Unusual tosyl transfer solvolysis reaction to 3‐n‐butyl‐4‐methyl‐5,5‐di‐p‐toluenesulfonyl‐ 3 ‐pyrrolin‐2‐one

The title compound ( 1 ) was isolated in 20‐30% recovery following solvolysis of a mixture of 5‐bromo‐3‐n‐butyl‐4‐methyl‐2‐p‐toluenesulfonylpyrrole ( 4b ) and 5‐bromo‐4‐n‐butyl‐3‐methyl‐2‐p‐toluenesulfonyl‐pyrrole ( 4a ) in trifluoroacetic acid and water, a reaction designed to produce 5‐p‐toluenesulfonyl‐3‐pyrrolin‐2‐ones, e.g., 5a and 5b .     

Synthesis and reactions of 3‐amino‐2‐methyl‐3H‐[1,2,4]triazolo[5,1‐b]‐quinazolin‐9‐one and 2‐hydrazino‐3‐phenylamino‐3H‐quinazolin‐4‐one

The reaction of 3‐N‐(2‐mercapto‐4‐oxo‐4H‐quinazolin‐3‐yl)acetamide ( 1 ) with hydrazine hydrate yielded 3‐amino‐2‐methyl‐3H‐[1,2,4]triazolo[5,1‐b]quinazolin‐9‐one ( 2 ). The reaction of 2 with o‐chlorobenzaldehyde and 2‐hydroxy‐naphthaldehyde gave the corresponding 3‐arylidene amino derivatives 3 and 4 , respectively. Condensation of 2 with 1‐nitroso‐2‐naphthol afforded the corresponding 3‐(2‐hydroxy‐naphthalen‐1‐yl‐diazenyl)‐2‐methyl‐3H‐[1,2,4]triazolo[5,1‐b]quinazolin‐9‐one ( 5 ), which on subsequent reduction by SnCl₂ and HCl gave the hydrazino derivative 6. Reaction of 2 with phenyl isothiocyanate in refluxing ethanol yielded thiourea derivative 7. Ring closure of 7 subsequently cyclized on refluxing with phencyl bromide, oxalyl dichloride and chloroacetic acid afforded the corresponding thiazolidine derivatives 8, 9 and 10 , respectively. Reaction of 2‐mercapto‐3‐phenylamino‐3H‐quinazolin‐4‐one ( 11 ) with hydrazine hydrate afforded 2‐hydrazino‐3‐phenylamino‐3H‐quinazolin‐4‐one ( 12 ). The reactivity 12 towards carbon disulphide, acetyl acetone and ethyl acetoacetate gave 13, 14 and 15 , respectively. Condensation of 12 with isatin afforded 2‐[N‐(2‐oxo‐1,2‐dihydroindol‐3‐ylidene)hydrazino]‐3‐phenylamino‐3H‐quinazolin‐4‐one ( 16 ). 2‐(4‐Oxo‐3‐phenylamino‐3,4‐dihydroquinazolin‐2‐ylamino)isoindole‐1,3‐dione ( 17 ) was synthesized by the reaction of 12 with phthalic anhydride. All isolated products were confirmed by their ir, ¹H nmr, ¹³C nmr and mass spectra.     

Synthesis and Reactions of the Novel 6‐ethyl‐4‐hydroxy‐2,5‐dioxo‐5,6‐dihydro‐2H‐pyrano[3,2‐c]quinoline‐3‐carboxaldehyde

The novel 6‐ethyl‐4‐hydroxy‐2,5‐dioxo‐5,6‐dihydro‐2H‐pyrano[3,2‐c]quinoline‐3‐carboxaldehyde ( 2 ) was efficiently synthesized from Vilsmeier–Haack formylation of 3‐(1‐ethy1‐4‐hydroxy‐2‐oxo‐(1H)‐quinolin‐3‐yl)‐3‐oxopropanoic acid ( 1 ). The aldehyde 2 was allowed to react with some nitrogen nucleophiles producing a variety of hydrazones 3 – 7 . Reaction of aldehyde 2 with hydrazine hydrate and hydroxylamine hydrochloride afforded pyrazole and isoxazole annulated pyrano[3,2‐c]quinoline‐2,5(6H)‐dione, respectively. The reactivity of aldehyde 2 was examined toward some active methylene nitrile, namely, malononitrile, ethyl cyanoacetate, and cyanoacetamide leading to 2‐iminopyrano[2′,3′:4,5]pyrano[3,2‐c]quinolines 10 – 12 , respectively. Also, some novel pyrazolo[4″,3″:5′,6′]pyrano[2′,3′:4,5]pyrano[3,2‐c]quinolines ( 13 , 14 ) and thiazolo[5″,4″:5′,6′]pyrano[2′,3′:4,5]pyrano[3,2‐c]quinolines ( 15 , 16 ) were synthesized. Structures of the new synthesized products were deduced on the basis of their analytical and spectral data.     

