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The nitrone 4 (4,5-dideoxy-4-hydroxylamino-3,4-O-isopropylidene-L-lyxofuranose) was synthesised from D-ribose and used as key intermediate for the preparation of fucosidase inhibitors. We describe two transformations of 4. Hydrolysis with aqueous sulfur dioxide gave the known potent nanomolar inhibitor 4-amino-4,5-dideoxy-L-lyxofuranose (3). 1,3-Dipolar cycloaddition with enol ethers led to the related 1,2,5,6-tetradeoxy-2,5-imino-L-altroheptonic ester 2a, acid 2b and the corresponding heptitol 2c. The new iminosugars have been evaluated for their inhibitory activity against α-L-fucosidase from bovine kidney. The alcohol 2c turned out to be a potent inhibitor in the same range as the amino-sugar 3 (K(i)=8 vs 10nM).

A concise and convergent total synthesis of the highly cytotoxic marine natural products iejimalide A-D (1-4) is reported, which relies on an effective ring-closing metathesis (RCM) reaction of a cyclization precursor containing no less than 10 double bonds. Because of the exceptional sensitivity of this polyunsaturated intermediate and its immediate precursors toward acid, base, and even gentle warming, the assembly process hinged upon the judicious choice of protecting groups and the careful optimization of all individual transformations. As a consequence, particularly mild protocols for Stille as well as Suzuki reactions of elaborate coupling partners have been developed that hold considerable promise for applications in other complex settings. Moreover, a series of non-natural "iejimalide-like" compounds has been prepared, differing from the natural lead in the polar head groups linked to the macrolide's N-terminus. With the aid of these compounds it was possible to uncover the hitherto unknown effect of iejimalide and analogues on the actin cytoskeleton. Their capacity to depolymerize this microfilament network rivals that of the latrunculins which constitute the standard in the field. Structural modifications of the peptidic terminus in 2 are thereby well accommodated, without compromising the biological effects. The iejimalides hence constitute an important new class of probe molecules for chemical biology in addition to their role as promising lead structures for the development of novel anticancer agents.

Some reactions of nitrone 4 are described, namely the nucleophilic addition of dialkyl phosphites, HOP(OR)2, 5a–c or of diethyl methylphosphonate 8 and the dipolar [2+3] cycloaddition of vinylphosphonate 11. Chemical transformations led to 4-amino-L-fucose derivatives bearing a phosphonate group in the 1α position linked to the pyrrolidine ring through a chain of 0–2 carbon atoms. The target compounds proved to be good-to-excellent α-L-fucosidase inhibitors. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Pyrrolidine amino-sugars, cyclic iminoalditols as well as linear aminoalditols in 4-amino- l -erythrose and 4-amino-5-deoxy- l -ribose series were synthesised by asymmetric hetero-Diels–Alder reaction followed by chemical transformations. 4-Amino-4-deoxy- l -erythrose and 4-amino-4,5-dideoxy- l -ribose were potent β- d -glucosidase, α- d -mannosidase, α- and β- d -galactosidase inhibitors. We have shown that the ribose derivative was a very potent inhibitor of α- d -mannosidase.

β-Aminohydroxamic acids 6a-d are prepared in 4 steps and 30-45% overall yield from nitrones la-d by 1,3-dipolar cycloaddition with phenyl vinyl ether, N-benzylation, thermal rearrangement, and nucleophilic substitution ofthe formed phenyl ester with hydroxylamine.

Cyclic D- and L-4-aminothreose were synthesised from ethyl D- and L-tartrate, respectively. D-aminothreose was a potent inhibitor of alpha-glucosidase and of alpha-mannosidase. From the glycosidase inhibition potencies of the four 4-amino-4-deoxy-tetroses, the contribution of binding of each functionality of the 5 and 6 membered ring amino-sugars towards the various glycosidases is discussed.

Nitrone 3 analogue of 5-deoxy- l -lyxose was derived from d -ribose. Its reduction with aqueous SO2 gave the corresponding 4-amino-sugar 2 , a potent α- l -fucosidase inhibitor. 1,3-Dipolar cycloaddition of 3 with alkenes allowed the synthesis of acetohydroxamic acid and ethane–phosphonate derivatives. Hydroxy-ethane derivative 15 is a nanomolar α- l -fucosidase inhibitor.