Rapid and Mild Synthesis of Amino Acid N‐Carboxy Anhydrides: Basic‐to‐Acidic Flash Switching in a Microflow Reactor

Polymerization of N‐carboxy anhydrides (NCAs) is the primary process used to prepare polypeptides. The synthesis of various pure NCAs is key to the efficient synthesis of polypeptides. The only practical method that can be used to synthesize NCAs requires harsh acidic conditions that make acid‐labile substrates unusable and results in an undesired ring opening of NCAs. Basic‐to‐acidic flash switching and subsequent flash dilution technology in a microflow reactor was used to demonstrate the synthesis of NCAs. It is both rapid (0.1 s) and mild (20 °C) and includes substrates containing acid‐labile functional groups. The basic‐to‐acidic flash switching enabled both an acceleration of the desired NCA formation and avoided the undesired ring opening of NCAs. The flash dilution precluded the undesired decomposition of acid‐labile functional groups. The developed process allowed the synthesis of various NCAs which cannot be readily synthesized using conventional batch methods.     

Water‐Insensitive Synthesis of Poly‐β‐Peptides with Defined Architecture

Biocompatible and proteolysis‐resistant poly‐β‐peptides have broad applications and are dominantly synthesized via the harsh and water‐sensitive ring‐opening polymerization of β‐lactams in a glovebox or using a Schlenk line, catalyzed by the strong base LiN(SiMe₃)₂. We have developed a controllable and water‐insensitive ring‐opening polymerization of β‐amino acid N‐thiocarboxyanhydrides (β‐NTAs) that can be operated in open vessels to prepare poly‐β‐peptides in high yields, with diverse functional groups, variable chain length, narrow dispersity and defined architecture. These merits imply wide applications of β‐NTA polymerization and resulting poly‐β‐peptides, which is validated by the finding of a HDP‐mimicking poly‐β‐peptide with potent antimicrobial activities. The living β‐NTA polymerization enables the controllable synthesis of random, block copolymers and easy tuning of both terminal groups of polypeptides, which facilitated the unravelling of the antibacterial mechanism using the fluorophore‐labelled poly‐β‐peptide.     

Stereocontrolled Synthesis of syn‐β‐Hydroxy‐α‐Amino Acids by Direct Aldolization of Pseudoephenamine Glycinamide

β‐Hydroxy‐α‐amino acids figure prominently as chiral building blocks in chemical synthesis and serve as precursors to numerous important medicines. Reported herein is a method for the synthesis of β‐hydroxy‐α‐amino acid derivatives by aldolization of pseudoephenamine glycinamide, which can be prepared from pseudoephenamine in a one‐flask protocol. Enolization of (R,R)‐ or (S,S)‐pseudoephenamine glycinamide with lithium hexamethyldisilazide in the presence of LiCl followed by addition of an aldehyde or ketone substrate affords aldol addition products that are stereochemically homologous with L ‐ or D ‐threonine, respectively. These products, which are typically solids, can be obtained in stereoisomerically pure form in yields of 55–98 %, and are readily transformed into β‐hydroxy‐α‐amino acids by mild hydrolysis or into 2‐amino‐1,3‐diols by reduction with sodium borohydride. This new chemistry greatly facilitates the construction of novel antibiotics of several different classes.     

Palladium‐Catalyzed Oxidative Carbonylation of N‐Allylamines for the Synthesis of β‐Lactams

β‐Lactam scaffolds are considered to be ideal building blocks for the synthesis of nitrogen‐containing compounds. A new palladium‐catalyzed oxidative carbonylation of N‐allylamines for the synthesis of α‐methylene‐β‐lactams is reported. DFT calculations suggest that the formation of β‐lactams via a four‐membered‐ring transition state is favorable.     

Regioselective Synthesis of Some New Pyrazolo[1,5‐a]pyrimidines,Pyrazolo[1,5‐a]quinazoline and Pyrimido[4′,5′:3,4]pyrazolo[1,5‐a] pyrimidines Containing Thiazole Moiety

A regioselective synthesis of novel pyrazolo[1,5‐a]pyrimidines, pyrazolo[1,5‐a]quinazoline and pyrimido[4′,5′:3,4]pyrazolo[1,5‐a]pyrimidines incorporating a thiazole moiety was described via the reactions of the versatile, readily accessible 5‐amino‐3‐(phenylamino)‐N‐(4‐phenylthiazol‐2‐yl)‐1H‐pyrazole‐4‐carboxamide 3 with appropriate 1,3‐biselectrophilic reagents namely, β‐diketones, enaminones, and α,β‐unsaturated cyclic ketone. The newly synthesized compounds were elucidated by elemental analysis, spectral data, and alternative synthetic route whenever possible.     

