Asymmetric 1,4-Addition Reactions Catalyzed by N-Terminal Thiourea-Modified Helical l-Leu Peptide with Cyclic Amino Acids

N-terminal thiourea-modified l -Leu-based peptide {(3,5-diCF₃Ph)NHC(=S)-(l -Leu-l -Leu-Ac₅c)₂-OMe} with five-membered ring α,α-disubstituted α-amino acids (Ac₅c) catalyzed a highly enantioselective 1,4-addition reaction between β-nitrostyrene and dimethyl malonate. The enantioselective reaction required only 0.5 mol % chiral peptide-catalyst in the presence of ⁱPr₂EtN (2.5 equiv.), and gave a 1,4-adduct with 93 % ee of an 85 % yield. As Michael acceptors, various β-nitrostyrene derivatives such as methyl, p-fluoro, p-bromo, and p-methoxy substituents on the phenyl group, 2-furyl, 2-thiophenyl, and naphthyl β-nitroethylenes could be applied. Furthermore, various alkyl malonates and cyclic β-keto-esters could be used as Michael donors. It became clear that the length of the peptide chain, a right-handed helical structure, amide N−Hs, and the N-terminal thiourea moiety play crucial roles in asymmetric induction.     

Facile synthesis of benzamides to mimic an α-helix

A new α-helix mimetic was designed by using a benzamide as a rigid scaffold. It presents three functional groups corresponding to side chains of amino acids found at the i, i + 4, and i + 7 positions of an ideal α-helix, which are displayed on the same helical face. Its efficient synthesis was achieved by employing simple alkylation and amidation reactions which can be easily adapted for solid-phase synthesis. As a result, two tris-benzamides were produced to mimic two helical regions found in a peptide hormone, glucagon.     

Enzymatic enantioselective reduction of α-ketoesters by a thermostable 7α-hydroxysteroid dehydrogenase from Bacteroides fragilis

A thermostable 7α-hydroxysteroid dehydrogenase (7-HSDH) from Bacteroides fragilis ATCC 25285 was cloned and over-expressed in E. coli, and its substrate specificity and stereoselectivity toward reduction of various ketones were examined. This alcohol dehydrogenase was active toward a series of aromatic and bulky aliphatic α-ketoesters. The substituents at the phenyl ring of aromatic α-ketoesters greatly affected the activity, but their effects on enantioselectivity were minimal. The synthetic application of this enzyme was then demonstrated through the preparation of a few α-hydroxy carboxylic acid esters of pharmaceutical interest.     

One-pot synthesis of polyfunctional pyrazoles: an easy access to α-diazoketones from arylglyoxal monohydrates and tosylhydrazine

A new and efficient method for the generation of α-diazoketones has been developed from arylglyoxal monohydrates and tosylhydrazine at room temperature. 1,3-Dipolar cycloaddition reactions were used to constructing polyfunctional pyrazole derivatives by the reaction of generated α-diazoketones in situ with electron-deficient alkenes, quinones and coumarins in one pot. The one-dimensional molecular packing of 1H-benzo[f]indazole-4,9-dione derivatives along the c direction demonstrated a helical chain formation via N–H?O hydrogen-bonding.     

α-萜品烯马来酰亚胺基酰腙衍生物的合成及杀菌活性研究

以α-蒎烯为原料,在质子酸催化下发生Wagner-Meerwein重排得到α-萜品烯,再与马来酸酐发生Diels-Alder环加成反应得到α-萜品烯马来酸酐(3),然后与水合肼反应制备N-氨基-α-萜品烯马来酰亚胺(4).在冰醋酸催化下,4与各种取代苯甲醛反应,合成得到17个新型α-萜品烯马来酰亚胺基酰腙化合物5a～5q.初步探索了合成条件,并利用元素分析,1H NMR,13C NMR,LC-MS,FT-IR等多种手段对目标产物作了分析表征.初步的生物活性测试表明,大部分化合物具有一定的杀菌活性,其中4-羟基-3-甲氧基苯基-α-萜品烯马来酰亚胺基酰腙(5n)在浓度为50 mg/L时对苹果轮纹病菌、花生褐斑病菌和番茄早疫病菌的抑制率分别达91%,83.3%和76.7%.     

