Concise and practical synthesis of (2S,3R,4R,5R) and (2S,3R,4R,5S)-1,6-dideoxy-1,6-iminosugars

The syntheses of (2S,3R,4R,5R) and (2S,3R,4R,5S)-1,6-dideoxy-1,6 iminosugars 1a and 1b, respectively, from d-glucose are described. The key transformations in this reaction sequence include regio-selective epoxide ring opening with N-benzylamine followed by intramolecular reductive amination of amino-aldehyde.     

An efficient asymmetric synthesis of Fmoc-l-cyclopentylglycine via diastereoselective alkylation of glycine enolate equivalent

Stereoselective alkylation of the enolate derived from benzyl (2R,3S)-(−)-6-oxo-2,3-diphenyl-4-morpholinecarboxylate (1) with cyclopentyl iodide afforded anti-α-monosubstituted product, benzyl (2R,3S,5S)-(−)-6-oxo-2,3-diphenyl-5-cyclopentyl-4-morpholinecarboxylate (3) in 60% yield. Catalytic hydrogenolysis over PdCl₂ cleaved the auxiliary ring system to give l-cyclopentylglycine (4) in 84% yield. Subsequent protection of the α-amino function with Fmoc-OSu gave Fmoc-l-cyclopentylglycine (5) in high yield.     

Emission of 2-phenylethanol from its β-d-glucopyranoside and the biogenesis of these compounds from [H8] l-phenylalanine in rose flowers

The hydrolysis of 2-phenylethyl β-d-glucopyranoside (3) was found to be partially inhibited by feeding with 2-phenyl-N-glucosyl-acetamidiumbromide (8), a β-glucosidase inhibitor, resulting in a decrease in the diurnal emission of 2-phenylethanol (2) from Rosa damascena Mill. flowers. Detection of [1,1,2,2′,3′,4′,5′,6′-²H₈]-2 and [1,2,2′,3′,4′,5′,6′-²H₇]-2 from R. ‘Hoh-Jun’ flowers fed with [1,1,2,2′,3′,4′,5′,6′-²H₈]-3 suggested that β-glucosidase, alcohol dehydrogenase, and reductase might be involved in scent emission. Comprehensive GC-SIM analyses revealed that [1,2,2,2′,3′,4′,5′,6′-²H₈]-2 and [1,2,2,2′,3′,4′,5′,6′-²H₈]-3 must be biosynthesized from [1,2,2,2′,3′,4′,5′6′-²H₈] l-phenylalanine ([²H₈]-1) with a retention of the deuterium atom at α-position of [²H₈]-1.     

Total synthesis of eurypamides, marine cyclic-isodityrosines from the Palauan sponge Microciona eurypa

Total synthesis of eurypamides A, B, and D, 1, 2, and 4, has been successfully accomplished. The Tl(NO₃)₃ (TTN) oxidation of the halogenated bisphenols, 14a, 14b, 24, and 43, effected regio-controlled cyclization to provide the corresponding diaryl ethers, 15a, 15b, 25, and 46. This investigation revealed a structural revision of eurypamide A as to possess (2″S,3″R,4″S)-configuration (47), along with the spectral data of pure 2 and 4, which were previously characterized in a mixture.     

Chemical synthesis and structural elucidation of a new serotonin metabolite: (4R)-2-[(5′-hydroxy-1′H-indol-3′-yl)methyl]thiazolidine-4-carboxylic acid

A new serotonin (5-hydroxytryptamine) metabolite, (4R)-2-[(5′-hydroxy-1′H-indol-3′-yl)methyl]thiazolidine-4-carboxylic acid (5′-HITCA), was synthesized in 30% overall yield. The key step involved oxidation of protected 5-hydroxytryptophol using IBX followed by spontaneous cyclization with l-cysteine. The stereochemistry of condensation product thiazolidine-4-carboxylic acid was studied using NMR spectroscopy techniques.     

