A novel improved synthesis of 3-aminopyrazine-2-carboxylic acid

A three step synthesis of 3-aminopyrazine-2-carboxylic acid ( 1 ) starting from pyrazine-2,3-dicarboxylic acid ( 5 ) is described. Diacid 5 is converted via the anhydride 6 into the ammonium salt of the half acid amide 7 which on Hofmann rearrangement gives the title compound in 55% overall yield.     

Parallel iterative solution-phase synthesis of 5-amino-1-aryl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid amide derivatives

The parallel iterative solution-phase synthesis of 5-amino-1-aryl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid amide derivatives is described. The key intermediate 2,6-bis-aminopyridine-4-carboxylic acid methyl ester was synthesised in a two step procedure in 64% overall yield and elaborated to a variety of triazolopyridine-5-carboxylic acid methyl ester by selective pyridine-N-amination, condensation of the adduct with a wide selection of aldehydes and subsequent cyclisation and oxidation. The desired esters were obtained in yields up to 70%. The final transformation to the amide derivatives was accomplished by application of carefully optimised reaction conditions thus giving access to a library of total 500 triazolopyridine amide derivatives. Iterative synthetic cycles (12-48 library members each) allowing for maximal flexibility in chemistry and maximal efficiency in in vitro biological activity optimisation guided by molecular modelling efforts constitute a synergistic procedure for rapid lead optimisation.     

一种新型噁唑烷酮类抗生素的合成

以2,4-二溴吡啶为原料,经Weinreb酰胺酰化、Noyori不对称氢转移反应、脱Boc保护基、环化、Suzuki偶联、磷酸单酯化及成盐共七步反应制得一种新型噁唑烷酮类抗生素【【(3R,3aS)-7-{6-［(S)3-甲基-2-噁唑烷酮-5-基］吡啶-3-基}-1-氧-1,3,3a,4-四氢苯并［b］噁唑［3,4-d］［1,4］噁嗪-3-基】甲基】磷酸单酯二钠盐,其结构经¹H NMR, ¹³C NMR和HR-MS（ESI）确征,总收率7%,纯度99.7%。     

Studies on the total synthesis of lactonamycin: synthesis of the CDEF ring system

A concise and efficient synthesis of the tetracyclic CDEF ring system of lactonamycin (1) is described. The key step involved the Lewis acid mediated, intramolecular Friedel-Crafts acylation of carboxylic acid 6 to produce the tetracyclic CDEF core structure of target 1. The synthesis of 6 was carried out using a high-yielding Negishi coupling of benzyl bromide 7 with triflate 8, which was accessible in 11 steps and 31% overall yield on a multigram scale starting from trihydroxy acid 9.     

Enantioselective [6pi]-photocyclization reaction of an acrylanilide mediated by a chiral host. Interplay between enantioselective ring closure and enantioselective protonation

The [6pi]-photocyclization of the anilides 1a and 5 was studied in the absence and in the presence of the enantiomerically pure chiral lactam 4. The relative configuration of the products was unambiguously established by single-crystal X-ray crystallography and by NMR spectroscopy. A significant enantiomeric excess was observed upon reaction of compound 1a to its photocyclization products at -55 degrees C employing lactam 4 as a chiral complexing agent in toluene as the solvent (66% yield). The trans product ent-3a was obtained in 57% ee, and the minor diastereoisomer (trans/cis = 73/27), cis product ent-2a, was obtained in 30% ee. DFT calculations were conducted modeling the complexation of intermediates 8 and ent-8 to host 4. In agreement with steric arguments concerning the conrotatory ring closure of 1a, the formation of ent-8 is favored leading to the more stable complex 4.ent-8 as compared to 4.8. Whereas the enantioselectivity in the photocyclization to trans compound ent-3a increased upon reduction in the reaction temperature, the enantiomeric excess in the formation of cis compound ent-2a went through a maximum at -15 degrees C (45% ee) and decreased at lower temperatures. Deuteration experiments conducted with the pentadeuterated analogue of 1a, d(5)-1a, revealed that the protonation of the intermediates 8 and ent-8 is influenced by chiral amide 4. In the formation of ent-3a/3a, both the enantioselective ring closure and the enantioselective protonation by amide 4 favor the observed (6aS,10aS)-configuration of the major enantiomer ent-3a. In the formation of ent-2a/2a, the enantioselective ring closure (and the subsequent diastereoselective protonation) favors the (6aR,10aS)-configuration that is found in compound 2a. Contrary to that, the enantioselective protonation by amide 4 shows a preference for ent-2a with the (6aS,10aR)-configuration.     

