Studies directed toward the synthesis of protein-bound GPI anchor

Mannobioside-linked phosphoethanolamine 10, a prototype model of the GPI anchor, was synthesized via glycosidation of the monosaccharide donor and acceptor, and subsequent phosphorylation. In order to test the reactivity of the amino group involved in 10 against the activated amino acid esters, 10 was reacted with N-protected amino acid pentafluorophenyl esters in the presence of HOBt. The reactions gave the aminoacylated products in moderate yields. When Fmoc-Ser-OPfp 12 and Fmoc-Cys(SBu^t)-OPfp 14 were reacted with 10, byproducts 19, 20 and 21 derived from N- and O-acylation were produced. In contrast, reactions of 10 and N-protected amino acid thioesters were promoted with AgNO₃, HOSu, and DIEA to afford the coupling products without the undesired O-acylation. Peptidylation of 10 with the synthesized oligopeptide thioesters 24 and 27 was also successful under the segment coupling conditions of the peptide thioester method as well as those of the native chemical ligation.     

The first synthesis of secondary sugar sulfonic acids by nucleophilic displacement reactions

The 4-deoxy-4-C-sulfonic acid and 6-deoxy-6-C-sulfonic acid derivatives of methyl α-d-gluco- and α-d-galactopyranosides were prepared by triflate-mediated nucleophilic displacement reactions, either with NaHSO₃ or with AcSK. The triflate esters of methyl 2,3,4-tri-O-benzyl- 1, methyl 2,3,6-tri-O-benzyl-α-d-glucopyranoside 9 and methyl 2,3,6-tri-O-benzyl-α-d-galactopyranoside 5 provided methyl 6-deoxy-6-C-sulfo-α-d-glucopyranoside 4, methyl 4-deoxy-4-C-sulfo-α-d-galactopyranoside 12 and α-d-glucopyranoside 8, respectively. The triflate derivative of methyl 2,3,4-tri-O-benzyl-α-d-galactopyranoside 13 gave methyl 3,6-anhydro-2,4-di-O-benzyl-α-d-galactopyranoside 14. Formation of the 3,6-anhydro derivative was prevented by using 3,4-O-isopropylidene acetal protection to obtain methyl 6-deoxy-6-C-sulfo-α-d-galactopyranoside 19. The aim of the research is to replace the sulfate esters by sulfonic acids in the repeating oligosaccharide units of glycosaminoglycans or in different oligosaccharide ligands.     

Stereospecific route to enantiopure all cis-2,3,6-trisubstituted piperidines. Facile synthesis of (−)-deoxocassine and (+)-azimic acid

Reduction of the enantiopure β-amino esters 10 provides the γ-amnio alcohol 11, which is condensed with 2,4-pentadione to afford 12. Stepwise cyclization of 12 produced the cyclic enamine 13, which is hydrogenated to deliver all cis-2,3,6-trisubstituted piperidine 14. Using this reaction sequence and subsequent Baeyer-Villiger oxidation as the key step (−)-deoxocassine and (+)-azimic acid are synthesized.     

Facile synthesis and biological activities of novel fluorine-containing pyrido[4,3-d]pyrimidines

Fourteen novel 3-substituted-5-methyl-4-methylene-7-alkylsulfanyl-3,4-dihydro-pyrido[4,3-d]pyrimidine-8-carbonitriles, compounds 4a-n, were designed and synthesized via a facile regioselective cyclization process. The intermediate 2 reacted with triethyl orthoformate (molar ratio is 1:4) in the presence of acetic anhydride to give formamidate 3, which was cycled to 4 regioselectively upon addition of different amines at mild condition. The structures of compounds 4a-n were confirmed by IR, ¹H NMR, MS and elemental analysis. The preliminary bioassay indicated that some compounds possess significant herbicidal activity against the roots of rape and barnyard grass, especially when the fluorine atom was introduced to the para position of the substitutents on pyrimidine ring; some compounds showed fungicidal activities against Rhizoctonia solani, Botrytis cinereapers, Gibberella zeae, Dothiorella gregaria, Colletotrichum gossypii as well, and the introduction of fluorine has negative effect on the antifungal activities.     

