Sequencing cross-metathesis and non-metathesis reactions to rapidly access building blocks for synthesis

The olefin cross-metathesis reaction has been sequenced with four common organic transformations in a one- or two-pot manner to rapidly access useful building blocks. Those reactions are: (1) phosphorus-based olefination (e.g., Wittig and Horner-Wadsworth-Emmons); (2) hydride reduction; (3) Evans propionate aldol reaction; (4) Brown allyl- and Roush crotyl-boration. The products of these reactions include stereodefined 2,4-dienoates, trans allylic alcohols, syn-propionate aldols, and chiral non-racemic homoallylic alcohols, respectively. Many of these intermediates have been carried further to natural products, demonstrating the utility of the methodology.     

Shortcut access to peptidosteroid conjugates: building blocks for solid-phase bile acid scaffold decoration by convergent ligation

We present three versatile solid-supported scaffold building blocks based on the (deoxy)cholic acid framework and decorated with handles for further derivatization by modern ligation techniques such as click chemistry, Staudinger ligation or native chemical ligation. Straightforward procedures are presented for the synthesis and analysis of the steroid constructs. These building blocks offer a new, facile and shorter access route to bile acid-peptide conjugates on solid-phase with emphasis on heterodipodal conjugates with defined spatial arrangements. As such, we provide versatile new synthons to the toolbox for bile acid decoration.     

Practical synthesis of iodo phenothiazines. A facile access to electrophore building blocks

Bromine-lithium exchange of the mono- and dibromophenothiazines 1 and 3a regiospecifically furnishes upon electrophilic trapping with iodine the iodo- and diiodophenothiazines 2, 3b, and 3d in excellent yield. The 3-bromo-7-iodophenothiazine 3d can be submitted to regioselective and sequential Suzuki coupling reactions with phenothiazine mono- and bisboronates 4 and 5 and/or (hetero)aryl boronic acids to give the bromodiphenothiazine 6a, the dibromo terphenothiazine 7, and the (hetero)aryl-substituted phenothiazine dyads 6b-d in moderate to good yields.     

Fluorination of α,α-dichlorosulfides: access to gem-difluorothioethers as useful building blocks

The synthesis of alkylsulfanyldifluoro-acetate and ketones by the Halex reaction is described. The remarkable reactivity of thiodifluoroacetate derivatives opened rapid access for the preparation of useful building blocks such as gem-difluoroketones and amides.     

Facile isolation of bisimines based on 3,3'-diaminobenzidine: direct access to unsymmetrical bimetallic salphen building blocks

Diimines obtained from 3,3'-diaminobenzidine and tert-butyl-substituted salicylaldehydes in MeOH can be readily isolated in 60-90% yield and were obtained as a mixture of geometrical isomers. Two distinct diimine intermediates (4 and 5) with a higher molecular symmetry as related to the other isomeric diimine products were both isolated by crystallization of which 5 was subsequently used to demonstrate that nonsymmetrical bis-salphen complexes with different functional groups and metal centers can be assembled via a three-component one-pot procedure.     

‘Green’ synthesis of important pharmaceutical building blocks: enzymatic access to enantiomerically pure α-chloroalcohols

Thirty one recombinant ketoreductase enzymes were screened for the reduction of six α-chloroketones, the precursors of pharmaceutically valuable α-chloroalcohols. Several highly active and enantioselective ketoreductases were found and their applications to the synthesis of both enantiomers of these α-chloroalcohols were demonstrated on a preparative scale. This offers a convenient, ‘green’ access to this type of important pharmaceutical building blocks.     

Weinreb amide based building blocks for convenient access to 1,1-diarylethenes and isocombretastatin analogues

A successful strategy based on the synthetic equivalent containing Weinreb amide functionality for the convenient access to 1,1-diarylethenes in general and for the isocombretastatin analogues in particular has been developed from the commercially available glyoxalic acid. The convenience with which the structural variations can be made in assembling the aryl residues shows generality associated with the developed strategy. The intermediates also provide access to 1,2,2-triarylethanones, represented by the synthesis of advanced intermediate of tamoxifen.     

