Pentannulation of N-heterocycles by a tandem gold-catalyzed [3,3]-rearrangement/Nazarov reaction of propargyl ester derivatives: a computational study on the crucial role of the nitrogen atom.

The tandem gold(I)-catalyzed rearrangement/Nazarov reaction of enynyl acetates in which the double bond is embedded in a piperidine ring was computationally and experimentally studied. The theoretical calculations predict that the position of the propargylic acetate substituent has a great impact on the reactivity. In contrast to our previous successful cyclization of the 2-substituted substrates, where the nitrogen favors the formation of the cyclized final product, the substitution at position 3 was computed to have a deleterious effect on the electronic properties of the molecules, increasing the activation barriers of the Nazarov reaction. The sluggish reactivity of 3-substituted piperidines predicted by the calculations was further confirmed by the results obtained with some designed substrates.

Pentannulation Reaction by Tandem Gold(I)-Catalyzed Propargyl Claisen Rearrangement/Nazarov Cyclization of Enynyl Vinyl Ethers.

The tandem gold(I)-catalyzed propargyl Claisen rearrangement/Nazarov cyclization of propargyl vinyl ether derivatives, followed by in situ reduction of the resulting carbonyl group, provides functionalized cyclopentadienes fused with various N-hetero- and carbacycles, including indoles, in good to excellent yields. The reaction occurs with high regioselectivity, with the position of the double bonds in the five-membered ring depending on the type of (hetero)cycle bearing the propargylic moiety and the side chain on the latter.

Construction of Cyclopenta[b]indol-1-ones by a Tandem Gold(I)-Catalyzed Rearrangement/Nazarov Reaction and Application to the Synthesis of Bruceolline H.

A tandem gold(I)-catalyzed rearrangement/Nazarov reaction of enynyl acetates which efficiently provides cyclopenta[b]indol-1-ones as useful precursors for the synthesis of natural and bioactive compounds is described. The synthetic potential of the methodology is demonstrated by the first total synthesis of bruceolline H.

Pentannulation of Heterocycles by Virtue of Precious Metal Catalysis.

Pentannulated heterocycles are the key structural subunit of many natural and biologically active compounds. Over the last decades, many precious metal-assisted pentannulations have been described as a consequence of an extensive research. This Focus Review gives an overview of precious metal-catalyzed reactions applied to the synthesis of cyclopenta-fused heterocycles in the last five years.

Cyclopropane pipecolic acids as templates for linear and cyclic peptidomimetics: application in the synthesis of an Arg-Gly-Asp (RGD)-containing peptide as an αvß3 integrin ligand.

The synthesis and evaluation of substituted cyclopropane pipecolic acids (CPA) as conformationally restricted templates for linear and cyclic peptidomimetics is reported. A variety of differently substituted (poly)hydroxy- and amino-2-azabicyclo[4.1.0]heptane-1-carboxylic acids were prepared by means of the Pd-catalyzed methoxycarbonylation of suitably functionalized lactam-derived enol phosphates, followed by OH-directed cyclopropanation. CPAs were successfully introduced into a linear peptide sequence to assess the cis/trans isomerism about the pipecolic acid peptide bond, and in a cyclic peptidomimetic that bore the Arg-Gly-Asp (RGD) sequence, which displayed nanomolar activity as antagonist of the αvß3 integrin in M21 human melanoma cells. Thus, CPAs appear to be suitable for the generation of novel peptidomimetics for drug discovery.

Methoxymethyl (MOM) group nitrogen protection of pyrimidines bearing C-6 acyclic side-chains.

Novel N-methoxymethylated (MOM) pyrimidine (4-13) and pyrimidine-2,4-diones (15-17) nucleoside mimetics in which an isobutyl side-chain is attached at the C-6 position of the pyrimidine moiety were synthesized. Synthetic methods via O-persilylated or N-anionic uracil derivatives have been evaluated for the synthesis of N-1- and/or N-3-MOM pyrimidine derivatives with C-6 acyclic side-chains. A synthetic approach using an activated N-anionic pyrimidine derivative afforded the desired N,N-1,3-diMOM and N-1-MOM pyrimidines 4 and 5 in good yield. Introduction of fluorine into the side-chain was performed with DAST as the fluorinating reagent to give a N,N-1,3-diMOM pyrimidine 13 with a 1-fluoro-3-hydroxyisobutyl moiety at C-6. Conformational study of the monotritylated N-1-MOM pyrimidine 12 by the use of the NOE experiments revealed the predominant conformation of the compound to be one where the hydroxymethyl group in the C-6 side-chain is close to the N-1-MOM moiety, while the OMTr is in proximity to the CH(3)-5 group. Contrary to this no NOE enhancements between the N-1-MOM group and hydroxymethyl or fluoromethyl protons in 13 were observed, which suggested a nonrestricted rotation along the C-6 side-chain. Fluorinated N,N-1,3-diMOM pyrimidine 13 emerged as a model compound for development of tracer molecules for non-invasive imaging of gene expression using positron emission tomography (PET).