Cyanuric and thiocyanuric esters as carriers of boron-containing fragments and their fragmentation in mass spectrometry

Tripropargylic esters 2 and 10 of cyanuric and thiocyanuric acids were synthesized. Interaction of these compounds with disubstituted amines gives monoaminoderivatives of dipropargyloxy-s-triazine 4 and 11. Diaminosubstituted propargyloxy-s-triazine 6 was prepared from the corresponding diaminochloroderivative 5. First examples of boron-containing s-triazines 7, 8, 12, 13 were prepared by reaction of propargyl esters 4, 6, 10, 11 with decaborane. New rearrangements of the molecular ions of the 2-aminoderivatives of 4,6-dipropargyloxy-1,3,5-triazine in mass spectrometry were found.     

Regiochemistry of an ambident cyclic ketene-N,O-acetal nucleophile and its anion toward electrophiles

The five-membered cyclic ketene-N,O-acetal, 2-oxazolidin-2-ylidene-1-phenylethanone 1, and its anion 2, formed on deprotonation, are ambident nucleophiles. Compound 1 was synthesized by benzoylation of 2-methyl-2-oxazoline to give a ring-opened N,C,O-trisbenzoylation product, 9, followed by N,O-double debenzoylation using methanolic KOH. Compound 1 reacted with benzoyl chloride to give N,C,O-trisbenzoylated 9, and reacted with phenyl chloroformate to give the similar ring-opened carbonic acid 3-[(2-chloro-ethyl)-phenoxycarbonyl-amino]-3-oxo-1-phenyl-propenyl ester phenyl ester, 13. In contrast, ambident anion 2 reacted with benzoyl chloride to give the β,β-bisbenzoylated cyclic ketene-N,O-acetal, 16, and reacted with phenyl chloroformate to give the novel heterocycle 3-(2-hydroxy-ethyl)-6-phenyl-[1,3]oxazine-2,4-dione, 17.     

Synthesis of α-substituted iminodiacetate ligands: α-hexadienyl derivatives for the selection of lipoxygenase mimics

Derivatives of iminodiacetic acid (IDA) are important as ligands for metal ions, having numerous applications in separations, sensing, catalysis and medicine. This report describes the preparation of two types of IDA derivatives (1, 2) that could be covalently attached to a polymer or protein surface via a variable length spacer chain. The parent compounds 1 (R′=H) were easily prepared via N-alkylation of dimethyl iminodiacetate with esters of 6-bromo-hexanoic acid and subsequent selective ester hydrolysis. Metal complexes of IDA derivatives having an α-dienyl side chain are required for the selection of histidine-rich proteins with potential lipoxygenase activity. The α-hexadienyl side chain of IDA derivative 2 was selectively introduced in the reaction of (2,4-hexadienyl acetate)Fe(CO)₃ with a glycine-derived TMS-enol ester. Subsequent demetallation, followed by N-carboxymethylation, N-deacylation, N-alkylation with a trichloroethyl 6-halohexanoate, and TCE-ester cleavage provided the desired α-hexadienyl IDA derivative 2. Amide formation with IDA acid 1b demonstrates the feasibility of conjugating the IDA ligands to polymers and proteins while Ni(II)-complexation with the derived IDA triacid 1e shows the complexing ability of the tethered IDA ligand.     

New derivatives of trifluoroacetyl acetaldehyde and trifluoroaldol

The reaction of β-ethoxyvinyl trifluoromethyl ketone 1 with O-nucleophiles such as alcohols and diols leads to various derivatives of trifluoroacetyl acetaldehyde, such as β-alkoxyvinyl trifluoromethyl ketones 3 and cyclic keto acetals 4. Several derivatives synthesized contain chiral auxiliaries. Reduction of the compounds 1, 3, 4 under various reaction conditions leads to the trifluoroaldol derivatives 6, 7, 9, 10 containing a protected aldehyde group. The compounds obtained are useful building blocks in fluoroorganic synthesis.     

