Acid 1b Research Articles

Preparation of enantiomerically pure (1 S,2 S)-1-aminocyclopropanephosphonic acid from methylcyclopropanone acetal via spirophosphonate intermediates

An easy and efficient one-pot reaction from readily available methylcyclopropanone acetal (2 S)- 4b gave the spirophosphonates 8a– b with excellent diastereoselectivity. These phosphonates, after catalytic hydrogenolysis and hydrolysis, furnished the enantiomerically pure (1 S,2 S)-1-amino-2-methylcyclopropanephosphonic acid 3b (analogue of (1 R,2 S)- allo-norcoronamic acid).

Polymerization of Glycidyl Phenyl Ether with Benzyl Phenylphosphonates as Novel Thermally Latent Initiators

The cationic polymerization of glycidyl phenyl ether (GPE) was examined with novel phosphonic acid esters, O,O-di-p-methylbenzyl phenylphosphonate (1a), O,O-dibenzyl phenylphosphonate (1b), and O,O-di-p-nitrobenzyl phenylphosphonate (1c), as initiators. GPE did not convert with 1a−c even at 210 °C in the absence of ZnCl2. In the presence of ZnCl2 along with phosphonic acid esters 1a, 1b, and 1c, the polymerization of GPE did not proceed below 90, 130, and 170 °C, respectively, but it rapidly proceeded to afford polyGPE with Mn of 2500−5000 above those temperatures. It was found that 1a, 1b, and 1c served as thermally latent initiators in the polymerization of GPE in the presence of ZnCl2. Electron-donating substituents on the benzyl group of the phosphonic acid esters increased the initiator activity. The initiation species was identified as a benzyl cation by 13C-labeled experiments.

18-Iodooctadeca-(8Z,11Z)-dienoic Acid as Useful Intermediate for the Synthesis of Special Lipoxygenase Substrates Bearing Bulky Substituents at the ω-Position

18-Iodooctadeca-(8Z,11Z)-dienoic acid (7) was synthesized in five steps starting from methyl 10-bromodec-7-ynoate (2) in an overall yield of 53%. The synthetic procedure involves Cu(I)-catalyzed cross-coupling of propargylic bromide 2 with 7-octyn-1-ol (3), followed by hydrogenation of the coupling product 4 to Z,Z-diene 5 on Lindlar's catalyst and subsequent substitution of the OH– group of 5 with iodine. Coupling of the resulting iodide 7 with low-order organic cuprates [t-Bu2CuLi or (PhCH2)2CuMgCl] leads to 19,19-dimethyleicosa-(8Z,11Z)-dienoic acid (1a) and 19-phenylnonadeca-(8Z,11Z)-dienoic acid (1b), respectively.

Retinoidal Pyrimidinecarboxylic Acids. Unexpected Diaza-Substituent Effects in Retinobenzoic Acids.

Several pyridine- and pyrimidine-carboxylic acids were synthesized as ligand candidates for retinoid nuclear receptors, retinoic acid receptors (RARs) and retinoic X receptors (RXRs). Although the pyridine derivatives, 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]pyri dine-3-carboxylic acid (2b) and 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]py ridine-3-carboxylic acid (5b) are more potent than the corresponding benzoic acid-type retinoids, Am80 (2a) and Am580 (5a), the replacement of the benzene ring of Am580 (5a), Am555 (6a), or Am55 (7a) with a pyrimidine ring caused loss of the retinoidal activity both in HL-60 cell differentiation assay and in RAR transactivation assay using COS-1 cells. On the other hand, pyrimidine analogs (PA series, 10 and 11) of potent RXR agonists (retinoid synergists) with a diphenylamine skeleton (DA series, 8 and 9) exhibited potent retinoid synergistic activity in HL-60 cell differentiation assay and activated RXRs. Among the synthesized compounds, 2-[N-n-propyl-N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)a mino]pyrimidine-5-carboxylic acid (PA013, 10e) is most active retinoid synergist in HL-60 assay.

