Sustainable Three‐Component Synthesis of Isothioureas from Isocyanides,Thiosulfonates, and Amines

Multiple applications of isothioureas as fine chemicals (or their precursors) are known, but a general sustainable method for their synthesis was hitherto unavailable. We report a novel general approach towards S‐alkyl and S‐aryl isothioureas through a copper(I)‐catalyzed three‐component reaction between amines, isocyanides, and thiosulfonates. The formal synthesis of a superpotent sweetener further illustrates the applicability of our method.     

Stereoselective Total Synthesis of (3S,5S)‐1,7‐Bis(4‐hydroxyphenyl)heptane‐3,5‐diol, (3S,5S)‐Alpinikatin,and Its Diastereoisomers

Stereoselective synthesis of the diarylheptanoids, (3S,5S)‐1,7‐bis(4‐hydroxyphenyl)heptane‐3,5‐diol ( 1 ), (3S,5S)‐alpinikatin ( 3 ), and their diastereoisomers ( 2 and 4 , resp.), was achieved from readily available 4‐hydroxybenzaldehyde. The synthetic sequences involve Browns's allylation and Et₂Zn mediated diastereoselective alkynylation reaction as key steps.     

An Improved Asymmetric Synthesis of Unusual Amino Acid (2S,3S)‐3‐Hydroxyproline

Abstract

An improved three‐steps method for the conversion of N‐benzyl (S)‐3‐hydroxypyrrolidin‐2‐one 6 to (2S,3S)‐3‐hydroxyproline 1 is reported. The key step is the reductive cyanation of 6. The synthesis of 1 constitutes a formal asymmetric synthesis of (2S,3S)‐3‐hydroxyproline betaines 2.     

Synthesis,Characterization, Thermal Decomposition,and Kinetic Studies of Binuclear Sulfur‐Coordinated Tungsten(V) Complexes with Piperidine‐1‐carbodithioate

We describe the synthesis, characterization by IR and electronic spectra, magnetic susceptibility measurements, analytical data, kinetic study by differential‐scanning calorimetry, and thermogravimetric analysis of the thermal decomposition under N₂ of the adducts 2 – 7 with pyridine or substituted pyridines of bis(piperidine‐1‐carbodithioato‐κS,κS′)di‐μ‐thioxodithioxoditungsten(V) ( 1 ), to which the general formula [W₂B₂(pipCS₂)₂S₂(μ‐S)₂] is assigned (pipCS₂=piperidine‐1‐carbodithioato and B=pyridine (py), 3‐methylpyridine (3‐Mepy), 4‐methylpyridine (4‐Mepy), 3,5‐dimethylpyridine (3,5‐Me₂py), pyridin‐3‐amine (3‐pyNH₂), and pyridin‐4‐amine (4‐pyNH₂)). For the endothermic process of loss of the coordinated base B, we calculated activation energies with a method reported previously by us; the mechanism and pre‐exponential Arrhenius factor of this reaction were also determined. A relationship between the pyridines' basicity, IR and electronic spectral data, and activation energies was established.     

A Convenient Approach to the Enantiopure （1S, 2S, 4S, 5S ）- and（ 1R, 2S, 4R, 5 S ）-2,5-Bis （ phenylmethyl）-l, 4-diazabicyclo[ 2.2.2 ] -octane

Cyclodipepflde (3S, 6S )-bis (phenylmethyl) piperazlne-2,5-dione was prelmred in high yield by heating phenylalanine methyl ester in toluene under reflux. The reduction of this cydodipeptide with sodium NaBH4-BF3 in DIME gave the (2S ,SS)-bis(phenyl-methyl)plperazine, which, on heating with ethylene bromide and triethyiamine, afforded the title compounds. This methodwas proved to be generally applicable to the synthesis of C2-symmetric 2, 5-disubsiituted=l, 4-diazabicyclo [ 2.2.2 ] octanefrom the corresponding natural or unnatural amino acid esters.     

Synthesis of (−)‐Pinellic Acid and Its (9R,12S,13S)‐Diastereoisomer

The total synthesis of (?)‐pinellic acid with (9S,12S,13S)‐configuration and its (9R,12S,13S)‐diastereoisomer was achieved in high overall yields from a common intermediate derived from (+)‐L ‐diethyl tartrate.     

