Studies on pyrrolidinones. Synthesis of methyl N-(4-nitrobenzyl)pyroglutamate

Methyl N-trimethylsilylpyroglutamate is reacted with 4-nitrobenzyl chloride to yield methyl N-(4-nitrobenzyl)pyroglutamate.     

Studies on pyrrolidones. Convenient syntheses of methyl,methyl N-methyl- and methyl N-methoxymethylpyroglutamate

Facile methods to prepare methyl pyroglutamate ( 2 ), methyl N-methylpyroglutamate ( 1 ) and methyl N-methoxymethylpyroglutamate ( 7 ) in one-step from pyroglutamic acid are described.     

Synthesis of Sialyl Lewis X Ganglioside Analogs Containing A Variable Length Spacer Between the Sugar and Lipophilic Moieties 1

Abstract

Five sialyl Lew is X ganglioside analogs containing 4-(2-tetradecylhexadecanoylamino)benzyl group in place of ceramide and a variety of lengths of ethylene glycol chains as the spacer, have been synthesized. Glycosidation of O-(methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-glacto-2-nonulopyranosylonate)-(2→3)-O-(4-O-acetyl-2,6-di-O-benzoyl-β-D-galactopyranosyl)-(1→4)-O-[(2,3,4-tri-O-acetylα-L-fucopyranosyl)-(1→3)]-2,4-di-O-benzoyl-α-D-glucopyranosyl trichloroacetimidate (13) with oligo ethyleneglycol monobenzyl ether derivatives 9, 10, 11 and 12, prepared from the corresponding oligo ethyleneglycols by 4-nitrobenzylation, reduction and N-acylation with 2-tetradecylhexadecanoic acid, using boron trifluoride etherate gave the corresponding glycolipid derivatives 14, 15, 16 and 17. A similar glycosidation of 13 with 4-nitrobenzyl alcohol gave the 4-nitrobenzyl glycoside 18, which was converted via reduction of nitro group and N-acylation into the corresponding glycolipid derivative 19. Compounds 14-17 and 19 were transformed into the title compounds by O-deacylation and hydrolysis of methyl ester group in good yields.

     

The matrix-isolation IR spectrum of the o-quinonoid intermediate in the photolysis of 2-nitrobenzyl methyl ether

Photolysis of 2-nitrobenzyl methyl ether in Ar and N₂ matrices at 12 K generated an intermediate with λ_max at 430 nm, and which was itself photolabile at 430–460 nm. Matrix IR spectra, as well as the UV-visible absorption, were obtained for this species. An analogous intermediate had previously been observed in flash-photolysis studies of 2-nitrobenzyl 4-cyanophenyl ether, and had been assigned an o-quinonoid structure on the basis of its kinetic behaviour and the position of its UV-visible absorption. In the matrix studies with 2-nitrobenzyl methyl ether, the IR spectra confirmed the o-quinonoid structure.     

<Emphasis Type="Italic">N</Emphasis>-(4-methoxy-3-nitrobenzyl) derivatives of some nitrogen-containing heterocycles

A number of nitrogen heterocycles reacted with 4-methoxy-3-nitrobenzyl chloride in dimethyl-formamide in the presence of potassium carbonate to give the corresponding N-(4-methoxy-3-nitrobenzyl) derivatives. The reaction of 5-fluoro-1,3-bis(4-methoxy-3-nitrobenzyl)pyrimidine-2,4(1H,3H)-dione with aqueous methylamine afforded N,N′-bis(4-methylamino-3-nitrobenzyl)urea, whereas analogous reaction with 1-(4-methoxy-3-nitrobenzyl)-2-(methylsulfanyl)-1H-benzimidazole resulted in substitution of the methoxy group by methylamino.     

Studies on pyrrolidinones: Some attempts to improve the synthesis of methyl n‐(3,4,4′,5‐tetramethoxybenzhydryl)pyroglutamate (hei 81) by using n‐acyl iminium salts methodologies

Some ways to use the N‐acyl iminium salt methodologies to synthesize a new inhibitor of tubulin polymerization, methyl N‐(3,4,4′,5‐tetramethoxybenzhydryl)pyroglutamate (HEI 81) were studied. The most interesting reactions utilize a new pyroglutamic lactone (3‐(3,4,5‐trimethoxyphenyl)dihydropy‐rrolo[1,2‐c]oxazole‐1,5‐dione).     

