Late-Stage 18O Labeling of Primary Sulfonamides via a Degradation-Reconstruction Pathway

A late-stage 18O labeling approach of sulfonamides that employs the corresponding unlabeled molecule as the starting material was developed. Upon deamination of the sulfonamide, a sulfinate intermediate was isotopically enriched using eco-friendly reagents H218O and 15NH3(aq) to afford a M+5 isotopologue of the parent compound. This degradation-reconstruction approach afforded isolated yields of up to 96% for the stable isotope labeled (SIL) sulfonamides, and was compatible with multiple marketed therapeutics, including celecoxib, on a gram scale. The SIL products also exhibited no 18O/16O back exchange under extreme conditions, further validating the utility of this green strategy for drug labeling for both in vitro and in vivo use. This procedure was also adapted to include pharmaceutically relevant methyl sulfones by using 13CH3, affording M+5 isotopic enrichment, thereby illustrating the broad utility of this methodology

Autoxidation Products of Betulonaldehyde

Three major degradation products resulted from the exposure of betulonaldehyde (<b>1</b>) to air in solution at room temperature. From HRMS and NMR data, the products, which were isolated by preparative supercritical fluid chromatography (SFC), were identified as betulonic acid (<b>2</b>) and C-17 hydroperoxide epimers <b>3</b> (β-OOH) and <b>4</b> (α-OOH). For <b>3</b> and <b>4</b>, the H-18 multiplet pattern of the isolated products established the configuration at C-17

Development of a Safe and High-Throughput Continuous Manufacturing Approach to 4‑(2-Hydroxy­ethyl)­thiomorpholine 1,1-Dioxide

Continuous processing enabled the highly energetic double conjugate addition of ethanolamine to divinylsulfone to prepare 2 kg of 4-(2-hydroxy­ethyl)­thio­morpholine 1,1-dioxide, as an intermediate in the synthesis of HIV Maturation Inhibitor BMS-955176. In situ IR was employed to monitor the steady state of the transformation for increased robustness via appearance of the thiomorpholine dioxide moiety and disappearance of the divinylsulfone. Surprisingly, a series of oligomers formed as intermediates, which converted to product with extended aging or heating, consistent with computational predictions. By running this process in flow, the highly exothermic reaction could be safely executed in an equal volume of water as the only solvent, despite an adiabatic temperature rise of 142 °C, leading to a streamlined and efficient process

Revisiting a Classic Transformation: A Lossen Rearrangement Initiated by Nitriles and “Pseudo-Catalytic” in Isocyanate

The direct conversion of a hydroxamic acid to an amine has been accomplished in a single step in the synthesis of HIV drug candidate BMS-955176. This process utilizes catalytic base and proceeds under mild conditions (CH₃CN, cat. DBU, 60 °C), without the need for strong electrophiles required for typical Lossen rearrangements, and can be applied to aliphatic and aromatic hydroxamic acids. Through investigation of the kinetics of this transformation, a mechanism was revealed involving a novel initiation pathway and a self-propagation cycle. The initiation pathway involves activation of hydroxamic acid by nitriles and subsequent Lossen rearrangement to generate the corresponding isocyanate. The isocyanate functions as a “pseudo-catalyst” for this system, leading to generation of product through a second Lossen rearrangement and regeneration of a new isocyanate molecule. Thorough mechanistic understanding allowed for this highly efficient process to be implemented on a 55 kg scale in 95.5% isolated yield

Unlocking the Potential of High-Throughput Experimentation for Electrochemistry with a Standardized Microscale Reactor

Organic electrochemistry has emerged as an enabling and sustainable technology in modern organic synthesis. Despite the recent renaissance of electrosynthesis, the broad adoption of electrochemistry in the synthetic community and, especially in industrial settings, has been hindered by the dearth of general, standardized platforms for high-throughput experimentation (HTE). Herein, we disclose the design of the HTe-Chem, a high-throughput microscale electrochemical reactor that is compatible with existing HTE infrastructure, and enables rapid evaluation of a broad array of electrochemical reaction parameters. Utilizing the HTe-Chem to accelerate reaction optimization, reaction discovery, and chemical library synthesis is illustrated using a suite of oxidative and reductive transformations under constant current, constant voltage, and electrophotochemical conditions

Unusual Pyrimidine Participation: Efficient Stereoselective Synthesis of Potent Dual Orexin Receptor Antagonist MK-6096

An asymmetric synthesis of dual orexin receptor antagonist MK-6096 (<b>1</b>) is described. Key steps for the <i>trans</i>-2,5-disubstituted piperidinyl ether fragment include a biocatalytic transamination, a <i>trans</i>-selective Mukaiyama aldol, and a regioselective pyridyl S_NAr process. The pyrimidyl benzoic acid was synthesized via a Negishi coupling and a nitrile hydrolysis. Coupling of the two fragments via a catalytic T3P-mediated amidation completed the synthesis. Unusual behaviors in the hydrolysis of pyrimidyl benzonitrile and the amide coupling of the pyrimidyl benzoic acid are also described

Regioselective Bromination of Fused Heterocyclic <i>N</i>‑Oxides

A mild method for the regioselective C2-bromination of fused azine <i>N</i>-oxides is presented, employing tosic anhydride as the activator and tetra-<i>n</i>-butylammonium bromide as the nucleophilic bromide source. The C2-brominated compounds are produced in moderate to excellent yields and with excellent regioselectivity in most cases. The potential extension of this method to other halogens, effecting C2-chlorination with Ts₂O/TBACl is also presented. Finally, this method could be incorporated into a viable one-pot oxidation/bromination process, using methyltrioxorhenium/urea hydropgen peroxide as the oxidant

A Mild, Functional Group Tolerant Addition of Organozinc Nucleophiles to <i>N</i>‑Activated Quinolines and Isoquinolines

An addition of organozinc nucleophiles to <i>N</i>-acyl activated quinolines and isoquinolines is described. Simple transmetalation with the corresponding Grignard reagents using ZnCl₂ forms organozinc compounds which are functional group tolerant and stable to reactive acyl chloride reagents for extended periods. A wide variety of substrates which include reactive electron-withdrawing groups are well tolerated to form 2-substituted dihydroquinolines and dihydroisoquinolines. This methodology has been applied toward an improved synthetic route of uncialamycin and its analogs