Lipase Catalyzed Resolution of (±)-2-Substituted 1-Propanol Derivatives Possessing an Aromatic Ring

For the purpose of the chiral synthesis of natural products, lipase-catalyzed kinetic resolutions of three types of 2-substituted 1-propanol derivatives (each having an aromatic ring) was investigated. In every case, chiral recognition of the primary alcohol unit took place to provide the corresponding alcohols and the acetates in high optical purity. The (2S,3S)-5-aryl-2-methyl-3-hydroxy-4E-pentenol 5 was formally converted into the antibiotic, (-)-oudemansin X.     

Ring Cleavage and Modification at C-2 of a 3,5′-Cyclonucleoside Derivative of Adenosine

It was shown that under alkaline conditions the cyclonucleoside 1 was converted to an imidazole cyclonucleoside 2, and under milder conditions it was converted to an amidine 3, which reacted with N,N′-thiocarbonyldiimidazole and cyanogen bromide as well as phosgene affording the corresponding ring closure products 8, 9 and 10.     

Ring Hydroxylation of p-Chlorophenylacetate by an Arthrobacter Strain

Resting cell suspensions of a strain of Arthrobacter grown on phenylacetate converted p-chlorophenylacetate to two products. One of the products was identified as 4-chloro-3-hydroxyphenylacetate.     

Conformationally Locked Nucleoside Analogs. Synthesis of 2′-Deoxy-2′-C, 4′-C-Bridged Bicyclic Nucleosides

Abstract

1-α-Methylarabinose was converted, in three steps, to 2-deoxy-2-methyleneribose derivative 3, which was subjected to hydroboration to give 2-α-hydroxymethyl derivative 4 exclusively. 4 was converted to 2,4-bis(hydroxymethyl)ribose derivative 6 in four steps. Mesylation, detritylation, and ring closure, followed by hydrolysis of the mesyl group at O5, gave 3,6-dioxabicyclo[3,2,1]octane derivative 8. After acetylation, 8 was coupled with silylated 6-chloropurine to give desired α- and β-bicyclic-sugar nucleosides.     

Novel Carbocyclic Nucleosides Containing A Cyclobutyl Ring. Guanosine and Adenosine Analogues

Abstract

(1R,cis)-2-(3-Amino-2,2-dimethylcyclobutyl)ethanol (4) was used as a precursor in the synthesis of cyclobutyl nucleoside analogues containing guanine, 8-azaguanine, adenine or 8-azaadenine. All the compounds were evaluated as antiviral agents in a variety of assay systems. Some activity was noted for compound 13, 17, 19 and 20 against vaccinia virus and for compounds 11, 12, 13, 17, 19 and 20 against herpes simplex virus, at concentrations that were up to 10-fold below the cytotoxic concentrations for the host cells.     

Synthesis and Properties of Oligoribonucleotide Analogues Having Amide (3″-CH2-CO-NH-5′) Internucleoside Linkages

Abstract

Amide linked ribonucleoside dimer 5 was prepared and converted into selectively protected H-phosphonate building block 9. Oligoribonucleotide duplexes having amide linkages at selected sites were synthesized and their stability was studied by UV melting experiments.     

Formation and Reactivity of 2,4-Ditriazolyl Pyrimidine C-Nucleoside Derived from Pseudouridine

Abstract

Thymine and 2′,3′,5′-tri-O-acetyl-Ψ-uridine (1) was converted into the corresponding 2,4-ditriazolyl derivatives 5 and 2, respectively. Of these two substituents, the C4-triazolyl group was found to be quite susceptible to nucleophilic substitution while the other triazolyl is resistant.     

Nucleoside Analogues of Purine with a 1,2-Disubstituted Cyclopentene Ring

Abstract

One, two-disubstituted carbonucleoside analogues of purine with unsaturated carbocyclic were synthesized by construction of the heterocyclic base about the primary amino group of the amino alcohol 4 intermediate, which was also synthesized in good yield starting from cyclopentadiene.     

A Temperature-Monitoring Vaginal Ring for Measuring Adherence

BackgroundProduct adherence is a pivotal issue in the development of effective vaginal microbicides to reduce sexual transmission of HIV. To date, the six Phase III studies of vaginal gel products have relied primarily on self-reporting of adherence. Accurate and reliable methods for monitoring user adherence to microbicide-releasing vaginal rings have yet to be established.MethodsA silicone elastomer vaginal ring prototype containing an embedded, miniature temperature logger has been developed and tested in vitro and in cynomolgus macaques for its potential to continuously monitor environmental temperature and accurately determine episodes of ring insertion and removal.ResultsIn vitro studies demonstrated that DST nano-T temperature loggers encapsulated in medical grade silicone elastomer were able to accurately and continuously measure environmental temperature. The devices responded quickly to temperature changes despite being embedded in different thickness of silicone elastomer. Prototype vaginal rings measured higher temperatures compared with a subcutaneously implanted device, showed high sensitivity to diurnal fluctuations in vaginal temperature, and accurately detected periods of ring removal when tested in macaques.ConclusionsVaginal rings containing embedded temperature loggers may be useful in the assessment of product adherence in late-stage clinical trials.     