Studies on pyrrolidinones: Some attempts to improve the anticancer properties of methyl n‐(3,4,4′,5‐tetramethoxybenzhydryl)pyroglutamate (HEI 81)

The synthesis of esters, amides, pyrrolidinone and succinimide analogs of a new inhibitor of tubulin polymerization, methyl N‐(3,4,4′,5‐tetramethoxybenzhydryl)pyroglutamate (HEI 81) was studied.     

The molecular structure and chemical reactivities of the condensation products of o-substituted benzylidenacetylacetone with hydrazine dihydrochloride

Reaction of o-nitrobenzylideneacetylacetone ( 1a ) with hydrazine dihydrochloride in methanol gave 4-(α-methoxy-o-nitrobenzyl)-3,5-dimethylpyrazole hydrochloride ( 4a ), whose structure was unambigously confirmed by an X-ray crystallographic analysis, via 4-(o-nitrobenzylidene)-3,5-dimethylisopyrazole ( 2a ). Compound 2a was synthesized by condensation of 1a with hydrazine dihydrochloride in acetonitrile. Analogously the corresponding o-chloro derivatives ( 2b, 4b ) were obtained. These were converted to N-methyl ( 6b ) and N-acetyl ( 7a,b ) derivatives and the behaviors on bromination and pyrolysis were investigated.     

Synthesis of isonipecotinoyl analogues of aminopterin and folic acid

The preparation of isonipecotinoyl analogues of aminopterin and methotrexate is described. Condensation of diethyl N-isonipecotinoyl-L-glutamate 4 with 2-amino-5-bromomethyl-3-cyanopyrazine 5 afforded diethyl N-(N-[(2-amino-3-cyanopyrazin-5-yl)methyl]isonipecotinoyl)-L-glutamate 6 . Cyclisation of 6 with guanidine followed by blocking group hydrolysis afforded N-([N-(2,4-diaminopteridin-6-yl)methyl]isonipecotinoyl)-L-glutamic acid 8 . Coupling of N-(2-amino-4(3H)ioxopteridin-6-yl]methyl)isonipecotinic acid 11 with diethyl L-glutamate gave diethyl N-[(N-[2-amino-4(3H)-oxopteridin-6-yl]methyl)isonipecotinoyl]-L-glutamate 12 . Blocking group hydrolysis afforded N-[(N-[2-amino-4(3H)-oxopteridin-6-yl]methyl)isonipecotinoyl]-L-glutamic acid 13 .     

The chemistry of 2H-3,1-benzoxazine-2,4(1H)-dione (Isatoic Anhydride). 19. Direct formation of 2-aminobenzyl alcohols from the reduction of N-substituted isatoic anhydrides

Isatoic anhydrides 1 are easily reduced with sodium borohydride to o-(substituted-amino)benzyl alcohols 3 in good yield. Sequential reduction of N-(2-nitrobenzyl)isatoic anhydride ( 5 ) with sodium borohydride followed by catalytic hydrogenation of the nitro group affords the naturally occurring 2-(2′-aminobenzylamino)-benzyl alcohol ( 4 ) in 72% yield.     

Synthesis of 4-substituted 1,4-benzodiazepine-3,5-diones

Synthetic routes leading to the preparation of 4-substituted 1,4-benzodiazepine-3,5-diones are described. Thus, 2-carbobenzoxyaminobenzoic acid was converted to its p-nitrobenzyl ester (I) and the decarbobenzoxylated product (II) gave, with ethyl α-bromoacetate, N-(2-carboxy p-nitrobenzylate)phenylglycine ethyl ester (III). The latter was hydrogenolyzed to N-(2-car-boxy)phenylglycine ethyl ester (IV), which was coupled with benzylamine to give N-(2-carboxy-benzylamido)phenylglycine ethyl ester (VIa). Saponification of VIa afforded N-(2-carboxy-benzylamido)phenylglycine (VIIa) which was cyclized with DCCI to produce 4-benzyl-2H-1,4-benzodiazepine-3,5(lH,4H)dione (VIIIa). Alternatively, 2-nitro-N-phenylbenzamide (Xb) was reduced to 2-amino-N-phenylbenzamide (XIb) which was converted to N-(2-carboxanih'do)-phenylglycine ethyl ester (VIb). The latter was converted to 4-phenyl-2H-1,4-benzodiazepine-3,5(1H,4H)dione (VIIIb) in an analogous fashion described for VIIIa.     

