Chiral Half-esters Research Articles

Cyclobutane-Containing Scaffolds as Useful Intermediates in the Stereoselective Synthesis of Suitable Candidates for Biomedical Purposes: Surfactants, Gelators and Metal Cation Ligands

Efficient and versatile synthetic methodologies are reported for the preparation of products that are suitable candidates to be used as surfactants, gelators for hydroxylic solvents or metal cation ligands, with potential use in several fields including biomedical applications. The common structural feature of all the synthesized products is the presence of a cis or trans-1,2- or cis-1,3-difunctionalized cyclobutane ring. In the two first cases, the key intermediates including enantiomerically pure 1,3-diamines and 1,3-amino alcohols have been prepared from β-amino acid derivatives obtained, in turn, from a chiral half-ester. This compound is also precursor of γ-amino esters. Furthermore, two kind of polydentate ligands have also been synthesized from a symmetric 1,5-diamine obtained from norpinic acid, which was easily prepared from commercial verbenone.

Novel synthesis of various orthogonally protected Cα-methyllysine analogues and biological evaluation of a Vapreotide analogue containing (S)-α-methyllysine

Prochiral malonic diesters containing a quaternary carbon center have been successfully transformed into a diverse set of (t)Boc-Fmoc-α(2,2)-methyllysine-OH analogues through chiral malonic half-ester intermediates obtained via enzymatic (Pig Liver Esterase, PLE) hydrolysis. The variety of chiral half-ester intermediates, which vary from 1 to 6 methylene units in the side chain, are achieved in moderate to high optical purity and in good yields. The PLE hydrolysis of malonic diesters with various side chain lengths appears to obey the Jones's PLE model according to the stereochemical configurations of the resulting chiral half-esters. The established synthetic strategy allows the construction of both enantiomers of α(2,2)-methyllysine analogues, and a (S)-β(2,2)-methyllysine analogue from a common synthon by straightforward manipulation of protecting groups. Two different straightforward and cost effective synthetic strategies are described for the synthesis of α(2,2)-methyllysine analogues. The described strategies should find significant usefulness in preparing novel peptide libraries with unnatural lysine analogues. A Vapreotide analogue incorporating (S)-α(2,2)-methyllysine was prepared. However, the Vapreotide analogue with (S)-α-methyl-α-lysine is found to lose its specific binding to somatostatin receptor subtype 2 (SSTR2).

ChemInform Abstract: Stereoselective Alkylation of Dianions Derived from Chiral Half-Esters of Monosubstituted Malonic Acids: Asymmetric Synthesis of α- Alkyl α-Amino Acids and Key Synthetic Intermediates for Hunteria and Aspidosperma Indole Alkaloids.

Substitution of the chiral half-esters of monosubstituted malonic acids with halides leads to the formations of mixtures of the diastereoisomeric alkyl- or benzyl-malonic half-esters. The (R)-isomers (13A and 15A–22A) were obtained from the phenylmenthyl half-ester 14 of methylmalonic acid in high diastereoisomeric excess. The same stereoisomers were also produced by reaction of the half-esters 9, 23 and 24 with methyl iodide. Their absolute configurations were determined by transforming the major products into the known α-alkyl α-amino acid derivatives 30, 33 and 35. The major product 43, prepared by allylation of the half-ester 9, was converted into two lactones 41 and 42, key intermediates for synthesis of indole alkaloids of the Hunteria and Aspidosperma types. The mechanism of the above alkylation is discussed.

Enantioselective Synthesis of α-Quaternary Amino Acid Derivatives by Sequential Enzymatic Desymmetrization and Curtius Rearrangement of α,α-Disubstituted Malonate Diesters

A convenient and versatile enantioselective synthesis of biologically important alpha-quaternary amino acid derivatives was based on the sequential double alkylation or arylation of dimethyl malonate, followed by desymmetrization with porcine liver esterase (PLE) and Curtius rearrangement. The PLE-mediated hydrolysis of the prochiral dialkylated malonate diesters produced the corresponding chiral half-esters in high yield and with enantiomeric excesses of 43% to >98%. Curtius rearrangement of the latter products, after trapping of the intermediate isocyanates with benzyl alcohol or amines, afforded the corresponding Cbz-protected amino esters or ureas. The absolute configurations of the major products in five examples were established by conversion to compounds with known specific rotations, or by X-ray crystallography of derivatives obtained with chiral amines of known configuration.

