Keitaro Suyama

Highly Enantioselective Hydrophosphonylation of Aldehydes: Base-Enhanced Aluminum–salalen Catalysis†

a-Hydroxy phosphonates and a-hydroxy phosphonic acids are an important class of molecules that are widely used in biological applications. The asymmetric hydrophosphonylation of aldehydes with phosphonates is a powerful and direct method for synthesizing enantioenriched a-hydroxy phosphonates. Thus, intense research has been devoted to developing highly enantioselective catalysts for this reaction, and it is now becoming an emerging area in organic chemistry. A variety of chiral Lewis acid and heterobimetallic catalysts have been reported and high enantioselectivities have been achieved. However, most of these methods require relatively high catalyst loading and a longer reaction time to obtain the products in acceptable yields. Dialkyl phosphonates exist in equilibrium between their phosphite and phosphonate forms. The phosphite form is thought to be the active species; however, under neutral conditions the equilibrium lies predominantly toward the phosphonate form, which leads to sluggish reactivity. Consequently, the facilitation of phosphite–phosphonate tautomerization is essential for achieving hydrophosphonylation with low catalyst loading. For example, Abell and Yamamoto utilized the reactive reagent (CF3CH2)2PO(OH) to achieve a highly enantioselective hydrophosphonylation with only 1 mol% of catalyst. Ooi and co-workers applied chiral triaminoiminophosphoranes as organic base catalysts and achieved high yield and enantioselectivity with low catalyst loading at 98 8C. 8] These results further highlighted the importance of rapid phosphite-phosphonate tautomerization. A simple technique for accelerating the phosphite– phosphonate tautomerization is the deprotonation of phosphonates using a base. However, the hydrophosphonylation of aldehydes is a well-known base-mediated process, and the participation of the base-mediated pathway is a critical problem for the enantioselective reaction. Nevertheless, we believed that a judicial choice of base and catalyst would facilitate the Lewis acid catalyzed asymmetric hydrophosphonylation reaction without eroding the enantioselectivity, presuming that the trapping of the phosphite anion by the catalyst and release of the hydrophosphonylation product could proceed rapidly enough for the catalytic process to exclusively occur before the non-catalytic process (Scheme 1). Herein, we report that inorganic bases significantly enhance the rate of reaction of the Al(salalen)catalyzed asymmetric hydrophosphonylation of aldehydes, in which high enantioselectivities ranging from 93 to 98 % ee were achieved for the reactions of both conjugated and nonconjugated aldehydes.

Asymmetric Lewis acid catalysis of aluminum(salalen) complexes: Friedel-Crafts reaction of indole

We examined the Lewis acid catalysis of chiral Al(salalen)X complexes and found that complex 1b (X = Br) serves as an efficient catalyst for the Friedel-Crafts reaction of indole with N-[(E)-alkenoyl]oxazolidin-2-ones. High enantioselectivity (up to 98% ee) was obtained under the optimized conditions.

Enhancement of Self-Aggregation Properties of Linear Elastin-Derived Short Peptides by Simple Cyclization: Strong Self-Aggregation Properties of Cyclo[FPGVG]n, Consisting Only of Natural Amino Acids

Elastin-like peptides (ELPs) consist of distinctive repetitive sequences, such as (VPGVG) n, exhibit temperature-dependent reversible self-assembly (coacervation), and have been considered to be useful for the development of thermoresponsive materials. Further fundamental studies evaluating coacervative properties of novel nonlinear ELPs could present design concepts for new thermoresponsive materials. In this study, we prepared novel ELPs, cyclic (FPGVG) n (cyclo[FPGVG] n, n = 1-5), and analyzed their self-assembly properties and structural characteristics. Cyclo[FPGVG] n ( n = 3-5) demonstrated stronger coacervation capacity than the corresponding linear peptides. The coacervate of cyclo[FPGVG]5 was able to retain water-soluble dye molecules at 40 °C, which implied that cyclo[FPGVG]5 could be employed as a base material of DDS (drug delivery system) matrices and other biomaterials. The results of molecular dynamics simulations and circular dichroism measurements suggested that a certain chain length was required for cyclo[FPGVG] n to demonstrate alterations in molecular structure that were critical to the exhibition of coacervation.

Stepwise Mechanism of Temperature-Dependent Coacervation of the Elastin-like Peptide Analogue Dimer, (C(WPGVG)3)2

Elastin-like peptides (ELPs) are distinct, repetitive, hydrophobic sequences, such as (VPGVG) n, that exhibit coacervation, the property of reversible, temperature-dependent self-association and dissociation. ELPs can be found in elastin and have been developed as new scaffold biomaterials. However, the detailed relationship between their amino acid sequences and coacervation properties remains obscure because of the structural flexibility of ELPs. In this study, we synthesized a novel, dimeric ELP analogue (H-C(WPGVG)3-NH2)2, henceforth abbreviated (CW3)2, and analyzed its self-assembly properties and structural factors as indicators of coacervation. Turbidity measurements showed that (CW3)2 demonstrated coacervation at a concentration much lower than that of its monomeric form and another ELP. In addition, the coacervate held water-soluble dye molecules. Thus, potent and distinct coacervation was obtained with a remarkably short sequence of (CW3)2. Furthermore, fluorescence microscopy, dynamic light scattering, and optical microscopy revealed that the coacervation of (CW3)2 was a stepwise process. The structural factors of (CW3)2 were analyzed by molecular dynamics simulations and circular dichroism spectroscopy. These measurements indicated that helical structures primarily consisting of proline and glycine became more disordered at high temperatures with concurrent, significant exposure of their hydrophobic surfaces. This extreme change in the hydrophobic surface contributes to the potent coacervation observed for (CW3)2. These results provide important insights into more efficient applications of ELPs and their analogues, as well as the coacervation mechanisms of ELP and elastin.

Dimerization effects on coacervation property of an elastin-derived synthetic peptide (FPGVG)5

Elastin, a core protein of the elastic fibers, exhibits the coacervation (temperature‐dependent reversible association/dissociation) under physiological conditions. Because of this characteristic, elastin and elastin‐derived peptides have been considered to be useful as base materials for developing various biomedical products, skin substitutes, synthetic vascular grafts, and drug delivery systems. Although elastin‐derived polypeptide (Val‐Pro‐Gly‐Val‐Gly)n also has been known to demonstrate coacervation property, a sufficiently high (VPGVG)n repetition number (n > 40) is required for coacervation. In the present study, a series of elastin‐derived peptide (Phe‐Pro‐Gly‐Val‐Gly)5 dimers possessing high coacervation potential were newly developed. These novel dimeric peptides exhibited coacervation at significantly lower concentrations and temperatures than the commonly used elastin‐derived peptide analogs; this result suggests that the coacervation ability of the peptides is enhanced by dimerization. Circular dichroism (CD) measurements indicate that the dimers undergo similar temperature‐dependent and reversible conformational changes when coacervation occurs. The molecular dynamics calculation results reveal that the sheet‐turn‐sheet motif involving a type II β‐turn‐like structure commonly observed among the dimers and caused formation of globular conformation of them. These synthesized peptide dimers may be useful not only as model peptides for structural analysis of elastin and elastin‐derived peptides, but also as base materials for developing various temperature‐sensitive biomedical and industrial products. Copyright