Cyclization of All-E- and 2Z-Geranylfarnesols by a Bacterial Triterpene Synthase: Insight into Sesterterpene Biosynthesis in Aleuritopteris Ferns

Aleuritopteris ferns produce triterpenes and sesterterpenes with tricyclic cheilanthane and tetracyclic 18-episcalarane skeletons. The structural and mechanistic similarities between both classes of fern terpene suggest that their biosynthetic enzymes may be closely related. We investigate here whether a triterpene synthase is capable of recognizing geranylfarnesols as a substrate, and is able to convert them to cyclic sesterterpenes. We found that a bacterial triterpene synthase converted all-E-geranylfarnesol (1b) into three scalarane sesterterpenes with 18αH stereochemistry (5, 7 and 8), as well as mono- and tricyclic sesterterpenes (6 and 9). In addition, 2Z-geranylfarnesol (4) was converted into an 18-episcalarane derivative (10), whose skeleton can be found in sesterterpenes isolated from Aleuritopteris ferns. These results provide insight into sesterterpene biosynthesis in Aleuritopteris ferns.     

Synthesis of Homo-C-D4T and Homo-C-Thymidine

Abstract

ß-C-Vinyl glycoside of D-arabinofuranose was converted to the β-C-hydroxymethyl glycoside 12 which was condensed with N-3-benzoyl thymine under Mitsunobu conditions to furnish homo-C-analog 14 of the 2′,3′-dideoxy-2′,3′-didehydrothymidine (D4T). Synthesis of the homo-C-thymidine 18 was accomplished by the same procedure from compound 15.     

Asymmetric Hydrolysis of Prochiral Diesters with Pig Liver Esterase. Preparation of Optically Active Intermediates for the Synthesis of (+)-Biotin and (+)-α-Methyl-3,4-dihydroxyphenylalanine

With pig liver esterase, 1,3-dibenzyl-4,5-cis-bis(alkyloxycarbonyl)-2-oxoimidazolidine (1) was asymmetrically hydrolyzed to (4S,5R)-1,3-dibenzyl-5-alkyloxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (2). This acid 2 was reduced with lithium borohydride to (4S,5R)-1,3-dibenzyl-5-hydroxymethyl-2-oxoimidazolidine-4-carboxylic acid lactone (3), which is known to be converted to (+)-biotin (4). With the same esterase, diethyl 3,4-dimethoxyphenylmethyl-(methyl)malonate (5) was asymmetrically hydrolyzed to (R)-ethyl hydrogen 3,4-dimethoxy-phenylmethyl(methyl)malonate (6), which can be converted to (S)-α-methyl-3,4-dihydroxyphenyl-alanine(l-α-methyldopa) (9).     

Synthesis of Three New Carbocyclic Analogues of 3′-Deoxy Purine Ribonucleosides

Abstract

The 1-hydroxymethyl-3-cyclopentene (4) was converted, after epoxidation, to two new exocyclic amino carbocyclic nucleosides (1, 2), and a new cyclopentane nucleoside analogue (3), with potential biological activities. The regioselectivity of the epoxidation (4), which is the key step, is governed by steric control using aryl and silyl hydroxyl protecting groups.     

Synthesis and characterization of poly-O-methyl-[n]-polyurethane from a d-glucamine-based monomer

Aminoalditol 1-amino-1-deoxy-d-sorbitol (1) was readily converted into 2,3,4,5-tetra-O-methyl derivative 5, a key precursor of a sugar-based [n]-polyurethane. For the polymerization, the free amino or primary hydroxyl groups of 5 were selectively activated and employed as starting monomers in two alternative procedures. Thus, the amino function of 5 was converted into the isocyanate derivative by treatment with di-tert-butyltricarbonate, and polymerized in situ in the presence of Zr(IV) acetylacetonate. The resulting poly(1-amino-1-deoxy-2,3,4,5-tetra-O-methyl-d-sorbitol)urethane (8) had a moderate molecular weight and showed the presence of urea units. The alternative synthesis of 8 involved the activation of the free hydroxyl group of 5 as the corresponding phenylcarbonate. The polymerization of this α-amino-ω-phenylcarbonate alditol monomer does not require a metal catalyst. The resulting material exhibited an improved molecular weight and higher purity than that obtained via the isocyanate. [n]-polyurethane 8 was highly soluble in water as well as in common organic solvents (chloroform, acetone, ethyl acetate, etc) and was obtained as an amorphous material which was characterized thermally and spectroscopically.     