New synthesis and reactivity of 3‐bromoacetyl‐4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐one with binucleophilic amines

3‐(Bromoacetyl)‐4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐one was synthesized by the reaction of dehydroacetic acid (DHAA) with bromine in glacial acetic acid. Novel heterocyclic products were synthesized from the reaction of bromo‐DHAA with alkanediamines, phenylhydrazines, ortho‐phenylenediamines, and ortho‐aminobenzenethiol. The obtained new products 3‐(2‐N‐substituted‐acetyl)‐4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐ones, 4‐hydroxy‐3‐[1‐hydroxy‐2‐(2‐phenylhydrazinyl)vinyl]‐6‐methyl‐2H‐pyran‐2‐one, 1‐(2,4‐dinitrophenyl)‐7‐methyl‐2,3‐dihydro‐1H‐pyrano[4,3‐c]pyridazine‐4,5‐dione, 3‐(3,4‐dihydroquinoxalin‐2‐yl)‐4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐one/3‐(3,4‐dihydroquinoxalin‐2‐yl)‐6‐methyl‐2H‐pyran‐2,4(3H)‐dione, 6‐methyl‐3‐(3,4‐dihydroquinoxalin‐2‐yl)‐2H‐pyran‐2,4(3H)‐dione, and (E)‐3‐(2H‐benzo[b][1,4]thiazin‐3(4H)‐ylidene)‐6‐methyl‐2H‐pyran‐2,4(3H)‐dione were fully characterized by IR, ¹H and ¹³C NMR, and mass spectra. J. Heterocyclic Chem., 2011.     

Synthesis of optically active af‐(1‐Ethyl‐3‐methylhexahydro‐1,3‐diazin‐5‐yl)‐ and N‐(1‐Ethyl‐5‐methyloctahydro‐1,5‐diazocin‐3‐yl)pyridine‐3‐carboxamides

As part of the structure‐activity relationship of the dopamine D₂ and serotonin 5‐HT₃ receptors antagonist 1, which is a clinical candidate with a broad antiemetic activity, the synthesis and dopamine D₂ and serotonin 5‐HT₃ receptors binding affinity of (R)‐5‐bromo‐N‐(1‐ethyl‐3‐methylhexahydro‐1,3‐diazin‐5‐yl)‐ and (R)‐5‐bromo‐N‐(1‐ethyl‐5‐methyloctahydro‐1,5‐diazocin‐3‐yl)‐2‐methoxy‐6‐methylaminopyridine‐3‐carboxam‐ides ( 2 and 3 ) are described. Treatment of 1‐ethyl‐2‐(p‐toluenesulfonyl)amino‐3‐methylaminopropane dihy‐drochloride ( 4a ) with paraformaldehyde and successive deprotection gave the 5‐aminohexahydro‐1,3‐diazine 6 in excellent yield. 3‐Amino‐1‐ethyl‐5‐methyloctahydro‐1,5‐diazocine ( 15 ) was prepared from 2‐(benzyloxycarbonyl)amino‐3‐[[N‐(tert‐butoxycarbonyl)‐N‐methyl]amino]‐1‐ethylaminopropane ( 9 ) through the intramolecular amidation of (R)‐3‐[N‐[(2‐benzyloxycarbonylamino‐3‐methylamino)propyl]‐N‐ethyl]aminopropionic acid trifluoroacetate ( 12 ), followed by lithium aluminum hydride reduction of the resulting 6‐oxo‐1‐ethyl‐5‐methyloctahydrodiazocine ( 13 ) in 41% yield. Reaction of the amines 6 and 15 with 5‐bromo‐2‐methoxy‐6‐methylaminopyridine‐3‐carboxylic acid furnished the desired 2 and 3 , which showed much less potent affinity for dopamine D₂ receptors than 1 .     

