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We report the development of aryl sulfones as Bradykinin B1 receptor antagonists. Variation of the linker region identified diol 23 as a potent B1 antagonist, while modifications of the aryl moiety led to compound 26, both of which were efficacious in rabbit biochemical challenge and pain models.

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Commercially available N-Boc-4-O-benzyl-L-homoserine was treated with trifluoroacetic acid and the corresponding, N-deprotected derivative was submitted to deamination to give 4-O-benzyl-3-deoxy-L-glycero-tetronic acid (5). In another approach to 3-deoxy-L-glycero-tetronic acid protected at position 4, the carboxylic groups in L-malic acid were reduced, and the resulting triol was benzylidenated. Oxidation of the 2,4-O-benzylidene derivative formed with CrO3-pyridine complex in the presence of t-butyl alcohol gave t-butyl 2,4-O-benzylidene-3-deoxy-L-glycero-tetronate (13). The latter was saponified with aqueous sodium hydroxide to give, after Na+ exchange for H+, 2,4-O-benzylidene-3-deoxy-L-glycero-tetronic acid (15). Opening of the acetal ring in 13, followed by hydrolytic cleavage of the t-butyl ester function gave material indistinguishable from 5 obtained in the original way. When tested for their efficiency of N-acylation of derivatives of D-perosamine, both acids 5 and 15 gave the corresponding tetronamido derivatives in high yields.

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A stereocontrolled synthesis of the title compound is described. Key steps are an allylsilane addition to a chiral acetal as the major coupling step and a Yamaguchi macrolactonization for ring closure.

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A practical synthesis of optically pure PPARalpha agonist, (R)-K-13675, is described. This process is based on the use of (S)-2-hydroxybutyrolactone, which can be transformed into the requisite n-butyl (S)-2-hydroxybutanoate in an efficient manner. A key reaction is the etherification between the phenol and n-butyl (S)-2-trifluoromethanesulfonyloxybutanoate to give the phenyl ether in excellent yield without loss of optical purity.

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Analogs of the methyl alpha-glycosides of the terminal residues of the O-specific polysaccharides (O-PS) of Vibrio cholerae O:1, serotype Inaba and Ogawa, have been prepared as probes to study their interaction with anti V. cholerae O:1 antibodies. They differ from the termini of the respective O-PSs in anomeric or absolute configuration of perosamine, position of the O-methyl group in d-perosamine, and nature of the N-acyl side chain.

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A process for producing optically active butyric acid compounds and intermediates for the production of the compounds in high yields at high optical purities. A process for the production of compounds (6), characterized by comprising preparing a compound (3) either by reacting a compound (1) with optically active 2-trifluoromethane- sulfonyloxybutyrolactone (2a) in the presence of a base or by reacting a compound (1) with optically active 2-hydroxy- butyrolactone (2b) under Mitsunobu reaction conditions, reacting the compound (3) with an alcohol and a halogenating reagent to form a compound (4), dehalogenating the compound (4) into a compound (5), and deesterifying the compound (5).Lambda”invention concerne un procede de preparation de composes optiquement actifs de type acide butyrique et les intermediaires pour la preparation des composes de grandes puretes optiques avec des rendements eleves. L”invention decrit un procede de preparation des composes (6), caracterise en ce qu”il comprend la preparation d”un compose (3) soit par la reaction d”un compose (1) avec la 2-trifluoromethanesulfonyloxybutyrolactone optiquement active (2a) en presence d”une base, soit par la reaction d”un compose (1) avec la 2-hydroxy-butyrolactone optiquement active (2b) dans les conditions de la reaction de Mitsunobu, la reaction du compose (3) avec un alcool et un reactif d”halogenation pour former un compose (4), la deshalogenation du compose (4) en un compose (5) et la desesterification du compose (5).

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Dienes 23 and 54, prepared from epoxy alcohol 9 via oxazolidinones 15 and 51, respectively, underwent ring-closing metathesis with Grubbs’s catalyst to give azacyclooctenes 26 and 55. Treatment of each azacyclooctene with m-chloroperoxybenzoic acid afforded beta-epoxide 28 from 26 and alpha-epoxide 61 from 60. Basic hydrolysis of each of these oxazolidinones was accompanied by transannular attack at the epoxide by nitrogen, resulting in 2-(O-benzyl)-7-deoxyalexine (29) and 1,2-di-(O-benzyl)australine (62). The latter was converted to the alkaloid australine (3) upon hydrogenolysis. Attempts to effect ring-closing metathesis of dienes 37, 38, and 46 were unsuccessful, suggesting that, while one allylic oxygen substituent can be tolerated by Grubbs’s catalyst, two cannot.

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(Chemical Equation Presented) Limitations of models in total synthesis are illustrated by a study towards the potent cytotoxic macrolide iejimalide B. Although the Yamaguchi protocol allowed for the esterification of elaborate segments, attempted macrolactonization of the seco acid met with failure (see scheme, Boc = tert-butyloxycarbonyl). The assembly of the seco acid involves some of the most advanced applications of the Julia olefination known to date.

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The interaction of two IR chromophores yields a strong vibrational circular dichroism couplet whose sign reflects the absolute configuration of the molecule. We present a method to determine absolute configuration of a chiral molecule based on this couplet without need of theoretical calculation. Not only can this method analyze various molecules whose absolute configuration is difficult to determine by other spectroscopic methods, but also it can significantly enhance VCD signals.

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A highly modular and stereoselective synthesis of tetrasubstituted helical alkenes is accomplished by a Pd-catalyzed norbornene-mediated domino reaction. This protocol features the rapid assembly of four C-C bonds via sequential C-H activations and carbopalladations along with efficient access to enantiopure bromoalkyl aryl alkyne precursors using homologative alkynylation as the key transformation. Three distinct elements of stereoselectivity were observed in the preparation of the chiral helical alkenes: retention of stereochemistry of the substrates, induced helical diastereoselectivity in the alkene formation, and the exclusive exo-facial selectivity of the norbornene incorporation.

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