrosynthetic analysis of modestly complex molecules has been automated over the course of decades, but the combinatorial explosion of route possibilities has challenged computer hardware and software until only recently. Here, we explore a computational strategy that merges computer-aided synthesis planning with molecular graph editing to minimize the number of synthetic steps required to produce alkaloids. Our study culminated in an enantioselective three-step synthesis of (-)-stemoamide by leveraging high-impact key steps, which could be identified in computer-generated retrosynthesis plans using graph edit distances.

Rapid planning and analysis of high-throughput experiment arrays for reaction discovery.

High-throughput experimentation (HTE) is an increasingly important tool in reaction discovery. While the hardware for running HTE in the chemical laboratory has evolved significantly in recent years, there remains a need for software solutions to navigate data-rich experiments. Here we have developed phactor™, a software that facilitates the performance and analysis of HTE in a chemical laboratory. phactor™ allows experimentalists to rapidly design arrays of chemical reactions or direct-to-biology experiments in 24, 96, 384, or 1,536 wellplates. Users can access online reagent data, such as a chemical inventory, to virtually populate wells with experiments and produce instructions to perform the reaction array manually, or with the assistance of a liquid handling robot. After completion of the reaction array, analytical results can be uploaded for facile evaluation, and to guide the next series of experiments. All chemical data, metadata, and results are stored in machine-readable formats that are readily translatable to various software. We also demonstrate the use of phactor™ in the discovery of several chemistries, including the identification of a low micromolar inhibitor of the SARS-CoV-2 main protease. Furthermore, phactor™ has been made available for free academic use in 24- and 96-well formats via an online interface.

Synthesis of carbazolones and 3-acetylindoles via oxidative C-N bond formation through PIFA-mediated annulation of 2-aryl enaminones.

A series of carbazolone derivatives and 3-acetylindoles have been achieved via PIFA-mediated intramolecular cyclization of 2-aryl enaminones. This process allows the N-moiety on the side-chain to be annulated to the benzene ring via the metal-free oxidative aromatic C-N bond formation.

Reinforcing the supply chain of umifenovir and other antiviral drugs with retrosynthetic software.

The global disruption caused by the 2020 coronavirus pandemic stressed the supply chain of many products, including pharmaceuticals. Multiple drug repurposing studies for COVID-19 are now underway. If a winning therapeutic emerges, it is unlikely that the existing inventory of the medicine, or even the chemical raw materials needed to synthesize it, will be available in the quantities required. Here, we utilize retrosynthetic software to arrive at alternate chemical supply chains for the antiviral drug umifenovir, as well as eleven other antiviral and anti-inflammatory drugs. We have experimentally validated four routes to umifenovir and one route to bromhexine. In one route to umifenovir the software invokes conversion of six C-H bonds into C-C bonds or functional groups. The strategy we apply of excluding known starting materials from search results can be used to identify distinct starting materials, for instance to relieve stress on existing supply chains.

Identification of a strong and specific antichlamydial N-acylhydrazone.

Sexually transmitted Chlamydia trachomatis is an extremely common infection and often leads to serious complications including infertility and pelvic inflammatory syndrome. Several broad-spectrum antibiotics are currently used to treat C. trachomatis. Although effective, they also kill beneficial vaginal lactobacilli. Two N-acylhydrazones, CF0001 and CF0002, have been shown previously to inhibit chlamydial growth without toxicity to human cells and Lactobacillus spp. Of particular significance, the rate of random mutation leading to resistance of these inhibitors appears to be extremely low. Here, we report three analogs of CF0001 and CF0002 with significantly stronger inhibitory effects on chlamydiae. Even though the new compounds (termed SF1, SF2 and SF3) displayed slightly decreased inhibition efficiencies for a rare Chlamydia variant selected for CF0001 resistance (Chlamydia muridarum MCR), they completely overcame the resistance when used at concentrations of 75-100 µM. Importantly, SF1, SF2 and SF3 did not shown any toxic effect on lactobacilli, whereas SF3 was also well tolerated by human host cells. An effort to isolate SF3-resistant variants was unsuccessful. By comparison, variants resistant to rifampin or spectinomycin were obtained from smaller numbers of chlamydiae. Our findings suggest that SF3 utilizes an antichlamydial mechanism similar to that of CF0001 and CF0002, and will be more difficult for chlamydiae to develop resistance to, potentially making it a more effective antichlamydial agent.

Intramolecular [3 + 2]-cycloadditions of azomethine ylides derived from secondary amines via redox-neutral C-H functionalization.

Azomethine ylides are accessed under mild conditions via benzoic acid catalyzed condensations of 1,2,3,4-tetrahydroisoquinolines or tryptolines with aldehydes bearing a pendent dipolarophile. These intermediates undergo intramolecular [3 + 2]-cycloadditions in a highly diastereoselective fashion to form polycyclic amines with four new stereogenic centers. Challenging substrates such as piperidine, morpholine, and thiomorpholine undergo the corresponding reactions at elevated temperatures.