Total Synthesis of Thiostrepton, Part 2: Construction of the Quinaldic Acid Macrocycle and Final Stages of the Synthesis

Abstract

In the preceding Communication in this issue [1] we described the construction of the thiazoline-containing macrocycle 2 as an advanced intermediate toward the total synthesis of thiostrepton (1). Herein we report the construction of suitable dipeptide (8, Scheme 1) and quinaldic acid (22, Scheme 2) fragments, their union with 2, and the final stages of the total synthesis of 1.Scheme 1 outlines the synthesis of the required dipeptide derivative 8 from 3, a known phenylseleno-substituted derivative of alanine.[2] Thus, 3 was converted into allyl ester 4, which was treated with TFA to effect its conversion into the amino derivative 5. Coupling of amine 5 with Boc-l-alanine

Engineering von Thiopeptiden: ein multidisziplinärer Weg zu neuen Wirkstoffen

“…[25] Bahnbrechende Arbeiten der Gruppe um Nicolaou führ-ten zur ersten Totalsynthese von Thiostrepton. [4,5] [31] unter Bildung von Aminen (6) [32] und Thioethern (7). [33] Erstere lassen sich in Harnstoffderivate (8) und Amide [34] überführen, letztere kçnnen unter milden Bedingungen in die entsprechenden Sulfone (9) umgewandelt werden.…”

Biomimetic Synthesis of Azole‐ and Aryl‐Peptide Alkaloids

“…Two total syntheses of thiostrepton and the very similar siomycin have been published, the former by the Nicolaou group [37][38][39][40] and the latter by Nakata et al [41,42]. Figure 9.6 summarizes the key disconnections.…”

How Thiostrepton Was Made in the Laboratory

“…Here is how this “odyssey” was planned and traveled, not without frustration, to its final destination, with much learning, satisfaction, and joy. [14,15] …”