A convenient transformation of α-alkylserines into α-halogenomethyl-α-alkylglycines

An efficient and facile synthesis of N-Boc-α-chloromethyl- and α-bromomethyl-α-alkylglycines is reported that involves cyclization of N-Boc-α-alkylserines to the corresponding β-lactones under Mitsunobu reaction conditions, followed by ring opening with anhydrous MgCl₂ or MgBr₂.     

Chameleonic reactivity of α-amino nitrile-derived ureas. Synthesis of highly functionalized imidazolidin-2-one and imidazolidine-2,4-dione derivatives

The potential of α-amino nitrile-derived ureas for the synthesis of imidazolidin-2-one derivatives has been studied in the context of a medicinal chemistry project focused on the search of antagonists of the thrombin receptor PAR1. In this study α-amino nitrile-derived ureas have shown chameleonic reactivity. Thus, under neutral, basic or mild acid media they cyclize to 4-iminoimidazolidin-2-one derivatives, which tautomerize to 4-amino-2,3-dihydro-1H-imidazol-2-ones. This tautomerism triggers epimerization at the C₅ of the imidazolidine ring, as well as its oxidation. However, they give stable highly functionalized hydantoin derivatives under strong acid media, by a no-epimerizing two-step hydrolysis.     

Chemoselective one-pot access to benzo[e]indole-4,5-diones and naphtho[2,1-b]thiophene-4,5-diones via copper-catalyzed oxidative [3 + 2] annulation of α-oxoketene N,S-acetals/β-ketothioamides with α-/β-naphthols

An operationally simple and efficient one-pot method for the synthesis of 1-aroyl (or alkanoyl)-2-thioalkyl-3-aryl (or alkyl)-3H-benzo[e]indole-4,5-diones and naphtho[2,1-b]thiophene-4,5-diones has been devised by copper-catalyzed cross-coupling of α-oxoketene N,S-acetals/β-ketothioamides with α-/β-naphthols in open air for the first time. The key to the success of this transformation is the room temperature oxidation of α-/β-naphthol to 1,2-naphthoquinone as a reactive species, which undergoes formal [3 + 2] annulation with α-oxoketene N,S-acetals/β-ketothioamides via cascade sequence of Michael addition/tautomerization/oxidation/cyclization/aromatization reactions, enabling addition of a pyrrole/thiophene ring onto naphthoquinone moiety. Further, benzo[e]indole-4,5-diones were transformed to pentacyclic fused phenazine derivatives under solvent-free conditions. Based on our experimental outcomes, a tentative mechanistic rationale for this chemoselective protocol is proposed, which is well validated and supported by the control experiments.     

Towards peptide versions of Cram's host-guest chemistry: the synthesis of C-disubstituted glycines with binaphthol-based crowned side-chains

Dietherification of the hydroxy groups of various α,α-disubstituted α-amino acids or their precursors, possessing either an achiral frame derived from α-hydroxymethylserine, or a 2,2′,6,6′-tetrasubstituted biphenyl frame with only an axial chirality, or a frame with α-carbon chirality derived from α-methyl-(L)-DOPA, using (R)-2,2′-bis-(5-tosyloxy-3-oxa-1-pentyloxy)-1,1′-binaphthyl as alkylating agent, gave a new series of amino acids bearing binaphthol-based crown-ethers, as building blocks for the construction of short-chain peptide helices with topologically well-localized receptors.     

The asymmetric synthesis of (S,S)-methylphenidate hydrochloride via ring-opening of an enantiopure aziridinium intermediate with phenylmagnesium bromide

The key step in our synthetic strategy towards (S,S)-methylphenidate hydrochloride employs the ring-opening of an in situ formed aziridinium intermediate. Treatment of an α-hydroxy-β-amino ester with methanesulfonic anhydride promoted aziridinium formation and the subsequent addition of phenylmagnesium bromide resulted in stereospecific and regioselective ring-opening to give the corresponding α-phenyl-β-amino ester with overall retention of configuration. Subsequent functional group manipulation followed by N-deprotection and cyclisation generated the piperidine ring within the target compound, and transesterification gave (S,S)-methylphenidate hydrochloride, in only 8 steps from 1,5-pentanediol, in 15% overall yield. These results demonstrate the synthetic utility of enantiopure aziridinium intermediates as substrates for the generation of stereodefined C–C bonds, and crucially this methodology provides access to α-substituted-β-amino ester substrates that are not accessible via enolate alkylation chemistry. The strategy reported herein is potentially applicable to all possible stereoisomers of methylphenidate as well as differentially substituted analogues.     

