Nucleoside optical activity

Levitt MS, RE Newton, SM Roberts, AJ Willetts (1990) Preparation of optically active 6 -fluorocarbocyclic nucleosides utilising an enantiospecific enzyme-catalysed Baeyer-Villiger type oxidation. J Chem Soc Chem Comm 619-620. 

RhH(PPh3)4 (1 mol%) exhibited higher catalytic activity and promoted a complete reversal in stereoselectivity to provide the trans isomer of 24 and 25 as the major reaction product. The czs-cyclopentane 29, derived from optically active 28, was converted to the differentially protected cyclopentane triol 29, which, in turn, converted to the differentially protected tetrad 30, a key intermediate in the synthesis of enantiopure bioactive carbo-cyclic nucleosides [19]. 

The reaction of silyl ketene acetal addition to nitrones has been used for the synthesis of optically active (2S,3S)-benzoyl- and /V- oc-phenyl isoserine (636a) of isoxazolidine nucleoside-analog of thymine polyoxine C(636b) and of... 

Tributyl tin radical mediated cyclization of the glucose derived exo-methylene furanose derivatives led to highly functionalized cA-fused bicyclic ethers. The product could subsequently be transformed into optically active tricyclic nucleoside analogue or oxepine derivative (Fig. 51).67... 

One drawback of biocatalysis is that enzymes are not available in both enantiomeric forms. Particularly where a class of enzymes whose natural substrates are optically active, such as nucleosides, it can be difficult if not impossible to find an alternative enzyme that will accept the unnatural substrate enantiomer. This is not insurmountable if directed-evolution approaches are used, but it can be prohibitively expensive, especially when the desired product is in an early stage of development or required for use only as an analytical reference or standard. 

Optically active icco-nucleosides of type 1.1 of 2-nitromidazole were prepared from tartaric acid ester by conversion to the dioxolan followed by reduction and acylation to give 1154, which was converted to 1155. Its coupling and deacylation gave 1156 (94MIP1). All the optically active isomers showed a radiation-sensitization effect equivalent to that of the racemate. 

Muller et al. determined the structure of />-toluoyl-protected tetrazole nucleoside 50 <2005CEJ6246>. The structures of optically active stereoisomers of antifungal agent 51 were solved <2001CPB1110>. Two polymorphic forms of the drug cilostazol 52 (inhibitor of phosphodiesterase III) have been characterized <2002AXCo525>. 

The adducts resulting from Diels-Alder reaction of pyridyl sulfoxides with furan have been used in the synthesis of a number of natural products. Thus, a new procedure for the total synthesis of optically actives C-nucleosides was reported by Koizumi et al. [38], who prepared D-showdomycin (19) and (D)-3,4-0-isopropylidene-2,5-anhidroallose (20) from the endo(t) 18a adduct (Scheme 10). (-i-)-Methyl 5-epishikimate (21) [39] and pentaacetyl- -D-mannopyranose (22) [40] were also obtained starting from endo(t) 18a (Scheme 10), the cleavage of the oxygenated bridge being the key step of these transformations. 

Circular dichroism (CD) and optical rotatory dispersion (ORD) spectra (71PMH(3)397) are very sensitive to the spatial disposition of the atoms in a molecule, and conformational changes may yield rather dramatic changes in the appearance of a CD or ORD spectrum of a chiral molecule. The analysis of the temperature dependence of the CD spectrum may give information on populations and free energy differences. Except for nucleosides, the use of the chiroptical method in conformational analysis is rather limited, which may be accounted for by the complexity of the theory for optical activity. 

V. E. Marquez, M. Lim, M. S. Khan, and B. Kaskar, (4R,5R)-(-)-3-(Benzyloxymethyl)-4,5-0-iso-propylidene-2-cyclopentenone-4,5-diol. An optically active a-, /1-unsaturated cyclopentenone for the synthesis of neplanocin A and other cyclopentene carbocyclic nucleosides, Nucleic Acid Chem., 4(1991)27-35. 

R,4S)-(+)-4-Hydroxy-2-cyclopentenyl acetate [(+)-1] is an important synthetic precursor. It provides optically active starting material via the versatile intermediate 4-oxo-2-cyclopentenyl acetate,7 for important cyclopentanoids such as the prostaglandins8 and carbocyclic nucleosides.9 Because of the medicinal significance of these compounds more efficient routes, with better enantioselectivities have been devised to nonracemic 1. Enzymatic catalysis has become the dominant methodology for induction of this optical activity. 

The critical temperature for the thermal rearrangement of 3a under various conditions (in the melt,96 in quinoline20 or naphthalene17) appears to be in the vicinity of 180°. The 3-methoxy derivative (70) isomerizes readily with lithium iodide (in methyl ethyl ketone at 64°).17,96 When ethyl iodide is added to this reaction, i r-methylsaccharin (8) and iV-ethylsaccharin (22) are formed together.96 Lithium iodide catalysis is particularly useful in rearranging nucleoside derivatives, e.g., 71.17 The 3-benzyloxy derivative (73) reacts with debenzylation.17 Even more complex systems like derivatives of steroid alcohols17,20 are isomerized on heating in reasonable yields. When the optically active 3-(2-(cZ)octyloxy)benz[d]isothiazole-l, 1-dioxide was thermally re-... 

Yoshikawa, M, Murakami, N, Inoue, Y, Hatakeyama, S, Kitagawa, I, A new approach to the synthesis of optically-active pseudo-sugar and pseudo-nucleoside — syntheses of pseudo-alpha-D-arabinofur-anose, (- -)-cyclaradine, and (-l-)-l-pseudo-beta-D-arabinofuranosyliiracil from D-arabinose, Chem. Pharm. Bull, 41, 636-638, 1993. 