A novel synthesis and herbicidal activity of fluorine-containing pyrazolo[3,4-d]pyrimidin-4-one derivatives

The 6-(4-alkoxycarbonylalkoxy)phenoxy-3-alkylthio-5-(fluoro-substituted)phenyl-1-phenylpyrazolo[3,4-d]pyrimidin-4-ones 6 have been successfully synthesized via a tandem aza-Wittig and annulation reactions of the corresponding iminophosphorances 4, aromatic isocyanate, and substituted phenols 2 in 59-69% isolated yields using actonitrile as solvent. These novel compounds 6 could be oxidized to sulfones 7 by hydrogen peroxide in satisfactory yields (57-93%). Their structures were clearly verified by spectroscopic data (IR, ¹H NMR, ¹³C NMR, MS, Elemental analysis or X-ray diffraction crystallography). The results of preliminary bioassay indicated that these compounds possess herbicidal activity against the root of rape and barnyard grass.     

Synthesis and properties of 3-arylcyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-diones and related compounds: photo-induced autorecycling oxidation of some amines

Novel 3-phenyl- and 3-(4-nitrophenyl)cyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-diones and the corresponding imino derivatives 5a,b and 6a,b were synthesized in modest to moderate yields by the abnormal and normal aza-Wittig reaction of 2-(1,3-diazaazulen-2-ylimino)triphenylphosphorane with aryl isocyanates and subsequent heterocyclization reaction with a second isocyanate. The related cationic compound, 1-methyl-3-phenylcyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-dionylium tetrafluoroborate 7a, was also prepared. The electrochemical reduction of these compounds exhibited more positive reduction potentials as compared with those of the related compounds of 3,10-disubstituted cyclohepta[4,5]pyrrolo[2,3-d]pyrimidine-2,4(1H,3H)-dione systems. In a search of the oxidizing ability, compounds 5a, 6a, and 7a were demonstrated to oxidize some amines to give the corresponding imines in more than 100% yield under aerobic and photo-irradiation conditions, while even benzylamine was not oxidized under aerobic and thermal conditions at 100 °C. The oxidation reactions by cation 7a are more efficient than that by 5a and 6a. Quenching of the fluorescence of 5a was observed, and thus, the oxidation reaction by 5a probably proceeds via electron-transfer from amine to the excited singlet state of 5a. In the case of cation 7a, the oxidation reaction is proposed to proceed via formation of an amine-adduct of 7a and subsequent photo-induced radical cleavage reaction.     

(2-Formyl-1-phenylcyclopropyl)phosphonates as building blocks for (2-aminomethyl-cyclopropyl)phosphonates

A diastereomeric mixture of dimethyl (2-formyl-2-methyl-1-phenylcyclopropyl)phosphonate ((Z)-6, (E)-6) was obtained by thermally induced cyclopropanation of α-methylacrolein with α-diazobenzylphosphonate 5. Application of proline or proline-derived organocatalysts accelerated the reaction, but had a minor effect on the Z/E ratio of 6. By reaction with benzylamine or methyl esters of glycine, (S)-alanine, and (S)-phenylalanine, the Z/E-mixture of 6 was converted into cyclopropylaldimines, which after reduction gave the corresponding N-substituted (2-aminomethyl-cyclopropyl)phosphonates.     

Synthesis, characterization, and derivatization of some novel types of fluorinated mono- and bis-imidazolidineiminothiones with antitumor, antiviral, antibacterial, and antifungal activities

