Enantioselective trapping of oxonium ylide intermediates by N-benzhydryl-α-imino ester:Synthesis of β-tetrasubstituted α-amino acids

A synergistic rhodium(Ⅱ)/phosphoric acid catalyzed three component reaction of 3-diazooxindoles,alcohols and N-benzhydryl-α-imino ester is developed for the efficient construction of chiral β-alkoxy C~β-tetrasubstituted α-amino acid derivatives in good yields and with excellent diastereoselectivities and high enantioselectivities.The synthetic application of the resulting products was illustrated by reducing with Pd/C under H_2 atmosphere followed reacting with CSCl_2 at room temperature to rapid afford 3-spirocyclic oxindole in a good yield with a chirality retainment.The three-component reaction is proposed to proceed through an electrophilic trapping of the oxonium ylides by N-benzhydryl-α-imino ester.     

Study on Fmoc Solid-phase Synthesis and Activity of Thymosin α1

Thymosin α1 (Tα1), an immunologically polypeptide, [1] is highly acidic composed of 28 amino acid residues with acetylserine as the NH2 terminus. The MW of this peptide is 3108, with pI 4.2. There are many Asp and Glu in this molecule and the complete amino acid sequence of Tα1 is Ac-Ser-Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu-IleThr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu-Ala-Glu-Asn-OH. This peptide has potent biological activity and has been found to be 10～ 1000 times as active as thymosin F5. In this paper, a Tα1 has been synthe sized by a solid-phase method. Peptide synthesis was performed manually by the stepwise solid-phase method using the base-labile Fmoc group for protecting the α-amino acid. [2]     

Improved synthesis of rupintrivir

An improved synthesis of rupintrivir (AG7088) was accomplished using three amino acids (L-glutamic acid, D-4-fluorophenylalanine, and L-valine) as the building blocks. The key fragment ketomethylene dipeptide isostere was constructed with the valine derivative and phenylpropionic acid derivative, followed by coupling with a lactam derivative and an isoxazole acid chloride to provide AG7088 totally in eight steps.     

A New Esterification Reaction in Synthesis of Gibberellins

Esterification is an important reaction in organic synthesis. In the synthesis of gibberellin derivative, a new es terification reaction was found. Ent-16-oxo-20-norgibberella-9-ene-7, 19-dioic acid 7-(methyl ester) (Ⅰ) is a key material in synthesis of GA73. [1] Ⅰ is dissolved in acetone, and treated with ICl and anhydrous K2CO3 at room temperature for 2 h to produce a new ester, ent-16-oxo-20-norgibberella-9-ene-7, 19-dioic acid 7-(methyl ester), 19-(oxopropyl ester ) (Ⅱ). The yield is above 90%. The structure of Ⅱ is confirmed by NMR and MS.     

Synthesis of N-(methoxycarbonyl or isopropylcarbamoyl- methoxyphosphonyl)-α-amino acid ester and their stereomers

N-(methoxycarbonyl-methoxyphosphonyl)-α-amino add esters (I) were synthesized via the reaction of the corresponding phosphonyl chloride with amino acid ester hydrochlorides in the presence of a base. Compound I was aminated to yield N-(isopropylcarbainoyl-methoxyphosphonyl)-α-amino acid esters (II). With l-amino acids as starting materials, the isomers of products I and II were separated and their configurations were confirmed by the single crystal X-ray diffraction of II.     

Synthesis of Some New Heterocycles Derived from Phenylacetyl Isothiocyanate

Phenylacetyl isothiocyanate (1) was reacted with benzoyl hydrazine (2a) in acetonitrile to give thiosemicarbazide derivative 3 which was cyclized by polyphosphoric acid to give 1,2,4-triazoline-5-thione derivative 4. Treatment of 1 with thiosemicarbazide (2b) yielded another 1,2,4-triazoline-5-thione derivative 5. Similar treatment of 1 with phenyl hydrazine (2c) in acetonitrile gave a differently substituted 1,2,4-triazoline-5-thione derivative 6 in one pot-reaction. On the other hand, when the reaction was carried out in acetone, a mixture of 6 and thiadiazolidine derivative 7 was obtained. However, reaction of 1 with hydrazine hydrate (2d) gave hydrazine derivative 8. Reaction of isothiocyanate 1 with anthranilic acid (9) gave benzo[d][1,3,6]oxazin-1-one derivative 10. Treatment of 1 with 2-aminothiophenol (11a), 2-aminophenol (11b) or o-phenylenediamine (11c) produced benzothiazole derivative 12a, benzoxazole derivative 12b and benzimidazole derivative 12c, respectively. The structures of all the products were confirmed by micro-analytical and spectral data.     

