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1.
J Org Chem ; 79(21): 10030-48, 2014 Nov 07.
Article in English | MEDLINE | ID: mdl-25247616

ABSTRACT

A detailed account of the development of a general strategy for synthesis of the C-19 methyl-substituted alkaloids including total synthesis of 19(S),20(R)-dihydroperaksine-17-al (1), 19(S),20(R)-dihydroperaksine (2), and peraksine (6) is presented. Efforts directed toward the total synthesis of macrosalhine chloride (5) are also reported. Important to success is the sequence of chemical reactions which include a critical haloboration reaction, regioselective hydroboration, and controlled oxidation (to provide sensitive enolizable aldehydes at C-20). In addition, the all-important Pd-catalyzed α-vinylation reaction has been extended to a chiral C-19 alkyl-substituted substrate for the first time. Synthesis of the advanced intermediate 64 completes an improved formal total synthesis of talcarpine (26) and provides a starting point for synthesis of macroline-related alkaloids 27-31. Similarly, extension of this synthetic strategy in the ring A oxygenated series should provide easy access to the northern hemisphere 32b of the bisindoles angustricraline, alstocraline, and foliacraline (Figure 4 ).


Subject(s)
Ajmaline/chemical synthesis , Indole Alkaloids/chemical synthesis , Ajmaline/chemistry , Indole Alkaloids/chemistry , Molecular Structure , Oxidation-Reduction , Oxindoles
2.
J Org Chem ; 78(13): 6471-87, 2013 Jul 05.
Article in English | MEDLINE | ID: mdl-23721107

ABSTRACT

The first regio- and stereocontrolled total synthesis of the bisphenolic, bisquaternary alkaloid (+)-dispegatrine (1) has been accomplished in an overall yield of 8.3% (12 reaction vessels) from 5-methoxy-d-tryptophan ethyl ester (17). A crucial late-stage thallium(III) mediated intermolecular oxidative dehydrodimerization was employed in the formation of the C9-C9' biaryl axis in 1. The complete stereocontrol observed in this key biaryl coupling step is due to the asymmetric induction by the natural sarpagine configuration of the monomer lochnerine (6) and was confirmed by both the Suzuki and the oxidative dehydrodimerization model studies on the tetrahydro ß-carboline (35). The axial chirality of the lochnerine dimer (40) and in turn dispegatrine (1) was established by X-ray crystallography and was determined to be P(S). Additionally, the first total synthesis of the monomeric indole alkaloids (+)-spegatrine (2), (+)-10-methoxyvellosimine (5), (+)-lochnerine (6), lochvinerine (7), (+)-sarpagine (8), and (+)-lochneram (11) were also achieved via the common pentacyclic intermediate 16.


Subject(s)
Alkaloids/chemical synthesis , Indole Alkaloids/chemical synthesis , Oxygen/chemistry , Alkaloids/chemistry , Indole Alkaloids/chemistry , Molecular Structure , Stereoisomerism
3.
Org Lett ; 14(23): 6096-9, 2012 Dec 07.
Article in English | MEDLINE | ID: mdl-23171471

ABSTRACT

An enantioselective [2 + 2 + 2] cycloaddition of ene-allenes with allenoates is described, which transforms simple π-components into stereochemically complex carbocycles in a single step. The rhodium(I)-catalyzed cycloaddition proceeds with good levels of enantioselectivity, and with high levels of regio-, chemo-, and diastereoselectivity. Our results are consistent with a mechanism involving an enantioselective intermolecular allene-allene oxidative coupling.

5.
J Nat Prod ; 75(2): 181-8, 2012 Feb 24.
Article in English | MEDLINE | ID: mdl-22257244

ABSTRACT

The development of an efficient diastereoselective method that permits rapid construction of the tetracyclic core 17 of the Strychnos-Aspidosperma alkaloids is described. Enaminone 16, synthesized in high yield, has been cyclized under the influence of a Brønsted acid to provide the core tetracyclic framework 17 of the Strychnos alkaloids in optically active form or alternatively to the ß-ketoester tetrahydro-ß-carboline (THBC) unit 18, by varying the equivalents of acid and the molar concentration. Attempts to utilize 18 to form the C7-C16 bond of the akuammiline related alkaloids represented by strictamine (22), using metal-carbenoid chemistry, are also described.


