Regioselective Transformations of 2′,3′-Seconucleosides into Anhydro Structures and Chiral Crown Ethers

Intramolecular cyclisation of properly protected and activated derivatives of 2′,3′-secouridine ( = 1-{2-hydroxy-1-[2-hydroxy-1-(hydroxymethyl)ethoxy]-ethyl}uracil; 1 ) provided access to the 2,2′-, 2,3′-, 2,5′-, 2′,5′-, 3′,5′-, and 2′,3′-anhydro-2′,3′-secouridines 5, 16, 17, 26, 28 , and 31 , respectively (Schemes 1–3). Reaction of 2′,5′-anhydro-3′-O-(methylsulfonyl)- ( 25 ) and 2′,3′-anhydro-5′-O-(methylsulfonyl)-2′,3′-secouridine ( 32 ) with CH₂CI₂ in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene generated the N(3)-methylene-bridged bis-uridine structure 37 and 36 , respectively (Scheme 3). Novel chiral 18-crown-6 ethers 40 and 44 , containing a hydroxymethyl and a uracil-1-yl or adenin-9-yl as the pendant groups in a 1,3-cis relationship, were synthesized from 5′-O-(triphenylmethyl)-2′,3′-secouridine ( 2 ) and 5′-O,N⁶-bis(triphenylmethyl)-2′,3′-secoadenosine ( 41 ) on reaction with 3,6,9-trioxaundecane-1,11-diyl bis(4-toluenesulfonate) and detritylation of the thus obtained (triphenylmethoxy) methylcompound 39 and 43 , respectively (Scheme 4).     

Synthesis of 1,2′,3,3′,5′,6′-hexahydro-3-phenylspiro[isobenzofuran-1,4′-thiopyrans] and 1,2′,3,3′,5′,6′-hexahydro-3-phenylspiro-[isobenzofuran-1,4′-pyrans]

The 1,2′,3,3′,5′,6′-hexahydro-3-phenylspiro[isobenzofuran-1,4′-thiopyran] ring system ( 2a ) has been prepared from o-bromobenzoic acid. The 1,2′,3,3′,5′,6′-hexahydro-3-phenylspiro[isobenzofuran-1,4′-pyran] ring system ( 3a ) has been prepared from 2-bromobenzhydrol methyl ether. Several 3-(dimethylaminoalkyl) derivatives of both 2a and 3a were prepared by lithiation followed by alkylation.     

Synthesis of racemic and enantiomerically pure 2′-thia-2′,3′-dideoxycytidine as potential anti-hepatitis B virus agents

A novel class of nucleosides with the C₁, atom bonded to three hetero atoms was synthesized. 2′-Thia-2′,3′-dideoxycytidine was the pilot compound of this series. (±)-β-2′-Thia-1′,3′-dideoxycytidine ( 6 ) and (±)-α-2′-thia-2′,3′-dideoxycytidine ( 7 ) were synthesized from (±)-3-mercapto-1,2-propanediol. The synthesis of the enantiomerically pure 2′-thia-2′,3′-dideoxycytidines (α-D-form, β-D-form, α-1-form and β-L-form) from optically pure (S)-(2,2-dimethyl-1,3-dioxalan-yl)methyl p-toluenesulfonate ( 8 ) and its (R)-isomer 18 was also described. The preliminary biological results showed that (+)-β-D-2′-thia-2′,3′-dideoxycytidine ( 26 ) was the most active against human hepatitis B virus with an ED₅₀ of 3 μM.     

