Discovery of a novel trans-1,4-dioxycyclohexane GPR119 agonist series.

The design and optimization of a novel trans-1,4-dioxycyclohexane GPR119 agonist series is described. A lead compound 21 was found to be a potent and efficacious GPR119 agonist across species, and possessed overall favorable pharmaceutical properties. Compound 21 demonstrated robust acute and chronic regulatory effects on glycemic parameters in the diabetic or non-diabetic rodent models.

Discovery of 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalen-4-carboxamides as potent and selective CB2 receptor agonists.

The design and synthesis of novel 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalen-4-carboxamide CB2 selective ligands for the potential treatment of pain is described. Compound (R,R)-25 has good balance between CB2 agonist potency and selectivity over CB1, and possesses overall favorable pharmaceutical properties. It also demonstrated robust in vivo efficacy mediated via CB2 activation in the rodent models of inflammatory and osteoarthritis pain after oral administration.

Discovery and optimization of 5-fluoro-4,6-dialkoxypyrimidine GPR119 agonists.

A series of 5-fluoro-4,6-dialkoxypyrimidine GPR119 modulators were discovered and optimized for in vitro agonist activity. A lead molecule was identified that has improved agonist efficacy relative to our clinical compound (APD597) and possesses reduced CYP2C9 inhibitory potential. This optimized lead was found to be efficacious in rodent models of glucose control both alone and in combination with a Dipeptidyl peptidase-4 (DPP-4) inhibitor.

An aryl to imidoyl palladium migration process involving intramolecular C-H activation.

Biologically interesting fluoren-9-one and xanthen-9-one derivatives have been prepared by a novel aryl to imidoyl palladium migration, followed by intramolecular arylation. The fluoren-9-one synthesis appears to involve both a palladium migration mechanism and a C-H activation process proceeding through an unprecedented organopalladium(IV) hydride intermediate. The results from deuterium labeling experiments are consistent with the proposed dual mechanism.

Syntheses of isochromenes and naphthalenes by electrophilic cyclization of acetylenic arenecarboxaldehydes.

Highly substituted 1H-isochromenes, isobenzofurans, and pyranopyridines can be prepared by allowing o-(1-alkynyl)arenecarboxaldehydes and ketones to react with I2, ICl, NIS, Br2, NBS, p-O2NC6H4SCl, or PhSeBr and various alcohols or carbon-based nucleophiles at room temperature. Naphthyl ketones and iodides are also readily prepared by the reaction of 2-(1-alkynyl)arenecarboxaldehydes with I2 and simple olefins or alkynes.

Synthesis of 3-iodoindoles by the Pd/Cu-catalyzed coupling of N,N-dialkyl-2-iodoanilines and terminal acetylenes, followed by electrophilic cyclization.

[reaction: see text] 3-Iodoindoles have been prepared in excellent yields by coupling terminal acetylenes with N,N-dialkyl-o-iodoanilines in the presence of a Pd/Cu catalyst, followed by an electrophilic cyclization of the resulting N,N-dialkyl-o-(1-alkynyl)anilines using I2 in CH2Cl2. Aryl-, vinylic-, alkyl-, and silyl-substituted terminal acetylenes undergo this process to produce excellent yields of 3-iodoindoles. The reactivity of the carbon-nitrogen bond cleavage during cyclization follows the following order: Me > n-Bu, Me > Ph, and cyclohexyl > Me. Subsequent palladium-catalyzed Sonogashira, Suzuki, and Heck reactions of the resulting 3-iodoindoles proceed smoothly in good yields.

Synthesis of 2,3-disubstituted benzo[b]furans by the palladium-catalyzed coupling of o-iodoanisoles and terminal alkynes, followed by electrophilic cyclization.

[reaction: see text] 2,3-Disubstituted benzo[b]furans are readily prepared under very mild reaction conditions by the palladium/copper-catalyzed cross-coupling of various o-iodoanisoles and terminal alkynes, followed by electrophilic cyclization with I2, PhSeCl, or p-O2NC6H4SCl. Aryl- and vinylic-substituted alkynes undergo electrophilic cyclization in excellent yields. Biologically important furopyridines can be prepared by this approach in high yields.

An efficient synthesis of coumestrol and coumestans by iodocyclization and Pd-catalyzed intramolecular lactonization.

[reaction: see text] The iodocyclization of acetoxy-containing 2-(1-alkynyl)anisoles and subsequent direct palladium-catalyzed carbonylation/lactonization provide an efficient route to naturally occurring coumestan and coumestrol, and their related analogues.

Total synthesis of the epoxy isoprostane phospholipids PEIPC and PECPC.

A total synthesis of the naturally occurring hydroxy ketone PEIPC 1, a compound that plays a role in endothelial activation in atherosclerosis, has been completed via a triply convergent preparation of a protected EI derivative 13 from 3,5-diacetoxycyclopentene 7, pentane-1,5-diol, and vinyllithium, using Sharpless epoxidation and enzymatic resolution as key steps. Final coupling with lyso-PC 16 and silyl group deprotection gave PECPC 2 and PEIPC 1, which showed the same activity as natural PECPC and PEIPC. [reaction: see text]

Efficient syntheses of heterocycles and carbocycles by electrophilic cyclization of acetylenic aldehydes and ketones.

Highly substituted oxygen heterocycles can be prepared in good yields at room temperature by reacting o-(1-alkynyl)-substituted arene carbonyl compounds with NBS, I(2), ICl, p-O(2)NC(6)H(4)SCl, or PhSeBr and various alcohols or carbon-based nucleophiles. Naphthyl ketones and iodides are readily prepared by the reaction of 2-(1-alkynyl)arene-carboxaldehydes with I(2) and simple olefins or alkynes.

Synthesis of 3-iodoindoles by electrophilic cyclization of N,N-dialkyl-2-(1-alkynyl)anilines.

[reaction: see text] A wide variety of N-alkyl-3-iodoindoles are readily prepared under very mild reaction conditions by the palladium/copper-catalyzed cross-coupling of N,N-dialkyl-o-iodoanilines and terminal alkynes, followed by electrophilic cyclization by I(2)(). Alkyl-, aryl-, and vinylic-substituted alkynes all undergo iodocyclization in excellent yields.

Synthesis of 2,3-disubstituted benzo[b]thiophenes via palladium-catalyzed coupling and electrophilic cyclization of terminal acetylenes.

2,3-Disubstituted benzo[b]thiophenes have been prepared in excellent yields via coupling of terminal acetylenes with commercially available o-iodothioanisole in the presence of a palladium catalyst and subsequent electrophilic cyclization of the resulting o-(1-alkynyl)thioanisole derivatives. I(2), Br(2), NBS, p-O(2)NC(6)H(4)SCl, and PhSeCl have been utilized as electrophiles. Aryl-, vinyl-, and alkyl-substituted terminal acetylenes undergo this coupling and cyclization to produce excellent yields of benzo[b]thiophenes. (Trimethylsilyl)acetylene also undergoes this coupling/cyclization process with I(2), NBS, and the sulfur and selenium electrophiles to afford the corresponding 2-(trimethylsilyl)benzo[b]thiophenes. However, cyclization of the silyl-containing thioanisole using Br(2) affords 2,3-dibromobenzo[b]thiophene.