New alternating poly(amide-ester)S: Synthesis and properties

New alternating poly(amide-ester)s derived from β-hydroxy acids and α-amino acids 3a,b or e-aminocaproic acid 4a-c were prepared. Two approaches were considered: (i) polycondensation of N-(β-hydroxyacyl)-amino acids la,b and 2b,c and (ii) ring-opening polymerization of cyclic amide-esters 5a-c and 6a-c. For all the linear precursors polycondensation reactions result in oligomers with number average molecular weights lower than 5000. The ring-opening polymerization of the cyclic precursors is substrate specific and is sensitive to changes in the polymerization conditions. For N-(3-hydroxybutyroyl)-e-aminocaproic acid lactone [c(3HB-eAC); 5b] (IUPAC nomenclature: 2-methyl-5-aza-1-oxa-cycloundecan-4, 11-dione) bulk and solution polymerizations result in oligomers with an alternating ester amide microstructure. Polymerization of N-(3-hydroxypropionyl)-e-aminocaproic acid lactone [c(3HP-eAC); 5a] (IUPAC nomenclature: 5-aza-1-oxa-cycloundecan-4-11-dione) in dimethylformamide solution and with Bu 2 Sn(OMe) 2 as initiator high molecular weight linear, semicrystalline polymers were obtained (T m = 145.9°C). Polymerization of N-(hydroxypivaloyl)-e-aminocaproic acid lactone [c(HPv-eAC); 5c] (IUPAC nomenclature: 3,3-dimethyl-5-aza-1-oxa-cycloundecan-4-11-dione) in bulk results in amorphous alternating poly(amide-ester)s with cyclic structure (Tg = 6.8°C). The fourteen membered cyclo(diamide-diester)s 6a-c (IUPAC nomenclatures:: 4,11-diaza-1,8-dioxa-cyclotetradecan-2,5,9,12-tetraone (6a), 7,14 dimethyl-4,11-diaza-1,8-dioxa-cyclotetradecan-2,5,9,12-tetraone (6b), 3,10-dimethyl-4,11-diaza-1,8-dioxa-cyclotetradecan-2,5,9,12-tetraone (6c) based on β-hydroxy acids and α-aminoacids could not be polymerized.

A Cost-Efficient Synthesis of Simvastatin via High-Conversion Methylation of an Alkoxide Ester Enolate

A cost-efficient synthesis of simvastatin (2), starting from mevinolin (lovastatin) (1a) or its precursor mevinolinic acid (1b), is reported. This synthesis involves the use of a new intermediate, ...

Synthesis of 9Z,11E-octadecadienoic and 10E,12Z-octadecadienoic acids, the major components of conjugated linoleic acid.

Linoleic acid was efficiently converted into the two major components of conjugated linoleic acid, 9Z,11E-octadecadienoic (1a) and 10E,12Z-octadecadienoic acid (1b) using either the superbase (n-butyllithium/potassium tert-butoxide) or by simply refluxing with KOH in 1-butanol. In turn, 1a and 1b were separated from each other using the lipase from Aspergillus niger via stereoselective esterification in 1-butanol. This enzyme has a preference for the 9Z,11E isomer, 1a, and has excellent selectivity. This method has allowed the ready preparation of gram quantities of 1a and 1b in their highly purified forms, which are not readily accessible by current methods.

Variability of human hepatic UDP-glucuronosyltransferase activity.

The availability of a unique series of liver samples from human subjects, both control patients (9) and those with liver disease (6; biliary atresia (2), retransplant, chronic tyrosinemia type I, tyrosinemia, Wilson's disease) allowed us to characterize human hepatic UDP-glucuronosyltransferases using photoaffinity labeling, immunoblotting and enzymatic assays. There was wide inter-individual variation in photoincorporation of the photoaffinity analogs, [32P]5-azido-UDP-glucuronic acid and [32P]5-azido-UDP-glucose and enzymatic glucuronidation of substrates specific to the two subfamilies of UDP-glucuronosyltransferases. However, the largest differences were between subjects with liver disease. Glucuronidation activities toward one substrate from each of the UDP-glucuronosyltransferases subfamilies, 1A and 2B, for control and liver disease, respectively, were 1.7-4.5 vs 0.4-4.7 nmol/mg x min for hyodeoxycholic acid (2B substrate) and 9.2-27.9 vs 8.1-75 nmol/mg x min for pchloro-m-xylenol (1A substrate). Microsomes from a patient with chronic tyrosinemia (HL32) photoincorporated [32P]5-azido-UDP-glucuronic acid at a level 1.5 times higher than the other samples, was intensely photolabeled by [32P]5-azido-UDP-glucose and had significantly higher enzymatic activity toward p-chloro-m-xylenol. Immunoblot analysis using anti-UDP-glucuronosyltransferase antibodies demonstrated wide inter-individual variations in UDP-glucuronosyltransferase protein with increased UDP-glucuronosyltransferase protein in HL32 microsomes, corresponding to one of the bands photolabeled by both probes. Detailed investigation of substrate specificity, using substrates representative of both the 1A (bilirubin, 4-nitrophenol) and 2B (androsterone, testosterone) families was carried out with HL32, HL38 (age and sex matched control) and HL18 (older control). Strikingly increased (5-8-fold) glucuronidation activity was seen in comparison to HL18 only with the phenolic substrates. The results indicate that one or more phenol-specific UDP-glucuronosyltransferase 1A isoforms are expressed at above normal levels in this tyrosinemic subject.

