Contributors: Krishna, Jonnada, Gopi Krishna Reddy, Alavala, Satyanarayana, Gedu
... Abstract A domino Pd-catalyzed reaction of 1-(2-bromophenyl)ethanones for the synthesis of novel 7-methyl-5H-dibenzo[a,c]annulen-5-ones, a carbon core structure present in colchicinoid natural products, is presented. The reaction is proposed to proceed via intermolecular homobiaryl coupling and intramolecular aldol condensation.
Contributors: Khan, Abu, Lal, Mohan, Sidick Basha, R.
... Abstract A wide variety of fused trans-2,3-dihydrofuran derivatives were synthesized through a one-pot three-component reaction of an aromatic aldehyde, a cyclic β-diketo compound, and an in situ-generated pyridinium ylide in refluxing. The pyridinium ylide was formed from either 2-bromo-1-phenylethanone or 4-nitrobenzyl bromide and pyridine in the presence of 10 mol% of sodium hydroxide. Pyridine plays crucial role in forming the pyridinium salt, which, in turn, forms a nitrogen ylide in the presence of sodium hydroxide. The ylide assists a Michael-initiated ring-closure reaction, but is not itself incorporated in the final product. The protocol is environmentally acceptable because no organic solvent is involved at any stage. Furthermore, the method is highly diastereoselective, gives good yields, and does not involve extensive workup procedures or chromatographic separations, as the desired products can be isolated by filtration and drying.
A Practical, Ligand-Free, Palladium-Catalyzed Isocyanide Insertion Reaction for the Construction of Novel Ring-Fused Quinazolinones
Contributors: Ji, Fei, Lv, Mei-fang, Yi, Wen-bin, Cai, Chun
... Abstract A high-yielding, ligand-free, palladium-catalyzed isocyanide insertion reaction for the synthesis of phthalazino[1,2-b]quinazolinones from the readily obtainable quinazolinones has been developed. Easily handled and relatively low-cost palladium(II) acetate was used as the catalyst, without an additional ligand. Preparation of the quinazolinones involved the cascade reaction of isatoic anhydrides, phenylhydrazines and 2-bromobenzaldehyde catalyzed by p-toluenesulfonic acid in one pot. This novel protocol may be applicable for the synthesis of other important ring-fused heterocyclic compounds.
Process Development of Halaven®: Synthesis of the C14–C35 Fragment via Iterative Nozaki–Hiyama–Kishi Reaction–Williamson Ether Cyclization
Contributors: Austad, Brian, Benayoud, Farid, Calkins, Trevor, Campagna, Silvio, Chase, Charles, Choi, Hyeong-wook, Christ, William, Costanzo, Robert, Cutter, James, Endo, Atsushi
... Abstract Multikilogram manufacturing process of the Halaven® C14–C35 fragment is described. The synthesis features convergent assembly of subunits by iterative asymmetric Ni/Cr-mediated coupling executed in fixed equipment.
Contributors: Wang, Man-Gang, Yu, Hua, Wu, Jun, Shang, Zhi-Cai
... Abstract The copper-catalyzed C–N cross-coupling of poorly nucleophilic acyclic secondary amides with sterically hindered substituted 2-halobenzoates has been demonstrated with 1,4-dimethyl-3,4-dihydro-1H-benzo[e][1,4]diazepin-5(2H)-one (DMBDO) as ligands for the first time. The protocol is effective for the synthesis of hindered tertiary amides. We also found that the alkoxycarbonyl (CO2R) group has a strong ortho-substituent effect on a Goldberg-type C–N coupling reaction.
Highly Regioselective Allylic Substitution Reactions Catalyzed by an Air-Stable (π-Allyl)iridium Complex Derived from Dinaphthocyclooctatetraene and a Phosphoramidite Ligand
Contributors: Ye, Ke-Yin, Zhao, Zhuo-An, Lai, Zeng-Wei, Dai, Li-Xin, You, Shu-Li
... Abstract An air-stable (π-allyl)iridium complex derived from dinaphthocyclooctatetraene and a phosphoramidite ligand has been synthesized and found to be highly efficient in iridium-catalyzed allylic substitution reactions. This catalyst features excellent regioselectivity and high stability. When NaCH(CO2Me)2 was used as the nucleophile, the catalyst loading in allylic alkylation reactions can be as low as 0.01 mol%.
Commercial Manufacture of Halaven®: Chemoselective Transformations En Route to Structurally Complex Macrocyclic Ketones
Contributors: Austad, Brian, Calkins, Trevor, Chase, Charles, Fang, Francis, Horstmann, Thomas, Hu, Yongbo, Lewis, Bryan, Niu, Xiang, Noland, Thomas, Orr, John
... Abstract The evolution of the synthesis of Halaven® (E7389, INN eribulin mesylate) from a medicinal chemistry process to the execution of the final process on pilot scale is described. The completion of the synthesis of Halaven® from C1–C13 ester and C14–C35 sulfone alcohol involves a series of chemo-, regio-, and stereoselective transformations. Furthermore, a high-dilution macrocyclization presented a number of challenges for industrial-scale manufacture (throughput, processing time, and side reactions). This paper describes studies at Eisai leading to an understanding, optimization, and control of the chemistry that realized the reproducible commercial production of Halaven®.
Contributors: Grove, Charles I., Fettinger, James C., Shaw, Jared T.
... Abstract Viriditoxin is a secondary metabolite isolated from Aspergillus viridinutans that has been shown to inhibit FtsZ, the bacterial homologue of eukaryotic tubulin. A streamlined, scalable, and highly diastereoselective synthesis of this complex natural product is described. Key advances include a more efficient synthesis of the requisite unsaturated pyranone, scalable assembly of the naphthopyranone monomer, and improved diastereoselectivity in the biaryl-coupling reaction. In addition, we disclose a serendipitous ruthenium-catalyzed anion dimerization resulting from trace metal left by an RCM reaction.
Contributors: Cooksey, John, Kocieński, Philip, Schmidt, Arndt, Snaddon, Thomas, Kilner, Colin
... Abstract The synthesis of the pseudopterosin A–F aglycone from 3-methylcatechol features (a) the use of asymmetric Ireland–Claisen and aryl Claisen rearrangements to install three of the four stereocentres present in the molecule and (b) an A→AB→ABC annulation strategy using ring-closing metathesis and cationic cyclisation reactions as the key steps.
Formal [4+1] Annulation of Cyclopropyl Amides and Water Mediated by Lewis Acid: A Novel Entry to γ-Butyrolactones
Contributors: Zhang, Dingyuan, Zhang, Rui, Liang, Yongjiu, Dong, Dewen
... Abstract An efficient one-pot synthesis of substituted γ-butyrolactones from cyclopropyl amides mediated by the Lewis acid SnCl4·5H2O is reported. A mechanism involving a tandem ring-opening reaction and intramolecular cyclization reaction is proposed.