Scott R. Gilbertson

The combinatorial synthesis of chiral phosphine ligands

Abstract Chemistry is reported that allows for the synthesis and screening of phosphine ligands by standard combinatorial technology. To demonstrate the method a 63 member library of phosphine containing peptides was synthesized. Rhodium was complexed to the phosphine ligands while they were attached to the synthesis support. Each member of the library was screened for its ability to catalyze the asymmetric hydrogenation of enamide ( 3 ). Some correlation between specific substitutions in the primary sequence of the peptide and the highest enantiomeric excesses was observed.

Cycloadditions and annulations of transition metal carbene complexes

Abstract The synthetic aspects of several reactions from the multifaceted chemistry of Fischer carbene complexes are examined. Their benzannulation reactions with acetylenes are utilized in the synthesis of anthracyclinones via two approaches which differ by beginning at opposite ends of the molecule with either an aryl or an alkenyl substituted chromium carbene complex. The latter has been employed in a formal synthesis of daunomycinone. The Diels-Alder reactions of α,β-acetylenic chromium carbene complexes provide for a facile entry into substituted cyclohexenyl chromium carbene complexes that are subsequently employed in benzannulation reactions. These tandem cycloaddition/annulation reactions are incorporated into model studies for the synthesis of anthracyclinones and wentilactone A. Their potential is also demonstrated for coupling to yet a third reaction of organochromium compounds ; aromatic nucleophilic substitutions on arene chromium tricarbonyl complexes. The annulations of β,β-disubstituted alkenyl complexes provides for a regio- and stereoselective synthesis of 2,4-cyclohexadienones under neutral conditions at near ambient temperatures.

Plasmodium Food Vacuole Plasmepsins Are Activated by Falcipains

Intraerythrocytic malaria parasites use host hemoglobin as a major nutrient source. Aspartic proteases (plasmepsins) and cysteine proteases (falcipains) function in the early steps of the hemoglobin degradation pathway. There is extensive functional redundancy within and between these protease families. Plasmepsins are synthesized as integral membrane proenzymes that are activated by cleavage from the membrane. This cleavage is mediated by a maturase activity whose identity has been elusive. We have used a combination of cell biology, chemical biology, and enzymology approaches to analyze this processing event. These studies reveal that plasmepsin processing occurs primarily via the falcipains; however, if falcipain activity is blocked, autoprocessing can take place, serving as an alternate activation system. These results establish a further level of redundancy between the protease families involved in Plasmodium hemoglobin degradation.

Selective serotonin 5-HT2C receptor activation suppresses the reinforcing efficacy of cocaine and sucrose but differentially affects the incentive-salience value of cocaine- vs. sucrose-associated cues

Serotonin (5-HT) controls affective and motivational aspects of palatable food and drug reward and the 5-HT(2C) receptor (5-HT(2C)R) has emerged as a key regulator in this regard. We have evaluated the efficacy of a selective 5-HT(2C)R agonist, WAY 163909, in cocaine and sucrose self-administration and reinstatement assays employing parallel experimental designs in free-fed rats. WAY 163909 dose-dependently reduced the reinforcing efficacy of cocaine (ID(50) = 1.19 mg/kg) and sucrose (ID(50) = 0.7 mg/kg) as well as reinstatement (ID(50) = 0.5 mg/kg) elicited by exposure to cocaine-associated contextual cues, but not sucrose-associated contextual cues. The ID(50) of WAY 163909 predicted to decrease the reinforcing efficacy of cocaine or sucrose as well as reinstatement upon exposure to cocaine-associated cues was ∼5-12-fold lower than that predicted to suppress horizontal ambulation (ID(50) = 5.89 mg/kg) and ∼2-5-fold lower than that predicted to suppress vertical activity (ID(50) = 2.3 mg/kg). Thus, selective stimulation of the 5-HT(2C)R decreases the reinforcing efficacy of cocaine and sucrose in freely-fed rats, but differentially alters the incentive-salience value of cocaine- vs. sucrose-associated cues at doses that do not impair locomotor activity. Future research is needed to tease apart the precise contribution of 5-HT(2C)R neurocircuitry in reward and motivation and the learning and memory processes that carry the encoding for associations between environmental cues and consumption of rewarding stimuli. A more complete preclinical evaluation of these questions will ultimately allow educated proof-of-concept trials to test the efficacy of selective 5-HT(2C)R agonists as adjunctive therapy in chronic health maladies including obesity, eating disorders and drug addiction.