Cycloalkyl indole-2-carboxylates as useful tools for mapping the "north-eastern" region of the glycine binding site associated with the NMDA receptor.

A novel series of indole-2-carboxylate analogues of GV 150526 (1) in which the terminal phenyl ring belonging to the side chain present in the position C-3 has been replaced with a bridged cycloalkyl group was synthesized and evaluated for its pharmacological profile. Modelling studies on this class of novel glycine antagonist allowed us to identify an asymmetric lipophilic pocket present in the "North-Eastern" region of the pharmacophoric model of the glycine binding site associated to the NMDA receptor. Among the derivatives prepared, 3-[2-(1-adamantylaminocarbonyl)ethenyl]-4,6-dichloroindole-2 -carboxylic acid 6b and 3-[2-(norbornylaminocarbonyl)ethenyl]-4,6-dichloroindole-2-c arboxylic acid 6l were found to be antagonists acting at the strychnine-insensitive glycine binding site, showing nanomolar affinity for the glycine binding site (Ki = 63 and 19 nM, respectively), coupled with high glutamate receptor selectivity (IC50 > 10(-5) M at the NMDA, AMPA, KA binding sites) and high in vivo potency after systemic administration by inhibition of convulsion induced by NMDA in mice.

Synthesis of 4-deoxyquinic, 4-deoxyshikimic and 4-deoxy-3-dehydroshikimic acids

The synthesis of 4-deoxyquinic acid (1b) from (–)-quinic acid (1a) and 4-deoxyshikimic acid (4b) from shikimic acid (4a) respectively are described. 4-Deoxyshikimic acid (4b) was converted enzymatically into 4-deoxy-3-dehydroshikimic acid (3b) using shikimate dehydrogenase. The C(4) hydroxy group is shown not to contribute significantly to substrate specificity for shikimate dehydrogenase. Attempts to synthesise 4-deoxy-3-dehydroquinic acid (2b) are described.

Synthesis of water-soluble, nonimmunogenic polyamide cross-linking agents.

Novel polyamides were developed that can be used as cross-linking agents for proteins such as hemoglobin. Water-soluble, nonimmunogenic polyamides containing oxygen and sulfur atoms in the backbone were prepared by the polycondensation of the diacids bis(carboxymethyloxyacetyl)-1,4-diaminobutane (1a) or 3, 3'-thiodipropionic acid (1b) with diethylene glycol bis(3-aminopropyl) ether (2). The resulting alpha,omega-diacids were converted to the corresponding activated esters using any of a variety of carboxylic acid activating reagents including the novel reagent diphenyl(1-methylimidazol-2-thiyl)phosphonate (9). The resulting polyamides could be activated with a broad spectrum of groups that allow for the cross-linking and surface modification of proteins.

Rearrangement of a 16alpha,17alpha-Epoxy-16beta-methylandrostane-17beta-carbothioic Acid to a 17beta-Mercapto-16beta-methylandrostane-17alpha,16alpha-carbolactone.

The 16alpha,17alpha-epoxy-16beta-methylandrostane-17beta-carbothioic acid 2b rearranges in solution at ambient temperature to the 17beta-mercapto-16beta-methylandrostane-17alpha,16alpha-carbolactone 6a, possibly via the spirocyclic alpha-thiolactone 5.

