Stereocontrolled Synthesis of the Aminocyclopentitol Core of Jogyamycin via an Ichikawa Rearrangement Reaction

Abstract

Jogyamycin is a member of the aminocyclopentitol class of natural products that exhibits significant antiprotozoal activities against diseases that include African sleeping sickness and malaria. Herein, we report a route to the core of this natural product via an underutilized Ichikawa rearrangement as a key step. This route efficiently forms the cyclopentane ring from simple and easily accessible starting materials, and rapidly installs the C1/C4/C5 polar functional groups. In addition, this strategy shows excellent potential for the preparation of analogues of jogyamycin to study how structural changes impact the selectivity in binding to the ribosome.

Progress Towards the Total Synthesis of Jogyamycin Using a Tandem Ichikawa/Winstein Rearrangement

“…The Schomaker group reported a sequential Ichikawa/ Overman rearrangement strategy towards 2 in 2019; while the Ichikawa rearrangement was successful in furnishing 8 (Scheme 1) after deprotection of the C4 alcohol, the allylic trichloroacetimidate precursor for the Overman rearrangement could not be successfully prepared. 16 Instead, the oxazoline 9 was observed as the major product; this is hypothesized to arise via reaction of the urea oxygen with trichloroacetonitrile, followed by attack of the C4 oxygen across the ring to displace trichloroacetamide. Attempts to initiate a second Ichikawa rearrangement from the carbamate of 8 resulted in an SN2' attack of the urea oxygen at C2 to give 10.…”

Strategies for the Syntheses of Pactamycin and Jogyamycin

“…To address concerns in their first‐generation approach, especially in forming the C2 amine, Schomaker envisaged a sequential Ichikawa/Overman rearrangement strategy reported in 2019 (Scheme 13 A). [21] The C2 amine is generated from Overman rearrangement of 13.15 , itself formed from Ichikawa rearrangement of carbamate 13.10 . The viability of this disconnection was strengthened by the potential to form the C2 amine via a second Ichikawa rearrangement, alleviating some risk if the Overman rearrangement were to fail.…”

Strategien für die Synthese von Pactamycin und Jogyamycin

“…eine sequenzielle Ichikawa/Overman‐Umlagerungsstrategie, die 2019 beschrieben wurde (Schema 13 A). [21] In der Retrosynthese wird das C2‐Amin durch Overman‐Umlagerung von 13.15 erzeugt, das wiederum durch Ichikawa‐Umlagerung von Carbamat 13.10 gebildet wird. Die Durchführbarkeit dieser Zerlegung wurde durch die Möglichkeit zur Bildung des C2‐Amins über eine zweite Ichikawa‐Umlagerung gestützt, was bei einem Scheitern der Overman‐Umlagerung weniger problematisch wäre.…”