Soluble peptidyl phosphoranes for metal-free, stereoselective ligations in organic and aqueous solution

Protocols for solid-phase syntheses of soluble peptidyl phosphoranes are presented. Various supported phosphoranylidene acetates were prepared on Rink amide or via alkylation of trialkyl- and triarylphosphines with bromoacetyl Wang ester. C-Acylation was conducted racemization-free with activated Fmoc-amino acids, followed by SPPS (solid-phase peptide synthesis). Acidic conditions released decarboxylated peptidyl phosphoranes into solution. The protocol allowed for the electronic variation of peptidyl phosphoranes which were investigated in ligation reactions with azides in organic and aqueous solvents.     

Solid phase synthesis of a molecular library of pyrimidines, pyrazoles, and isoxazoles with biological potential

A small molecular library of 40 pyrimidine, pyrazole, and isoxazole derivatives, bearing structural features for a promising binding of therapeutically interesting enzymes, was designed and prepared. An efficient and straightforward solid phase synthesis was envisaged and carried out on a Rink amide resin. The assistance of microwave heating in any step reduced the reaction time, increased the reaction yields, and allowed an easy work-up and purification of the targeted compounds.     

Solid‐Phase Synthesis of N‐Aryl‐N′‐Carboalkoxy Guanidines by the Mitsunobu Reaction of Fmoc‐Guanidines

Abstract

A new method for the solid‐phase synthesis of N‐aryl‐N′‐carboalkoxy guanidines is described. Aromatic amines were reacted with Fmoc‐isothiocyanate to provide Fmoc‐thioureas, which were coupled with Rink amide resin to provide the corresponding resin‐bound Fmoc‐guanidines. Subsequent Mitsunobu alkylation with a variety of alcohols delivered N‐aryl‐N′ carboalkoxy guanidines in good to high purity after resin cleavage.     

Development of a recyclable fluorous chiral phase-transfer catalyst: application to the catalytic asymmetric synthesis of alpha-amino acids

[structure: see text] A recyclable fluorous chiral phase-transfer catalyst was synthesized and successfully applied for the catalytic asymmetric synthesis of both natural and unnatural alpha-amino acids. The reaction involves alkylation of a glycine derivative followed by extractive recovery of the chiral phase-transfer catalyst using fluorous solvent.     

Design of N-spiro C2-symmetric chiral quaternary ammonium bromides as novel chiral phase-transfer catalysts: synthesis and application to practical asymmetric synthesis of alpha-amino acids

A series of C(2)-symmetric chiral quaternary ammonium bromides 10 and 11 have been designed as a new, purely synthetic chiral phase-transfer catalyst, and readily prepared from commercially available optically pure 1,1'-bi-2-naphthol as a basic chiral unit. The details of the synthetic procedures of each requisite chiral binaphthyl subunit have been disclosed, and the structures of the assembled N-spiro chiral quaternary ammonium bromides 11a and 11f were unequivocally determined by single-crystal X-ray diffraction analysis. The reactivity and selectivity of these chiral ammonium bromides as chiral phase-transfer catalysts have been evaluated in the asymmetric alkylation of the benzophenone Schiff base of glycine ester 7 under mild liquid-liquid phase-transfer conditions, and the optimization of the reaction variables (solvent, base, and temperature) has also been conducted. Further, the scope and limitations of this asymmetric alkylation have been thoroughly investigated with a variety of alkyl halides, in which the advantage of the unique N-spiro structure of 11 and dramatic effect of the steric as well as the electronic properties of the aromatic substituents on the 3,3'-position of one binaphthyl moiety have been particularly emphasized. Finally, the potential synthetic utility of the present method for the practical asymmetric synthesis of structurally diverse natural and unnatural alpha-amino acids has been demonstrated by its successful application to the facile asymmetric syntheses of (S)-N-acetylindoline-2-carboxylate, a key intermediate in the synthesis of the ACE inhibitor, and l-Dopa (l-3,4-dihydroxyphenylalanine) ester and its analogue.     

