Abstract

Abstract

The facile synthesis of linear and cyclic chiral oligo(4-α/β-methyl)thiazolines is described. Linear oligothiazolines have been efficiently synthesized by the iterative formation of thiazoline rings and two-directional block condensation. The construction of 24- to 36-membered cyclic oligothiazolines was achieved through the head-to-tail cyclo-oligomerization of doubly deprotected linear fragments. Studies of the interactions of both the linear and cyclic oligomers with chiral compounds revealed that cyclic oligomers displayed a strong binding affinity towards mandelic acid, whereas linear oligomers showed a poor affinity. Linear oligomers have been proven to inhibit the cell growth of the cancer cell lines HPAC, PC-3, and HCT-116. Studies of the structure–activity relationships showed that the IC₅₀ values are clearly dependent on both the length and the terminal functionalities of the linear oligomers. Longer derivatives showed more potent activity (e.g., hexi- and octithiazolines exhibit IC₅₀<1 μM) against all three cancer cell lines. In sharp contrast, cyclic oligomers were inactive to all three cell lines.

Keep it simple: Still in hot demand, the influenza drug (−)-oseltamivir phosphate (tamiflu; see scheme) has now been synthesized from pyridine by using inexpensive reagents. A strict minimum of purification steps are required in a synthetic route which features an asymmetric Diels–Alder reaction, a bromolactonization, a Hofmann rearrangement, and a domino transformation of a bicyclo[2.2.2] system into an aziridine intermediate.

So einfach wie möglich: Das immer noch stark nachgefragte Grippemedikament (−)-Oseltamivir-Phosphat (Tamiflu; siehe Schema) wurde ausgehend von Pyridin mithilfe billiger Reagentien synthetisiert, wobei die Zahl an Reinigungsschritten konsequent gering gehalten wurde. Die Syntheseroute umfasst eine asymmetrische Diels-Alder-Reaktion, eine Bromlactonisierung, eine Hofmann-Umlagerung und eine Dominoreaktion eines Bicyclo[2.2.2]-Systems in ein Aziridinintermediat.

Intramolecular hydroxylamination of ω-formyl nitrobenzene 1 followed by stereoselective hydroxymethylation led to the formation of N-hydroxybenzazocine 2, a key intermediate in the enantioselective total synthesis of the antitumor antibiotic FR900482 (3).

Eine intramolekulare Hydroxylaminierung des ω-Formylnitrobenzols 1 und anschließende stereoselektive Hydroxymethylierung führten zum N-Hydroxybenzazocin 2, einem Schlüsselintermediat der enantioselektiven Totalsynthese des antitumorwirksamen Antibiotikums FR900482 (3).

Development of indole synthesis by tin-mediated radical cyclization of o-alkenylphenyl isocyanide is described. Upon heating o-alkenylphenyl isocyanide in the presence of tri-n-butyltin hydride and AIBN, 2-stannyl-3-substituted indole was formed via 5-exo-trig cyclization of the imidoyl radical intermediate. After acidic workup, 3-substituted indoles were isolated. For substrates bearing simple alkyl groups, a substantial amount of tetrahydroquinoline derivatives were generated through 6-endo-trig cyclization. This undesired cyclization was suppressed by using an excess amount (five equivalents based on o-alkenylphenyl isocyanide) of ethanethiol instead of tri-n-butyltin hydride. The 2-stannylindole intermediates proved to be a suitable substrate for Stille coupling, giving 2,3-disubstituted indoles in a one-pot procedure. In addition, the 2-stannylindole intermediates could be converted to 2-iodoindoles by treatment with iodine or N-iodosuccinimide. The 2-iodoindoles thus obtained served as good substrates for Heck reactions, Stille couplings, Suzuki couplings, and palladium-mediated carbonylations, to afford a variety of 2,3-disubstituted indoles. The utility of this protocol was demonstrated by application to synthetic studies on gelsemine and discorhabdin A, and the total synthesis of an aspidosperma alkaloid, (–)-vindoline. © 2002 The Japan Chemical Journal Forum and John Wiley & Sons, Inc. Chem Rec 2: 37–45, 2002