Substrate specific closed-loop optimization of carbohydrate protective group chemistry using Bayesian optimization and transfer learning.

A new way of performing reaction optimization within carbohydrate chemistry is presented. This is done by performing closed-loop optimization of regioselective benzoylation of unprotected glycosides using Bayesian optimization. Both 6--monobenzoylations and 3,6--dibenzoylations of three different monosaccharides are optimized.

Two-chamber hydrogen generation and application: access to pressurized deuterium gas.

Hydrogen and deuterium gas were produced and directly applied in a two-chamber system. These gaseous reagents were generated by the simple reaction of metallic zinc with HCl in water for H2 and DCl in deuterated water for D2. The setup proved efficient in classical Pd-catalyzed reductions of ketones, alkynes, alkenes, etc.

An air-tolerant approach to the carbonylative Suzuki-Miyaura coupling: applications in isotope labeling.

Carbonylative Suzuki-Miyaura coupling conditions have been developed that proceed without the exclusion of oxygen and in the presence of nondegassed and nondried solvents. By adapting the method to a two-chamber setup, the direct handling of carbon monoxide, produced from stable CO precursors, is avoided. The protocol afforded the desired benzophenones with excellent functional group tolerance and in good yields.

Identifying ligand-binding hot spots in proteins using brominated fragments.

High-quality crystals of Thermus thermophilus EF-Tu in the GTP-bound conformation at 1.7-2.7 Å resolution were used to test 18 small organic molecules, all brominated for confident identification in the anomalous difference maps.

Reductive carbonylation of aryl halides employing a two-chamber reactor: a protocol for the synthesis of aryl aldehydes including 13C- and D-isotope labeling.

A protocol has been developed for conducting the palladium-catalyzed reductive carbonylation of aryl iodides and bromides using 9-methylfluorene-9-carbonyl chloride (COgen) as a source of externally delivered carbon monoxide in a sealed two-chamber system (COware), and potassium formate as the in situ hydride source. The method is tolerant to a wide number of functional groups positioned on the aromatic ring, and it can be exploited for the isotope labeling of the aldehyde group. Hence, reductive carbonylations run with (13)COgen provide a facile access to (13)C-labeled aromatic aldehydes, whereas with DCO2K, the aldehyde is specifically labeled with deuterium.

Effective palladium-catalyzed hydroxycarbonylation of aryl halides with substoichiometric carbon monoxide.

A protocol for the Pd-catalyzed hydroxycarbonylation of aryl iodides, bromides, and chlorides has been developed using only 1-5 mol % of CO, corresponding to a p(CO) as low as 0.1 bar. Potassium formate is the only stoichiometric reagent, acting as a mildly basic nucleophile and a reservoir of CO.

Pd-catalyzed thiocarbonylation with stoichiometric carbon monoxide: scope and applications.

A general protocol for the Pd-catalyzed thiocarbonylation of aryl iodides with stoichiometric carbon monoxide has been established employing a catalytic system composed of Pd(OAc)(2) and DPEphos with low catalyst loading (1 mol %). Both electron-rich and -deficient aryl iodides proved effective for these couplings with aryl and alkyl thiols. The choice of the metal ligands and the solvent system was crucial for the efficiency and chemoselectivity of these transformations.

Palladium-catalyzed double carbonylation using near stoichiometric carbon monoxide: expedient access to substituted 13C2-labeled phenethylamines.

A novel and general approach for (13)C(2)- and (2)H-labeled phenethylamine derivatives has been developed, based on a highly convergent single-step assembly of the carbon skeleton. The efficient incorporation of two carbon-13 isotopes into phenethylamines was accomplished using a palladium-catalyzed double carbonylation of aryl iodides with near stoichiometric carbon monoxide.

Isotope-labeling of the fibril binding compound FSB via a Pd-catalyzed double alkoxycarbonylation.

We have synthesized two isotopically labeled variants of the β-amyloid binding compound FSB possessing (13)C-labels on the two terminal aryl carboxylic acid moieties. One of these was also fully deuterated on the olefinic spacers. The (13)C-isotope labeling was achieved applying a Pd-catalyzed methoxycarbonylation of the corresponding aryl chlorides with externally (ex situ) generated (13)C-labeled CO.

