Terpyridine Diphosphine Ruthenium Complexes as Efficient Photocatalysts for the Transfer Hydrogenation of Carbonyl Compounds

The cationic achiral and chiral terpyridine diphosphine ruthenium complexes [RuCl(PP)(tpy)]Cl (PP=dppp ( 1 ), (R,R)-Skewphos ( 2 ) and (S,S)-Skewphos ( 3 )) are easily obtained in 85–88 % yield through a one-pot synthesis from [RuCl₂(PPh₃)₃], the diphosphine and 2,2′:6′,2′′-terpyridine (tpy) in 1-butanol. Treatment of 1 – 3 with NaPF₆ in methanol at RT affords quantitatively the corresponding derivatives [RuCl(PP)(tpy)]PF₆ (PP=dppp ( 1 a ), (R,R)-Skewphos ( 2 a ) and (S,S)-Skewphos ( 3 a )). Reaction of [RuCl₂(PPh₃)₃] with (S,R)-Josiphos or (R)-BINAP in toluene, followed by treatment with tpy in 1-butanol and finally with NaPF₆ in MeOH gives [RuCl(PP)(tpy)]PF₆ (PP=(S,R)-Josiphos ( 4 a ), (R)-BINAP ( 5 a )) isolated in 78 % and 86 % yield, respectively. The chiral derivatives have been isolated as single stereoisomers and 3 a , 4 a have been characterized by single crystal X-ray diffraction studies. The tpy complexes with NaOiPr display high photocatalytic activity in the transfer hydrogenation (TH) of carbonyl compounds using 2-propanol as the only hydrogen donor and visible light at 30 °C, at remarkably high S/C (up to 5000) and TOF values up to 264 h⁻¹. The chiral enantiomers 2 , 2 a and 3 , 3 a induce the asymmetric photocatalytic TH of acetophenone, affording (S)- and (R)-1-phenylethanol with 51 and 52 % ee, respectively, in a MeOH/2-propanol mixture.     

1,3-Dioxanone Derivatives from β-Hydroxy-carboxylic Acids and Pivalaldehyde. Versatile Building Blocks for Syntheses of Enantiomerically Pure Compounds. A Chiral Acetoacetic Acid Derivative Preliminary Communication

(R)-3-Hydroxybutyric acid (from the biopolymer PHB) and pivalaldehyde give the crystalline cis - or (R,R)-2-(tert-butyl)-6-methyl-1,3-dioxan-4-one ( 1a ), the enolate of which is stable at low temperature in THF solution and can be alkylated diastereoselectively ( →3, 4, 5 , and 7 ). Phenylselenation and subsequent elimination give an enantiomerically pure enol acetal 10 of aceto-acetic acid. Some reactions of 10 have been carried out, such as Michael addition (→ 11 ), alkylation on the CH₃ substituent (→ 13 ), hydrogenation of the C?C bond (→ 1a ) and photochemical cycloaddition (→ 16 ). The overall reactions are substitutions on the one stereogenic center of the starting β-hydroxy acid without racemization and without using a chiral auxiliary.     

Enantioselektive Reaktionen an porphinoiden Nickelkomplexen

Enantioselective Reactions on Porphine Type Nickel Complexes The thermodynamically controlled addition of alcohols to (+)-(1R)-[1-methyl-8H-HDP]nickelperchlorate ( 1 ; e.e. 92%) yields exclusively the corresponding cis-1,11-disubstituted porphinoids. Chemical transformation of functional groups in the alkoxy side-chain of the chiral addition product followed by acid catalyzed elimination yields the derived alcohols and 1 . By this procedure, the following enantioselective transformations were studied: methylation of meso-2,3-butandiol ( 5 ) to (+)-(2R,3S)-3-methoxy-2-butanol ( 8a ; e.e. 87%), diimide reduction of 2-ethylallyl alcohol ( 9 ) to (+)-(2R)-2-methyl-1-butanol ( 12a ; e.e. 15%), and hydride reduction of 4-hydroxy-2-butanone ( 13 ) to (+)-(3S)-1,3-butandiol ( 16a ; e.e. 20%). Addition of 2,2-dimethyl-1,3-propandiol ( 17 ) to 4 , followed by esterification of the free hydroxy group with trifluoromethanesulfonic anhydride and solvolysis of the sulfonate 19 yielded a bridged complex with unrearranged alkyl chain for which structure 20 is proposed.     