Rhodium catalyzed intramolecular [4+2] cycloisomerization reactions

A rhodium catalyst is reported that catalyzes the cycloisomerization of dieneynes and trienes. This cycloisomerization reaction, formally the equivalent of an unactivated Diels-Alder reaction, proceeds at room temperature with [Rh(DIPHOS)(CH2Cl2)2] SbF6 as the catalyst.

THE PARALLEL SYNTHESIS OF PEPTIDE BASED PHOSPHINE LIGANDS

Abstract Chemistry is reported that allows for the synthesis and screening of phosphine ligands by standard combinatorial technology. To demonstrate the method, libraries of phosphine containing peptides were synthesized. Rhodium was complexed to the phosphine ligands while they were attached to the synthesis support. Each member of the library was screened for its ability to catalyze the asymmetric hydrogenation of enamides.

Reactions of cobalt carbene complexes with alkynes. .eta.4-Vinylketene-complexed intermediates and a novel synthesis of bovolide.

The combination of resonance Raman and isotopic work thus demonstrates conclusively that, for Rh2(02CCH3)4(PPh3)2, v(RhRh) is a t 289.3 cm-I. Since the RhRh bond length in this complex is 2.4505 (2) A, longer than in the analogous AsPh3 (2.427 (1) A),2 SbPh, (2.421 (4) A),* and H20 (2.3855 (5) A)I6 complexes, the implication is that v(RhRh) in these complexes must all lie above 289.3 cm-I, as indeed is found to be the case for the AsPh3 and SbPh, derivatives (vide supra). The high value for v(RhRh) is thought to arise from the significant contribution to the RhRh restoring force brought about by the four chelating acetate groups (primarily via the four OCO bending coordinates, which are coupled only in second order to the RhRh stretching coordinate). Full details of these and related studies will be published elsewhere.

Synergism between a serotonin 5-HT2A receptor (5-HT2AR) antagonist and 5-HT2CR agonist suggests new pharmacotherapeutics for cocaine addiction.

Relapse to cocaine dependence, even after extended abstinence, involves a number of liability factors including impulsivity (predisposition toward rapid, unplanned reactions to stimuli without regard to negative consequences) and cue reactivity (sensitivity to cues associated with cocaine-taking which can promote cocaine-seeking). These factors have been mechanistically linked to serotonin (5-hydroxytryptamine, 5-HT) signaling through the 5-HT(2A) receptor (5-HT(2A)R) and 5-HT(2C)R; either a selective 5-HT(2A)R antagonist or a 5-HT(2C)R agonist suppresses impulsivity and cocaine-seeking in preclinical models. We conducted proof-of-concept analyses to evaluate whether a combination of 5-HT(2A)R antagonist plus 5-HT(2C)R agonist would have synergistic effects over these liability factors for relapse as measured in a 1-choice serial reaction time task and cocaine self-administration/reinstatement assay. Combined administration of a dose of the selective 5-HT(2A)R antagonist M100907 plus the 5-HT(2C)R agonist WAY163909, each ineffective alone, synergistically suppressed cocaine-induced hyperactivity, inherent and cocaine-evoked impulsive action, as well as cue- and cocaine-primed reinstatement of cocaine-seeking behavior. The identification of synergism between a 5-HT(2A)R antagonist plus a 5-HT(2C)R agonist to attenuate these factors important in relapse indicates the promise of a bifunctional ligand as an anti-addiction pharmacotherapeutic, setting the stage to develop new ligands with improved efficacy, potency, selectivity, and in vivo profiles over the individual molecules.

Proline-Based P,N Ligands in Palladium-Catalyzed Asymmetric π-Allyl Additions

Excellent yields and at least 95 % ee can be achieved for the addition of dimethyl malonate to cycloalkenyl acetates by using a palladium complex of the new phosphanyldihydrooxazole ligand L as a catalyst (see scheme). The ligand L can be synthesized from commercially available trans 4-hydroxy-L-proline in four steps. BOC=tert-butoxycarbonyl.

Asymmetric hydrogenation of aromatic olefins catalyzed by iridium complexes of proline derived phosphine–oxazoline ligands

Abstract The synthesis of a series of phosphine–oxazoline ligands is reported. This ligands are synthesized by reaction of a phosphine chloride with the secondary nitrogen of proline. Upon coordination to iridium the resulting complexes can be used in the asymmetric hydrogenation of simple olefins. The effect of different counter ions and substitution at the oxazoline and the phosphine is reported.