Synthesis of (±)-Muscone from Ethyl 6-Methyl-8-oxopentadecanedioate

(±)-Muscone (3-methylcyclopentadecanone) (8) was synthesized from ethyl 6-methyl-8-oxopentadecanedioate (1) in a 31.9% over-all yield. Ethylene ketal (2) of 1 was cyclized to the acyloin mixture (3) by the acyloin condensation. Reduction of 3 gave 9,9-ethylenedioxy-7-methylcyclopentadecane-1,2-diol (4) which afforded 1,2-ditosyloxy derivative (5). By detosylation according to the Tipson-Cohen procedure, 5 was converted to 9,9-ethylenedioxy-7-methylcyclopentadec-1-ene (6) which was hydrogenated to 8.     

An Improved Synthesis of 2′-Deoxy-9-deazaadenosine and an N-7 Blocked Derivative Useful for the Synthesis of Modified Oligonucleotides Containing 2′-Deoxy-9-deazaadenosine

Abstract

As an epimerization resistant synthon in the synthesis of oligo-nucleotides consisting of C-nucleoside analogues, hitherto unknown 5-benzyloxy-methyl-3-(2-deoxy-β-D-erythro-pentofuranosyl)pyrrolo[3,2-d]pyrimpyrimidine (7-benzyloxymethyl-2′-deoxy-9-deazaadenosine) was prepared in seven steps from the known 3-amino-2-cyano-4-(2,3-O-isopropylidene-5-O-trityl-β-D-ribofuranosyl)-pyrrolpyrrole (1). Treatment of 1 with benzyl chloromethyl ether in the presence of potassium t-butoxide and 18-crown-6 afforded the N-protected pyrrole 2, which was converted into the 9-deazapurine derivative 3 in high yield by heating in EtOH. 7-Benzyloxymethyl-9-deazaadenosine 4 was obtained from 3 by acid hydrolysis in 2.5% methanolic hydrogen chloride. After protection of the hydroxyl groups of 4 with Markievicz's reagent, the product 5 was converted into the 2′-O-phenoxythiocarbonyl derivative 6. Reduction of 6 with butyltin hydride in the presence of 2,2′-azobis(2-methylpropionitrile), followed by desilylation with triethylammonium fluoride, afforded the desired 7-benzyloxymethyl-2′-deoxy-9-deazaadenosine (8) in high overall yield. The benzyloxymethyl group of 8 was removed by hydrogenolysis over palladium hydroxide (Degussa type) to give 2′-deoxy-9-deazaadenosine (9) in quantitative yield. The structure of 9 is discussed.     

Highly Stereoselective Synthesis and Biological Properties of Nucleoside Analogues Bearing a Spiro Inserted Oxirane Ring

Abstract

Starting from 2′,5′-di-O-TBDMS-3′-ketouridine 1 or its thymine analogue 2, both xylo (3–10) and ribo (20) epimers of a series of 3″-substituted 3′-spironucleosides have been obtained in good yields and with a total stereoselectivity. Most new compounds were moderately cytotoxic with in some cases slightly selective antiproliferative activities. None of these compounds was active against HIV, but some other antiviral activities against HSV-2, CMV, EBV, or VZV, in the micromolar range, were noted in specific cases.     

Synthesis of Oligodeoxyribonucleotide Analogues by Use of Deoxyribonucleoside-3′-yl O-bis(1,1,1,3,3,3-Hexafluoro-2-Propyl) Phosphites as New Key Intermediates

Abstract

The deoxyribonucleoside-3′-yl O-bis(1,1,1,3,3,3-hexafluoro-2-propyl) phosphite units (3) could be converted into the O-nucleosidyl phosphonate, O-2-cyanoethyl O-nucleosidyl phosphonate, and O-1,1,1,3,3,3-hexafluoro-2-propyl O-nucleosidyl phosphonothioate. Compound 3a was activated by methylimidazole to give the dithymidylate derivatives (8). The appropriately protected nucleosidyl phosphonates (3) were applied to the synthesis of oligodeoxyribonucleotides used as antisense oligonucleotides.     

The Synthesis and Biological Activity of 1-(2-Deoxy-4-Thio-α;-L-Threo-Pentofuranosyl)Thymine

Abstract

The procedure of Huang and Hui (Nucleosides & Nucleotide 1993, 12, 139-147) was found to give benzyl 3,5-di-O-benzyl-2-deoxy-1,4-dithio-α-L-threo-pentofuranoside (6) rather than the claimed D-erythro isomer. This sugar was converted to an anomeric mixture of the thymine nucleosides. The mixture was separated and the α-anomer (α-10) was found to be cytotoxic, whereas theβ-anomer (β-10) was inactive.     

Synthesis and Biological Activity of 4′-Thionucleosides of 2-Chloroadenine1

Abstract

1,2,3,5-Tetra-O-acetyl-4-thio-D-riboruranose, prepared from 2,3,5-tri-O-benzyl-D-ribofuranose in four steps, was converted to the corresponding 2-chloroadenine nucleoside (8), which was deoxygenated to obtain 2-chloro-2′-deoxy-4′-thioadenosine (12). This is the first report of a 2′-deoxy-4′-thioribonucleoside of a purine rather than a pyrimidine. These novel nucleosides (8 and 12) were cytotoric to several human tumor cell lines in culture.