Synthesis of (S)-Propranolol by Chemicoenzymatic Approach

(S)-Propranolol, [1-isopropylamino-3-(1-naphthoxy)-2-propanol], which possesses important β-adrenergic blocking activity, has been synthesized by a chemicoenzymatic approach. The 2S-absolute configuration was created by the enzyme-mediated asymmetric hydrolysis of the (±)-2-acetoxy-1-chloro-3-(1-naphthoxy)-2-naphthoxy)-2-propanol. The enzymatically produced chiral intermediate was then chemically converted to optically pure (S)-propranolol.     

Synthesis and absolute configuration of clemastine and its isomers (author's transl)]

Synthesis and Absolute Configuration of Clemastine and its Isomers. Condensation of 4-chloro-α-methylbenzhydrylalkohol ( 1 ) with 2-(2-chloroethyl)-1-methylpyrrolidine ( 2 ) gave an isomeric mixture of 2-[2-(p-chloro-α-methyl-=-phenylbenzyloxy)ethyl]-1-methylpyrrolidine ( 3 ) and 4-(p-chloro-=-phenylbenzyloxy)-1-methyl-hexahydroazepin ( 4 ). The separation of the four possible optically active isomers of 3 is described and their absolute configuration established by degradation to (R)- and (S)-1-methyl-2-pyrrolidineethanol ( 6 ), respectively, and by an X-ray cristallographic analysis of the quarternary methiodide of the isomer 3-A . Clemastine (3-A) is (+)-(2R)-2-[2-((αR)-(p-chloro-α-methyl-α-phenylbenzyloxy)ethyl)]-1-methylpyrrolidine.     

Chiral cyclohexene block from <Emphasis Type="Italic">R</Emphasis>-(−)-carvone

The oxidation with SeO₂ of a methyl group linked to an sp²-hybridized carbon in the product of the intramolecular iodoetherification of cis-carveol afforded (1R,5R,7S)-7-iodomethyl-7-methyl-6-oxabicyclo[3.2.1]-oct-3-en-4-carbaldehyde and [(1R,5R,7S)-7-iodomethyl-7-methyl-6-oxabicyclo[3.2.1]oct-3-en-4-yl]methanol that were oxidized to methyl (1R,5R,7S)-7-iodomethyl-7-methyl-6-oxabicyclo[3.2.1]oct-3-en-4-carboxylate. The latter by the Zn-promoted opening of the γ-oxide ring was converted into the target chiral block, methyl (4R,6R)-6-hydroxy-4-(prop-1-en-2-yl)cyclohex-1-encarboxylate.     

EPC-Synthesis of Tetrahydroisoquinolines by Diastereoselective Alkylation at the 1-Position of Phenylalanine-Derived Precursors. Synthesis of the Alkaloid (+)-Corlumine

The 1,2,3,4-tetrahydro-N-pivaloyl-isoquinoline-3-carboxylic acids 1d , 2d , and 3d , derived from (R)- or (S)-phenylalanine, (S)-dopa, and (S)-α-methyldopa, respectively, are doubly deprotonated with (tert-butyl)lithium in THF and alkylated at the 1-position (products 5 – 10 ). The major diastereoisomers formed are the result of electrophilic attack from the face opposite to the carboxylate group (rel. topicity ul-1,3). Even the addition to benzaldehyd (→ 7,8 ) is highly stereoselective (one of four diastereoisomers is formed exclusively (300-MHz ¹H-NMR analysis)), if MgBr₂ etherate is added prior to the electrophile. Some of the obtained amino-acid derivatives are decarboxylated by anodic oxidation in MeOH (→ 11 , 12 , 17 ) and NaBH₃CN reduction, and converted to the known 1-methyl- and 1-benzyltetrahydroisoquinolines ( 15 , 16 ) of > 95% ee as well as to the phthalide isoquinoline alkaloid (+)-corlumine of ≥80% ee. The synthetic approach described here is compared with other methods of synthesizing enantiomerically pure 1-substituted tetrahydroisoquinolines (and thus an important group of alkaloids, Scheme 1).     