Kinetic Comparison of Trifluoroacetic Acid Cleavage Reactions of Resin-Bound Carbamates, Ureas, Secondary Amides, and Sulfonamides from Benzyl-, Benzhydryl-, and Indole-Based Linkers

The kinetics of cleavage reactions of 16 resin-bound carbamates, ureas, secondary amides, and sulfonamides from four different acid labile linkers including benzyl, benzhydryl, and indole linkers has been investigated. The optimized cleavage conditions are generally milder than those commonly used and reported (e.g., 0.5% TFA as opposed to 5%). Among various linkers studied in this work, the indole linker has been found to be the most acid labile followed by the Rink linker. The rate of cleavage of compounds linked to the resin via various functional groups can be summarized as follows: sulfonamide >carbamate approximately urea > amide. This study shows that cleavages of 16 compounds from four different acid labile linkers have been optimized to much milder conditions in terms of TFA concentration and the reaction time. It also demonstrates that single bead FTIR is an effective tool for optimizing cleavage conditions.     

Solid-phase synthesis and structural characterization of highly substituted hydroxyproline-based 2,5-diketopiperazines

Two general solid-phase methods for the synthesis of a new class of 2,5-diketopiperazines (DKPs) containing the trans-4-hydroxy-L-proline amino acid residue (Hyp) have been developed. An N-protected hydroxyproline methyl ester was linked through the hydroxyl function to the Ellman resin. The synthesis procedures were conceived to enable a sequence of Hyp alkylation, Hyp N-acylation, cyclization, and amide bond alkylation. Up to three different centers of molecular diversity were introduced around the DKP scaffold. Highly functionalized bicyclic compounds were obtained in good yield and purity. The alkylation of hydroxyproline alpha CH was performed without control of the diastereoselectivity. During the final alkylation of the backbone, amide bond epimerization at the alpha-carbon atoms of the two amino acid residues was observed. The structures of representative DKPs were elucidated with multidimensional NMR experiments. The described reaction pathways can be applied to the identification of heterocyclic molecule inhibitors to diverse enzyme targets.     

自组装多功能反应器固相合成依非巴特

采用集反应、搅拌、鼓泡、N2气保护和过滤五重功能的自组装反应器,研究了树脂种类、溶剂、缩合试剂和反应时间对环肽依非巴特产率的影响。结果表明,以Rink Amide AM树脂为固相载体,HBTU/HOBt/DIEA为肽键缩合剂,DMF为溶剂,反应2 h,粗肽得率高达86.6%,经液相色谱纯化后纯度达98%以上。     

Tailoring ultraresins based on the cross-linking of polyethylene imines. Comparative investigation of the chemical composition, the swelling, the mobility, the chemical accessibility, and the performance in solid-phase synthesis of very high loaded resins

Ultraresins have been prepared from polyethyleneimines and cross-linking molecules and have been provided with various degrees of cross-linking. The total nitrogen loading and the loading with secondary and with tertiary amines have been determined in all products. Nitrogen loadings of the novel resins were up to 15 mmol/g, reactive secondary amines up to 13.8 mmol/g. In addition to the exceptionally high loading, the novel resins displayed efficient swelling volumes in polar and nonpolar solvents. The mobility of resin-bound species as determined by EPR-spectroscopy, depending on the amount of cross-linker, indicated good flexibility and reactivity of this resin type. The novel, high-loaded resins have been investigated subsequently in solid-phase synthesis. The Rink amide linker and two different hydroxy linkers (hydroxyacetamide, HMPB) have been attached to the resin. Despite the high loadings, the secondary amines were easily accessible and could be functionalized exhaustively. Reactivity of the linker-coupled resins was found to be closely related to the resin composition. Increased resin cross-linking led to reduced swelling, reduced mobility, and reduced reactivity in the synthesis of a medium-sized model peptide. As the result of the systematic investigation of structure-property relations in Ultraresins, a support material was identified that combined high reactivity and a mobility in the range of the extremely flexible Tentagel supports. In the optimized Ultraresin, >95% of all available secondary nitrogens could be coupled with Rink linker or with the small 2-hydroxyacetamide anchor, resulting in loadings from 2.7 to 6.8 mmol/g, respectively. A resin with an attached HMPB linker and spacer delivered analytically pure peptides in solid-phase synthesis, fully exploiting the exceptionally high loadings.     

