The acylation of 5H-2,3-benzodiazepines

The products obtained from the acylation of 4-phenyl-5$\text{H}$-2,3-benzodiazepine (5) are strongly dependent on the nature of the acylating agent and the reaction conditions. Reaction with acid anhydrides followed by a nucleophile gives the 1-substituted 2-acylbenzodiazepines (10) and (11) while reaction with acyl or sulphonyl halides either induces a ring transformation to give the 3-phenylisquinoline $\text{N}$-imine salts (12) or results in the formation of the acylated dimer (13) $\text{via}$ a dehydrochlorinated intermediate (15).     

Nickel or Palladium‐Catalyzed Decarbonylative Transformations of Carboxylic Acid Derivatives

Carboxylic acid derivatives containing acyl halides, anhydrides, esters, amides and acyl nitriles are highly appealing electrophiles in transition‐metal‐catalyzed carbon‐carbon bond‐forming reactions due to their ready availability and low cost, which can provide divergent transformations of carboxylic acids into other value‐added products. In this Minireview, we focus on the recent advances of decarbonylative transformations of carboxylic acid derivatives in carbon‐carbon bond formations using Ni or Pd catalysts. A series of reaction types, product classifications and reaction pathways are presented herein, which show the advantageous features of carboxylic acid derivatives as alternative to aryl or alkyl halides in terms of reactivity and compatibility. The well‐accepted mechanism of nickel‐ or palladium‐catalyzed decarbonylative transformations involves initial oxidative addition of carboxylic acid derivatives, followed by decarbonylation or transmetalation (or insertion), and reductive elimination to generate the products, thereby regenerating the catalysts.     

Solution phase synthesis of esters within a micro reactor

A range of techniques are demonstrated for the solution phase synthesis of esters within an EOF-based borosilicate glass micro reactor, including the use of mixed anhydrides and the in situ preparation of acyl halides.     

Synthesis and biological activity of tetralone abscisic acid analogues

Bicyclic analogues of the plant hormone abscisic acid (ABA) were designed to incorporate the structural elements and functional groups of the parent molecule that are required for biological activity. The resulting tetralone analogues were predicted to have enhanced biological activity in plants, in part because oxidized products would not cyclize to forms corresponding to the inactive catabolite phaseic acid. The tetralone analogues were synthesized in seven steps from 1-tetralone and a range of analogues were accessible through a second route starting with 2-methyl-1-naphthol. Tetralone ABA 8 was found to have greater activity than ABA in two bioassays. The absolute configuration of (+)-8 was established by X-ray crystallography of a RAMP hydrazone derivative. The hydroxymethyl compounds 10 and 11, analogues for studying the roles of 8- and 9-hydroxy ABA 3 and 6, were also synthesized and found to be active.     

Method for the solid-phase parallel synthesis of a 6-alkylamino-2-(functionalized-aminomethyl)-2H-1-benzopyran Library

A 2000-member library of benzopyran analogues was prepared by using a solid-phase synthesis protocol. Polymer-bound 6-alkylaminobenzopyrans 7 were synthesized as part of a first generation diversification step by employing reactions of a variety of alkyl halides with the amine 6. Transformations of the resin-bound intermediates 8 formed in this manner by reactions with acid halides, sulfonyl chlorides, and isocyanates leads to introduction of the second level of diversification found in the series of 6-alkylamino-2-(functionalized-aminomethyl)-2-methyl-2H-1-benzopyran analogues 11 and 12.     

Palladium mediated synthesis of conjugated E or Z enones and unsymmetrical divinyl ketones. one-pot preparation of isoegomaketone

The palladium (o) catalyzed coupling of acyl halides or anhydrides with alkenyl copper reagents furnishes α,β ethylenic ketones and α,β-α,β' diethylenic ketones in high yield. The substitution pattern of the alkenyl copper reagent, directly obtained by carbocupration of alkynes, is fully retained. Anhydrides of Z-ethylenic acids also retain their Z stereochemistry. β-halogeno-vinyl ketones react under the above conditions to afford α,β-γ,δ dienones. An efficient one-pot synthesis of Z or ε isoegomaketone is reported.     