Synthesis of (R)-quinuclidine-2-carboxylic acid in enantiomerically pure form

Enantiomerically pure (R)-quinuclidine-2-carboxylic acid has been prepared by following two related 7 step synthetic routes in 16% and 19% overall yield, respectively, from a 1,2,4-trisubstituted piperidine that is easily prepared from inexpensive d-mannitol.     

On the isomerization of ent-kaurenic acid

Kaurenic acid (1a) is a tetracyclic diterpene that has an exocyclic double bond at delta16. Isokaurenic acid (2a) has an endocyclic delta15double bond. This compound has been isolated from Espeletia tenore (Espeletinae), a resinous plant from the Venezuelan Andes, but its occurrence is rare. In order to obtain a larger amount of 2a, the isomerization of la, which is easily obtained from other Espeletinae, was tried. Kaurenic acid methyl ester (1b) was treated with dil. HCl in CH3Cl/EtOH, after 6 h under reflux a yield of 41.5% isokaurenic acid methyl ester (2b) was obtained but 35.7% 16alpha-ethoxy-kauran-19-oic acid methyl ester (3b) had formed as a byproduct. Treating 1b with CF3COOH in refluxing CH2Cl2 permitted to obtain a yield of 66.6% of 2b in 4 h and only traces of 16alpha-hydroxy-kauran-19-oic acid methyl ester (3a) as a byproduct. Both isomers were separated on a silica gel column impregnated with 20% AgNO3. Treating 2b with KOH in refluxing DMSO yielded pure isokaurenic acid, no back isomerization was observed.     

Efficient synthesis of 2-aminoindane-2-carboxylic acid via dialkylation of nucleophilic glycine equivalent

An efficient, easy to scale-up method for preparing 2-aminoindane-2-carboxylic acid via two-step alkylation of a Ni(II)-complex of glycine Schiff base with 2-[N-(alpha-picolyl)amino]benzophenone (PAAP) (2b) with o-dibromoxylylene (3) is reported. The first step, monoalkylation of 2b with 3, conducted under phase-transfer conditions, gave the corresponding complex 6 in excellent chemical yield (97.2%). Without any purification the intermediate 6 was cyclized under homogeneous conditions (DMF, NaO-t-Bu) to give the product 7 in high chemical yield (93.1%). Decomposition of prepared 7 afforded the target amino acid 2-aminoindane-2-carboxylic acid (1) in 97.9% yield, along with recovery of ligand 8, which was converted back to the starting glycine complex 2b. Operationally convenient experimental procedures, mild reaction conditions, as well as high chemical and volume yields render the method practical for preparing amino acid 1 and its analogues.     

Combined directed ortho metalation/cross-coupling strategies: synthesis of the tetracyclic A/B/C/D ring core of the antitumor agent camptothecin

A convergent synthesis of the A/B/C/D ring fragment 5 of camptothecin using a combination of directed ortho metalation and Negishi cross-coupling is described. The key features of the synthetic sequence are an anionic ortho-Fries rearrangement (10 --> 12), a Negishi cross-coupling (7 --> 6), and a terminal modified von Braun reaction (16 --> 5) that leads to tetracyclic derivative 5 in 7 steps and 11% overall yield.     

Total syntheses of (+)-chloropuupehenone and (+)-chloropuupehenol and their analogues and evaluation of their bioactivities