Synthesis and characterization of second‐generation S,S‐dialkyl‐S‐(dimethylhydroxyphenyl)sulfonium salt photoinitiators

A new, simplified method has been developed for the synthesis of S,S‐dialkyl‐S‐(dimethylhydroxyphenyl)sulfonium salt cationic photoinitiators. This novel method has successfully been used for the preparation of S,S‐dialkyl‐S‐(3,5‐dimethyl‐4‐hydroxyphenyl)sulfonium and S,S‐dialkyl‐S‐(3,5‐dimethyl‐2‐hydroxyphenyl)sulfonium salts showing a wide variation in the length and structure of the alkyl chains on the positively charged sulfur atom. These photoinitiators can also be prepared with a wide variety of different anions. The manipulation of the lengths of the alkyl chains permits the design of compatible photoinitiators for highly nonpolar monomers and oligomers such as epoxy‐functional silicones, epoxidized polybutadiene, and epoxidized vegetable oils. This article describes the synthesis and characterization of these photoinitiators. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 2556–2569, 2003     

Synthesis and biological activity of l‐aminoindan‐l,3‐dicarboxylic acid,a benzo‐analogue of (1S, 3R)‐ACPD

Amino acids 1 and 2 were designed and synthesized as the conformationally constrained analogues of (1S, 3R)‐ or (1S, 3S)‐ACPDs, and the selective agonists of mGluRs. The synthesis started from (R)‐phenylglycine using Seebach′s stereocenter self‐regeneration method and intramolecular acylation as key steps. No activity was found when 1 and 2 were tested as either mGluR agonist or antagonist.     

New Convenient Reagents for Chemoselective N‐Alkoxycarbonylation of (S)‐Isoserine: Application in the Isepamicin Synthesis

A synthesis of a series of N‐alkoxycarbonyl mercaptobenzothiazoles (MBTs) and their application as reagents for chemoselective protection of amino group are presented herein. It was shown that all new reagents, Z‐MBT, Fmoc‐MBT, Phoc‐MBT, and Tec‐MBT, are highly effective in the selective N‐alkoxycarbonylation of (S)‐isoserine. The transformation is a simple, fast, and low‐cost protocol, which is applicable in scale‐up experiments. The starting MBT was fully recovered at the end of the process, which is an additional advantage of the method. The efficiency of the Z‐reagent was also demonstrated by the selective protection of both gentamicin B and (S)‐isoserine before their peptide‐type coupling in the synthesis of the aminoglycoside antibiotic isepamicin.     

General Formation of MxCo3−xS4 (M=Ni,Mn, Zn) Hollow Tubular Structures for Hybrid Supercapacitors

A simple and versatile method for general synthesis of uniform one‐dimensional (1D) M_xCo_3?xS₄ (M=Ni, Mn, Zn) hollow tubular structures (HTSs), using soft polymeric nanofibers as a template, is described. Fibrous core–shell polymer@M‐Co acetate hydroxide precursors with a controllable molar ratio of M/Co are first prepared, followed by a sulfidation process to obtain core–shell polymer@M_xCo_3?xS₄ composite nanofibers. The as‐made M_xCo_3?xS₄ HTSs have a high surface area and exhibit exceptional electrochemical performance as electrode materials for hybrid supercapacitors. For example, the MnCo₂S₄ HTS electrode can deliver specific capacitance of 1094 F g^?1 at 10 A g^?1, and the cycling stability is remarkable, with only about 6 % loss over 20 000 cycles.     

General Formation of MxCo3−xS4 (M=Ni,Mn, Zn) Hollow Tubular Structures for Hybrid Supercapacitors

A simple and versatile method for general synthesis of uniform one‐dimensional (1D) M_xCo_3−xS₄ (M=Ni, Mn, Zn) hollow tubular structures (HTSs), using soft polymeric nanofibers as a template, is described. Fibrous core–shell polymer@M‐Co acetate hydroxide precursors with a controllable molar ratio of M/Co are first prepared, followed by a sulfidation process to obtain core–shell polymer@M_xCo_3−xS₄ composite nanofibers. The as‐made M_xCo_3−xS₄ HTSs have a high surface area and exhibit exceptional electrochemical performance as electrode materials for hybrid supercapacitors. For example, the MnCo₂S₄ HTS electrode can deliver specific capacitance of 1094 F g⁻¹ at 10 A g⁻¹, and the cycling stability is remarkable, with only about 6 % loss over 20 000 cycles.     