Chemoenzymatic synthesis of cryptophycin anticancer agents by an ester bond-forming non-ribosomal peptide synthetase module

Cryptophycins (Crp) are a group of cyanobacterial depsipeptides with activity against drug-resistant tumors. Although they have been shown to be promising, further efforts are required to return these highly potent compounds to the clinic through a new generation of analogues with improved medicinal properties. Herein, we report a chemosynthetic route relying on the multifunctional enzyme CrpD-M2 that incorporates a 2-hydroxy acid moiety (unit D) into Crp analogues. CrpD-M2 is a unique non-ribosomal peptide synthetase (NRPS) module comprised of condensation-adenylation-ketoreduction-thiolation (C-A-KR-T) domains. We interrogated A-domain 2-keto and 2-hydroxy acid activation and loading, and KR domain activity in the presence of NADPH and NADH. The resulting 2-hydroxy acid was elongated with three synthetic Crp chain elongation intermediate analogues through ester bond formation catalyzed by CrpD-M2 C domain. Finally, the enzyme-bound seco-Crp products were macrolactonized by the Crp thioesterase. Analysis of these sequential steps was enabled through LC-FTICR-MS of enzyme-bound intermediates and products. This novel chemoenzymatic synthesis of Crp involves four sequential catalytic steps leading to the incorporation of a 2-hydroxy acid moiety in the final chain elongation intermediate. The presented work constitutes the first example where a NRPS-embedded KR domain is employed for assembly of a fully elaborated natural product, and serves as a proof-of-principle for chemoenzymatic synthesis of new Crp analogues.     

A new synthesis of perfluoroacyl halides and anhydrides from perfluorocarboxylate salts. A synthetic study

The nucleophilic cleavage of difluorophosphine esters of perfluorocarboxylic acids by halide ions to form acyl halides has not been previously reported. Furthermore, the reactions between halophosphoryldifluorides or the anhydrides, P₂O₅F₂ and P₂O₃F₄, and perfluorocarboxylate salts produce acyl halides or acyl anhydrides, respectively.     

全氟和多氟烷基磺酸的研究 IX. 5-卤-3-氧杂-全氟戊磺酰氟的化学转化

5-Halo-3-oxa-perfluoropentanesulfonic acids 2,4 were obtained in high yields by treating the corresponding sulfonyl fluorides successively with KOH and concentrated H2SO4: Treatment of the acids with P2O5 gave corresponding anhydrides 3, 5. 3 reacted with various alcohols in the presence of pyridine to yield sulfonates 6. 5-Iodo-3-oxa-perfluoropentanesulfonyl fluoride (1) was converted to the acyl fluoride 9 by fuming sulfuric acid. Depending on the reaction temperature 9 can be hydrolyzed to fluorosulfonyl perfluoroalkanoic acid 10 and/or mixed dibasic acid 11. A similar phenomenon was also observed in the case of hydrolysis of fluorocarbonyl-perfluoromethanesulfonyl fluoride(13). Alcohol reacted readily with the acyl fluoride group but not with the sulfonyl group in 9 giving carboxylic esters, which can be further transformed to the corresponding sulfonates. Perfluoroalkoxide ion -O(CF2)2O(CF2)2SO2F prepared from 9 and F- reacted with active alkyl halides yielding the corresponding ethers. The interaction of 5-halo-3-oxa-perfluoroalkane-sulfonyl fluoride with AlCl3 was investigated. Friedel-crafts acylation of aromatic compounds with 9 in the presence of anhydrous AlCl3 is also reported. The yields of the desired ketones can be improved by using CCl4 as a solvent and changing the order of addition of reactants.     