Tetracyclic pyrans (+)-chloropuupehenone (1) and (+)-chloropuupehenol (5) and its C8-R-isomer (+)-3 were synthesized via a one-pot condensation of 1-chloro-2-lithio-3,5,6-tris(tert-butyldimethylsilyloxy)benzene (8) with (4aS,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2,5,5,8a-tetramethylnaphthalene-1-carboxaldehyde (7). The major condensation product, (4aS,6aR,12bS)-2H-9,10-bis(tert-butyldimethylsilyloxy)-11-chloro-1,3,4,4a,5,6,6a,12b-octahydro-4,4,6a,12b-tetramethyl-benzo[a]xanthene (4), after desilylation provided tetracyclic pyran (+)-(4aS,6aR,12bS)-2H-11-chloro-1,3,4,4a,5,6,6a,12b-octahydro-4,4,6a,12b-tetramethyl-benzo[a]xanthene-9,10-diol (3). At a dosage of 42 mg/rat over 8 h, pyran diol 3 inhibited the intestinal absorption of cholesterol by 71% in rats. Tetracyclic pyran 4 was also converted to o-quinone 28, which inhibited cholesteryl ester transfer protein (CETP) activity and L1210 leukemic cell viability with IC(50) values of 31 and 2.4 microM, respectively. Diol (+)-5 inhibited CETP activity with an IC(50) value of 16 microM. The minor condensation product, (4aS,6aS,12bS)-2H-9,10-bis(tert-butyldimethylsilyloxy)-11-chloro-1,3,4,4a,5,6,6a,12b-octahydro-4,4,6a,12b-tetramethyl-benzo[a]xanthene (6), was transformed into (+)-5 and (+)-1. A stepwise stereoselective synthesis of (+)-1 was also developed utilizing an oxyselenylation ring-closure reaction. The synthetic sequence also produced four biologically active naturally occurring drimanic sesquiterpenes, (+)-drimane-8alpha,11-diol (34), (-)-drimenol (38), (+)-albicanol (39), and (-)-albicanal (31) as intermediates.     

Structure of amauromine,a new hypotensive vasodilator produced by amauroascus sp.

The structure of amauromine, a novel alkaloid with potent vasodilating activity was determined chemically and spectroscopically to be (5aS, 7aS, 8aR, 13aS, 15aS, 16aR)-8a, 16a-bis-(1,l-dimethyl-2-propenyl)-5a, 8,8a,13,13a,15a,16,16a-octahydropyrazino [1',2':1, 5;4', 5':1',5']dipyrrolo[2,3-b:2',3'-b']- diindole-7, 15(5H,7aH)-dione.     

Amination of 4-nitropyridazine 1-oxides by liquid ammonia/potassium permanganate

Treatment of 4-nitropyridazine 1-oxide ( 1a ) 3-methoxy-6-chloro-4-nitropyridazine 1-oxide ( 1b ) or 3,6-dimethoxy-4-nitropyridazine 1-oxide ( 1c ) with a solution of potassium permanganate in liquid ammonia gives in reasonable-to-good yields the corresponding 5-amino-4-nitropyridazine 1-oxides (75%, 54% and 62%, respectively). 3,6-Dimethoxypyridazine ( 4a ) and 3-methoxypyridazine ( 4b ) are converted into the corresponding 4-aminopyridazines 6a,6b on treatment with potassium amide/liquid ammonia/potassium permanganate (yield 50 and 22% respectively). In the last-mentioned reaction besides 6b 3,3′-dimethoxy 4,4′-bipyridazine (7, 23%) was obtained. It is suggested that the neutral 1:1 σ-adducts formed between ( 1a–1c ) and liquid ammonia and the anionic σ-adducts, formed between ( 5a–5b ) and potassium amide are intermediates in this amino-oxidation reaction.     

Synthèses dans la série des bis-indéno-fluorénes III [1]. Dihydro-14, 15-13H-bis-indéno[2,1-a;1′,2′,-i]fluorène et dihydro-14, 15-8H-bis-indéno [2, 1-a;2′,1′-h]fluorène

Starting from 2-bromo-9-oxo-fluorene-1-carboxylic acid the biangular bis-indenofluorene 14, 15-dihydro-13H-diindeno[2, 1-a; 1′, 2′-1]fluorene (VIII) and the monoangular 14, 15-dihydro-8H-diindeno[2, 1-a; 2′, 1′-h]fluorene (XI) have been synthesised in 6 resp. 7 steps (overall yield 22% resp. 18%). As intermediate compounds the 14-oxoderivatives of VIII and XI were also obtained.     

