Diphenylalanine

Smith AM, Williams RJ, Tang C et al (2008) Fmoc-diphenylalanine self assembles to a hydrogel via a novel architecture based on pi-pi interlocked beta-sheets. Adv Mater 20 37-41... 

The use of rhodium catalysts for the synthesis of a-amino acids by asymmetric hydrogenation of V-acyl dehydro amino acids, frequently in combination with the use of a biocatalyst to upgrade the enantioselectivity and cleave the acyl group which acts as a secondary binding site for the catalyst, has been well-documented. While DuPhos and BPE derived catalysts are suitable for a broad array of dehydroamino acid substrates, a particular challenge posed by a hydrogenation approach to 3,3-diphenylalanine is that the olefin substrate is tetra-substituted and therefore would be expected to have a much lower activity compared to substrates which have been previously examined. 

Although the asymmetric hydrogenation route to 3,3-diphenylalanine via this modified substrate preparation was not developed further, Dowpharma had a requirement to rapidly develop and scale up the manufacture of a related 3,3-diarylalanine product. The work to 3,3-diphenylalanine centred around substrate preparation and removal of impurities leading to high activity associated with the PhanePhos catalyst system allowed for a facile transfer from laboratory scale experiments to the commercial manufacture of the related diphenylalanine derivative by a robust, reproducible and scaleable procedure. 

FIGURE 5.16 AB3 self-immolative dendritic system with diphenylalanine end units and a trigger designed for activation by PGA. 

In order to evaluate the release and self-assembly of the diphenylalanine end groups, dendron 22 was incubated in PBS, pH 7.4, without PGA at a concentration of 1.5 mM. Transmission electron microscopy (TEM) analysis revealed that attachment of the diphenylalanine to the dendritic platform prevented self-assembly, and therefore, no organized structures were observed (Fig. 5.17a). Then, dendron... 

FIGURE 5.17 TEM micrographs of diphenylalanine peptide nanotubes self-assembled after the enzymatic cleavage, (a) TEM images of 22 prior to the enzymatic cleavage, (b and c) TEM images of 22 after the enzymatic cleavage. 

AB3 dendritic platform 23 functioned as an efficient carrier for the controlled formation of diphenylalanine nanotubes (Fig. 5.19). First, it prevented the formation of any organized structures when the peptides were attached. Second, the three units of diphenylalanine were rapidly released upon cleavage of the trigger. Finally, the platform allowed control of the release of the end units through a variety of triggering agents. 

FIGURE 5.19 Controlled formation of diphenylalanine peptide nanotubes. 

Tang C, Smith AM, Colhns RE, UUjn RV, Saiani A (2009) Fmoc-diphenylalanine self-assembly mechanism induces apparent pK(a) shifts. Langmuir 25 9447-9453... 

Figure 12.10 Formation of a silver nanowire inside a channel of a short-chain diphenylalanine peptide tube.

Figure 7 Scanning electron microscopy image of vertically aligned diphenylalanine-based peptide nanotubes assembled on a glass surface. The scale bar is 10 lm in length. Reprinted by permission from Macmillan Publishers Ltd., Nature Nanotechnology (Reches and Gazit, 2006), copyright 2006 (http //www.nature.com/nnano/index.html).

Larger patterned surfaces can also be achieved using inkjet printing. This technique has been used to create micron-sized letters of the alphabet containing diphenylalanine peptide nanotubes [tertbutoxycarbonyl-Phe-Phe-OH (Boc-Phe-Phe-OH)] on either transparent foil or indium-tin oxide (Adler-Abramovich and Gazit, 2008) as shown in Figure 13. This later... 

The diphenylalanine nanotube sensors were based on the observation that peptide nanotubes improve the electrochemical properties of graphite and gold electrodes when deposited directly onto the electrode surface (Yemini et al., 2005b). The high surface area of the nanotubes and the potential alignment of aromatic residues are thought to contribute to the observed increase in conductivity. This property makes nanotube-coated electrodes and hydrophobin-coated electrodes suitable for use as amperometric biosensors that produce a current in response to an electrical potential across two electrodes. 

Figure 18 Schematic of a glucose biosensor assembled from diphenylalanine peptide nanotubes. The enzyme GOX has been cross-linked to these nanotubes, which are further linked to the gold (Au) electrode and immobilized in a polyethyleneimine (PEI) matrix. The nanofibers act in two ways they immobilize the sensing enzyme and enhance the transducer. Reprinted in part with permission from Yemini et al. (2005a) (copyright 2005 American Chemical Society).

Other research has focused on the interaction of cells with peptide structures that assemble via aromatic interactions. Cells have been grown on the surface of gels formed by Fluorenylmethoxycarbonyl (FMOC) modified diphenylalanine nanotubes (Mahler et al., 2006). Although cells were only grown for short time frames (24 h), the cells were viable on these scaffolds. 

Gorbitz, C.H. The structure of nanotubes formed by diphenylalanine, the core recognition motif of Alzheimer s j8-amyloid polypeptide, ChemComm. 22 (2006) 2332-2334. 

The new diphenylalanine-derived oxazolidinone, 15, is particularly effective when used as an auxiliary on radical 29. The auxiliary can be used in a propagation sequence that involves radical addition followed by trapping of the addition radical with allylstannane or allylsilanes, Eq. (21). Excellent yield and diastereoselectivity are observed if the reaction is carried out in the presence of Lewis acids such as magnesium bromide or lanthanide triflates at —78°C. The reaction promoted by magnesium bromide, for example, provides a diastereomer mixture in excess of 100 1 with a yield of 85%. Sc, Yb, Y, La, or Sm triflates provide similar results in reactions usually carried out in ether. 

J. Ryu and C. B. Park, Synthesis of diphenylalanine/polyanihne core/sheU conducting nanowires by peptide self-assembly, Angew. Chem. Int. Ed., 48, 4820-4823 (2009). 

Reches M, Gazit E (2005) Self-assembly of peptide nanotubes and amyloid-like structures by charged-termini-capped diphenylalanine peptide analogues. Isr J Chem 45(3) 363-371... 

Peptide-based self-assembly is capable of synthesizing nanomaterials with various microstructures from tubes to spheres. Dipeptides, probably the simplest building blocks with a versatility in controlling microstructures, can form tubular, spherical, fibrous, or bundle, and array structures by modifying motifs on the dipeptides and/or altering synthesis conditions (Figure 6.4a). For example, the Alzheimer s p-amyloid peptide with diphenylalanine motif forms multiwaUed nanotubes when the peptide is... 

L-Diphenylalanine is a constrained amino acid which has been used for structure-activity studies on the tachykinin receptor.25.26 Despite its steric hindrance, this amino acid... 

---