Catalytic asymmetric syntheses of remote quaternary stereocenters have been developed by copper-catalyzed 1,4-hydrosilylation of γ,γ-disubstituted cyclohexadienones. A variety of cyclohexenones have ...been synthesized in good yield and excellent enantioselectivity. Versatile 2-silyloxy diene intermediates bearing γ,γ-disubstituted all carbon stereogenic centers can be isolated from the mild reaction conditions. The utility of this strategy is exemplified in a catalytic asymmetric total synthesis of (+)-mesembrine.
A Cu-catalyzed synthesis of amides from alcohols and secondary amines using the oxygen in air as the terminal oxidant has been developed. The methodology is operationally simple requiring no high ...pressure equipment or handling of pure oxygen. The commercially available, nonprecious metal catalyst, Cu(phen)Cl2, in conjunction with di-tert-butyl hydrazine dicarboxylate and an inorganic base provides a variety of benzamides in moderate to excellent yields. The pK a of amine conjugate acid and electronics of alcohol were shown to impact the selection of base for optimal reactivity. A mechanism consistent with the observed reactivity trends, KIE, and Hammett study is proposed.
Oxidopyrylium-alkene 5 + 2 cycloaddition conjugate addition cascade (C3) sequences are described. Intramolecular cycloadditions involving terminal alkenes, enals, and enones were investigated. ...Substrates with tethers of varying lengths delivered five- and six-membered carbocycles and heterocycles thus demonstrating the scope and limitation of the cycloaddition–conjugate addition cascade. Several experiments and theoretical calculations provide evidence for the proposed mechanistic pathway.
Unique reactivity of anti- and syn-acetoxypyranones was observed in oxidopyrylium-alkene 5 + 2 cycloadditions. The subtle interplay between the corresponding acetoxypyranone conformation and steric ...bulk of tertiary amine bases causes syn-acetoxypyranones to undergo 5 + 2 cycloaddition appreciably faster than anti-acetoxypyranones. Additionally, the efficiency of a cascade process that afforded a novel tetracyclic lactol was determined to be dependent on the relative stereochemistry of each diastereomer, the amine base utilized, and the addition of water.
A scalable process to produce glucocorticoid-bearing drug-linker 1, utilized in the conjugation with the monoclonal antibody (mAb) adalimumab, has been developed. The route improves upon the ...first-generation approach through a more convergent assembly of the linker and warhead. Optimization and insights into the key transformations are discussed, including a challenging acetonide deprotection, acetal formation under strongly acidic conditions, and amide coupling and purification.
Pyrrolobenzodiazepine (PBD) dimers, such as that found in SG3259, are fully synthetic highly potent (subnanomolar) small molecules currently being developed as warheads for antibody–drug conjugates ...(ADCs). The complete synthetic route toward the linker drug SG3259 has 17 steps, and 10–20 g of drug was needed prior to antibody conjugation for IND-enabling toxicological studies and Phase I clinical trials. Herein, we disclose the enabling route to SG3259, with the final four steps being conducted under GMP conditions. Significant effort was spent developing the preparatory scale reverse-phase HPLC purification of the final linker drug. SG3259 suffers from poor solubility; acid-, light-, and oxygen-sensitivity; and extremely high potency, factors which make this a challenging target for gram-scale development.
Foslevodopa (FLD, levodopa 4′-monophosphate, 3) and foscarbidopa (FCD, carbidopa 4′-monophosphate, 4) were identified as water-soluble prodrugs of levodopa (LD, 1) and carbidopa (CD, 2), ...respectively, which are useful for the treatment of Parkinson’s disease. Herein, we describe asymmetric syntheses of FLD (3) and FCD (4) drug substances and their manufacture at pilot scale. The synthesis of FLD (3) employs a Horner–Wadsworth–Emmons olefination reaction followed by enantioselective hydrogenation of the double bond as key steps to introduce the α-amino acid moiety with the desired stereochemistry. The synthesis of FCD (4) features a Mizoroki–Heck reaction followed by enantioselective hydrazination to install the quaternary chiral center bearing a hydrazine moiety.