Reactions of 2,2′,5′,2′-terfuran

Formylation of 2,2′,5′,2′-terfuran ( 1 ) with N-methylformanilide and phosphorus oxychloride gave 5-formyl-2,2′,5′,2′-terfuran ( 2 ) and 5,5′-diformyl-2,2′5′,2′-terfuran ( 3 ). Reduction of 2 and 3 afforded 5-hydroxymethyl-2,2′,5′,2′-terfuran ( 4 ) and 5,5′ dihydroxymethyl-2,2′,5′,2′-terfuran ( 5 ), respectively. Terfuran 1 reacted with phenylmagnesium bromide to give 5-(phenylhydroxymethyl)-2,2′,5′,2′-terfuran ( 6 ), and was carbonated to 5-carboxy 2,2′,5′,2′-terfuran ( 7 ) and 5,5′-dicarboxy-2,2′,5′,2′-terfuran ( 8 ). Bromination of 1 with N-bromosuccinimide gave 5,5′-dibromo 2,2′,5′,2′-terfuran ( 9 ).     

Mammalian Alkaloids: Configurations of Optically Active Salsoline- and 3′,4′-Dideoxynorlaudanosoline-1-carboxylic Acids

Synthesis of the optical isomers of (±)-methyl 6,7-dimethyl-3′,4′-dideoxynorlaudanosoline-1-carboxylate ((±)- 2 ) was accomplished by reaction of (±)- 2 with (+)-(R)-1-phenylethyl isocyanate, separation of the urea diastereoisomers (?)- 4A and (+)- 4B , and alcoholysis of the ureas in refluxing BuOH. Optically active isoquinoline-carboxylates 2A , B and hydantoins 8A , B isolated were characterized. The absolute configuration of the reaction products was established by X-ray analysis of the optically active hydantoin (+)- 8A . Hydrolysis of the methyl isoquinolinecarboxylates 2A , B with 48% HBr soln. at reflux afforded the desired optically active 3′,4′-dideoxynorlaudanosoline-1-carboxylic acids 1A , B required for enzyme-inhibition studies. Details of the X-ray diffraction analysis of (+)-methyl salsoline-1-carboxylate hydrobromide ((+)- 11A ·HBr) prepared earlier are included. CD spectra of (+)-(S)-methyl 6,7-dimethyl-3′,4′-dideoxynorlaudanosoline-1-carboxylate hydrobromide ((+)- 2A . HBr) and (?)-(R)-methyl salsoline-1-carboxylate hydrochloride ((?)- 11B ·HCl) confirmed the assignment of their (S)- and (R)-configurations, respectively.     

Angiotensin-II Analogues. I: Synthesis and incorporation of the halogenated amino acids 3-(4′-iodophenyl)alanine, 3-(3′,5′-dibromo-4′-chlorophenyl)alanine, 3-(3′,4′,5′-tribromophenyl)alanine,and 3-(2′,3′,4′,5′,6′-pentabromophenyl)alanine

The synthesis of the polyhalogenated phenylalanines Phe(3′,4′,5′-Br₃) ( 3 ), Phe(3′,5′-Br₂-4′-Cl) ( 4 ) and DL -Phe (2′,3′,4′,5′,6′-Br₅) ( 9 ) is described. The trihalogenated phenylalanines 3 and 4 are obtained stereospecifically from Phe(4′-NH₂) by electrophilic bromination followed by Sandmeyer reaction. The most hydrophobic amino acid 9 is synthesized from pentabromobenzyl bromide and a glycine analogue by phase-transfer catalysis. With the amino acids 4, 9 , Phe(4′-I) and D -Phe, analogues of [1-sarcosin]angiotensin II ([Sar¹]AT) are produced for structure-activity studies and tritium incorporation. The diastereomeric pentabromo peptides L - and D - 13 are separated by HPLC. and identified by catalytic dehalogenation and comparison to [Sar¹]AT ( 10 ) and [Sar¹, D -Phe⁸]AT ( 14 ).     

