Jack B. Deeter

A83543A-D, unique fermentation-derived tetracyclic macrolides

Abstract A multi-factored complex of structurally-unique macrolides was isolated from culture broths of a new species of Saccharopolyspora. The core structure consists of a 5,6,5-cis-anti-trans-tricyclic ring system fused to a 12-membered macrocyclic lactone, which is further substituted by an amino- and a neutral sugar.

Asymmetric synthesis and absolute stereochemistry of LY248686

Abstract Reduction of 3-(dialkylamino)-1-aryl-1-propanones with a 2:1 complex of [(2R,3S-(+)-4--dimethylamino-l,2-diphenyl-3-methyl-2-butanol] (8) and lithium aluminum hydride (LAH) provided the corresponding 1,3-aminoalcohols in high ees (80–88%). This process was developed and applied to the synthesis of LY248686 (1), a potent inhibitor of serotonin (5HT) and norepinephrine (NE) uptake. Absolute configurations have been established by single crystal x-ray analysis.

Molecular modeling of γ-lactam analogues of β-lactam antibacterial agents: synthesis and biological evaluation of selected penem and carbapenem analoques

Abstract Computational chemistry made possible the prediction of the three-dimensional structures of γ-lactam analogues of penems and carbapenems before the analogues were made. Molecular superpositioning showed that these novel structures with a 7β-acylamino side-chain present the pharmacophoric groups in close spatial similarity to the groups in biologically active cephalosporin and penicillin antibiotics. This suggests that 8-oxo-7-acylamino-1-azabicyclo[3.3.0]-oct-2-ene-2-carboxylates and the 4-thia-analogues can be accommodated in the same active sites of essential bacterial penicillin-binding proteins where cephalosporins and penicillins are recognized. The syntheses of these compounds are reported. The γ-lactams exhibit low, but detectable levels of antibacterial activity and suggest promise that substantial activity can be achieved with other γ-lactams.

Synthesis of the individual enantiomers of the benzoquinolinone human type 1 steroid 5-α-reductase inhibitors LY191704 and LY266111

Abstract The first syntheses of the individual enantiomers of the benzoquinolinone class of selective inhibitors of human Type 1 steroid 5-α-reductase are described. For benzoquinolinones lacking an angular substituent, the approach relies upon an enamine acryloyl chloride cyclization followed by non-stereoselective reduction and diastereomer separation. Absolute configuration was established by single crystal x-ray diffraction analysis. The angularly methylated benzoquinolinones are prepared in an enantiospecific (deracemizing) fashion from 1-methyl-6-chloro-2-tetralone in 5 steps, employing a “formal 3 + 3 aza-annulation” sequence, with (R) or (S) α-phenethylamine as the source of chirality.

Stereoselective synthesis of cis-substituted azetidinones from penicillin : a formal total synthesis of loracarbef

Abstract A new method for the synthesis of chiral azetidinones bearing a carbon-carbon bond at the 4-position is described. The preparation involves a stereoselective alkylation-reduction of a silylated 4-phenylsulfonyl azetidinone. The utility of this method was demonstrated by a formal total synthesis of loracarbef.

Synthesis of enantioenriched 4-thiazolidinone (−)-LY213829 by chemoselective benzylamide cleavage in the presence of a C-S bond

Abstract ( R )-2-Methylbenzylamine has been used to covalently “resolve” thiol acid 7 and assemble 4-thiazolidinone 8a in one step. Selective deprotection of the 2-methylbenzylamide using lithium in ammonia/THF has been achieved in the presence of a readily hydrogenolyzed C-S bond. Enantioenriched (−)-LY213829 ( 1 ) of 98% ee has been prepared by this five step route in 25% yield from aldehyde 2 .

Chiral recognition of the angiotensin II (AT1) receptor by a highly potent phenoxyproline octanoamide

Abstract The synthesis and in vitro biological evaluation of a novel series of diastereomeric phenoxyproline octanoamides ( 3–h ) as angiotensin II (AT 1 ) receptor antagonists are reported.

Structures of A88696 C,D and F: Gastric ATP-ase inhibitors

Abstract The structures of A88696C ( 1 ), D ( 2 ) and F ( 3 ), isolated from Streptomyces sclerotialus , are described on the basis of spectroscopic analysis. 1 and 3 are spirotetronic acid-containing macrolides, and 2 is the β-dicarbonyl tautomer with a spiroepoxide at the α-site of the lactone ring.

Unusual stereochemical preferences of decahydroisoquinoline-3-cargoxylic acid competitive NMDA antagonists

Abstract We report the synthesis and characterization of the enantiomers of some C-6 epimeric tetrazole- and phosphonic acid-substituted decahydroisoquinoline competitive NMDA antagonists. We found that the absolute stereochemistry of the amino acid center was different for the active enantiomers of each C-6 epimer.

Synthesis and structural determination of stereoisomers of muscarinic ligands of the (3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicycloalkane type

Methods for the synthesis of each of the four stereoisomers of 6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]oc tane (10, 11, 12, and 13) and 3-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[2.2.1]he ptane (18, 19, 20, and 21), and the two stereoisomers of 3-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[2.2.2]oc tane (27 and 28) were developed. The relative configuration of the compounds was determined on the basis of previously described 1H NOE experiments, and the absolute configuration of 6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]oc tanes (10, 11, 12, and 13) and 3-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[2.2.2]oc tane (27 and 28) was determined by single crystal X-ray crystallography. Optical purity was determined by capillary electrophoresis (CE) using chiral selectors as trimethyl-beta-cyclodextrin and heparin dissolved in the running buffer. All the 3-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicycles had low nanomolar affinity for muscarinic receptors as determined by displacement of radiolabelled oxotremorine-M (3H-Oxo-M) and pirenzepine (3H-Pz) from cortical rat brain homogenates. The binding assay discriminated between diastereomers, but only a minor degree of enantioselectivity was observed in the binding assays.