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

Abstract

Proof-of-concept is provided that al arge estate of 16-membered macrolide antibiotics can be reached by a"unified" approach. The key building blockwas formed on scale by an asymmetric vinylogous Mukaiyama aldol reaction;i ts alkene terminus was then converted either into the corresponding methyl ketone by Wacker oxidation or into ac hainextended aldehyde by catalyst-controlled branch-selective asymmetric hydroformylation. These transformations ultimately opened access to two structurally distinct series of macrolide targets.N otable late-stage maneuvers comprise ar are example of ar uthenium-catalyzed redox isomerization of an 1,3-enyne-5-ol into a1,3-diene-5-one derivative,aswell as the elaboration of atertiary propargylic alcohol into an acyloin by trans-hydrostannation/Chan-Lam-type coupling.M oreover,t his case study illustrates the underutilized possibility of forging complex macrolactone rings by transesterification under essentially neutral conditions.

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

“…[27,28] Once again, the faithful delivery of the Bu 3 Sn-residue to the C-atom of the triple bond proximal to the directing propargylic -OH group is noteworthy,asisthe unorthodox trans-selective course of the addition process itself that violates conventional logic. [29] At this stage,the use of Cu(tfa) 2 instead of Cu(OAc) 2 for the subsequent Chan-Lam-type coupling,which has already been alluded to in the accompanying paper, [1,30] proved instrumental:a lthough Cu-(OAc) 2 transformed the alkenylstannane into the targeted ketone,i ts use inevitably leads to acylation of the adjacent hydroxy group; [30] the resulting tertiary acetate,h owever,i s unstable under the reaction conditions and succumbed to elimination as can be judged from the isolation of small amounts of the exocyclice none 27 from one of the resulting mixtures.T his fatal path is prevented with Cu(tfa) 2 as the reagent, which furnished the desired unprotected acyloin 28 in 61 %yield [31] in readiness for attachment of the yet missing mycinopyranose and completion of the total synthesis.…”

“…We hence conclude that this second foray into the aldgamycin family of antibiotics based on an "early" glycosidation event proved successful. When taken together with the total synthesis of mycinolide IV described in the accompanying paper, [1] the overall project goes beyond the conquest of two individual targets; [36,37] rather,itprovides the tantalizing outlook that alarger ensemble of bioactive macrolides of this challenging molecular estate can be made from ar ather small number of building blocks. [38] Most notably,asingle fragment sufficed to cover both basic formats of their eastern sectors;t he different levels of unsaturation featured in the western parts of this target class can be encoded as readily accessible alkynes.P ermutation of these modules and the basic operations for their assembly,i nc oncord with proper glycosidation events,s hould bring ac onsiderable number of natural and non-natural antibiotics of this type into reach for biological and pharmacological evaluation.…”

“…As outlined in the accompanying paper,w es aw the opportunity to assemble anumber of 16-membered macrolide antibiotics by au nified approach that requires as ingle building block representing the "eastern" sector of these targets. [1] Divergent functionalization of the alkene terminus of fragment A by either Wacker oxidation or ab ranchselective asymmetric hydroformylation opens entry into the two basic subsets of these antibiotics,which differ from each other in the oxygenation pattern at C8 (Scheme 1). Mycinolide IV (2)i sr epresentative for the first series distinguished by asimple methyl branch adjacent to the invariable carbonyl group at C9; [2] its total synthesis is described in the accompanying paper.…”

“…[3] Although the viability of all key steps leading from A to 1 could indeed be demonstrated, the final conquest of this challenging target failed because of an unforeseen transannular cyclization engaging the C5-OH and the ketone at C9 in lactol formation (H/I); this incident prevented the introduction of the eponymous aldgaropyranose at the proper site in the penultimate step of the synthesis prior to global deprotection. [1,4,5] In conceptual terms,itshould suffice to change the order of events to bring aldgamycin N( 1)i nto reach (Scheme 1). Thestaging point for the introduction of the sugar,however, deserves careful consideration as it is arguably of paramount importance for the overall efficiencyofthe route:this unusual eight-carbon branched monosaccharide should be carried through as few steps of the longest linear sequence as possible.I nc onsideration thereof,t he critical glycosidation was timed after closure of the macrocycle just before the carbonyl group is unveiled by formal hydration of the triple bond at the more hindered site (G !…”

Total Synthesis of Mycinamicin IV as Integral Part of a Collective Approach to Macrolide Antibiotics

“…While the assembly of the macrocyclic cores 9 and 15 along this integral blueprint proceeded well, the final glycosylation phase proved far from trivial. Most notable is the fact that all attempts at unveiling the free alcohol 9 b and reacting it with an appropriate glycosyl donor met with failure because of competing transannular ketalization with irreversible formation of 10 [8] . To remedy this issue, the eponymous aldgarose [26] had to be introduced at an earlier stage ( 8 → 11 ) and carried through several steps of the longest linear sequence; such a tactic, however, can only be justified if the de novo synthesis of this intricate branched octopyranose is short and efficient.…”