Preparation of perhydroisoquinolines via the intramolecular Diels-Alder reaction of N-3,5-hexadienoyl ethyl acrylimidates: a formal synthesis of (+/-)-reserpine

The intramolecular Diels-Alder reaction of N-3,5-hexadienoyl ethyl acrylimidates provides an efficient method for the synthesis of cis-fused hexahydroisoquinolones. As a demonstration of the stereochemical control offered by this cycloaddition, two approaches to the construction of the DE rings of reserpine are reported. In the second entry, N-((4-(trimethylsilyl)ethoxymethoxy)methyl-6-benzyloxy-3Z,5E-hexadienoyl)-1-aza-2-ethoxy-1,3-butadiene (40) undergoes cycloaddition to produce as the major product (4aS,7R,8aS)-7-benzyloxy-5-((2-trimethylsilyl)ethoxymethoxy)methyl-3,4,4a,7,8,8a-hexahydroisoquinol-3-one (41). Cycloadduct 41 is then stereospecifically elaborated to (4aS,5S,6R,7R,8aR)-6-methoxy-5-methoxycarbonyl-7-(3,4,5-trimethoxy)benzoyldecahydroisoquinoline-2-carboxylic acid methyl ester (3), a key intermediate previously transformed to reserpine.     

New polymer syntheses. 60. Thermostable polymers of 2-(hydroxyaryl)benzoxazole-5-carboxylic acids

Tristrimethylsilyl-3-amino-4-hydroxybenzoic acid was condensed with various aromatic acetoxy carboxylic acid chlorides in Marlotherms-S® at 20–350°C. Under these conditions formation of an amide group, ring closure to benzoxazole groups and polycondensation occur step by step in a “one-pot procedure”. The crude polyesters were hydrolyzed to yield pure 2-(hydroxyaryl) benzoxazole-5-carboxylic acids which were acetylated and polycondensed. The pure polyesters obtained in this way were characterized by viscosity and DSC measurements, WAXS-powder patterns, and thermogravimetric analyses. The polyester of 2-(4-hydrophenyl) benzoxazole-5-carboxylic acid has a degree of crystallinity > 90% and a short term in thermostability in air up to 500°C.     

Polycondensed heterocycles. I. Synthesis of 11-oxo-5H, 11H-pyrrolo[2,1-c][1,4]benzothiazepine,Derivative of a novel ring system

The synthesis of the title compound 4 by cyclization of 1-(2-ethoxycarbonylthiobenzyl)pyrrole 9 , prepared by treating with ethyl chloroformate the 1-(2-mercaptobenzyl)pyrrole 7 previously obtained by debenzylation of 1-(2-benzylthiobenzyl)pyrrrole 6 , failed. On the other hand 4 was successfully synthesized by intramolecular cyclization of 1-(2-mercaptobenzyl)pyrrole-2-carboxylic acid 15 by DMAP -catalyzed DCC method. The pyrrole 6 and 1-(2-benzylthiobenzyl)pyrrole-2-carboxaldehyde 11 were useful as starting materials to obtain 1-(2-benzylthiobenzyl)pyrrole-2-carbonitrile 13 , which was hydrolyzed to corresponding amide 16 . Debenzylation of 16 afforded 1-(2-mercaptobenzyl)pyrrole-2-carboxyamide 17 , whose hydrolysis led to required acid 15 .     

Studies with 3‐functionally substituted 2‐arylhydrazononitriles: A new route to 3‐substituted‐2‐arylhydrazononitriles, 4‐amino‐pyrazole‐5‐carbonitriles,azadienes and cinnolines

3‐Amino‐3‐phenyl‐2‐phenylazoacrylonitrile 6 is obtained in good yield via reaction of 5 with phenyl magnesium bromide. The compound 6 is readily converted into 4a . The so formed alkanenitrile reacted with phenylmagnesium bromide to yield 8 . Compound 8 could be also obtained from reaction of 9 with phenylmagnesium bromide. The arylhydrazononitriles 8 and 4a reacted with chloroacetonitrile to yield the 4‐aminopyrazoles 12a,b . Compound 12a reacted with acetic anhydride to yield the 15a and with benzoyl chloride to yield the pyrazole 16 which was converted into 15b . Refluxing 10 in acetic acid gave a mixture of the azadiene 21 and the cinnoline 22 is obtained. The azadiene 21 is converted into 22 either thermally or photochemically.     

