Preparation of enantiomerically pure (R)- and (S)-3-amino-3-phenyl-1-propanol via resolution with immobilized penicillin G acylase

Ethyl 2,4-dioxo-4-phenylbutyrate, obtained by condensation of acetophenone with diethyl oxalate, was converted to 3-oxo-3-phenyl-1-propanol in 90% yield by reaction with baker’s yeast. Reductive amination with sodium cyanoborohydride in the presence of ammonium acetate gave the racemic 3-amino-3-phenyl-1-propanol in 65% yield. Enzymatic resolution of the corresponding N-phenylacetyl derivative with penicillin G acylase, immobilized on an epoxy resin gave (S)-amide and (R)-amino alcohol in high enantiomeric purity (ee >99%) and >45% yields for each enantiomer.     

The chemistry of polycyclic arene imine. VI. 1-[N,N-di-(2-propenyl)-9-phenanthreneamine-10-yl]-1a,9b-dihydrophenanthro[9,10-b]azirine an unusual allylation product of phenanthrene 9,10-imine

Phenanthrene 9,10-imine (1) was shown to react with allyl bromide and 50% aqueous sodium hydroxide under phase transfer catalysis conditions to give the title compound 3 as the only product. The starting imine 1 is assumed to undergo initially bis alkylation to form an N,N-di-(2-propenyl)phenanthrene 9,10-iminium salt (4) which, in turn, is attacked by a deprotonated phenanthrene imine anion (5). The structure of 3 has been determined by a single crystal X-ray diffraction analysis.     

A formal total synthesis of (-)-cephalotaxine.

A formal total synthesis of (-)-cephalotaxine (1) has been achieved. The key step is an intramolecular aldol condensation of the diketone 9, which in turn was obtained in three steps from the azabicyclic compound 6 derived from D-proline according to Seebach's procedure. Treatment of 9 with a catalytic amount of sodium 2-methyl-2-butanolate in benzene at room temperature gave the alpha, beta-unsaturated ketone 8 in 43% yield. Catalytic hydrogenation of 8 followed by reduction of the ketone 22 with sodium borohydride and acetylation of the resulting alcohol 23 gave the acetoxy derivative 24, which, after deprotection, was acylated with (methylthio)acetic acid to give the amide 26. Compound 26 was converted into optically active ketolactam 4 following the synthetic operations developed for the synthesis of the racemic compound.     

Synthesis and electrochemical studies of CoII complex with 3-phenyl-5(Z)-(pyridin-2-ylmethylidene)-2-selenohydantoin

A reaction of the sodium salt of 3-phenyl-5(Z)-(pyridin-2-ylmethylidene)-2-selenoxoimidazolidin-4-one (NaL) with CoCl₂·6 H₂O in MeCN gave rise to the complex CoL₂ in 56% yield. Cyclic voltammetry showed that the coordination compound formed was reversibly reduced “at the metal”. According to the CVA data, the product of its reduction, in contrast to the earlier synthesized sulfur-containing analog, undergoes alkylation with n-butyl iodide at the organic ligand fragment.     

(Z)-3-丁烯基-4-羟基苯酞的合成

（Ｚ）－３－丁烯基－４－羟基苯酞的合成李绍白,王志伟,方小平,李裕林（兰州大学应用有机化学国家重点实验室,兰州,７３００００）关键词（Ｚ）－３－丁烯基－４－羟基苯酞,苯酞,３－丙基－５－羟基异香豆素,异香豆素,合成（Ｚ）－３－丁烯基－４－羟基苯酞（１...     

[2+3]Cycloadditions of fluoroolefins: synthesis of 3,4-difluoro-1-t butyl-pyrrole

3,4-Difluoro-1-t-butyl-pyrrole was synthesized by the thermal [2+3] cycloaddition of 2-carbomethoxy-1-t-butyl-aziridine with chlorotrifluoro- ethylene, followed by treatment with sodium methoxide then with alcoholic potassium hydroxide. Thermal decarboxylation afforded the title compound.     

Intramolecular Diels-Alder Reactions via 3-(Phenylthio)-4-(Trimethylsilyl)-3-Sulfolene

Deprotonation of the title compound 2 followed by treatment with 5-iodo-1-pentene or 6-iodo-l-hexene gave the alkylated products 3 and 4 which upon refluxing in toluene yielded the dienes 8a and 8b. Intramolecular Diels-Alder reactions were achieved by heating the dienes 8a and 8b in toluene in a sealed tube at 160–180°C to give bicyclo[4.3.0]nonene 9 and bicyclo[4.4.0]decene 10, respectively, in good yield. The stereochemistry of the cyclization products was determined, and was rationalized by comparison of the possible transition states involved.     