Crystal structure of 1,3-diphenyladamantane and trans-1,4-diphenylcyclohexane: torsion angles about C-Ph bonds in α,ω-diphenyl(alicyclic hydrocarbon)

The orientation of the two phenyl rings in α,ω-diphenylalkanes with rigid carbon skeletons is investigated through characterization of the crystal and molecular structures of 1,3-diphenyladamantane (1) and trans-1,4-diphenylcyclohexane (2). The two phenyl rings in 1 have different conformations about the C-Ph bonds, with torsion angles between the phenyl ring and the C1-C2-C3 plane of 0.65 and 71.7°. A hydrogen atom at the meta-position of one of the phenyl rings contact intermolecularly with a tertiary hydrogen atom at C5 of adamantane within the sum of van der Waals radii. Due to the helical conformation, the short CH?HC contacts (2.231 Å) construct supramolecular triple helical strands. In contrast to 1, the phenyl rings in 2 have identical configurations, with equatorial position and bisected conformation as expected from density functional calculations. The molecular packing of 2 exhibits a herringbone pattern of (aromatic)C-H?π contacts.     

Synthetic studies toward miroestrols: trials for elongation of the methyl group of 5-substituted 2-methyl-2-cyclohexanone to 3-methyl-2-butenyl function

Toward total synthesis of miroestrols (miroestrol and deoxymiroestrol), 3-methyl-2-butenyl function (endo-C5 unit) on D ring as a carbon chain for C and E rings was prepared by elongation of the methyl group in α-methyl-α,β-unsaturated ketone unit, and 3,5-dinitrobenzoyl group was introduced as a potential leaving group for the construction of B ring. The former was accomplished through a sequence of epoxide ring-opening, microwave-irradiated siloxy-Cope rearrangement, and isomerization of 3-methyl-3-butenyl function (exo-C5 unit) to endo-C5 unit.     

硫原子团簇负离子的螺旋结构

在使用B3LYP密度泛函进行几何构型优化和振动频率计算得到的硫原子团簇负离子的结构中,分子的总能量最低的S9- 到 S13-的同分异构体呈螺旋状构型。另外也计算了螺旋状的Sn- (n = 14~20)的结构。大多数的的硫负离子是链状结构,这与相应中性硫原子团簇的环状构型完全不同。     

Helical secondary structures in 2:1 and 1:2 α/γ-peptide foldamers

Oligomers containing both α- and γ-amino acid residues in a 1:1 alternating pattern have recently been shown by several research groups to adopt helical secondary structures. We have begun to explore the folding behavior of oligomers with different α-residue/γ-residue backbone patterns. Previously we reported that the γ-amino acids bearing a cyclohexyl constraint at the C_β–C_γ bond and a variable side chain at C_α strongly promote a helical conformation containing 12-atom CO(i)?H–N(i+3) hydrogen bonds for 1:1 α:γ backbones. Here we report synthesis and crystallographic analysis of 2:1 and 1:2 α/γ-peptides that adopt CO(i)?H–N(i+3) hydrogen-bonded helical conformations.     

Cyclophanes—13: Crystal and molecular structure of [2.2][2,5]furano(1,4)naphthalenophane