硅胶键合的N-丙基三亚乙基四胺氨基磺酸作为可回收固体酸催化剂催化合成2-氨基-4,6-二芳基烟腈(英文)

A simple and efficient procedure for the preparation of silica-bound N-propyl triethylenetetramine sulfamic acid(SBPTETSA) by the reaction of silica-bound N-propyl triethylenetetramine(SBPTET) with chlorosulfonic acid in chloroform is described.Silica-bound N-propyl triethylenetetramine sulfamic acid was employed as a recyclable catalyst for the synthesis of 2-amino-4,6-diarylnicotinonitriles from the multi-component reaction of an acetophenone derivative,an aromatic aldehyde,malononitrile,and ammonium acetate under solvent-free conditions at 100 °C.The heterogeneous catalyst was recycled for five consecutive runs in the optimized multi-component reaction of 4-chloroacetophenone,4-chloroenzaldehyde,malononitrile,and ammonium acetate without significant loses to its catalytic activity.     

Asymmetric Addition of Diethylzinc to Aldehydes Using SPINOL Derivatives

Lewis acid catalyzed enantioselective carbon-carbon bond formation is one of the most interesting challenges in catalytic asymmetric synthesis. A convenient route for this synthesis is the addition of organozinc to aldehydes.[1]1,1'-Spirobiindane-7,7'-diol (SPINOL), a new reported C2 symmetrical diol, was recently proven to be an excellent framework for chiral ligands.[2] In this paper, interestingly, we describe the preparation of SPINOL derivatives and application of these ligands to asymmetric addition of diethylzinc to aldehydes as model reaction. Previously, an improved method for the resolution of C2-symmetric spirocyclic SPINOL was presented with crude menthyl chloroformate as resolving reagent.[3] Then (R)-SPINOL with C2-symmetric spirocyclic framework was applied in the asymmetric diethylzinc addition to aromatic aldehydes, which induced high conversions and moderate enantioselectivities for the production of chiral secondary alcohols. Further work of other SPINOL derivative ligands for asymmetric diethylzinc addition to aromatic aldehydes and developing further new SPINOL-based Lewis acid catalyzed asymmetric synthesis are underway.     

Synthesis of novel fullerene α-amino acid conjugates

Aspartic acid and glutamic acid with protectedα-amino andα-carboxyl groups had been used to react with the activated hydroxyl group of N-substituted 3,4-fullero pyrrolidine.The products were deprotected,affording two monofullereneα-amino acids,monofullerene aspartic acid(mFas)and monofullerene glutamic acid(mFgu).Then a bifullerene glutamic acid conjugate (bFguC)was synthesized by reaction of mFgu containing protected amino group with N-substituted 3,4-fullero pyrrolidine.     

Synthesis of 1-Bromo-3-methoxy-4-propoxy-5-iodobenzene——A Novel Efficient Process for the Synthesis of Brominated Aromatic Compound

The reaction of aromatic carboxylic acid with oxalyl chloride gives rise to the corresponding acid chloride which without purification is treated with the sodium salt of mercaptopyridine oxide in the presence of 2,2-azo-bisisobutyronitrile (AIBN), radical initiator to give a brominated aromatic compound. After etherification and oxidation, 5-iodovaniline was converted to trisubstituted benzene carboxylic acid which give 1-bromo-3-methoxy-4-propoxy-5-iodobenzene by this new brominating process with a yield of 74%.     

ASYMMETRIC ADDITION OF (+)-CAMPHOR SULFINIMINES WITH DIETHYLALUMINUM CYANIDE

The development of new and improved methods for the asymmetric synthesis of α-amino acids is of considerable current interest because of their importance in biological systems and their exceptional utility as chiral building blocks. Of the many methods used to prepare α-amino acids, the asymmetric Strecker synthesis should hold particular prominence because of its simplicity¹. Recently, F. A. Davis and his coworkers reported that diethylaluminum cyanide (Et₂AlCN) adds to enantiopure p-tolylsulfinimines to give α-sulfinamino nitriles at 82-84% diastereoselectivity. Treatment of α-sulfinamino nitriles with acid removes the chiral auxiliary p-tolylsulfinyl group and hydrolyzes the nitrile to give α-amino acids without epimerization². This research was quoted in Highlight by Chemistry & Industry as an improved asymmetric Strecker synthesis³. However, the diastereoselectivity of this addition reaction needs to be improved more high, and moreover, the preparation of p-tolylsulfinimines from nonracemic p-tolylsulfinamides and aldehydes needs strong organic metallic bases^2b, so it is desirable to design an easier prepared and effective optical sulfinimines.     

Determination of glyoxylic acid in urine by liquid chromatography with fluorescence detection, using a novel derivatization procedure based on the Petasis reaction

The Petasis reaction is the multi-component reaction of a carbonyl compound, amine, and arylboronic acid to form an α-amino acid or a β-aminoalcohol. In this work, as the first analytical application of the Petasis reaction, a high-performance liquid chromatographic (HPLC) method with fluorescence detection was developed for determination of glyoxylic acid. The glyoxylic acid was derivatized with 1-pyreneboronic acid, as fluorescent arylboronic acid, in the presence of N-methylbutylamine, as amine, to give a fluorescent α-amino acid. HPLC separation of the fluorescent derivative was performed within 30 min on an octyl column eluted with a gradient prepared from acetonitrile and 50 mmol L(-1) acetate buffer (pH 4.0). The detection limit (S/N=3) for glyoxylic acid was 5.0 nmol L(-1) (20 fmol/injection). The method can be used to determine the concentration of glyoxylic acid in human urine without interference from biological components.     