(R,R)-2,3-Butanediol and (s)-pinanediol allylboronates in chiral synthesis of (2S,3S)-3-methyl-5-hexen-2-ol

(R,R)-Butanediol (dichloromethyl)boronate ( 1 ) with 1 equiv. allylmagnesium halide yields (R,R)-2,3-butanediol (1S)-(1-chloro-3-butenyl)boronate ( 3 ) together with the diallylated product (R,R)-2,3-butanediol (1-allyl-3-butenyl)boronate ( 4 ). The formation of 4 is unprecedented in reactions of α-chloroboronic esters with Grignard reagents. With methylmagnesium bromide 3 yielded (R,R)-2,3-butanediol (1S)-(1-methyl-3-butenyl)boronate ( 5 ), which failed to hydrolyze with water. Hydrolysis of 3 yielded impure α-chloroboronic acid, which was esterified with pinacol and treated with methylmagnesium bromide to form 6 , which with (dichloromethyl)lithium followed by methylmagnesium bromide yielded diastereomeric boronic esters 7 and 8 . Oxidation by hydrogen peroxide yielded (2S,3S)- and (2R,3S)-3-methyl-5-hexen-2-ol ( 9 and 10 , ees unknown). Treatment of (s)-pinanediol allylboronate ( 11 ) with (dichloromethyl)lithium at −100°C followed by zinc chloride at up to 25°C has proceeded in the normal way to form (s)-pinanediol (1S)-(1-chloro-3-butenyl)-boronate ( 12 ), which has been elaborated via 13 , 14 , and 15 to (2S,3S)-3-methyl-5-hexen-2-ol ( 9 ) in 95% de.     

Enantioselective Addition of Chiral Organotitanium Derivatives to Aldehydes

Alkoxy- and aryloxy-organotitanium compounds 2–4 derived from (S)-2-methyl-1-butanol, (R)-2-butanol, (-)-menthol, quinine, cinchonine, and (S)-1.1′-binaphthol are added to aromatic aldehydes to give optically active alcohols 5–10 in enantioselectivities of up to 88% e. e., with nucleophilic transfer of methyl, phenyl, and 1-naphthyl groups. The Tables 1–3 list the effects of varying the reagents, the substrates, and the reaction conditions of the new asymmetric synthesis.     

Intermediates of Asymmetric Oxidation Processes Catalyzed by Vanadium(V) Complexes

The [VO(acac)₂]/Schiff base [R-2-(N-3,5-di-tert-butylsalicylidene)amino-2-phenyl-1-ethanol, S-2-(N-3,5-di-tert-butylsalicylidene)amino-3,3-dimethyl-1-butanol, S-2-(N-3,5-di-tert-butylsalicylidene)amino-3-methyl-1-butanol, or R-2-(N-3,5-di-tert-butylsalicylidene)amino-3-phenyl-1-propanol]/H₂O₂ catalytic systems for the asymmetric oxidation of sulfides and the [VO(acac)₂]/(3bR,4aR)-2-(3,4,4-trimethyl-3b,4,4a,5-tetrahydrocyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)ethanol/tert-butyl hydroperoxide/TBHP and VO(OAlkyl)₃/[2,2]paracyclophane-4-carboxylic acid N-(1,1-dimethylethyl)-N-hydroxamide/TBHP catalytic systems for the asymmetric epoxidation of allylic alcohols were studied using ¹³C, ⁵¹V, and ¹⁷O NMR spectroscopy. The key intermediates of these systems (peroxo and alkylperoxo complexes of vanadium(V)) were detected, their structures in solution were studied, and the reactivity was evaluated.     

