Strategies for the Syntheses of Pactamycin and Jogyamycin

Abstract

Pactamycin and jogyamycin are aminocyclopentitol natural products, where each core carbon bears a stereodefined alcohol or amine moiety. Their structural complexity, coupled with the diversity of functional groups coexisting in a condensed space, make them fascinating synthetic targets in their own right. Pactamycin and its derivatives bind to the 30S ribosomal subunit and display activity against parasites responsible for drug‐resistant malaria and African sleeping sickness; however, efforts to develop their therapeutic potential have been hampered by their cellular toxicity. Interestingly, bioengineered analogues display differences in selectivity and toxicity towards mammalian cells, spurring efforts to develop flexible strategies to thoroughly probe structure–activity relationships (SAR), particularly in analogues lacking the C7 hydroxyl group of pactamycin. This review compares and contrasts approaches towards pactamycin and jogyamycin, including two successful total syntheses of the former. The implications of each route for preparing analogues to inform SAR and lead to compounds with increased selectivity for binding malarial over human ribosomes are briefly discussed.

Palladium-Catalyzed Regioselective Arylation of Unprotected Allylamines

“…4 They have also served as useful building blocks in complex molecule synthesis. 5 − 9 As a result, there are numerous approaches to their synthesis. 10 − 13 A powerful approach for the arylation of olefins is the Mizoroki–Heck (MH) reaction, 14 , 15 though internal olefin substrates often require directing groups to achieve reasonable regioselectivity.…”

“…Allylamines are an important class of compounds that have seen use as antifungals, antihistimines, antidepressants, and even as a treatment for male sexual dysfunction . They have also served as useful building blocks in complex molecule synthesis. − As a result, there are numerous approaches to their synthesis. − A powerful approach for the arylation of olefins is the Mizoroki–Heck (MH) reaction, , though internal olefin substrates often require directing groups to achieve reasonable regioselectivity. − In the case of allylamine substrates, protection of the amine has been required (Scheme a) to achieve these reactions, − and the reactions are limited to a single arylation except in a few circumstances (Scheme b). − We therefore decided that the direct arylation of unprotected or free cinnamylamines, and subsequently diarylation of terminal allylamines, would provide rapid access to new therapeutic targets which had previously been challenging to directly access via conventional methods. Moreover, by omitting the need for a protection and deprotection step, the transformations could be achieved with improved step and atom economy.…”

Stereo‐Controlled Synthesis of Vicinal Tertiary Carbinols: Application in the Synthesis of a Diol Substructure of Zaragozic Acid, Pactamycin and Ryanodol

“…As such, a single, stereochemically defined “common intermediate” 3 could potentially be utilized in the divergent synthesis of every stereoisomer of any targeted vicinal tertiary carbinol ( 4 , 4’ , ent ‐ 4 , and ent ‐ 4’ , Figure 1b). We envisioned this approach may offer a strategically unified entry point in our target‐oriented investigations of vicinal tertiary carbinol containing natural products, for example, in the synthesis of zaragozic acid, [8] pactamycin, [9] and ryanodol [10] (Figure 1c).…”

The chemistry and biology of natural ribomimetics and related compounds

“…31). [165][166][167] Modifications of the urea moiety of pactamycin generally led to a loss or reduction of antibacterial, cytotoxic, and antimalarial activities. 166 Replacement of the 3-aminoacetophenone moiety…”

“…31). 165–167 Modifications of the urea moiety of pactamycin generally led to a loss or reduction of antibacterial, cytotoxic, and antimalarial activities. 166 Replacement of the 3-aminoacetophenone moiety with several aniline derivatives also affects their biological activities, more prominently on cytotoxicity and antimalarial activity.…”