Amidocarbonylation-An Efficient Route to Amino Acid Derivatives

Atom efficient, multicomponent reactions that lead to high-value products from inexpensive starting materials are of both economic and ecological interest for industrial organic synthesis. alpha-Amino acids are amongst the most important compounds in chemistry and biology. As well as their biochemical significance as building blocks of peptides and proteins, alpha-amino acids are also becoming increasingly interesting as fine chemicals. Possibly one of the key reactions in the preparation of these compounds is transition metal catalyzed amidocarbonylation, where the alpha-amino acid framework is constructed in a single step from an aldehyde, an amide, and carbon monoxide. This article gives a current overview of transition metal catalyzed amidocarbonylation reactions used in the synthesis of alpha-amino acids derivatives. A classification and summary of the significant features of this three component reaction is first presented together, with an historical introduction. This section is followed by two sections on cobalt- and palladium-catalyzed amidocarbonylation. A discussion of the mechanism of each of the different amidocarbonylation variants form an introduction. Overviews on further synthetic development of the methodology, such as the domino reaction with an amidocarbonylation step and the expansion of the range of starting materials, form the main topics of both variants. The potential of the method is demonstrated with the help of examples of special synthetic utility (for example, the preparation of arylglycines). Finally, possibilities for future developments in transition metal catalyzed amidocarbonylation reactions are proposed on the basis of the current state of knowledge.     

Highly enantioselective phase-transfer-catalyzed alkylation of protected alpha-amino acid amides toward practical asymmetric synthesis of vicinal diamines, alpha-amino ketones, and alpha-amino alcohols

Highly enantioselective alkylation of protected glycine diphenylmethyl (Dpm) amide 1 and Weinreb amide 10 has been realized under phase-transfer conditions by the successful utilization of designer chiral quaternary ammonium salts of type 4 as catalyst. Particularly, remarkable reactivity of the chiral ammonium enolate derived from 1b and 4c allowed the reaction with less reactive simple secondary alkyl halides with high efficiency and enantioselectivity. An additional unique feature of this chiral ammonium enolate is its ability to recognize the chirality of beta-branched primary alkyl halides, which provides impressive levels of kinetic resolution and double stereodifferentiation during the alkylation, allowing for two alpha- and gamma-stereocenters to be controlled. Combined with the subsequent reduction using LiAlH4 in cyclopentyl methyl ether (CPME), this system offers a facile access to structurally diverse optically active vicinal diamines. Furthermore, the optically active alpha-amino acid Weinreb amide 11 can be efficiently converted to the corresponding amino ketone by a simple treatment with Grignard reagents. In addition, reduction and alkylation of the optically active alpha-amino ketone into both syn and anti alpha-amino alcohols with almost complete relative and absolute stereochemical control have been achieved. With (S,S)- and (R,R)-4 in hand, the present approach renders both enantiomers of alpha-amino amides including Weinreb amides readily available with enormous structural variation and also establishes a general and practical route to vicinal diamines, alpha-amino ketones, and alpha-amino alcohols with the desired stereochemistry.     