Synthesis of (3′R,5′S)-3′-hydroxycotinine using 1,3-dipolar cycloaddition of a nitrone

To synthesize (3′R,5′S)-3′-hydroxycotinine [(+)-1], the main metabolite of nicotine (2), cycloaddition of C-(3-pyridyl)nitrones 3a, 3c, and 15 with (2R)- and (2S)-N-(acryloyl)bornane-10,2-sultam [(2R)- and (2S)-8] was examined. Among them, l-gulose-derived nitrone 15 underwent stereoselective cycloaddition with (2S)-8 to afford cycloadduct 16, which was elaborated to (+)-1.     

Polyhydroxylated pyrrolidines, III. Synthesis of new protected 2,5-dideoxy-2,5-iminohexitols from d-fructose

The readily available 3-O-benzoyl-4-O-benzyl-1,2-O-isopropylidene-β-d-fructopyranose (6) was straightforwardly transformed into 5-azido-3-O-benzoyl-4-O-benzyl-5-deoxy-1,2-O-isopropylidene-β-d-fructopyranose (8), after treatment under modified Garegg's conditions followed by reaction of the resulting 3-O-benzoyl-4-O-benzyl-5-deoxy-5-iodo-1,2-O-isopropylidene-α-l-sorbopyranose (7) with lithium azide in DMF. O-debenzoylation at C(3) in 8, followed by oxidation and reduction caused the inversion of the configuration to afford the corresponding β-d-psicopyranose derivative 11 that was transformed into the related 3,4-di-O-benzyl derivative 12. Cleavage of the acetonide of 12 to give 13 followed by O-tert-butyldiphenylsilylation afforded a resolvable mixture of 14 and 15. Compound 14 was transformed into (2R,3R,4S,5R)- (17) and (2R,3R,4S,5S)-3,4-dibenzyloxy-2′,5′-di-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (18) either by a tandem Staudinger/intramolecular aza-Wittig process and reduction of the resulting intermediate Δ²-pyrroline (16), or only into 18 by a high stereoselective catalytic hydrogenation. When 15 was subjected to the same protocol, (2S,3S,4R,5R)- (21) and (2R,3S,4R,5R)-3,4-dibenzyloxy-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (22) were obtained, respectively.     

A new efficient and practical synthesis of 2-deoxy-l-ribose

An efficient and practical route for large-scale synthesis of 2-deoxy-l-ribose starting from l-ascorbic acid was developed in eight steps without chromatographic purification for all intermediates. Additionally, (2S,3R)-3,4-epoxy-1,2-O-isopropylidenebutane-1,2-diol, a versatile intermediate in carbohydrate synthesis, was also prepared readily in excellent yield as a key intermediate.     

Polyhydroxylated pyrrolidines. Part 4: Synthesis from d-fructose of protected 2,5-dideoxy-2,5-imino-d-galactitol derivatives

The readily available 3-O-benzoyl-4-O-benzyl-1,2-O-isopropylidene-5-O-methanesulfonyl-β-d-fructopyranose (5) was straightforwardly transformed into its d-psico epimer (8), after O-debenzoylation followed by oxidation and reduction, which caused the inversion of the configuration at C(3). Compound 8 was treated with lithium azide yielding 5-azido-4-O-benzyl-5-deoxy-1,2-O-isopropylidene-α-l-tagatopyranose (9) that was transformed into the related 3,4-di-O-benzyl derivative 10. Cleavage of the acetonide in 10 to give 11, followed by regioselective 1-O-pivaloylation to 12 and subsequent catalytic hydrogenation gave (2R,3S,4R,5S)-3,4-dibenzyloxy-2,5-bis(hydroxymethyl)-2′-O-pivaloylpyrrolidine (13). Stereochemistry of 13 could be determined after O-deacylation to the symmetric pyrrolidine 14. Total deprotection of 14 gave 2,5-imino-2,5-dideoxy-d-galactitol (15, DGADP).     

