Showing papers in "Synlett in 1998"

Polysaccharide-based chiral lc columns

Abstract: Liquid chromatographic (LC) enantioseparations of various racemates on polysaccharide-based chiral stationary phases (CSPs) are mainly described. The wide applicability and usefulness of this technique in analysis and preparation of optical isomers (enantiomers) have been demonstrated by a comprehensive survey of the literature.

Pro-Nucleotides - Recent Advances in the Design of Efficient Tools for the Delivery of Biologically Active Nucleoside Monophosphates

Abstract: A summary of the most recent advances to the design of pronucleotides will be presented. Approaches that have been designed to be activated by enzymes such as carboxyesterases [bis(POM)-, bis(POC)-, bis(SATE)-, bis(AB) phosphotriesters and the arylphosphoramidates] or by reductases [bis(SDTE) approach] will be discussed as well as the amino acids phosphoramidate diester concept with its still unknown delivery mechanism and the cycloSal approach that releases the nucleotides by an induced tandem reaction. Nucleoside analogues, e.g. 2',3'-dideoxy-2',3'-didehydrothymidine 1 (d4T), 3'-azido-2',3'-dideoxythymidine 2 (AZT) or 5-fluoro-2'deoxyuridine 3 (5-FdU), are structurally different as compared to the corresponding natural DNA or RNA nucleosides with regard to modification of the glycon as well as the aglycon residue. Due to this modified structure, these compounds are widely used as antiviral or antitumor drugs in chemotherapy (Figure 1) (1). Since the discovery of AZT 2 as the first nucleoside drug for the treatment of AIDS, considerable efforts have been made to develop new nucleoside analogues that would be more active, less toxic inhibitors of the HIV-1 reverse transcriptase (RT) (2). The general mode of action of nucleoside analogues is the inhibition of the HIV-1 RT by acting as competitive inhibitors or as DNA chain terminators. To act as DNA chain termination agents or RT inhibitors, intracellular conversion of the nucleoside analogues into their 5'-mono-, 5'-dior 5'-triphosphates is a prerequisite after cell penetration (3). The enormous disparity in antiHIV activity that is evident for a large number of dideoxynucleoside analogues belies their apparent structural similarity. Due to these structural differences as compared to natural nucleosides the metabolization to the corresponding dideoxynucleoside triphosphates is often inefficient and consequently the therapeutic efficacy is sometimes limited(4). For example, in the case of the anti-HIV active dideoxynucleoside analogue d4T 1 (Stavudine, Zerit ®)(5) the first phosphorylation to d4T 5'-monophosphate 4 catalyzed by thymidine kinase (TK) is the rate-limiting step in human cells (6). More striking, however is 2',3'-dideoxyuridine triphosphate (ddUTP) which is one of the most powerful and selective inhibitors of HIV reverse transcriptase (Ki = 0.05 μM) while the parent nucleoside 2',3'-dideoxyuridine 5 (ddU) is virtually ineffective at blocking HIV infection in cultured cells. Biochemical and pharmacological studies in three different human T cell lines (CEM, ATH8 and Molt-4) showed that ddU 5 itself was not anabolized to the 5'-monophosphate, most apparently because it was a poor substrate for cellular nucleoside kinases because of the considerable substrate specificity of these enzymes (7). In contrast, in a few cases the limited efficacy is also due to a catabolic enzymatic reaction. For example, 2',3'-dideoxyadenosine 6 (ddA) is rapidly intracellularly deaminated to ddI 7 by adenosine deaminase (ADA) (8,9). As a consequence, ddI 7 has to be converted into its ultimate bioactive metabolite ddATP via ddAMP 8 by five enzymatic steps (5'nucleotidase, adenylosuccinate synthase, adenylosuccinate lyase and two nucleotide kinases) (8,9). Finally, the resistance of the human immunodeficiency virus to the clinically used antiviral dideoxynucleoside AZT 2 (Zidovudine, Retrovir ®)(10) is on the one hand directly related to multiple point mutations within the HIV-1 r verse transcriptase gene of the virus but may on the other hand be also due to lower susceptibility of resistant target cells to the drug related with a decreased activity or inability of the enzyme thymidine kinase to phosphorylate AZT 2 to the dideoxynucleoside monophosphate AZTMP 9(11). Consequently, direct administration of the nucleotides d4TMP 4, ddAMP 8 and AZTMP 9 should bypass these limiting steps and hence has advantages for the biological activity. Unfortunately, because of the high polarity of the nucleoside monophosphates (nucleotides), these compounds are not able to easily penetrate cellular membranes or the blood-brain barrier. However, the phosphate moiety offers a suitable site to attach degradable lipophilic carrier residues. As a result, one effort to improve the therapeutic potential of nucleoside analogues is the delivery of the corresponding nucleotide from neutral, membranepermeable prodrugs (Pro-Nucleotide Approach ; Figure 2) (12). T hi s do cu m en t w as d ow nl oa de d fo r pe rs on al u se o nl y. U na ut ho riz ed d is tr ib ut io n is s tr ic tly p ro hi bi te d. 234 C. Meier SYNLETT So, a lipophilic phosphotriester may penetrate into the target cell where first partial and at the end complete hydrolysis delivers the nucleotide. A