Studies on pyrrolidinones. On the carbamoylation of some pyroglutamic derivatives

The carbamoylation of some lactams derivatived from pyroglutamic acid as been studied; better yields were obtained starting from the unsubstitued lactam (toluene, 80°) rather than starting with the N-silyllactam (room temperature), although these latter reaction conditions could be interesting for heat sensitive compounds. Methyl and phenyl isothiocyanate react only with the sodium salt of methyl pyroglutamate, giving 1,5-diaddition products.     

Studies on pyrrolidinones. Synthesis and cyclization of N‐[α‐naphthyl‐(3,4,5‐trimethoxyphenyl)‐methyl]pyroglutamic acid

Condensation of trimethoxyphenyl naphthylcarbinol trimethylsilyl ether with methyl N‐trimethylsilyl‐pyroglutamate yields two separable esters. The Friedel‐Crafts cyclization of the acids obtained after saponification gives analogs of azapodophylloxin. Reduction and treatment of the obtained products with hydrobromic acid yields analogs of azatoxin.     

A facile synthesis of 3-substituted 2-cyanoquinazolin-4(3H)-ones and 3-alkyl-2-cyanothieno[3,2-d]pyrimidin-4(3H)-ones via 1,2,3-dithiazoles

The reaction of methyl anthranilate with 4,5-dichloro-1,2,3-dithiazolium chloride (Appel's salt) in the presence of pyridine (2 equivalents) in dichloromethane at room temperature gave methyl N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)anthranilate ( 3a ) (50% yield), which reacted with sterically less hindered primary alkylamines to give directly 3-alkyl-2-cyanoquinazolin-4(3H)-ones 5 in moderate to good yields. With tert-butylamine, N-(2-methoxycarbonylphenyl)iminocyanomethyl N-(tert-butyl) disulfide 7 and methyl 2-(N-cyanothioformamido)anthranilate ( 8 ) were isolated in 33% and 59% yields, respectively. The cyano group of quinazoline 5a (R = CH₃) is readily displaced by various nucleophiles to give 2-substituted quinazolinones 11–19 , which indicates that compounds 5 can be utilized as starting materials for the synthesis of new 2-substituted quinazolines. Similarly 3-alkyl-2-cyanomieno[3,2,-d]pyrimidin-4(3H)-ones 22 were prepared from methyl 3-[N-(4-chloro-5H-1,2,3-dimiazol-5-ylidene)]-2-thiophencarboxylate ( 21 ) in moderate to good yields.     

Alternating copolymerization of methyl acrylate with donor monomers having a protected amine group

Attempts were made to copolymerize p-aminostyrene, p-acetamidostyrene, N-methyl-p-aceta-midostyrene, N-(4-vinylphenyl) phthalimide, N-vinyl succinimide, and N-vinyl phthalimide with methyl acrylate complexed with ethyl aluminum sesquichloride. Only reactions involving N-(4-vinylphenyl)phthalimide and N-vinyl phthalimide yielded alternating copolymers. N-vinyl succinimide gave nonalternating copolymers insoluble in common solvents and the other monomers did not copolymerize. In some cases, the conventional radical copolymers were prepared for comparison purposes. The reactivity ratios of the free-radical initiated copolymerization of methyl acrylate (I) with N-(4-vinylphenyl)phthalimide (II) were r₁ = 0.14 and r₂ 1.56. The alternating copolymers were studied by ¹H-NMR and ¹³C-NMR spectroscopy. The alternating copolymer of N-(4-vinylphenyl)phthalimide with methyl acrylate was hydrazinolyzed to form the alternating copolymer of methyl acrylate with p-aminostyrene. Hydrazinolysis of the alternating copolymer of methyl acrylate with N-vinyl phthalimide removed the phthalimide moiety and generated vinyl amine units which readily cyclized with neighboring methyl acrylate units to form copolymers that contained five-membered lactam rings. The infrared (IR) spectra of the hydrazinolyzed products contain bands due to amine or amide groups and are devoid of the characteristic bands of the phthalimide ring.     

Three‐Component Reactions with (S)‐Methyl Pyroglutamate: An Efficient Way to Diversely Substituted Asymmetric Amidocyclohexenes

Chiral N‐dienyl lactams are crucial building blocks for the synthesis of complex organic compounds. However, their generation is rather challenging. This paper reports the novel one‐pot reaction of (S)‐methyl pyroglutamate as the a mide component with different a ldehydes and d ienophiles (AAD reaction) to give novel chiral 1‐amido‐2‐cyclohexenes. The corresponding N‐dienyl lactams generated in situ undergo subsequent Diels–Alder reactions in good yield and diastereoselectivity. The scope and limitations of the three‐component protocol were investigated. X‐ray and NMR spectroscopic analysis of the products as well as DFT calculations of the intermediates were also performed to explain the observed stereoselectivity and structural features.     