Novel thermally stable and chiral poly(amide-imide)s bearing from N,N′-(4,4′-diphthaloyl)-bis-l-isoleucine diacid: Synthesis and characterization

Novel optically active aromatic poly(amide-imide)s (PAIs) were prepared from newly synthesized N,N′-(4,4′-diphthaloyl)-bis-l-isoleucine diacid (3) via polycondensation with various diamines. The diacid was synthesized by the condensation reaction of 3,3′,4,4′-biphenyltetracarboxylic dianhydride (1) with l-isoleucine (2) in a mixture of acetic acid and pyridine (3:2 v/v). All the polymers were obtained in quantitative yields with inherent viscosities of 0.20-0.43 dL g⁻¹. All the polymers were highly organosoluble in solvents like N-methyl-2-pyrrolidinone (NMP), N,N-dimethylacetamide (DMAc), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran, γ-butyrolactone, cyclohexanone and chloroform at room temperature or upon heating. These poly(amide-imide)s had glass transition temperatures between 198 and 231 °C, and their 10% weight-loss temperatures were ranging from 368 to 398 °C and 353 to 375 °C under nitrogen and air, respectively. The polyimide films had tensile strengths in the range of 63-88 MPa and tensile moduli in the range of 0.8-1.4 GPa. These poly(amide-imide)s possessed chiral properties and the specific rotations were in the range of −3.10° to −72.92°.     

New organotin(IV) complexes with l-Arginine, Nα-t-Boc-l-Arginine and l-Alanyl-l-Arginine: Synthesis, structural investigations and cytotoxic activity

Novel diorganotin(IV) derivatives of l-Arginine (HArg), N_α-(tert-Butoxycarbonyl)-l-Arginine (Boc-Arg-OH) and l-Ala-l-Arg (H₂Ala-Arg), H₂NC(NH)NH(CH₂)₃CH(NHR′)CO₂H, where R′ = H in HArg, R′ = C(O)OC(CH₃)₃ in Boc-Arg-OH, R′ = H₂NCH(CH₃)CO in H₂Ala-Arg and triorganotin(IV) derivatives of Boc-Arg-OH have been synthesized and structurally characterized. The complexes were investigated by FT-IR and ¹¹⁹Sn Mössbauer in the solid state and by ¹H, ¹³C, ¹¹⁹Sn and ¹H-¹H COSY NMR spectroscopy, in solution. The spectroscopic characterization leading to the proposed molecular structures was accomplished on the basis of these experiments. l-Arginine appears to behave as a chelating ligand through carboxylate and -NH₂ groups in Me₂Sn(Arg)₂, while in N_α-t-Boc-l-Arginine complex, the N_α-protected amino group being exempted from coordination, only the carboxylate groups are effectors of bonding to the organometallic moieties. FT-IR spectra give a clear indication that guanidino groups in all the complexes are not involved in coordination, since ν(CN-H) frequency of the terminal guanidino group is fairly constant and unshifted relative to the free ligand. The biological activity of organotin(IV)-complexes was also investigated by use of human HT29 colorectal carcinoma cells. The cytotoxic activity of the compounds was determined by the MTT quantitative colorimetric assay, capable of detecting viable cells in comparison with that exerted by cisplatin. A marked cytotoxic activity for nearly all complexes, is evident being higher than that exerted by cisplatin, while no significant improvement of activity was observed for Me₂Sn(Arg)₂ and Me₂Sn(Ala-Arg), which was confirmed by IC₅₀ values. Then, we assessed whether the cytotoxicity induced by organotin(IV) complexes was associated with the induction of apoptosis. Light microscopy analysis, performed to study the morphological changes induced in HT29 cells, confirmed the results obtained with MTT test. No significant morphological alterations were observed in HT29 cells after treatment with Me₂Sn(Ala-Arg) and Me₂Sn(l-Arg)₂. Cells treated with ⁿBu₂Sn(Boc-Arg)₂, ⁿBu₂Sn(Ala-Arg), ⁿBu₃Sn(Boc-Arg) and Me₃Sn(Boc-Arg), appeared rounded, isolated and detached from culture substrate, indicating the commitment to apoptotic cell death.     

