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The simple synthesis of new O,N,O′-tridentate ligands derived from carbohydrates is illustrated. The ligands are obtained by condensing 2-amino-α- d -glucosides or 2-amino-α- d -alloside with several 3,5-disubstituted-2-hydroxybenzaldehydes. The efficiency of the imines in the V(IV)-promoted asymmetric oxidation of thioanisole has been examined and ee's up to 60% have been achieved.

International audience; Baeyer-Villiger monooxygenases (BVMOs) catalyze the transformation of linear and cyclic ketones into their corresponding esters and lactones by introducing an oxygen atom into a C-C bond. This bioreaction has numerous advantages compared to its chemical version; it does not induce the use of potentially harmful reagents (i.e., green chemistry) and displays significant better enantio- and regio-selectivity. New potential BVMOs were searched using sequence homology for type I BVMO proteins. 116 new sequences were identified as new putative BVMOs respecting the defined selection criteria. Multiple sequence alignments were carried out on the selected sequences to study the conservation of structurally and/or functionally important amino acids during evolution. Type I BVMO signature motif was found to be conserved in 94.8% of the sequences. We noticed also the highly conserved - but previously unnoticed - Threonine 167 (93.1%), located in the signature motif; this position could be added in the pattern used to characterize specific Type I enzymes. Amino acids at the vicinity of the FAD and NADPH cofactors were found also to be highly conserved and the details of the interactions were emphasized. Interestingly, residues at the enzyme binding site were found less conserved in terms of sequence evolution, leading sometimes to some important amino acid changes. These behaviors could explain the enzyme selectivity and specificity for different ligands.

Enantioselective acetylation (desymmetrization) of prochiral 2-(ferrocenylmethyl)propane-1, 2-diol (1), 2-(2-ferrocenylethyl)propane-1, 2-diol (2) and 2-(3-ferrocenylpropyl)propane-1, 2-diol (3) into chiral monoacetates [(+)-4-(+)-6], with a series of microbial lipases in benzene at 27_oC, revealed the lipase from Pseudomonas sp (PSL) as the most selective. Acetylation was fastest and the most enentioselective for conversion 1 to (+)-4 by PSL (97% e.e.). By comparison of the compounds (+)-4-(+)-6 with their benzene analogues of the known (R) absolute configuration, on the basis of their elution orders on Chiracel OD, and the same direction of their optical rotations, an R-configuration is proposed for (+)-monoacetates 4-6.

