ABSTRACT
A three-component method for the synthesis of γ-lactams from commercially available maleimides, aldehydes, and amines was adapted to parallel library synthesis. Improvements to the chemistry over previous efforts include the optimization of the method to a one-pot process, the management of by-products and excess reagents, the development of an automated parallel sequence, and the adaption of the method to permit the preparation of enantiomerically enriched products. These efforts culminated in the preparation of a library of 169 γ-lactams.
ABSTRACT
The palladium-catalyzed nucleophilic substitution of (coumarinyl)methyl acetates is described. The reaction proceeds though a palladium π-benzyl-like complex and allows for many different types of C-, N-, and S-nucleophiles to be regioselectively added to the biologically active coumarin motif. This new method was utilized to prepare a 128-membered library of aminated coumarins for biological screening.
ABSTRACT
A tandem Prins/Friedel-Crafts reaction useful for the construction of the indeno-tetrahydropyridine core of the haouamine alkaloids and a formal synthesis of (-)-haouamine A are described.
Subject(s)
Alkaloids/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Alkaloids/chemistry , Animals , Heterocyclic Compounds, 4 or More Rings/chemistry , Molecular Structure , Stereoisomerism , Urochordata/chemistryABSTRACT
The construction of a 225-member (3 × 5 × 15) library of thiadiazepan-1,1-dioxide-4-ones was performed on a Chemspeed Accelerator (SLT-100) automated parallel synthesis platform, culminating in the successful preparation of 184/225 sultams. Three sultam core scaffolds were prepared based upon the utilization of an aza-Michael reaction on a multifunctional vinyl sulfonamide linchpin. The library exploits peripheral diversity in the form of a sequential, two-step [3 + 2] Huisgen cycloaddition/Pd-catalyzed Suzuki-Miyaura coupling sequence.
Subject(s)
Azepines/chemistry , Combinatorial Chemistry TechniquesABSTRACT
A synthetic approach to the A-B ring system within the fusicoccane family of diterpenes is presented. Key steps in this approach are a diastereoselective Pauson-Khand reaction, a Norrish 1 photofragmentation, a Charette cyclopropanation, and a ring-closing metathesis process.
Subject(s)
Diterpenes/chemical synthesis , Catalysis , Crystallography, X-Ray , Cyclization , Cyclopropanes/chemistry , Magnetic Resonance Spectroscopy , Photochemistry , StereoisomerismABSTRACT
The parallel synthesis of gamma-turn-inspired peptidomimetic libraries has been demonstrated through two approaches toward the preparation of 1,4-diazepin-5-ones. In the first approach, 1,4-diazepin-5-ones scaffolds were prepared on gram scale and subsequently diversified to produce libraries. In a second approach, libraries of 1,4-diazepin-5-ones were produced directly through a three-component strategy that maximizes the diversity obtained in a single step.
Subject(s)
Azepines/chemical synthesis , Molecular Mimicry , Peptides/chemistry , Acylation , Alkylation , Azepines/chemistryABSTRACT
Bicyclic iminium ethers can be synthesized by the reactions of ketones with hydroxyalkyl azides. These cationic species react with a variety of nucleophiles via two possible pathways. The initially formed, kinetic product arises from direct addition to the iminium carbon in the substrate. In some cases, the initial adduct reverts to the starting iminium ether and the ultimate product arises from nucleophilic displacement at the O-alkyl group to afford the terminally functionalized N-substituted amide. The behavior of a range of nucleophiles was studied by using several iminium ethers. In general, the relevant pathway could be identified by characterization of the product formed. For hydroxide addition, which can afford only one product regardless of mechanism, the reaction was shown to arise by the kinetic pathway, using (18)O-labeled hydroxide. A one-pot synthesis of functionalized lactams entailing treatment of ketones first with hydroxyalkyl azides followed by nucleophilic addition was also developed.
Subject(s)
Ethers/chemistry , Heterocyclic Compounds/chemical synthesis , Imines/chemistry , Ketones/chemical synthesis , Heterocyclic Compounds/chemistry , Ketones/chemistry , Molecular Structure , StereoisomerismABSTRACT
The conversion of sterically hindered carboxylic acids to N-methoxy-N-methyl amides can be efficiently carried out with 1.1 equiv of methanesulfonyl chloride, 3 equiv of triethylamine, and 1.1 equiv of N-methoxy-N-methylamine. Yields for this process range from 59% to 88%. The major byproduct in these reactions, N-methoxy-N-methylmethanesulfonamide, can be removed by placing the product mixture under vacuum for 14-24 h.
