Novel resolution of the anthracyclinone intermediate by the use of (2r, 3r)-(+)- and (2s, 3s)-(-).1,4-bis(4-chlorobenzyloxy)butane-2,3-diol: a simple and efficient synthesis of optically pure 4-demethoxydaunomycinone and 4-demethoxyadriamycinone

(±)-7-Deoxy-4-demethoxydaunomycinone((±)-3) was found to be cleanly resolved by forming a mixture of the diastereomereic acetals((-)-9and(+)-10 or(+)-9 and(-)-10)with the title vicinal-diol(+)-or ( )-5), affording optically pure (R)-( )-3. The resolving agents (( + )- and ( )-5) were readily synthesized from unnatural(2S,3S)-(-)-tartaric acid((-)-6)or D-(-)-mannitol and natural (2R,3R)-(+)-tartaric acid((+)6), respectively. The undesired enantiomer ((S)-(+ )-3) obtained by the optical resolution could be racemized by heating with trifluoromethanesulfonic acid in aq acetic acid. Optically pure (R)-3 was elaborated to optically pure (+)-4-demethoxydaunomycinone ((+)-2b) and (+)-demethoxyadriamycinone ((+)-2a) by featuring highly stereoselective ( ? 20:1) introduction of the OH group into the C₇-position as a key step.     

Asymmetric synthesis of optically pure (R)(−)-2-acetyl-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthol,a key intermediate for optically active anthracyclinone synthesis

Asymmetric reduction of 2-acetyl-5,8-dimethoxy-3,4-dihydronaphthalene(3) with lithium aluminum hydride partially decomposed with (?)-N-methylephedrine and N-ethylaniline was found to give the optically active allylic alcohol((?)-4) in 92% optical yield. Optically pure (?)-4 obtained in 87% yield based on 3 by recrystallization, was elaborated to the title compound((R)(?)-1) according to the reaction scheme exploited in the preceding paper.     

A convergent synthesis of (+)-4-demethoxydaunomycinone and ( + )-daunomycinone

A convergent synthesis of (+)-4-demethoxydaunomycinone and (+)-daunomycinone via annelation of a functionalized quinone monoketal with the anion of the corresponding 3-cyano-l(3H)isobenzofuranone is reported. The quinone monoketal, sequence, was prepared without chromatography from 2,5-dimethoxybenzaldehyde in sixteen steps. The monoketal of proper absolute configuration was obtained by resolution of the imine from (?)-α-methylbenzylamine and 1,2,3,4,-tetrahydro - 5,8 - dim cyclic 4-(ethylene mercaptole).Two noteworthy aspects of the synthesis were the highly selective reduction of a bicyclic β-hydroxyketone to afford a diol with the required cis-stereochemistry at the eventual C-7 and C-9 positions of the anthracyclinone and the regioselective hydrolysis of the quinone bisketal to afford the monoketal of proper regiochemistry for the synthesis of( + )-daunomycinone. Thus, ( + )-daunomycinone and (+)-4-demethoxydaunomycinone were prepared in nineteen steps from 2,5-dimethoxybenzaldehyde in respective overall yields of 3 and 5% (the overall yield for the racemic material was 13%). This synthetic strategy allows a convergent approach to a variety of D-ring analogs.     

Stereochemical studies-LVIII: Synthesis of optically active compounds by the novel use of meso-compound-2. efficient synthesis of an optically pure steroid intermediate

In order to explore the general application of a novel method for preparing optically active compounds, synthesis of the optically pure steroid intermediate((?)-1) has been examined by employing the diol(2) as a meso-compound and N-mesyl-(S)-phenylalanyl chloride(3) as a source of the optically active functional group.     

Chemoenzymatic synthesis of (R)-(+)-2-methylbutan-1-ol,a chiral synthon for the preparation of optically active pheromones

Optically active (R)-(+)-2-methylbutan-1-ol (which is not commercially available) was prepared by a chemoenzymatic synthesis, in which the key step involved a reduction catalyzed by baker's yeast. The synthon was used in the synthesis of (R)-10-methyldodecan-1-yl acetate, the chiral methyl-branched pheromone of Adoxophyes sp.     

An efficient synthesis of optically pure (S)-2-functionalized 1,2,3,4-tetrahydroquinoline

Using a copper-catalyzed coupling reaction of amino acid and aryl halide, followed by intramolecular cyclization of N-aryl-1-hydroxyl-3-propylamines under the Swern’s condition as the key steps, (S)-2-hydroxymethyl-1,2,3,4-tetrahydroquinoline was synthesized as an example of optically pure 2-functionalized 1,2,3,4-tetrahydroquinolines.     

