Use Of Triflate Research Articles

Stereoselective Synthesis of 5-epi-α-Sialosides Related to the Pseudaminic Acid Glycosides. Reassessment of the Stereoselectivity of the 5-Azido-5-deacetamidosialyl Thioglycosides and Use of Triflate as Nucleophile in the Zbiral Deamination of Sialic Acids.

With a view to the eventual synthesis of glycosyl donors for the stereocontrolled synthesis of pseudaminic acid glycosides, the stereocontrolled synthesis of a d-glycero-d-gulo sialic acid adamantanylthioglycoside carrying an axial azide at the 5-position is described. The synthesis employs levulinic acid as nucleophile in the oxidative deamination of an N-acetylneuraminic acid thioglycoside leading to the formation of a 3-deoxy-d-glycero-d-galacto-2-nonulosonic acid (KDN) derivative selectively protected as 5-O-levulinate. Replacement of the levulinate by triflate enables introduction of the axial azide and hence formation of the glycosyl donor. A shorter synthesis uses trifluoromethanesulfonate as nucleophile in the oxidative deamination step when the 5-O-triflyl KDN derivative is obtained directly. Glycosylation reactions conducted with the 5-azido-d-glycero-d-gulo-configured sialyl adamantanylthioglycoside at -78 °C are selective for the formation of the equatorial glycosides, suggesting that the synthesis of equatorial pseudaminic acid glycosides will be possible as suitable donors become available. A comparable N-acetylneuraminic acid adamantanylthioglycoside carrying an equatorial azide at the 5-position was also found to be selective for equatorial glycoside formation under the same conditions, suggesting that reinvestigation of other azide-protected NeuAc donors is merited. Glycosylation stereoselectivity in the d-glycero-d-gulo series is discussed in terms of the side-chain conformation of the donor.

Nobel Prize Awarded for Catalysis

Finally, Richard Heck, Ei-ichi Negishi, and Akira Suzuki (pictured) have been awarded the Nobel Prize in Chemistry for palladium-catalyzed cross-coupling in organic synthesis, a long-awaited award that has been celebrated by all organic and organometallic chemists. The impact of the Heck reaction and palladium-catalyzed cross-couplings has been enormous, having totally changed the practice of organic synthesis in research laboratories and in industry. Along with (π-allyl)palladium chemistry, cross-coupling reactions have made palladium the most important transition metal in organic synthesis.1 Although the scope of the palladium-catalyzed alkenylation of aryl, heteroaryl, and alkenyl halides was well established by Heck’s highly detailed experimental work, published in the late 1960s and early 1970s, the importance of this reaction for the synthesis of natural products was not immediately recognized by the community of organic chemists. However, applications of the Heck reaction in total synthesis flourished in the 1980s and nowadays it is one of the methods of choice to create complex organic architectures, as exemplified by Köhler et al. on page 1467 ff. Heck also made seminal contributions in (π-allyl)palladium chemistry and other areas of organometallic chemistry. The development of metal-catalyzed cross-coupling reactions of aryl and alkenyl halides can be traced back to the pioneering work of Kharasch and, later, Kochi, Kumada, Tamao, Corriu, and Sonogashira, among others. However, the full importance of these palladium-catalyzed processes became fully appreciated after contributions made by the late Stille, Negishi, and Suzuki in the 1970s and early 1980s. These discoveries were soon followed by the use of organosilanes as coupling partners by the group of Hiyama. It is important to note that, although Negishi’s work in this area is now associated to the cross-coupling of organozinc reagents, a reaction that carries his name, a perusal of the early literature reveals that Negishi’s group had already examined a wide variety of organometallic nucleophiles as coupling partners, including alanes, zirconium reagents, boron derivatives, and stannanes. The Suzuki cross-coupling of organoboron compounds (also known as the Suzuki–Miyaura reaction, as employed by Klein Gebbink et al. on page 1425 ff.) and the Stille reaction of organostannanes were initially established as the most general and selective palladium-catalyzed cross-coupling reactions. A particularly significant advance was made by the use of triflates and other sulfonates as organic electrophiles in couplings with organostannanes and in Heck alkenylations, which allowed the use of phenols and carbonyl compounds as starting materials. The field matured further thanks to the more in-depth understanding of the mechanisms of these reactions, which led to the development of palladium complexes with very bulky ligands that enable the coupling of alkyl halides and many other organic electrophiles with a wide variety of mild organometallic reagents. The latest flourishing advance in cross-coupling chemistry has been the incorporation of nickel and copper as alternative catalysts and the use of alcohols and amines as the nucleophiles (Buchwald–Hartwig reactions), which has revolutionized heterocyclic synthesis. Needless to say, without the contributions made by Heck, Negishi, and Suzuki, the field of organic chemistry today would look somewhat different, and I, on behalf of ChemCatChem, would like to congratulate them on their achievements.1

Synthesis of Tetrahydrofurfurylamines Related to Muscarine

A methodology that involves mesylation of readily available tetrahydrofuryl diols and subsequent displacement with selected amines to afford novel muscarine analogs has been outlined. Displacement of the primary mesylate takes place smoothly, while displacement of the secondary mesylate occurs in low yield. The use of triflates as an alternative has been sketched.

Direct synthesis of N-protected chiral amino acids from imidodicarbonates employing either Mitsunobu or triflate alkylation. Feasibility study using lactate with particular reference to 15N-labelling

Two novel approaches to N,N-diprotected chiral α-amino acid esters, based on selected imidodi-carbonates as amine synthons, have been explored. Thus, N-alkylation of these substrates was smoothly accomplished by the Gabriel or Mitsunobu methods as well as by the use of triflates. Ethyl (R,S)-2-bromopropionate underwent nucleophilic substitution when treated with the potassium salt of selected imidodicarbonates in dry dimethylformamide to furnish the corresponding fully blocked (R,S)-alanines in high yield. The chirality of ethyl (S)-lactate was largely conserved when it was condensed with free imidodicarbonates and tosylcarbamates under conventional Mitsunobu conditions. The yield of the corresponding N,N-di-protected ethyl (R)-alaninate was strongly dependent on the electron-withdrawing properties of the imidodicarbonate alkyl groups. Thus, Boc2NH gave < 5% of the product whereas Troc-NH-Z afforded the corresponding analogue in 83% yield under comparable conditions. On the other hand, triflates of various lactic acid esters reacted smoothly with the lithium salt of Boc2NH, also with clean inversion, as a result of which, after selective removal of two blocking groups, the N-protected alanine of opposite configuration could be isolated in high yield and excellent stereochemical purity. Both methods have been used for the synthesis of 15N-labelled N-protected (R)- and (S)-alanines, suitable for direct application to peptide synthesis.