Total Synthesis of Kendomycin:  A Macro−C−Glycosidation Approach

Abstract

Kendomycin, also known as (-)-TAN 2162, is a novel polyketide-derived ansamycin isolated from Streptomyces sp., which exhibits potent antagonist and agonist activities at the endothelin and calcitonin receptors, respectively. This bacterial metabolite also possesses a strong antibiotic activity against a range of gram-positive and -negative bacteria and cytostatic effects on the growth of human cancer cell lines. When a novel macroglycosidation reaction is employed as the key step, the first enantioselective total synthesis of kendomycin has been accomplished. A Friedel-Crafts-type ring closure of the acyclic precursor containing tetrahydropyran and benzofuran moieties produces the macrocycle as a single stereoisomer in good yield, thus establishing the aryl C-glycosidic linkage of the ansa core. This reaction requires a phenolic glycosyl acceptor and appears to proceed through a rapid O-glycosidation followed by a slow rearrangement to an aryl C-glycoside. The requisite secomacrocycle is prepared by the Pd(0)-catalyzed B-alkyl Suzuki-Miyaura cross-coupling of two subunits, which in turn can be expeditiously assembled from readily available building blocks in a modular fashion.

A Highly Stereoselective and Flexible Strategy for the Convergent Synthesis of Long‐Chain Polydeoxypropionates: Application towards the Synthesis of the Glycolipid Membrane Components Hydroxyphthioceranic and Phthioceranic Acid

“…[23] With the requisite coupling partners for the critical SuzukiMiyaura cross-coupling reaction in our hands we felt that conditions, which were originally developed by the groups of Marshall and Lee for sp 2 -sp 3 couplings and later employed by Rychnovsky et al in similar settings, were most promising for our endeavor as well. [24] Thus, iodide 11 was first converted into a reactive alkyl lithium-boranate complex through halogen-metal exchange with tBuLi and subsequent reaction with B-OMe-9-BBN (9-BBN = 9-borabicyclo[3.3.1]nonane). [25] This reactive alkyl metal compound was then treated with MOM-protected vinyl iodide 15 (1.3 equiv) in the presence of 5 mol % [PdCl 2 (dppf)] (1,1'-bis(diphenylphosphino)ferrocene) and K 3 PO 4 in DMF at room temperature to afford the trisubstituted olefin 18 in 92 % yield under very mild conditions (Scheme 6).…”

“…To put these plans into practice, we started from racemic propargylic alcohol 25, which was conveniently obtained in good yield through Grignard addition of ethynylmagnesium bromide to palmitic aldehyde, further obtained by reductionoxidation reaction of commercially available palmitic acid (24). For the sake of practicality and the production of large amounts of material, we opted for an enzymatic kinetic resolution strategy over alternative enantioselective protocols.…”

Enantiomeric Separation of 1-(Benzofuran-2-yl)alkylamines on Chiral Stationary Phases Based on Chiral Crown Ethers

“…Optically active 2-substituted benzofurans might be the precursors of biologically active compounds, 8 and the preparation of optically active 2-substituted benzofurans required during the development of chiral drugs has been reported by a limited number of papers.…”

A highly enantio- and diastereoselective 1,3-dimethylallylation of aldehydes

“…Separation of the major isomer by flash column chromatography (silica gel, hexanes/toluene=15/1 to 10/1 to 4/1) afforded pure 15a (790 mg, 35% after a single separation; the mixed fractions could be collected and further purified) as a colorless liquid: 6,127.1,77.25,46.2,41.7,37.6,35.6,27.7,25.5,23.6,22.9,20.7,18.1,15.8,13.6; 19.8 mmol) were added a few drops of dibromoethane followed by slow addition of dimethylallyl chloride 12 (1.04 g, 10.0 mmol) at room temperature. Upon completion of the addition, the suspension was stirred for 1 h and filtered through a sintered glass funnel under argon.…”