A Second Generation Synthesis of Roseophilin and Chromophore Analogues

Abstract

A concise, flexible, and high-yielding synthesis of the macrocyclic compound 4 is outlined which served as a key intermediate in a previous total synthesis of the antitumor active alkaloid roseophilin 1. The key steps of this approach consist of a Pd(0)-catalyzed reaction of vinyloxirane 6 with sulfone 7 and in a subsequent ring closing metathesis (RCM) reaction for the formation of the 13-membered ring catalyzed by the ruthenium carbene Cl₂(PCy₃)₂Ru=CHCH=CPh₂ introduced by Grubbs. Moreover, nitrile ylide cycloaddition reactions are used for the preparation of roseophilin side chain mimics. Finally, the synthesis of various chromophore analogues of 1 is reported, including deschloro-desmethoxyroseophilin 12 which is the most elaborate derivative of this complex target reported so far

Palladiumkatalysierte Kreuzkupplungen in der Totalsynthese

“…Tsuji-Trost-Reaktionen in der Totalsynthese von Roseophilin (269) (Fürstner und Weintritt, 1998). [221] C-C-Kupplungen…”

Palladium‐Catalyzed Cross‐Coupling Reactions in Total Synthesis

“…An elegant example of the scope of this process is the total synthesis of the architecturally unique alkaloid roseophilin (269, Scheme 49) by Fürstner and Weintritt. [221,222] The central synthetic challenges confronting these researchers were the formation of both the azafulvene-type chromophore and the rather strained ansa 12-membered carbocyclic ring; the Tsuji-Trost reaction proved to be instrumental in addressing both these issues. Thus the initial formation of the macrocyclic ring was effected by the addition of a dilute solution of allylic epoxide 263 to catalytic amounts of [Pd(PPh 3 ) 4 ] and dppe in refluxing THF to generate compound 266 in an impressive 85 % yield (Scheme 49).…”

“…Sequential use of Tsuji-Trost reactions in the total synthesis of roseophilin (269) (Fürstner and Weintritt, 1998). [221] CÀC Coupling…”

Chemie und Biologie des Roseophilins und der Prodigiosin‐Alkaloide: 2500 Jahre im Überblick

“…Formale Totalsynthese von rac-Roseophilin nach Fuchs et al [73] [75] Während die genannten Beispiele dafür sprechen, dass es zur Bildung gespannter Produkte durch RCM eines günstigen konformativen Zuschnitts des jeweiligen Substrats bedarf, zeigt ein komplementärer Ansatz unserer Arbeitsgruppe, wie sich relativ spannungsfreie Makrocylen auch ohne diese Vorkehrungen mit guten Ausbeuten herstellen lassen (Schema 23). [74] Hierbei wurde zunächst das bekannte Sulfoniumsalz 49 in zwei Stufen in die Metathesevorstufe 124 überführt, die in Gegenwart katalytischer Mengen an [Ru] [83] problemlos cyclisierte. Dieses Ergebnis verweist zudem auf die hervorragende Toleranz des Grubbs-Carbenkomplexes gegen funktionelle Gruppen.…”