Syntheses of novel 4-tert-alkyl ether proline-based 16- and 17-membered macrocyclic compounds

Starting from N-Cbz-4-hydroxyproline methyl ester 1, a boron trifluoride-diethyl etherate-catalyzed reaction provided 4-tert-alkyl ether proline 4. Two deprotections and amide bond formations furnished the phenol alcohol 2. The macrocyclization of 2 was accomplished through a Mitsunobu reaction using triphenylphosphine and 1,1'-(azodicarbonyl)dipiperidine (ADDP), to afford novel 16- and 17-membered proline-based macrocyclic compounds of type 3.     

Synthesis of a hydroxyethylene isostere of the tripeptide Arg-Gly-Leu via a convergent acyl-like radical addition strategy

[reaction: see text] A hydroxyethylene isostere of the tripeptide Arg-Gly-Leu, representing an important fragment of a novel cyclic-peptide-based uPA inhibitor, was synthesized in few steps employing as the key step a samarium diiodide promoted coupling of either the 4-thiopyridyl ester of N(alpha)-Fmoc- or N(alpha)-Cbz-protected L-ornithine with the N-acryloyl derivative of L-leucine methyl ester. Epimerization under the coupling conditions at the chiral center in the alpha-position to the ketone was demonstrated not to take place. A stereoselective reduction of the Cbz-protected aminoketone obtained from this radical reaction was promoted by the same single-electron reducing agent in the presence of methanol providing the syn-amino alcohol with a diastereoselectivity of 85:15. With the use of lithium tri-tert-butoxyaluminum hydride in methanol, the corresponding anti-isomer was obtained almost exclusively. Subsequent elaboration of the ornithine moiety in the anti-isomer by introduction of the guanidine group followed by hydrolysis of the C-terminal ester bond and protection of the alcohol as its tert-butyldimethylsilyl ether provided the desired tripeptide mimic. The long reaction times required for the radical addition reactions with N(delta)-Boc-L-ornithine (up to 5 days) led to a short study where a series of 4-thiopyridyl esters of Cbz-protected amino acids were reacted with two acrylates. Whereas N(delta)-Boc-L-ornithine, alanine, phenylalanine, proline, and leucine all provided the aminoketone in 43-79% yield, valine only afforded traces of the coupling product.     

Synthesis of homopropargyl alcohols via sonochemical Barbier-type reaction

A series of homopropargyl alcohols were synthesized from the reaction mixture of zinc powder, 1,2-diiodoethane, 3-bromo-1-propyne and aldehyde or ketone in anhydrous THF under ultrasound. The homopropargyl alcohols were obtained as the only product in all cases when aldehydes were reacted with 3-bromo-1-propyne under this sonochemical Barbier-type reaction condition. The homopropargyl alcohol was produced as the major product and the low contamination of allenyl alcohol was also obtained when ketone was used as substrate under the reaction condition.     

Fluorescence Assay of Proline: Competitive Inhibition of Fluorescamine Reaction

Abstract

The rate of reaction of fluorescamine with proline is faster than with primary amino acids. Proline competitively inhibits the fluorogenic reaction of primary amines with fluorescamine, the degree of inhibition being proportional to the amount of proline. Under the conditions described, 5×10^?7 M proline produces a 10% diminution of fluorescence. An assay of proline or hydroxyproline based on fluorescence inhibition would be more sensitive than colorimetric assays based on ninhydrin or fluorescamine.     

A study of glutamine interference in the acidified ninhydrin reaction for proline

In the application of the acidified ninhydrin reaction to the estimation of free proline in plant extracts, glutamine was a major source of interference, all others being minor, absent or removable with Permutit. Some characteristics of glutamine interference in this reaction are described. A ratio of linear errors method for the correction of proline values to the glutamine free state is introduced. The glycine and proline concentration in the reaction mixtures are prime factors in obtaining a ratio of linear errors by spectrophotometric measurement at 2 wavelengths.     

A Diels-Alder Reaction Conducted Within the Parameters of Aqueous Organocatalysis: Still Just Smoke and Mirrors

Conducting reactions using water as solvent is a highly prized goal for the organic chemist. Based upon recent literature and our continuing interest in the field of aqueous organocatalysis, we tested the scope of an enamine based Diels-Alder reaction using (±)-nornicotine, proline, and a proline derivative as aqueous organocatalysts. Unfortunately, none of the examined catalysts under aqueous conditions proved useful, leaving the aqueous Diels-Alder reaction as an elusive goal.     