Subject(s)
Indole Alkaloids/chemistry , Indole Alkaloids/chemical synthesis , Strychnos/chemistry , Alkaloids/chemical synthesis , Alkaloids/chemistry , Cyclization , Molecular Structure , Stereoisomerism
6.
Org Lett ; 13(19): 5216-9, 2011 Oct 07.
Article in English | MEDLINE | ID: mdl-21877687

ABSTRACT

The optically active tetracyclic ketone 8 was converted into the pentacylic core 14 of the C-19 methyl substituted N(a)-H sarpagine and ajmaline alkaloids via a critical haloboration reaction. The ketone 14 was then employed in the total synthesis of 19(S),20(R)-dihydroperaksine-17-al (1) and 19(S),20(R)-dihydroperaksine (2). The key regioselective hydroboration and controlled oxidation-epimerization sequence developed in this approach should provide a general method to functionalize the C(20)-C(21) double bond in the ajmaline-related indole alkaloids.


Subject(s)
Indole Alkaloids/chemistry , Indole Alkaloids/chemical synthesis , Acetylene/chemistry , Methylation , Models, Molecular , Molecular Structure , Oxidation-Reduction , Stereoisomerism
7.
Neuropharmacology ; 59(7-8): 612-8, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20727364

ABSTRACT

Conflict procedures can be used to study the receptor mechanisms underlying the anxiolytic effects of benzodiazepines and other GABA(A) receptor modulators. In the present study, we first determined the efficacy and binding affinity of the benzodiazepine diazepam and recently synthesized GABA(A) receptor modulators JY-XHe-053, XHe-II-053, HZ-166, SH-053-2'F-S-CH3 and SH-053-2'F-R-CH3 at GABA(A) receptors containing α1, α2, α3 and α5 subunits. Results from these studies suggest that each compound displayed lower efficacy at GABA(A) receptors containing α1 subunits and varying degrees of efficacy and affinity at GABA(A) receptors containing α2, α3 and α5 subunits. Next, we assessed their anxiolytic effects using a rhesus monkey conflict procedure in which behavior was maintained under a fixed-ratio schedule of food delivery in the absence (non-suppressed responding) and presence (suppressed responding) of response-contingent electric shock. Relatively non-selective compounds, such as diazepam and JY-XHe-053 produced characteristic increases in rates of suppressed responding at low to intermediate doses and decreased the average rates of non-suppressed responding at higher doses. XHe-II-053 and HZ-166 also produced increases in suppressed responding at low to intermediate doses, but were ineffective at decreasing rates of non-suppressed responding, consistent with their relatively low efficacy at GABA(A) receptors containing α1 and α5 subunits. In contrast, SH-053-2'F-S-CH3 and SH-053-2'F-R-CH3 produced only partial increases in suppressed responding and were ineffective on non-suppressed responding, consistent with their profiles as partial agonists at GABA(A) receptors containing α2, α3 and α5 subunits. These behavioral effects suggest that the anxiolytic and rate-reducing effects of GABA(A) receptor positive modulators are dependent on their relative efficacy and affinity at different GABA(A) receptor subtypes.


Subject(s)
Alkynes/pharmacology , Anti-Anxiety Agents/pharmacology , Benzodiazepines/pharmacology , Conflict, Psychological , Diazepam/analogs & derivatives , GABA Modulators/pharmacology , Imidazoles/pharmacology , Alkynes/chemistry , Animals , Benzodiazepines/chemistry , Binding, Competitive , Cell Line , Diazepam/chemistry , Diazepam/pharmacology , Female , Humans , Imidazoles/chemistry , In Vitro Techniques , Macaca mulatta , Male , Oocytes/drug effects , Oocytes/physiology , Patch-Clamp Techniques , Radioligand Assay , Rats , Receptors, GABA-A/metabolism , Stereoisomerism , Structure-Activity Relationship , Xenopus laevis
8.
Prog Neuropsychopharmacol Biol Psychiatry ; 34(2): 376-86, 2010 Mar 17.
Article in English | MEDLINE | ID: mdl-20074611

