Scalable De Novo Synthesis of Aldgarose and Total Synthesis of Aldgamycin N

Abstract

Since the accompanying study had shown that the introduction of the eponymous aldgarose sugar to the C5-OH group of the macrocyclic aglycone of aldgamycin Ni sm ost difficult, if not even impossible,the synthesis route was revised and the glycosidation performed at an earlier stage.T omitigate the "cost" of this strategic amendment, apractical and scalable de novo synthesis of this branched octose was developed. The glycoside formation required mild conditions;i tc ommenced with the reaction of the aglycone with the trichloroacetimidate donor to give atransient orthoester,which slowly rearranged to the desired aldgaropyranoside.T he presence of the polar peripheral groups in the product did not impede the selective late-stage functionalization of the macrolide ring itself:t he contained propargylic alcohol entity was readily transformed into the characteristic acyloin motif of the target by ar uthenium-catalyzed trans-hydrostannation followed by amodified Chan-Lam-type coupling.

Total Synthesis of Mycinolide IV and Path‐Scouting for Aldgamycin N

“…Gratifyingly,s tannoxane 25 a proved adequate in that it allowed lactone 20 to be formed in 68 %y ield on ad ecent scale (> 400 mg, single largest batch). [46] Thei someric addition product 8-epi-18 was processed analogously to the corresponding epimeric lactone (see the SI);i tw as at this stage that the configuration of the C8-stereocenter could be tentatively assigned, which was later confirmed by the total synthesis of aldgamycin N. [47] In the end, this transesterification saved astep in the longest linear sequence as it rendered the formation of the seco-acid obsolete.Itisalso notable that this example seems to be only the second successful application of this methodology to the synthesis of am acrolide natural product. [48][49][50][51] With the macrocyclic frame closed, we faced the challenge of transforming the propargylic entity of 20 into the acyloin motif characteristic of aldgamycin N( 1)b yr egioselective hydration of the triple bond at the more hindered site.T his goal was reached by resorting to am ethod previously developed in our laboratory, [52] which was slightly modified and further improved for this particular application.…”

“…Thep rice to pay is the need to carry this precious monosaccharide through anumber of steps along the longest linear sequence;t he accompanying paper describes how this challenge has been met and an efficient synthesis of 1 been accomplished. [47] From ap urely strategic perspective,h owever,i tw as deemed essential to first validate the projected route to the "B-series", which constitutes an equally integral part of the proposed "unified" approach shown in Scheme 1. It was arguably most important to check whether the common building block 7 is amenable to ac atalyst-controlled branchselective asymmetric hydroformylation or not.…”