An efficient asymmetric synthesis of (4R,8R)‐4,8‐dimethyldecanal,the most active component of natural Tribolure

An asymmetric synthesis of (4R,8R)‐4,8‐dimethyldecanal, the most active component of natural tribolure, was achieved through an asymmetric methylation as a key step and chiral‐pool strategy. Natural tribolure is a mixture of four stereoisomers, (4R,8R)/(4R,8S)/(4S,8R)/(4S,8S), and their ratio is 4/4/1/1. However, the (4R,8R)‐isomer is the most active one. Based on a chiral‐pool strategy, we used a recycled chiral molecular (R)‐4‐(Benzyloxy)‐3‐methylbutanal that we exploited in our previous article. After executing a C5 + C5 + C2 synthetic plan, the target molecule was obtained in nine linear steps and in 36.8% overall yield.     

Asymmetric Synthesis of All Possible Stereomers of 4‐Aminoglutamic Acid via Michael Condensation of Chiral Ni(II) Complexes of Glycine and Dehydroalanine

A new method for asymmetric synthesis of all possible stereomers of 4‐aminoglutamic acid has been developed. The method is based on asymmetric Michael condensation of the nucleophilic moiety of glycine and electrophilic moiety of dehydroalanine in their chiral Ni(II) complexes of the Schiff's bases with (S)‐ and (R)‐2‐N‐(N′‐benzylprolyl)aminobenzophenones, resulting in the formation of dimeric complexes of 4‐aminoglutamic acid. Stereoselectivity of the asymmetric condensation of the complexes exceeded 94%. The condensation of nucleophilic and electrophilic complexes in four possible combinations has resulted in the formation of dimeric complexes of all the stereomers of 4‐aminoglutamic acid: (2S,4S), (2S,4R)‐meso and (2R,4R). Optically active stereomers of 4‐aminoglutamic acid with high optical purity were isolated after decomposition of the dimeric complexes.     

Absolute Asymmetric Synthesis of Enantiopure Organozinc Reagents,Followed by Highly Enantioselective Chlorination

We report the absolute asymmetric synthesis (AAS) of indenylzinc reagents by using total spontaneous resolution followed by enantiospecific conversion into 1‐chloroindene. The chiral complex [Zn(dcp)(ind)(tmeda)] (dcp=2,6‐dichlorophenoxy and tmeda=N,N,N′,N′‐tetramethylethylenediamine) ( 3 ) was prepared from the achiral starting materials indene, potassium, zinc chloride, TMEDA, and 2,6‐dichlorophenol. The reagent resolved spontaneously on crystallization, and single crystals of 3 react with N‐chlorosuccinimide in the presence of benzoquinone in 2‐propanol to give 1‐chloroindene in >98 % enantiomeric excess. It was found that (R)‐ 3 gave (R)‐1‐chloroindene upon reaction, indicating an S_E2′‐mechanism. Since bulk samples of 3 gave optically active product upon chlorination, total spontaneous resolution must have occurred. This demonstrates that enantiopure products can be obtained through the absolute asymmetric synthesis of organometallic reagents starting from achiral materials. The general absolute asymmetric synthesis (AAS) method offers easy access to both enantiomers and an almost limitless variation in the design of the product.     

Regio‐ and Stereoselective Allylic Substitutions of Chiral Secondary Alkylcopper Reagents: Total Synthesis of (+)‐Lasiol, (+)‐13‐Norfaranal,and (+)‐Faranal

Chiral secondary alkylcopper reagents were prepared from chiral secondary alkyl iodides by a retentive I/Li exchange followed by a retentive transmetalation with CuBr?P(OEt)₃. Switching the solvent to THF significantly increased their configurational stability and made these copper reagents suitable for regioselective allylic substitutions. The optically enriched copper species underwent S_N2 substitutions with allylic bromides (up to >99 % S_N2 regioselectivity). The addition of ZnCl₂ and the use of chiral allylic phosphates allowed to switch the regioselectivity towards S_N2′ substitution (up to >99 % S_N2′ regioselectivity) and to perform highly selective anti‐S_N2′ substitutions with absolute control over two adjacent stereocenters. This method was applied in the total synthesis of the three ant pheromones (+)‐lasiol, (+)‐13‐norfaranal, and (+)‐faranal (up to 98:2 dr, 99 % ee).     

