M. Isabel Matheu

An Efficient and General Enantioselective Synthesis of Sphingosine, Phythosphingosine, and 4-Substituted Derivatives†

A general and efficient protocol for the enantioselective synthesis of sphingosine, phythosphingosine, and 4-substituted derivatives was established. These compounds were obtained from a common intermediate prepared from butadiene monoepoxide by a synthetic sequence involving enantioselective allylic substitution, cross-metathesis, and dihydroxylation.

Chemo-, Regio-, and Stereoselective Silver-Catalyzed Aziridination of Dienes: Scope, Mechanistic Studies, and Ring-Opening Reactions

Silver complexes bearing trispyrazolylborate ligands (Tp(x)) catalyze the aziridination of 2,4-diene-1-ols in a chemo-, regio-, and stereoselective manner to give vinylaziridines in high yields by means of the metal-mediated transfer of NTs (Ts = p-toluensulfonyl) units from PhI═NTs. The preferential aziridination occurs at the double bond neighboring to the hydroxyl end in ca. 9:1 ratios that assessed a very high degree of regioselectivity. The reaction with the silver-based catalysts proceeds in a stereospecific manner, i.e., the initial configuration of the C═C bond is maintained in the aziridine product (cis or trans). The degree of regioselectivity was explained with the aid of DFT studies, where the directing effect of the OH group of 2,4-diene-1-ols plays a key role. Effective strategies for ring-opening of the new aziridines, deprotection of the Ts group, and subsequent formation of β-amino alcohols have also been developed.

Synthesis of d- and l-Carbocyclic Nucleosides via Rhodium-Catalyzed Asymmetric Hydroacylation as the Key Step

D- and L-carbocyclic nucleosides were obtained by a new procedure involving an enantioselective rhodium/duphos-catalyzed hydroacylation reaction as the key step. The 3-hydroxymethyl-cyclopentanol intermediate was obtained by stereoselective reduction of ketone and by dynamic kinetic resolution (DKR).

Synthesis of 2-deoxy-3,5-di-O-benzoyl-2,2-difluoro-D-ribose from D-glucose and D-mannose. A formal synthesis of gemcitabine

Abstract The title compound 2-Deoxy-3,5-di-O-benzoyl-2,2-difluoro-D-ribose (17), was synthesised from D-glucose and from D-mannose. The key steps of the synthesis from D-glucose are obtaining the 3,3-difluoropyranose 9 by reacting the ulose 7 with DAST, and their conversion into the difluorofuranoside 17 by a degradative reaction of diol 16. Starting from D-mannose the synthesis obtains the 3,3-difluoroglycal 22 by reaction of the ulose 18 with DAST and oxidation-elimination of selenoglycoside 21. Ozonolysis of 22 gives the difluorofuranose 17.

The reaction of pyranoside 2-uloses with DAST revised. Synthesis of 1-fluoro-ketofuranosyl fluorides and their reactivity with alcohols

Abstract We have reinvestigated the reaction of α-pyranosides-2-uloses 13 , 14 , 19 and 24 with DAST and shown that the 1,2-difluorinated compounds 17 , 18 and 25 are produced by a ring-contraction reaction. The reaction of 18 with benzyl alcohol gives the tri-benzyl derivative 26 or compound 27 , depending on the reaction conditions. Treating 17 with 2-naphthol produced the spiranic compounds 29 – 31 . The reaction of 17 with bis(trimethylsilyl)uracil produced the mononucleoside 28 , which preserves the fluorine atom in the more substituted carbon.

Short and General Procedure for Synthesizing Cis-1,2-Fused 1,3-Oxathiolan-, 1,3-Oxaselenolan-, and 1,3-Oxazolidin-2-imine Carbohydrate Derivatives

Novel cis-1,2-fused 1,3-oxathiolan-, 1,3-oxaselenolan-, and 1,3-oxazolidin-2-imine carbohydrate derivatives have been prepared by treatment of the corresponding 1,2-anhydrosugars with potassium thiocyanate, potassium selenocyanate, and sodium cyanamide, respectively. The procedure is compatible with several protecting groups such as acyl, benzyl, and silyl and also with sugars of different configurations.