A divergent approach to the preparation of cysteine and serine analogs

Malonate diesters containing a prochiral quaternary carbon have been successfully transformed into analogs of cysteine and serine. The chiral half-esters are obtained in good yield, and enantioselectivity by selective hydrolysis using Pig-Liver Esterase (PLE) as the catalyst. The resulting half-ester intermediates are transformed into alpha2, 2-, beta2, 2-, and beta3, 3-analogs of cysteine and serine. The methodology described here allows for the preparation of both enantiomers of the amino-acid analogs by selective manipulation of the ester and acid functionalities. This divergent strategy allows a common synthetic strategy to be used to prepare a variety of unnatural amino-acid classes from a common intermediate which should prove useful in the design of novel peptide libraries.

Practical Syntheses of Chiral α-Amino Acids and Chiral Half-Esters by Kinetic Resolution of Urethane-Protected α-Amino Acid N-Carboxyanhydrides and Desymmetrization of Cyclic meso-Anhydrides with New Modified Cinchona Alkaloid Catalysts

The large-scale applications of the kinetic resolution of urethane-protected α-amino acid N-carboxyanhydrides (UNCAs) and the desymmetrization of cyclic meso-anhydrides using modified cinchona alkaloids are described. These asymmetric reactions are effective organocatalytic methods for the synthesis of chiral α-amino acids 6 and chiral half-esters 2 on an industrial scale, because the organocatalyst recovery and product purification can be carried out by a simple extractive procedure obviating a chromatographic purification step. The modified cinchona alkaloid catalysts (DHQD)2AQN and (DHQ)2AQN, as reported by Deng and co-workers, are not readily available and therefore not suitable for industrial-scale synthesis. Various O-alkylated quinidine and quinine derivatives were prepared and screened as catalysts for the kinetic resolution of phenylalanine UNCA with alcohol. The readily prepared O-propargylquinidine (OPQD) and O-propargylquinine (OPQ) were discovered to be highly enantioselective and practical catalysts. These new catalysts were applied to the synthesis of chiral propargylglycine 24 and the key intermediate of BAY10-8888/PLD-118, 26, on an industrial scale, by the kinetic resolution of UNCA 22 and the desymmetrization of cyclic meso-anhydride 25, respectively.

Total synthesis of antitumor macrolide, rhizoxin and chemistry of acylsilane

The first total synthesis of the antitumor macrolide rhizoxin in a highly stereo-controlled manner was described. The construction of the key building fragments required for the total synthesis of the antitumor macrolide rhizoxin, that arose from our retrosynthetic analysis of rhizoxin in an optically pure form by concise and efficient sequence analyses was described. Synthesis of the right-wing was started from the chiral half-ester generated by asymmetric hydrolysis of the corresponding meso-diester using pig liver esterase. The remaining chiral centers of the fragment was constracted by cyclic hydroboration. Synthesis of the left-wing was also accomplished starting from (S)-methyl 3-hydroxy-2-methylpropionate which had been prepared by enzyme mediated transformation. Coupling of the right-wing and the left-wing was accomplished by Julia coupling, and the macrocyclic lactone was constructed by the intramolecular Horner-Emmons reaction. The control of the stereoselective epoxidations was well achieved after the formation of an unsaturated 16-membered macrocyclic lactone. Chromophore-side-chain moiety was constructed at the final stage by the reaction of the phosphineoxide in 80% yield with high selectivity (E/Z = > 20/1). The present methodology will be useful for the synthesis of the homologues and man-made rhizoxin.

