Regioselective Ring‐Opening of Amino Acid‐Derived Chiral Aziridines: an Easy Access to cis‐2,5‐Disubstituted Chiral Piperazines

An efficient four‐step synthetic strategy for cis‐2,5‐disubstituted chiral piperazines derived from amino‐acid‐based aziridines is described. The key steps in this strategy are the highly regioselective boron trifluoride diethyl etherate (BF₃ ⋅ OEt₂)‐mediated ring‐opening of less‐reactive N‐Ts chiral aziridines by α‐amino acid methyl ester hydrochloride followed by Mitsunobu cyclization. This protocol has been used in an attempt to construct the piperazine core framework of natural product (+)‐piperazinomycin.     

α‐Amino Acid‐Isosteric α‐Amino Tetrazoles

The synthesis of all 20 common natural proteinogenic and 4 otherα‐amino acid‐isosteric α‐amino tetrazoles has been accomplished, whereby the carboxyl group is replaced by the isosteric 5‐tetrazolyl group. The short process involves the use of the key Ugi tetrazole reaction followed by deprotection chemistries. The tetrazole group is bioisosteric to the carboxylic acid and is widely used in medicinal chemistry and drug design. Surprisingly, several of the common α‐amino acid‐isosteric α‐amino tetrazoles are unknown up to now. Therefore a rapid synthetic access to this compound class and non‐natural derivatives is of high interest to advance the field.     

Chiral Amino Acids‐Derived Catalysts and Ligands

Transforming amino acids into novel catalysts and ligands is a remarkable subset of new catalyst development in order to imitate enzymatic efficiencies. Their ability to perform a variety of asymmetric catalytic reactions is complimented by their ready availability, rich transformations, stability and easy procedure. Herein, we focused on describing our endeavor of developing new catalysts and ligands from primary and secondary amino acids. It includes C₂‐symmetric N,N'‐dioxides, guanidine‐amides, bispidine‐based diamines, and other organic salts. The account covered a brief introduction about their discovery, representative applications and related mechanisms.     

Organocatalysts Derived from Unnatural α‐Amino Acids: Scope and Applications

The organocatalytic properties of unnatural α‐amino acids are reviewed. Post‐translational derivatives of natural α‐amino acids include 4‐hydroxy‐l ‐proline and 4‐amino‐l ‐proline scaffolds, and also proline homologues. The activity of synthetic unnatural α‐amino acid‐based organocatalysts, such as β‐alkyl alanines, alanine‐based phosphines, and tert‐leucine derivatives, are reviewed herein. The organocatalytic properties of unnatural monocyclic, bicyclic, and tricyclic proline derivatives are also reviewed. Several families of these organocatalysts permit the efficient and stereoselective synthesis of complex natural products. Most of the reviewed organocatalysts accelerate the reported reactions through covalent interactions that raise the HOMO (enamine intermediates) or lower the LUMO (iminium intermediates).     

Amino Acid‐Specific,Ribonucleotide‐Promoted Peptide Formation in the Absence of Enzymes

Nucleic acids and polypeptides are at the heart of life. It is interesting to ask whether the monomers of these biopolymers possess intrinsic reactivity that favors oligomerization in the absence of enzymes. We have recently observed that covalently linked peptido RNA chains form when mixtures of monomers react in salt‐rich condensation buffer. Here, we report the results of a screen of the 20 proteinogenic amino acids and four ribonucleotides. None of the amino acids prevent phosphodiester formation, so all of them are compatible with genetic encoding through RNA chain growth. A reactivity landscape was found, in which peptide formation strongly depends on the structure of the amino acid, but less on the nucleobase. For example, proline gives ribonucleotide‐bound peptides most readily, tyrosine favors pyrophosphate and phosphodiester formation, and histidine gives phosphorimidazolides as dominant products. When proline and aspartic acid were allowed to compete for incorporation, only proline was found at the N‐terminus of peptido chains. The reactivity described here links two fundamental classes of biomolecules through reactions that occur without enzymes, but with amino acid specificity.     

Seeded Polymerization through the Interplay of Folding and Aggregation of an Amino‐Acid‐based Diamide

Amino acid based diamides are widely used as a substructure in supramolecular polymers and are also key components of polypeptides that help to understand protein folding. The interplay of folding and aggregation of a diamide was used to achieve seed‐initiated supramolecular polymerization. For that purpose, a pyrene‐substituted diamide was synthesized in which pyrene is used as a tracer to monitor the supramolecular polymerization. Thermodynamics and time‐dependent studies revealed that the folding of the diamide moiety, via the formation of intramolecular hydrogen bonds, effectively prevents a spontaneous nucleation that leads to supramolecular polymerization. Under such out‐of‐equilibrium conditions, the addition of seeds successfully initiates the supramolecular polymerization. These results demonstrate the utility of such amino acid based diamides in programmable supramolecular polymerizations.     