Reductive cleavage of the Se–Se bond in diselenides by the Sm/HgCl2 system: Formation and reactions of samarium selenolates

Treatment of diaryl diselenides and dialkyl diselenides with metallic samarium and mercury (II) chloride in tetrahydrofuran conveniently gave samarium arylselenolates and alkylselenolates. These “living” species reacted with acyl chlorides, acid anhydrides, methyl chloroformate, organic halides, epoxides, α,β‐unsaturated esters, and an α,β‐unsaturated nitrile to afford selenoesters, selenoformates, and unsymmetrical selenides in good yields under mild and neutral condition. © 1999 John Wiley & Sons, Inc. Heteroatom Chem 10: 203–208, 1999     

Rapid and facile synthesis of acyl azides from acyl halides using a polymer-supported azide ion under heterogeneous conditions

In this article a rapid and facile method for synthesis of acyl azide is described. The cross-linked poly(N-methyl-4-vinylpyridinium) azide ion, [P₄-VP]N₃ is prepared and used as an efficient polymeric reagent for synthesis of acyl azides from acyl halides at room temperature under heterogeneous conditions. Various benzoyl halides, with electron-withdrawing groups as well as electron-donating groups, were transformed into the corresponding benzoyl azides in high to excellent yields in short reaction times. The acyl azide products were characterized by FT-IR, and some of them were also characterized by ¹H-and/or ¹³C-NMR spectroscopy, and physical properties were compared to literature values of known compounds. The spent polymeric reagents can be regenerated and reused for several times without losing their activity. Relative to the reported methods, the present method has the advantages of operational simplicity, mild reaction conditions, fast reaction rates, simple reaction work-up and lower hazardous and potentially explosive nature. Also the present method is the first procedure for the synthesis of acyl azides from acyl halides by using a polymer-supported azide ion under heterogeneous conditions.     

Samarium diiodide induced reductive cleavage of the Te–Si bond in phenyltellurotrimethylsilane: A novel method for the synthesis of alkylphenyl tellurides,telluroesters, and β‐phenyltelluro esters (nitriles)

Phentyltellurotrimethylsilane (1) was reduced by samarium diiodide in tetrahydrofuran (THF) to produce samarium phenyltellurolate. This new tellurolate anion reacted smoothly with alkyl and benzyl halides to give alkyl and benzyl‐phenyl tellurides in good yields under mild and neutral conditions. The samarium tellurolate also reacted with acyl halides or anhydrides to give telluroesters, and the 1,4‐addition of samarium tellurolate to α, β‐unsaturated esters (nitriles) gave β‐phenyltelluro esters (nitriles). © 1999 John Wiley & Sons, Inc. Heteroatom Chem 10: 471–474, 1999     

Characterization of prednisone, prednisolone and their metabolites by gas chromatography-mass spectrometry

Human urinary metabolites of the synthetic corticosteroids prednisone and prednisolone were detected in the course of gas chromatographic steroid profiling as methoxime-trimethylsilyl derivatives. Metabolites were provisionaly identified by combined gas chromatography-mass spectrometry. The major metabolites were 11-keto/11-hydroxy conversion products, 20-hydroxy and 4,5-dihydro analogues of the parent drugs. Cortisone, 6-hydroxy and fully saturated A-ring compounds were minor metabolites. Retention indices and mass spectral data are presented.     

Generation and Reactivity of C(1)-Ammonium Enolates by Using Isothiourea Catalysis

C(1)-Ammonium enolates are powerful, catalytically generated synthetic intermediates applied in the enantioselective α-functionalisation of carboxylic acid derivatives. This minireview describes the recent developments in the generation and application of C(1)-ammonium enolates from various precursors (carboxylic acids, anhydrides, acyl imidazoles, aryl esters, α-diazoketones, alkyl halides) using isothiourea Lewis base organocatalysts. Their synthetic utility in intra- and intermolecular enantioselective C−C and C−X bond forming processes on reaction with various electrophiles will be showcased utilising two distinct catalyst turnover approaches.     

A striking difference between the stereochemical course of the photolysis of 5-hydroxy 6-oxo steroids and their bicyclic analogues

While 5α- and 5β-hydroxy 6-oxo steroids undergo stereospecific photoisomerization, their bicyclic analogues give identical product mixtures on photolysis. This is attributed to equilibration of the intermediate acyl alkyl diradicals in the bicyclic case, which does not occur in the steroid case because of slowing of rotation about the C-9 – C-10 bond.     