Chemoenzymatic preparation of optically active trans-cyclohexane-1,2-diamine derivatives: an efficient synthesis of the analgesic U-(-)-50,488

Stereoespecific syntheses of (+/-)-trans-N,N-cyclohexane-1,2-diamines ((+/-)-4 a-g) were carried out from the corresponding (+/-)-trans-N,N-dialkylaminocyclohexanols by successive treatment with mesyl chloride and aqueous ammonia. The stereochemical outcome indicates the formation of a meso-aziridinium ion intermediate. Kinetic resolutions of diamines (+/-)-4 were efficiently accomplished in aminolysis reactions catalyzed by lipase B from Candida antarctica with ethyl acetate as the solvent and acyl donor. Acetamides and the remaining diamines, isolated as the benzyloxycarbonyl derivatives, were obtained with very high ee values (92-99%). One of the carbamates was used as a precursor of the analgesic U-(-)-50,488.     

Chemistry of baker's yeast reduction products: Use of optically active (S)-(+)-1-(p-toluenesulfonyl)propan-2-ol and (S)-(+)-1-(phenylsulfonyl)propan-2-ol in synthesis.

The utility of the title compounds in the preparation of optically active lactones and alcohols is detailed.     

Optically active palladacycles containing imines derived from 1-(1-naphthyl)ethylamine: new resolving agents for P-chiral phosphines

The synthesis of the new palladium metallacycles containing imines derived from 1-(1-naphthyl)ethylamine is reported. These new organometallic complexes have been used to resolve the P-chiral ligand benzylcyclohexylphenylphosphine. The absolute configuration of (R_C,S_P)-[PdCl{2-[HCN-CH(Me)C₁₀H₆]-3-ClC₆H₃}(PBzCyPh)] has been determined by single crystal X-ray analysis.     

Efficient synthesis of optically active 1-(2-carboxymethyl-6-ethylphenyl)-1H-pyrrole-2-carboxylic acid: a novel atropisomeric 1-arylpyrrole derivative

An efficient synthesis and resolution of (±)-1-(2-carboxymethyl-6-ethylphenyl)-1H-pyrrole-2-carboxylic acid has been developed for the preparation of novel optically active atropisomers. The ee values were measured by a ¹H NMR spectroscopic method using quinidine as the chiral complexing agent. Absolute configurations of the separated enantiomers were determined using single crystal X-ray diffraction measurements of both the disodium salt and the (R)-1-phenylethylamine salt of the enantiomerically pure dicarboxylic acid, separately. The analysis of the CD spectra with the aid of TD-DFT quantum chemical calculations confirmed the assignment of configurations.     

An efficient synthesis of 1,3-bis(1,4,7-triazacyclonon-1-yl)-2-hydroxypropane, [1,3-bis(TACN)-2-propanol]

Abstract

An efficient synthesis of 1,3-bis(1,4,7-triazacyclonon-1-yl)-2-hydroxypropane is described. In contrast to earlier procedures, an improved synthetic strategy led to the selection of suitable reagents and conditions that afforded the title compound in excellent overall yield with improved process efficiency and scalability. Moreover, the mildness and synthetic efficiency of the chosen conditions were particularly well-suited for the large-scale synthesis of the title compound, which is in increasing demand for a variety of applications, including the preparation of stationary phases for immobilized metal-ion affinity chromatography of recombinant proteins.     

Versatile synthons for optically pure alpha-amino aldehydes and alpha-amino acids: (+)- and (-)-4,5-dialkoxy-2-oxazolidinones

Both enantiomers of trans-5-benzyloxy-4-methoxy- (BMOx) and trans-4,5-dimethoxy-2-oxazolidinones (DMOx), which are readily accessible from simple 2-oxazolone heterocycles, represent good candidates for a new class of chiral synthons for use in the preparation of optically pure alpha-amino aldehydes and alpha-amino acids, respectively.     

Highly efficient total synthesis of the marine natural products (+)-avarone, (+)-avarol, (-)-neoavarone, (-)-neoavarol and (+)-aureol

Biologically important and structurally unique marine natural products avarone (1), avarol (2), neoavarone (3), neoavarol (4) and aureol (5), were efficiently synthesized in a unified manner starting from (+)-5-methyl-Wieland-Miescher ketone 10. The synthesis involved the following crucial steps: i) Sequential BF(3)Et(2)O-induced rearrangement/cyclization reaction of 2 and 4 to produce 5 with complete stereoselectivity in high yield (2 --> 5 and 4 --> 5); ii) strategic salcomine oxidation of the phenolic compounds 6 and 8 to derive the corresponding quinones 1 and 3 (6 --> 1 and 8 --> 3); and iii) Birch reductive alkylation of 10 with bromide 11 to construct the requisite carbon framework 12 (10 + 11 --> 12). An in vitro cytotoxicity assay of compounds 1-5 against human histiocytic lymphoma cells U937 determined the order of cytotoxic potency (3 > 1 > 5 > 2 > 4) and some novel aspects of structure-activity relationships.     

