A Convenient Stereoselective Synthesis of (1R,2S,3R,4S)-3-(Neopentyloxy)isoborneol

A convenient preparation of (1R,2S,3R,4S)-3-(neopentyloxy)isoborneol (= (1R,2S,3R,4S)-3-(2,2-dimethyl-propoxy)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol; 1a ), a valuable chiral auxiliary, is described. The synthesis involves six steps starting from the readily available camphorquinone ( 5 ) and gives 1a in 48% overall yield. The key step is the chemoselective hydrolysis of the less hindered 1,3-dioxolane moiety in the camphorquinone di-acetal 4 .     

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.     

A two-step method for the preparation of homochiral cathinones

A simple method for the preparation of homochiral ring-substituted 1-aryl-2-aminopropanones 2 (‘cathinones’) is described, involving initial Friedel–Crafts acylation of aromatics with (S)- or (R)-N-trifluoroacetylalanyl chloride, followed by acid hydrolysis of the intermediate trifluoroacetamido intermediates 1, for which X-ray diffraction analysis confirmed the structures.     

Preparative scale synthesis of (S)-2-hydroxypropoxyamine hydrochloride

A simple preparation of (S)-2-hydroxypropoxyamine hydrochloride by baker's yeast reduction of prochiral N-(2-oxopropoxy)phthalimide followed by acid hydrolysis is described.     

Diastereoselective Electrophilic Amination of Chiral 1‐Benzoyl‐2,3,5,6‐tetrahydro‐3‐methyl‐2‐(1‐methylethyl)pyrimidin‐4(1H)‐one for the Asymmetric Syntheses of α‐Substituted α,β‐Diaminopropanoic Acids

The chiral compounds (R)‐ and (S)‐1‐benzoyl‐2,3,5,6‐tetrahydro‐3‐methyl‐2‐(1‐methylethyl)pyrimidin‐4(1H)‐one ((R)‐ and (S)‐ 1 ), derived from (R)‐ and (S)‐asparagine, respectively, were used as convenient starting materials for the preparation of the enantiomerically pure α‐alkylated (alkyl=Me, Et, Bn) α,β‐diamino acids (R)‐ and (S)‐ 11 – 13 . The chiral lithium enolates of (R)‐ and (S)‐ 1 were first alkylated, and the resulting diasteroisomeric products 5 – 7 were aminated with ‘di(tert‐butyl) azodicarboxylate’ (DBAD), giving rise to the diastereoisomerically pure (≥98%) compounds 8 – 10 . The target compounds (R)‐ and (S)‐ 11 – 13 could then be obtained in good yields and high purities by a hydrolysis/hydrogenolysis/hydrolysis sequence.     

A simple procedure for the synthesis of 3-(substituted-sulfanyl)-4-hydroxy-6-substituted-pyran-2-ones

A series of 3-(substituted sulfanyl)-4-hydroxy-6-substituted-pyran-2-ones were synthesized for Human immunodeficiency virus-1 protease inhibition. These compounds were synthesized in a simple and convergent fashion to allow us a rapid preparation of many structurally diversified analogues. Thus the condensation of trimethylsilyl enol ethers of corresponding ketones, with 2-(S-substituted)propane-1,3-dioates afforded the corresponding pyrones in 24–70% isolated yields.     

A DFT study on the hydrolysis mechanism of NH‐tautomeric antitumors of [HL][trans‐RuCl4L(dmso‐S)]

The hydrolysis process of Ru (III) complex [Htrz][trans‐RuCl₄(1‐H‐1,2,4‐triazole)(dmso‐S)] 1 , a potential antitumor complex similar to the well‐known anticancer agent [ImH][trans‐RuCl₄(Im)(dmso‐S)] (NAMI‐A), has been investigated by using density functional theory (DFT) method, and the solvent effect was also considered and calculated by conductor‐like polarizable calculation model (CPCM). Meanwhile, the hydrolysis process of the NH‐tautomeric isomer, [Htrz][trans‐RuCl₄(4‐H‐1,2,4‐triazole)(dmso‐S)] 2 , was also modeled and predicted by the same methods. The structural characteristics and the detailed energy profiles for the hydrolysis processes of two isomers have been obtained. The analysis of thermodynamic and kinetic characteristics of hydrolysis reaction suggests the following: for the first hydrolysis step, the Complex 1 has lower hydrolysis rate than the reported anticancer drug NAMI‐A, and the result is in accordance with experimental one. However, Complex 1 has obviously higher hydrolysis rate than its isomer Complex 2 , and the result was reasonably explained in theory. For the second hydrolysis step, the formation of cis‐diaqua species is thermodynamic preferred to that of trans isomers. In addition, the trend in nucleophilic attack abilities (A) of hydrolysis products by pertinent biomolecules was revealed and predicted. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2010     

Chiral nucleophilic glycine and alanine synthons: nickel(II) complexes of Schiff bases of (S)-N-(2,4,6-trimethylbenzyl)proline (2-benzoylphenyl)amide and glycine or alanine

A new chiral auxilliary, (S)-N-(2,4,6-trimethylbenzyl)proline (2-benzoylphenyl)amide, has been synthesised as a potential building block for the preparation of chiral synthons of amino acids. The nickel(II) complex of its Schiff base derivative with glycine has been methylated with 97% d.e. (diastereomeric excess), whilst the nickel(II) complex of its Schiff base derivative with (RS)alanine has been ¹³C-methylated with 66% d.e.     