Studies on pyrrolidinones. On the application of copper-catalyzed arylation of methyl pyroglutamate to obtain a new benzo[de]quinoline scaffold

Optimized conditions for copper-catalyzed N-arylation of methyl pyroglutamate are described. These studies permitted the synthesis of methyl N-naphthylpyroglutamate, which was then cyclized to a ketone. The known dehydration of amidoketones by PPA was extended to this new scaffold to lead to a novel condensed benzo[de]quinoline with potential antioxidative activity.     

The synthesis of azahomotryptophane derivatives. The transformation of N-trifluoroacetyl-5-bromo-4-oxonorvaline methyl ester into 4-(imidazo[1,2-a]azinyl-3)-4-oxohomoalanine derivatives

Azatryptophane homologues, 4-(imidazo[1,2-a]pyridinyl-3)- 9a-9f and 4-(imidazo[1,2-a]pyrimidinyl-3)-4-oxohomoalanine derivatives 9g-91 , were prepared from N,N-dimethyl-N′-(pyridinyl-2)- 6a-6f and N,N-dimethyl-N-(pyriniidinyl-2)formamidines 6g-6i , and (S)-N-trifluoroacetyl-5-bromo-4-oxonorvaline methyl ester ( 2 ) and its (R,S)-isomer.     

α-Methylidene- and α-Alkylidene-β-lactams from Nonproteinogenic Amino Acids

Treatment of methyl 2-(1-hydroxyalkyl)prop-2-enoates 1 with conc. HBr solution afforded methyl (Z)-2-(bromomethyl)alk-2-enoates 2 , which were transformed regioselectively into N-substituted methyl (E)-2- (aminomethyl)alk-2-enoates 3 (S_N2 reaction) and into N-substituted methyl 2-(1-aminoalkyl)prop-2-enoates 4 (S_N2′ reaction). Regiocontrol of nucleophilic attack by amine was accomplished simply by choice of solvent, the S_N2 reaction occurring in MeCN and the S_N2′ reaction in petroleum ether. Hydrolysis and lactamization afforded β-lactams 7 and 8 , containing an exocyciic alkylidene and methylidene group at C(3), respectively.     

Study on the reaction of methyl N‐Methyl‐N‐(6‐substituted‐5‐nitropyrimidin‐4‐yl)glycinates with sodium alkoxides

Methyl N‐methyl‐N‐(6‐substituted‐5‐nitropyrimidin‐4‐yl)glycinates ( 4a‐n ), obtained from 6‐substituted‐4‐chloro‐5‐nitropyrimidines and sarcosine methyl ester (methyl 2‐(methylamino)acetate), in the reaction with sodium alkoxides underwent transformations to give different products. N‐methyl‐N‐(5‐nitropyrimidin‐4‐yl)glycinates ( 4a,i,j ) bearing amino and arylamino groups in the position 6 of the pyrimidine ring gave corresponding 6‐substituted‐4‐methylamino‐5‐nitrosopyrimidines ( 5a,i,j ). In the reaction of N‐(6‐alkylamino‐5‐nitropyrimidin‐4‐yl)‐N‐methylglycinates ( 4b,f‐h ) with sodium alkoxides the corresponding 6‐alkylamino‐4‐methylamino‐5‐nitrosopyrimidines ( 5b,f‐h ) and 5‐hydroxy‐8‐methyl‐5,8‐dihydropteridine‐6,7‐diones ( 6b,f‐h ) were formed. The main products of the reaction of N‐(6‐dialkylamino‐5‐nitropyrimidin‐4‐yl)‐N‐methylglycinates ( 4c‐e,k,l ), after work‐up, were the corresponding 6‐dialkylamino‐9‐methylpurin‐8‐ones ( 7c‐e,k,l ) and 8‐alkoxy‐6‐dialkylamino‐9‐methylpurines ( 9c,1,10c,l ). Methyl N‐methyl‐N‐{[6‐(2‐methoxy‐oxoethyl)thio]‐5‐nitropyrimidin‐4‐yl}glycinate ( 4n ) under the same conditions gave methyl 7‐methylaminothiazolo[5,4‐d]pyrimidine‐2‐carboxylate ( 13 ). Mechanisms of the observed transformations are discussed.