Sequential Directed Epoxydation-Acidolysis from Glycals with MCPBA. A Flexible Approach to Protected Glycosyl Donors

4,6-Di-O-protected glucal and allal derivatives react with MCPBA to afford manno- and allo-1-O-m-chlorobenzoate derivatives, respectively, as a result of a syn epoxidation directed by the allylic hydroxyl group, and consecutive ring-opening by m-ClBzOH. When glucal and allal derivatives are fully protected, initial epoxidation proceeds mainly anti to the allylic group to give, after ring-opening, the corresponding pyranosyl chlorobenzoates. Stereoselectivity in the reaction of fully protected galactal derivatives was complete, although only a moderate increase in the syn epoxidation product was observed in 4,6- and 3,4-di-O-protected derivatives. 1-O-m-Chlorobenzoate 18 was selectively protected and activated as donor in the synthesis of disaccharide 21.

Tuning the stereoelectronic properties of 1-sulfanylhex-1-enitols for the sequential stereoselective synthesis of 2-deoxy-2-iodo-β-D-allopyranosides.

The preparation of challenging 2-deoxy-2-iodo-β-D-allo precursors of 2-deoxy-β-D-ribo-hexopyranosyl units and other analogues is reported using a robust olefination-cyclization-glycosylation sequence. Here, we particularly focus on tuning the stereoelectronic properties of the alkenyl sulfides intermediates in order to improve the diastereoselectivity of the cyclization step and, hence, the efficiency of the overall transformation. Phosphine oxides with the general formula Ph2P(O)CH2SR (R = t-Bu, Cy, p-MeOPh, 2,6-di-ClPh, and 2,6-di-MePh) were easily synthesized and subsequently used in the olefination reaction with 2,3,5-tri-O-benzyl-D-ribose and -D-arabinose. The corresponding sugar-derived alkenyl sulfides were submitted to a 6-endo [I(+)]-induced cyclization, and the resulting 2-deoxy-2-iodohexopyranosyl-1-thioglycosides were used as glycosyl donors for the stereoselective synthesis of 2-deoxy-2-iodohexopyranosyl glycosides. Among the different S-groups studied, t-Bu derivative was the best performer for the synthesis of cholesteryl 2-deoxy-2-iodomannopyranosides, whereas for the synthesis of 2-deoxy-2-iodoallopyranosides none of the derivatives here studied proved superior to the phenyl analogue previously described. Glycosylation of cholesterol with different d-allo and d-manno derivatives produced 2-deoxy-2-iodoglycosides with stereoselectivities in the same order in each case, reinforcing the involvement of an oxocarbenium ion as the common intermediate of this crucial glycosylation step.

Studies on the Zn(II)-mediated electrophilic selenocyclization and elimination of 3,4-O-isopropylidene-protected hydroxyalkenyl sulfides: synthesis of a 2-phenylselenenyl glycal

Herein, we describe a mild and efficient Zn(II)-mediated electrophilic selenocyclization reaction of readily available and stable 3,4-O-isopropylidene-protected hydroxyalkenyl sulfides to 2-deoxy-2-phenylselenenyl-1-thio-glycosides. This material was transformed into a 2-phenylselenenyl glycal in a controlled manner using an activation-elimination sequence.

Chemical Access to d-Sarmentose Units Enables the Total Synthesis of Cardenolide Monoglycoside N-1 from Nerium oleander

Herein we present a chemical approach for the ready preparation of d-sarmentosyl donors enabling the first total synthesis and structure validation of cardenolide N-1, a challenging 2,6-dideoxy-3-O-methyl-β-d-xylo-hexopyranoside extracted from Nerium oleander twigs that displays anti-inflammatory properties and cell growth inhibitory activity against tumor cells. The strategy highlights the synthetic value of the sequential methodology developed in our group for the synthesis of 2-deoxyglycosides. Key steps include Wittig-Horner olefination of a d-xylofuranose precursor, [I+]-induced 6-endo cyclization, and 1,2-trans stereoselective glycosylation.