Toward the synthesis of the carbacylic ansa antibiotic kendomycin

Abstract

The convergent synthesis of a benzofuran analog of the carbacyclic ansa compound kendomycin has been achieved by assembling three major fragments by means of epoxide opening and directed ortho lithiation. The crucial tetrahydropyran ring was formed by a highly stereoselective cationic cyclization. Analysis of all synthesized tetrahydropyran-arene compounds reveals a hindered sp 2 -sp 3 rotation, which results in rotational isomers or atropisomers affecting macrocyclization reactions. The latter could only be achieved by means of Horner-Wadsworth-Emmons olefination.O rganic compounds derived from nature have been an abundant source of drugs and drug leads and have provided a rich array of interesting synthetic targets. Among various selection criteria, novel and complex structural features combined with interesting biological activities might be the most important ones to promote a molecule to a target for natural product synthesis. Kendomycin (1), a novel streptomyces metabolite, which was presented at a meeting in 1999, consummately meets all the requirements and thus was selected as a target for our research one year later. Originally, 1 had been published as (Ϫ)-TAN 2162 in the patent literature as a potent endothelin receptor antagonist and antiosteoporotic compound (1-3). With its reisolation from a different streptomyces strain, the absolute configuration of 1 has been determined. Additionally, the biosynthetic pathway and further antibiotic and cytotoxic activities have been reported (4, 5). The structure of 1 (Fig. 1) features an aliphatic ansa chain that is attached by carbons C5 and C18 to a quinone methide core. Thus, 1 is one of the very few ansa-carbon natural products that have been isolated so far. Likewise, the quinone methide structure, which can be regarded as a 1,6-oxidation product of the corresponding benzofuran, has no precedence in natural product chemistry.Particular attention should be devoted to the fully substituted tetrahydropyran ring, which is, combined with the quinone methide, a sterically encumbered region in the molecule, possibly prone to atropisomeric phenomena. In this contribution we give a progress report on our total synthesis of kendomycin (6-8). First-Generation ApproachOur initial synthetic plan (Fig. 2) focused on a ring-closing metathesis (RCM) macrocyclization of the seco intermediates 2 or 3. It was obvious that the formation of the quinone methide chromophore should be deferred to the end of the synthesis, envisaging either an oxidation of the corresponding benzofuran or a 1,6-elimination. Key intermediates 2 and 3 were to be assembled either by a Heck coupling of alkene 4 and arylbromide 5 or an epoxide opening reaction of 5 with epoxide 6. The tetrahydropyran ring should be formed by an intramolecular hetero-Michael addition of enone 7, which should be derived from a Horner-Wadsworth-Emmons (HWE) olefination of aldehyde 8 with ␤-ketophosphonate 9.As outlined in Fig. 3, the stereotetrad of the tetrahydropyran ring was constructed by aldol addition methodology and...

Recent Applications of Olefin Ring-Closing Metathesis (RCM) in the Synthesis of Biologically Important Alkaloids, Terpenoids, Polyketides and Other Secondary Metabolites

“…The current synthesis [30] started with steps were therefore needed to invert the olefin configuration, and finally the aromatic ring was oxidized to give 145 in low yield. Remarkably, similar attempts to close the ansa bridge across a benzofuran core via RCM failed [31].…”

Die Prins‐Makrocyclisierung als effiziente Ringschluss‐Strategie in der Naturstoffsynthese

“…Vorausgegangene Synthesen durch Mulzer, [49] Smith [50] und Arimoto et al [51] [52] Durch eine Suzuki-Miyaura-Kupplung des Homoallylalkohols 38 und der aus dem Iodalkan 39 erzeugten Borsäure wurde der Hauptkern der Makrocyclisierungsvorstufe erzeugt, der weiter modifiziert wurde, um die C5-Aldehydfunktion einzuführen. Selektive Sulfonierung an der Phenolfunktion an C4 ergab die Vorstufe 40 (Schema 13).…”

“…Vorausgegangene Synthesen durch Mulzer, [49] Smith [50] und Arimoto et al [51] [58] Paquette [59] und White et al [60] hatten auf einer Makrolactonisierung beruht, wogegen Woo und Lee eine Prins-Makrocyclisierung zum Einsatz bringen wollten. Die Makrocyclisierungsvorstufe 52 wurde rasch in zwölf Stufen aus vier einfachen Fragmenten aufgebaut und in der bewährten Reaktion mit TESOTf in Essigsäure umgesetzt, die das Makrolid 53 in 69 % Ausbeute (d.r.…”

In Pursuit of a Competitive Target: Total Synthesis of the Antibiotic Kendomycin

“…As was soon evident, the RCM of either diene 32 or 34 failed, and a HWE reaction was set up as an alternative ring-closure protocol. [17] To this end, 35 was converted into keto phosphonate 36, which underwent macrocyclization into 37 upon treatment with LiOH (Scheme 8). Removal of the undesired carbonyl group at C15 proved difficult but was finally achieved by Luche reduction, xanthate formation, and then Barton-McCombie deoxygenation.…”