Design and synthesis of trans-3-aminopyran-2-carboxylic acid (APyC) and α/β-peptides with 9/11-helix

A new β-amino acid, trans-3-aminopyran-2-carboxylic acid (APyC), was designed and synthesized from (R)-glyceraldehyde derivative and used in the synthesis of α/β-peptides in a 1 : 1 alternating pattern with d-Ala. The presence of oxygen atom at the Cβ(2)-position in APyC was envisaged to provide opportunity for additional interaction. These hybrid peptides have shown the presence of 9/11-helix through extensive NMR and MD studies. The amide protons of d-Ala, in addition to participating in 9-mr H-bonding with CO of succeeding β-residue, were also involved in additional electrostatic interaction with pyran ring oxygen of preceding β-residue, which facilitated further stabilization to the 9/11-mixed helix. The study thus results in a new 'motif' for a 9/11-helix, and the first example from a cyclic β-amino acid.     

New chiral phase-transfer catalysts possessing a 6,6′-bridged ring on the biphenyl unit: application to the synthesis of α,α-dialkyl-α-amino acids

A new chiral phase-transfer catalyst possessing a 6,6′-bridged ring on the biphenyl unit has been developed for the practical synthesis of α,α-dialkyl-α-amino acids. This catalyst shows very high activity for the asymmetric alkylation of an alanine derivative to give α,α-dialkyl-α-amino acid derivatives with high enantioselectivities.     

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.     

Stereoselectivity in the construction of rigidified homoserine analogues

Methyl substituted cyclohexyl-1-amino-3-hydroxy-1-carboxylic acid derivatives have been prepared from 5,5-tethered dienes of (2R)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazine in stereoselective syntheses. Ring closing metathesis reaction of the diene 2 afforded a heterospirenone which was the substrate for conjugate addition with an alkyl cuprate. Reduction of the adduct followed by hydrolytic cleavage of the heterocyclic ring provided a cyclic α-amino acid derivative. The absolute configuration at the new stereocenters in the products were established by X-ray crystallography analyses.     

Synthesis and application of enantioenriched functionalized α-tetrasubstituted α-amino acids from biocatalytic desymmetrization of prochiral α-aminomalonamides

Catalyzed by Rhodococcus erythropolis AJ270, an amidase-containing microbial whole cell catalyst in neutral phosphate buffer at 30 °C, a number of prochiral α-substituted α-aminomalonamides underwent highly efficient and enantioselective hydrolytic desymmetrization to afford functionalized α-tetrasubstituted α-amino acids in 74-98% chemical yields and 94.0 to >99.5% ee. The presence of a free α-amino (NH(2)) substituent in the substrates was deemed important to ensure high biocatalytic efficiency and enantioselectivity. The synthetic application of biocatalytic desymmetrization was demonstrated by practical chemical transformations of (R)-2-amino-2-carbamoylpent-4-enoic acid to α-substituted serine analogues and a bioactive diamino alcohol derivative.     

Direct Trapping of Ketene Intermediate by Internal Nucleophile:A New Approach for the Synthesis of γ-Lactams

The application of Wolff rearrangement of the diazoketones derived from α-amino acids has been well documented.¹ It has been generally observed that if the rearrangement is performed in aqueous solution, homologated acid is the expected products, while if the reaction is run in methanol or ammonia, the corresponding homologated ester or amide will be obtained. In connection with other synthetic work, we unexpectedly observed that the Wolff rearrangement of diazoketone 1 in anhydrous methanol gave exclusively γ-lactam 3 in excellent yield.(Scheme 1) The formation of this intramolecular cyclization product was apparently due to the nucleophilic attack of the intermediate ketene 2 by the tosyl protected amino group. Although the solvent methanol can serve as nucleophile, the exclusive formation of γ-lactam indicates the intermolecular nucleophilic attack of the ketene intermediate 2 by methanol is not effective enough to compete with intramolecular nucleophilic attack by the tosyl protected amino group. This observation aroused our interest in the generality of this reaction and its potential as a novel method for the direct synthesis of γ-lactams. We report here the results of the investigation of Wolff rearrangement of several diazoketones derived from N-tosyl protected α-amino acids and β-amino acids.     

A Diels-Alder approach for the synthesis of highly functionalized benzo-annulated indane-based α-amino acid derivatives via a sultine intermediate

The synthesis of various highly functionalized benzo-annulated indane-based α-amino acid (AAA) derivatives are reported via a [4+2] cycloaddition strategy using a sultine derivative, containing an AAA moiety, as a reactive diene component. By adopting this strategy, a new α,α-dialkylated indane-based C₆₀ fullerene containing a constrained AAA unit is reported.     

Novel syntheses of hydantoin derivativesK

N-Substituted hydantoin derivatives have been synthesized by the condensation of an α-amino acid derivative, a primary amine and diphenyl carbonate. The method has been applied to the synthesis of hydantoin derivatives with two hydroxyl and/or carboxyl groups.