Facile access to some chiral building blocks. Synthesis of verbalactone and exophilin A

d-Glucono-1,5-lactone, an inexpensive carbohydrate, was elaborated into chiral building blocks readily applicable in synthesis via practical routes without involving any expensive reagents or tedious operations. Application of such chiral building blocks in total synthesis is then exemplified through construction of verbalactone and exophilin A. The latter compound has not been synthesized to date.     

Stereoselective access to fluorinated and non-fluorinated quaternary piperidines: synthesis of pipecolic acid and iminosugar derivatives

The preparation of optically pure quaternary piperidines, both fluorinated and non-fluorinated, has been achieved from a chiral imino lactone derived from (R)-phenylglycinol. In the case of the fluorinated derivatives, the addition of (trifluoromethyl)trimethylsilane (TMSCF(3)) followed by iodoamination and migration of the CF(3) group allowed access to four derivatives of α-(trifluoromethyl)pipecolic acid. A theoretical study of the CF(3)-group rearrangement has been carried out to help establish the reaction mechanism of this uncommon transformation. Moreover, a route to trifluoromethyl-substituted iminosugars was also developed through the diastereoselective dihydroxylation of suitable synthetic intermediates. Conversely, alkylation of the starting substrate and subsequent cross-metathesis and aza-Michael reactions led to α-alkyl derivatives of the target compounds.     

Enyne cross-metathesis with strained, geminally-substituted alkenes: direct access to highly substituted 1,3-dienes

Angle strain in methylene cyclobutane was used to drive a cross-enyne metathesis with 1-alkynes, giving 1,1,3-trisubstituted 1,3-dienes in good isolated yields. An extensive survey of Grubbs' second-generation catalysts led to an optimized reaction conducted at 0 degrees C.     

Synthesis of tetrazolopiperazine building blocks by a novel multi-component reaction

A novel Ugi-five-centre-four-component reaction (U-5C-4CR) of aldehydes, primary amines, trimethylsilylazide and 2-isocyanoethyltosylate yielding tetrazolopiperazine building blocks is described.     

General access to a novel class of silyl heterocycles

2-Trimethylsilyl-substituted five-membered heterocycles can be accessed through the reaction of bromo(methoxy)methyltrimethylsilane with 1,2-dithiols, 1,2-mercapto alcohols, 1,2-mercapto amines, and 1,2-hydroxy amines, leading to the formation of several 2-silylated 1,3-dithiolanes,-oxathiolanes,-thiazolidines, and-oxazolidines. Dedicated to Prof. Edmunds Lukevics on the occasion of his 70th birthday __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1838–1844, December, 2006.     

Macrocycles from simple building blocks by a multifold Heck-type coupling reaction

Diiodobenzenes and bisallylic alcohols—two equivalents of each—were coupled under palladium catalysis to give oxofunctionalized macrocycles as 2:2 products. The 1:1 products as medium sized rings were disfavoured and not observed.     

P-heterocyclic building blocks: application to the stereoselective synthesis of P-sugars

A strategy relying on the utilization of stereoselective additions to allyldiphenylphosphonate esters and subsequent ring-closing metathesis (RCM) to access P-chiral P-heterocyclic building blocks for the synthesis of phosphono sugars is described. These building blocks possess several attractive components, including the following: (i) P(2) and C(6) stereogenic centers for directing stereoselective transformations; (ii) an activated C(3) methylene group that promotes base-mediated olefin transposition to generate vinyl phosphonates available for further stereoselective reactions; and (iii) a P(2)-stereogenic center containing an exchangeable phosphonate ester armed to attenuate the "stereochemical environment" at phosphorus. Taken collectively, these attributes contribute to a concise method for the stereoselective synthesis of an array of P-sugars.     

Lewis acid-assisted olefin cross-metathesis reaction: an efficient approach for the synthesis of glycosidic-pyrroloquinolinone based novel building blocks of camptothecin and evaluation of their antitumor activity

A series of glycosidic-pyrroloquinolinone based novel building blocks of camptothecin (2a–g) were synthesized via Lewis acid-assisted olefin cross-metathesis reaction using Ti(OⁱPr)₄ 30 mol % and 10 mol % of Grubb’s second generation catalyst with good to excellent yields. Most of these compounds exhibited significant growth inhibitory effects on all the tested cancer cell lines and three compounds (2c, 2d and 2e) showed potent cytotoxic activity.     