Selenium‐Containing Heterocycles from Isoselenocyanates: Synthesis of 5‐Amino‐2,4‐dihydro‐3H‐1,2,4‐triazole‐3‐selones

The reaction of S‐methylisothiosemicarbazide hydroiodide (=S‐methyl hydrazinecarboximidothioate hydroiodide; 1 ), prepared from thiosemicarbazide by treatment with MeI in EtOH, and aryl isoselenocyanates 5 in CH₂Cl₂ affords 3H‐1,2,4‐triazole‐3‐selone derivatives 7 in good yield (Scheme 2, Table 1). During attempted crystallization, these products undergo an oxidative dimerization to give the corresponding bis(4H‐1,2,4‐triazol‐3‐yl) diselenides 11 (Scheme 3). The structure of 11a was established by X‐ray crystallography.     

Synthesis of Bis‐Heterocyclic 1H‐Imidazole 3‐Oxides from 3‐Oxido‐1H‐imidazole‐4‐carbohydrazides

The reaction of 1H‐imidazole‐4‐carbohydrazides 1 , which are conveniently accessible by treatment of the corresponding esters with NH₂NH₂?H₂O, with isothiocyanates in refluxing EtOH led to thiosemicarbazides (=hydrazinecarbothioamides) 4 in high yields (Scheme 2). Whereas 4 in boiling aqueous NaOH yielded 2,4‐dihydro‐3H‐1,2,4‐triazole‐3‐thiones 5 , the reaction in concentrated H₂SO₄ at room temperature gave 1,3,4‐thiadiazol‐2‐amines 6 . Similarly, the reaction of 1 with butyl isocyanate led to semicarbazides 7 , which, under basic conditions, undergo cyclization to give 2,4‐dihydro‐3H‐1,2,4‐triazol‐3‐ones 8 (Scheme 3). Treatment of 1 with Ac₂O yielded the diacylhydrazine derivatives 9 exclusively, and the alternative isomerization of 1 to imidazol‐2‐ones was not observed (Scheme 4). It is important to note that, in all these transformations, the imidazole N‐oxide residue is retained. Furthermore, it was shown that imidazole N‐oxides bearing a 1,2,4‐triazole‐3‐thione or 1,3,4‐thiadiazol‐2‐amine moiety undergo the S‐transfer reaction to give bis‐heterocyclic 1H‐imidazole‐2‐thiones 11 by treatment with 2,2,4,4‐tetramethylcyclobutane‐1,3‐dithione (Scheme 5).     

Generation and reactivity of 3‐carbethoxy‐5‐phenyl‐5H,7H‐thiazolo[3,4‐c]oxazol‐4‐ium‐1‐olate

3‐Carbethoxy‐5‐phenyl‐5H,7H‐thiazolo[3,4‐c]oxazol‐4‐ium‐1‐olate was generated from (2R,4R)‐N‐ethoxyoxalyl‐2‐phenylthiazolidine‐4‐carboxylic acid and its reactivity studied. This münchnone showed low reactivity as dipole although from the reaction with dimethyl acetylenedicarboxylate the corresponding (3R)‐3‐phenyl‐17H,3H‐pyrrolo[1,2‐c]thiazole‐5,6,7‐tricarboxylate could be isolated. The thermolysis of (2R,4R)‐N‐ethoxyoxalyl‐2‐phenylthiazolidine‐4‐carboxylic acid in refluxing acetic anhydride led to the synthesis of N‐(1‐ethoxycarbonyl‐2‐phenylvinyl)‐2‐phenyl‐4‐thioxo‐1,3‐thiazolidine. The structure of methyl (2R,4R)‐N‐ethoxyoxalyl‐2‐phenylthiazoliddine‐4‐carboxylate was determined by X‐ray crystallography.     

(2S,3S)‐2,6‐Dimethylheptane‐1,3‐diol,the oxygenated side chain of 22(S)‐hydroxycholestrol,and its synthetic precursor (R)‐4‐benzyl‐3‐[(2R,3S)‐3‐hydroxy‐2,6‐dimethylheptanoyl]‐1,3‐oxazolidin‐2‐one

(2S,3S)‐2,6‐Dimethylheptane‐1,3‐diol, C₉H₂₀O₂, (I), was synthesized from the ketone (R)‐4‐benzyl‐3‐[(2R,3S)‐3‐hydroxy‐2,6‐dimethylheptanoyl]‐1,3‐oxazolidin‐2‐one, C₁₉H₂₇NO₄, (II), containing C atoms of known chirality. In both structures, strong hydrogen bonds between the hydroxy groups form tape motifs. The contribution from weaker C—H...O hydrogen bonds is much more evident in the structure of (II), which furthermore contains an example of a direct short Osp³...Csp² contact that represents a usually unrecognized type of intermolecular interaction.     

