Abstract

The glycosidation of a polymer-supported glycosyl donor, N-phenyltrifluoroacetimidate, with various glycosyl acceptors is reported. The application of the polymer-supported N-phenyltrifluoroacetimidate is demonstrated in the synthesis of vancomycin derivatives. 2-O-[2-(azidomethyl)benzoyl]glycosyl imidate was attached to a polymer support at the 6-position by a phenylsulfonate linked with a C13 alkyl spacer. Solid-phase glycosidation with a vancomycin aglycon, selective deprotection of the 2-(azidomethyl)benzoyl group, and glycosylation of the resulting 2-hydroxy group with a vancosamine unit were performed. Nucleophilic cleavage from the polymer support with acetate, chloride, azido, and thioacetate ions provided vancomycin derivatives in pure form after simple purification. The semisynthesis of vancomycin was achieved by deprotection of the acetate derivative.

Ohne jede Spur: Der Naturstoff Epigallocatechingallat (siehe Schema rechts) und eine Bibliothek von Derivaten wurden an fester Phase synthetisiert. Eine reduktive Veretherung bei der Freisetzung des intermediären α-Acyloxyketons vom Harz lieferte die gewünschten Epicatechin-Derivate. Bn: Benzyl, PS: Polystyrol, TFA: Trifluoressigsäure.

Without a trace… The natural product epigallocatechin gallate (see scheme, right) and a library of derivatives were synthesized on a solid phase. Reductive etherification upon the release of the α-acyloxy ketone intermediate from the resin provided the desired epicatechin derivatives. Bn=benzyl, PS=polystyrene, TFA=trifluoroacetic acid.

Short and sweet: Glycosidation of 2-deoxyglycosyl imidates with I₂ as shown in the scheme (Bn=benzyl, Bz=benzoyl, MS=molecular sieves) proceeds smoothly to provide the corresponding β-linked 2-deoxyglycosides in excellent yields and selectivity. This coupling method has been shown to be adaptable to the synthesis of various β-linked oligosaccharides containing 2,6-dideoxy- and 2,3,6-trideoxyglycosides.

Kurz und süß: Die im Schema beschriebene Glycosidierung von 2-Desoxyglycosylimidaten mit I₂ (Bn=Benzyl, MS=Molekularsieb) verläuft glatt und liefert selektiv die entsprechenden β-verknüpften 2-Desoxyglycoside in ausgezeichneter Ausbeute. Diese Kupplungsmethode ließ sich für die Synthese vieler β-verknüpfter Oligosaccharide mit 2,6-Didesoxy- und 2,3,6-Tridesoxyglycosideinheiten anpassen.

A 36-step synthesis was carried out in automated synthesizers to provide a synthetic key intermediate of taxol. A key step involved a microwave-assisted alkylation reaction to construct the ABC ring system from an AC precursor. Subsequent formation of the D ring afforded baccatin III, a well-known precursor of taxol.

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 μM). 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.

Iodalkoxylierung (siehe Schema) eines Glycals mit einer acyclischen Saccharidvorstufe führt stereoselektiv zu Di- und Tri-α(2,8)-3-desoxy-D-manno-2-octulosonsäure (KDO; siehe Bild). Das Glycal bildet α-verknüpfte 3-Iod-KDO-Derivate. Die Öffnung des Pyranrings erhöht die Reaktivität der Hydroxygruppe an C8.

Neue Strategien für die Zuckersynthese: Ein Prä-Linker mit einer Dihydropyranyleinheit und einem aktivierten Ester kann an einen Zucker gebunden werden. Nach dem Laden auf einen Amino-modifizierten Träger durch Amidierung sind Standard-Schutzgruppenmanipulationen möglich. Das Abspalten des Linkers unter milden sauren Bedingungen liefert dann die vollständig entschützten Oligosaccharide.

New strategies in sugar synthesis: A prelinker containing a dihydropyranyl moiety and an activated ester can be attached to a sugar, which is then loaded onto an amino-modified support by amidation. Standard protecting-group manipulations are possible. Final cleavage of the linker under mildly acidic conditions provides the fully deprotected oligosaccharides. TFA=trifluoroacetic acid.

An efficient solution-phase synthesis of rac-15-deoxy-Δ^12,14-PGJ₂ (15dPGJ₂) derivatives that contain variable α and ω chains based on a polymer-assisted strategy and their neurite-outgrowth-promoting activity are described. The strategy for the synthesis of PGJ₂ derivatives involves the use of a vinyl iodide bearing cyclopentenone as a key intermediate, which undergoes Suzuki–Miyaura coupling and subsequent Lewis acid catalyzed aldol condensation for incorporation of the ω and α chains, respectively. For easy access to the PGJ₂ derivatives, a polymer-supported catalyst and scavengers were adapted for use in these four diverse steps, in which workup and purification can be performed by simple filtration of the solid-supported reagents. By using this methodology, we succeeded in the synthesis of 16 PGJ₂ derivatives with four alkyl boranes and four aldehydes. The neurite-outgrowth-promoting activity of the 16 synthetic compounds in PC12 cells revealed that the side-chains play a major role in modulating their biological activity. The carboxylic acid on the α chain improved the biological activity, although it was not absolutely required. Furthermore, a PGJ₂ derivative with a phenyl moiety on the ω chain was found to exhibit an activity comparable to that of natural 15dPGJ₂.

We describe an efficient synthesis of 2,6- and 2,3-sialyl T antigens linked to serine in a one-pot glycosylation. We first investigated the glycosidation of thiosialosides by varying the N-protecting group. Modification of the C-5 amino group of β-thiosialosides into the N-9-fluorenylmethoxycarbonyl, N-2,2,2-trichloroethoxycarbonyl (N-Troc), and N-trichloroacetyl derivatives enhanced the reactivity of these compounds towards glycosidation. Addition of a minimum amount of 3 Å molecular sieves was also effective in improving the yield of α-linked sialosides. Next, we conducted one-pot syntheses of the glycosyl amino acids by using the N-Troc sialyl donor. The N-Troc derivative can be converted into the N-acetyl derivative without racemization of the amino acids. Branched-type one-pot glycosylation, initiated by regioselective glycosylation of the 3,6-dihydroxy galactoside with the N-Troc-β-thiophenyl sialoside, provided the protected 2,6-sialyl T antigen in good yield. Linear-type one-pot glycosylation, initiated by chemoselective glycosylation of galactosyl fluoride with the N-Troc-β-thiophenyl sialoside, afforded the protected 2,3-sialyl T antigen in excellent yield. Both protected glycosyl amino acids were converted into the fully deprotected 2,6- and 2,3-sialyl T antigens linked to serine in good yields.

Totalsynthese an der Festphase: Bei der kombinatorischen Synthese einer Macrosphelid-Bibliothek mit 122 Verbindungen, darunter Macrosphelid A, C, E und F, hilft eine neuartige Dreikomponentenkupplungs-Strategie an der Festphase: Eine chemoselektive Palladium-katalysierte Carbonylierung mit anschließender Makrolactonisierung führt zu den gewünschten Produkten (siehe Schema).

Supported total synthesis: The combinatorial synthesis of a 122-membered macrosphelide library including macrosphelides A, C, E, and F (see picture) has been achieved based on a unique strategy for a three-component coupling utilizing a palladium-catalyzed chemoselective carbonylation and an unprecedented macrolactonization on a polymer support.