Asymmetric synthesis of α,α-difluoro-β-amino phosphonic acids using sulfinimines

Addition of diethyl lithiodifluoromethylphosphonate to enantiopure sulfinimines afforded the corresponding N-sulfinyl α,α-difluoro-β-amino phosphonates with good diastereoselectivity. A two-step deprotection involving treatment of diastereomerically pure N-sulfinyl α,α-difluoro-β-amino phosphonates with trifluoroacetic acid in EtOH followed by refluxing with 10 N HCl afforded enantiopure α,α-difluoro-β-amino phosphonic acids.     

Enantioselective synthesis of β-amino alcohols and α-amino acids via a copper catalyzed addition of diorganozinc reagents to N-phosphinoylimines

Enantioenriched β-amino alcohols were prepared via an asymmetric addition of diethylzinc, catalyzed by the BozPHOS·Cu(I) complex, on in situ formed N-phosphinoylimines. The nature of the hydroxyl protecting groups was found to affect the enantioselectivities. Subsequent deprotection and oxidation of N-phosphinoyl β-amino alcohols afforded optically active α-amino acids (97% ee).     

Hormone-receptor interactions. Syntheses of alpha-melanotropin and of informational sequences thereof with the aid of alcali-labile protecting groups (author's transl)]

Hormone-Receptor Interactions. Synthesses of α-Melanotropin and of Informational Sequences thereof with the Aid of Alcali-Labile Protecting Groups. The aim of this investigation was to prepare α-melanotropin and partial sequences thereof for biological investigations in as pure a state as possible. Classical synthesis in solution was chosen as the general approach, because it allows for extensive purification and identification of all intermediates, thus warranting the chemical identity of the products (in contrast to the solidphase methods). The scheme of protection was as follows: for the N^α-amino groups mostly t-butoxycarbonyl (BOC-), sometimes benzyloxycarbonyl (Z-), for the N^?-amino group of lysine-(11) 2-(methylsulfonyl)-ethoxycarbonyl (MSOC-), and for the carboxylic acid group of C-terminal glycine-(10) 2-(4-tolyl-sulfonyl)-ethoxy (-OTSE). This provides for facile and mild selective deprotection of either the α-amino groups by acidolysis or of the ?-amino group (α-carboxyl group) by β-elimination in alcali. A slight molar excess of 0.12N HCl in HCOOH proved to be the method of choice for removing BOC-; MSOC- is stable in acid (even for 30 min in liquid HF) and easily removed in a few minutes by 0.05--0.1N Ba(OH)₂; -OTSE is removed similarly. Condensation of amino-acid and peptide derivatives (formation of the peptide link) was performed using active esters (-ONP; -OSU), dicyclohexyl-carbodiimide (DCCI) with or without 1-hydroxy-benzotriazole (HOBT), or carboxylic acid azides wherever histidine was the carboxylic component. More than 50 compounds are described. Those characterized by arabic numerals served to prove that α-MSH contains two message sequences that are able to trigger melanocyte response: one in the central region -His-Phe-Arg-Trp-, the other in the C-terminal portion -Gly-Lys-Pro-Val · NH₂ of the molecule [3].     

Synthesis of Tri-, Penta-, and Heptapeptides Containing and (R)-2-alkyl-2-amino-3-(methylamino)-propionic acid residue in the central position

By conventional peptide-coupling methods (C to N direction; mixed anhydride, bis(2)-oxooxazolidin-3-yl)phosphinoyl chloride (Bop-Cl), or dicyclohexylcarbodiimide (DCC), 2-amino-2-methyl-3-(methylamino)-propionic acid and 2-amino-2-ethyl-3-(methylamino)propionic acid ( = 2-amino-2-[(methylamino)methyl]butanoic acid) are incorporated in the central position of tri-, penta-, and heptapeptides (see 3 – 7 , 21 , and 22 ). The fragment coupling of the β -amino group of the diamino-acid moiety in a tetrapeptide led to partial epimerization, and thus, two epimeric heptapeptide derivatives were actually obtained ( 7 and epi- 7 ). The final deprotection to the free heptapeptide (involving a Me₃SiI cleavage of BocNH and MeOCONH, a saponification with NaOH, and HPLC purification) gave both the desired product (isopeptide 21 ), with the β -amino group inside the peptide backbone, and a product (peptide 22 ) of transpeptidation, with the α-amino group of the diamino acid incorporated and a (methylamino)methyl group as the side chain. Peptide 22 is completely converted to the isopeptide 21 by prolonged treatment with base. The heptapeptide 21 was analyzed by elaborate 2QF-COSY and NOESY NMR measurements in H₂O/CD₃OD at ?5° (Table, Fig.); there is no indication for β -sheet or helical structures, a fact which was also confirmed by CD measurements.     