Synthesis,Crystal Structure and Hydrolysis of a Novel Anhydrogalactosucrose: 2′‐Methoxyl‐O‐1′,4′:3′,6′‐dianhydro‐β‐D‐fructofuranosyl 3,6‐anhydro‐4‐chloro‐4‐deoxy‐α‐D‐galactopyranoside

A novel anhydrogalactosucrose derivative 2′‐methoxyl‐O‐1′,4′:3′,6′‐dianhydro‐β‐D‐fructofuranosyl 3,6‐anhydro‐4‐chloro‐4‐deoxy‐α‐D‐galactopyranoside ( 4 ) was prepared from 3,6:1′,4′:3′,6′‐trianhydro‐4‐chloro‐4‐deoxy‐galactosucrose ( 3 ) via a facile method and characterized by ¹H NMR, ¹³C NMR and 2D NMR spectra. The single crystal X‐ray diffraction analysis shows that the title molecule forms a two thee‐dimensional network structure by two kinds of hydrogen bond interactions [O(2) H(2)···O(7), O(5) H(5)···O(8)]. Its stability was investigated by acid hydrolysis reaction treated with sulfuric acid, together with the formation of 1,6‐Di‐O‐methoxy‐4‐chloro‐4‐deoxy‐β‐D‐galactopyranose ( 5 ) and 2,2‐Di‐C‐methoxy‐1,4:3,6‐dianhydromannitol ( 6 ). According to the result, the relative stability of the ether bonds in the structure is in the order: C(1) O C(5)≈C(3′) O C(6′)≈C(1′) O C(4′)>C(3) O C(6)≈C(1) O C(2′)>C(2′) O C(5′).     

Saturated heterocycles. 242. Synthesis of 2-substituted-6-(6′,7′-dimethoxy-3′,4′-dihydro-1′-isoquinolyl)-5,6,7,8-tetrahydro- quinazolin-4(3H)-one Derivatives

In the reactions of the recently synthesized β-ketoesters 1-[(3′-methoxycarbonyl- and 1-[(3′-ethoxycarbonyl-4′-oxo)-1′-cyclohexyl]-3,4-dihydroisoquinoline 4, 5 with amidines or cyclic guanidines, a number of 2-substituted-6-(6′,7′-dimethoxy-3′,4′-dihydro-1′-isoquinolyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one derivatives 6–8 were prepared. The new compounds possess various pharmacological actions.     

5-(α-Fluorovinyl)tryptamines and 5-(α-Fluorovinyl)-3-(N-methyl-1′,2′,5′,6′,-tetrahydropyridin-3′- and -4′-yl)indoles—5-(α-Fluorovinyl)tryptamines

5-(α-Fluorovinyl)tryptamines 4a, 4b and 5-(α-fluorovinyl)-3-(N-methyl-1′,2′,5′,6′-tetrahydropyridin-3′- and -4′-yl) indoles 5a, 5b were synthesized using 5-(α-fluorovinyl)indole ( 7 ). The target compounds are bioisosteres of 5-carboxyamido substituted tryptamines and their tetrahydropyridyl analogs.     

Five-membered 2.3-dioxo heterocycles: LXVIII. Three pathways in the reaction of methyl 3-aroyl-1-aryl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates with 3-amino-5,5-dimethylcyclohex-2-en-1-one

Methyl 3-aroyl-1-aryl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates reacted with 3-amino-5,5-dimethylcyclohex-2-en-1-one having no substituent on the nitrogen atom to give 3-aroyl-4-arylamino-6′,6′-dimethyl-6′,7′-dihydro-5H-spiro[furan-2,3′-indole]-2′,4′,5′(1′H,5′H)-triones or methyl 12-aroyl-11-aryl-9-hydroxy-5,5-dimethyl-3,10-dioxo-8,11-diazatricyclo[7.2.1.0^2,7]dodec-2(7)-ene-1-carboxylates. The latter underwent thermal recyclization to 3′-aroyl-1′-aryl-4′-hydroxy-6,6-dimethyl-6,7-dihydrospiro[indole-3,2′-pyrrole]-2,4,5′(1H,1′H,5H)-triones.     

