Simonetta Benetti

Synthetic Routes to Chiral Nonracemic and Racemic Dihydro- And Tetrahydrothiophenes

Natural and man-made organosulfur compounds play important roles in biological and medicinal chemistry. Among the various classes of organic sulfur compounds, dihydroand especially tetrahydrothiophenes have attracted particular attention because of the widespread occurrence as ring system motifs in natural and nonnatural products displaying a broad spectrum of biological activities. Tetrahydrothiophene-based compounds include the essential coenzyme biotin 1, a water-soluble vitamin involved in important biological functions, and the potent α-glucosidase inhibitors salacinol 2 6 and kotalanol 3, isolated from several Salacia plant species. Recently, the related compounds salaprinol 4 and ponkoranol 5 were isolated from Salacia prinoides, and significant efforts to prepare these cyclic sulfonium salts and synthetic analogues, including 6 and 7, have been made in the past few years (Figure 1). Further representative compounds are the 40-thioadenosine derivative 8, a highly potent and selective A3 adenosine receptor antagonist; the 40-thiocytidine nucleoside 9, active against HSV-1 and HSV-2; the cholecystokinin type-B receptor antagonist tetronothiodin 10; and (R)-tetrahydrothiophen-3-ol 11, 18 a pivotal intermediate to obtain the potent antibacterial Sulopenem 12 (Figure 2). The field of applications of tetrahydrothiophenes is impressively wide in scope: these compounds have been employed as templates to assist and control various chemical transformations, including asymmetric hydrogenation, catalytic asymmetric epoxidation, and catalytic intramolecular cyclopropanation. Moreover, adsorption of tetrahydrothiophene on gold has emerged as a powerful tool to obtain self-assembled monolayers (SAMs), which can be used to control physical and chemical properties of surfaces for various technological purposes. The dihydrothiophene ring system is a common structural feature of many bioactive compounds, some of which are shown in Figure 3. In particular, (S)-ethyl 4-amino-4,5-dihydrothiophene-2-carboxylate 13 inhibits copper amine oxidases (CAOs), the unnatural L-nucleoside 14 displays potent anti-HIV activity without significant toxicity, and 4,5-dihydrothiophene-3-carbonitrile 15 exhibits antibacterial and antifungal properties. Interestingly, it has been demonstrated that calicheamicin becomes active Figure 1.

Diastereoselective synthesis of β-amino-α-hydroxy phosphonates via oxazaborolidine catalyzed reduction of β-phthalimido-α-keto phosphonates

Abstract Reduction of β-phthalimido-α-keto phosphonates, obtained through an Arbuzov reaction between the appropriate acid chloride and triethyl phosphite, with boranes and oxazaborolidine as catalyst, afforded β-phthalimido-α-hydroxy phosphonates in good yields and high diastereoselectivity. Deprotection of the amino group gave the title compounds.

A unified asymmetric approach to substituted hexahydroazepine and 7-azabicyclo[2.2.1]heptane ring systems from D(−)-quinic acid: Application to the formal synthesis of (−)-balanol and (−)-epibatidine

3,4-O-Isopropylidene-3(R),4(S)-dihydroxycyclohexanone 7, a chiron easily prepared through a five step sequence from D(-)-quinic acid 1, has been efficiently utilized as the starting building block for the enantioselective syntheses of (3R,4S)-N-p-toluenesulfonyl-3,4-epoxy-hexahydroazepine 17 and (1R,4S)-N-tert-butoxycarbonyl-7-azabicyclo[2.2.1]heptan-2-one 43, advanced intermediates already taken to (-)-balanol and (-)-epibatidine respectively. While the nitrogen atom ring-insertion via Beckmann rearrangement was the key step for the construction of the hexahydroazepine ring of 17, a regio- and stereospecific intramolecular nucleophilic ring opening of an intermediate cyclic sulfate featured the approach to the substituted 7-azabicyclo[2.2.1]heptane nucleus of 43.

Tandem michael reactions for the construction of pyrrolidine and piperidine ring systems

Abstract A convergent one-pot construction of disubstituted pyrrolidine and piperidine frameworks has been accomplished through a simple protocol involving intermolecular conjugate addition of a nitrogen nucleophile to an electrophilic olefin followed by intramolecular trapping of the generated enolate by a built-in α,β,-unsaturated acceptor.

Synthetic studies towards forskolin

Abstract A model tricyclic system incorporating the complete array of oxygenated functions of the AB portion of forskolin has been synthetized. The highly substituted decalin unit of the natural target has been in turn assembled in a convenient way utilizing an intramolecular nitrile oxide cycloaddition reaction as key step.

Polymer-bound 4-benzylsulfonyl-1-triphenylphosphoranylidene-2-butanone as a tool for the solid-phase synthesis of substituted piperidin-4-one derivatives.

Abstract An efficient method for the construction of 2-substituted-piperidin-4-one derivatives on solid support has been developed using polymer-bound 4-benzylsulfonyl-1-triphenylphosphoranylidene-2-butanone as a convenient precursor for substituted divinyl ketones in the heterocyclization reaction with amines. The resin was released in a recyclable sulfinate form.

Enantioselective synthesis of (+)- and (−)-α-allokainic acid

Abstract A concise enantioselective route to (+)- and (−)-a-allokainic acid from D- and L-serine respectively has been established by enantio- and diastereo-selective tandem Michael reaction methodology for the construction of three chiral centers in a single stage.

Enantioselective approach to 7-azabicyclo[2.2.1]heptane ring systems using D-(−)-quinic acid as the chiral educt: Application to the formal synthesis of (+)-epibatidine

By utilizing D-(−)-quinic acid as the chiral starting material the optically pure 7-[(1,1-dimethylethoxy)carbonyl]-7-azabicyclo[2.2.1.]heptan-2-one 2, an advanced intermediate already taken to (+)-epibatidine 1, a non-opioid analgesic isolated from Ecuadorian poison frogs, was synthetized through a facile, regioselective intramolecular nucleophilic ring opening of a cyclic sulfate moiety.

Generation and cycloaddition reactions of 3-substituted-2-nitro-1,3-dienes

Abstract Two procedures for the regiospecific preparation of 3-substituted-2-nitro-1,3-dienes have been developed. The cycloaddition chemistry of the in situ generated dienes has been investigated.

Enantiodivergent synthesis of 2-hydroxymethyl-3-hydroxy-4-nitro-pyrrolidines through tandem Michael-Henry reaction using L-serine as the chiral educt

Abstract By utilizing L-serine, both enantiomers of all trans 2-hydroxymethyl-3-hydroxy-4-nitro-pyrrolidine were efficiently prepared through tandem Michael-Henry methodology. Their stereochemistry has been assigned through conversion of one of them to trans 2-hydroxymethyl-3-hydroxypyrrolidine, a naturally occurring compound recently isolated from Castanospermum australe.