Rink Amide树脂结构对多肽合成的影响研究

研究了Rink Amide树脂取代度、溶胀度及肽链的长度不同对肽合成收率的影响,并对影响Rink Amide树脂溶胀度的因素进行了研究,结果表明,合成长肽时低取代度、高溶胀度的Rink Amide树脂能获得较好的肽收率。     

Solid phase synthesis of purines from pyrimidines

In this paper the solid phase synthesis of various substituted purines is described starting from 4,6-dichloro-5-nitropyrimidine. The 4,6-dichloro-5-nitropyrimidine was coupled to Rink amide resin followed by displacement of the second chloride by an amino compound. Reduction of the nitro compound proved to be problematic but was achieved using lithium aluminum hydride/aluminum trichloride. The diamines (13) were then elaborated to purines by three different routes.     

Solid-phase synthesis of N-acyl-N′-carbamoylguanidines

Amino acids immobilized on polystyrene-Wang or Rink amide resin were reacted with p-nitrophenyl chloroformate to give an activated urethane that was displaced by S-methylisothiourea. Following N-acylation with an acid chloride, the thiomethyl group was displaced by primary or secondary amines with the aid of mercury (II) chloride to yield the unsymmetrically substituted title compounds after resin cleavage.     

CamTHP*OH: a camphor-derived delta-lactol auxiliary for the effective desymmetrization of attached glycinamide residues. Asymmetric synthesis of alpha-amino carbonyl compounds

Stereoselective allylation of camphor and subsequent terminal hydroformylation affords a new delta-lactol auxiliary (camTHP*OH) on multigram scale. Stereoselective condensation with glycine dimethylamide and Cbz protection affords a camTHP*-desymmetrized glycinamide building block which undergoes efficient and highly diastereoselective metal enolate alkylation reactions. Acid-mediated deprotection affords the N-Cbz-protected alpha-amino amide products which may be converted directly to alpha-amino ketones on treatment with Grignard or organolithium reagents without loss of stereochemical integrity. [reaction: see text]     

A highly efficient, asymmetric synthesis of benzothiadiazine-substituted tetramic acids: potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase

[reaction: see text] An efficient two-pot, asymmetric synthesis of benzothiadiazine-substituted tetramic acids is reported. Starting from commercially available alpha-amino acids or esters, reductive amination followed by a novel one-pot amide bond formation/Dieckmann cyclization provided the desired products in high yield and optical purity. An analogous solid-phase approach to the same targets is also presented. These compounds were found to be potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase.     

New heterocyclic beta-sheet ligands with peptidic recognition elements

A detailed and comprehensive overview is presented about the design, modeling, and synthesis, as well as spectroscopic characterization, of a new class of beta-sheet ligands. The characteristic feature of these compounds is a peptidic chimeric structure formed from a specific combination of aminopyrazolecarboxylic acids with naturally occurring alpha-amino acids. These hybrid peptides are designed with the aid of molecular modeling to exist mainly in an extended conformation. All their hydrogen bond donors and acceptors can be aligned at the bottom face in such a way that a perfect complementarity toward beta-sheets is obtained. Thus the aminopyrazoles impart rigidity and a highly efficient DAD sequence for the recognition of whole dipeptide fragments, whereas the natural alpha-amino acids are designed to mimick recognition sites in proteins, ultimately leading to sequence-selective protein recognition. The synthetic protocols either rely upon solution phase peptide coupling with a PMB protecting group strategy or solid-phase peptide coupling based on the Fmoc strategy, using the same protecting group. In solution, a key building block was prepared by catalytic reduction of a nitropyrazolecarboxylic acid precursor. Subsequently, it was (N-1)-protected with a PMB group, and elongated by HCTU- or T3P-assisted peptide coupling with dipeptide fragments, followed by PyClop-assisted coupling with another nitropyrazolecarboxylic acid building block. Final simultaneous deprotection of all PMB groups with hot TFA completed the high-yield protocol, which works racemization-free. After preparing a similar key building block with an Fmoc protection at N-3, we developed a strategy suitable for automated synthesis of larger hybrid ligands on a peptide synthesizer. Attachment of the first amino acid to a polystyrene resin over the Sieber amide linker is followed by an iterative sequence consisting of Fmoc deprotection with piperidine and subsequent coupling with natural alpha-amino acid via HATU/HOAt. High yields of free hybrid peptides are obtained after mild acidic cleavage from the resin, followed by deprotection of the PMB groups with hot TFA. The new aminopyrazole peptide hybrid compounds were characterized by various spectroscopic measurements including CD spectra, VT, and ROESY NMR experiments. All these accumulated data indicate the absence of any intramolecular hydrogen bonds and strongly support an extended conformation in solution, ideal for docking on to solvent-exposed beta-sheets in proteins. Initial results from aggregation tests of pathological proteins with these and related ligands look extremely promising.     

