Total synthesis of woodrosin I--part 2: final stages involving RCM and an orthoester rearrangement

The completion of the first total synthesis of the complex resin glycoside woodrosin I (1) is outlined using the building blocks described in the preceding paper. Key steps involve the TMSOTf-catalyzed coupling of diol 2 with trichloroacetimidate 3 which leads to the selective formation of orthoester 5 rather than to the expected tetrasaccharide. Diene 5, on treatment with catalytic amounts of the Grubbs carbene complex 6 or the phenylindenylidene ruthenium complex 7, undergoes a high yielding ring closing olefin metathesis reaction (RCM) to afford macrolide 8. Exposure of the latter to the rhamnosyl donor 4 in the presence of TMSOTf under "inverse glycosylation" conditions delivers compound 9 by a process involving glycosylation of the sterically hindered 2'-OH group and concomitant rearrangement of the adjacent orthoester into the desired beta-glycoside. This transformation constitutes one of the most advanced applications of the Kochetkov glycosidation method reported to date. Cleavage of the chloroacetate followed by exhaustive hydrogenation completes the total synthesis of the targeted glycolipid 1.     

Total synthesis of macroviracin D (BA-2836-4)

The first total synthesis of the complex glycolipid macroviracin D (BA-2836-4) (1) is described. This antivirally active metabolite isolated from the mycelium extracts of Streptomyces sp. BA-2836 incorporates a unique 46-membered macrodilactone motif decorated with glycosylated fatty acid appendices. Compound 1 consists of three identical subunits which are closely related to one of the segments found in cycloviracin B(1) (2), another antiviral glycoconjugate previously synthesized in our laboratory. Key steps of the synthesis route to 1 involve the stereoselective, ligand-controlled addition of the functionalized diorganozinc derivative 9 to aldehydes 8 a, b, a series of beta-selective glycosidation reactions using appropriately protected trichloroacetimidate donors, and three esterifications via the Yamaguchi method; one of them is performed intramolecularly to forge the macrocyclic lactone ring of the target in 89 % isolated yield. This total synthesis also firmly establishes the absolute configuration of the subunits of compound 1 as 3R,17S,23R.     

Total synthesis of gambierol: the generation of the A-C and F-H subunits by using a C-glycoside centered strategy

Gambierol, a representative of the marine ladder toxin family, consists of eight ether rings, 18 stereocenters, and two challenging pyranyl rings having methyl groups that are in a 1,3-diaxial orientation to one another. Herein we describe the generation of gambierol's A-C and F-H ring systems and demonstrate the versatility of the glycosyl anhydride, enol ether-olefin RCM strategy to fused polycyclic ethers. This work has both enabled us to generate sufficient quantities of the gambierol precursors and has enabled us to better understand the chemical transformations that were key to these efforts. Fundamental work included efforts to C-glycosides and C-ketosides, Claisen rearrangements, and enol ether-olefin RCM reactions.     

Discovery,Total Synthesis and Key Structural Elements for the Immunosuppressive Activity of Cocosolide,a Symmetrical Glycosylated Macrolide Dimer from Marine Cyanobacteria

A new dimeric macrolide xylopyranoside, cocosolide ( 1 ), was isolated from the marine cyanobacterium preliminarily identified as Symploca sp. from Guam. The structure was determined by a combination of NMR spectroscopy, HRMS, X‐ray diffraction studies and Mosher's analysis of the base hydrolysis product. Its carbon skeleton closely resembles that of clavosolides A–D isolated from the sponge Myriastra clavosa, for which no bioactivity is known. We performed the first total synthesis of cocosolide ( 1 ) along with its [α,α]‐anomer ( 26 ) and macrocyclic core ( 28 ), thus leading to the confirmation of the structure of natural 1 . The convergent synthesis featured Wadsworth–Emmons cyclopropanation, Sakurai annulation, Yamaguchi macrocyclization/dimerization reaction, α‐selective glycosidation and β‐selective glycosidation. Compounds 1 and 26 potently inhibited IL‐2 production in both T‐cell receptor dependent and independent manners. Full activity requires the presence of the sugar moiety as well as the intact dimeric structure. Cocosolide also suppressed the proliferation of anti‐CD3‐stimulated T‐cells in a dose‐dependent manner.     

Hydrotalcite catalysis for the synthesis of new chiral building blocks

The use of hydrotalcites for the synthesis of two chiral building blocks in a simple way is described as a new and green methodology. The synthesis of these compounds implies a regioselective Baeyer–Villiger reaction in a very selective way with ulterior opening and lactonisation. This methodology should be considered green for the use of hydrogen peroxide as the only oxidant and hydrotalcites as the catalyst, and because no residues are produced apart from water. The procedure is very adequate for using in gram scale, in order to increase the value of the obtained compounds. The conditions are excellent and can be applied for nonstable compounds, as they are very mild. The synthesised compounds are magnific starting materials for the synthesis of biologically active or natural compounds. The use of a cheap, commercial and chiral compound as carvone disposable in both enantiomeric forms adds an extra value to this methodology.