(S)-和(R)-普萘洛尔的不对称合成

普萘洛尔是一种临床上广泛使用的β受体阻断剂, 介绍了一种不对称合成(S)-和(R)-普萘洛尔的方法. 以手性Salen-Co^III催化剂水解动力学拆分外消旋环氧氯丙烷得到高光学纯度的(S)-环氧氯丙烷和(R)-3-氯-1,2-丙二醇, 以(S)-环氧氯丙烷为手性原料先水解得(S)-3-氯-1,2-丙二醇, 其与1-萘酚反应得(S)-3-(1-萘基)-丙烷-1,2-二醇, 再与氯化亚砜反应得环状亚硫酸酯, 最后和异丙胺作用得(S)-普萘洛尔, 总收率80.9%, 光学纯度大于99%; 而同样以(S)-环氧氯丙烷为手性原料直接与1-萘酚反应得(2R)-3-(1-萘氧基)-1,2-环氧丙烷, 再与异丙胺作用得(R)-普萘洛尔, 总收率74.5%, 光学纯度大于99%.     

Synthesis of chiral 3-substituted-3-aminomethyl-pyrrolidines and related compounds

The preparation of a series of chiral 3-methyl-3-substituted-pyrrolidines/pyrrolidinones starting from (R)-4-(methoxycarbonyl)-1-(1R-phenethyl)-2-pyrrolidinone ( 1 ) is described. The chiral α-methylbenzyl functionality serves not only as a nitrogen protecting group for the pyrrolidine nitrogen, but also as a chiral auxillary. The synthesis of the 4-position enantiomers was accomplished by converting the ester of 1 to the ketone, protecting the ketone as the benzyloxime and separation by chromatography. These key intermediates were converted to the (R) and (S)-3-methyl-3-aminomethylpyrrolidines by removal of the benzyl group followed by oxidation. The 3-methyl-3-(1-aminoethyl)pyrrolidines were obtained via a two step reduction of the corresponding oximes. The stereochemical assignments were determined by X-ray crystallography.     

Chiral Recognition of Propranolol with <Emphasis Type="Bold">β</Emphasis>-Cyclodextrin in the Presence of 1- and 2-Butanol

The purpose of this work is to investigate the chiral recognition characteristics of β-cyclodextrin with two propranolol enantiomers in the presence of organic additives. Steady-state fluorescence measurements of propranolol β-cyclodextrin (β-CD) complexes were performed for solutions containing either 1- or 2-butanol. For each 2-butanol isomer solution, the interactions were assessed by comparing the changes in the fluorescence of (R)-(+)- propranolol versus (S)-(-)-propranolol as a function of CD concentration. A similar comparison study was done for the propranolol enantiomers in the presence of 1-butanol. The intensity changes for propranolol are relatively small upon addition of β-CD in the presence of the butanol alcohol. However, the present work shows that the interaction of (R)-(+)-propranolol with β-CD is influenced by the chirality of 2-butanol in contrast to (S)-(-)-propranolol.This revised version was published online in July 2005 with a corrected issue number.     

Enantioselective transesterification of (RS)-1-chloro-3-(3,4-difluorophenoxy)-2-propanol using Pseudomonas aeruginosa lipases

Lipases from the bacterial strain, Pseudomonas aeruginosa, isolated from the soil by enrichment techniques, are assessed for the enantioselective transesterification of (RS)-1-chloro-3-(3,4-difluorophenoxy)-2-propanol (rac-CDPP) to (R)-1-chloro-3-(3,4-difluorophenoxy)-2-propanol, a key intermediate in the synthesis of the chiral drug (S)-Lubeluzole. The lipases produced by the organism yielded the (S)-ester and the (R)-alcohol as the remaining substrate with an excellent yield (>49.9%) and almost complete enantioselectivity (ee >99.9%) in the presence of vinyl butyrate as an acyl donor in an organic medium. In contrast, purified and expensive commercially available lipases of Candida rugosa and porcine pancreas achieved much lower conversion with enantioselectivities of 15% and 5%, respectively. A well-mixed (∼1000 rev min⁻¹) batch reactor having the aqueous phase finally dispersed in hexane was used in these studies. The parameters of the transesterification reaction were optimized and the optimal concentrations of rac-CDPP and vinyl butyrate were found to be 5 and 150 mM at 30 °C. A preparative-scale reaction yielded the (S)-ester at 42% conversion and ee >99%.     