suitable nucleotide prodrug has to fulfill two requirements: i) it has to be lipophilic enough for passive diffusion of the membrane and bloodbrain barrier; ii) furthermore, it should be able to deliver the nucleoside hydrolytically or enzymatically leaving a non-toxic masking group (13). In principle, two different concepts for prodrug design are known: bipartate and tripartate prodrugs. In the former concept the drug is modified by a one-component masking group. In this form the drug is biologically inactive. After a simple cleavage of the mask, the active drug is liberated (Figure 3). In the latter concept, the drug is modified by a two-component masking group. Again, the drug is biologically inactive in this bound form. The mechanism of liberation involves a first chemical or enzymatic reaction under cleavage of part I of the masking moiety. The drug is still inactive but the effect of this first reaction is an activation of the remaining masking group II with the consequence of a spontaneous successive cleaving reaction releasing the now bioactive drug (Figure 3) (14). In the case of a nucleotide prodrug one should take into account that under physiological conditions two negatively charged phosphate oxygen's have to be masked in order to obtain a neutral, lipophilic phosphate ester. Consequently, not only one masking group is necessary but two. So, the efficient intracellular delivery of nucleotides from a prodrug requires the existence of a specific delivery mechanism or different rates of conversion of the prodrug to the drug intracellularly versus extracellularly. One comment with respect to toxic side events should be given. Neutral phosphorus derivatives with a good leaving group attached to the phosphorus are known to be toxic suicide inhibitors of acetylcholinesterase (15). The anti-acetylcholinesterase activity of phosphorus derivatives is an inverse function of the pK a of the leaving group on the phosphorus atom and parallels the rate of spontaneous hydrolysis by P-O bond cleavage (16). In order to circumvent the possible problem of anti-cholinesterase activity, neutral phosphate ester prodrugs should be designed to undergo heterolytic cleavage of the C-O bond rather than the P-O bond of the ester. Many strategies have been developed to achieve this goal. As a general motive, uncharged nucleotide triesters are used as membrane-permeable nucleotide precursors (12). The major differences of these approaches are the delivery mechanisms to the nucleotides. First attempts have been made with simple dialkyl phosphotriesters. These compounds generally belong to the class of bipartate prodrug systems. After a first, sometimes selective hydrolysis of the phosphotriester via a nucleophilic reaction at the phosphorus center, the resulting phosphodiester is often extremely stable against a further chemical hydrolysis due to the charge at the phosphate which prevents a second nucleophilic reaction (17). Even if the subsequent hydrolysis is possible, one should take the pseudorotation phenomenon into account that excludes a selective delivery of the nucleotide(18). As a consequence, almost all approaches based on chemical hydrolysis reported so far were unable to deliver the nucleotide selectively except the cycloSal approach that will be discussed later. For this reason, the newer pro-nucleotide approaches are based on the concept of a tripartate prodrug system (14) and are based on the general idea of a selective chemical or enzymatic reaction within the masking group which leads to a second, spontaneous successive reaction yielding the charged phosphate ester. These approaches utilize and exploit the differences in reducing potentials, enzyme activity, and pH value. The concepts working with enzymatic trigger processes (bis(POM)-, bis(POC)-, bis(DTE)-, bis(SATE)-, bis(AB)and the arylphosphoramidate concept) as well as the cycloSal approach based on a pH-driven degradation have demonstrated the successful intracellular delivery of free nucleotides from lipophilic precursors. It should be added, that it is not the intention of the author to give an entire overview of the pro-nucleotide field. The current review highlights some approaches that have been designed to deliver the nucleotide selectively by a special mechanism. With this selection, the author wants to point out that designing a delivery mechanism and bypassing a certain limiting metabolization the inherent biological potential of an already known nucleoside analogue could be used to a higher extent and consequently, the improvement in antiviral activity could be, in many cases, better than synthesizing new potential nucleoside analogues. Furthermore, this review is restricted to the delivery mechanism and so the synthesis of the compounds may be leaned from the original literature. Chris Meier, born 1962 in Berlin, was trained in Chemistry at the University of Marburg. He passed his Diploma and Ph.D. thesis in the group of Prof. G. Boche in Organic Chemistry. Then he moved as postdoc fellow to the Pasteur-Institute in Paris where he started his work in nucleoside and oligonucleotide chemistry. In 1991 he joined the group of Prof. J.W. Engels at the University of Frankfurt/Ma

Mild Preparation of Haloarenes by Ipso-Substitution of Arylboronic Acids with N-Halosuccinimides

