Diastereocontrolled Construction of Pactamycin’s Complex Ureido Triol Functional Array

Abstract

An advanced intermediate in a projected synthesis of pactamycin has been prepared. Early installation of the C1-dimethylurea functionality allows for its participation in a diastereoselective, chelation-controlled addition of organometal nucleophiles to the C5 prochiral ketone. Four of the molecule’s six stereocenters are set with a ketone functional handle provided for subsequent manipulation.

Asymmetric Synthesis of the Aminocyclitol Pactamycin, A Universal Translocation Inhibitor

“…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. The Hanessian group observed of numerous side reactions due to functional group propinquity.…”

“…In the development of a synthesis plan, we took note of these issues and sought to develop a synthesis of 1 that rapidly assembled the core structure and incorporated all unique functionality in the absence of non-strategic redox and protecting group manipulations. 16 In 2012, we presented an initial report on our efforts toward a synthesis of 1, 15 and earlier this year this work culminated in a 15-step asymmetric total synthesis. 17 Herein, we present a full account of our studies on pactamycin encompassing a modification of our original route to accommodate early-stage incorporation of the C2 amine functionality.…”

“…15 Ester 11, prepared via the strategy outlined in Scheme 1, was treated with Me 3 SiCH 2 Li to afford β-silyloxyketone 12 poised for nucleophilic addition. From 12, a screen of nucleophiles and conditions were investigated for access to the requisite C5 alcohol; however, while addition of a model 2-propenylmetal nucleophile mediated by CeCl 3 proceeded in good yield, this reaction gave consistent preference for the undesired epimeric C5 configuration (13).…”

Asymmetric Synthesis of the Aminocyclitol Pactamycin, a Universal Translocation Inhibitor

“…In 2012, we presented an initial report on our efforts toward a synthesis of 1 , 15 and earlier this year this work culminated in a 15-step asymmetric total synthesis. 17 Herein, we present a full account of our studies on pactamycin encompassing a modification of our original route to accommodate early-stage incorporation of the C2 amine functionality.…”

“…15 Ester 11 , prepared via the strategy outlined in Scheme 1, was treated with Me 3 SiCH 2 Li to afford β-silyloxyketone 12 poised for nucleophilic addition. From 12 , a screen of nucleophiles and conditions were investigated for access to the requisite C5 alcohol; however, while addition of a model 2-propenylmetal nucleophile mediated by CeCl 3 proceeded in good yield, this reaction gave consistent preference for the undesired epimeric C5 configuration ( 13 ).…”