One of the initial steps in the development of therapeutic agents is the identification of lead compounds that bind to the receptor or enzyme target of interest. Many analogs of these lead compounds are then synthesized to define the key recognition elements for maximal activity. In general, many compounds must be evaluated in both the lead identification and optimization steps. Increasing burdens have been placed on these efforts due to the large number of new therapeutic targets that continue to be identified thorough modern molecular biology methods.1 To address this demand, very powerful chemical and biological methods have been developed for the generation of large combinatorial libraries of peptides2 and oligonucleotides3 that are then screened against a receptor or enzyme to identify high-affinity ligands or potent inhibitors, respectively. While these studies have clearly demonstrated the power of library synthesis and screening strategies, peptides and oligonucleotides generally have poor oral activities and rapid in vivo clearance;4 therefore their utility as bioavailable therapeutic agents is often limited. Due to the favorable pharmacokinetic properties of many small organic molecules (<600-700 molecular weight),5 the design, synthesis, and evaluation of libraries of these compounds6 has rapidly become a major frontier in organic chemistry. Lorin A. Thompson was born in Lexington, KY, in 1970. He received the Bachelor of Science degree from the University of North Carolina, Chapel Hill, in 1992 where he worked under the guidance of Joseph Desimone. He is currently pursuing his doctorate in the laboratory of Jonathan Ellman at UC Berkeley where he is the 1994 Glaxo-Wellcome fellow. His research interests include the development of synthetic methodology for organic library construction.

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Synthesis and Applications of Small Molecule Libraries.

This review summarizes research directed towards the formation of carbocyclic adducts from donor–acceptor cyclopropanes. The focus of the review is on annulation and cycloaddition reactions (both inter- and intramolecularly) mediated by Lewis or protic acid, bases, or thermal conditions. Rearrangements resulting in carbocycles and those reactions mediated by transition metal catalysis have been excluded.

Carbocycles from donor–acceptor cyclopropanes

Synthesis of Polyquinane Natural Products: An Update.

Design, Synthesis, and Evaluation of Small-Molecule Libraries

This full account presents the background on, discovery of, and extensive insight that has been gained into the oxidative intermolecular coupling of two different carbonyl species. Optimization of this process has culminated in reliable and scalable protocols for the union of amides, imides, ketones, and oxindoles using soluble copper(II) or iron(III) salts as oxidants. Extensive mechanistic studies point to a metal-chelated single-electron-transfer process in the case of copper(II), while iron(III)-based couplings appear to proceed through a non-templated heterodimerization. This work presents the most in-depth findings on the mechanism of oxidative enolate coupling to date. The scope of oxidative enolate heterocoupling is extensive (40 examples) and has been shown to be efficient even on a large scale (gram-scale or greater). Finally, the method has been applied to the total synthesis of the unsymmetrical lignan lactone (-)-bursehernin and a medicinally important 2,3-disubstituted succinate derivative.

Intermolecular Enolate Heterocoupling: Scope, Mechanism, and Application

A novel one-flask cyclopentannulation involving a dilithiomethane equivalent as a β-connector of two enones. A highly efficient total synthesis of (±)-hirsutene

Regioselective Preparation of 4-Formyl-3,5-dimethoxyphenol, an Intermediate in the Synthesis of the PAL Solid-Phase Peptide Synthesis Handle

A process for the preparation of a tautomeric mixture of compounds of formulae
    wherein W is hydrogen or C₆H₁₃, 
which comprises treating a compound of the formula
 wherein R is unsubstituted or substituted alkoxy, arylalkoxy, aryloxy or amine and R¹ is hydrogen or when R is alkoxy, substituted alkoxy, substituted amine, unsubstituted or substituted arylalkoxy R¹ can also be metal, with a compound of formula
    wherein one of X and Y is a reducible group and the other is hydrogen or a reducible group, and Z is hydroxy or a leaving group, 
and the obtained compound of formula
 is treated with a low valent metal to form a tautomeric mixture of compounds of formulas I and Ia, which are useful in the synthesis of tetrahydrolipstatin.

Process for the preparation of pyranones and pyrandiones

A process for the preparation of a tautomeric mixture of compounds of the formulas ##STR1## wherein W is hydrogen or C6 H13, which comprises treating a compound of the formula ##STR2## wherein R is unsubstituted or substituted alkoxy, arylalkoxy, aryloxy or amine and R1 is hydrogen or when R is alkoxy, substituted alkoxy, substituted amine, unsubstituted or substituted arylalkoxy R1 can also be metal, with a compound of the formula ##STR3## wherein W is as described above, both X and Y are reducible groups or X is hydrogen and Y is a reducible group or Y is hydrogen and X is a reducible group and, Z is hydroxy or a leaving group to form the compound of formula IV ##STR4## wherein W, X, Y and R are as defined above, the compound of formula IV is treated with a low valent metal to form a tautomeric mixture of compounds of formulas I and Ia, which are useful in the synthesis of tetrahydrolipstatin.

John J. Landi

Papers

A novel one-flask cyclopentannulation involving a dilithiomethane equivalent as a β-connector of two enones. A highly efficient total synthesis of (±)-hirsutene

Regioselective Preparation of 4-Formyl-3,5-dimethoxyphenol, an Intermediate in the Synthesis of the PAL Solid-Phase Peptide Synthesis Handle

Process for the preparation of pyranones and pyrandiones

Process for the preparation of (R)-3-hexyl-5,6-dihydro-4-hydroxy-6-undecyl-2H-pyran-2-one and (R)-5,6-dihydro-6-undecyl-2H-pyran-2,4 (3H)-dione

The Use of P-Toluenesulfonic Acid for Removal of the N-T-Butoxy-Carbonyl Protecting Group in Solid Phase Peptide Synthesis