Reactivity study on morpholine‐1‐carbothioic acid (2‐phenyl‐3H‐quinazolin‐4‐ylidene) amide

Regioselective reactions of morpholine‐1‐carbothioic acid (2‐phenyl‐3H‐quinazolin‐4‐ylidene) amide ( 1 ) with electrophiles and nucleophiles were studied. The compound ( 1 ) reacts with alkyl halides in basic medium to afford S‐substituted isothiourea derivatives, with amines to give 1,1‐disubstituted‐3‐(2‐phenyl‐3H‐quinazolin‐4‐ylidene) thioureas and l‐substituted‐3‐(2‐phenyl‐quinazolin‐4‐yl) thioureas via transami‐nation reaction. The reaction of ( 1 ) with amines in the presence of H₂O₂ provided N⁴‐disubstituted‐N'⁴‐(2‐phenylquinazolin‐4‐yl)morpholin‐4‐carboximidamide via oxidative desulfurization. Estimation of reactivity sites on ( 1 ) was supported using the ab initio (HF/6‐31G**) quantum chemistry calculations. The ir, ¹H nmr, ¹³C nmr, mass spectroscopy and x‐ray identified the isolated products.     

Catalytic Enantioselective Synthesis of a 3‐Aryl‐3‐benzyloxindole (=3‐Aryl‐3‐benzyl‐1,3‐dihydro‐2H‐indol‐2‐one) Exhibiting Antitumor Activity

A palladium‐catalyzed intramolecular α‐arylation of an amide in the presence of a bulky chiral N‐heterocyclic carbene ligand is the key step in the first catalytic synthesis of (3R)‐6‐chloro‐3‐(3‐chlorobenzyl)‐1,3‐dihydro‐3‐(3‐methoxyphenyl)‐2H‐indol‐2‐one ((R)‐ 5 ). This oxindole, in racemic form, had been shown previously to be an anticancer agent. (R)‐ 5 was obtained with an overall yield of 45% and with 96% enantioselectivity.     

Synthesis of 15‐Cyano‐12‐oxopentadecano‐15‐lactone and 15‐Cyano‐ 12‐oxopentadecano‐15‐lactam

15‐Cyano‐12‐oxopentadecano‐15‐lactone was synthesized in 59% total yield starting from 2‐nitrocyclododecanone by Michael addition to acrylaldehyde, followed by reaction with trimethylsilylcyanide, hydrolysis, ring‐expansion, and Nef reaction. A two‐step, one‐pot synthesis of intermediate 2‐hydroxy‐4‐(1‐nitro‐2‐oxycyclododecyl)butanenitrile from 3‐(1‐nitro‐2‐oxocyclododecyl)propanal was developed and the conditions for the Nef reaction were studied. 15‐Cyano‐12‐oxopentadecano‐15‐lactam was synthesized in 40% total yield starting from 2‐nitrocyclododecanone by Michael addition to acrylaldehyde, followed by Strecker reaction, ring‐expansion, and Nef reaction. The conditions for the Strecker and Nef reactions were studied. The structures of the target compounds, intermediates, and by‐product were characterized by IR, ¹H‐ and ¹³C‐NMR, and elemental analysis or MS.     

Synthesis and Heterocyclization of 1‐Aryl‐2‐methyl‐4‐oxo‐1,4,5,6‐tetrahydropyridine‐3‐carboxylates

A series of novel isoxazole, dihydropyrazolone, and tetrahydropyridine derivatives were synthesized by the reaction of corresponding ethyl 1‐substituted aryl‐2‐methyl‐4‐oxo‐1,4,5,6‐tetrahydropyridine‐3‐carboxylates with different hydrazines and hydroxylamine. Reaction of tetrahydropyridone with N ,N‐dimethylformamide dimethyl acetal provided 1‐(5‐chloro‐2‐methylphenyl)‐2‐[2‐(dimethylamino)ethenyl]‐4‐oxo‐1,4,5,6‐tetrahydropyridine‐3‐carboxylate, which was cyclized into a bicyclic compound on treatment with ammonium acetate. The structures of all synthesized compounds were confirmed by IR, ¹H NMR, and ¹³C NMR spectroscopy data. The structure of 5‐(5‐chloro‐2‐methylphenyl)‐4‐methyl‐2‐phenyl‐2,5,6,7‐tetrahydro‐3H‐pyrazolo[4,3‐c]pyridin‐3‐one was unambiguously assigned by means of X‐ray analysis data.     

