Trading N and O: asymmetric syntheses of β-hydroxy-α-amino acids via α-hydroxy-β-amino esters

Both diastereoisomers of 2-amino-3-hydroxybutanoic acid and 2-amino-3-hydroxy-3-phenylpropanoic acid have been prepared from enantiopure α-hydroxy-β-amino esters via the intermediacy of the corresponding cis- and trans-aziridines. Aminohydroxylation of two α,β-unsaturated esters produced enantiopure 2,3-anti-α-hydroxy-β-amino esters in >99:1 dr. Subsequent epimerisation at the C(2)-position via a sequential oxidation/diastereoselective reduction protocol gave the corresponding enantiopure 2,3-syn-α-hydroxy-β-amino esters in >99:1 dr. These syn- and anti-substrates were then converted into the corresponding N-Boc protected cis- and trans-aziridines, respectively, via a three step reaction sequence: (i) hydrogenolysis and in situ N-Boc protection; (ii) OH-activation; and (iii) aziridine formation. Subsequent regioselective ring-opening of the C(3)-methyl-aziridines with Cl₃CCO₂H proceeded with inversion of configuration to give the corresponding 2-amino-3-trichloroacetate esters, whereas the analogous reaction with the C(3)-phenyl-aziridines resulted in rearrangement to the corresponding oxazolidin-2-ones with retention of configuration. In each case, hydrolysis of the products from these ring-opening reactions produced the corresponding enantiopure β-hydroxy-α-amino acids as single diastereoisomers.     

Trifluoroethanol as a metal-free, homogeneous and recyclable medium for the efficient one-pot synthesis of α-amino nitriles and α-amino phosphonates

Trifluoroethanol is found to be an efficient and recyclable medium in promoting one-pot, three-component coupling reactions of aldehydes or ketones, amines and trimethylsilyl cyanide or trimethyl phosphite to afford the corresponding α-amino nitriles or α-amino phosphonates in high yields. This protocol does not require the use of an acid or base catalyst.     

Transition metal-catalyzed formation of CF3-substituted α,β-unsaturated alkene and the synthesis of α-trifluoromethyl substituted β-amino ester

A new transition metal-catalyzed formation of CF₃-substituted α,β-unsaturated alkenes through the ylide intermediate from the reaction between methyl 3,3,3-trifluoro-2-diazopropionate 1 and aryl aldehydes has been developed. Further transformation of the alkene affords the α-trifluoromethyl substituted β-amino ester, a valuable intermediate in the synthesis of fluorine-containing amino acids with potential biological application.     

Darzens reaction as a convenient method for the synthesis of α-chloroketones, α-chloroepoxides,and symmetrically substituted dioxines

Summary TheDarzens reaction of dichloroacetophenone (DCAP) with substituted benzaldehydes has been studied. The structure of the products was shown to depend on the phenyl group substituents. Reaction of benzaldehyde, 4-bromo-, and 2,4-dichlorobenzaldehydes results in 1-phenyl-3-aryl-3-chloropropane-1,2-diones (2a–c), reaction ofpara- ormeta-nitrobenzaldehydes yields 1-phenyl-2-chloro-3-aryl-2,3-epoxypropane-1-ones (3a, b). Upon the introduction of an alkoxy group into the phenyl ring of benzaldexyde and/or dichloroacetophenone, symmetrically substituted dioxines were obtained (6a–c). The structure of the reaction products has been established by single crystal X-ray investigations.

---

Darzens-Reaktion als bequemes Verfahren zur Synthese von -Chloroketonen, -Chloroepoxiden und symmetrisch substituierten Dioxinen

Zusammenfassung DieDarzens-Reaction von Dichloracetophenon (DCAP) mit substituierten Benzaldehyden wurde untersucht. Die Struktur der Produkte ist von den Substituenten an der Phenylgruppe abhängig. Die Umsetzung mit Benzaldehyd, 4-Brom- und 2,4-Dichlorbenzaldehyd liefert 1-Phenyl-3-aryl-3-chloropropan-1,2-dione (2a–c), die Reaktion vonpara- odermeta-Nitrobenzaldehyd 1-Phenyl-2-chloro-3-aryl-2,3-epoxipropan-1-one (3a,b). Durch Einführung einer Alkoxygruppe in den Phenylring des Benzaldehyds und/oder des Dichloracetophenons erhält man symmetrisch substituierte Dioxine (6a–c). Die Struktur der Reaktionsprodukte wurde mittels Röntgenstrukturanalyse bestätigt.

     

Synthesis of (E)- and (Z)-α,β-difluorourocanic acid

Horner-Emmons fluoroolefination of an aryl aldehyde followed by introduction of a second fluorine via “FBr” addition provides an original approach to the preparation of 1-alkyl-2-aryl-1,2-difluoroethenes. The utility of this procedure is demonstrated by the preparation of (E and Z)-α,β-difluorourocanic acid.     

