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 the potent androgen receptor antagonist (-)-arabilin: a strategic, biomimetic [1,7]-hydrogen shift

The first total synthesis of (-)-arabilin, a Streptomyces metabolite that inhibits hormone activation of the androgen receptor, has been completed. The key step, a [1,7]-hydrogen shift, establishes the enol ether-containing skipped-tetraene substructure. This nonenzymatic pericyclic reaction is considered to be biomimetic.     

Preparation of non-peptide,highly potent and selective antagonists of arginine vasopressin V1A receptor by introduction of alkoxy groups

A series of compounds structurally related to 4'-[(4,4-difluoro-5-methylidene-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl)carbonyl]benzanilide were synthesized and evaluated for arginine vasopressin (AVP) antagonistic activity. Compounds with alkoxy groups (especially ethoxy group) at the 2'-position of benzanilide possessed potent affinity and selectivity for the V1A receptor versus V2 receptor. Further study has shown that the introduction of 4,4-dimethylaminopiperidino and morpholino groups at carbonylmethylene exhibited more potent affinity and selectivity for V1A receptors. Consequently, we found that the (Z)-4'-([4,4-Difluoro-5-[(4-dimethylaminopiperidino)carbonylmethylene]-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl]carbonyl)-2-ethoxybenzanilide monohydrochloride (8d) and the (Z)-4'-[(4,4-Difluoro-5-morpholinocarbamoylethylene-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl)carbonyl]-2-ethoxybenzanilide (8q) exhibited potent and selective V1A receptor antagonist activity. The synthesis and pharmacological properties of these compounds are detailed in this paper.     

Total synthesis of proposed amphidinolide A via a highly selective ring-closing metathesis

[structure: see text] A highly convergent synthesis of the proposed structure of amphidinolide A is reported. Instructive applications of several organometallic processes are illustrated, including a highly selective ring-closing metathesis reaction.     

An improved synthesis of cis-4-phenyl-2-propionamidotetralin (4-P-PDOT): a selective MT(2) melatonin receptor antagonist

A novel, efficient and diastereoselective procedure was developed for the gram-scale synthesis of cis-4-phenyl-2-propionamidotetralin (4-P-PDOT), a selective MT(2) melatonin receptor antagonist. The synthetic strategy involved the conversion of 4-phenyl-2-tetralone to enamide followed by diastereoselective reduction affording cis-4-P-PDOT in good yield. The mechanism of the reduction step was explored by employing deuterated reagents.     

Preparation of highly potent and selective non-peptide antagonists of the arginine vasopressin V1A receptor by introduction of a 2-ethyl-1H-1-imidazolyl group

To find a new series of arginine vasopressin (AVP) V1A receptor antagonists, the influence of the 2-phenyl group of 2-phenyl-4'-[(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]benzanilide (7) was investigated. Replacement of the 2-phenyl group by a 2-ethyl-1H-imidazol-1-yl group was effective in yielding a V1A-selective compound. Moreover, this imidazolyl group was introduced in the same position in YM-35471 (6), and further studies of these compounds were performed. Consequently, we found that the (Z)-4'-({4,4-difluoro-5-[(N-cyclopropylcarbamoyl)methylene]-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl}carbonyl)-2-(2-ethyl-1H-1-imidazol-1-yl)benzanilide (9f) exhibited highly potent affinity and selectivity, and was the most potent antagonist for the V1A receptor among our compounds. The synthesis and pharmacological evaluation of these compounds are described in this paper.     

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.     

Total synthesis and biological evaluation of 11-desmethyllaulimalide, a highly potent simplified laulimalide analogue

[reaction: see text] A step-economical synthesis of 11-desmethyllaulimalide (2) is reported. This simplified analogue is available through an improved second-generation synthetic approach to the laulimalides, in a shorter step count and from much less expensive starting material than the parent compound. This new lead retains the anticancer function of laulimalide.     