Unexpected Thermal Transformation of Aryl 3‐Arylprop‐2‐ynoates: Formation of 3‐(Diarylmethylidene)‐2,3‐dihydrofuran‐2‐ones

A number of aryl 3‐arylprop‐2‐ynoates 3 has been prepared (cf. Table 1 and Schemes 3 – 5). In contrast to aryl prop‐2‐ynoates and but‐2‐ynoates, 3‐arylprop‐2‐ynoates 3 (with the exception of 3b ) do not undergo, by flash vacuum pyrolysis (FVP), rearrangement to corresponding cyclohepta[b]furan‐2(2H)‐ones 2 (cf. Schemes 1 and 2). On melting, however, or in solution at temperatures >150°, the compounds 3 are converted stereospecifically to the dimers 3‐[(Z)‐diarylmethylidene]‐2,3‐dihydrofuran‐2‐ones (Z)‐ 11 and the cyclic anhydrides 12 of 1,4‐diarylnaphthalene‐2,3‐dicarboxylic acids, which also represent dimers of 3 , formed by loss of one molecule of the corresponding phenol from the aryloxy part (cf. Scheme 6). Small amounts of diaryl naphthalene‐2,3‐dicarboxylates 13 accompanied the product types (Z)‐ 11 and 12 , when the thermal transformation of 3 was performed in the molten state or at high concentration of 3 in solution (cf. Tables 2 and 4). The structure of the dihydrofuranone (Z)‐ 11c was established by an X‐ray crystal‐structure analysis (Fig. 1). The structures of the dihydrofuranones 11 and the cyclic anhydrides 12 indicate that the 3‐arylprop‐2‐ynoates 3 , on heating, must undergo an aryl O→C(3) migration leading to a reactive intermediate, which attacks a second molecule of 3 , finally under formation of (Z)‐ 11 or 12 . Formation of the diaryl dicarboxylates 13 , on the other hand, are the result of the well‐known thermal Diels‐Alder‐type dimerization of 3 without rearrangement (cf. Scheme 7). At low concentration of 3 in decalin, the decrease of 3 follows up to ca. 20% conversion first‐order kinetics (cf. Table 5), which is in agreement with a monomolecular rearrangement of 3 . Moreover, heating the highly reactive 2,4,6‐trimethylphenyl 3‐(4‐nitrophenyl)prop‐2‐ynonate ( 3f ) in the presence of a twofold molar amount of the much less reactive phenyl 3‐(4‐nitrophenyl)prop‐2‐ynonate ( 3g ) led, beside (Z)‐ 11f , to the cross products (Z)‐ 11fg , and, due to subsequent thermal isomerization, (E)‐ 11fg (cf. Scheme 10), the structures of which indicated that they were composed, as expected, of rearranged 3f and structurally unaltered 3g . Finally, thermal transposition of [¹⁷O]‐ 3i with the ¹⁷O‐label at the aryloxy group gave (Z)‐ and (E)‐[¹⁷O₂]‐ 11i with the ¹⁷O‐label of rearranged [¹⁷O]‐ 3i specifically at the oxo group of the two isomeric dihydrofuranones (cf. Scheme 8), indicating a highly ordered cyclic transition state of the aryl O→C(3) migration (cf. Scheme 9).     

Synthesis of benzyl O-(2,3,3'-tri-O-acetyl-β-D-apiofuranosyl)-(1→3)-2,4-di-O-benzoyl-α-D-xylopyranoside and its X-ray structure

The protected apiose-containing disaccharide, benzyl O-(2,3, 3'-tri-O-acetyl-β-D-apiofuranosyl)-( 1→3)-2, 4-di-O-benzoyl-α-D-xylopyranoside, was synthesized and its X-ray structure provided.     