The synthesis of 132, starting from S-benzyloxy propanal (131), involved the ring opening of an optically active epoxide 133 with a xanthate anion (Scheme 37)J22 Stereoselective synthesis of 133 by Sharpless epoxidation allowed preparation of the 2-deoxy-4-thio-D- and L-ezyr/zro-pentoses, " which were transformed into the corresponding pyrimidine nucleosides with silylated uracil and McaSiOTf. and then deprotected with Bu NF. 

Abstraction at acetal centers. Simpkins used a hydrogen atom abstraction from tetrahydrofuranyl and tetrahydropyranyl acetals for the preparation of spiroketals (Scheme 41, Eq. 41.1)] [137]. Malacria has inserted this process in a cascade reaction leading to functionalized cyclopentanone (Eq. 41.2) [138], Bertrand and Crich applied this reaction for the preparation of optically active cyclopentane derivative under chiral auxiliary control (Eq. 41.3) [139]. The synthesis of anomeric spiro-nucleosides was reported independently by Chatgilialoglu [46] and Kittaka [140]. In the example reported in Eq. (41.4), the gem-dibromovinyl derivative was treated with hexabutyldistannane to afford the desired spiro derivatives. This kind of reac-... 

Carvone was used as a precursor for the synthesis of the cyclohexene 159, and this was used to make the cyclohexenyl nucleoside analogue 160. The same chiral precursor was also manipulated to give the enantiomers of 159 and 160. Both enantiomers of 160 showed potent antiherpetic activity. Molecular modelling of the binding of both compounds to the active site of HSV-1 thymidine kinase was carried out, and a model for the binding of both enantiomers was proposed.An analogue of carbocyclic 2 -deoxyuridine, conforma-tionally-restricted due to a 6,6 -oxido-link (Vol. 32, p. 278), has now been reported in optically-active form, in the L-series. ... 

The endo cycloadducts resulting from the cycloaddition of optically active 3-(2-pyridylsulfinyl)acrylates and simple dienes such as cyclopentadiene and furan have been utilized successfully in the asymmetric synthesis of several natural products [166-170]. For example, cycloadduct (197), synthesized as a single diastereoisomer from the reaction of (5)-3-(2-pyridylsulfinyl)acrylate with cyclopentadiene, was converted to the lactone (198) [166], a key intermediate in the synthesis of the carbocyclic nucleosides (-)-aristeromycin (199) and (-)-neplanocin A (200) (Scheme 5.65) [167]. 

A modification of the trans-esterification process has found favour with synthetic chemists. The use of vinyl acetate (often as the solvent) for the acetylation of chiral secondary alcohols leads to the formation of vinyl alcohol, which rapidly tautomerizes to acetaldehyde. Acetaldehyde does not take part in a back-reaction (but can form a Schiff base derivative with the enzyme, which may affect the catalyst s activity). For example, the alcohol (31) is readily formed from cyclopentadiene and is enantiospecifi-cally acylated under the influence of Pseudomonas fluorescens lipase (Scheme 3.20) to furnish the acetate (32) and the recovered, optically active alcohol. The unreacted alcohol (—)-(31) was chemically acetylated and converted into the biological active carbocyclic nucleoside aristeromycin. For another example involving this protocol, see Chapter 5 (p. 133). 

Despite several synthetic approaches to the cyciopentane moiety of carbocyclic nucleosides, starting from noncarbohydrate synthons or readily available meso intermediates, no universally applicable methodology is yet available for the asymmetric synthesis of these compounds (28-31). An efficient access to chirality is via enantioselective resolution of a prochiral or a meso intermediate prior to the addition of the purine or pyrimidine base. For example, pig liver esterase (PLE) has been used in a chemoenzymatic approach to the synthesis of optically active (-l-aristeromycin and (-)-neplanocin (32), whereas cyclic y-acetamido esters were resolved to obtain (-)-4 d5-amino-2,3-trflTis-dihy-droxy hydroxymethyl cyciopentane as a key intermediate in the synthesis of carbocyclic nucleosides (33). Although hydrolytic enzymes often display a limited degree of enan-tiospecificity with such unnatural substrates, reaction conditions can in many cases be optimized to improve the enantioselectivity (34). 

The enantioselective synthesis of phosphonothioate (146) and fluoromethylene phosphonate (147) analogues of cyclic phosphatidic acid, the novel antagonists of lysophosphatidic acid receptors, has been presented. Synthesis of difluoromethy-lene analogue of sphingomyelin (148) in optically active form as a new sphingomyelinase inhibitor has been achieved. The synthesis and biological evaluation of 9-(5, 5 -difluoro-5 -phosphonopentyl)guanine derivatives (149), for use as a purine nucleoside phosphorylase inhibitor, has been described. 

The monocyclopropylmethyl ester of phosphoric acid has been used for phos-phorylating nucleosides, and it provides a new and better route to nucleotides, since hydrolysis of the cyclopropylmethyl function can be readily effected in the range 2.5—2.8 pH units. Optically active polyamides have been produced from (- -)-(S)-trans-cyclopropanedicarboxylic acid. ... 

Bell AF, Hecht L and Barron LD (1997) Vibrational Raman optical activity of pyrimidine nucleosides.of the Chemical Society, Faraday Transactions 93 553-562. 

The application of coupled oscillator and related theories to the investigation of nucleic acids and polynucleotides has been reviewed by Brahms. The optical activities of single nucleosides and derivatives have been calculated by a coupled oscillator theory in which the tt-tt transitions of the bases were decomposed into individual bond-bond transition moments which were then coupled by the dipolar coupling mechanism. Apparently such a treatment was necessary to account for deficiencies in the simple approach of chromophore-centered dipole transition moments. 

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