Generation of functionalized azomethine ylides and their application to stereoselective heterocycle synthesis: an equivalent process of C-unsubstituted nitrile ylide cycloaddition reaction

The synthetic process equivalent to C-unsubstituted (CH) nitrile ylides cycloaddition reaction is achieved via cycloaddition of NH-azomethine ylide and the following fission reaction of the cycloadducts under acidic conditions. Cycloaddition of NH-azomethine ylide generated by a thermal 1,2-prototropy in 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde system with maleimides provides proline derivatives under extremely mild conditions. Heating their adducts in AcOH at 85 °C causes a cleavage of C-C bond between the proline and heterocyclic moiety to give the parent heterocyclic system and dehydroproline derivatives, which is regarded as a cycloadduct of C-unsubstituted (CH) nitrile ylide. This cycloaddition-fission reaction sequences can be applied to one-pot three-component reaction.     

Diastereoselectivities realized in the amino acid catalyzed aldol cyclizations of triketo acetonides of differing ring size

A study designed to assess the diastereoselectivity of the intramolecular aldol reaction of two differently sized monocyclic 1,3-diketones bearing a chiral, oxygenated side chain has been undertaken. The cyclizations were brought about under catalysis by pyrrolidine, a series of D- and L-amino acids including proline, and several proline derivatives. The levels of selectivity were found to be consistently higher with the six-membered ring system than its cycloheptane counterpart.     

Stereoselective synthesis of methyl branched chiral deoxypropionate units: a new route for synthesis of insect pheromone (−)-lardolure and (2R,4R,6R,8R) 2,4,6,8-tetramethylundecanoic acid

(−)-Lardolure and (2R,4R,6R,8R)-2,4,6,8-tetramethylundecanoic acid have been synthesized via lipase catalyzed desymmetrization strategy to create two methyl chiral centers. Other key steps involved in the synthesis are Wittig reaction, Evan’s asymmetric alkylation, Grignard reaction, Pd-catalyzed isomerization of primary allylic alcohol to corresponding saturated aldehyde, and PhNO/proline catalyzed MacMillan α-hydroxylation.     

Proline catalyzed two-component, three-component and self-asymmetric Mannich reactions promoted by ultrasonic conditions

The proline catalyzed two-component and three-component asymmetric Mannich reaction with hydroxyacetone and self-Mannich reaction with propanal were performed successfully under ultrasonic conditions in 1 h to afford Mannich products in 90-98% isolated yields and 81-99% ees with excellent diastereoselectivities.     

Probing the active catalyst in product-accelerated proline-mediated reactions

A new catalytic cycle involving only soluble proline complexes or adducts is proposed for the reactions in eq 1 based on kinetic observations and molecular modeling studies. This reaction pathway circumventing free proline and incorporating hydrogen-bonded reaction product helps to rationalize the observations of accelerating reaction rate in both the alpha-aminooxylation and alpha-amination reactions.     

Enantiospecific and Stereoselective Synthesis of Polyhydroxylated Pyrrolidines and Indolizidines from trans-4-Hydroxy-L-proline

We have developed a short, efficient, and stereoselective synthesis of polyhydroxylated pyrrolidine and indolizidine glycosidase inhibitors starting from 4-hydroxy-L-proline. The regio- and stereoselective hydroxylation of an N-Pf-4-oxoproline enolate and the stereoselective reduction of the resulting keto alcohol allowed us to introduce the cis diol present in the target compounds. The different side chains needed to complete the syntheses of the target compounds were introduced by reduction of the ester group of a substituted proline or by reaction of organolithium or organomagnesium reagents with the same group followed by stereoselective reduction of the resulting ketones. Hydrogenolysis of the alcohols thus obtained gave the hydrochlorides of the desired pyrrolidine glycosidase inhibitors, which were obtained in nine steps in overall yields greater than 50%. The indolizidine glycosidase inhibitor 8-epi-swainsonine was also prepared using this approach.     

The Ugi reaction with 2-substituted cyclic imines. Synthesis of substituted proline and homoproline derivatives

The Ugi three-component reaction with 2-substituted five-, six-, and seven-membered cyclic imines was investigated. The reaction opens a new route to substituted proline and homoproline derivatives. It was shown that the method is efficient for the one-step preparation of seminatural dipeptides containing natural amino acid residues, and fragments of substituted proline or pipecolinic acid. The scope and limitation of the approach are discussed.     