Silacarboxylic acids as efficient carbon monoxide releasing molecules: synthesis and application in palladium-catalyzed carbonylation reactions.

Silacarboxylic acids have been demonstrated to be easy to handle, air-stable carbon monoxide precursors. Different silacarboxylic acids were synthesized from the corresponding chlorosilanes and carbon dioxide, and their decarbonylation, upon treatment with an array of activators, was evaluated. The release of CO from crystalline MePh(2)SiCO(2)H proved to be highly efficient, and it was successfully applied in a selection of palladium-catalyzed carbonylative couplings using near-stoichiometric quantities of carbon monoxide precursor.

Palladium-catalyzed approach to primary amides using nongaseous precursors.

A simple protocol is reported for the preparation of primary aryl amides under Pd-catalyzed carbonylation chemistry applying a two-chamber system with crystalline and nontransition metal based sources of carbon monoxide and ammonia. The method is suitable for the synthesis of a number of primary amides with good functional group tolerance. Incorporation of (13)CO into the primary amide group was also found to be effective making this approach useful for accessing carbon isotope labeled derivatives.

Carbonylative Heck reactions using CO generated ex situ in a two-chamber system.

A carbonylative Heck reaction of aryl iodides and styrene derivatives employing a two-chamber system using a stable, crystalline, and nontransition metal based carbon monoxide source is reported. By applying near-stoichiometric amounts of the carbon monoxide precursor, an effective exploitation of the hazardous CO gas is obtained affording chalcone derivatives in good yields. Application to isotope labeling, incorporating (13)CO, was further established.

Ex situ generation of stoichiometric and substoichiometric 12CO and 13CO and its efficient incorporation in palladium catalyzed aminocarbonylations.

A new technique for the ex situ generation of carbon monoxide (CO) and its efficient incorporation in palladium catalyzed carbonylation reactions was achieved using a simple sealed two-chamber system. The ex situ generation of CO was derived by a palladium catalyzed decarbonylation of tertiary acid chlorides using a catalyst originating from Pd(dba)(2) and P(tBu)(3). Preliminary studies using pivaloyl chloride as the CO-precursor provided an alternative approach for the aminocarbonylation of 2-pyridyl tosylate derivatives using only 1.

Importance of C-N bond rotation in N-acyl oxazolidinones in their SmI2-promoted coupling to acrylamides.

A detailed mechanistic investigation was undertaken to determine the dominating factors of the postelectron transfer steps in the SmI(2)-promoted carbon-carbon bond forming reaction between N-acyl oxazolidinones and acrylamides. Competition experiments were performed by reacting two N-acyl oxazolidinones with a limiting amount of N-t-butyl acrylamide, and from the product distribution, the relative reactivity values (RV) for a series of N-acyl oxazolidinones were then calculated against N-pivaloyl oxazolidinone as the reference. An almost linear correlation was obtained for the simple alkyl N-acyl oxazolidinones when ln RV was plotted against the activation barriers for C-N bond rotation (s-trans to s-cis) obtained by DFT calculations, implying that C-N bond rotation from the s-trans to s-cis conformation is one of the essential parameters controlling the reactivity.

Creating carbon-carbon bonds with samarium diiodide for the synthesis of modified amino acids and peptides.

In this perspective, an overview of our experiences on the application of samarium diiodide in organic synthesis for the preparation of amino acid and peptide analogues is presented. Three different carbon-carbon bond forming reactions are discussed, including side chain introductions, gamma-amino acid synthesis and acyl-like radical additions for the construction of C-C mimics of the peptidic bonds.

Can decarbonylation of acyl radicals be overcome in radical addition reactions? En route to a solution employing N-acyl oxazolidinones and SmI2/H2O.

The application of acyl radicals in radical addition reactions in the absence of a CO atmosphere is generally limited to aryl or alpha-unsubstituted alkyl acyl radicals due to competing decarbonylations where the rate constant for this degradation process surpasses 104 s-1. In this work, a potential solution to avoid the problem of decarbonylations is presented employing N-acyl oxazolidinones which are reduced to acyl radical equivalents in the presence of samarium diiodide and water. In the company of an acrylamide, acrylate, or acrylonitrile, the product from a formal acyl radical addition is obtained in yields up to 87%.