Convenient and useful synthesis of N‐carboxyanhydride monomers through selective cyclization of urethane derivatives of α‐amino acids

A new convenient synthesis of N‐carboxyanhydrides (NCAs) of α‐amino acids was achieved by selective cyclization of urethane derivatives of α‐amino acids. The urethanes were readily synthesized via N‐carbamoylation of α‐amino acids by bis(4‐nitrophenyl)carbonate quantitatively. These urethanes having 4‐nitrophenoxy moiety were tolerant to air and moisture to allow their facile purification and storage. When the obtained urethanes were heated in 2‐butanone at 60 °C, they underwent the selective cyclization via intramolecular nucleophilic attack of the carboxyl moiety to the urethane moiety with releasing 4‐nitrophenol, leading to the successful formation of the corresponding NCAs. Addition of carboxylic acids remarkably stabilized the formed NCAs during the reaction, allowing their isolation in high yields. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 3839–3844, 2009     

New Approach to N‐substituted‐1,2,3,6‐tetrahydro‐pyridine‐4‐carbaldehyde,a Precursor for Synthesizing Aricept®, Isoguvacine,and Deethylibophyllidine

A new route towards the synthesis of N‐substituted‐4‐formylpiperidine using N‐benzyl or tryptaminyl‐sulfonylacetamide and α,β‐unsaturated ester as starting materials is described. Formal synthesis of Aricept^®, deethylibophyllidine, and isoguvacine, which have potential biological activities, were synthesized via this strategy.     

Synthesis of β‐Arylacyl/β‐Heteroarylacyl‐β‐alkylidene Malonates and Their Application in Substituted Pyridone Synthesis

A novel approach has been developed for the synthesis of β‐arylacyl/β‐heteroarylacyl‐β‐alkylidine malonates in moderate to good yields by the reaction of Stork aryl and heteroaryl enamine with β‐chloroalkylidene malonates. The reaction involves conjugate (Michael) addition of Stork enamine on β‐chloroalkylidene malonates and elimination of chloride ion. These Michael adducts were utilized as intermediates for the synthesis of highly substituted 1,4‐dialkyl‐2‐oxo‐6‐aryl/hetreoaryl‐1,2‐dihydro‐pyridine‐3‐carboxylic acid ethyl esters via 5 + 1 ring annulation protocol.     

Synthesis and Conformational Analysis of Hybrid α/β‐Dipeptides Incorporating S‐Glycosyl‐β2,2‐Amino Acids

We synthesized and carried out the conformational analysis of several hybrid dipeptides consisting of an α‐amino acid attached to a quaternary glyco‐β‐amino acid. In particular, we combined a S‐glycosylated β^2,2‐amino acid and two different types of α‐amino acid, namely, aliphatic (alanine) and aromatic (phenylalanine and tryptophan) in the sequence of hybrid α/β‐dipeptides. The key step in the synthesis involved the ring‐opening reaction of a chiral cyclic sulfamidate, inserted in the peptidic sequence, with a sulfur‐containing nucleophile by using 1‐thio‐β‐D ‐glucopyranose derivatives. This reaction of glycosylation occurred with inversion of configuration at the quaternary center. The conformational behavior in aqueous solution of the peptide backbone and the glycosidic linkage for all synthesized hybrid glycopeptides was analyzed by using a protocol that combined NMR experiments and molecular dynamics with time‐averaged restraints (MD‐tar). Interestingly, the presence of the sulfur heteroatom at the quaternary center of the β‐amino acid induced θ torsional angles close to 180° (anti). Notably, this value changed to 60° (gauche) when the peptidic sequence displayed aromatic α‐amino acids due to the presence of CH–π interactions between the phenyl or indole ring and the methyl groups of the β‐amino acid unit.     

Palladium‐Catalyzed [3+3] Annulation between Diarylamines and α,β‐Unsaturated Acids through CH Activation: Direct Access to 4‐Substituted 2‐Quinolinones

A C?H activation strategy has been successfully employed for the high‐yielding synthesis of a diverse array of 4‐substituted 2‐quinolinone species by a palladium‐catalyzed dehydrogenative coupling involving diarylamines. This intermolecular annulation approach incorporates readily available α,β‐unsaturated carboxylic acids as the coupling partner by suppressing the facile decarboxylation. Based on preliminary mechanistic studies, a reaction sequence is proposed, involving ortho palladation, π‐coordination, β‐migratory insertion, and β‐hydride elimination.     

β‐cyclodextrin‐based polymeric nano‐receptor: the self‐assembly of cyclodextrin‐appended comb‐copolymer

Well‐defined β‐cyclodextrin (β‐CD)‐appended biocompatible comb‐copolymer ethyl cellulose‐graft‐poly (ε‐caprolactone) (EC‐g‐PCL) was synthesized via the combination of ring‐opening polymerization (ROP) and click chemistry. The resulting products were characterized by ¹H NMR, FT‐IR spectroscopy, and GPC. The synthesized comb‐copolymer could assemble to micelles, with the surface covered by β‐CD. The inclusion with ferrocene derivation was investigated by cyclic voltammetric (CV) experiments, which indicated the potential application of the micelles as nano‐receptors for molecule recognization and controlled drug release. Copyright © 2011 John Wiley & Sons, Ltd.     

