A Versatile Bis-Allylboron Reagent for the Stereoselective Synthesis of Chiral Diols.

Allylboron reagents are popular in synthesis owing to their versatility and the predictable stereochemical outcomes of their reactions with carbonyl compounds. Herein, we describe the synthesis of (Z,Z)-hexadienyl bis-boronate 1, a configurationally stable, crystalline, and easy to handle compound, which represents a class of bis-allylic boron reagents with heretofore untapped synthetic potential. In combination with a chiral phosphoric acid catalyst, the reagent can be employed for the enantioselective allyl transfer reaction to a variety of one-pot transformations, enabling swift access to functionalized 1,n-diols. The in situ conversion of the reagent into the corresponding bis-borinic ester allows for the direct and diastereoselective two-fold allyl transfer to aldehydes. This affords C2 - or Ci -symmetric stereotetrads containing a 1,4-diol moiety for natural product synthesis. The usefulness of our method was demonstrated with a short synthesis of the lignan (±)-neo-olivil.

Enantioselective Synthesis and Racemization of (-)-Sinoracutine.

Sinoracutine is a recently isolated alkaloid with unusual stereochemical and biological properties. It features an unprecedented tetracyclic 6/6/5/5 skeleton that bears an N-methylpyrrolidine ring fused to a cyclopentenone. Interestingly, both enantiomers of sinoracutine have been independently isolated from the same plant, yet the molecule does not appear to occur as a racemate. Here, we present a short synthesis of (-)-sinoracutine that relies on a highly diastereoselective Pauson-Khand reaction and a Mandai-Claisen reaction to install the quaternary stereocenter. Our work establishes the absolute configuration of the levorotatory isomer and suggests that the optical purity of sinoracutine varies in nature due to its gradual racemization. Experimental evidence supports this proposal, and a plausible mechanism for the racemization is provided.

CIME4R: Exploring iterative, AI-guided chemical reaction optimization campaigns in their parameter space.

Chemical reaction optimization (RO) is an iterative process that results in large, high-dimensional datasets. Current tools allow for only limited analysis and understanding of parameter spaces, making it hard for scientists to review or follow changes throughout the process. With the recent emergence of using artificial intelligence (AI) models to aid RO, another level of complexity has been added. Helping to assess the quality of a model's prediction and understand its decision is critical to supporting human-AI collaboration and trust calibration. To address this, we propose CIME4R-an open-source interactive web application for analyzing RO data and AI predictions. CIME4R supports users in (i) comprehending a reaction parameter space, (ii) investigating how an RO process developed over iterations, (iii) identifying critical factors of a reaction, and (iv) understanding model predictions. This facilitates making informed decisions during the RO process and helps users to review a completed RO process, especially in AI-guided RO. CIME4R aids decision-making through the interaction between humans and AI by combining the strengths of expert experience and high computational precision. We developed and tested CIME4R with domain experts and verified its usefulness in three case studies. Using CIME4R the experts were able to produce valuable insights from past RO campaigns and to make informed decisions on which experiments to perform next. We believe that CIME4R is the beginning of an open-source community project with the potential to improve the workflow of scientists working in the reaction optimization domain. SCIENTIFIC CONTRIBUTION: To the best of our knowledge, CIME4R is the first open-source interactive web application tailored to the peculiar analysis requirements of reaction optimization (RO) campaigns. Due to the growing use of AI in RO, we developed CIME4R with a special focus on facilitating human-AI collaboration and understanding of AI models. We developed and evaluated CIME4R in collaboration with domain experts to verify its practical usefulness.

Open-Source Chromatographic Data Analysis for Reaction Optimization and Screening.

Automation and digitalization solutions in the field of small molecule synthesis face new challenges for chemical reaction analysis, especially in the field of high-performance liquid chromatography (HPLC). Chromatographic data remains locked in vendors' hardware and software components, limiting their potential in automated workflows and data science applications. In this work, we present an open-source Python project called MOCCA for the analysis of HPLC-DAD (photodiode array detector) raw data. MOCCA provides a comprehensive set of data analysis features, including an automated peak deconvolution routine of known signals, even if overlapped with signals of unexpected impurities or side products. We highlight the broad applicability of MOCCA in four studies: (i) a simulation study to validate MOCCA's data analysis features; (ii) a reaction kinetics study on a Knoevenagel condensation reaction demonstrating MOCCA's peak deconvolution feature; (iii) a closed-loop optimization study for the alkylation of 2-pyridone without human control during data analysis; (iv) a well plate screening of categorical reaction parameters for a novel palladium-catalyzed cyanation of aryl halides employing O-protected cyanohydrins. By publishing MOCCA as a Python package with this work, we envision an open-source community project for chromatographic data analysis with the potential of further advancing its scope and capabilities.

A Study in Scaffold Hopping: Discovery and Optimization of Thiazolopyridines as Potent Herbicides That Inhibit Acyl-ACP Thioesterase.

In the search for new chemical entities that can control resistant weeds by addressing novel modes of action (MoAs), we were interested in further exploring a compound class that contained a 1,8-naphthyridine core. By leveraging scaffold hopping methodologies, we were able to discover the new thiazolopyridine compound class that act as potent herbicidal molecules. Further biochemical investigations allowed us to identify that the thiazolopyridines inhibit acyl-acyl carrier protein (ACP) thioesterase (FAT), with this being further confirmed via an X-ray cocrystal structure. Greenhouse trials revealed that the thiazolopyridines display excellent control of grass weed species in pre-emergence application coupled with dose response windows that enable partial selectivity in certain crops.

Total Synthesis of (±)-Exotine B.

The heterodimeric indole/coumarin natural product exotine B was synthesized for the first time. The carbon skeleton of the natural product was formed rapidly by a palladium-catalyzed Suzuki cross-coupling reaction and a gallium-catalyzed three-component [4 + 3] cycloaddition reaction. An alternative biosynthesis of exotine B is proposed based on the total synthesis. Improved syntheses of coumarin natural products gleinadiene and coumurrayin are also reported.