Synthetic 2-amino alcohol derivatives as chiral auxiliaries

Both enantiomers of cis-4,5-disubstituted 2-oxazolidinones, DHAOx (4,5-(9,10-dihydroanthraceno)oxazolidin-2-one), DMAOx (4,5-(9,10-dihydro-9,10-dimethylanthraceno)oxazolidin-2-one) , CPAOx (4,5-(1,4-cyclopentano)oxazolidin-2-one), HMCOx (4,5-[3,5-(1,2,3,4,4,5-hexamethyl-1,4-cyclopenteno)]-oxaz olidin-2-one) and BPSOx (4,5-[1,4-(2-tert-butyldiphenylsilyloxy)cyclopenteno]oxazoli dine-2-one), which are sterically congested and conformationally fixed by bicyclo[2.2.1] and [2.2.2] ring systems are newly prepared by the Diels-Alder reactions of 2-oxazolone with the cyclic dienes such as anthracenes and cyclopentadienes followed by optical resolution with MAC acid (2-methoxy-1-apocamphanecarboxylic acid). These compounds, particularly DMAOx, HMCOx and BPSOx, serve well as the most powerful 2-oxazolidinone chiral auxiliaries reported so far for the asymmetric reactions such as alkylations, the Diels-Alder reactions, the Michael-type additions and aldol reactions. Sterically congested 2-aminoalcohol derivatives derived from the ring-opening of these 2-oxazolidinones are shown to be highly useful auxiliaries for enantioselective additions of diethylzinc to aldehydes and enantiodivergent conversion of meso-dicarboxylic anhydrides to chiral half-esters.

抗腫よう性マクロリド，リゾキシンの全合成

The first total synthesis of the antitumor macrolide rhizoxin in a highly stereocontrolled manner has been achieved. The efficient construction of optically pure key building fragments designed based on rational retrosynthetic analysis was accomplished in a concise manner. Synthesis of the Right-Wing started from the chiral half-ester generated by asymmetric hydrolysis of the corresponding meso-diester using pig liver esterase. The remaining chiral centers of the fragment were constructed by cyclic hydroboration. Synthesis of the LeftWing was accomplished starting from methyl (S) -3-hydroxy-2-methylpropionate which in turn had been prepared again by enzyme mediated transformation.Coupling of Right-Wing and Left-Wing was carried out by Julia condensation, and the macrocyclic lactone was constructed by intramolecular Horner-Emmons reaction. Finally, the stereoselective epoxidation was achieved cleanly after formation of unsaturated 16-membered macrocyclic lactone. Chromophore-side-chain moiety was constructed at final stage by reaction of the phosphineoxide in 80% yield with high selectivity (E/Z= >20/1).The present methodology will be useful for the synthesis of the homologues or man-made rhizoxins.

Stereoselective alkylation of dianions derived from chiral half-esters of monosubstituted malonic acids: asymmetric synthesis of α-alkyl α-amino acids and key synthetic intermediates for Hunteria and Aspidosperma indole alkaloids

Substitution of the chiral half-esters of monosubstituted malonic acids with halides leads to the formations of mixtures of the diastereoisomeric alkyl- or benzyl-malonic half-esters. The (R)-isomers (13A and 15A–22A) were obtained from the phenylmenthyl half-ester 14 of methylmalonic acid in high diastereoisomeric excess. The same stereoisomers were also produced by reaction of the half-esters 9, 23 and 24 with methyl iodide. Their absolute configurations were determined by transforming the major products into the known α-alkyl α-amino acid derivatives 30, 33 and 35. The major product 43, prepared by allylation of the half-ester 9, was converted into two lactones 41 and 42, key intermediates for synthesis of indole alkaloids of the Hunteria and Aspidosperma types. The mechanism of the above alkylation is discussed.

ChemInform Abstract: Synthesis of Nucleosides and Their Related Compounds. Part 12. Menthyl 2,4‐Dioxo‐1,3‐oxazine‐5‐carboxylates: New Dienophiles for the Asymmetric Diels‐Alder Reaction Directed Towards Synthesis of Carbocyclic C‐Nucleosides.

AbstractFormyl Meldrum's acid (I) is converted to the cyclic acetals (V) via the chiral half esters (III).

Asymmetric syntheses of chiral propane-1,3-diols starting from malonic acid

Syntheses of chiral intermediates having one tertiary asymmetric centre were carried out via chiral half-esters of monoalkylmalonic acids. The menthyl half-ester of ethylmalonic acid afforded a single diastereoisomer through crystallisation-induced asymmetric transformation (second-order asymmetric transformation). Furthermore enantioselective preparation of unsymmetrical propane-1,3-diol derivatives was achieved by the use of 8-phenylmenthyl half-esters.