Lewis Acid‐Mediated Addition of Amino Acid‐Substituted α‐Allylsilanes to Aromatic Acetals

Unnatural amino acids extend the pharmacological formulator's toolkit. Strategies to prepare unnatural amino acid derivatives using Lewis acid‐activated allylsilane reactions are few. In this regard, we examined the utility of allylsilanes bearing an amino acid substituent in the reaction. Diastereoselective addition of methyl 2‐(N‐PG‐amino)‐3‐(trimethylsilyl)pent‐4‐enoate and methyl (E)‐2‐(N‐PG‐amino)‐3‐(trimethylsilyl)hex‐4‐enoate (PG=protecting group), 2 and 13 , respectively, to aromatic acetals in the presence of Lewis acids is described. Of those examined, TiCl₄ was found to be the most effective Lewis acid for promoting the addition. At least 1 equiv. of TiCl₄ was required to achieve high yields, whereas 2 equiv. of BF₃?OEt₂ were required for comparable outcomes. Excellent selectivity (>99% syn/anti) and high yield (up to 89%) were obtained with halo‐substituted aromatic acetals, while more electron‐rich electrophiles led to both lower yields and diastereoselectivities.     

Helical poly(phenylacetylene) derived from L‐tyrosine: A promising candidate for functional helical polymers carrying transformable N‐ and C‐termini

A novel optically active phenylacetylene derivative, N‐(tert‐butoxycarbonyl)‐4‐ethynyl‐L ‐phenylalanine methyl ester ( 1 ), was synthesized from L ‐tyrosine and polymerized with a rhodium catalyst. The corresponding polymer [poly( 1 )] with a moderate molecular weight was obtained in a high yield. The alkaline hydrolysis of poly( 1 ) gave poly[N‐(tert‐butoxycarbonyl)‐4‐ethynyl‐L ‐phenylalanine] [poly( 2 )] carrying free carboxy groups. Polarimetric, CD, and UV–vis spectroscopy analyses revealed that poly( 1 ) took a predominantly one‐handed helical structure in MeOH and toluene, and poly( 2 ) took a helical structure in MeOH. The secondary structures of poly( 1 ) and poly( 2 ) could be tuned with heat and solvents. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 1691–1698, 2007     

Polymorphism of Amino Acid‐Based Dendrons: From Organogels to Microcrystals

There is a delicate balance for a low‐weight molecule to behave as a gelator or crystal. The synthesis of two novel amino acid‐based naphthalene‐dendrons, Nap ‐ G1 and Nap ‐ G2 is described. Both dendrons display polymorphic properties in organic solvents. Nap ‐ G1 developed a fibrous network with β‐sheet architecture in cyclohexane but exhibited a spherulitic network in mixed solvents (chloroform/petroleum ether 1:5, v/v). On the other hand, Nap ‐ G2 acted as an efficient organogelator in chloroform but formed crystalline fibers in relatively high polarity solvents (such as acetone and methanol). Combinations of characterizations have been employed to study the polymorphism.     

Synthesis and chiroptical properties of L‐valine‐containing poly(phenylacetylene)s with (a)chiral pendant terminal groups

Poly(phenylacetylene)s containing L ‐valine residues (P 1 ) with (a)chiral pendant terminal groups R^(*) [?(HC?C{C₆H₄CONHCH[CH(CH₃)₂]COO? R^(*)})_n?]; R^(*) = 1‐octyl (P 1 o), (1S,2R,5S)‐(+)‐menthyl [P 1 (+)], (1R,2S,5R)‐(?)‐menthyl [P 1 (?)] are designed and synthesized. The polymers are prepared by organorhodium catalysts in high yields (yield up to 88%) with high molecular weights (M_w up to ?6.4 × 10⁵). Their structures and properties are characterized by NMR, IR, TGA, UV, and circular dichroism analyses. All the polymers are thermally fairly stable (T_d ≥ 320 °C). The chiral moieties induce the poly(phenylacetylene) chains to helically rotate in a preferred direction. The chirality of the pendant terminal groups affects little the helicity of the polymers but their bulkiness stabilizes the helical conformation against solvent perturbation. The backbone conjugation and chain helicity of the polymers can be modulated continuously and reversibly by acid. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 2117–2129, 2006     

Spontaneous Formation of Biocompatible Vesicles in Aqueous Mixtures of Amino Acid‐Based Cationic Surfactants and SDS/SDBS

The spontaneous formation of vesicles by six amino acid‐based cationic surfactants and two anionic surfactants (sodium dodecylbenzene sulfonate (SDBS) and sodium dodecyl sulfate (SDS)) is reported. The head‐group structure of the cationic surfactants is minutely altered to understand their effect on vesicle formation. To establish the regulatory role of the aromatic group in self‐aggregation, both aliphatic and aromatic side‐chain‐substituted amino acid‐based cationic surfactants are used. The presence of aromaticity in any one of the constituents favors the formation of vesicles by cationic/anionic surfactant mixtures. The formation of vesicles is primarily dependent on the balance between the hydrophobicity and hydrophilicity of both cationic and anionic surfactants. Vesicle formation is characterized by surface tension, fluorescence anisotropy, transmission electron microscopy, dynamic light scattering, and phase diagrams. These vesicles are thermally stable up to 65 °C, determined by temperature‐dependent fluorescence anisotropy. According to the MTT assay, these catanionic vesicles are nontoxic to NIH3T3 cells, thus indicating their wider applicability as delivery vehicles to cells. Among the six cationic surfactants examined, tryptophan‐ and tyrosine‐based surfactants have the ability to reduce HAuCl₄ to gold nanoparticles (GNPs), which is utilized to obtain in‐situ‐synthesized GNPs entrapped in vesicles without the need for any external reducing agent.     