Synthesis of β‐Substituted γ‐Aminobutyric Acid Derivatives through Enantioselective Photoredox Catalysis

β‐Substituted chiral γ‐aminobutyric acids feature important biological activities and are valuable intermediates for the synthesis of pharmaceuticals. Herein, an efficient catalytic enantioselective approach for the synthesis of β‐substituted γ‐aminobutyric acid derivatives through visible‐light‐induced photocatalyst‐free asymmetric radical conjugate additions is reported. Various β‐substituted γ‐aminobutyric acid analogues, including previously inaccessible derivatives containing fluorinated quaternary stereocenters, were obtained in good yields (42–89 %) and with excellent enantioselectivity (90–97 % ee). Synthetically valuable applications were demonstrated by providing straightforward synthetic access to the pharmaceuticals or related bioactive compounds (S)‐pregabalin, (R)‐baclofen, (R)‐rolipram, and (S)‐nebracetam.     

Diphenylprolinol Silyl Ether Catalyzed Asymmetric Michael Reaction of Nitroalkanes and β,β‐Disubstituted α,β‐Unsaturated Aldehydes for the Construction of All‐Carbon Quaternary Stereogenic Centers

The asymmetric Michael reaction of nitroalkanes and β,β‐disubstituted α,β‐unsaturated aldehydes was catalyzed by diphenylprolinol silyl ether to afford 1,4‐addition products with an all‐carbon quaternary stereogenic center with excellent enantioselectivity. The reaction is general for β‐substituents such as β‐aryl and β‐alkyl groups, and both nitromethane and nitroethane can be employed. The addition of nitroethane is considered a synthetic equivalent of the asymmetric Michael reaction of ethyl and acetyl substituents by means of radical denitration and Nef reaction, respectively. The short asymmetric synthesis of (S)‐ethosuximide with a quaternary carbon center was accomplished by using the present asymmetric Michael reaction as the key step. The reaction mechanism that involves the E/Z isomerization of α,β‐unsaturated aldehydes, the retro‐Michael reaction, and the different reactivity between nitromethane and nitroethane is discussed.     

Benzylamine as Hydrogen Transfer Agent: Cobalt‐Catalyzed Chemoselective C=C Bond Reduction of β‐Trifluoromethylated α,β‐Unsaturated Ketones via 1,5‐Hydrogen Transfer

An efficient cobalt‐catalyzed chemoselective reduction of β‐CF₃‐α,β‐unsaturated ketones using benzylamine as hydrogen transfer agent involving intramolecular 1,5‐hydrogen transfer is reported. The reaction proceeded smoothly with a relatively wide range of substrates including those bearing aromatic heterocycles such as a furyl ring system in high yields (74–92 %). This provides an efficient method for the synthesis of β‐CF₃ saturated ketones in one‐pot. This methodology was also applied to the selective C=C reduction of other enone substrates bearing no β‐CF₃‐substituent, of which β‐substituted or β,β‐disubstituted enones are tolerated, giving the desired products in good yields (72–75 %). Mechanistic studies indicate that the reaction involves 1,5‐hydrogen transfer.     

Synthesis of polypeptides from activated urethane derivatives of α‐amino acids

A series of activated urethane‐type derivatives of α‐amino acids were synthesized and applied to polypeptide synthesis. The urethane used herein, N‐(4‐nitrophenoxycarbonyl)‐α‐amino acids 1 , were synthesized by N‐carbamoylation of γ‐benzyl‐L ‐glutamate, β‐benzyl‐L ‐aspartate, L ‐leucine, L ‐phenylalanine, and L ‐proline, with 4‐nitrophenyl chloroformate. When 1 was dissolved in N,N‐dimethylacetamide (DMAc) and heated at 60 °C, it was smoothly converted into the corresponding polypeptides with releasing 4‐nitrophenol and carbon dioxide. Spectroscopic analyses of the obtained polypeptides revealed that they were comparable with the authentic polypeptides synthesized by the ring‐opening polymerizations of amino acid N‐carboxyanhydrides (NCAs). Besides the successful polycondensations of a series of 1 , their polycondensations of 1a and other 1 were also successfully carried out to obtain the corresponding statistic copolypeptides. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 2525–2535, 2008     

Water Solubilization of Fullerene Derivatives by β‐(1,3‐1,6)‐d‐Glucan and Their Photodynamic Activities toward Macrophages