The crystal and molecular structure of [2.2](2,5)furano(1,4)naphthalenophane (1) was determined by X-ray crystallography. The molecule exists in the anti-conformation and the study represents the first instance in which the structural features of a naphthalenoid ring within a cyclophane were determined. Crystals of cyclophane 1 are orthorhombic, space group Pbca, with a = 7.859(2). b = 11.482(3) and c = 28.818(8) Å. While the nonbridged portion of the naphthalenoid ring is planar, the portion which is bridged to the furanoid ring through its 1 and 4 C atoms is puckered and boat-shaped. These C atoms are positioned 14° out of the plane of the other four C atoms of this ring. The furanoid ring is essentially planar but is not parallel to the naphthalenoid ring. It is inclined 22° to the least squares plane of the bridged portion of the naphthalenoid ring. This angle of inclination staggers the atoms of the furanoid and bridged naphthalenoid ring and positions the 3 and 4 C atoms, the 2 and 5 C atoms and the 0 atom of the furanoid ring 3.4. 2.9 and 2.6 Å. respectively, from the least squares plane of the bridged portion of the naphthalenoid ring. While the internal angles around the bridging C atoms α- to the naphthalenoid ring are 109°, those α- to the furanoid ring are 113°. In addition unusually large bond angles ($\text{\$}\text{?}$137°) at the 2 and 5 C atoms of the furanoid ring, external to the ring, are also observed. The distortions are considered with respect to the strain within the cyclophane macrocycle and are compared with other similar systems.     

X=y-zh systems as potential 1,3-dipoles—5 : Intramolecular cycloadditions of imines of α-amino acid esters

Azomethine ylides are readily generated from imines of α-amino acid esters by a formal 1,2-H shift. A suitably positioned unactivated double or triple bond in either of the two precursors of the imines (aldehyde or α-amino ester) leads to an intramolecular cycloaddition generating fused ring systems in good yield. Cis stereochemistry is assigned to the newly created ring junction of the cycloadducts based on NOE difference spectroscopy and, in the case of 8a, by a single crystal X-ray structure. Equilibration of the kinetically formed dipole leads to mixtures of epimeric cycloadducts for imines of phenylglycine methyl ester but equilibration is not observed for other imines. Reasons for this are discussed. The intramolecular cycloaddition is sensitive to ring size with 6/5 and 5/5 cis-fused systems being most easily formed depending in which moiety (aldehyde or amino acid) the dipolarophile is located. Intramolecular trapping of the azomethine ylide by an alkyne is accompanied by variable amounts of aromatized pyrrolic products.     

1-(N-Acylamino)-1-triphenylphosphoniumalkylphosphonates: General synthesis and prospects for further synthetic applications

A general approach for the synthesis of 1-(N-acylamino)-1-triphenylphosphoniumalkylphosphonates from readily accessible alkyl imidate hydrochlorides has been developed. The three-step synthesis involves acylation of the imidate hydrochloride with an acyl chloride, the Michaelis–Becker-like addition of diethyl phosphite to the N–acylimidate and subsequent nucleophilic substitution of the ethoxy group of the 1–ethoxyphosphonate derivative with triphenylphosphonium tetrafluoroborate. 1–(N–Acylamino)-1-triphenylphosphoniumalkylphosphonates were demonstrated to be promising intermediates for further synthetic transformations toward α-functionalized derivatives of α–aminophosphonic acids and α,β-dehydro-α-aminophosphonates.     

Efficient synthesis of α-substituted-α-arylmethyl phosphonates using trichloroacetimidate CC coupling method

A simple convenient protocol for the synthesis of diethyl α,α-diaryl methylphosphonate derivatives 5a-f, 6b-f, 7a-f and 8a-f, diethyl α-alkenyl α-aryl methylphosphonates 9a-d and 10a-d and α-(oxoalkyl) α-aryl methylphosphonate 11a-d and 12a-d is described. Trichloroacetimidates 3a-d were treated with activated arenes, styrene, allyltrimethylsilane or silylenol ethers C-nucleophiles in the presence TMSOTf to afford the desired products in good yields and short reaction time.     

α-萘乙酸的高效液相色谱分析

采用高效液相色谱法 ,hypersil 5μmC1 8柱 ( 4 .6× 2 50mm) ,以pH =3～ 4的V(甲醇 )∶V(水 )∶V(磷酸 )=60∶40∶0 .35为流动相 ,检测波长 2 72nm ,测定α -萘乙酸的含量。在 0 .0 1 6～ 1 .0 0 0 g/L范围内 ,浓度与峰面积线性关系良好 (r =0 .9997) ,精密度RSD为 0 .8% (n =5) ,方法简便 ,准确。