Total Synthesis of Pactamycin and Pactamycate: A Detailed Account

Abstract

This article describes synthetic studies that culminated in the first total synthesis of pactamycin and pactamycate and, in parallel, the two known congeners, de-6-MSA-pactamycin and de-6-MSA-pactamycate, lacking the 6-methylsalicylyl moiety. Starting with L-threonine as a chiron, a series of stereocontrolled condensations led to a key cyclopentenone harboring a spirocyclic oxazoline. A series of systematic functionalizations led initially to the incorrect cyclopentanone epoxide, which was "inverted" under solvolytic conditions. Installation of the remaining groups and manipulation of the oxazoline eventually led to pactamycin, pactamycate, and their desalicylyl analogues.

Total synthesis and structure–activity relationship studies of a series of selective G protein inhibitors

“…2). Starting from either the commercially available or synthesized fragments D-Pla, Thr/β-HyLeu, N,O -Me 2 Thr 27 or β-HyLeu, and using standard coupling conditions and fine-tuning of protecting groups 28,29 , we obtained ester building blocks 10a–10c and 8a and 8b (Supplementary Fig. 2).…”

Asymmetric Synthesis of the Aminocyclitol Pactamycin, a Universal Translocation Inhibitor

“…9,10 A five-step sequence from 48 provided the correct epoxide stereochemistry for synthesis completion. Greaney and coworkers likewise observed this facial preference in the addition of an alkyllithium nucleophile to ketone 49 in their syntheses of merrilactone A and anislactone A.…”

“…The Hanessian group observed of numerous side reactions due to functional group propinquity. 9,10 Looper and Haussener also noted the importance of the order in which functional group manipulations were executed. 13 Approaches to introducing the unique C1 dimethylurea have heretofore relied largely upon the use of oxazoline or oxazolidinone protecting groups, necessitating downstream deprotection and chemoselective acylation.…”

Asymmetric Synthesis of the Aminocyclitol Pactamycin, A Universal Translocation Inhibitor

“…A similar approach had been employed by Hanessian and coworkers for introduction of the C3/C4 transanilinoalcohol whereupon the requisite aniline was incorporated via its m-propenyl derivative. 9,10 The necessary acetophenone was later revealed via oxidative cleavage of the olefin. By contrast, we hoped that the required aniline could be installed in its native form, obviating downstream introduction of the ketone.…”

“…These issues have been addressed in a number of approaches as synthetic interest in pactamcyin has flourished over the past decade. Hanessian and coworkers reported the landmark total synthesis in 2011, 9,10 and Isobe, Knapp, Looper, Nishikawa, and our group have disclosed access to advanced core intermediates by varying methods. [11][12][13][14][15] An inspection of these approaches reveals two common challenges one faces in assembling the core structure: i) execution of chemo-and stereoselective reactions in a highly congested chemical environment and ii) the method by which the unusual functionality of 1 is introduced.…”