Solid‐Phase Synthesis of Peptide Libraries Combining α‐Amino Acids with Inorganic and Organic Chromophores

The synthesis of two series of peptidic chains composed of bis(terpyridine)ruthenium(II) acceptor units and organic chromophores (coumarin, naphthalene, anthracene, fluorene) by stepwise solid‐phase peptide synthesis (SPPS) techniques is described. The first series of dyads comprises directly amide linked chromophores, while the second one possesses a glycine spacer between the two chromophores. All dyads were studied by UV/Vis and NMR spectroscopy, steady‐state luminescence, luminescence decay and electrochemistry, as well as by DFT calculations. The results of these studies indicate weak electronic coupling of the chromophores in the ground state. Absorpion spectra of all dyads are dominated by metal‐to‐ligand charge‐transfer (MLCT) bands around 500 nm. The bichromophoric systems, especially with coumarin as organic chromophore, display additional strong absorptions in the visible spectral region. All complexes are luminescent at room temperature (³MLCT). Efficient quenching of the fluorescence of the organic chromophore by the attached ruthenium complex is observed in all dyads. Excitation spectra indicate energy transfer from the organic dye to the ruthenium chromophore.     

Polyoxometalate Clusters Integrated into Peptide Chains and as Inorganic Amino Acids: Solution‐ and Solid‐Phase Approaches

General synthetic methods for the grafting of peptide chains onto polyoxometalate clusters by the use of general activated precursors have been developed. Using a solution‐phase approach, pre‐synthesized peptides can be grafted to a metal oxide cluster to produce hybrids of unprecedented scale (up to 30 residues). An adapted solid‐phase method allows the incorporation of these clusters, which may be regarded as novel hybrid unnatural amino acids, during the peptide synthesis itself. These methods may open the way for the automated synthesis of peptides and perhaps even proteins that contain “inorganic” amino acids.     

Synthesis of β3‐Homophenylalanine‐Derived Amino Acids and Peptides by Suzuki Coupling in Solution and on Solid Support

β‐Peptides and, to a certain extent, also mixed α,β‐peptides, are resistant to degradation by a variety of proteolytic enzymes that rapidly degrade natural α‐peptides. This is one of many characteristics that make β‐peptides an attractive class of compounds for drug‐discovery studies. On the other hand, modern organometallic reactions such as the Suzuki–Miyaura cross‐coupling have become standard tools in industry laboratories to derivatize side chains of α‐peptidic compounds to build up libraries of unnatural peptides. Combining both features, we prepared (4‐bromo)‐β³‐homophenylalanine derivatives 3 – 5 and 12 as precursors for Suzuki–Miyaura couplings. From these bromo compounds, we synthesized biaryl‐substituted β‐homoamino acids 6 , and analogs 13 and 15 of the anti‐AIDS drug Saquinavir.     

A Facile Solid‐Phase Synthesis of (+)‐(S)‐Clopidogrel

Enantiomerically pure (+)‐(S)‐clopidogrel was prepared by solid‐phase synthesis using the commercially available Wang resin. This method offers mild reaction conditions and provides the (+)‐(S)‐clopidogrel in overall 52% yield over six steps and with optical purity of 98.0% ee.     

Solid‐Phase Synthesis of 2‐Alkenamides from Polystyrene‐Supported α‐Selenocarboxylic Acids

The polystyrene‐supported α‐selenoacetic acid and α‐selenopropionic acid were prepared and used for the synthesis of 2‐alkenamides from primary and secondary amines in good yields and high purities.     

Mild and Efficient Synthesis of Carboxylic Acid Anhydrides from Carboxylic Acids and Triazine Coupling Reagents

Abstract

Anhydrides of carboxylic acids were obtained in 53%–95% yield by treatment of appropriate carboxylic acids with 2‐chloro‐4,6‐dimethoxy‐1,3,5‐triazine (CDMT) or 2,4‐dichloro‐6‐methoxy‐1,3,5‐triazine (DCMT) in the presence of N‐methylmorpholine. It has been proved that synthesis proceeds via triazine active esters 3a,b, which are able to acylate carboxylate anion but not less nucleophilic carboxylic acid.     

The ‘Azirine/Oxazolone Method’ on Solid Phase: Introduction of Various α,α‐Disubstituted α‐Amino Acids

Peptides containing various α,α‐disubstituted α‐amino acids, such as α‐aminoisobutyric acid (Aib), 1‐aminocyclopentane‐1‐carboxylic acid, α‐methylphenylalanine, and 3‐amino‐3,4,5,6‐tetrahydro‐2H‐pyran‐3‐carboxylic acid have been synthesized from the N‐ to the C‐terminus by the ‘azirine/oxazolone method’ under solid‐phase conditions. In this convenient method for the synthesis of sterically demanding peptides on solid‐phase, 2H‐azirin‐3‐amines are used to introduce the α,α‐disubstituted α‐amino acids without the need for additional reagents. Furthermore, the synthesis of poly(Aib) sequences has been explored.     

Preparation of the β2‐Homoselenocysteine Derivatives Fmoc‐(S)‐β2hSec(PMB)‐OH and Boc‐(S)‐β2hSec(PMB)‐OH for Solution and Solid‐Phase Peptide Synthesis

Fmoc‐β²hSer(^tBu)‐OH was converted to Fmoc‐β²hSec(PMB)‐OH in five steps. To avoid elimination of HSeR, the selenyl group was introduced in the second last step (Fmoc‐β²hSer(Ts)‐OAll→Fmoc‐β²hSec(PMB)‐OAll). In a similar way, the N‐Boc‐protected compound was prepared. With the β²hSe‐derivatives, 21 β²‐amino‐acid building blocks with proteinogenic side chains are now available for peptide synthesis.     

Solid‐Phase Organic Synthesis of Aryl Vinyl Ethers Using Sulfone‐Linking Strategy

A novel facile solid‐phase organic synthesis of aryl vinyl ethers by reaction of polystyrene‐supported 2‐phenylsulfonylethanol with phenols under Mitsunobu conditions and subsequent elimination reaction with DBU has been developed. The advantages of this method include straightforward operation, good yield and high purity of the products. Alternatively, a typical example of Suzuki coupling reaction on‐resin was further applied to prepare 4‐phenylphenyl vinyl ether for extending this method.