A series of thirty eight novel imidazolidineiminothiones (6a-g, 10a-h, 13a,b, 15a-d, and 16a), 5-thioxoimidazolidine-2,4-diones (7a-d, 11a-e, 14a,b, and 16b), and bis-imidazolidineiminothiones (17-20) with various fluorinated aromatic substituents at N-(1) and N-(3) were prepared in 75-85% yields. The imidazolidineiminothiones were synthesized from fluorinated N-arylcyanothioformanilides and substituted aromatic isocyanates, and by the reactions of fluorinated aromatic isocyanates with fluorinated and non-fluorinated aromatic N-arylcyanothioformanilides. Subsequent hydrolysis of selected products produced the corresponding 5-thioxoimidazolidine-2,4-diones. Preliminary screening of several compounds against Ehrlich ascites carcinoma (EAC) cells indicated that 6f and 16a were the most active (90% and 80% inhibition, respectively). Further evaluation for cytotoxicity against other tumor cell lines gave IC₅₀ values ranging from 0.67 to 3.83 μg/mL, where compounds 15a and 16a were markedly active against all cell lines. This highlights the synergistic effect of the suitably positioned fluorinated substituents on N-(1) and N-(3) of the imidazolidineiminothiones. Compounds 6a,e-g, 10a-c, 13b, 15a-d, and 17-20 were tested against microbial organisms (Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Salmonella typhi, and Sarcina lutea), and fungal strains (Candida albicans, Aspergillus niger, and Aspergillus flavus). Whereas compound 6a exhibited the highest antibacterial activity against Gram positive and Gram negative bacteria, 13b displayed the strongest antifungal activity against all fungal strains, reaching as high as 30 mm. Finally, 15a,b,d were subjected to in vitro testing of antiviral activity against hepatitis A virus (HAV), human herpes simplex virus 1 (HSV1), and Coxsackie B4 (COxB4) viral strain, where 15b was the most effective, reducing virus plaque count of HSV1 and COxB4 by 50% and 60%, respectively.     

Synthesis of new tetracyclic 7-oxo-pyrido[3,2,1-de]acridine derivatives

A series of (±)3-hydroxyl- and 2,3-dihydroxy-2,3-dihydro-7-oxopyrido[3,2,1-de]acridines were synthesized for antitumor evaluation. These agents can be considered as analogues of glyfoline or (±)1,2-dihydroxyacronycine derivatives. The key intermediates, 3,7-dioxopyrido[3,2,1-de]acridines (15a,b or 24a,b), for constructing the target compounds were synthesized either from 3-(N,N-diphenylamino)propionic acid (14a,b) by treating with Eaton’s reagent (P₂O₅/MsOH) (Method 1) or from (9-oxo-9H-acridin-10-yl)propionic acid (23a-c) via ring cyclization under the same reaction conditions (Method 2). Compounds 15a,b and 24a,b were converted into (±)3-hydroxy derivatives (25a-d), which were then further transformed into pyrido[3,2,1-de]acridin-7-one (28a-d) by treating with methanesulfonic anhydride in pyridine via dehydration. 1,2-Dihydroxylation of 28a-d afforded (±)cis-2,3-dihydroxy-7-oxopyrido[3,2,1-de]acridine (29a-d). Derivatives of (±)3-hydroxy (25a,b) and (±)cis-2,3-dihydroxy (29a-d) were further converted into their O-acetyl congeners 26a,b and 30a-d, respectively. We also synthesized 2,3-cyclic carbonate (31, 32, and 33) from 29a-c. The anti-proliferative study revealed that these agents exhibited low cytotoxicity in inhibiting human lymphoblastic leukemia CCRF-CEM cell growth in culture.     

Aza-Michael addition of chiral hydrazines to alkylidene malonates

The conjugate spontaneous addition of chiral N,N-dialkylhydrazines 1 to dimethyl alkylidene/arylidene malonates 2, 5-10 affords the corresponding β-hydrazino esters in moderate-to-good yields and selectivities. d-Mannitol-derived hydrazine 1a afforded best results, mainly due to the higher stability of the products 3, 11-16.     

Synthesis of γ-fluoro-α-amino acids by Claisen rearrangement

A series of N-protected glycine and alanine esters 4-7 of different fluorinated allylic alcohols 1 was prepared using the dicyclohexylcarbodiimide/dimethylaminopyridine method. All fluorinated esters of this type failed to react in an esterenolate Claisen rearrangement under the general conditions of the Kazmaier variant of this rearrangement. Change of the solvent from tetrahydrofuran to the less coordinating diethyl ether enabled the rearrangement of N-Boc-protected glycine esters 4a-c of 2-fluoroalken-3-ols 1a-c to form N-Boc-2-amino-4-fluoroalk-4-enecarboxylic acids 8a-c, while the rearrangement failed with N-Boc-alanine esters and all amino acid esters of 2-fluoroallylic alcohol (1e). This might be due to competing deprotonation of the position β to fluorine. Similarly to the esters 4a-c, the TFA-protected glycine esters 5a-c of 2-fluoroalken-3-ols 1a-c were rearranged. Deprotection of the Boc or the TFA group under salt-free conditions yielded the free amino acids 11a-c, which might be seen as mimics for N-alkylasparagines a group of lipoproteins.     

