Synthesis of a polymer-bound galactosylamine and its application as an immobilized chiral auxiliary in stereoselective syntheses of piperidine and amino acid derivatives

A 2,3,4-tri-O-pivaloylated beta-D-galactopyranosyl azide bearing a hydroxy-functionalized spacer unit at the C-6 position of the galactose was synthesized and immobilized on the solid phase by using a polymer-bound chlorosilane. The azide was reduced to the corresponding galactopyranosylamine, which served as a versatile chiral auxiliary in highly diastereoselective Ugi four-component condensation reactions at ambient temperature. Fluoride-induced cleavage from the polymeric support furnished N-glycosylated N-acylated alpha-amino acid amides. The reaction of the immobilized galactosylamine with aldehydes gave rise to the corresponding aldimines, which underwent a domino Mannich-Michael condensation reaction with Danishefsky's diene at ambient temperature to yield 2-substituted 5,6-didehydropiperidin-4-ones on the solid phase. Subsequent cleavage with tetra-n-butylammonium fluoride delivered the N-glycosylated products in high yields, purities, and diastereoselectivities. A chemoselective 1,4-hydride addition to the polymer-bound dehydropiperidinones was achieved in the presence of the bulky oxygenophilic Lewis acid methylaluminum [bis(2,6-di-tert-butyl-4-methylphenoxide)]. The conjugate addition of cyano-modified Gilman reagents to the immobilized dehydropiperidinones furnished 2,6-cis-substituted piperidine derivatives as the major diastereomers that were isolated after cleavage from the support.     

Solid-phase oligosaccharide synthesis of a small library of N-glycans

Solid-phase oligosaccharide synthesis is based on a hydroxymethylbenzyl benzoate spacer linker which is connected to the Merrifield resin (1 P). Glycosylation was performed with O-glycosyl trichloroacetimidates of glucosamine, mannose, and galactose permitting chain extension (2e, 5e), branching (4b, 7b, 8b), and chain termination (3t, 6t, 9t) with the use of O-benzyl, O-benzoyl, and N-dimethylmaleoyl as permanent and O-fluorenylmethoxycarbonyl (Fmoc) and O-phenoxyacetyl (PA) as temporary protecting groups. The steps required on solid phase are i) glycosylation under TMSOTf catalysis, ii) selective cleavage of the temporary protecting groups, Fmoc with NEt3 and PA with 0.5 equivalents of NaOMe in CH2Cl2/MeOH, and iii) product cleavage from the resin with 4.0 equivalents of NaOMe in CH2Cl2/MeOH and following O-acetylation for convenient product isolation. Thus a highly successful synthesis of a small library of seventeen N-glycan structures was made possible comprising the N-glycan pentasaccharide core structure 53 and two further chain extended hexa- and heptasaccharide N-glycans with a glucosamine or a lactosamine residue, respectively, which is attached to one of the mannose residues of the core structure (56 and 59).     

Diastereoselective solution and multipin-based combinatorial array synthesis of a novel class of potent phosphinic metalloprotease inhibitors

The solution-phase synthesis and resolution of new phosphinopeptidic building blocks containing a triple bond was realized in high yields and optical purities (units 3 a-d). The absolute configuration of the target compounds was unambiguously established by NMR studies. A post-assembly diversification strategy of these blocks was developed through 1,3-dipolar cycloaddition of a variety of in situ prepared nitrile oxides. This strategy led to the rapid and efficient diastereoselective preparation of a novel class of isoxazole-containing phosphinic peptides (peptides 5 a-i). Solid-phase version of this strategy was efficiently achieved on multipin solid technology, by developing a new protocol for the coupling of P-unprotected dipeptidic blocks with solid supported amino acids in a quantitative and diastereoselective manner. Optimization of dipolar cycloadditions onto pin-embodied phosphinic peptides allowed the convenient preparation of this new class of pseudopeptides. The crude phosphinic peptides (9 a-k) were obtained in high yields and purity as determined by RP-HPLC. Inhibition assays of some of these peptides revealed that they behave as very potent inhibitors of MMPs, outmatching previously reported phosphinic peptides, in terms of potency (K(i) in the range of few nM).     

Solid-phase synthesis and biological activity of a combinatorial cross-conjugated dienone library

The solid-phase synthesis of a combinatorial cross-conjugated dienone library based on the structure of clavulones and their biological activity are reported. Clavulones are a family of marine prostanoids, and are composed of a cross-conjugated dienone system bearing two alkyl side-chains. The cross-conjugated dienone system irreversibly reacted with two nucleophiles. Our strategy for the solid-phase synthesis of the cross-conjugated dienones involves the Sonogashira-coupling reaction of a solid-supported cyclopentenone 10 bearing an acetylene group, followed by aldol condensation with aldehydes. The diphenyl derivative 7 aA was prepared from the solid-supported cyclopentenone 10 in 56% total yield. Combinatorial synthesis of a small library using twelve halides and eight aldehydes resulted in the production of 74 desired compounds from 98 candidates, and were detected by their mass spectra. Antiproliferative effects of the crude compounds against HeLaS3 cells showed that eleven samples showed strong antitumor activity (IC50<0.05 microM). Further biological examination of four purified compounds by using five tumor cell lines (A549, HeLaS3, MCF7, TMF1, and P388) revealed strong cytotoxicity comparable to that of adriamycin.     

A Method of Orthogonal Oligosaccharide Synthesis Leading to a Combinatorial Library Based on Stationary Solid‐Phase Reaction

A new, efficient synthesis of oligosaccharides, which involves solid‐phase reactions without mixing in combination with an orthogonal‐glycosylation strategy, is described. Despite a great deal of biological interest, the combinatorial chemistry of oligosaccharides is an extremely difficult subject. The problems include 1) lengthy synthetic protocols required for the synthesis and 2) the variety of glycosylation conditions necessary for individual reactions. These issues were addressed and solved by using the orthogonal‐coupling protocol and the application of a temperature gradient to provide appropriate conditions for individual reactions. Furthermore, we succeeded in carrying out solid‐phase reactions with neither mechanical mixing nor flow. In this report, the synthesis of a series of trisaccharides, namely, α/β‐L ‐Fuc‐(1→6)‐α/β‐D ‐Gal‐(1→2/3/4/6)‐α/β‐D ‐Glc‐octyl, is reported to demonstrate the eligibility of the synthetic method in combinatorial chemistry.     

Development of the traceless phenylhydrazide linker for solid-phase synthesis

The hydrazide group is a new oxidatively cleavable traceless linker for solid-phase chemistry. It can be readily introduced by hydrazide formation between a carboxy-functionalized resin and different substituted hydrazines. In order to achieve high yields in this step, new carboxylic acid resins were developed that are not prone to undesired imide formation upon activation of the carboxylic acid. The polymer-bound acyl hydrazides were successfully employed in various transformations, namely Heck, Suzuki, Sonogashira, and Stille couplings, as well as Wittig and Grignard reactions. Traceless release of the coupling products from the solid support is achieved selectively under mild conditions and in high purity by oxidation of the aryl hydrazides to acyl diazenes with Cu(II) salts or N-bromosuccinimide (NBS) and subsequent nucleophilic attack of the acyl diazene intermediates. Traceless cleavage by oxidation with NBS can be carried out as a two-step process in which stable acyl diazenes are first generated by treatment with NBS in the absence of a nucleophile. After removal of the reagents by simple resin washing, the traceless release is effected by the addition of methanol, which leads to products of high purity without any additional separation steps.