Synthesis and configuration determination of all enantiopure stereoisomers of the melatonin receptor ligand 4-phenyl-2-propionamidotetralin using an expedient optical resolution of 4-phenyl-2-tetralone

An efficient and practical approach for the synthesis of all four stereoisomers of the MT(2) melatonin receptor ligand 4-phenyl-2-propionamidotetralin (4-P-PDOT), each in enantiomerically pure form (ee > 99.9%), was developed. The strategy involved an optical resolution procedure of the key precursor (±)-4-phenyl-2-tetralone with the unusual resolving agent (S)-mandelamide, through the formation of four dihydronaphtalene-spiro-oxazolidin-4-one diastereomers. Interestingly, NMR experimental observations in combination with geometric calculations, provided unambiguous configuration assignments of all stereocenters of the key spiro stereoisomers. Cleavage of each single spiro diastereomer under acidic conditions gave enantiopure (R)- or (S)-4-phenyl-2-tetralone, which were then converted to each 4-P-PDOT single enantiomer by using stereoselective reactions.     

Practical asymmetric synthesis of a selective endothelin A receptor (ETA) antagonist

[structure: see text]. A practical, chromotography-free asymmetric synthesis was developed for the large scale preparation of an endothelin receptor antagonist 2. This synthesis includes a new efficient process for the preparation of 6-bromo-2,3-dihydrobenzofuran, a stereoselective conjugate addition of an aryllithium followed by stereospecific addition of the Grignard reagent of the top aryl bromide, and an aminophosphate-mediated sterospecific intramolecular enolate alkylation, which led to the formation of the five-membered ring bearing three contiguous asymmetric centers.     

Asymmetric synthesis of a selective endothelin A receptor antagonist

An asymmetric synthesis of a selective endothelin A receptor antagonist 1b is described. Asymmetric conjugate addition of aryllithium derived from 18 to the chiral oxazoline 17 followed by hydrolysis afforded 15 in 96% ee via purification as (S)-(-)-1-phenylethylamine salt. Pd(OAc)(2)/dppf (1,1'-bis(diphenylphosphino)ferrocene) catalyzed carbonylation followed by chemoselective addition of aryllithium derived from 23 which gave ketone 24. Diastereoselective reduction of the ketone with catecholborane followed by concomitant activation of the resulting alcohol and cyclization gave the late intermediate 26. Introduction of amino moiety on the pyridine ring by imidoyl rearrangement followed by deprotection and purification by crystallization furnished the enantiomerically pure target molecule 1b in 8% overall yield from 16.     

Total synthesis of SR 121463 A, a highly potent and selective vasopressin v(2) receptor antagonist

SR 121463 A, 1, is a promising nonpeptide prototype for potent and selective antagonism of the vasopressin V(2) receptor subtype and, thus, a candidate for control of the clinically debilitating condition of hyponatremia and its associated syndromes. In the present work, we present a novel and stereoselective synthesis that stems from the preparation of three key intermediates: the substituted benzenesulfonyl chloride 2, the N-protected oxindole 3, and protected dibromide 4. The synthesis of 1 has been achieved in good overall yield, each step proceeding in greater than 80% yield. In addition, intermediate 2 and the syn isomer of 1 were prepared with complete control of stereochemistry. The latter reduction appears to proceed by lithium cation mediated chelation control. Molecular mechanics calculations with the MM3* and MMFF force fields underscore geometric and energetic aspects of the reaction.     

An improved synthesis of (4S,5S)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-amine

The title compound is prepared in 78% yield using an improved one-pot procedure which does not require final purification.     

An improved synthesis of enantiomerically pure CIP-AS,a potent and selective AMPA-kainate receptor agonist

CIP-AS (−)-2, a chiral amino acid structurally related to glutamic acid, behaves as a potent agonist at the ionotropic AMPA-kainate receptors and was previously prepared in low overall yield through the 1,3-dipolar cycloaddition of ethoxycarbonylformonitrile oxide to N-BOC-3,4-didehydro-(S)-proline methyl ester (−)-6. Herein, we report an alternative strategy based on the cycloaddition of the same dipolarophile to N-(4-methoxybenzyl)-α-ethoxycarbonylnitrone 12. The mixture of stereoisomeric 3-ethoxycarbonyl-N-(4-methoxybenzyl)isoxazolidinyl prolines 13 was then converted into the corresponding 3-ethoxycarbonyl-Δ²-isoxazolinyl prolines by DDQ mediated oxidation. The new strategy yielded the precursor of CIP-AS in satisfactory overall yield and represents an improvement upon the existing procedure in terms of yield and efficiency.     

An improved and practical synthesis of 5,5-dimethyl-3-(2-propoxy)-4-(4-methanesulfonylphenyl)-2-(5H)-furanone (DFP—a selective inhibitor of cyclooxygenase-2)

DFP, a highly selective and potent COX-2 inhibitor, has been synthesized by a modified approach. Three modifications of the existing method enabled us to prepare DFP in good quantity.     

