Andrew J. Carpenter

High-yield syntheses of 2,3-disubstituted furans and thiophenes

Abstract The course of lithiation of furan- and thiophene-2-carboxylic acids is critically dependent on the identity of the lithium base allowing high-yielding syntheses of 2,3- and 2,5-disubstituted thiophenes: the proposed use of a trimethylsilyl blocking group to control metallation in the furan acid provides a useful route to 2,3-disubstituted furans.

High-yielding syntheses of 4(5)-substituted imidazoles via organolithium intermediates. the utility of sulphonamide n-protection and silicon-containing blocking groups

Abstract N -Protection of imidazole as its N , N -dimethyl-sulphonamido derivative, and blocking of the 2-position with the triethylsilyl group permits regioselective 5-metallation with sec-butyl-lithium. The resulting organolithium intermediates react with a range of electrophiles and the products are easily deprotected to give the 4(5)-substituted NH-free imidazoles in good to excellent yields. Isolation of the silicon-blocked intermediate is unnecessary and, indeed, is disadvantageous to final yields, making the procedure attractively economical of time.

Chemoselective protection of heteroaromatic aldehydes as imidazolidine derivatives. Preparation of 5-substituted furan- and thiophene-2-carboxaldehydes via metallo-imidazolidine intermediates

Abstract Furan-, thiophene- and N -methylpyrrole-2-carboxaldehydes may be transformed into the corresponding N , N -dimethylimidazolidines in a reaction not requiring acid catalysis. The resulting furan and thiophene (but not N -methylpyrrole) derivatives may be metallated in high yields [predominantly at the 5 (α-) positions of the heteroaromatic rings] and the carboxaldehyde functionality regenerated under very mild conditions. Treatment of the aldehydoketone 2-acetyl-5-formylthiophene with N , N -dimethylethylenediamine gives only the product of reaction at the aldehyde function thus establishing this methodology as a potentially valuable method for the protection of an aldehyde in the presence of a ketone.

Regioselective α- and β-metallations of thiophene derivatives bearing the 4,4-dimethyloxazolin-2-yl group. Application of the method to syntheses of 2,3- and 2,5-disubstituted thiophene derivatives

The effects of change of solvent, metallating agent, reaction time and temperature, and of the presence or absence of agents capable of complex formation with either the lithium cation or the oxazoline moiety, on the lithiation of 4,4-dimethyl-2-(2-thienyl)oxazoline are explored. Conditions are thereby estab-lished for high-yielding syntheses of the 3- and 5-lithio-intermediates and for control of regioselectivity of metallation. The nucleophilicity of the 3-lithio-intermediate is profoundly solvent dependent, and appropriate conditions for reaction of both 3- and 5-lithiated species with a wide variety of electrophiles are presented. Syntheses of a range of 2,3- and 2,5-disubstituted thiophene derivatives have thereby been achieved, utilising, in addition, a new method for the transformation of oxazolino into carboxy functionality.The balance between basicity and nucleophilicity of the 3-lithio-intermediate in its reaction with [1H6]- and [2H6]-acetone is shown to be sensitive to isotope effects.

Facile Reductive Amination of Aldehydes with Electron-Deficient Anilines by Acyloxyborohydrides in TFA: Application to a Diazaindoline Scale-Up

A scale-up of diazaindoline 1 was achieved in four stages and 32% overall yield. The key step involved rapid reductive amination of aldehyde 8 with aniline 5 by sodium triacetoxyborohydride (STAB-H) and TFA followed by ring closure of intermediate amine 9 to compound 1 in the same pot. These reaction conditions were also applied to facile reductive aminations with anilines known to have little reactivity under STAB-H/AcOH conditions. Spectral data supported the tris(trifluoroacetoxy)borohydride anion (16) as the active reducing agent.

Dimetallations of 2-substituted furans and thiophenes: approaches to the 2,3,5-trisubstituted heterocycles

Abstract The preparation and reactions of 3,5-dilithiated furan and thiophene derivatives bearing the 4,4-dimethyloxazolin-2-yl 2-substituent are reported. The 2-tert-butoxycarbonyl analogues cannot be prepared by direct dimetallation of the corresponding esters but sequential monometallation with in situ trapping by Me3 SiCl ultimately affords the 3,5-disilylated products: the 3-metallation of the 5-silylated intermediate is accelerated by LiCl.

Discovery of 6,7-Dihydro-5H-pyrrolo[2,3-a]pyrimidines as Orally Available G Protein-Coupled Receptor 119 Agonists

GPR119 is a 7-transmembrane receptor that is expressed in the enteroendocrine cells in the intestine and in the islets of Langerhans in the pancreas. Indolines and 6,7-dihydro-5H-pyrrolo[2,3-a]pyrimidines were discovered as G protein-coupled receptor 119 (GPR119) agonists, and lead optimization efforts led to the identification of 1-methylethyl 4-({7-[2-fluoro-4-(methylsulfonyl)phenyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)-1-piperidinecarboxylate (GSK1104252A) (3), a potent and selective GPR119 agonist. Compound 3 showed excellent pharmacokinetic properties and sufficient selectivity with in vivo studies supporting a role for GPR119 in glucose homeostasis in the rodent. Thus, 3 appeared to modulate the enteroinsular axis, improve glycemic control, and strengthen previous suggestions that GPR119 agonists may have utility in the treatment of type 2 diabetes.

Discovery of Novel and Long Acting GLP-1 Analogs

Glucagon Like Peptide-1 (GLP-1) is a 30 amino acid gut hormone produced by intestinal L cells and pancreatic α cells. GLP-1 induces post prandial glucose-dependent insulin secretion and inhibits gastric secretion and motility, thus reducing circulating glucose levels and increasing satiety. These physiological effects make GLP-1 an interesting target for both diabetes and obesity therapy. However, GLP-1 lacks the therapeutic potential due to its very short half-life. Described are our efforts using ortholog screening and fragment substitution to discover novel and long acting GLP-1 analogues with modifications in the GLP-1 sequence, HGEGTFTSDLTEYLEEEAVREFIEWLKNGGPKKIRYS-NH2. These analogs have desired potency and efficacy over endogenous GLP-1 with a 15h duration of action in an acute food intake reduction mouse model.