Tautomer chemistry of thiazolidines. 1-Thia-4-azaspiro[4,5] decanes

The thiazolidine, 1-thia-4-azaspiro[4,5] decane (Ia), which is derived from cyclohexanone and 2-aminoethanethiol (X), forms a thiazolidone (VIII) with mercaptoacetic acid more slowly and in lower yield than with 2-phenylthiazolidine, a case reported previously. A thiazolidine which is related to a non-conjugate chain tautomer such as Ic, might be expected to behave in this way. Alkylation, as another possible example of tautomer chemistry, was studied, and N-, S-, and C-alkylation were all observed under varying circumstances. Thus, thiazolidine la undergoes alkylation with methyl iodide in ethanol to form the N-methylthiazolidine (IIa), and in sodium-liquid ammonia to give the S-methyl derivative (III). In the latter case, alkylation occurs with reductive cleavage. Although no trace of other tautomer derivatives (IV, V) was to be found in the methyl iodide alkylation, I with acrylonitrile did in fact give C-alkylation. An analytically pure mixture of tautomers was obtained, from which 2-oxocyclohexanepropionitrile (VI) was isolated on hydrolysis. In a manner similar to the formation of III, IIa was S-alkylated by treatment with sodium-liquid ammonia followed by benzyl chloride to give a saturated product (XVII). Although such a process might be identified with a chain tautomer (IIb), the evidence is to the contrary, since the intermediate (XIV), which might be involved in such a process, fails to undergo a similar reduction with sodium-liquid ammonia. A greatly improved procedure for the preparation of thiazolidine (XI, 86% yield) is also reported.     

A Valuable Synthetic Route to the Enantiopure Functionalized N-Substituted Aziridines

Chiral butyrolacto[3,4-b]-2(S)-6(R)-1-N-akylaziridines 7 were synthesized in enantiopure form utilizing racemic 5-methoxy-3-bromo-2(5H)-furanone (5) and available amines (6) as key precursors. After highly effective reduction of 7, the functionaiized 2(S),3(R)-dihyroxymethyl-N-alkylaziridines (8) were obtained in good yields with ≥98% ee. This is a simple and pratical method for the preparation of enantiopure aziridines which are important intermediates in the synthesis of biologic active molecules.     

Conversion of Amines into Phenylsulfides and Phenylselenides via Ditosylamides

Amines are converted in good to excellent yields to phenylsulfides or phenyl-selenides via nucleophilic displacement on the corresponding ditosylamides. The conversion of (?)-(S)-1-phenylethylamine to the chiral phenylsulfide 6 was found to proceed with inversion of configuration. A simple one-pot procedure for the preparation of ditosylamides is reported.     

A Simple Biosystem for the High-Yielding Cascade Conversion of Racemic Alcohols to Enantiopure Amines

The amination of racemic alcohols to produce enantiopure amines is an important green chemistry reaction for pharmaceutical manufacturing, requiring simple and efficient solutions. Herein, we report the development of a cascade biotransformation to aminate racemic alcohols. This cascade utilizes an ambidextrous alcohol dehydrogenase (ADH) to oxidize a racemic alcohol, an enantioselective transaminase (TA) to convert the ketone intermediate to chiral amine, and isopropylamine to recycle PMP and NAD⁺ cofactors via the reversed cascade reactions. The concept was proven by using an ambidextrous CpSADH-W286A engineered from (S)-enantioselective CpSADH as the first example of evolving ambidextrous ADHs, an enantioselective BmTA, and isopropylamine. A biosystem containing isopropylamine and E. coli (CpSADH-W286A/BmTA) expressing the two enzymes was developed for the amination of racemic alcohols to produce eight useful and high-value (S)-amines in 72–99 % yield and 98–99 % ee, providing with a simple and practical solution to this type of reaction.     

An Efficient Synthesis of Isomeric 1‐(1‐Alkyl‐1H‐pyrazolyl) Ethanones

A simple and versatile general method for the preparation of N‐substituted 3‐, 4‐, or 5‐acetylpyrazoles from corresponding acids via hydrolysis and decarboxylation of substituted diethyl [(1‐alkyl‐1H‐pyrazolyl)carbonyl]malonates was developed. Title compounds were prepared in three steps without isolation of intermediates in 48–82% overall yield.     

A Synthesis of (S)-3-(Phenylmethyl)morpholine from (S)-Phenylalanol.

A preparation of (S)-3-(phenylmethyl)morpholine from (S)-phenylalanol is described.     