La síntesis de nucleósidos carbocíclicos es un tema de gran interés que ha sido muy desarrolladodurante los últimos años debido a la importancia de estos compuestos como agentes antivirales yantitumorales. La idea original en la que se basó el diseño de esta familia de compuestos es el aumento dela estabilidad de la unión glicosídica C-N produciendo los menores cambios estructurales posibles. Essabido que la conformación juega un papel muy importante en la modulación de la actividad biológica deuna droga. Debido a la ausencia del átomo de oxígeno del anillo furanósico, la conformación de loscarbanucleósidos suele diferir de la que presentan los nucleósidos convencionales en solución y, por estemotivo, en general son menos efectivos. lnspirados en la estructura cristalina del nucleósido carbocícliconatural neplanocina C (147), se sintetizaron carbanucleósidos conformacionalmente restringidos con unsistema bicíclico[3.1.0]hexano como unidad de pseudoazúcar los cuales eran capaces de imitar a laconformación de los nucleósidos convencionales. En esta tesis se sintetizaron por primera vez nucleósidos carbocíclicos conformacionalmenterestringidos construidos con un sistema 6-oxabicíclico[3.1.0]hexano como unidad de pseudoazúcar. Sepresenta la sintesis de 5'-nor-2',3'-didesoxiderivados de neplanocina C diseñados como inhibidores de laenzima S-adenosil-L-homocisteína hidrolasa. Se presenta también la primera síntesis enantioselectiva deneplanocina C (147) y del isómero no natural de neplanocina F (207), otro componente de la familia denucleósidos carbocíclicos naturales conocida con el nombre de neplanocinas. Por otro lado, (N)-metano-carba-timidina (7) es un nucleósido carbocíclico muy potente como agenteantiherpético, más efectivo en ensayos in vitro que las drogas utilizadas en la actualidad para el tratamientode estas infecciones. Se realizó la sintesis enantioselectiva de 2'-desoxiderivados de neplanocina C con elobjeto de evaluar su efectividad como agentes antivirales y como bloques de construcción deoligonucleótidos modificados. Por último. se presenta la primer síntesis enantioselectiva de (1R,2R,5S)-1{5-(Hidroximetil)biciclo[3.1.0]hex-3-en-2-il}-5-metil-1,3-dihidropirimidina-2,4-diona (310) y de (1R,2R,5S)-1-{ 5-(Hidroximetil)biciclo[3.1.0]hex-2-il}-5-metil-5,3-dihidropirimidina-2,4-diona ((—)-156) diseñados comoanálogos de d4T (311) y 2'-desoxitimidina (145) y como herramientas para el estudio de la preferenciaconformacional de las enzimas involucradas en la activación in vivo de 7. En todos los casos se utilizó unaestrategia convergente a través de una reacción de tipo Mitsunobu como método de acoplamiento del anillocarbocíclico y la base purinica o pirimidínica. The field of carbocyclic nucleosides Chemistry is a topic of great interest which experienced aphenomenal growth in the last years due to the increasing importance of these compounds as antiviral andantitumor agents. The original underlying concept for the synthesis of carbocyclic nucleosides was to seek astable C-N bond, while causing minimal structural disturbances. It is well known that the conformation of thesugar moiety plays a critical role in modulating biological activity. Because of the loss of the furan oxygenatom, the conformation of the ciclopentane ring in carbocyclic nucleosides differs from that displayed byconventional nucleosides in solution. This conformational difference could explain why certain carbocyclicnucleosides are generally less effective than convetional nucleosides. The bicyclo[3.1.0]hexane system wasused as the pseudosugar moiety to prepare a new family of rigid nucleosides with a conformation thatmimics conformations of conventional nucleosides. These compoundos were envisioned by the cristalstructure of neplanocina C (147), a naturally occurring carbocyclic nucleoside. In this Thesis, conformationally locked carbocyclic nuclesides built on an oxabicyclo[3.1.0]hexaneunit as pseudosugar moiety were synthesized for the first time. The synthesis of 5'-nor-2’,3'-dideoxyderivativesof neplanocin C is presented. These compounds were designed as S-adenosyl-L-homocysteinehydrolase inhibitors. The first enantioselective synthesis of neplanocin C (147) and theunnatural isomer of neplanocin F ((+)-207), another component of the neplanocin family of carbocyclicnucleosides were also presented. On the other hand, (N)-methano-carba-thymidine (7) is a carbocyclic nucleside that exhibits verypotent action as antiherpetic agent. In in vitro assays, it is more effective than the drugs currently in use forthe treatment of herpetic infections.The enantioselective syntheses of 2'-deoxyderivatives of neplanocin Cwas carried out aim at evaluating their antiviral potency and as building blocks of modified oligonucleotides. Finally, the enantioselective synthesis of (1R,2R,5S)-1-{5-(Hydroxymethyl)bicyclo[3.1.0]hex-3-en-2-yl}- 5-methyl-1,3-dihydropyrimidine-2,4-dione (311) and (1R,2R,5S)-1-{5-(Hydroxymethyl)bicyclo[3.1.0]hex-2-y|}-5-methyl-1.3-dihydropyrimidine-2,4-dione((—)-156)is presented. These compounds were designed asd4T (311) and 2'-deoxythymidine (145) analogs and as tools for studying the conformational preferences ofenzymes involved in the in vivo activation of 7. In all cases, a convergent approach employing the Mitsunobu reaction was used for coupling the carbocyclic ring with the corresponding purinic and pyrimidinicbases. Fil: Comin, María Julieta. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.