ChemInform Abstract: Stereocontrolled Synthesis of 4‐Substituted (.+‐.)‐Kainic Acids.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis and antitumor evaluation of cis-(1,2-diaminoethane) dichloroplatinum (II) complexes linked to 5- and 6-methyleneuracil and -uridine analogues.

The search for platinum (II)-based compounds with improved therapeutic properties was prompted to design and synthesize a new family of water-soluble, third generation cis-diaminedichloroplatinum (II) complexes linked to uracil and uridine. Six heretofore unreported uracil and uridine-platinum (II) complexes are; [N-(uracil-5-yl-methyl)ethane-1,2-di-amine]dichloroplatinum (II) (3a), [N-(uracil-6-yl-methyl)ethane-1,2-diamine] dichloroplatinum (II) (3b), ¿[N-(2', 3',5'-tri-O-acetyl)uridine-5-yl-methyl] ethane-1,2-diamine¿dichloroplatinum (II) (6a), ¿[N-(2',3', 5'-tri-O-acetyl) uridine-6-yl-methyl)ethane-1,2-diamine¿dichloroplatinum (II) (6b), [N-(uridine-5-yl-methyl)ethane-1,2-diamine]dichloroplatinum (II) (7a), [N-(uridine-6-yl-methyl)ethane-1,2-diamine]dichloroplatinum (II) (7b). These analogues were prepared from the key starting materials, 5-chloromethyluracil (1a) and 6-chloromethyluracil (1b) which were reacted with ethylenediamine to afford the respective 5-[(2-aminoethyl)amino] methyluracil (2a) and 6-[(2-aminoethyl)amino]methyluracil (2b). The cis-platin complexes 3a and 3b were obtained through the reaction of the respective 2a and 2b with potassium tetrachloroplatinate (II). The heterocyclic nucleic acid bases 1a and 1b were efficiently introduced on the beta-D-ribose ring via a Vorbruggen-type nucleoside coupling procedure with hexamethyldisilazane, trimethylchlorosilane and stannic chloride under anhydrous acetonitrile to yield the stereospecific beta-anomeric 5-chloromethyl-2',3',5'-tri-O-acetyluridine (4a) and 6-chloromethyl-2',3',5'-tri-O-acetyluridine (4b), respectively. The nucleosides 4a and 4b were coupled with ethylenediamine to provide the respective 5-[(amino-ethyl)amino]methyl-2',3',5'-tri-O-acetyluridine (5a) and 6-[(aminoethyl)amino] methyl-2',3',5'-tri-O-acetyluridine (5b). The diamino-uridines 5a and 5b were reacted with potassium tetrachloroplatinate (II) to give the novel nucleoside complexes, 6a and 6b, respectively which were deacetylated into the free nucleosides, 7a and 7b by the treatment with CH3ONa. The cytotoxic activities were evaluated against three cell lines (FM-3A, P-388 and J-82) and none of the synthesized compounds showed any significant activity.

Synthesis of poly(succinimide-amide) by acid-catalyzed polycondensation of L-aspartic acid and aromatic aminocarboxylic acid

The polycondensations of L-aspartic acid (1) with aromatic aminocarboxylic acid, 4-aminobenzoic acid (2a), 4-aminophenylacetic acid (2b), 4-aminomethylbenzoic acid (2c), 4-(4-aminophenyl)butyric acid (2d), and 4-aminocinnamic acid (2e) were carried out using phosphoric acid as a catalyst. The obtained copolymers consiting of the succinimide and amide units, poly(succinimide-co-amide) (3), were soluble in DMF and DMSO except for that with 2e. The thermal properties differed with varying the 2 unit in 3, i.e., the Tgs of 3a–c (99 ∼ 138°C) were higher than those of 3d (81 ∼ 1 01°C), the apparent difference in the Tm between 3a–d did not observed, and the Td decreased in the order of 3a, 3c > 3d > 3b.