An efficient approach to d-threo-3-hydroxyaspartic acid for the synthesis of novel l-threo-oxazolines as selective blockers of glutamate reversed uptake

An efficient, stereoselective synthetic strategy to d-threo-3-hydroxyaspartic acid was developed. Starting from l-(2S,3S)-N-benzoyl-3-hydroxyaspartic acid dimethyl ester by a Deoxo-fluor-catalyzed cyclization reaction, an inversion of configuration at the β-center (erythro isomer), was observed. A base-induced epimerization reaction led to the d-trans-isomer, which was hydrolyzed to give d-threo-3-hydroxyaspartic acid with excellent stereoselectivity and overall yield. Starting from d-threo-3-hydroxyaspartic acid, l-threo-oxazolines can be stereoselectively synthesized.     

Synthesis and structure of diastereomers of pentenocin B produced by Trichoderma hamatum FO-6903

All diastereomers of pentenocin B, an inhibitor of interleukin-1β converting enzyme produced by Trichoderma hamatum FO-6903, were synthesized in chiral forms starting from l-threonine. Absolute configurations of natural pentenocin B were clarified to be 4S, 5R, and 6R.     

Synthesis and anti-HIV activity of l-β-3′-C-cyano-2′,3′-unsaturated nucleosides and l-3′-C-cyano-3′-deoxyribonucleosides

An efficient synthetic method was developed for l-β-3′-C-cyano-2′,3′-unsaturated nucleosides and l-3′-C-cyano-3′-deoxyribonucleosides. The key intermediate 11 was obtained from l-xylose, from which a series of pyrimidine and purine nucleosides were prepared in high yield by the coupling of 11 and various silyl-protected bases in the presence of TMSOTf. These nucleosides were eliminated, followed by deprotecting to give l-β-3′-C-cyano-2′,3′-unsaturated nucleosides. When selectively deprotected by hydrazine hydrate in buffered acetic acid-pyridine followed by treatment with potassium carbonate in methanol, l-3′-C-cyano-3′-deoxyribonucleosides were obtained. The synthesized nucleosides were tested for anti-HIV activity.     

A d,l-proline catalyzed diastereoselective trimolecular condensation: an approach to the one-pot synthesis of perhydrofuro[3,2-b]pyran-5-ones

d,l-Proline was found to catalyze efficiently the one-pot trimolecular condensation of indoles, a sugar hydroxyaldehyde, and Meldrum’s acid followed by intramolecular cyclization with evolution of carbon dioxide and elimination of acetone to afford 7-(1H-3-indolyl)-2,3-dimethoxyperhydrofuro[3,2-b]pyran-5-ones. The reaction proceeded cleanly at ambient temperature to afford the products in good yields with high diastereoselectivity.     

Hydrolysis of the amide bond in N-acetylated l-methionylglycine catalyzed by various platinum(II) complexes under physiologically relevant conditions

The hydrolytic reactions between various Pt(II) complexes of the type [Pt(L)Cl₂] and [Pt(L)(CBDCA-O,O′] (L is ethylenediamine, en; (±)-trans-1,2-diaminocyclohexane, dach; (±)-1,2-propylenediamine, 1,2-pn and CBDCA is the 1,1-cyclobutanedicarboxylic anion) and the N-acetylated l-methionylglycine dipeptide (MeCOMet-Gly) were studied by ¹H NMR spectroscopy. All reactions were realized at 37 °C with equimolar amounts of the Pt(II) complex and the dipeptide at pH 7.40 in 50 mM phosphate buffer in D₂O. Under these experimental conditions, a very slow cleavage of the Met-Gly amide bond was observed and this hydrolytic reaction proceeds through the intermediate [Pt(L)(H₂O)(MeCOMet-Gly-S)]⁺ complex. In general, it can be concluded that faster hydrolytic cleavage of the MeCOMet-Gly dipeptide was observed in the reaction with the chloride complex than with corresponding CBDCA Pt(II) complexes. The steric effects of the Pt(II) complex on the hydrolytic cleavage of the amide bond in the MeCOMet-Gly dipeptide were also investigated by ¹H NMR spectroscopy. It was found that the rate of hydrolysis decreases as the steric bulk of the CBDCA and chlorido Pt(II) complexes increase (en > 1,2-pn > dach). These results contribute to a better understanding of the toxic side effects of Pt(II) antitumor drugs and should be taken into consideration when designing new potential Pt(II) antitumor drugs with preferably low toxic side effects.     

