The bis-pyridinylidene 13 converts aliphatic and aryl triflate esters to the corresponding alcohols and phenols respectively, using DMF as solvent, generally in excellent yields. While the deprotection of aryl triflates has been seen with other reagents and by more than one mechanism, the deprotection of alkyl triflates is a new reaction. Studies with (18)O labelled DMF indicate that the C-O bond stays intact and hence it is the S-O bond that cleaves, underlining that the cleavage results from the extraordinary electron donor capability of 13. Trifluoromethanesulfonamides are converted to the parent amines in like manner, representing the first cleavage of such substrates by a ground-state organic reducing reagent.
The alkynylpyrrolidine 4 was made via a dearomatising cyclisation of an aromatic amide, and was elaborated by stannylcupration and palladium-catalysed coupling to achieve the first total synthesis of three members of the isodomoic acid family; the same alkyne can be envisaged as a precursor to several more of this class of amnesic shellfish toxins.
We here present an optimized, scalable synthesis of bromodomain and extra-terminal (BET) inhibitor BMS-986378 (CC-90010). The original route and process 1A was 7 steps with 33.8% yield and featured numerous problematic solvents, process safety concerns, difficult to scale unit operations, and challenging to control impurities. Reaction optimization to remove or mitigate these challenges resulted in our first scale-up route and process, 2A. Subsequent challenges encountered on scale-up of route and process 2A warranted the creation and implementation of an enhanced process, which eliminated dichloromethane from a phenol bromination, improved catalyst performance in the penultimate cross-coupling, and finally developed a concomitant solvent charging process for form control in the final API crystallization. The resulting scale-up route and process, 2B, was demonstrated on a >50 kg scale and afforded the final product in 49% yield over 7 steps in >99.9% assay and area purity, meeting all ICH requirements for quality.
A General Synthetic Approach to the Amnesic Shellfish Toxins: Total Synthesis of (-)-Isodomoic Acid B (I), (-)-Isodomoic Acid E (II) and (-)-Isodomoic Acid F (III). -(LEMIERE, G.; SEDEHIZADEH, S.; TOUEG, J.; FLEARY-ROBERTS, N.; CLAYDEN*, J.; Chem. Commun. (Cambridge) 47 (2011) 13, 3745-3747, http://dx.doi.org/10.1039/c1cc00048a ; Sch. Chem., Univ. Manchester, Manchester M13 9PL, UK; Eng.) -R. Staver 30-203
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