A novel synthetic method for optically active terpenes by the ring-opening reaction of (R)-(+)-β-methyl-β-propiolactone

Optically active terpene such as (R)-(+)-citronellol, (R)-(+)-pulegone or (S)-ar-turmerone is prepared in high enantiomeric excess from an intermediate, (R)-(+)-citronellic acid or (S)-(+)-3-p-tolylbutyric acid, which is easily prepared by the Sn2 type of ring opening reaction of (R)-(+)-β-methyl-β-propiolactone with homoprenylmagnesium bromide in the presence of a copper(I) salt or di-p-tolylcuprate.     

The first synthesis of (-)-asperpentyn and efficient syntheses of (+)-harveynone, (+)-epiepoformin and (-)-theobroxide

A generally applicable strategy for the synthesis of a range of polyoxygenated cyclohexane natural products has been developed. The enantioselective syntheses of (-)-theobroxide, a polyoxygenated cyclohexane natural compound with potent growth inducing properties in potato microtubers has been achieved via a 1,2 O-silyl migration between trans-hydroxyl groups and a remote hydroxyl directed epoxidation of an enone derived from quinic acid. A thus derived alpha-iodoenone was subjected to Stille coupling with tetramethylstannane to afford the first title compound. A similar strategy enabled a route to the complete asymmetric synthesis of the acetylenic phytotoxin (+)-harveynone. By selective reduction of (-)-theobroxide, (+)-epiepoformin was also prepared in enantiopure form and similarly, stereoselective reduction of (+)-harveynone completed the first enantioselective synthesis of (-)-asperpentyn, another natural compound with antimicrobial activity.     

A facile synthesis of novel optically active R,R-2-(4-(2-(4-(5-chloro-3-halo-pyridin-2-yloxy)-phenoxy)-propionyloxy)-phenoxy)-propionic acid esters using cyanuric chloride as potential herbicide

A facile method for the synthesis of a new series of R,R-2-(4-(2-(4-(5-chloro-3-halopyridin-2-yloxy)-phenoxy)-propionyloxy)-phenoxy) -propionic acid ester derivatives containing a halo-substituted pyridine carrying two R,R chiral centers from(R)-2-(4- hydroxyphenoxy)propionic acid,halopyridines and alcohols using base/cyanuric chloride/catalyst system is reported.Their herbicidal activities against grass weeds and crops selectivity were evaluated.     

Concise,efficient and highly selective asymmetric synthesis of (+)-(3S,4R)-cisapride

A concise asymmetric synthesis of the gastroprokinetic agent (+)-(3S,4R)-cisapride {(+)-(3S,4R)-N(1)-[3′-(4″-fluorophenoxy)propyl]-3-methoxy-4-(2″′-methoxy-4″′-amino-5″′-chlorobenzamido)piperidine} from commercially available starting materials has been developed. The key step of this synthesis employs the diastereoselective conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl 5-[N-3′-(4″-fluorophenoxy)propyl-N-allylamino]pent-2-enoate and in situ enolate oxidation with (?)-camphorsulfonyloxaziridine to set the (3S,4R)-configuration found within the piperidine ring of the product. This synthesis proceeds in 9 steps from commercially available 1-(4′-fluorophenoxy)-3-bromopropane with an overall yield of 19%.     

New Chiral Diamines of the Dioxolane Series: (+)-(4S,5S)-2,2-Dimethyl-4,5-bis(diphenylaminomethyl)- 1,3-dioxolane and (+)-(4S,5S)-2,2-Dimethyl-4,5-bis(methyl- aminomethyl)-1,3-dioxolane

The reaction of sodium diphenylamide with 2,2-dimethyl-4,5-bis(tosyloxymethyl)-1,3-dioxolane gave (+)-(4S,5S)-2,2-dimethyl-4,5-bis(diphenylaminomethyl)-1,3-dioxolane, which was brought into complex formation with cobalt chloride. Treatment of 2,2-dimethyl-4,5-bis(tosyloxymethyl)-1,3-dioxolane with sodium N-methylanilide resulted in cleavage of the SÄO bond in the p-toluenesulfonate moiety with formation of N-methyl-N-phenyl-p-toluenesulfonamide and 4,5-bis(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane disodium salt. Diethyl (4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate reacted with methylamine to give the corresponding dicarboxamide which was reduced with lithium aluminum hydride to (4S,5S)-2,2-dimethyl-4,5-bis(methylaminomethyl)-1,3-dioxolane having chiral carbon and nitrogen atoms.