Asymmetric Synthesis of （R）- and （S）-Moprolol

A simple and effective procedure for the enantioselective synthesis of （R）- and （S）-moprolol was described. The key step was the asymmetric synthesis of enantiopure （R）- and （S）-guaifenesin, which were synthesized from enantioenriched （R）-3-chloro-l,2-propanediol and （S）-epichlorohydrin via kinetics of hydrolysis resolution of racemic epichlorohydrin by chiral Salen-Co^Ⅲ complex. The e.e. values of both the optical compounds were above 98%, and the chemical structures of the target compounds were confirmed by ^1H NMR, ^13C NMR, IR, and MS.     

Lipase-mediated partial resolution of 1,2-diol and 2-alkanol derivatives: towards chiral building-blocks for pheromone synthesis

1,2-Propanediol 5, 1-chloro-2-propanol 8 and its related 2-O-acetate 9 were partially resolved by chemoenzymatic acetylation and deacetylation, in the presence of Pseudomonas fluorescens lipase (Amano P.; PFL), to (R)-(−)-1-acetoxy-2-propanol 6, (R)-(+)-2-acetoxy-1-chloropropane 9 and (R)-(−)-1-chloro-2-propanol 8, respectively. On the other hand, treatment of (2RS)-2 with vinyl acetate in ether and Chirazyme^® L-2 gave 2-O-acetyl-1,3,4-trideoxy-5,6:7,8-di-O-isopropylidene-β-d-manno-non-5-ulo-5,9-pyranose 1 and 1,3,4-trideoxy-5,6:7,8-di-O-isopropylidene-β-d-gluco-non-5-ulo-5,9-pyranose 11, respectively. Compound 10 was subsequently deacylated to 12. Both alcohols 11 and 12 were treated with Me₂CO/H⁺ to cause their rearrangement to (2S,5R,8R,9R,10S)-10-hydroxy-8,9-isopropylidenedioxy-2-methyl-1,6-dioxaspiro[4.5]decane 3 and its (2R)-epimer 4, which closely matched the skeleton of the odour bouquet minor components of Paravespula vulgaris (L.).     

Photochemische Umsetzung von optisch aktiven 2-(1′-Methylallyl)anilinen mit Methanol

Photochemical Reaction of Optically Active 2-(1′-Methylallyl)anilines with Methanol It is shown that (?)-(S)-2-(1′-methylallyl)aniline ((?)-(S)- 4 ) on irradiation in methanol yields (?)-(2S, 3R)-2, 3-dimethylindoline ((?)-trans- 8 ), (?)-(1′R, 2′R)-2-(2′-methoxy-1′-methylpropyl)aniline ((?)-erythro- 9 ) as well as racemic (1′RS, 2′SR)-2-(2′-methoxy-1′-methylpropyl) aniline ((±)-threo- 9 ) in 27.1, 36.4 and 15.7% yield, respectively (see Scheme 3). By deamination and chemical correlation with (+)-(2R, 3R)-3-phenyl-2-butanol ((+)-erythro- 13 ; see Scheme 4) it was found that (?)-erythro- 9 has the same absolute configuration and optical purity as the starting material (?)-(S)- 4 . Comparable results are obtained when (?)-(S)-N-methyl-2-(1′-methylallyl)aniline ((?)-(S)- 7 ) is irradiated in methanol, i.e. the optically active indoline (+)-trans- 10 and the methanol addition product (?)-erythro- 11 along with its racemic threo-isomer are formed (cf. Scheme 3). These findings demonstrate that the methanol addition products arise from stereospecific, methanol-induced ring opening of intermediate, chiral trans, -(→(?)-erythro-compounds) and achiral cis-spiro [2.5]octa-4,6-dien-8-imines (→(±)-threo-compounds; see Schemes 1 and 2).     