Total synthesis of (-)-crambidine and definition of the relative configuration of its unique tetracyclic guanidinium core

Total syntheses of the 3S,8S,10S,19R,43S isomer 4a and the 3S,8S,10S,19R,43R isomer 4b of the unique crambescidin alkaloid crambidine are reported. These studies confirm the tetracyclic structure proposed by Braekman and co-workers for crambidine, and establish the rel-3R,8R,10R,19S relative configuration for this moiety. Natural crambidine is most likely the 3S,8S,10S,19R,43S isomer 4a. These syntheses were completed in five steps and approximately 14% overall yield from 1-iminohexahydro[1,2-c]pyrimidine carboxylic ester 10, an intermediate in our earlier total synthesis of 13,14,15-isocrambescidin 800 (3). The signature step in the total syntheses of crambidine and several stereoisomers is chemoselective dehydrogenation of the tethered Biginelli adduct 10 or the derived tetracyclic intermediate 17. Additionally, these studies reveal the unprecedented ring-chain isomerization of the crambidine ring system exemplified by the interconversion of isomers 15a and 15b.     

An efficient synthesis of 5-bromo-2-methoxy-6-methylaminopyridine-3carboxylic acid

An efficient synthesis of 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxylic acid (1), a carboxylic acid moiety of a potent dopamine D2 and D3 and serotonin-3 (5-HT3) receptors antagonist, (R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1 ,4-diazepin-6-yl)-2-methoxy-6-methylaminopyridine-3-carboxamide, is described. Reaction of methyl 2,6-difluoropyridine-3-carboxylate (12) with methylamine in EtOH at -25 degrees C gave a mixture of methyl 2-fluoro-6-methylaminopyridine-3-carboxylate (13) and the regioisomer 14 in a ratio of 57 : 43. On the other hand, reaction of 12 and methyl 2,6-dichloropyridine-3-carboxylate (16) with sodium methoxide in tetrahydrofuran (THF) and CH2Cl2 provided the 2-methoxypyridine-3-carboxylic esters 20 and 23, respectively, as main products. Similar reaction of 16 in N,N-dimethylformamide (DMF) and MeOH proved to be highly regioselective for the 6-position. A much greater regioselectivity for substitution at the 6-position (>97%) was observed when 16 was treated with 4-methylbenzenethiolate anion in DMF (quantitative yield). After methoxylation of methyl 2-chloro-6-(4-methylbenzenethio)pyridine-3-carboxylate (25b) and successive oxidation of the 6-benzenethio moiety, nucleophilic substitution of the sulfoxide derivative 28 with methylamine gave the 6-methylamino derivative 8. Finally, bromination of 8 and alkaline hydrolysis produced the desired product 1 in an overall yield of 67%.     

Intermolecular Michael addition of substituted amines to a sugar-derived alpha,beta-unsaturated ester: synthesis of 1-deoxy-D-gluco- and -L-ido-homonojirimycin, 1-deoxy-castanospermine and 1-deoxy-8a-epi-castanospermine

The synthesis of polyhydroxylated piperidine alkaloids, namely, 1-deoxy-D-gluco-homonojirimycin 3a, 1-deoxy-L-ido-homonojirimycin 3b, and indolizidine alkaloids 1-deoxy-castanospermine 5a and 1-deoxy-8a-epi-castanospermine 5b, has been achieved. The key step involved is the intermolecular Michael addition of benzylamine to alpha,beta-unsaturated ester 1, derived from D-glucose, which afforded diastereomeric mixture of beta-amino esters 6a and 6b with D-gluco- and L-ido- configuration at C5, respectively. Attempts were made to increase and/or alter the diastereoselectivity at the newly generated stereocenter. The high stereoselectivity, in favor of L-ido-isomer 6b, was achieved under kinetically controlled conditions by using lithium N-benzyl amide as a Michael donor. The beta-amino esters 6a and 6b represent common intermediates to target molecules. Thus, LAH reduction of 6a and 6b, individually, gave beta-amino alcohol 7a and 7b. Sequential hydrogenolysis, selective protection of the amino group, followed by hydrolysis of the 1,2-acetonide functionality, and hydrogenation gave 3a and 3b, respectively. On the other hand, the beta-amino ester 6a was converted to gamma-amino ester 13a by Arndt-Eistert synthesis, which on hydrogenolysis and treatment with sodium acetate gave gamma-lactam 14a. The LAH reduction afforded pyrrolidene. The N-protection-hydrolysis-hydrogenation cascade successfully executed, and 1-deoxy-castanospermine 5a was obtained in good yield. The same sequence of reactions was applied to beta-amino ester 6b, which afforded 1-deoxy-8a-epi-castanospermine 5b.