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...

[reaction: see text] A convergent and concise route to an advanced precursor 2b of kendomycin (1) has been developed by applying a S(N)1 ring cyclization as a key step. The resulting C-aryl glycoside was initially isolated as a rotameric mixture, but after MOM protection of the o-hydroxyl of the phenol, the conformation was frozen to the desired kendomycin-like atropisomer.

[reaction: see text] The synthesis of two model p-quinone methide ring systems of the antibiotic and antiosteoporotic compound kendomycin is reported. Two approaches were examined in detail, and the two-step (i) demethylation and (ii) DMDO oxidation were found to be reliable and generally applicable. Additionally, it was found that oxidation of a benzofuran by NaIO(4) on silica produced a long-lived semiquinone radical.

A Novel Approach Toward the Synthesis of Kendomycin (I): Selective Synthesis of a C-Aryl Glycoside as a Single Atropisomer (II). -(PICHLMAIR, S.; MARQUES, M. M. B.; GREEN, M. P.; MARTIN, H. J.; MULZER*, J.; Org. Lett. 5 (2003) 24, 4657-4659; Inst. Org. Chem., Univ. Wien, A-1090 Wien, Austria; Eng.) -Steudel 15-202