Evaluation of pH-sensitive poly(β-amino ester)-graft-poly(ethylene glycol) and its usefulness as a pH-sensor and protein carrier

In this study, some possible biomedical applications of a pH-sensitive and amphiphilic copolymer as a pH sensor and protein delivery system are reported. PAE-g-PEG was used as a pH-sensitive polymer that can exhibit a sharp pH-dependent transition. Various fluorescent dyes including pyrene and RITC can be used to label the pH-sensitive polymer PAE-g-PEG, which was evaluated for protein encapsulation. pH-sensing was possible by observing excimer formation of the labeled pyrene via pH-dependent expansion of the polymeric chain. Also, it was confirmed that FITC-BSA could be entrapped in RITC-labeled pH-sensitive micelles of PAE-g-PEG by FRET. As a result, PAE-g-PEG can be a pH sensor and carrier for protein delivery.     

Practical method for the synthesis of (R)-homopipecolinic acid and (R)-homoproline esters from ω-chloroalkanoic acids and available chiral amines

A practical synthesis of (R)-homopipecolinic acid methyl ester 1 and (R)-homoproline methyl ester 2 was performed utilizing (i) a direct intramolecular cyclization of ω-chloro-β-enamino esters 11 and 12, which were prepared from available (S)-1-phenylethylamine or (S)-1-(1-naphthyl)ethylamine and ω-chloro-β-keto esters 5 and 10, respectively and (ii) a highly diastereoselective NaBH₄ reduction followed by hydrogenolysis. The present method is a short-step process using inexpensive and readily available substrates and reagents with fewer wasted materials.     

Temperature and pH Dually-responsive Poly(β-amino ester) Nanoparticles for Drug Delivery

Stimuli-responsive polymers have undoubtedly been of great interest in the past decades due to a variety of their potential applications in biomedical territory. However, their non-degradability limits their in vivo applications. Herein, we report a novel pH and temperature dual-stimuli responsive-poly(β-amino ester). The pH/temperature sensitivities are interrelated and can be easily tuned by changing PEG-diacrylate chain length and the percentage of biamines in the feed ratio. These dual-responsive polymers are very useful in drug delivery. Reaction of methyl ether poly(ethylene glycol)(MPEG) and poly(β-amino ester) resulted in an amphiphilic MPEG-PBAE block copolymer which could form nanoparticles by selfassembly. A hydrophobic drug(DOX) was loaded in the self-assembled nanoparticles at low temperature without using organic solvents. The loaded drug was released very slowly and steadily at 37 ℃ under physiological conditions(p H 7.4), but rapidly released from the micelles in weakly acidic environments(pH 6.4 and 5.0) for intracellular drug release. Thus, these poly(β-amino ester) polymers constitute ideal drug carriers since their thermal sensitivity allows the drug loadings without using organic solvent and their pH sensitivity permits fast intracellular drug release.     

Synthesis ofN-(amidomethyl)- andN- (imidomethyl)-α-amino acid esters by reactions of α-amino acid esters with formaldehyde and amides or imides

Reactions of hydrochlorides of glycine, alanine, phenylalanine, L-isolcucinc, and L-valine esters with aromatic and heteroaromatic carboxamides afforded hydrochlorides of the correspondingN-(amidomethyl)--amino acid esters.N-(Phthalimidomethyl)--amino acid esters were obtained by reactions of -amino acid esters containing free amino groups with formaldehyde and phthalimide, The¹H NMR studies demonstrated that the chiral centers of -amino acids may be retained in the course of condensation. Reactions of the Mannish bases obtained and their hydrochlorides with acetic anhydride and tosyl chloride afforded the correspondingN-aryl andN-sulfonyl derivatives.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp, 1761–1769, July, 1996.     

(Z)-2,2-Dimethyl-5-carboxymethylene-1,3-dioxolan-4-one: a new synthon for the synthesis of α,γ-diketoacid derivatives

The synthesis and reactivity of (Z)-2,2-dimethyl-5-carboxymethylene-1,3-dioxolan-4-one, a new and versatile synthon useful for the synthesis of selectively protected α,γ-diketoacid derivatives, are described. This new, protected form of hydroxyl fumaric acid along with its acid chloride was used to prepare ester, amide, and aryl derivatives. The dioxolane moiety was found to be a convenient functionality that facilitated ready unmasking by straightforward hydrolysis to reveal α,γ-diketoacid derivatives or derivatization to yield ester, amide, and 2,3-pyrrolidinedione derivatives.     

Improved synthesis of (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one, a building block for γ-secretase inhibitors

An improved synthesis of (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one (1), involving a selective crystallization of epimeric menthylcarbamates for the resolution step followed by simultaneous cleavage of the carbamate and the lactam protecting group is described. Epimerization conditions of the undesired epimer have also been determined.     

Synthesis of β-chloro α-amino acids: (2S,3R)- and (2S,3S)-3-chloroleucine

The first syntheses of (2S,3R)- and (2S,3S)-3-chloroleucine (3-chloro-d-leucines 1 and 2) have been achieved from d-3-hydroxyleucine and allo-d-3-hydroxyleucine, respectively, through the formation of the corresponding N-Cbz β-lactones, followed by a ring opening promoted by lithium chloride and a debenzylation process.     