Synthesis,Characterization and Reactions of 4‐Hydrazino‐2‐methylpyrimidino[4′5′:4,5]thiazolo[3,2‐a]benzimidazole

4‐Hydrazino‐2‐methylpyrimidino[4′,5′:4,5]thiazolo[3,2‐a]benzimidazole ( 4 ) was obtained from hydrazinolysis of the 4‐chloro derivative 3 with hydrazine hydrate. The hydrazino derivative 4 was further cyclized to the corresponding pyrazole 5 , pyrazolone 6 and 5‐methyl‐1,2,4‐triazolo[1″,5″:3′,4′]pyrimidino[5′,6′:5,4]‐thiazolo[3,2‐a]benzimidazole ( 9 ) and 5‐methy‐1,2,4‐triazolo[4″,3″:3′,4′]pyrimidino[5′,6′:5,4]thiazolo‐[3,2‐a]benzimidazole ( 10 ), respectively. The triazolo derivative 10 was isomerized to the triazolo derivative 9 under a variety of reaction conditions.     

2′, 3′-Dideoxy-3′-fluorotubercidin and Related Dideoxyribonucleosides:. Synthesis via a 2′-deoxy-3′-oxoribofuranoside intermediate and conformation studies

An efficient synthesis of the unknown 2′-deoxy-D-threo-tubercidin ( 1b ) and 2′, 3′-dideoxy-3′-fluorotubercidin ( 2 ) as well as of the related nucleosides 9a, b and 10b is described. Reaction of 4-chloro-7-(2-deoxy-β-D-erythro-pentofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine ( 5 ) with (tert-butyl)diphenylsilyl chloride yielded 6 which gave the 3′-keto nucleoside 7 upon oxidation at C(3′). Stereoselective NaBH₄ reduction (→ 8 ) followed by deprotection with Bu₄NF(→ 9a )and nucleophilic displacement at C(6) afforded 1b as well as 7-deaza-2′-deoxy-D-threo-inosine ( 9b ). Mesylation of 4-chloro-7-{2-deoxy-5-O-[(tert-butyl)diphenylsilyl]-β-D-threo-pentofuranosyl}-7H-pyrrolo[2,3-d]-pyrimidine ( 8 ), treatment with Bu₄NF (→ 12a ) and 4-halogene displacement gave 2′, 3′-didehydro-2′, 3′-dideoxy-tubercidin ( 3 ) as well as 2′, 3′-didehydro-2′, 3′-dideoxy-7-deazainosne ( 12c ). On the other hand, 2′, 3′-dideoxy-3′-fluorotubercidin ( 2 ) resulted from 8 by treatment with diethylamino sulfurtrifluoride (→ 10a ), subsequent 5′-de-protection with Bu₄NF (→ 10b ), and Cl/NH₂ displacement. ¹H-NOE difference spectroscopy in combination with force-field calculations on the sugar-modified tubercidin derivatives 1b , 2 , and 3 revealed a transition of the sugar puckering from the ^3′T_2′ conformation for 1b via a planar furanose ring for 3 to the usual ^2′T_3′ conformation for 2.     

Aziridination of the uracil 5,6-olefinic bond of 3-N-3′,5′-Di-O-tribenzoyl-5-vinyl-2′-deoxyuridine

Oxidation of N-aminophthalimide with lead tetra-acetate at -50° gives N-acetoxyaminophthalimide ( 3 ) which selectively aziridinates the 5,6-double bond present in 3-N-3′,5′-di-O-tribenzoyl-5-vinyl-2′-deoxyuridine ( 1a ) to yield 2-[1′-(2′-deoxy-β-D-ribofuranosyl)]-7-(1-phthalimido)-4-N-3′,5′-di-O-tribenzoyl-6-vinyl-2,4,7-triazabicyclo[4.1.0]heptan-3,5-dione ( 5 ).     