The Enantioselective Synthesis of β-Amino Acids,their α-hydroxy derivatives,and the N-terminal components of bestatin and microginin

L -Aspartic acid by tosylation, anhydride formation, and reduction with NaBH₄ was converted into (3S)-3-(tosylamino)butan-4-olide ( 8 ; Scheme 1). Tretment of 8 with ethanolic trimethylsilyl iodide gave the N-protected deoxy-iodo-β-homoserine ethyl ester 9 . The latter, on successive nucleophilic displacement with lithium dialkyl-cuprates ( → 10a–e ), alkaline hydrolysis ( → 11a–e ), and reductive removal of the tosyl group, produced the corresponding 4-substituted (3R)-3-aminobutanoic acids 12a–e (ee > 99%). Electrophilic hydroxylation of 8 ( → 19 ; Scheme 3), subsequent iodo-esterification ( → 21 ; Scheme 4), and nucleophilic alkylation and phenylation afforded, after saponification and deprotection, a series of 4-substituted (2S, 3R)-3-amino-2-hydroxybutanoic acids 24 including the N-terminal acids 24e ( = 3 ) and 24f ( = 4 ) of bestatin and microginin (de > 95%), respectively.     

Enantioselective synthesis of (S)-α-methylphenylalanine using (S)-BINOLAMs as new phase-transfer catalysts

A series of (S)-bis(aminomethyl)binaphthols [(S)-BINOLAMs] 4 have been prepared and used as catalysts in the enantioselective C-alkylation reaction of the aldimine Schiff bases of alanine esters 5 under solid–liquid phase-transfer catalysis (PTC) conditions employing NaOH as base in toluene at room temperature. (S)-3,3′-Bis[(diethylamino)methyl]-2,2′-dihydroxy-1,1′-binaphthalene 4a gave the best e.e.s. (S)-α-Methylphenylalanine 7 was isolated, after hydrolysis of the iminoester, in 85% yield with an e.e. of 68%.     

Preparation of the enantiomers of 1-phenylethan-1,2-diol. Regio- and enantioselectivity of acylase I and Candida antarctica lipases A and B

Acylase I and Candida antarctica lipases A (CAL-A) and B (CAL-B) were evaluated for the preparation of the enantiomers of 1-phenylethan-1,2-diol. In the presence of CAL-B, the sequential one-pot methanolysis of the diacetate in acetonitrile allowed the preparation of (S)-diol (e.e. 97%) and (R)-1-acetoxy-1-phenylethanol (e.e. 94%). Base-catalyzed methanolysis of the monoacetate resulted in the corresponding (R)-diol. When one of the diol enantiomers was subjected to Mitsunobu esterification, inversion of configuration occurred, allowing transformation of the initially racemic mixture to one enantiomer. Acylase I-catalysis led to the chemo- and enantioselective formation of (S)-1-acetoxy-1-phenylethanol (e.e. 97%) in the presence of the primary hydroxyl function through acetylation of the secondary hydroxyl group. The low chemical yield (ca. 25%) was due to the moderate enzymatic regioselectivity. CAL-A behaved in a similar way to acylase I.     

Direct Resolution of the Enantiomers of Betaxolol and Related Intermediates,and Its Application

An OJ-H chiral column has been used for direct resolution of the enantiomers of betaxolol and related intermediates in the preparation of (S)-betaxolol. The enantiomers can be excellently resolved (R _S > 2) within 9.4 min with high peak symmetry. The enantiomers of some acetylated intermediates, which cannot be resolved on an OD-H column, can also be resolved. The method is simple and suitable for routine determination of ee values in the preparation of (S)-betaxolol.

     

Rapid and Efficient Synthesis of (R)-Aryloxypropionic Acid Esters Under Microwave Irradiation

A series of (R)-(+)-ethyl aryloxypropionates (4a–4p) have been synthesized by the reaction of substituted phenols with ethyl (S)-(?)-tosyloxy lactate under the conditions of microwave irradiation and without solvents. The reaction conditions have been optimized. A good method for the preparation of (R)-(+)-ethyl aryloxypropionate was developed, with good yields, high enantiomer excess, short reaction times, easy workup, and simple procedure.     

A Highly Convergent Total Synthesis of (+)-Myxovirescine M2. Preliminary Communication

The antibiotic myxovirescine M₂ was synthesized from seven building blocks ( 1 – 7 , Scheme 1), with the following chiral starting materials being employed: (S)-malic acid, (+)-D -ribonolactone, (S)-2-(hydroxymethyl)butanoate, and (2R,4S)-5-hydroxy-2,4-dimethylpenLanoate. Three new nucleophilic reagents, 8 – 10 , for C-C bond formation have been used. The key steps of the synthesis are: a Suzuki coupling between an alkyl borane and a vinyl bromide ( 4 + 12e → 13 ), a Julia olefinalion ( 14 + 17 → 18 ), and a Yamaguchi macrolactonizalion to form the 28-membered lactone ( 18 → 19 ), This extremely convergenl synthetic approach will allow the preparation of a number of the 31 known myxovirescine molecules.