Anionic and neutral fullerene derivatives were dissolved in water by using β‐(1,3‐1,6)‐d ‐glucan (β‐1,3‐glucan) as a solubilizing agent. In the water‐solubilized complexes, the concentrations of fullerene derivatives were ≈0.30 mm and the average particle sizes were ≈90 nm. The β‐1,3‐glucan‐complexed fullerene derivative with a carboxylic acid was found to have higher photodynamic activity toward macrophages under visible‐light irradiation (λ >610 nm) than other β‐1,3‐glucan‐complexed fullerene derivatives. This result suggests that carboxylic acid moieties in the complex enhance the binding affinity with β‐1,3‐glucan receptors on the surface of macrophages when the β‐1,3‐glucan is recognized. In contrast, all β‐1,3‐glucan‐complexed fullerene derivatives showed no photodynamic activity toward HeLa cells under the same conditions.     

Protonation‐Assisted Conjugate Addition of Axially Chiral Enolates: Asymmetric Synthesis of Multisubstituted β‐Lactams from α‐Amino Acids

β‐Lactams with contiguous tetra‐ and trisubstituted carbon centers were prepared in a highly enantioselective manner through 4‐exo‐trig cyclization of axially chiral enolates generated from readily available α‐amino acids. Use of a weak base (metal carbonate) in a protic solvent (EtOH) is the key to the smooth production of β‐lactams. Use of the weak base is expected to generate the axially chiral enolates in a very low concentration, which undergo intramolecular conjugate addition without suffering intermolecular side reactions. Highly strained β‐lactam enolates thus formed through reversible intramolecular conjugate addition (4‐exo‐trig cyclization) of axially chiral enolates undergo prompt protonation by EtOH in the reaction media (not during the work‐up procedure) to give β‐lactams in up to 97 % ee.     

Poly(4‐acryloylmorpholine) oligomers carrying a β‐cyclodextrin residue at one terminus

A straightforward synthesis of amphiphilic β‐cyclodextrin‐poly(4‐acryloylmorpholine) (β‐CD‐PACM) polymers of controlled molecular weight, consisting of the radical polymerization of 4‐acryloylmorpholine in the presence of 6‐deoxy‐6‐mercapto‐β‐cyclodextrin (β‐CD‐SH) as chain‐transfer agent, has been established. These derivatives carry a single β‐cyclodextrin (β‐CD) moiety at one terminus and their average molecular weight is in the order of 10⁴. Thus, their β‐CD content is ～ 10% by weight. No evidence of un‐functionalized PACM was found in the final products. The chain‐transfer constant (C_T) of β‐CD‐SH was found to be 1.30 by independently determining the reaction constants of both chain‐transfer and propagation reactions. This ensures that the molecular weight, hence the β‐CD content of the polymers, does not significantly vary with conversion. These β‐CD‐PACM polymers are highly soluble in water as well as in several organic solvents such as chloroform and lower alcohols. They proved capable of solubilizing in water poorly soluble drugs such as 9‐[(2‐hydroxyethoxy)methyl]guanine (Acyclovir) and of gradually releasing them in aqueous systems. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 1607–1617, 2008     

Synthesis and biological activity of novel N‐benzoyl‐N‐tert‐butyl‐N′‐(β‐triphenylgermyl)propionylhydrazines

A series of new N‐benzoyl‐N‐tert‐butyl‐N′‐(β‐triphenylgermyl)propionylhydrazines were synthesized by the condensation reaction of β‐triphenylgermyl propanoic acid with N‐benzoyl‐N‐tert‐butylhydrazines in good yields by using N,N′‐dicyclohexylcorbodiimide as dehydrating agent. These title compounds were evaluated for molting hormone mimicking activity. The results of bioassay showed that the compounds exhibit moderate larvicidal activity, and toxicity assays indicated that the title compounds can induce a premature, abnormal and lethal larval molt. We found that the title compounds possess potential anticancer activities in vitro. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of β-（ 1→6）-Branched （ 1→3）-Glucononaoside with Alter-nate β- and α-Bonds in the Backbone

Lauryl glycoside of β-D-Glcp-(1→3)-[β-D-Glcp-(1→6)-]α-D-Glcp-(1→3)-β-D-Glcp-(1→3)-[β-D-Glcp-(1→6)-]α-D-Glcp-(1→3)-β-D-Glcp-(1→3)-[β-D-Glcp-(1→6)-]β-D-Glcp was synthesized through 3 3 3 strategy. 3-O-Allyl-2,4,6-tri-O-benzoyl-β-D-glucopyranosyl-(1→3)- -[2, 3, 4, 6-tetra-O-benzoyl-β-D-glucopyranosyl-(1→6)-] 1,2-O-isopropylidene-α-D-glucofuranose was used as the key intermediate which was converted to the corresponding trisaccharide donor and acceptor readily.