Heterogeneous metallo-organocatalysis for the selective one-pot synthesis of 2-benzylidene-indoxyl and 2-phenyl-4-quinolone

One-pot tandem heterogeneously catalyzed procedures for the selective synthesis of 2-benzylidene-indoxyl and 2-phenyl-4-quinolone have been developed. For this purpose, heterogeneous palladium-, amine-, and phosphine-catalysts were prepared by post-synthetic grafting onto SBA silica. The state of the hybrid materials was characterized using a wide variety of molecular and solid-state techniques. These materials exhibit high activities as 2-benzylidene-indoxyl was obtained in 81% yields through {[Pd]@SBA-15+PPh₃} catalysis while 2-phenyl-4-quinolone was prepared by a fully heterogeneous {[Pd]@SBA-15+[AMINE]@SBA-3} protocol in 61-75% isolated yield. For the later, we demonstrated that the catalysts mixture could be reused up to three runs without strong deactivation.     

Asymmetric synthesis of a prostaglandin D2 receptor antagonist

An asymmetric synthesis was developed for the production of a prostaglandin D(2) receptor antagonist for the treatment of allergic rhinitis. The stereogenic center was set using asymmetric allylic alkylation chemistry, and the core of the structure was constructed via Pd-catalyzed N-cyclization/Heck methodology. The synthesis relies on a late stage indoline oxidation which does not racemize the product.     

Laboratory and practical synthesis of Suvorexant,a selective dual orexin receptor antagonist

The development of a laboratory and practical synthesis of Suvorexant 1, using intramolecular Mitsunobu cyclization reaction of intermediate 5 as the key reaction, has been reported. Compound 5 was obtained from known chiral ester 2 in three steps, and the key cyclization proceeded smoothly to provide the core seven-membered ring compound 6, which was transformed into 1 by an additional four-step sequence. The procedure described here needs no chiral-HPLC separation, no classical resolution, and no unique enzyme reactions, and offers an alternative practical synthesis of 1.     

A convenient synthesis of cis-4-(sulfomethyl)-piperidine-2-carboxylic acid: NMR assignment

cis-4-(Sulfomethyl)piperidine-2-carboxylic acid was obtained in 22% overall yield from 4-(hydroxymethyl)-pyridine via the o-silyl N-oxide and trimethylsilylcyanide. The cis configuration of 5 was unambiguously assigned by 200 MHz ¹H nmr and cosy experiments.     

Synthesis of GR 125487, a selective 5-HT4 receptor antagonist

The 5-HT₄ receptor (5-HT₄R) agonists are important in treating gastrointestinal motility disorders. Their role is currently being evaluated for the treatment of cognitive and mood disorders. A selective 5-HT₄R antagonist GR 125487 is used in many biological assays to cross confirm the 5-HT₄R agonist’s activity. A practical synthesis of GR 125487 is developed so as to have it in desired quantities. The synthesis consists of seven steps starting from commercially available methyl 5-fluoroindole 3-carboxylate. The GR 125487 thus synthesized was used in blocking the activity of 5-HT₄R agonist compound in animal models of cognition.     

An improved synthesis of 1,1,1-trichloro-2-methyl-2-propanol (chlorobutanol)

Varying reaction time, temperature, and the amount of catalyst and reactants the synthesis of chlorobutanol from chloroform and acetone with KOH as catalyst is optimized to 71% yield.     

An improved synthesis of haloacetamidine-based inactivators of protein arginine deiminase 4 (PAD4)

Protein arginine deiminase 4 (PAD4) is an enzyme that hydrolyzes peptidyl arginine residues to form citrulline and ammonia. This enzyme has been implicated in several disease states, for example, rheumatoid arthritis, and therefore represents a unique target for the development of a novel therapeutic. A solution-phase synthesis of Cl-amidine, the most potent PAD4 inactivator described to date, has been developed. This synthesis proceeds in 80% yield over four steps at a significantly (12-fold) lower cost.     

An improved synthesis of bis(cyclopentadienone)

<正>An improved strategy for the synthesis of 3,3'-(oxy-p-phenylene)bis(2,4,5-triphenylcyclopentadienone) was developed,which includes three steps:Friedel-Crafts reaction,oxidation and condensation.Importantly,the use of KMnO_4 made the second step simple and efficient,which has potential application to synthesis of bis(cyclopentadienone)s.The course of oxidation has been confirmed by isolated intermediates.     

A facile synthesis of novel unsymmetrical N-(4-oxo-2-phenyl-3(4H)-quinazolinoyl)-N-(aryl)acetamidines

<正>A series of novel unsymmetrical N-(4-oxo-2-phenyl-3(4H)-quinazolinoyl)-N-(aryl) acetamidines was synthesized by reacting ethyl(1H)-N-(4-oxo-2-phenylquinazolin-3(4H)-y1)ethanimidoate(2) and suitable reactive aromatic amines.Structures' determination of the synthesized compounds was carried out using spectroscopic techniques including IR,~1H NMR,and mass spectrometry. Structural effects on reactivity were also studied.