Preparation of optically pure α-trifluoromethyl-α-amino acids from N-tosyl-2-trifluoromethyl-2-alkyloxycarbonyl aziridine

The preparation of optically pure α-trifluoromethyl-α-amino acids from N-tosyl-2-trifluoromethyl-2-alkyloxycarbonylaziridine is described. Optically pure aziridine was prepared with a 60% yield via three steps from optically pure 2,3-epoxy-1,1,1-trifluoropropane (TFPO). Ring-opening reactions of the aziridine with a variety of nucleophiles and subsequent deprotection of the N-tosyl moieties gave the optically pure β-substituted-α-trifluoromethyl-α-amino acids in moderate to good yields (up to 85%) without racemization at the quaternary stereogenic center of the amino acid.     

Elaboration and structural studies of cyclo 1:1-[α/α-N-amino]mers

In order to investigate the ability of self-organization of the alternance of α-amino and α-N-amino-acids the synthesis of cyclo 1:1-[α/α-N-amino]mers has been achieved by an iterative sequence of deprotection and coupling reactions followed by a macrocyclization step. The self-assembling of N-amino deprotected cyclo-oligomers has been characterized using X-ray diffraction experiments and FT-IR analysis.     

Regioselective electrophilic substitution of 2,3-aziridino-γ-lactones: preliminary studies aimed at the synthesis of α,α-disubstituted α- or β-amino acids

2,3-Aziridino-γ-lactones are versatile synthons for the preparation of polysubstituted α- or β-amino acids. With the intention of preparing α,α-disubstituted α- or β-amino acids, regioselective electrophilic substitution of aziridino-γ-lactones at C2 was realized using two different methods. In the first, the anion was generated at C2 with LDA in the presence of the electrophilic agent. In the second method, the anion was trapped with TMS. Subsequent treatment of the C2 silylated product with a fluoride ion source regenerated the anion, which then reacted in situ with various electrophiles. Intramolecular aziridine opening of the C2 benzyl derivative prepared by the first method allowed access to a novel furan derivative, a direct precursor of an α,α-disubstituted β-amino acid.     

Chiral imidazole derivatives synthesis from enantiopure N-protected α-amino acids

A route to the preparation of enantiopure ligands based on a 2-phenylimidazol ring is described. The stereogenic centre is placed into the chain bonded to the fourth carbon of the imidazole ring. The synthesis starts from inexpensive and readily available N-protected α-amino acids, as the source of chirality, which are converted into appropriate α-diazoketones and, consequently, into α-bromoketones. These α-bromoketones are good precursors for reactions with amidines to provide the imidazole ring. The deprotection into the final products was carried out using hydrogen.     

Synthesis of chiral non-racemic intermediates and Arg-Gly-Asp mimetics by CaLB-catalyzed resolution

The reactivity of both the ester and amine functions present in β-amino esters was tested in order to obtain the synthesis of enantiopure αvβ3 and α5β1 integrin ligands. CaLB successfully catalyzed both the enantioselective transesterification and the N-acylation of racemic β-amino esters, allowing the isolation of intermediates for the preparation of Arg-Gly-Asp (RGD) mimetic compounds. In particular, a CaLB-catalyzed amidation reaction with unprotected p-aminobenzylamine reduced the number of synthetic steps, thus avoiding protection and deprotection of the intermediate compounds. Following this procedure, RGD mimetics were isolated with high yields and enantiomeric purities.     

A practical approach for the chemical synthesis of 2′-deoxyguanosine-C8 adducts with mutagenic/carcinogenic amino- or nitro-arenes

Synthetic methods for the preparation of 2′-deoxyguanosine-C8 (dG-C8) adducts with several mutagenic and carcinogenic amino- or nitro-arenes were developed using the palladium-mediated cross-coupling reaction of protected 8-amino-dG with bromoarenes in around 80% yields, followed by conventional deprotection procedures. This approach can be applied to preparation of a variety of authentic dG-C8 adducts with amino or nitro-arenes.     

Asymmetric synthesis of fluorine-containing amines, amino alcohols, α- and β-amino acids mediated by chiral sulfinyl group