Abstract: Aryl and heteroaryl boronic acids react with N-iodosuccinimide and N-bromosuccinimide to give the corresponding iodoand bromoarenes in good to excellent yields . The reaction is usually highly regioselective and yields only the ipso -substituted product . Esters of arylboronic acids react similarly, but less readily. It was recently reported that alkenyl boronic acids can be converted into alkenyl halides by reaction with N-halosuccinimides . 1 The reaction is believed to proceed via a boron activation / direct displacement mechanism , affording geometrically pure products with retention of configuration . Herein we report the analogous conversion of arylboronic acids to the corresponding haloarenes . Arylboronic acids2 are readily available and easy to handle compounds, which have recently become important substrates in organic synthesis as aryl group donors in the Suzuki coupling reaction .3 They are generally less reactive than alkenyl boronic acids and are not expected to react with N-halosuccinimides via an addition / elimination mechanism. Haloarenes are valuable synthetic intermediates and various methods for their preparation have been developed. While electrophilic aromatic halogenation works well for the preparation of chloroarenes and bromoarenes , the direct iodination of arenes with iodine is generally not feasible4 and a number of different methods for the preparation of iodoarenes have been developed .5 These include : (a) the use of strong oxidizing reagents to activate the halogens ,6 (b) various methods involving the use of highly reactive and toxic aromatic mercury7 and thalliums compounds , and (c) the Sandmeyer reaction ,9 involving the regioselective introduction of chlorine, bromine and iodine via aryl diazonium ions under acidic conditions. The procedure reported herein , involving the use of N-halosuccinimides as sources of electrophilic halogen , is milder and complementary to the above methods and may be applied when harsh reaction conditions must be avoided . In certain cases the preparation of haloarenes from aryl boronic acids may not be useful since the aryl boronic acids themselves are prepared from haloarenes . However, a number of substituted arylboronic acids are available via a directed metallation approach.10 In addition , the boronic acid functionality could serve as a protecting group for haloarenes , which can be easily regenerated under mild conditions by the reaction with N-halosuccinimides . This process may be particularly useful for the preparation of radiolabelled iodoarenes, which have found many applications as research tools and as components of diagnostic and therapeutic agents ." Typically, the preparation of these compounds require the efficient and regioselective introduction of radioactive iodine in one of the final steps of a multi-step synthesis by using Na125I. Several examples of iodoarenes (2) synthesized from aryl boronic acids (1) using Niodosuccinimide (NIS) in acetonitrile are shown below.12 Generally, only the ipso-substituted iodoarenes were observed as products , irrespective of the influence of directing groups on the aromatic ring. The method tolerates various functionalities and affords the product in good to excellent yields except for the strongly deactivated 3-nitrophenylboronic acid ( lg). NIS can also be generated in situ by reacting sodium iodide with N -chlorosuccinimide in acetonitrile . The yields for this procedure are the same within experimental error as for the procedure with commercially available NIS. The formation of NIS is rapid and an excess of sodium iodide is not needed . The fact that sodium iodide can be employed is important, since it is the most common source for radioactive iodine.

Tungsten Hexachloride (WCl6) as an Efficient Catalyst for Chemoselective Dithioacetalization of Carbonyl Compounds and Transthioacetalization of Acetals

Abstract: A variety of aldehydes, ketones and O,O-acetals were efficiently converted to the corresponding 1,3-dithianes and 1,3dithiolanes by using catalytic amounts of tungsten hexachloride (WCl6) in CH2Cl2 under mild conditions. The wide use of 1,3-dithianes and 1,3-dithiolanes as protecting groups for the carbonyl functionality,1 as nucleophilic acyl anion equivalents,2 and as masked methylene functions3 demands an intense search for new synthetic methods of these compounds. Dithioacetals are usually prepared by the acid catalyzed condensation of carbonyl compounds with thiols.1 Several types of acid catalysts used for this purpose including BF3.Et2O, 4 ZnCl2, 5 LnCl3, 6 AlCl3, 7 TiCl4, 8 TeCl4, 9 SiCl4, 10 (CH3)3SiCl, 11 Zn(OTf)2 and Mg(OTf)2, 12 MgI2.Et2O complex, 13 SnCl2.2H2O, 14 BiCl3 and Bi2(SO4)3. 15 A 5M ethereal solution of LiClO4 (LPDE) which works under neutral conditions, 16 as well as some supported reagent systems such as FeCl3-SiO2, 17 ZrCl4-SiO2, 18 SiO2-SOCl2 19 and inorganic solid acids such as Nafion-H20 and acidic ion exchange21 have also been developed. However, many of these methods require long reaction time, stoichiometric use of expensive reagent, and give poor selectivity when applied to the mixture of aldehydes and ketones. In continuation of our research on studying new applications of tungsten hexachloride (WCl6) in organic synthesis, 22 we now disclose the highly efficient and selective dithioacetalization of structurally different aldehydes, ketones, and related compounds such as acetals under mild reaction conditions in the presence of catalytic amounts of WCl6 (Scheme, Table 1).