lunes, 29 de marzo de 2010
martes, 23 de marzo de 2010
Lactobacillus reuteri 2'-Deoxyribosyltransferase, a Novel Biocatalyst for Tailoring of Nucleosides
J. FERNANDEZ LUCAS, C. ACEBAL, J.V. SINISTERRA, M. ARROYO, I. DE LA MATABiocatalytic Strategies for the Asymmetric Synthesis of alpha-Hydroxy Ketones
P. HOYOS, J.V. SINISTERRA, F. MOLINARI, A.R. ALCANTARA, P. DOMINGUEZ DE MARIAPilar Hoyos was born in Madrid (Spain) in 1980, and she received her B.S. degree in Pharmacy (2003) and Ph.D. in Chemistry (2008) from Complutense University of Madrid. Her ongoing research as a member of the Biotransformations Group inside the Department of Organic and Pharmaceutical Chemistry (Complutense University of Madrid) focuses on the chemoenzymatic synthesis of optically pure secondary alcohols and α-hydroxycarbonyl compounds as chiral building blocks for drugs, mainly by means of hydrolases, lyases, and oxido-reductases.
Josep-Vicent Sinisterra was born in Madrid (Spain) in 1950 and received his B.S. (1972) and Ph.D. (1975) degrees in Chemistry from the University Complutense de Madrid (UCM). He was a postdoctoral fellow (1981−1982) at the Ecole Polytechnique (Toulouse, France), and invited professor in the Enzymatic technology laboratory of CNRS - Marseille (1986−87), and in the Biology Department (University of Warwick (1996). Since 1988, he has been a full professor in Organic & Pharmaceutical Chemistry at the Faculty of Pharmacy (UCM) as well as director of the Biotransformations Group, qualified as a research quality group in Spain. In addition, he is director of Industrial Biotransformations Service, a R+D+i institute in the Parque Cientifico de Madrid. His major research lines are whole-cell-biocatalyzed reactions, preparation of biocatalysts, and chemoenzymatic production of chiral building blocks for drugs and food additive synthesis. He has published more than 260 papers in international journals of Biocatalysis, Biotransformations, and Organic Chemistry.
Francesco Molinari was born in 1961 in Milano, Italy. He received a B.S. in chemistry (1986) under the supervision of Prof. Francesco Sannicol and Ph.D. (1991) under the supervision of Prof. Cesare Gennari. During these years, his fields of interest were organic synthesis applied to problems of molecular recognition, bifunctional catalysis, and stereoselective carbon−carbon formation. He was a postdoctoral fellow at the Instituto Tecnico of Lisbon working on extractive bioconversions with Prof. Joaquim Cabral. He began his independent career at the Industrial Microbiology Section of the Department of Food Science and Microbiology, University of Milano in 1992. Since 2000, he has been Professor of Chemistry and Biotechnology of Fermentations at the University of Milano. Prof. Molinari’s research interests include (stereo)-selective biotransformations, production and isolation of microbial secondary metabolites, and wine fermentations. He has been member of the Scientific Board of the Italian Society of General Microbiology and Microbial Biotechnology (SIMGBM) and of the Italian Association of Biocatalysis and Bioseparations (AIBB).
The development of efficient syntheses for enantiomerically enriched α-hydroxy ketones is an important research focus in the pharmaceutical industry. For example, α-hydroxy ketones are found in antidepressants, in selective inhibitors of amyloid-β protein production (used in the treatment of Alzheimer’s), in farnesyl transferase inhibitors (Kurasoin A and B), and in antitumor antibiotics (Olivomycin A and Chromomycin A3). Moreover, α-hydroxy ketones are of particular value as fine chemicals because of their utility as building blocks for the production of larger molecules. They can also be used in preparing many other important structures, such as amino alcohols, diols, and so forth. Several purely chemical synthetic approaches have been proposed to afford these compounds, together with some organocatalytic strategies (thiazolium-based carboligations, proline α-hydroxylations, and so forth). However, many of these chemical approaches are not straightforward, lack selectivity, or are economically unattractive because of the large number of chemical steps required (usually combined with low enantioselectivities).
In this Account, we describe three different biocatalytic approaches that have been developed to efficiently produce α-hydroxy ketones:
(i) The use of thiamine diphosphate-dependent lyases (ThDP-lyases) to catalyze the umpolung carboligation of aldehydes. Enantiopure α-hydroxy ketones are formed from inexpensive aldehydes with this method. Some lyases with a broad substrate spectrum have been successfully characterized. Furthermore, the use of biphasic media with recombinant whole cells overexpressing lyases leads to productivities of 80−100 g/L with high enantiomeric excesses (up to >99%).
(ii) The use of hydrolases to produce α-hydroxy ketones by means of (in situ) dynamic kinetic resolutions (DKRs). Lipases are able to successfully resolve racemates, and many outstanding examples have been reported. However, this approach leads to a maximum theoretical yield of 50%. As a means of overcoming this problem, these traditional lipase-catalyzed kinetic resolutions are combined with racemization of remnant substrate, which can be done in situ or in separate compartments. Examples showing high conversions (>90%) and enantiomeric excesses (>99%) are described.
(iii) Whole-cell redox processes, catalyzed by several microorganisms, either by means of free enzymes (applying a cofactor regeneration system) or by whole cells. Through the use of redox machineries, different strategies can lead to high yields and enantiomeric excesses. Some enantiopure α-hydroxy ketones can be formed by reductions of diketones and by selective oxidations of vicinal diols. Likewise, some redox processes involving sugar chemistry (involving α-hydroxy ketones) have been developed on the industrial scale. Finally, the redox whole-cell concept allows racemizations (and deracemizations) as well.
These three strategies provide a useful and environmentally friendly synthetic toolbox. Likewise, the field represents an illustrative example of how biocatalysis can assist practical synthetic processes, and how problems derived from the integration of natural tools in synthetic pathways can be efficiently tackled to afford high yields and enantioselectivities.
Enzyme-catalyzed synthesis of unnatural or modified nucleosides
JOSE VICENTE SINISTERRA; ANDRÉS-RAFAEL ALCÁNTARA; MARCOS ALMENDROS; MARÍA JOSÉ HERNÁIZ; JOSÉ-MARÍA SANCHEZ-MONTERO; JORGE TRELLESGreen glycosylation using ionic liquid to prepare alkyl glycosides for studying carbohydrate–protein interactions by SPR
F. J. MUÑOZ, S. ANDRE, H.J. GABIUS, J.V. SINISTERRA, M.J. HERNAIZ, R.J. LINHARDT 
http://dx.doi.org/10.1039/b814171a
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