Design and synthesis of 3,5-disubstituted 1,2,4-oxadiazole containing retinoids from a retinoic acid receptor agonist

We previously synthesized novel retinoid libraries, and after screening for bioactivity found one compound BT10 that functions as a specific agonist for retinoic acid receptors. This lead compound was further derivatized using SAR and LRD to obtain 3,5-disubstituted-1,2,4-oxadiazole-containing retinoids. The new oxadiazole (amide bioisosters)-containing retinoids (compounds 1, 2, 3, 4, 5, and 6) were synthesized in 42-65% yield by reacting with (E)-4-((3-ethyl,2-4,4,4-trimethylcyclohex-2-enylidene)methyl)benzoic acid and phenyl substituted amidoxime in DMF using CDI as the coupling reagent. The biological activities of the synthesized compounds are currently being evaluated.     

Dihydronaphthalenones from endophytic fungus Fusarium sp. BCC14842

Eleven new dihydronaphthalenones 1-11, together with five known compounds; 5-hydroxydihydrofusarubin C (12), javanicin, bostrycoidin, anhydrofusarubin, and 3-O-methylfusarubin, were isolated from the endophytic fungus Fusarium sp. BCC14842. Structures were elucidated by analyses of the NMR spectroscopic and mass spectrometry data. Javanicin, 3-O-methylfusarubin, compounds 3 and 7 exhibited antimycobacterial and cytotoxic activities. Javanicin also displayed antifungal activity with IC₅₀ of 6.16 μg/mL, while compounds 2, 4, 5, 8, and 12 showed only cytotoxic activity.     

Self-assembly of di- and triorganotin(IV) complexes: Syntheses, characterization and crystal structures of 1D polymeric chain containing O,O-diethyl or O,O-diisopropyl phosphoric acid ligands

A series of organotin(IV) complexes with O,O-diethyl phosphoric acid (L¹H) and O,O-diisopropyl phosphoric acid (L²H) of the types: [R₃Sn · L]_n (L = L¹, R = Ph 1, R = PhCH₂2, R = Me 3, R = Bu 4; L = L², R = Ph 9, R = PhCH₂10, R = Me 11, R = Bu 12), [R₂Cl Sn · L]_n (L = L¹, R = Me 5, R = Ph 6, R = PhCH₂7, R = Bu 8; L = L², R = Me 13, R = Ph 14, R = PhCH₂15, R = Bu 16), have been synthesized. All complexes were characterized by elemental analysis, TGA, IR and NMR (¹H, ¹³C, ³¹P and ¹¹⁹Sn) spectroscopy analysis. Among them, complexes 1, 2, 3, 5, 8, 9 and 11 have been characterized by X-ray crystallography diffraction analysis. In the crystalline state, the complexes adopt infinite 1D infinite chain structures which are generated by the bidentate bridging phosphonate ligands and the five-coordinated tin centers.     

Novel electrosynthesis of a condensed thioheterocyclic system containing a 1,2,4-triazole ring

An efficient and convenient electrosynthesis of thioheterocyclic compounds 6a-d is described via a one-pot, two-component condensation of triazoles (1a,b) or triazine (1c) with acetylenedicarboxylic acid esters (2a,b).     

Efficient and versatile synthesis of (2S,3R)-sphingosine and its 2-azido-3-O-benzylsphingosine analogue

The title compounds (1, 2) were synthesized from (2R,3S)-2-O-benzyl-3,4-O-(3′-pentylidene)-2,3,4-trihydroxybutanal (5). Installation of the E-double bond and aliphatic chain into the sphingosine base was effected by a sequence of Horner-Wadsworth-Emmons olefination of 5, conversion to allylic acetate 8, and copper-mediated Grignard coupling. The method is versatile, allowing a broad variety of aliphatic chains to be introduced in the organocuprate coupling step.