David M. Fink

Scope and stereochemical course of the (trimethylsilyl)cyclopentene annulation

Abstract A new, regiospecific [3 + 2] annulation approach to highly substituted 5-membered carbocycles has been developed. The “TMS-cyclopentene annulation” involves the reaction of (trimethylsilyl)allenes with electron-deficient alkenes and alkynes in the presence of titanium tetrachloride to afford, in a single step, a functionalized and highly substituted TMS-cyclopentene derivative. Annulations employing ⇌, β-unsaturated ketones proceed stereoselectively via suprafacial addition to the enone. Some useful transformations of the annulation products are also described; for example, treatment with K 2 CO 3 -methanol or HF in acetonitrile effects isomerization and desilylation yielding ⇌,β-unsaturated ketones.

The reaction of allenylsilanes with α,β-unsaturated acylsilanes: new annulation approaches to five and six-membered carbocyclic compounds

Abstract The reaction of α,β-unsaturated acylsilanes with allenylsilanes can be directed to produce either five or six-membered carbocyclic compounds.

Imino 1,2,3,4-tetrahydrocyclopent[b]indole carbamates as dual inhibitors of acetylcholinesterase and monoamine oxidase

Abstract A series of imino 1,2,3,4-tetrahydrocyclopent[b]indole carbamates was prepared and evaluated as dual acetylcholinesterase (AChE) and monoamine oxidase (MAO) inhibitors. Halogen substitution ortho to the carbamate functionality in the eight position resulted in a significant increase in binding affinity for both AChE and MAO-A.

Conjugate addition of allylsilanes to α,β-unsaturated acylsilanes

Abstract α,β-Unsaturated acylsilanes serve as highly reactive carboxylic acid equivalents in conjugate allylation reactions with allylsilane derivatives.

Synthesis and preliminary structure-activity relationships of 1-[(3-fluoro-4-pyridinyl)amino]-3-methyl-1H-indol-5-yl methyl carbamate (P10358), a novel acetylcholinesterase inhibitor

Abstract A series of carbamate analogs of besipirdine (HP 749) was synthesized as potential agents with enhanced cholinomimetic properties for the treatment of Alzheimers disease. Compound 5a (P10358, 1-[3-fluoro-4-pyridinyl)amino]-3-methyl-1H-indol-5-yl methyl carbamate) emerged as a potent, reversible acetylcholinesterase inhibitor that significantly enhanced performance on oral or parenteral administration in learning and memory paradigms.

Preparation of 3-(4-pyridinylamino)-1,2-benzisoxazoles via a nucleophilic aromatic substitution reaction

Abstract An efficient three step process for the preparation of secondary 3-amino-1,2-benzisoxazoles is described. The key step is the isomerization/cyclization of an ortho halo or nitro amidoxime. The nucleophilic substitution reaction is successful with a wide variety of substituents on the aromatic ring, including an electron donating substituent para to the site of attack.

Synthesis and carbamoylation of 1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol: bridged analogues of physostigmine

Abstract The synthesis and carbamoylation of 2,6-methano-1,3-benzodiazocin-8-ol is described. A one pot silyl-aryl ether to carbamate transformation was developed. The compounds are analogues of the cholinesterase inhibitor physostigmine.

Preparation of 6-fluorobenzisothiazoles via a regioselective nucleophilic aromatic substitution reaction

Abstract An efficient three step procedure for the preparation of 6-fluoro-1,2-benzisothiazoles is described. The key step is a regioselective nucleophilic aromatic substitution reaction in which the carbonyl group of a ketone or aldehyde directs nucleophilic displacement to the ortho position in preference to the para position.

P11467: An Orally-Active Acetylcholinesterase Inhibitor and α 2 -Adrenoceptor Antagonist for Alzheimer’s Disease

Alzheimer’s disease (AD) is a complex and multifaceted neurodegenerative disease characterized by cognitive and behavioral abnormalities. The primary cognitive deficit has been correlated with extensive cholinergic dysfunction and the efficacy of cholinergic therapies in this disease validates and supports the cholinergic hypothesis of AD (Weinstock, 1995). To date, tacrine has shown clinical efficacy in 20 to 30% of AD patients and remains the only acetylcholinesterase inhibitor (AChEI) to receive FDA approval for symptomatic treatment (Knapp et al., 1994). However, the limited efficacy of pure cholinergic therapies suggests that other neurochemical deficiencies are involved.