Novel and enantioselective syntheses of (R)- and (S)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid: a synthon for sitagliptin and its derivatives

A new synthetic strategy for (R)- and (S)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid, a building block in the preparation of sitagliptin and its derivatives, was developed. Pd(OAc)₂ catalyzed coupling of 2,4,5-trifluoro-1-iodobenzene with allyl alcohol gave 3-(2,4,5-trifluorophenyl)propanal in a yield of 95%. l-Proline catalyzed reaction of the 3-phenylpropanal (in only 1.2 molar equiv) with nitrosobenzene followed by reduction with NaBH₄ and Pd/C catalyzed hydrogenation gave (R)-3-(2,4,5-trifluorophenyl)propane-1,2-diol with >99% ee and 65% yield. Selective tosylation of primary hydroxyl group of the 1,2-propandiol unit followed by cyanide displacement afforded (R)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanenitrile (80%). The nitrile was converted to the title β-hydroxy acid under basic hydrolysis in a yield of 90%. Thus, (R)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid was prepared enantioselectively from the starting material in four steps and 45% overall yield. The reaction sequence was repeated with d-proline as the catalyst to give (S)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid in 45% overall yield and >99% enantiomeric excess.     

Synthesis of (R)-, (S)-, and (RS)-hydroxymethylmexiletine,one of the major metabolites of mexiletine

Hydroxymethylmexiletine (HMM), one of the main metabolites of mexiletine, has been synthesized in both racemic and optically active forms following two alternative routes. The ee values for both HMM enantiomers were 98%, as assessed by ¹H NMR analysis in the presence of (−)-(R)-(2-naphthyloxy)phenylacetic acid as a chiral solvating agent and electrophoretic analysis using β-cyclodextrine sulfated sodium salt as a chiral auxiliary.     

Thermal polymerizations of alkali 4-(2-bromoethyl)benzoates in bulk

Thermal polymerizations of alkali 4-(2-bromoethyl)benzoates (2-BEBAs) were investigated. The polymerization of the lithium salt at 220°C for 2 h under reduced pressure in bulk, followed by esterification, produced poly(methyl 4-vinylbenzoate), having a number-average molecular weight (M̄_n) of 9500 in a 54% yield. Thus, elimination of hydrogen bromide to form a double bond occurred, followed by vinyl polymerization. In contrast, polymerization of the potassium salt at 200°C for 2 h afforded poly(oxycarbonyl-1,4-phenylene-ethylene) (polyester 1), having an inherent viscosity of 0.19 dL g⁻¹ in a 95% yield: i.e., polycondensation proceeded to afford the polyester. Reaction of the sodium salt at 220°C for 2 h produced polyester 1 having M̄_n of 4000 in a 28% yield as well as 4-vinylbenzoic acid in a 9% yield. In the reaction of the sodium salt, both polycondensation and double bond formation occurred. Thus, these polymerizations depended on the counter cations of 2-BEBAs. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 2055–2060, 1999     

Synthesis and resolution of diethyl (1S,2S)-1-amino-2-vinylcyclopropane-1-phosphonate for HCV NS3 protease inhibitors

We herein describe an efficient synthesis of optically active diethyl 1-amino-2-vinylcyclopropane-1-phosphonate (analogous to 1-amino-2-vinylcyclopropane-1-carboxylate). The racemic phosphonate diethyl ester was obtained from an imine derived from aminomethylphosphonate diester and trans-1,4-dibromo-2-butene. Crystallizations of the dibenzoyl-l-tartaric acid salt allowed for separation of enantiomers. The enantiomerically pure material was used to synthesize an extremely potent tripeptide phosphonate inhibitor of HCV NS3 protease. X-ray crystal structure of the inhibitor bound to the HCV NS3 protease confirmed the absolute stereochemistry of the title compound.     

A crystallization-induced asymmetric transformation to prepare (R)-4-chlorophenylalanine methyl ester

A second order asymmetric transformation of racemic 4-chlorophenylalanine methyl ester was achieved via salt formation with (2S,3S)-(−)-tartaric acid in the presence of salicylaldehyde to afford the desired (R)-enantiomer of 4-chlorophenylalanine methyl ester in good yield and high enantiomeric purity.     

Hydroxide-promoted redox reactions in water of α-Phenyl-4-nitro-benzenemethanol, α-(p-Nitrophenyl)-4-pyridinemethanol,and α-(p-Nitrophenyl)-4-Pyridinemethanol N-Oxide steric inhibition of resonance

α-Phenyl-4-nitrobenzenemethanol ( 3 ) reacted with 1 M sodium hydroxide to yield 4, 4′-dibenzoyl-azoybenzene ( 5 ) (51%), 4-hydroxy-4′-benzoylazobenzene ( 6 ) and benzoic acid (12% each), and smaller amounts of 4-aminobenzophenone and 4-nitrobenzophenone. Both α-phenyl-2-nitrobenzenemethanol ( 9 ) and 3, 5-dimethyl-4-nitrobenzenemethanol ( 10a ) did not react with 1 M sodium hydroxide, presumably due to steric hindrance. α-(p-Nitrophenyl)-4-pyridinemethanol ( 14 ) and its N-oxide 11 with 1 M sodium hydroxide yielded 4,4′-diaroylazoxybenzenes 15a and 12a , respectively, 4,4′-diaroylazobenzenes 15b and 12b , respectively, as well as 4-hydroxy-4′-aroylazobenzenes 16 and 13 , respectively. The relative reaction rates were 11 > 14 > 3 . Studies with 11 showed that the nitro group is involved in the redox reaction in preference to the N-oxide group.     

