Carlos Lamas

Synthesis and Pharmacological Characterization of C4-Disubstituted Analogs of 1S,2S,5R,6S-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylate: Identification of a Potent, Selective Metabotropic Glutamate Receptor Agonist and Determination of Agonist-Bound Human mGlu2 and mGlu3 Amino Terminal Domain Structures.

As part of our ongoing research to identify novel agents acting at metabotropic glutamate 2 (mGlu2) and 3 (mGlu3) receptors, we have previously reported the identification of the C4α-methyl analog of mGlu2/3 receptor agonist 1 (LY354740). This molecule, 1S,2S,4R,5R,6S-2-amino-4-methylbicyclo[3.1.0]hexane-2,6-dicarboxylate 2 (LY541850), exhibited an unexpected mGlu2 agonist/mGlu3 antagonist pharmacological profile, whereas the C4β-methyl diastereomer (3) possessed dual mGlu2/3 receptor agonist activity. We have now further explored this structure-activity relationship through the preparation of cyclic and acyclic C4-disubstituted analogs of 1, leading to the identification of C4-spirocyclopropane 5 (LY2934747), a novel, potent, and systemically bioavailable mGlu2/3 receptor agonist which exhibits both antipsychotic and analgesic properties in vivo. In addition, through the combined use of protein-ligand X-ray crystallography employing recombinant human mGlu2/3 receptor amino terminal domains, molecular modeling, and site-directed mutagenesis, a molecular basis for the observed pharmacological profile of compound 2 is proposed.

Synthesis of isoquinoline alkaloids through a 10-membered lactam obtained by radical macrocyclisation

Abstract A new versatile method for the synthesis of isoquinoline alkaloids 3 and 5 is based on transannular cyclisation of a key macrocycle 2b obtained by an intramolecular addition of an aryl radical to a trimethylsilylacetylene.

Conformationally constrained serotonin analogues: Stereoselective synthesis of trans-3-(2-aminocycloalkyl)indoles by aziridine ring opening

Abstract Trans -3-(2-aminocyclopentyl)indoles 9a,c and trans -3-(2-aminocyclohexyl)indoles 9b,d have been stereoselectively prepared by nucleophilic ring opening reaction of N -Boc cycloalkylaziridines 6a,b and the “lower order” magnesium cuprate II , generated from the corresponding indolilmagnesium bromides derived from 7a,b .

Suzuki-type cross-coupling reaction of 1-benzyl-2-iodo-1H-benzimidazoles with aryl boronic acids: A regioselective route to N-alkylated 6-alkoxy-2-aryl-1H-benzimidazoles

Abstract The Suzuki-type cross-coupling reaction of 6-substituted 1-benzyl-2-iodo-1H-benzimidazoles with aryl boronic acids provided an efficient synthesis of the corresponding 2-ary-1H-benzimidazoles. The reaction was catalyzed by palladium(0) under different conditions depending on the aryl group substitution.

Stereoselective synthesis of 1,3,4-substituted tetrahydro-β-carbolines from indoles based on selective transformations

Abstract 1, 3, 4-Substituted tetrahydro β-carbolines 4 have been prepared from indoles 6 by two selective transformations: first, nucleophilic aziridine ring opening with a lower order indolyl magnesium cuprate obtaining the α,β-substituted tryptamines 5 and secondly, a “Pictet-Spengler-like” reaction between azalactones 12 and tryptamines 5. Under the acidic reaction conditions used, the thermodynamically favoured tetrahydro β-carbolines 4 are obtained due to the conformational restrictions imposed by the tryptamine substituents.

Regioselective synthesis of 7,8-dioxygenated-3,4-dihydroisoquinolinesby metalation of β-phenethylamines

Abstract A new, one-pot procedure for the synthesis of the title compounds isdescribed which is based on the thermodynamic metalation of thecorresponding β-(3,4-dialkoxyphenyl)ethylamine.

Use of azalactones in a “Pictet-Spengler-like” reaction. Stereoselective synthesis of 1,3,4-substituted tetrahydro-β-carbolines

A “Pictet-Spengler-like” reaction between azalactones 1 and conformationally constrained tryptamines 4 in refluxing 1N HCl over 72 h. gave the corresponding tetrahydro-β-carbolines 3 in moderate to good yields. The observed equatorial orientation of the C-1 substituent in the THBCs results from a combination of the thermal reaction conditions and conformational constraints imposed by the starting tryptamines.

Conversion of dibenzoxepinones to aristocularine alkaloids

Abstract A new synthesis of the aristocularine alkaloids, from the corresponding dibenzoxepinones, is described.

Unexpected highly regioselective macrocyclization of o-allylic N-carbonyl substituted anilines

An unexpected bromocyclocarbamoylation of o -allylic N -BOC-anilines has been observed producing 2-oxo-3,1-benzoxazocine derivatives through an 8- endo - trig process, which on heating ring-transformed into a [6.5.5] tricyclic fused oxazolidinone compounds. A mixture of both heterocycles was obtained when the starting N -BOC anilines were heated with NBS in THF. The process seems to be general for related N -carbonyl substituted anilines.

A new synthesis of 10,11-dihydrodibenz(b,f)oxepin-10-ones: Key intermediates to cularine alkaloids

Abstract A new synthesis of the title compounds is described, providing a route to key intermediates for the preparation of cularine alkaloids.