Asymmetric Synthesis of All Four Isomers of an Unusual Heterocycle‐Containing Amino Acid: 2‐Amino‐3‐furan‐2‐yl‐pentanoic Acid

All four isomers of a novel β‐branched unusual amino acid were designed and synthesized with high stereoselectivity (>90% de) and in 33% –44% overall yields by the use of 4(R/S)‐5,5‐dimethyl‐4‐phenyl‐oxazolidin‐2‐one as the chiral auxiliary via asymmetric 1,4‐Michael addition, direct or indirect azidation, hydrolysis and hydrogenation reactions.     

Boosting the Peroxidase‐like Activity of Cobalt Ions by Amino Acid‐based Biological Species and Its Applications

Enzyme mimics have been widely used as alternatives to natural enzymes, owing to their high stability and low cost. However, the activity and atom economy of enzyme mimics still need to be improved. Herein, we report the boosting effects of amino acids, peptides and proteins on the peroxidase‐like activity of Co²⁺. Among 20 amino acids, tryptophan (Trp) enhanced the activity of Co²⁺ approximately 8 times and was identified as the best stimulator. The study revealed the synergy of amino acids‐based species and HCO₃^? for efficient catalysis. Co²⁺ is proposed to bind simultaneously to HCO₃^? and Trp, and to form a ternary catalyst which facilitates the generation of reactive oxygen species. Based on the selective boosting by Trp, a simple and low‐cost Co²⁺ sensor with high sensitivity was developed, which showed a linear range of 10–300 μM and a limit of detection of 0.4 μM for Co²⁺.     

Helical Substituted Polyacetylene‐Derived Fluorescent Microparticles Prepared by Precipitation Polymerization

This article reports the first fluorescent microparticles (MPs, approximately 600 nm in diameter) constructed using helical substituted polyacetylene and prepared via a precipitation polymerization approach. The MPs judiciously combine this interesting helical conjugated acetylene, fluorescent material and polymeric particles in one entity. The monomer containing a dansyl group undergoes precipitation polymerization in butanone/n‐heptane mixed solvent, with (nbd)Rh⁺B⁻(C₆H₅)₄ as a catalyst. MPs with a regular morphology are formed in a high yield (>80 wt%). UV‐vis spectroscopy demonstrates that the polymer chains making up the MPs adopt helical structures. The MPs show considerable fluorescence emission (λ_max, 500 nm; excited at 340 nm). Based on SEM and fluorescence images, the formation mechanism of the MPs is proposed. This methodology opens up new ways to prepare functional microstructured materials derived from substituted polyacetylenes, and may also result in opportunities for new practical applications of polyacetylene and its derivatives.

     

Multiply Nitrated High‐Energy Dense Oxidizers Derived from the Simple Amino Acid Glycine

Various energetic polynitro esters, carbamates, and nitrocarbamates that were derived from the amino acid glycine were fully characterized by single‐crystal X‐ray diffraction, vibrational spectroscopy (IR and Raman), multinuclear NMR spectroscopy, elemental analysis, and differential scanning calorimetry (DSC). Owing to their positive oxygen balance, the suitability of these compounds as potential oxidizers in energetic formulations was investigated and discussed. In addition, the heats of formation of the products were calculated by using the Gaussian 09 program package at the CBS‐4M level of theory. From these values and the calculated densities (from the X‐ray data), several detonation parameters, such as detonation pressure, velocity, energy, and temperature, were computed by using the EXPLO5 code. Furthermore, their sensitivities towards impact, friction, and electrostatic discharge were tested by using a drop hammer, a friction tester (both BAM certified), and a small‐scale electrical‐discharge device, respectively.     

Recent Advances in the Base‐Induced Sommelet–Hauser Rearrangement of Amino Acid Derived Ammonium Ylides

The Sommelet–Hauser rearrangement of N‐benzylic ammonium ylides generated from ammonium salts is an interesting and useful transformation that enables one to convert a readily accessible C–N bond into a new C–C bond to an aromatic ring. The rearrangement was discovered by Sommelet in 1937, studied in detail by Hauser, and applied to organic synthesis by Sato until 1999. Further studies have not advanced because several competitive side reactions and structural limitations of the products severely limit the substrate scope and synthetic applications. In this Personal Account, a history of the research in problem solving and recent advances in the base‐induced Sommelet–Hauser rearrangement are described. This synthetic method developed by my group provides efficient access to various types of α‐aryl‐α‐amino acid and α‐aryl‐β‐amino acid derivatives.