Stereocontrolled Synthesis of 4-Substituted (±)-Kainic Acids

Racemic 4-substituted kainic acids 4a,b have been synthesized from ethyl (1SR,2SR,5RS,6RS)-N-(benzyloxycarbonyl)-3-aza-6-hydroxy-6-methylbicyclo[3.3.0]octane-2-carboxylate (7) after its transformation in the pyroglutamate derivative 6. The key step in the synthesis has been the regioselective alkylation of 6 to obtain 11a,b, without compromising the stereogenic integrity of the potentially labile C-2 center. The elaboration of the C-3 and C-4 substituents of kainic acid over 11 was achieved after double bond isomerization of 11, oxidative double bond cleavage of 5, and chemoselective aldehyde reduction of 16 followed by Wittig olefination reaction of 17 and final alcohol oxidation and hydrolysis over 18 to the corresponding 4-methyl kainic acid 4a and 4-benzyl kainic acid 4b. The relatively small changes introduced in the structure of kainic acid 1 have been found to lead to a loss of affinity for kainate receptors.

An Efficient Asymmetric Route to 2,3-Diaminobutanoic Acids

An Efficient Asymmetric Route to 2,3-Diaminobutanoic Acids

Facile access to optically active ring C aromatic diterpene derivatives from manool. Highly efficient syntheses of (+)-12-methyl-7-oxo-podocarpa-8,11,13-triene-13-carboxylic acid, (+)-13-methyl-7-oxopodocarpa-8,11,13-triene-12-carboxylic acid and (+)-nimbiol

The extension of our recently developed strategy using the key intermediate 2, obtainable in two steps (52% overall yield) from manool 1, to the synthesis of naturally occurring ring C aromatic diterpene derivatives provides in three steps (+)-12-methyl-7-oxopodocarpa-8,11,13-triene-13-carboxylic acid 4b and its isomer 6b, and in seven steps (+)-nimbiol 11b, in good overall yields. This synthesis discloses that the structure 4b assigned to margolone isolated from Azadirachta indica A. Juss is incorrect and needs to be reinvestigated.

Hydrolytic enzymes in the synthesis of carba-sugars: application of the lipase from Pseudomonas fragi

Pig liver esterase-catalysed hydrolysis of (±)-endo-2-methoxycarbonyl-7-oxabicyclo[2.2.1]hept-5-ene 1a provides (–)-endo-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid 1b and (+)-endo-2-methoxycarbonyl-7-oxabicyclo[2.2.1]hept-5-ene 1a in 36 and 57% ee, respectively. Transesterification between (±)-2-exo-hydroxy-4,8-dioxatricyclo[4.2.1.03,7]nonan-5-one 2a and vinyl acetate catalysed by the lipase from Pseudomonas fragi gives the acetate (–)-2b and alcohol (+)-2a in 91 and 94% ee, respectively. Optically pure acetate (–)-2b is obtained after removal of contaminating racemate from the impure acetate by crystallisation of (–)-2b of 91% ee (EtOH).

Saturated heterocycles. 254. synthesis and stereochemistry of saturated or partially saturated pyridazino‐[6,1‐b]‐ and phthalazino[1,2‐b]quinazolinones

AbstractBy the reaction of anthranilic hydrazide 1 with cis‐2‐(p‐methylbenzoyl)‐1‐cyclohexanecarboxylic acid 2a or diendo‐3‐(p‐methylbenzoyl)bicyclo[2.2.1]heptane‐2‐carboxylic acid 2b, fused tetra‐ and pentacyclic ring systems 3a, b were prepared, trans‐2‐Amino‐1‐cyclohexanecar‐bohydrazide 4b was reacted with 3‐(p‐chlorobenzoyl)propionic acid 5 to yield the pyridazino[6,1‐b]quinazolinone 6. From the reaction of cis‐2‐amino‐1‐cyclohexanecarbohydrazide 4a with 2a, three isomeric partially saturated 8H‐phthalazino[1,2‐b]quinazolin‐8‐ones 7a‐c were formed. The reaction of diexo‐2‐aminobicyclo[2.2.1]heptane‐3‐carbohydrazide 4c and 2a furnished the pentacyclic derivatives 8 and 9 containing a 3‐aryl‐4,5‐dihydropyridazine or 3‐arylhexahydropyridazine ring C with cis annelated C/D rings. The formation of 8 and 9 involving different ring systems can be rationalized by two reaction pathways: (i) in the bislactam 9 the carboxyl group acylates the hydrazide, while (ii) in 8 it forms a pyridazine ring with the cyclic amino group by cyclocondensation. The structures of the products were elucidated by 1H and 13C nmr methods, including DEPT, DNOE and 2D‐HSC measurements.