Synthesis of a key intermediate of novel galbonolide analogues via efficient construction of a conjugated diene system

The development of an efficient synthetic method enabled multi-gram synthesis of a key intermediate, which is useful for the modification at the C6-functional group of galbonolide analogues. The structure of a key intermediate including a conjugated diene was afforded by Horner-Emmons reaction, alkylation of Weinreb amide with alkyl lithium and a subsequent Wittig reaction.     

C9 Fraction Alkylation Desulfurization over Amberlyst 36 Resin:The Kinetics of 2‐Ethylthiophen, 2,5‐Dimethylthiophene,and 2‐n‐Propylthiophene with Isoamylene

C₉ fraction is the by‐products of catalytic reforming and ethylene cracker; it is considered as a kind of petroleum resin raw material. Recently, it was studied for the use as a gasoline additive to enhance the economic benefits. However, C₉ fractions are getting higher in sulfur contents. As conventional hydrotreating technology leads to significant octane number loss and processing costs, the alkylation desulfurization process, which could reduce the sulfuric compounds to hydrogen sulfide by catalytic alkylation with olefins and distillation followed by, is a rather attractive way of reducing the sulfur of C₉ fraction. In this paper, different kinds of thiophenic compounds, including 2‐ethylthiophen, 2,5‐dimethylthiophene, and 2‐n‐propylthiophene, were selected as the model compounds. Thiophenic compounds were studied first by the alkylation reaction over macroporous sulfonic resin Amberlyst 36, and the octane number of C₉ fraction was measured. It was found that isoamylene and Amberlyst 36 resin had a significant effect on the alkylation desulfurization of thiophenic compounds with the conversion, reaching to above 99%. And the octane number of C₉ fraction was increased by alkylation desulfurization over Amberlyst 36 resin. Moreover, the alkylation of thiophenic sulfurs could be described as a pseudo–first–order reaction as well as the reaction rate constant, and the activation energy of alkylation reactions was calculated.     

Solid-phase synthesis and spectral properties of 2-alkylthio-6H-pyrano[2,3-f]benzimidazole-6-ones: a combinatorial approach for 2-alkylthioimidazocoumarins

The solid-phase synthesis of 2-alkylthio-6H-pyrano[2,3-f]benzimidazole-6-ones (2-alkylthioimidazocoumarins) is described. 7-Fluoro-4-methyl-6-nitro-2-oxo-2H-1-benzopyran-3-carboxylic acid was coupled to Rink amide resin via its carboxyl group. The resin-bound scaffold then underwent aromatic nucleophilic substitution with primary amines, followed by reduction of the nitro group with tin (II) chloride. Subsequent cyclization of the o-dianilino intermediates with thiocarbonyldiimidazole (TCD) afforded resin-bound 1,3-dihydro-2-thioxo-6H-pyrano[2,3-f]benzimidazole-6-ones, which were then S-alkylated with alkyl halides in the presence of N,N-diisopropylethylamine (DIEA). The desired products were obtained in good yield with high purity after trifluoroacetic acid cleavage. The unique spectral properties of 2-alkylthioimidazocoumarins indicate that they may be useful in photodynamic therapy.