Synthesis of valuable terpyridine building blocks to generate a variety of metallodendrons by the convergent approach

Efficient strategies for the synthesis of three building-blocks 4′-(functionalized)-2,2′:6′,2″-terpyridine have been developed for the convergent synthesis of metallodendrons; these strategies provide a practical approach for the rational design of highly conjugated metallodendrimers.     

Synthesis of phytosphingosine using olefin cross-metathesis: a convenient access to chain-modified phytosphingosines from d-lyxose

This work establishes a general protocol for synthesizing phytosphingosines with various lengths of lipid chains. The synthetic strategy included the Wittig reaction and olefin cross-metathesis as key steps. Combining these two C-C bond formation methods provide rapid access to adequately protected phytosphingosine backbones.     

Efficient synthetic access to cationic dendrons and their application for ZnO nanoparticles surface functionalization: new building blocks for dye-sensitized solar cells

A new concept for the efficient synthesis of cationic dendrons, 4-tert-butyl-1-(3-(3,4-dihydroxybenzamido)benzyl)pyridinium bromide (17), 1,1'-(5-(3,4-dihydroxybenzamido)-1,3-phenylene)bis(methylene)bis(4-tert-butylpyridinium) bromide (18), N1,N7-bis(3-(4-tert-butyl-pyridium-methyl)phenyl)-4-(3-(3-(4-tert-butyl-pyridinium-methyl)phenyl-amino)-3-oxopropyl)-4-(3,4-dihydroxybenzamido)heptanediamide tribromide (19), and N1,N7-bis(3,5-bis(4-tert-butyl-pyridium-methyl)phenyl)-4-(3-(3,5-bis(4-tert-butyl-pyridinium-methyl)phenylamino)-3-oxopropyl)-4-(3,4-dihydroxybenzamido)heptanediamide hexabromide (20), and their facile binding to zinc oxide (ZnO) nanostructures is introduced. Dendrons containing highly reactive benzylic bromides reacted readily with 4-tert-butyl-pyridine and resulted in cationic dendrons. Furthermore, these permanently positively charged dendrons were equipped with a catechol anchor group. This enabled ZnO surface functionalization by simple immersion. The adsorption of 17, 18, 19, and 20 on the colloidal nanoparticles was monitored by Langmuir isotherms. The highest obtained experimental loadings correspond to 99.5%, 98.6%, 99.1%, and 42.5% of the particle surface for 17, 18, 19, and 20, respectively. These results indicate insufficient adsorption of the largest molecule 20 leading to reduced colloidal stability of the nanoparticles, while an enhanced stability after grafting with 17, 18, and 19 was observed. Mesoporous films suitable for the use as electrodes in dye-sensitized solar cells (DSSCs) were prepared. Subsequently, the films were functionalized with 18, 19, or 20 and sensitized with zinc-5,15-bis-[2',6'-bis-{2',2'-bis-(carboxy)-ethyl}-methyl-4'-tert-butyl-pheny]-10,20-bis-(4'-tert-butylphenyl)porphyrin-octasodium-salt. UV-vis absorption spectra confirmed that 18, 19, and 20 are suitable for the stable electrostatic attachment of the dye. Current-voltage characteristics of complete cells demonstrated that increasing positive functionalization of the ZnO surface leads to decreased open circuit voltages (V(oc)). All V(oc) values were around 0.4 V with a maximum for the 18 functionalized ZnO film of 0.45 V. The maximum cell efficiency obtained (0.31%) is rather high, considering the narrow spectral absorption of the dye and the rather thin ZnO films used. Finally, incident photon to current efficiency (IPCE) measurements confirmed photoinduced electron injection from the dye. These features are important assets for applications in particle technology and even facilitated advanced devices like a supramolecular DSSC complete with a subsequent layer of negatively charged porphyrins.     

Boron-substituted difluorocyclopropanes: new building blocks of gem-difluorocyclopropanes

Cycloaddition of difluorocarbene to alkenyl boronates 3 gave boron-substituted gem-difluorocyclopropanes 2 in stereospecific fashion. Upon treatment with lithium carbenoids, cyclopropyl boronates 2 underwent one-carbon homologation to afford a variety of gem-difluorocyclopropanes in good yields.