Syntheses and Reactions of 1′,2′-Unsaturated 2′,3′-Seconucleoside Analogues

The 1′,2′-unsaturated 2′,3′-secoadenosine and 2′,3′-secouridine analogues were synthesized by the regioselective elimination of the corresponding 2′,3′-ditosylates, 2 and 18 , respectively, under basic conditions. The observed regioselectivity may be explained by the higher acidity and, hence, preferential elimination of the anomeric H–C(1′) in comparison to H? C(4′). The retained (tol-4-yl)sulfonyloxy group at C(3′) of 3 allowed the preparation of the 3′-azido, 3′-chloro, and 3′-hydroxy derivatives 5–7 by nucleophilic substitution. ZnBr₂ in dry CH₂Cl₂ was found to be successful in the removal (85%) of the trityl group without any cleavage of the acid-sensitive, ketene-derived N,O-ketal function. In the uridine series, base-promoted regioselective elimination (→ 19 ), nucleophilic displacement of the tosyl group by azide (→ 20 ), and debenzylation of the protected N(3)-imide function gave 1′,2′-unsaturated 5′-O-trityl-3′-azido-secouridine derivative 21 . The same compound was also obtained by the elimination performed on 2,2′-anhydro-3′-azido-3′-azido-3′-deoxy-5′-O-2′,3′-secouridine ( 22 ) that reacted with KO(t-Bu) under opening of the oxazole ring and double-bond formation at C(1′).     

Synthesis of 3′,5′‐Cyclic Phosphate and Thiophosphate Esters of 2′‐C‐Methyl Ribonucleosides

2′‐C‐Methylnucleosides are known to exhibit antiviral activity against Hepatitis C virus. Since the inhibitory activity depends on their intracellular conversion to 5′‐triphosphates, dosing as appropriately protected 5′‐phosphates or 5′‐phosphorothioates appears attractive. For this purpose, four potential pro‐drugs of 2′‐C‐methylguanosine, i.e., 3′,5′‐cyclic phosphorothioate of 2′‐C‐methylguanosine and 2′‐C,O⁶‐dimethylguanosine, 1 and 2 , respectively, the S‐[(pivaloyloxy)methyl] ester of 2′‐C,O⁶‐dimethylguanosine 3′,5′‐cyclic phosphorothioate and the O‐methyl ester of 2′‐C,O⁶‐dimethylguanosine 3′,5′‐cyclic phosphate, 3 and 4 , respectively, have been prepared.     

Folic acid analogs. Modifications in the benzene-ring region. 5. 2′,6′-diazafolic acid

The synthesis of 2′,6′-diazafolic acid was accomplished by the condensation of 2-acetylamino-4(3H)pteridinone-6-earboxaldehyde (XIV) with diethyl N-[(5-amino-2-pyrimidinyl)carbonyl]-L-glutamate (XIII) followed by reduction of the anil double bond and alkaline hydrolylic cleavage of the N²-acetyl and ethyl ester protecting groups. Intermediate XIII was prepared by starling with 5-nitro-2-styrylpyrimidine (VI) and proceeding via 5-arnino-2-styrylpyrimidine (IX). The henzyloxycarbonyl derivative of IX was prepared and oxidized to the corresponding 5-benzyloxycarbonylaminopyrimidine-2-carboxylic acid (XI). The coupling of XI with diethyl L-glutamate followed by hydrogenolysis of the henzyloxycarbonyl function afforded the desired intermediate XIII. 2′,6′-Diazafolic acid was a potent inhibitor of Streptococcus faecium and displayed marginal activity against leukemia 1,1210 in mice.     