Synthesis and evaluation of fully (5-amidoisophthalic acid)-functionalised polyacrylamides as selective inhibitors of the beta crystal polymorph of l-glutamic acid

Poly-N-5-acrylamidoisophthalic acid (4), poly-N-(5-(N′-(3,5-dicarboxyphenyl)carbamoyl)pentyl)acrylamide (10a) and poly-N-(11-(N′-(3,5-dicarboxyphenyl)carbamoyl)undecyl)acrylamide (10b) were prepared and assessed as polymorph-selective crystallization inhibitors of the stable β form of l-glutamic acid. Polymerization was carried out as the final step in the preparation of 10a and 10b to ensure the preparation of fully functionalized polymers. Polymers 4, 10a and 10b were effective as complete inhibitors of the stable β form of l-glutamic acid in quantities of 0.5% w/w or greater, whereas the corresponding ‘monomeric’ additives 2 and 11 required quantities of 3% or greater to completely inhibit the β form, demonstrating a cooperative binding effect by the polymeric additives. Within the series of polymers 4, 10a and 10b, polymer 10a, which features a short tethering chain, was the most effective.     

Tandem catalysis for the synthesis of 2-alkylidene cyclohexenones

(5R,6S,E)-5-Alkyl-2-(2-(methoxymethoxy)ethylidene)-6-(phenylsulfonyl)cyclohex-3-enones, have been obtained by a domino reaction using tandem catalysis with a Nazarov reagent 3, and several unsaturated aldehydes.     

Effects of molecular weight and small amounts of d-lactide units on hydrolytic degradation of poly(l-lactic acid)s

Films of poly(l-lactic acid) (PLLA) with different number-average molecular weights (M_n) and d-lactide unit contents (X_d) were made amorphous and the effects of molecular weight and small amounts of d-lactide units on the hydrolytic degradation behavior in phosphate-buffered solution at 37 °C of PLLA were investigated. The degraded films were investigated using gravimetry, gel permeation chromatography, polarimetry, differential scanning calorimetry, X-ray diffractometry, and tensile testing. To exclude the effects of crystallinity on the hydrolytic degradation, the films were made amorphous by melt-quenching. The incorporation of small amounts of d-lactide units drastically enhanced the hydrolytic degradation of PLLA. In the period of 0-32 weeks, the hydrolytic degradation rate constant (k) of PLLA films increased with increasing X_d, while the k values did not depend on M_n. This means that the effects of X_d on the hydrolytic degradation rate of the films are higher than those of M_n. In contrast, in the period of 32-60 weeks neither X_d nor M_n was a crucial parameter to determine k values, probably because in addition to these parameters the differences in the amount of catalytic oligomers accumulated in films and crystallinity affect the hydrolytic degradation behavior of the films. The initially amorphous PLLA films remained amorphous even after the hydrolytic degradation for 60 weeks.     

(3R,4S)-3,4,5-Trihydroxy-4-methylpentylphosphonic acid, an isosteric phosphonate analogue of 2-C-methyl-d-erythritol 4-phosphate, a key intermediate in the new pathway for isoprenoid biosynthesis

2-C-Methyl-d-erythritol 4-phosphate (MEP) is the first intermediate in the mevalonate-independent pathway for isoprenoid biosynthesis presenting the branched C₅ isoprene skeleton. Enantiopure (3R,4S)-3,4,5-trihydroxy-4-methylpentylphosphonic acid (MEP_N), an isosteric phosphonate analogue of MEP was synthesized from 1,2-O-isopropylidene-α-d-xylofuranose.