N-Glycosylation with sulfoxide donors for the synthesis of peptidonucleosides.

The synthesis of glycopyranosyl nucleosides modified in the sugar moiety has been less frequently explored, notably because of the lack of a reliable method to glycosylate pyrimidine bases. Herein we report a solution in the context of the synthesis of peptidonucleosides. They were obtained after glycosylation of different pyrimidine nucleobases with glucopyranosyl donors carrying an azide group at the C4 position. A methodological study involving different anomeric leaving groups (acetate, phenylsulfoxide and ortho-hexynylbenzoate) showed that a sulfoxide donor in combination with trimethylsilyl triflate as the promoter led to the best yields.

Synthesis and biological activity of simplified belactosin C analogues.

Successful biochemical studies of the natural products belactosin A and C and their acylated congeners have shown a ß-lactonecarboxamide moiety to be a possible core structure of powerful proteasome inhibitors. As a part of further investigations, variously decorated simplified ß-lactonecarboxamides have been synthesized in order to understand structure-biological activity relations in detail, to find ways of improving their biological activity and stability and to reduce the complexity of their preparation. Biological tests showed that the best compounds possess a high potential against phytopathogenic fungi in the greenhouse.

A modular sydnone cycloaddition/Suzuki-Miyaura cross-coupling strategy to unsymmetrical 3,5-bis(hetero)aromatic pyrazoles.

The [3 + 2] dipolar cycloaddition of 4-halosydnones with 1-haloalkynes opens a straightforward access to 3,5-dihalopyrazoles, valuable scaffolds for the elaboration of unsymmetrically 3,5-substituted pyrazole derivatives via site-selective Pd-catalyzed cross-coupling reactions. For instance, the flexible introduction of different (hetero)aryl substituents at the C-5 and C-3 positions of the PMP-protected pyrazole nucleus was achieved in a one-pot operation via sequential reactions with various boronic acids.

Facile synthesis of structurally diverse 5-oxopiperazine-2-carboxylates as dipeptide mimics and templates.

A sequence of Michael addition of a primary amine onto methyl 2-chloro-2-cyclopropylidene-acetate (1), acylation of the adduct with alpha-bromo acid chlorides under modified Schotten-Baumann conditions and ring-closing twofold nucleophilic substitution on the thus formed bishalides 3a-e with aliphatic or aromatic amines according to a very simple protocol with final acid/base extraction or filtration over silica gel for purification leads to the 3-spirocyclopropanated 5-oxopiperazine-2-carboxylates 2 or in two cases, after intermolecular transesterification of 2, to bicyclic oxopiperazines 6, with a remarkable variability of the substituents R1-R3 in 39-99% yields (20 examples). Starting with alpha-bromophenylacetic acid chloride, the trans-configured 6-phenyl-5-oxopiperazine-2-carboxylates are formed preferentially.

High yielding selective access to spirocyclopropanated 5-oxopiperazine-2-carboxylates and 1,4-diazepane-2,5-diones from methyl 2-chloro-2-cyclopropylideneacetate.

The 2-spirocyclopropanated methyl 5-oxopiperazine-2-carboxylate and the 3-spirocyclopropanated 6-chloro-1,4-diazepane-2,5-dione could both be prepared at choice in 93 and 88% yield, respectively, from methyl 2-chloro-2-cyclopropylideneacetate () in a sequence of Michael addition of 3-benzyloxypropylamine, peptide coupling with N-Boc-glycine, Boc-group removal and cyclization. Transformation of the benzyloxypropyl side chain, peptide coupling with N-Boc-(S)-asparagine, deprotection and repeated cyclization led to the octahydro[2H]pyrazino[1,2-a]pyrazinetrione scaffold containing a rigidified mimic of a tripeptide with a DGR motif. The overall yield of after deprotection of (a total of 13 steps in 8 distinct operations) was 30%.

Solid supported fluoronitroaryl triazenes as immobilized and convertible Sanger reagents--synthesis and SNAr reactions towards a novel preparation of 1-alkyl-5-nitro-1H-benzotriazoles.

Synthesis of novel fluoronitroaryl triazenes in liquid phase and on solid support have been described; mild displacement of the fluoride ion with various nucleophiles provides access to substituted arenes which in turn can be cleaved to provide a unique access to 1-alkyl-5-nitro-1H-benzotriazole.

A new highly efficient three-component domino Heck-Diels-Alder reaction with bicyclopropylidene: rapid access to spiro[2.5]oct-4-ene derivatives.

Bicyclopropylidene (1) was found to surpass even methyl acrylate (17 a) in its rate of undergoing carbopalladation with aryl- or alkenylpalladium species, leading to substituted allylidenecyclopropanes 5, 7 and 10, mostly in high yields (37-78 %). These dienes and cross-conjugated trienes react in a Diels-Alder mode with dienophiles to give spiro[2.5]octenes 18 a-Ph, 18 b-Ph and 18 a-Vin, respectively, in good yields (89, 69 and 65 %). The overall transformation can be achieved as a one-pot three-component reaction with a variety of dienophiles to furnish the domino Heck-Diels-Alder products 18 regioselectively in most cases in good to very high yields (49-100 %). The reaction of 1 with iodobenzene (2-Ph) and 17 a gave 18 a-Ph in virtually quantitative yield-also on a gram scale-using only 1 mol % of catalyst, and even bromobenzene (22) gave 18 a-Ph in 59 % yield. Bicyclopropylidene (1), in the presence of palladium acetate/triphenylphosphane underwent rearrangement to allylidenecyclopropane (5-H), which in turn dimerized (73 %) in the absence of other reaction partners, or could be trapped by diethyl fumarate (17 c) to give the Diels-Alder adduct 18 c-H in 45 % yield. The coupling of oligoiodobenzenes with 1 and subsequent cycloaddition could be extended to a multicomponent reaction. In this way, 1,4-diiodobenzene (37), 1 and an alkyl acrylate gave the products 38 of a twofold Heck-Diels-Alder reaction in up to 87 % yield, 1,3,5-triiodobenzene (39) reacted in up to 72 % yield and ultimately 1,2,4,5-tetraiodobenzene (41) gave the fourfold domino Heck-Diels-Alder product 42 in 47 % isolated yield, in a single operation in which 12 new carbon-carbon bonds were formed.

Imidazo[5,1-f]triazin-4(3H)-ones, a new class of potent PDE 5 inhibitors.

2-aryl-substituted imidazo[5,1-f][1,2,4]triazin-4(3H)-ones represent a new class of potent cGMP-PDE 5 inhibitors that prove to be superior to other purine-isosteric inhibitors. Subnanomolar inhibitors of PDE 5 with activity in in vivo models for erectile dysfunction have been identified. BAY 38-9456 (Vardenafil-hydrochloride) has been selected for clinical studies in the indication of erectile dysfunction.