Nucleic acid related compounds. 114. Synthesis of 2,6‐(disubstituted)purine 2′,3′‐dideoxynucleosides and selected cytotoxic,anti‐hepatitis b,and adenosine deaminase substrate activities

Selected 2,6‐(disubstituted)purine 2′,3′‐didehydro‐2′,3′‐dideoxynucleosides and 2′,3′‐dideoxynucleosides were prepared and evaluated. Treatment of 5′‐protected ribonucleosides with phenoxythiocarbonyl chloride and 4‐(dimethylamino)pyridine, or under Schotten‐Baumann conditions, gave high yields of 2′,3′‐O‐thiono‐carbonates that underwent Corey‐Winter elimination. Treatment of unprotected ribonucleosides with α‐ace‐toxyisobutyryl bromide in “moist” acetonitrile gave trans 2′,3′‐bromohydrin acetate mixtures that underwent reductive elimination with zinc‐copper couple or zinc/acetic acid. Catalytic hydrogenation of the resulting 2′,3′‐enes gave 2′,3′‐dideoxynucleosides. Treatment of the 2‐amino‐6‐chloropurine and 6‐amino‐2‐fluoro‐purine derivatives with nucleophiles gave 2,6‐(disubstituted)purine 2′,3′‐dideoxynucleosides. 2′,3′‐Dideoxyguanosine and the 2‐amino‐6‐[amino ( 16d ), methoxy ( 16b ), ethoxy ( 16c ), and methylamino ( 16j )]purine 2′,3′‐dideoxynucleosides showed good anti‐hepatitis B activity with infected primary duck hepatocytes. Cytotoxic effects with selected analogues were evaluated in human T‐lymphoblastic and promyelocytic leukemia cell lines. The 2‐amino‐6‐fluoro derivative 16m was the most cytotoxic of the 2‐amino‐6‐(substituted)purine 2′,3′‐dideoxynucleosides, and 2‐fluoro‐2′,3′‐dideoxyadenosine ( 21a ) was the most cytotoxic compound. The order of efficiency of hydrolysis of the 6‐substituent from 2‐amino‐6‐(sub‐stituted)purine 2′,3′‐dideoxynucleosides (V_max/K_m) with adenosine deaminase from calf intestine was: 2‐amino‐6‐[amino ( 16d ) > methoxy ( 16b ) > ethoxy ( 16c )], all of which were ≤3% of the efficiency with adenosine. The 6‐methylamino derivative 16j , as well as 16b , 16c , and 16d were readily converted into 2′,3′‐dideoxyguanosine by duck cell supernatants.     

New heterocyclic derivatives of 1′- and 3′-amino-5′,6′,7′,8′-tetrahydro-2′-acetonaphthones

The preparation of 1′-and 3′-amino-5′,6′,7′,8′-tetrahydro-2′-acetonaphthones (IIIa and IIIb) is described, by reduction of the low temperature nitration products of 5′,6′,7′,8′-tetrahydro-2′-acetonaphtone (I). The structures of the nitro isomers (IIa and IIb), and the reduction products, IIIa and IIIb, were elucidated spectroscopically. By known reactions, a series of new heterocyclic compounds prepared from the o-aminoketones, IIIa and IIIb, resulted in two series of new heterocyclic compounds.     

Facile Synthesis of 2′-Deoxyisoguanosine and Related 2′,3′-Dideoxyribonucleosides

The 2′-deoxyisoguanosine ( 1 ) was synthesized by a two-step procedure from 2′-deoxyguanosine ( 5 ). Amination of silylated 2′-deoxyguanosine yielded 2-amino-2′-deoxyadenosine ( 6 ) which was subjected to selective deamination of the 2-NH₂ group resulting in compound 1 . Also 2′,3′-dideoxyisoguanosine ( 2 ) was prepared employing the photo-substitution of the 2-substituent of 2-chloro-2′,3′-dideoxyadenosine ( 4 ). The latter was synthesized by Barton deoxygenation from 2-chloro-2′-deoxyadenosine ( 3 ) or via glycosylation of 2,6-dichloropurine ( 12 ) with the lactol 13 . Compound 1 was less stable at the N-glycosylic bond than 2′-deoxyguanosine ( 5 ). The dideoxynucleoside 2 was deaminated by adenosine deaminase affording 2′,3′-dideoxyxanthosine ( 17 ).