Disulfonimide‐Catalyzed Asymmetric Reduction of N‐Alkyl Imines

A chiral disulfonimide (DSI)‐catalyzed asymmetric reduction of N‐alkyl imines with Hantzsch esters as a hydrogen source in the presence of Boc₂O has been developed. The reaction delivers Boc‐protected N‐alkyl amines with excellent yields and enantioselectivity. The method tolerates a large variety of alkyl amines, thus illustrating potential for a general reductive cross‐coupling of ketones with diverse amines, and it was applied in the synthesis of the pharmaceuticals (S)‐Rivastigmine, NPS R‐568 Hydrochloride, and (R)‐Fendiline.     

Synthesis of Glycoborine,Glybomine A and B,the Phytoalexin Carbalexin A and the β‐Adrenoreceptor Antagonists Carazolol and Carvedilol

We describe a regioselective synthesis of 4‐ or 5‐substituted carbazoles by oxidative cyclisation of meta‐oxygen‐substituted N‐phenylanilines. Using the regiodirecting effect of a pivaloyloxy group, we prepared 4‐hydroxycarbazole, a precursor for the enantiospecific synthesis of the β‐adrenoreceptor antagonists (?)‐(S)‐carazolol ( 5 ) and (?)‐(S)‐carvedilol ( 6 ). Regioselective palladium(II)‐catalysed cyclisation of different diarylamines led to total synthesis of glycoborine ( 7 ) and the first total syntheses of the phytoalexin carbalexin A ( 8 ), glybomine A ( 9 ) and glybomine B ( 10 ). For glybomine B ( 10 ), a 5‐hydroxycarbazole was converted into the corresponding triflate and utilized for introduction of a prenyl substituent.     

Total Synthesis and Structure Elucidation of JBIR‐39: A Linear Hexapeptide Possessing Piperazic Acid and γ‐Hydroxypiperazic Acid Residues

The total synthesis and stereochemical structural elucidation of JBIR‐39, containing four nonproteinogenic piperazic acid (Piz) residues, is reported. The synthesis includes Sc(OTf)₃‐catalyzed acylation of a Piz(γ‐OTBS) derivative with piperazic acid chloride, providing the desired Piz‐Piz(γ‐OTBS) dipeptide in high yield without epimerization. After assembling two additional Piz moieties and (S)‐isoleucic acid at the N‐terminus, amidation with the (R)‐α‐methylserine ester at the C‐terminus, and deprotection afforded the desired (2R,8S)‐hexapeptide, which is the assumed structure of JBIR‐39. Although the spectral data of the (2R,8S)‐hexapeptide was not identical to JBIR‐39, further synthesis of three stereoisomers confirmed the stereochemical structure of JBIR‐39 to be (2S,6S,8S,11R,16S,21R,26S,27S).     

Synthesis and characterization of soluble low‐bandgap oligothiophene‐[all]‐S,S‐dioxides‐based conjugated oligomers and polymers

The synthesis and characterization of a new family of soluble oligothiophene‐S,S‐dioxides and their use as building blocks to form polythiophene‐S,S‐dioxides via microwave‐assisted Stille coupling polymerization are described. Incorporation of the sulfone group into the polythiophene backbone leads to narrowing of the polymer bandgap, and while the energies of both Frontier orbitals in polythiophene‐S,S‐dioxide are lower with respect to polythiophenes, this tendency is considerably stronger for the lowest unoccupied molecular orbital than for the highest occupied molecular orbital, resulting in greater electron‐accepting ability. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Novel Bis(2‐cyanoketene‐S,S‐/S,N‐acetals): Versatile Precursors for Novel Bis(aminopyrazole) Derivatives

A synthesis of novel bis(aminopyrazoles) by the reaction of hydrazine hydrate with the appropriate bis(2‐cyanoketene‐S,N‐acetals) was reported. The latter compounds were prepared by treatment of bis(cyanoacetamides) with phenyl isothiocyanate in KOH/EtOH and subsequent alkylation with methyl iodide. The utility of bis(2‐cyanoketene‐S,S‐acetals) as building blocks for novel bis(aminopyrazoles) was also investigated.