A Concise Total Synthesis of (−)-Quinocarcin via Aryne Annulation

Abstract

Described in this report is a rapid asymmetric total synthesis of the tetrahydroisoquinoline antitumor antibiotic (−)-quinocarcin. The sequence employs a mild fluoride-induced aryne annulation developed in our laboratories to build a key isoquinoline-containing intermediate comprising the entire carbon scaffold of the natural product. This intermediate is advanced through six additional steps to the target alkaloid, providing the shortest synthetic route to (−)-quinocarcin reported to date.

Arine und Cyclohexin in der Naturstoffsynthese

“…[22] Die Synthese startete mit der stereoselektiven Herstellung von 28 in einer [1,3]-dipolaren Cycloaddition des Oxidopyraziniumsalzes 26 mit dem Acrylamid des Oppolzer-Sultams (27,Schema 4). Dieses einfach auszuführende Protokoll (TBAT, THF, RT) ermçglicht schnellen Zugang zu 1,2-and 1,2,3-substituierten Indolinen.…”

“…Dabei handelt es sich um die derzeit kürzeste Synthese dieses Alkaloids. [22] Die Synthese startete mit der stereoselektiven Herstellung von 28 in einer [1,3]…”

Syntheses of 4‐Substituted 2‐(Trichloromethyl)quinazolines under Mild Conditions by Benzyne [4+2] Cycloaddition

“…The classical synthetic approach to aromatic trichloromethylated heterocycles involves methyl group chlorination usually by using the highly corrosive PCl 5 /PCl 3 mixture. It is important to note that the use of benzyne in Diels-Alder-type cycloadditions has recently also been successfully applied in natural product syntheses, [27][28][29] and the [3+2] cycloaddition of benzyne has been used to generate benzotriazoles, [30] indazoles, [31] and dihydrobenzisoxazoles. [20] This compound has then been used as a source of various 4-substituted 2-(trichloromethyl)quinazolines, such as the 4-alkylamino, 4arylamino, 4-phenoxy, and 4-sulfonamido derivatives, [13,21] as well as 4-substituted compounds produced through a Suzuki-Miyaura cross-coupling process.…”

Solvent-free microwave-assisted synthesis of tetrahydrooxazolo[3,2-a]pyrazolo[1,5-d]pyrazin-5-ones

“…3 Among the heterocycles, the piperazine ring is a structural motif found in numerous pharmaceutically active natural products, such as tetrazomine and quinocarcin ( Figure 1), and in many polycyclic compounds of biological and industrial significance. [4][5][6][7] On the other hand, pyrazoles have occupied a unique position in the design and synthesis of novel biologically active agents and still continue to attract considerable attention due to their broad range of biological activities. Among them, pyrazole fused heterocycles are an interesting class of compounds with wide range of biological activities such as analgesic, anticancer, antibacterial, antifungal, radioprotective, antiproliferative and antimalarial.…”