This review article provides a critical overview of several different synthetic approaches developed for asymmetric preparation of fluorine-containing amines, amino alcohols, α- and β-amino acids. The common feature of these methods is the application of sulfinyl group as a chiral auxiliary to control the stereochemical outcome of the reactions under study. In particular, the following general methods are critically discussed: diastereoselective methylene transfer from diazomethane to the carbonyl of β-keto-γ-fluoroalkyl sulfoxides as a general approach for preparation of various α-fluoroalkyl α-sulfinylalkyl oxiranes. The resulting compounds were used as true chiral synthons for their further elaboration via oxidative or reductive desulfurization, to numerous fluorine-containing and biologically relevant amino- and hydroxy-containing derivatives. Another general approaches discussed here are asymmetric additions to CN double bond. One of them is addition of chiral sulfoxide stabilized carbon nucleophiles to fluorine-containing imines, leading to convenient preparation of alpha-fluoroalkyl derivatives of alpha amino acids and amines. Another approach is asymmetric Reformatsky reaction between N-sulfinyl imines and ethyl bromodifluoroacetate allowing operationally convenient preparation of α,α-difluoro-β-amino acids in enantiomerically pure form. Finally, structurally similar but mechanistically different addition reactions of diethyl difluoromethylphosphonate to N-sulfinyl imines, as a general approach to asymmetric synthesis of α,α-difluoro-β-aminophosphonates and phosphonic acids, are discussed. Effect of fluorine on the mechanism and stereochemical outcome of these reactions is discussed in detail and compared, where it is possible, with that of the analogous reactions of fluorine-free substrates.     

Facile solid phase synthesis of N-cycloguanidinyl-formyl peptides

A novel strategy of solid phase synthesis of N-cycloguanidinyl-formyl peptides has been established and investigated which involved coupling orthogonal protected diaminoacid with resin bound peptide, α-amino group deprotection, guanidinylation of α-amino group by bis-Cbz-1H-pyrazole-1-carboxamidine followed by cleavage and cyclization in solution, and finally removing Cbz by palladium catalyzed hydrogenation. Through this method, cycloguanidine could be introduced to either N-terminus or sidechain of designated peptides. The reaction conditions were facile, straightforward, and totally adaptive to common solid phase peptide synthesis strategy.     

Synthèse de deux nouveaux acides amines phénoliques comportant un cycle 1,2,4-oxadiazole

Synthesis of two phenolic amino acids containing the 1,2,4-oxadiazole ring The synthesis of α-amino-β [3-(p-hydroxyphenyl)-1,2,4, oxadiazol-5-yl]propionic acid (9) and its β-amino isomer (10) (see scheme 3) is reported. By condensation of p-benzyloxy-benzamide oxime and N-benzyloxycarbonyl asparagine the derivatives 4 and 5 (see scheme 1) are obtained leading after deprotection to 9 and 10 . The synthesis of N-carboxyanhydride of 4 (6) and its corresponding amino acid (7) and amide (8) is also described.     

Oxidations of some α-amino acids under mitsunobu reaction conditions

Reactions of α-amino acids with azodicarboxylates and Ph₃P results in oxidation at the α-carbon. N-acyl or carbamoyl amino acid esters give azodicarobxylate adducts, whereas free α-amino acid esters are converted to the corresponding α-keto esters.     

Stereoselective Synthesis of Unsaturated and Functionalized l-NHBoc Amino Acids, Using Wittig Reaction under Mild Phase-Transfer Conditions

The stereoselective synthesis of a new amino acid phosphonium salt was described by quaternization of melting triphenylphosphine with the γ-iodo NHBoc-amino ester, derived from l-aspartic acid. The deprotection of the carboxylic acid function to afford the phosphonium salt with a free carboxylic acid group was achieved by a palladium-catalyzed desallylation reaction. This phosphonium salt was used in the Wittig reaction with aromatic or aliphatic aldehydes and trifluoroacetophenone, under solid-liquid phase-transfer conditions in chlorobenzene and in the presence of K(3)PO(4) as weak base, to afford the corresponding unsaturated amino acids without racemization. Thus, the reaction with substituted aldehydes allows to graft various functionalized groups on the lateral chain of the amino acid, such as trifluoromethyl, cyano, nitro, ferrocenyl, boronato, or azido. In addition, the reaction of the amino acid Wittig reagent with α,β-unsaturated aldehydes leads to amino acids bearing a diene on the lateral chain. Finally, this amino acid phosphonium salt appears to be a new powerful tool for the preparation of unsaturated and non-proteinogenic α-amino acids, directly usable for the synthesis of customized peptides.     

