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.     

Facile Synthesis of Internal and C‐Terminal Peptide α‐Ketoamides with Fmoc‐Solid Phase Peptide Synthesis

We report a general and operationally simple method for the solid phase synthesis of α‐ketoamide peptides using standard Fmoc solid phase peptide synthesis. The method delivers deprotected peptide α‐ketoamides directly upon resin cleavage without any additional steps, and tolerates all side chain functional groups. A small collection of C‐terminal and internal α‐ketoamide peptides – including two reported protease inhibitors (HCV and SUB1) – were prepared in good yields. In addition, we demonstrate that our method serves as versatile platform for the convenient preparation of cyclic α‐ketoamide peptides, photocagged peptide α‐ketoamides, and fluorescently labeled peptides.     

Enantioselective Solid‐Phase Peptide Synthesis Using Traceless Chiral Coupling Reagents and Racemic Amino Acids

The enantioselective condensing reagent 4,6‐dimethoxy‐1,3,5‐triazine (DMT)/strychnine/BF$\rm{{_{4}^{-}}}$ was obtained by treatment of 2‐chloro‐4,6‐dimethoxy‐1,3,5‐triazine (CDMT) with strychnine tetrafluoroborate. The reagent was useful under typical conditions of solid‐phase peptide synthesis (SPPS) with enantiomerically homogeneous substrates. By SPPS, desired dipeptides were obtained in 84–94% yield using 4 equiv. of racemic Fmoc‐Ala, Fmoc‐Phe, and/or Fmoc‐Tyr for 1 equiv. of Wang resin loaded with Gly, Ala, Leu, Phe, Glu(^tBu), and/or Pro, respectively. For all three Fmoc‐protected amino acids, the configuration of the enantiomer preferred under SPPS conditions was independent of the structure of the acylated component and identical to that established in condensations proceeding in solution. In all cases, the enantiomer ratios L /D (er) were in a similar range, and varied from 9 : 92 to 2 : 98 for alanine, and from 90 : 10 to 100 : 0 for aromatic amino acids. The synthesis of Ac‐L ‐Lys(Ac)‐D ‐Ala‐D ‐Ala‐OH from racemic Fmoc‐Ala gave an L /D ratio of 10 : 90 for the esterification of Wang resin, and 0 : 100 for the formation of peptide bonds.     

Quaternary β2,2‐Amino Acids: Catalytic Asymmetric Synthesis and Incorporation into Peptides by Fmoc‐Based Solid‐Phase Peptide Synthesis

β‐Amino acid incorporation has emerged as a promising approach to enhance the stability of parent peptides and to improve their biological activity. Owing to the lack of reliable access to β^2,2‐amino acids in a setting suitable for peptide synthesis, most contemporary research efforts focus on the use of β³‐ and certain β^2,3‐amino acids. Herein, we report the catalytic asymmetric synthesis of β^2,2‐amino acids and their incorporation into peptides by Fmoc‐based solid‐phase peptide synthesis (Fmoc‐SPPS). A quaternary carbon center was constructed by the palladium‐catalyzed decarboxylative allylation of 4‐substituted isoxazolidin‐5‐ones. The N?O bond in the products not only acts as a traceless protecting group for β‐amino acids but also undergoes amide formation with α‐ketoacids derived from Fmoc‐protected α‐amino acids, thus providing expeditious access to α‐β^2,2‐dipeptides ready for Fmoc‐SPPS.     

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.     

Automated Solid‐Phase Synthesis of a β‐(1,3)‐Glucan Dodecasaccharide

β‐Glucans are a group of structurally heterogeneous polysaccharides found in bacteria, fungi, algae and plants. β‐(1,3)‐D ‐Glucans have been studied in most detail due to their impact on the immune system of vertebrates. The studies into the immunomodulatory properties of these glucans are typically carried out with isolates that contain a heterogeneous mixture of polysaccharides of different chain lengths and varying degrees of branching. In order to determine the structure–activity relationship of β‐(1,3)‐glucans, access to homogeneous, structurally‐defined samples of these oligosaccharides that are only available through chemical synthesis is required. The syntheses of β‐glucans reported to date rely on the classical solution‐phase approach. We describe the first automated solid‐phase synthesis of a β‐glucan oligosaccharide that was made possible by innovating and optimizing the linker and glycosylating agent combination. A β‐(1,3)‐glucan dodecasaccharide was assembled in 56 h in a stereoselective fashion with an average yield of 88 % per step. This automated approach provides means for the fast and efficient assembly of linker‐functionalized mono‐ to dodecasaccharide β‐(1,3)‐glucans required for biological studies.     

Efficient Solid‐Phase Synthesis of Sulfotyrosine Peptides using a Sulfate Protecting‐Group Strategy

Double protection : Efficient Fmoc‐based solid‐phase synthesis (SPPS) of sulfotyrosine (sY) peptides is achieved by incorporating the sY residue(s) as a dichlorovinyl‐protected (DCV) sulfodiester(s) and using 2‐methylpiperidine for Fmoc removal. After removal of the other protecting groups, the DCV group could be cleaved by mild hydrogenolysis giving the sY peptides in good yield.

     

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.