Conversion of γ-substituted bicyclo[2.2.1] (Z)-vinylsulfones to the corresponding (E)-allylsulfones

The preparation of bicyclo[2.2.1] (E)-allylsulfones starting from the corresponding (Z)-vinylsulfones is described. Starting from 2,3-bis(phenylsulfonyl)norbornadiene 1, the Michael addition of organometallic reagents followed by the base catalyzed isomerization affords (E)-allylsulfones in high yields. The procedure allows to obtain vinylidenic norbornenes which are characteristic nuclei of valuable biologically active compounds.     

Enantiospecific synthesis of α-amino acid semialdehydes: a key step for the synthesis of unnatural unsaturated and saturated α-amino acids

The enantiospecific synthesis of unnatural unsaturated and saturated α-amino acids based on a Wittig type reaction is described. The versatile synthetic intermediates, l-glutamic and l-aspartic acid semialdehydes, are obtained from the corresponding N,N-di-Boc-diesters, by the selective reduction of the ω-ester with DIBAL^® under controlled conditions. The semialdehydes are chemically stable for a prolonged time and react with various phosphorous ylides, under controlled conditions, to produce the enantiomerically pure unsaturated α-amino acids in high yields. The method is equally applicable to homologated diesters obtained by the presented methodology providing unsaturated amino acids with variable unsaturated positions and geometries. The corresponding saturated products can be obtained by simple hydrogenation.     

(+)-proto-Quercitol, a natural versatile chiral building block for the synthesis of the α-glucosidase inhibitors, 5-amino-1,2,3,4-cyclohexanetetrols

An efficient synthesis of diastereomerically pure 5-amino-1,2,3,4-cyclohexanetetrols (6 and 11) and quercitol derivatives from naturally available (+)-proto-quercitol (1) is described. The stereochemistry of 1 is perfectly set up for regioselective protection of the hydroxy group which was further functionalized into the target aminocyclitol in a straightforward manner. The present approach provides a protocol for preparing aminocyclitols in large quantities. In addition, the absolute stereochemistry of (+)-proto-quercitol was addressed using the modified Mosher’s method. Of the synthesized aminocyclitols, 11 potentially inhibits α-glucosidase with an IC₅₀ value of 12.5 μM, which is 45 times greater than that of the standard antidiabetes drug, Acarbose^®.     

Diphenylparabanic acid as a synthon for the synthesis of α-diketones and α-ketocarboxylic acids

Diphenylparabanic acid was found to react with >2 equiv of organolithiums at -78 °C to effectively give the corresponding symmetrical α-diketones. However, upon treatment with 1 equiv of organolithium, the parabanic acid gave mainly 5-substituted 5-hydroxyimidazolidine-2,4-diones. On the other hand, Grignard reagents were less reactive toward the parabanic acid at low temperature, and selectively gave the corresponding 5-hydroxyimidazolidine-2,4-diones even if more than 1 equiv of the reagents was used. A tandem process in which the parabanic acid was first reacted with a Grignard reagent and then reacted in one-pot with an organolithium effectively gave the unsymmetrical α-diketone. 5-Substituted 5-hydroxyimidazolidine-2,4-diones were useful as versatile precursors for preparing α-ketocarboxylic acids as well as unsymmetrical α-diketones.     

A d-ribose-derived α-amino nitrile as a versatile intermediate for the collective synthesis of piperidine-type iminosugar C-glycosides

Iminosugar C-glycosides are valuable entities in medicinal chemistry. Herein we disclose a collective synthesis approach to such compounds, in a route that features a remarkably stable, fully characterised, ribose-derived iminium salt as a key intermediate. Addition of organometallic reagents to this key intermediate delivers a variety of iminosugar C-glycoside products in high yields and with excellent stereocontrol.     

2-Allyl-N-benzyl substituted α-naphthylamines as building blocks in heterocyclic synthesis. New and efficient syntheses of benz[e]naphtho[1,2-b]azepine and naphtho[1,2-b]azepine derivatives

A new series of 13-acetyl-7,12-dihydro-7-ethylbenz[e]naphtho[1,2-b]azepine (4a-d) and 2-aryl-4-hydroxy-2,3,4,5-tetrahydronaphtho[1,2-b]azepine derivatives (6a-d) have been synthesized from N-allyl-N-benzyl substituted α-naphthylamines (1a-d) by utilizing aromatic amino-Claisen rearrangement, intramolecular Friedel-Crafts alkylation and intramolecular dipolar 1,3-cycloaddition nitrone-olefin reactions.     

A facile and efficient synthesis of fully substituted pyridin-2(1H)-ones from α-oxoketene-S,S-acetals

A facile and efficient synthesis of fully substituted pyridin-2(1H)-ones has been developed by the reaction of readily available α-oxoketene-S,S-acetals with malononitrile in the presence of sodium methoxide in methanol under reflux.     

Silver-promoted trans-hydrofluorination of ynamides: a regio- and stereoselective approach to (Z)-α-fluoroenamides

A highly regio- and stereoselective trans-hydrofluorination of N-sulfonyl ynamides has been realized with AgF as the fluorination reagent, affording (Z)-α-fluoroenamides in good to excellent yields. The reaction proceeds under mild reaction conditions and shows good functional group compatibility.