An enantioselective synthesis of a key intermediate to thienamycin by chemicoenzymatic approach

A key intermediate to thienamycin is synthesized enantioselectively under complete stereo- and regio-chemical control starting from a chiral half ester 5 enzymatically generated.

Enantioselective hydrolysis of dialkyl 3-monosubstituted glutarates with pig liver esterase: Structure-optical purity relationships

Dialkyl 3-monosubstituted glutarates are subjected to hydrolysis with pig liver esterase to afford the corresponding chiral half-esters. Synthetically useful half-esters of higher optical purity are obtained from the prochiral substrates of more hydrophobic nature.

An Enantioselective Synthesis of (−)-Fortamine1)

Abstract The aminocyclitol moiety of fortimicin A, (−)-fortamine, was synthesized in an enantioselective manner starting from the chiral half ester, easily available by the enantioselective hydrolysis of a symmetrical diester with pig liver esterase. The present approach provides a general and efficient route to variously substituted 1,4-diaminocyclitol-derivatives.

Ｓｙｍｍｅｔｒｉｚａｔｉｏｎ‐ａｓｙｍｍｅｔｒｉｚａｔｉｏｎ Ｃｏｎｃｅｐｔに基づく抗生物質の全合成

We have shown that the enantioselective total synthesis of some useful antibiotics can be efficiently achieved by reasonable combination of enzymatic and non-enzymatic procedures. Our synthetic strategy for such optically active natural products is designed by the following principle.(1) Symmetrization : retrosynthesis is performed to generate, from the target molecule, a simplified symmetric diester in the prochiral or meso form as shown in Figure 1.(2) Asymmetrization : the symmetric diester is subjected to asymmetric hydrolysis with pig liver esterase (PLE) to generate the corresponding chiral half-ester (Enzymatic conversion of σ-symmetry substrate to C1-symmetry intermediate) (3) Non-enzymatic procedures : the chiral half-ester is converted to the target molecule and related molecules by means of usual organic synthesis, including some new method developed by us. Thus, various types of carbapenem antibiotics, negamycin, showdomycin, 6-azapseudouridine, cordycepin, aristeromycin, neplanocin A, and aminocyclitol-derivatives of fortimicin were efficiently synthesized with the desired absolute configurations.

Creation of novel chiral synthons with enzymes: application to enantioselective synthesis of antibiotics.

Retrosynthesis was carried out to generate, from a target molecule, a symmetric diester in the prochiral or meso form. The symmetric diester was subjected to asymmetric hydrolysis with pig liver esterase to create the corresponding chiral half-ester. The chiral half-ester was converted into the target molecule by organic synthesis. Thus, various types of carbapenem antibiotics, negamycin, showdomycin, 6-azapseudouridine, cordycepin, aristeromycin, neplanocin A, and precursors of fortimicin were efficiently synthesized with the desired absolute configuration. The methods for asymmetric synthesis starting from substrates with sigma-symmetry have been extensively developed.

Creation of novel chiral synthons with enzymes and applications to natural product synthesis. 15. Efficient introduction of chiral centers into cyclohexane ring

The chiral half-ester 2 obtained by asymmetric hydrolysis of the symmetric diester 1 with pig liver esterase has been shown to be a versatile synthon for various chiral cyclohexane derivatives.

Synthetic studies on biologically active natural products by a chemicoenzymatic approach: Enantioselective synthesis of C- and N-nucleosides, showdomycin, 6-azapseudouridine and cordycepin

An efficient synthesis of C- and N-nucleosides has been developed in an enantioselective and stereocontrolled manner starting from Diels-Alder adduct of furan and dimethyl acetylenedicarboxylate by chemicoenzymatic strategy. The symmetric unsaturated dimethyl esters 2 and 3 were almost quantitatively hydrolysed with pig liver esterase to yield half-esters 4 and 5 with reasonably high optical yields. Decarboxylative ozonolysis of the chiral half-esters 4 followed by chemical transformation afforded methyl L -riboside 12, but after the enantiomer conversion ( 4 to 13 and 5 to 28) the methyl D -riboside ( 17), ( + )-showdomycin ( 22), and ( − )-6-azapseudouridine ( 27), were obtained from 13, and ( − )-cordycepin ( 32) was obtained from 28.