Hydrogen‐bonding patterns in three substituted N‐benzyl‐N‐(3‐tert‐butyl‐1‐phenyl‐1H‐pyrazol‐5‐yl)acetamides

The molecules of N‐(3‐tert‐butyl‐1‐phenyl‐1H‐pyrazol‐5‐yl)‐2‐chloro‐N‐(4‐methoxybenzyl)acetamide, C₂₃H₂₆ClN₃O₂, are linked into a chain of edge‐fused centrosymmetric rings by a combination of one C—H...O hydrogen bond and one C—H...π(arene) hydrogen bond. In N‐(3‐tert‐butyl‐1‐phenyl‐1H‐pyrazol‐5‐yl)‐2‐chloro‐N‐(4‐chlorobenzyl)acetamide, C₂₂H₂₃Cl₂N₃O, a combination of one C—H...O hydrogen bond and two C—H...π(arene) hydrogen bonds, which utilize different aryl rings as the acceptors, link the molecules into sheets. The molecules of S‐[N‐(3‐tert‐butyl‐1‐phenyl‐1H‐pyrazol‐5‐yl)‐N‐(4‐methylbenzyl)carbamoyl]methyl O‐ethyl carbonodithioate, C₂₆H₃₁N₃O₂S₂, are also linked into sheets, now by a combination of two C—H...O hydrogen bonds, both of which utilize the amide O atom as the acceptor, and two C—H...π(arene) hydrogen bonds, which utilize different aryl groups as the acceptors.     

Synthesis and Characterization of 11‐Amino‐3‐methoxy‐8‐substituted‐12‐aryl‐8,9‐dihydro‐7H‐chromeno[2,3‐b]quinolin‐10(12H)‐one Derivatives

A series of 2‐amino‐7‐methoxy‐4‐aryl‐4H‐chromene‐3‐carbonitrile compounds 2 were obtained by condensation of 3‐methoxyphenol with β‐dicyanostyrenes 1 in absolute ethanol containing piperidine. The intermediate enamines 3 were prepared by compounds 2 with 5‐substituted‐1,3‐cyclohexanedione using p‐toluenesuflonic acid (TsOH) as catalyst. The title compounds 11‐amino‐3‐methoxy‐8‐substituted‐12‐aryl‐8,9‐dihydro‐7H‐chromeno[2,3‐b]quinolin‐10(12H)‐one 4 were synthesized by cyclization of the intermediate enamines 3 in THF with K₂CO₃ /Cu₂Cl₂ as catalyst. The structures of all compounds were characterized by elemental analysis, IR, MS, and ¹H NMR spectra. The crystal structure of compound 4i was determined by single‐crystal X‐ray diffraction analysis.     

Synthesis and Conformational Analysis of 1′‐ and 3′‐Substituted 2‐Deoxy‐2‐fluoro‐D‐ribofuranosyl Nucleosides

Convergent syntheses of the 9‐(3‐X‐2,3‐dideoxy‐2‐fluoro‐β‐D ‐ribofuranosyl)adenines 5 (X=N₃) and 7 (X=NH₂), as well as of their respective α‐anomers 6 and 8 , are described, using methyl 2‐azido‐5‐O‐benzoyl‐2,3‐dideoxy‐2‐fluoro‐β‐D ‐ribofuranoside ( 4 ) as glycosylating agent. Methyl 5‐O‐benzoyl‐2,3‐dideoxy‐2,3‐difluoro‐β‐D ‐ribofuranoside ( 12 ) was prepared starting from two precursors, and coupled with silylated N⁶‐benzoyladenine to afford, after deprotection, 2′,3′‐dideoxy‐2′,3′‐difluoroadenosine ( 13 ). Condensation of 1‐O‐acetyl‐3,5‐di‐O‐benzoyl‐2‐deoxy‐2‐fluoro‐β‐D ‐ribofuranose ( 14 ) with silylated N²‐palmitoylguanine gave, after chromatographic separation and deacylation, the N⁷‐β‐anomer 17 as the main product, along with 2′‐deoxy‐2′‐fluoroguanosine ( 15 ) and its N⁹‐α‐anomer 16 in a ratio of ca. 42 : 24 : 10. An in‐depth conformational analysis of a number of 2,3‐dideoxy‐2‐fluoro‐3‐X‐D ‐ribofuranosides (X=F, N₃, NH₂, H) as well as of purine and pyrimidine 2‐deoxy‐2‐fluoro‐D ‐ribofuranosyl nucleosides was performed using the PSEUROT (version 6.3) software in combination with NMR studies.     