α-Alkylation of Amino Acids without Racemization. Preparation of Either (S)- or (R)-α-Methyldopa from (S)-Alanine

Enantiomerically pure cis- and trans-5-alkyl-1-benzoyl-2-(tert-butyl)-3-methylimidazolidin-4-ones ( 1, 2, 11, 15, 16 ) and trans-2-(tert-butyl)-3-methyl-5-phenylimidazolidin-4-one ( 20 ), readily available from (S)-alanine, (S)-valine, (S)-methionine, and (R)-phenylglycine are deprotonated to chiral enolates (cf. 3, 4, 12, 21 ). Diastereoselective alkylation of these enolates to 5,5-dialkyl- or 5-alkyl-5-arylimidazolidinones ( 5, 6, 9, 10, 13a-d, 17, 18, 22 ) and hydrolysis give α-alkyl-α-amino acids such as (R)- and (S)-α-methyldopa ( 7 and 8a , resp.), (S)-α-methylvaline ( 14 ), and (R)-α-methyl-methionine ( 19 ). The configuration of the products is proved by chemical correlation and by NOE ¹H-NMR measurements (see 23, 24 ). In the overall process, a simple, enantiomerically pure α-amino acid can be α-alkylated with retention or with inversion of configuration through pivaladehyde acetal derivatives. Since no chiral auxiliary is required, the process is coined ‘self-reproduction of a center of chirality’. The method is compared with other α-alkylations of amino acids occurring without racemization. The importance of enantiomerically pure, α-branched α-amino acids as synthetic intermediates and for the preparation of biologically active compounds is discussed.     

手性硼酸酯介入的不对称合成3† (R)-或(S)-1,1'-联-2-萘酚硼酸-(S)-脯氨酸酐促进的前手性亚胺的不对称硼烷还原

手性螺硼酸酯(R)-或(S)-1,1'-联-2-萘酚硼酸-(S)-脯氨酸酐[(R,S)-1或(S,S)-1]对前手性亚胺硼烷还原的不对称催化活性被观察到. 在(R,S)-1或 (S,S)-1存在下, 由前手性二烷基酮或烷基苯酮与苯胺缩合生成的前手性亚胺在THF中被硼烷还原, 高产率地给出手性仲胺, 其对映体纯度高达74% ee. 其中, 三种手性仲胺[N-(2-戊基)苯胺, N-(3-甲基-2-丁基)苯胺和N-(4-甲基-2-戊基)苯胺]系首次合成.     

2′, 3′-Dideoxy-3′-fluorotubercidin and Related Dideoxyribonucleosides:. Synthesis via a 2′-deoxy-3′-oxoribofuranoside intermediate and conformation studies

An efficient synthesis of the unknown 2′-deoxy-D-threo-tubercidin ( 1b ) and 2′, 3′-dideoxy-3′-fluorotubercidin ( 2 ) as well as of the related nucleosides 9a, b and 10b is described. Reaction of 4-chloro-7-(2-deoxy-β-D-erythro-pentofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine ( 5 ) with (tert-butyl)diphenylsilyl chloride yielded 6 which gave the 3′-keto nucleoside 7 upon oxidation at C(3′). Stereoselective NaBH₄ reduction (→ 8 ) followed by deprotection with Bu₄NF(→ 9a )and nucleophilic displacement at C(6) afforded 1b as well as 7-deaza-2′-deoxy-D-threo-inosine ( 9b ). Mesylation of 4-chloro-7-{2-deoxy-5-O-[(tert-butyl)diphenylsilyl]-β-D-threo-pentofuranosyl}-7H-pyrrolo[2,3-d]-pyrimidine ( 8 ), treatment with Bu₄NF (→ 12a ) and 4-halogene displacement gave 2′, 3′-didehydro-2′, 3′-dideoxy-tubercidin ( 3 ) as well as 2′, 3′-didehydro-2′, 3′-dideoxy-7-deazainosne ( 12c ). On the other hand, 2′, 3′-dideoxy-3′-fluorotubercidin ( 2 ) resulted from 8 by treatment with diethylamino sulfurtrifluoride (→ 10a ), subsequent 5′-de-protection with Bu₄NF (→ 10b ), and Cl/NH₂ displacement. ¹H-NOE difference spectroscopy in combination with force-field calculations on the sugar-modified tubercidin derivatives 1b , 2 , and 3 revealed a transition of the sugar puckering from the ^3′T_2′ conformation for 1b via a planar furanose ring for 3 to the usual ^2′T_3′ conformation for 2.