ABSTRACT

Over the last years, genetic studies have greatly improved our knowledge on the receptor subtypes mediating various pharmacological effects of positive allosteric modulators at GABA(A) receptors. This stimulated the development of new benzodiazepine (BZ)-like ligands, especially those inactive/low-active at GABA(A) receptors containing the alpha(1) subunit, with the aim of generating more selective drugs. Hereby, the affinity and efficacy of four recently synthesized BZ site ligands: SH-053-2'N, SH-053-S-CH3-2'F, SH-053-R-CH3-2'F and JY-XHe-053 were assessed. They were also studied in behavioral tests of spontaneous locomotor activity, elevated plus maze, and water maze in rats, which are considered predictive of, respectively, the sedative, anxiolytic, and amnesic influence of BZs. The novel ligands had moderately low to low affinity and mild to partial agonistic efficacy at GABA(A) receptors containing the alpha(1) subunit, with variable, but more pronounced efficacy at other BZ-sensitive binding sites. While presumably alpha(1) receptor-mediated sedative effects of GABA(A) modulation were not fully eliminated with any of the ligands tested, only SH-053-2'N and SH-053-S-CH3-2'F, both dosed at 30 mg/kg, exerted anxiolytic effects. The lack of clear anxiolytic-like activity of JY-XHe-053, despite its efficacy at alpha(2)- and alpha(3)-GABA(A) receptors, may have been partly connected with its preferential affinity at alpha(5)-GABA(A) receptors coupled with weak agonist activity at alpha(1)-containing subtypes. The memory impairment in water-maze experiments, generally reported with BZ site agonists, was completely circumvented with all four ligands. The results suggest that a substantial amount of activity at alpha(1) GABA(A) receptors is needed for affecting spatial learning and memory impairments, while much weaker activity at alpha(1)- and alpha(5)-GABA(A) receptors is sufficient for eliciting sedation.


Subject(s)
Binding, Competitive/physiology , Motor Activity/physiology , Protein Subunits/metabolism , Receptors, GABA-A/chemistry , Receptors, GABA-A/physiology , Analysis of Variance , Animals , Benzodiazepines/pharmacology , Binding Sites/drug effects , Binding Sites/physiology , Binding, Competitive/drug effects , Dose-Response Relationship, Drug , Female , GABA Agents/pharmacology , Ligands , Maze Learning/drug effects , Maze Learning/physiology , Membrane Potentials/drug effects , Membrane Potentials/genetics , Motor Activity/drug effects , Oocytes , Patch-Clamp Techniques/methods , Protein Binding/drug effects , Protein Subunits/drug effects , Protein Subunits/genetics , Protein Subunits/physiology , Rats , Receptors, GABA-A/drug effects , Receptors, GABA-A/genetics , Structure-Activity Relationship , Transduction, Genetic/methods , Xenopus
9.
Curr Opin Drug Discov Devel ; 12(6): 752-71, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19894188

ABSTRACT

This review describes the most recent synthetic routes directed toward the construction of structurally complex indole alkaloids, many syntheses of which contain the asymmetric Pictet-Spengler reaction as a key stereochemical step. A kinetic and conformational study of the epimerization of cis 1,2,3-trisubstituted tetrahydro-beta-carbolines into their trans counterparts is described, because this is key to complete asymmetric induction in the Pictet-Spengler reaction. A mechanistic study of the enzyme-catalyzed Pictet-Spengler reaction is also included. The total synthesis of the opioid agonist mitragynine, as well as corynantheidol and the oxindole alstonisine is presented. With regard to bisindole alkaloids, the total synthesis of the antileishmanial bisindoles accedinisine and N'-demethylaccedinisne is described.


Subject(s)
Chemistry, Pharmaceutical/methods , Chemistry, Pharmaceutical/trends , Indole Alkaloids/chemical synthesis , Catalysis , Isomerism , Models, Chemical , Molecular Structure , Stereoisomerism
10.
J Med Chem ; 52(7): 1795-8, 2009 Apr 09.
Article in English | MEDLINE | ID: mdl-19275170

ABSTRACT

The antiseizure activity of benzodiazepines (BDZs) 1-5 in mice and rats as animal models is described. These BDZs have selective efficacy for alpha2beta3gamma2 and alpha3beta3gamma2 GABA(A)-receptors. Significant anticonvulsant activity with little or no motor impairment and therapeutic indexes (TI) of 2.8-44 (mice, ip) were observed for compounds 2-4 in the subcutaneous metrazole seizure (scMET) test. In rats, orally (po) the TI was >5 to 105. These compounds represent novel leads in the search for anticonvulsants devoid of sedative, ataxic, and amnestic side effects.


Subject(s)
Anticonvulsants/chemical synthesis , Benzodiazepines/chemical synthesis , Receptors, GABA-A/metabolism , Animals , Anticonvulsants/pharmacology , Anticonvulsants/toxicity , Benzodiazepines/pharmacology , Benzodiazepines/toxicity , Convulsants , Hippocampus/drug effects , Hippocampus/physiopathology , Kindling, Neurologic/drug effects , Ligands , Mice , Pentylenetetrazole , Rats , Seizures/chemically induced , Seizures/drug therapy , Structure-Activity Relationship
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