Andrea Goti

Metal-catalysed 1,2-diamination reactions.

The 1,2-diamine motif is present in a number of natural products with interesting biological activity and in many important pharmaceutical agents. Chiral 1,2-diamines are also widely used as the control elements in asymmetric synthesis and catalysis. Such compounds are thus an attractive target for the synthetic chemist. Although the diamination of an alkene seems an obvious route to these structures, far less research has been devoted to it than to the analogous dihydroxylation or aminohydroxylation reactions that are well-established processes in asymmetric synthesis. Here, we examine recent advances in metal-catalysed diamination reactions and their asymmetric variants. Given the prevalence of these structures, it seems likely that they will find extensive application in the construction of natural products and drug molecules in the near future.

Stereocontrolled Cyclic Nitrone Cycloaddition Strategy for the Synthesis of Pyrrolizidine and Indolizidine Alkaloids

The synthesis of polyhydroxylated indolizidines and pyrrolizidines belonging to the class of iminosugars, endowed with a vast and assorted biological activity, can be achieved in a straightforward manner by a general strategy consisting of a highly stereoselective 1,3-dipolar cycloaddition of polyhydroxylated pyrroline-N-oxides followed by simple transformations of the isoxazolidine adducts. The strategy allows the complete control of the relative and absolute stereochemistry of the numerous stereogenic centers decorating these compounds.

1,3-Aminoalcohols by reductive cleavage of isoxazolidines with molybdenum hexacarbonyl

Abstract Isoxazolidines are reductively cleaved to 1,3-aminoalcohols by reacting with Mo(CO) 6 and water. Reaction conditions are simple, mild and selective giving good yields of highly functionalized products with complete retention of configuration of the stereocenters. The reduction fails when steric hindrance is experienced by the nitrogen atom.

Total syntheses of hyacinthacine A2 and 7-deoxycasuarine by cycloaddition to a carbohydrate derived nitrone

Practical syntheses of nitrone 8 by two different approaches from sugars are reported. Its use as a versatile intermediate in highly selective 1,3-dipolar cycloaddition reactions constitutes the key step for novel total syntheses of hyacinthacine A2 (3) and 7-deoxycasuarine (20) by simple transformations of a common isoxazolidine adduct.

Synthesis of nitrones by methyltrioxorhenium catalyzed direct oxidation of secondary amines

Abstract Oxidation of secondary amines catalyzed by methyltrioxorhenium (MTO) with H 2 O 2 or urea-hydrogen peroxide complex (UHP) at room temperature gives the corresponding nitrones in good yields.

Manganese dioxide oxidation of hydroxylamines to nitrones

Abstract Several structurally differentiated N,N-dialkylhydroxylamines were oxidised to the corresponding nitrones using MnO2. Manganese dioxide revealed an efficient and mild reagent for oxidation of hydroxylamines, showing a level of regioselectivity comparable to HgO. Its non-toxicity makes MnO2 the reagent of choice for replacing HgO in this oxidation.

Catalytic oxidation of secondary amines with tetra-n-propylammonium perruthenate

Abstract Oxidation of secondary amines by N-methylmorpholine N-oxide and catalytic amounts of tetra-n-propylammonium perruthenate (TPAP) affords straightforwardly the corresponding imines in good yields.

(1S,2S,7R,8aS)- and (1S,2S,7S,8aS)-trihydroxyoctahydroindolizine: Two new glycosidase inhibitors by nitrone cycloaddition strategy

Abstract The two new epimeric (1 S ,2 S ,7 R ,8a S )- and (1 S ,2 S ,7 S ,8a S )-1,2,7-trihydroxyoctahydroindolizines 4 and 5 have been synthesized via methylenecyclopropane-nitrone cycloaddition-rearrangement methodology employing an enantiomerically pure l -tartaric acid derived nitrone 7b . Highly stereoselective reductions of the intermediate indolizidinone 10b and final deprotection furnished the two title indolizidinetriols 4 and 5 , the inhibiting abilities of which toward 24 commercially available glycosidases were tested. Both 4 and 5 are good competitive inhibitors of amyloglucosidases with K i values of ca. 6 and 75 μM, respectively. Compared with (+)-lentiginosine 3, 4 and 5 are less powerful inhibitors but, in contrast to 3 , the (7 R )-hydroxy analogue 4 possesses a weak inhibiting activity toward α- l -fucosidase from bovine epididymis. A model to rationalize the structure-activity relationship of (+)-lentiginosine and the two new 7-hydroxylentiginosines toward glucoamylases is proposed on the basis of their structural comparison with known inhibitors and with the natural enzymes substrate amylose.

Total syntheses of casuarine and its 6-O-alpha-glucoside: complementary inhibition towards glycoside hydrolases of the GH31 and GH37 families

Total synthesis of naturally occurring casuarine (1) and the first total synthesis of casuarine 6-O-alpha-glucoside (2) were achieved through complete stereoselective nitrone cycloaddition, Tamao-Fleming oxidation and selective alpha-glucosylation as key steps. Biological assays of the two compounds proved their strong and selective inhibitory properties towards glucoamylase NtMGAM and trehalase Tre37A, respectively, which place them among the most powerful inhibitors of these enzymes. The structural determination of the complexes of NtMGAM with 1 and of Tre37A with 2 revealed interesting similarities in the catalytic sites of these two enzymes which belong to different families and clans.

Straightforward Access to Enantiomerically Pure, Highly Functionalized Pyrrolizidines by Cycloaddition of Maleic Acid Esters to Pyrroline N-Oxides Derived from Tartaric, Malic and Aspartic Acids − Synthesis of (−)-Hastanecine, 7-epi-Croalbinecine and (−)-Croalbinecine

The cycloaddition reactions of dimethyl maleate to three functionalized enantiopure pyrroline N-oxides and one related racemic nitrone are reported. The study of the diastereoselectivity in the cycloaddition has been carried out by ample variation of the substituents at both the dipole and dipolarophile counterparts. The major cycloadducts, derived from the preferred exo-anti transition states and formed with 62−90% diastereoselectivity, have been subjected to Mo(CO)6-induced reductive ring-opening to afford directly highly functionalized enantiopure pyrrolizinone derivatives, valuable as synthetic intermediates. Applications of this strategy to a straightforward formal synthesis of (−)-hastanecine and to the total synthesis of the novel 7-epi-croalbinecine and of (−)-croalbinecine are reported.