Total synthesis and biological evaluation of pederin, psymberin, and highly potent analogs

The potent cytotoxins pederin and psymberin have been prepared through concise synthetic routes (10 and 14 steps in the longest linear sequences, respectively) that proceed via a late-stage multicomponent approach to construct the N-acyl aminal linkages. This route allowed for the facile preparation of a number of analogs that were designed to explore the importance of the alkoxy group in the N-acyl aminal and functional groups in the two major subunits on biological activity. These analogs, including a pederin/psymberin chimera, were analyzed for their growth inhibitory effects, revealing several new potent cytotoxins and leading to postulates regarding the molecular conformational and hydrogen bonding patterns that are required for biological activity. Second generation analogs have been prepared based on the results of the initial assays and a structure-based model for the binding of these compounds to the ribosome. The growth inhibitory properties of these compounds are reported. These studies show the profound role that organic chemistry in general and specifically late-stage multicomponent reactions can play in the development of unique and potent effectors for biological responses.     

A potent and highly selective sulfotransferase inhibitor

In the present work, we have used a newly developed, fluorescence-based assay to screen a library of >30 000 compounds as potential beta-arylsulfotransferase-IV inhibitors. A total of 11 inhibitors were discovered. Most of the compounds discovered showed low micromolar inhibition, but one of the compounds showed potent inhibition (Ki = 96 nM). The most potent of these inhibitors was tested against a variety of other purine binding enzymes and showed remarkable specificity.     

Design and synthesis of 5'-deoxy-5'-phenyladenophostin A, a highly potent IP3 receptor ligand

[structure: see text] 5'-Deoxy-5'-phenyladenophostin A (5), designed as a useful IP(3) receptor ligand based on the previous structure-activity relationship studies, was successfully synthesized via two key stereoselective glycosidation steps. This compound proved to be a highly potent IP(3) receptor agonist.     

Enantiospecific synthesis of SB 214857, a potent, orally active, nonpeptide fibrinogen receptor antagonist

An enantiospecific synthesis of SB 214857, a potent, nonpeplide fibrinogen receptor antagonist, is reported. The synthetic route employs as a key step an intramolecular aryl fluoride displacement to form the sevenmembered ring of the 1,4-benzodiazepine system.     

A highly efficient synthesis of potent and selective butyrolactam inhibitors of 11beta-HSD1

A convergent synthesis of structurally novel butyrolactam 11beta-HSD1 inhibitors is described. The approach features an efficient Ireland-Claisen reaction to construct a highly substituted aldehyde building block which is converted to a lactam via a tandem reductive amination/cyclization sequence. The generality of the synthetic sequence is demonstrated during the preparation of two additional potent 11beta-HSD1 inhibitors.     

Total synthesis of the potent antitumor polyketide (-)-callystatin A

A highly convergent and efficient total synthesis of the potent antitumor polyketide (-)-callystatin A is described. The synthesis required 19 steps from N-propionyl oxazolidinone 23 and produced the desired product in 3.5% overall yield.     

Total synthesis of (S)-(-)-(E)-15,16-dihydrominquartynoic acid: a highly potent anticancer agent

The conjugated entriyne natural product, (S)-(E)-15,16-dihydrominquartynoic acid (1), is synthesized in five linear steps and 30% overall yield from the known aldehyde 11. The key step is a one-pot in situ desilylation/Cadiot-Chodkiewicz coupling reaction affording the entriyne unit. The bromoalkyne 6 with an omega-carboxylic acid group was found to undergo a copper-catalyzed cross-coupling reaction producing the desired diyne intermediate 10, while the corresponding omega-ester bromoalkyne 14 failed to couple with triethylsilylacetylene under a variety of conditions.     

Total synthesis of spiruchostatin A, a potent histone deacetylase inhibitor

The total synthesis of spiruchostatin A was accomplished, unambiguously confirming its structure. Key steps included the use of the Nagao thiazolidinethione auxiliary for a diastereoselective acetate aldol reaction and as an activated acylating agent for amide formation, and macrolactonization by the Yamaguchi protocol. Spiruchostatin A is shown to have biological activity similar to that of FK228, a potent histone deacetylase (HDAC) inhibitor in clinical trials. The spiruchostatin A analogue, epimeric at the beta-hydroxy acid, is inactive, highlighting the importance of stereochemistry at this position for interactions with HDACs.     

Total synthesis of landomycin A, a potent antitumor angucycline antibiotic

The first total synthesis of landomycin A, the longest and most potent antitumor angucycline antibiotic, has been achieved in 63 steps and 0.34% overall yield starting from 2,5-dihydroxybenzoic acid, 3,5-dimethylphenol, triacetyl d-glucal, and d-xylose, with a convergent linear sequence of 21 steps.     

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.