5‐Hydroxyalkyl derivatives of tert‐butyl 2‐oxo‐2,5‐dihydro‐1H‐pyrrole‐1‐carboxylate: diastereoselectivity of the Mukaiyama crossed‐aldol‐type reaction

The title compounds, rac‐(1′R,2R)‐tert‐butyl 2‐(1′‐hydroxyethyl)‐3‐(2‐nitrophenyl)‐5‐oxo‐2,5‐dihydro‐1H‐pyrrole‐1‐carboxylate, C₁₇H₂₀N₂O₆, (I), rac‐(1′S,2R)‐tert‐butyl 2‐[1′‐hydroxy‐3′‐(methoxycarbonyl)propyl]‐3‐(2‐nitrophenyl)‐5‐oxo‐2,5‐dihydro‐1H‐pyrrole‐1‐carboxylate, C₂₀H₂₄N₂O₈, (II), and rac‐(1′S,2R)‐tert‐butyl 2‐(4′‐bromo‐1′‐hydroxybutyl)‐5‐oxo‐2,5‐dihydro‐1H‐pyrrole‐1‐carboxylate, C₁₃H₂₀BrNO₄, (III), are 5‐hydroxyalkyl derivatives of tert‐butyl 2‐oxo‐2,5‐dihydropyrrole‐1‐carboxylate. In all three compounds, the tert‐butoxycarbonyl (Boc) unit is orientated in the same manner with respect to the mean plane through the 2‐oxo‐2,5‐dihydro‐1H‐pyrrole ring. The hydroxyl substituent at one of the newly created chiral centres, which have relative R,R stereochemistry, is trans with respect to the oxo group of the pyrrole ring in (I), synthesized using acetaldehyde. When a larger aldehyde was used, as in compounds (II) and (III), the hydroxyl substituent was found to be cis with respect to the oxo group of the pyrrole ring. Here, the relative stereochemistry of the newly created chiral centres is R,S. In compound (I), O—H...O hydrogen bonding leads to an interesting hexagonal arrangement of symmetry‐related molecules. In (II) and (III), the hydroxyl groups are involved in bifurcated O—H...O hydrogen bonds, and centrosymmetric hydrogen‐bonded dimers are formed. The Mukaiyama crossed‐aldol‐type reaction was successful when using the 2‐nitrophenyl‐substituted hydroxypyrrole, or the unsubstituted hydroxypyrrole, and boron trifluoride diethyl ether as catalyst. The synthetic procedure leads to a syn configuration of the two newly created chiral centres in all three compounds.     

Oligonucleotides Containing Novel 4′‐C‐ or 3′‐C‐(Aminoalkyl)‐Branched Thymidines

The synthesis of four novel 3′‐C‐branched and 4′‐C‐branched nucleosides and their transformation into the corresponding 3′‐O‐phosphoramidite building blocks for automated oligonucleotide synthesis is reported. The 4′‐C‐branched key intermediate 11 was synthesized by a convergent strategy and converted to its 2′‐O‐methyl and 2′‐deoxy‐2′‐fluoro derivatives, leading to the preparation of novel oligonucleotide analogues containing 4′‐C‐(aminomethyl)‐2′‐O‐methyl monomer X and 4′‐C‐(aminomethyl)‐2′‐deoxy‐2′‐fluoro monomer Y (Schemes 2 and 3). In general, increased binding affinity towards complementary single‐stranded DNA and RNA was obtained with these analogues compared to the unmodified references (Table 1). The presence of monomer X or monomer Y in a 2′‐O‐methyl‐RNA oligonucleotide had a negative effect on the binding affinity of the 2′‐O‐methyl‐RNA oligonucleotide towards DNA and RNA. Starting from the 3′‐C‐allyl derivative 28 , 3′‐C‐(3‐aminopropyl)‐protected nucleosides and 3′‐O‐phosphoramidite derivatives were synthesized, leading to novel oligonucleotide analogues containing 3′‐C‐(3‐aminopropyl)thymidine monomer Z or the corresponding 3′‐C‐(3‐aminopropyl)‐2′‐O,5‐dimethyluridine monomer W (Schemes 4 and 5). Incorporation of the 2′‐deoxy monomer Z induced no significant changes in the binding affinity towards DNA but decreased binding affinity towards RNA, while the 2′‐O‐methyl monomer Z induced decreased binding affinity towards DNA as well as RNA complements (Table 2).