Synthesis of Protein Farnesyltransferase and Protein Geranylgeranyltransferase Inhibitors: Rapid Access to Chaetomellic Acid A and Its Analogues

A facile two-step stereospecific synthesis of the protein farnesyltransferase inhibitor chaetomellic acid A (1) and its analogues was developed. Addition of organocuprates derived from Grignard reagents (e.g. tetradecylmagnesium chloride and CuBr.Me(2)S) to dimethyl acetylenedicarboxylate (DMAD) in tetrahydrofuran containing hexamethylphosphoramide was followed by capture of the resulting copper enolates with a variety of electrophiles (e.g. methyl iodide) to give dimethyl cis-butenedioate derivatives 4-11. Hydrolysis with lithium hydroxide generated the corresponding lithium carboxylates, which readily closed to 2,3-disubstituted maleic anhydrides 17-20 upon acid treatment. Compound 16, an analogue wherein the tetradecyl group of 1 is replaced by a farnesyl moiety, is 7-fold more potent than 1 as an inhibitor of protein farnesyltransferase from yeast and displays a 100:1 selectivity for this enzyme relative to yeast protein geranylgeranyltransferase. In contrast, analogue 15, which contains a geranylgeranyl side chain, shows ca. 10:1 selectivity for the latter enzyme.     

Construction of a 2,6-difunctionalized 2-methyl-2H-1-benzopyran library by using a solid-phase synthesis protocol

[reaction: see text] A library containing 1200 analogues of 2,6-difunctionalized 2-methyl-2H-1-benzopyran was constructed by using a solid-phase synthesis protocol. Polymer-bound 6-amido-, 6-sulfonamido-, and 6-uredo-functionalized 2-hydroxymethyl-2-methylbenzopyrans 10 were prepared as part of a first-generation diversification step by employing reactions of respective acid halides, sulfonyl chlorides, and isocyanates with the amine precursor 7. Transformations of the resin-bound intermediates 10 by reactions with alkyl and acid halides were then used to produce a diverse series of 2,6-difunctionalized 2-methyl-2H-1-benzopyran analogues 12 and 14.     

Synthesis of S-Alkylisothiuronium Halides by Reaction of Thiourea with ω-(4-Hydroxyaryl)alkyl Halides

A number of new S-alkylisothiuronium salts were synthesized by reaction of -[4-hydroxy(methoxy)aryl]alkyl halides with thiourea. The resulting isothiuronium salts in aqueous solution react with sodium (potassium) halides to form halogen exchange products.     

Construction of 6-amino-2,2-dimethyl-3,4,6-trisubstituted-2H-1-benzopyran library by solid phase synthesis

We report the solid-phase library construction of 2000 analogues of 6-amino-2,2-dimethyl-3,4,6-trisubstituted-2H-1-benzopyran. The polymer-bound hydroxyalkoxychromanes 5, produced by nucleophilic reactions with various alcohols on epoxides generated in situ, served as key intermediates for subsequent diversification. Further reactions on these hydroxyalkoxychromanes 5 with various electrophiles, such as alkyl halides and acid halides, produced the desired 6-amino-2,2-dimethyl-3,4,6-trisubstituted-2H-1-benzopyran analogues 9, 10, and 11. The progress of reactions could be monitored as solid-bound intermediates by ATR-FTIR or HR-MAS-NMR spectroscopy. The final compounds, obtained in good yields and high purity upon cleavage from the resins, were characterized by LC/MS, HRMS, (1)H NMR, and (13)C NMR spectroscopy.     

Study on the Reductive Acylation of Azo Compounds by SmI2/THF in One Pot

Azobenzene compounds without big substituents were conveniently reduced by a system consisting of SmI₂/THF and successively reacted smoothly with analogous aliphatic acyl chlorides or acid anhydrides to afford corresponding mono‐acyl symmetrical hydrazobenzene under mild and neutral conditions in one pot; while other azo compounds reacted under similar conditions, amides were the terminate products.