Type 3 ring opening reaction of cyclopropanated oxabenzonorbornadienes with alcohol nucleophiles

The first examples of a Type 3 ring opening reaction of cyclopropanated oxabenzonorbornadiene (CPOBD) were found to occur using alcohol nucleophiles under acid catalyzed conditions, yielding seven-membered rings via ring expansion. Optimization of the reaction determined the ideal conditions to be 10?mol% pTsOH at 40?°C using excess alcohol nucleophile as the solvent. The scope of the reaction investigated diverse alcohol nucleophiles and bridgehead substituents on the CPOBD; in both cases the steric properties of the substituent was found in influence the yield of the reaction. Alternative Type 3 products were observed when the bridgehead substituent was an ethyl or hydroxymethyl group and limited examples of Type 3 products were formed using a palladium catalyst with alcohol nucleophiles. Mechanisms have been proposed for the formation of the Type 3 product as well as the alternative Type 3 products.     

One-pot two-step reaction of selenosulfonate with isocyanides and allyl alcohol under aqueous conditions:Atom-economic synthesis of selenocarbamates and allyl sulfones

In many reactions involving selenosulfonate or thiosulfonate,the sutfone group often leaves in form of benzenesutfinic acid or sodium benzenesulfinate.A one-pot two-step reaction of selenosulfonate with isocyanides and allyl alcohol under aqueous conditions to afford selenocarbamates and allyl sulfone compounds is reported.The sulfinic acid as the first-step side product is converted to the allyl sulfone compound by water promoted reaction with allyl alcohol.Water acts as both an oxygen source of selenocarbamates and as a promoter to drive the second step reactio n.The reactions have the advantages of mild conditions,green,environment-friendly,and high atomic economy.     

One pot,three component 1,3 dipolar cycloaddition: Regio and diastereoselective synthesis of spiropyrrolidinyl indenoquinoxaline derivatives

A competent and highly discriminating one-pot synthesis of highly diversified novel functionalized indenoquinoxalone grafted spiropyrrolidine linked chromene-3-carbonitrile conjugates accumulating three pharmocophoric cores, heterocyclic indenoquinoxalone, pyrrolidines and chromene-3-carbonitrile in a single molecular framework by means of 1,3-dipolar cycloaddition reaction between indenoquinoxalone, proline/benzyl amine and chromene-3-carbonitrile in ethanol under classical and microwave conditions is described. The three component 1,3-dipolar cycloaddition reaction proceeds via in situ generation of azomethine ylides by the decarboxylative condensation of indenoquinoxalone with proline/benzyl amine and their selectivity towards the endo cyclic double bonds of dipolarophile (chromene-3-carbonitrile) leading to the formation of highly functionalised regio- and diastereoselective molecular hybrids. This methodology exemplifies the green chemistry protocol such as mild reaction conditions, high yields, one-pot procedure and operational simplicity.     

Zn取代的磷钨酸季铵盐无溶剂氧化苯甲醇合成苯甲醛

合成了一系列过渡金属Zn取代的Keggin型磷钨杂多酸的季铵盐,采用傅里叶变换红外光谱(FTIR)、X射线衍射(XRD)等方法表征了杂多化合物的结构.并将其用于苯甲醇无溶剂氧化合成苯甲醛的反应,考察了催化剂种类、反应条件对苯甲醇氧化的影响.实验结果表明,在无任何溶剂的情况下,Zn取代的Keggin型磷钨四丁基铵盐具有最佳的催化活性,反应时间仅为30 min,苯甲醇的转化率可以达到95.6%,苯甲醛的选择性达到了96.4%.在对杂多酸季铵盐结构的研究基础上,对可能的反应机理进行了初步探讨.     

Study of asymmetric aldol and Mannich reactions catalyzed by proline–thiourea host–guest complexes in nonpolar solvents

A proline–thiourea host–guest complex has been described as a good catalyst for asymmetric reactions such as aldol and Mannich reactions. High stereoselectivities were obtained under optimal conditions. Thiourea was observed to have an important effect on the reactivity and selectivity, even in an unconventional nonpolar reaction medium and without the need to utilize low temperatures. This proline–thiourea host–guest system has the ability to participate in a hydrogen bonding network.     

Facile transformation of glutamic acid into proline residue inside a tripeptide backbone

In this Letter we present a simple reaction pathway which allows the conversion of the glutamic acid residue of a tripeptide into a proline residue. The reaction was performed by using Boc-Val-Glu-Phe-NH₂ as a starting material and is based on a NaH-induced intraresidue alkylation under reaction conditions analogous to that adopted during the Freidinger lactams formation.     

Highly enantioselective organocatalysis of the Hajos-Parrish-Eder-Sauer-Wiechert reaction by the beta-amino acid cispentacin

The beta-amino acid cispentacin promotes the Hajos-Parrish-Eder-Sauer-Wiechert reaction with levels of enantioselectivity comparable to or higher than proline.