Aqueous synthesis of sialylglycopeptide-grafted glycopolymers with high affinity for the lectin and the influenza virus hemagglutinin

Glycopolymers with pendant complex-type sialyl N-glycans containing heptapeptides, that is, sialylglycopeptides (SGPs), were synthesized using a water soluble polymer backbone bearing N-hydroxysulfosuccinimidyl esters by post-polymerization modification in water. Although SGP has three amino groups on the peptide chain, the substitution reaction occurs preferentially at the N-terminus α-amino group in the lysine residue onto the polymer side chain because the reactivity of such α-amino group is higher than that of the ε-amino group in the lysine residue under mild acidic aqueous condition. The resulting SGP-grafted glycopolymers exhibited strong interaction with the lectin Sambucus sieboldiana agglutinin and the human influenza A virus hemagglutinin, with higher binding associate constant values than those of free saccharide according to quartz crystal microbalance analysis. © 2020 Wiley Periodicals, Inc. J. Polym. Sci. 2020 , 58, 548–556     

Diels-Alder reactions of 3-(1H-tetrazol-5-yl)-nitrosoalkenes: synthesis of functionalized 5-(substituted)-1H-tetrazoles

A general route to 1,2-oxazines and open chain oximes bearing a 1H-tetrazolyl substituent via Diels-Alder reaction of 3-(tetrazol-5-yl)-nitrosoalkenes is reported. It was also demonstrated that reduction of these adducts followed by deprotection of the tetrazolyl group give 5-(1-aminoalkyl)-1H-tetrazoles, α-amino acid analogues.     

新型两亲性生物降解聚酯单体的合成及其开环聚合

以3-氯代丙二醇为起始原料,通过3-苄氧基甘油酸(3-O-BGA)为中间体,首次合成了作为一种新型聚羟基酸前体的,具有苄氧保护基的六元环状二交酯—3-苄氧次甲基-1,4-二氧六环-2,5-二酮(3-BMG)。该单体具有通常交酯的聚合特性,很容易以辛酸亚锡为催化剂,在140℃下开环聚合得到高分子量的聚合物。在双金属(Al/Zn)烷氧化合物引发体系下也能够进行开环聚合。所得聚合物在Pd/C催化下氢解,可以定量地去除苄基保护基,从而得到侧链带有羟基的新型功能性可生物降解聚酯。DSC实验结果显示脱保护的聚合物的玻璃化转化温度下降,并在120℃附近出现熔点。通过吸水率与动态接触角的测定,脱保护后聚合物的亲水性显著提高,明显高于传统的聚酯。     

Asymmetric synthesis of d-fagomine and its diastereoisomers

A divergent strategy for the asymmetric syntheses of d-fagomine and three of its diastereoisomers has been developed. The diastereoselective conjugate addition of an enantiopure lithium amide to an α,β-unsaturated ester was used as the key step to install the correct configuration required for the C(5)-stereogenic centre within the targets. In situ enolate oxidation generated the corresponding anti-α-hydroxy-β-amino ester, which possessed the correct configuration required for the C(4)-stereogenic centre within both d-fagomine and d-3-epi-fagomine. Subsequent epimerisation of this key anti-α-hydroxy-β-amino ester upon oxidation and diastereoselective reduction gave the corresponding syn-α-hydroxy-β-amino ester, which possessed the correct configuration required for the C(4)-stereogenic centre within both d-4-epi-fagomine and d-5-epi-fagomine. Elaboration of both α-hydroxy-β-amino esters upon reduction to the corresponding aldehydes followed by aldol reaction generated the requisite C(3)-stereogenic centres within the target compounds, then cyclisation and deprotection gave the enantiopure iminosugars in good overall yields, as single diastereoisomers (>99:1 dr).     

Studies on the Selectivity Between Nickel-Catalyzed 1,2-cis-2-Amino Glycosylation of Hydroxyl Groups of Thioglycoside Acceptors with C(2)-Substituted Benzylidene N-Phenyl Trifluoroacetimidates and Intermolecular Aglycon Transfer of the Sulfide Group

The stereoselective synthesis of saccharide thioglycosides containing 1,2-cis-2-amino glycosidic linkages is challenging. In addition to the difficulties associated with achieving high α-selectivity in the formation of 1,2-cis-2-amino glycosidic bonds, the glycosylation reaction is hampered by undesired transfer of the anomeric sulfide group from the glycosyl acceptor to the glycosyl donor. Overcoming these obstacles will pave the way for the preparation of oligosaccharides and glycoconjugates bearing the 1,2-cis-2-amino glycosidic linkages because the saccharide thioglycosides obtained can serve as donors for another coupling iteration. This approach streamlines selective deprotection and anomeric derivatization steps prior to the subsequent coupling event. We have developed an efficient approach for the synthesis of highly yielding and α-selective saccharide thioglycosides containing 1,2-cis-2-amino glycosidic bonds, via cationic nickel-catalyzed glycosylation of thioglycoside acceptors bearing the 2-trifluoromethylphenyl aglycon with N-phenyl trifluoroacetimidate donors. The 2-trifluoromethylphenyl group effectively blocks transfer of the anomeric sulfide group from the glycosyl acceptor to the C(2)-benzylidene donor and can be easily installed and activated. The current method also highlights the efficacy of the nickel catalyst selectively activating the C(2)-benzylidene imidate group in the presence of the anomeric sulfide group on the glycosyl acceptors.