Large scale synthesis and absolute configuration of (-)-3-ppp,a selective dopamine autoreceptor agonist

A large scale synthesis for (-)-3-PPP has been developed. The racemic methoxy compound $\text{1}$ was prepared in a three step procedure in 63% yield. This was resolved as a diastereomeric salt by crystallization of the (-)-di-p-toluoyltartrate. Two crystallizations gave the pure (-)-enantiomer $\text{2}$ in 50% of the theoretical yield and with an enantiomeric excess of >95%. Demethylation using aqueous HBr gave (-)-3-PPP, ($\text{3}$). Compound $\text{2}$ was also prepared in a stereoselective synthesis from $\text{S}$-(-)- N-propyl-2- chloromethylpyrrolidine $\text{4}$. By X-ray crystallography it was shown that (-)-3-PPP has the $\text{S}$-configuration at the chiral carbon.     

Optimization of the synthesis of phenanthrene-2- and -3-sulfonyl chlorides

Sulfonation of phenanthrene with sulfuric acid, followed by neutralization with sodium hydroxide, gave a mixture of isomeric sodium phenanthrenesulfonates in an overall yield of 83%. Sodium phenanthrene-2-, -3-, and -9-sulfonates were isolated in 17, 43, and 4% yield, respectively. Sulfonation of phenanthrene with ClSO₃H or SO₃ did not improve the yields of phenanthrene-2- and -3-sulfonic acids. Treatment of sodium phenanthrene-2- and -3-sulfonates with PCl₅-POCl₃ or SOCl₂-DMF afforded the corresponding sulfonyl chlorides in 89 and 87 or 69 and 70% yield, respectively. Pure phenanthrene-2- and -3-sulfonyl chlorides were also synthesized in 27 and 51% yield by reaction of a mixture of 2- and 3-sulfonates with PCl₅-POCl₃.     

Synthesis of both enantiomers of cyclic methionine analogue: (R)- and (S)-3-aminotetrahydrothiophene-3-carboxylic acids

A method of synthesizing an optically active cyclic methionine analogue, 3-aminotetrahydrothiophene-3-carboxylic acid (At₅c), is described. A Bucherer–Bergs reaction of 4,5-dihydro-3(2H)-thiophenone and the subsequent alkaline hydrolysis of a hydantoin, followed by Cbz protection of the amine, afforded racemic Cbz-At₅c (±)-3 in excellent yield. Diastereomeric esters derived from Cbz-At₅c (±)-3 and (R)-BINOL could be separated by column chromatography to give both diastereomers with >99% de. X-ray crystallographic analysis revealed the absolute configuration of the synthesized amino acid derived from the less polar diastereomeric ester to be (S).     

An improved synthesis of 1-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)ethanone,isoarecolone

A convenient synthesis of 1-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)ethanone, isoarecolone, starting with 4-acetylpyridine is presented. 4-Acetylpyridine was protected as the ketal followed by reaction with iodomethane to give the quaterary salt. The quaterary salt was reduced with sodium borohydride followed by deprotection to give isoarecolone in 80% overall yield.     

A facile preparation, the crystal structure, the chemical and electrochemical properties of [4-(dimethylamino)phenyl]-3-guaiazulenylmethylium tetrafluoroborate

Reaction of guaiazulene (1) with p-dimethylaminobenzaldehyde in methanol in the presence of tetrafluoroboric acid gives the title monocarbocation compound, [4-(dimethylamino)phenyl]-3-guaiazulenylmethylium tetrafluoroborate (2), in 90% yield. The title investigations of compound 2 compared with those of two other monocarbocations stabilized by a 3-guaiazulenyl group (i.e. phenyl-3-guaiazulenylmethyl and [4-(isopropyl)phenyl]-3-guaiazulenylmethyl cations) are reported.     

A practical synthesis of (3R,4R)-N-tert-butoxycarbonyl-4-hydroxymethylpyrrolidin-3-ol

The title compound (+)-, required for production of transition state analogue inhibitors of enzymes involved in T-cell-dependent disorders, was synthesized in five steps. A 1,3-dipolar cycloaddition of the nitrone formed from formaldehyde and N-benzylhydroxylamine to diethyl maleate gave the racemic cis-isoxazolidine (+/-)-. Reduction of the N-O bond of this compound gave pyrrolidone (+/-)- in excellent yield. A very efficient enzymic resolution of this racemic product led to the title enantiomer (+)-. This route employs only one chromatographic purification.