In situ generation of acyloxyphosphoniums for mild and efficient synthesis of thioesters.

We present a novel approach for in situ generation of acyloxyphosphoniums by premixing iodobenzene dicarboxylates and triphenylphosphine, resulting in efficient thioester synthesis (up to 100% yield). Stable solid iodobenzene dicarboxylates, achieved via carboxylate exchange, serve as hypervalent iodine precursors. The resulting acyloxyphosphoniums allow convenient one-pot thioester synthesis under mild conditions. Our method demonstrates facile acyloxyphosphonium production from iodobenzene dicarboxylates and Ph3P, enabling diverse thioester preparation. ESI-MS analysis confirms acyloxyphosphonium ion formation, pivotal in acylation. This strategy holds potential for combinatorial thioester synthesis and broader nucleophile modification applications.

Total synthesis of aspidostomide G from a brominated tryptamine.

The first total synthesis of aspidostomide G using a brominated tryptamine is described. The synthetic route features several notable aspects: (a) the starting material, compound 13, contains a built-in hydroxy group and was transformed to the Sonogashira reaction precursor; (b) the construction of the indole ring was achieved through a transition-metal catalyzed synthesis and a 5-endo-dig cyclization. The desired indole 9 was synthesized in only 7 steps with an overall yield of 54% and required only three columns; (c) a late C2-bromination was achieved by using the 4-acetoxyindole analogue 14c.

Recyclable and reusable ionic liquid-supported azo precursors in Mitsunobu reactions.

A new type of azo precursor, ionic liquid-supported hydrazidecarboxylate, was synthesized and applied in Mitsunobu reactions. The developed reagent is recyclable during the reaction and reusable after recovery by the ionic liquids. The ionic liquid-based azo precursor in conjugation with PhI(OAc)2 has been proved to be useful in the formation of carbon-oxygen, carbon-nitrogen, and carbon-sulfur bonds.

A combinatorial approach towards the synthesis of non-hydrolysable triazole-iduronic acid hybrid inhibitors of human α-l-iduronidase: discovery of enzyme stabilizers for the potential treatment of MPSI.

Preparation of substituent-diverse, triazole-iduronic acid hybrid molecules by click reaction of an azido iduronic acid derivative with randomly chosen alkynes is described. Library members were screened for their ability to inhibit α-l-iduronidase, and hit molecules and analogues were then investigated for their ability to stabilize rh-α-IDUA in a thermal denaturation study. This work resulted in the discovery of the first small molecules that can be used to stabilize exogenous rh-α-IDUA protein in vitro.

Effect of the lipid II sugar moiety on bacterial transglycosylase: the 4-hydroxy epimer of lipid II is a TGase inhibitor.

Lipid II analogues bearing major modifications on the second sugar (GlcNAc) were synthesized and evaluated for their substrate activity toward TGases. Unexpectedly, N-deacetyled lipid II decreased its activity dramatically, and the C4-axial OH lipid II became an inhibitor (IC50 = 8 µM) with an approximately 14-fold increase in binding affinity toward TGase (25 vs. 27).

Design and Synthesis of Orthogonally Protected d- and l-ß-Hydroxyenduracididines from d-lyxono-1,4-Lactone.

A practical synthesis of the orthogonally protected d- and l-ß-hydroxyenduracididines (d- and l-ßhEnds), the unique, nonproteinogenic α-amino acids found in mannopeptimycin antibiotics, is described. We appropriately applied d-lyxono-1,4-lactone derivatives as a starting template and investigated two transformations: (i) reduction of the lactone in a two-step sequence and (ii) regioselective ring opening of the benzylidene acetal. By careful evaluation of reaction conditions, multigram amounts of both orthogonally protected d- and l-ßhEnds were successfully prepared.

Structural Investigation of Park's Nucleotide on Bacterial Translocase MraY: Discovery of Unexpected MraY Inhibitors.

Systematic structural modifications of the muramic acid, peptide, and nucleotide moieties of Park's nucleotide were performed to investigate the substrate specificity of B. subtilis MraY (MraYBS). It was found that the simplest analogue of Park's nucleotide only bearing the first two amino acids, l-alanine-iso-d-glutamic acid, could function as a MraYBS substrate. Also, the acid group attached to the Cα of iso-d-glutamic acid was found to play an important role for substrate activity. Epimerization of the C4-hydroxyl group of muramic acid and modification at the 5-position of the uracil in Park's nucleotide were both found to dramatically impair their substrate activity. Unexpectedly, structural modifications on the uracil moiety changed the parent molecule from a substrate to an inhibitor, blocking the MraYBS translocation. One unoptimized inhibitor was found to have a Ki value of 4 ± 1 µM against MraYBS, more potent than tunicamycins.

A concise approach to the synthesis of the unique N-mannosyl d-ß-hydroxyenduracididine moiety in the mannopeptimycin series of natural products.

The asymmetric synthesis of the orthogonally protected N-mannosyl d-ß-hydroxyenduracididine (N-Man-d-ßhEnd) is described, starting from enantiopure silylated (S)-serinol. The key steps are: (i) glycosylamine formation between protected serinol and a benzylated d-mannose; (ii) guanidinylation; and (iii) cyclic guanidine formation. This synthesis constitutes a breakthrough in our studies towards a total synthesis of mannopeptimycin and should also allow for other studies in the field of mannopeptimycin research, including the synthesis of derivatives.

Synthesis of 1-C-Glycoside-Linked Lipid†II Analogues Toward Bacterial Transglycosylase Inhibition.

Preparation of Lipid II analogues containing an enzymatically uncleavable 1-C-glycoside linkage between the disaccharide moiety and the pyrophosphate- or pyrophosphonate-lipid moiety is described. The synthesis of a common 1-C-vinyl disaccharide intermediate has been developed that allows easy preparation of both an elongated sugar-phosphate bond and a sugar-phosphonate moiety, which are coupled with the polyprenyl phosphate to give the desired molecules. Inhibition studies show how a subtle structural modification results in dramatically different potency toward bacterial transglycosylase (TGase), and the results identify Lipid II-C-O-PP (IC50 =25 µM) as a potential TGase inhibitor.

Synthesis of novel polyhydroxylated pyrrolidine-triazole/-isoxazole hybrid molecules.

A straightforward synthesis of novel, 2-heterocyclyl polyhydroxylated pyrrolidines is described. Stereocontrolled additions of nucleophiles to cyclic nitrones generated the corresponding 2,3-trans adducts, allowing the synthesis of the corresponding pyrrolidines via key intermediates bearing an alkyne and a nitrile oxide. Three hybrid systems, including a pyrrolidine with two isoxazoles and one triazole, are efficiently prepared via 1,3-dipolar cycloaddition. Biological testing of the product alkaloids showed that subtle structural variations have drastic effects on their inhibitory activities against glucosidases.

Expeditious synthesis of enantiopure, orthogonally protected bis-α-amino acids (OPBAAs) and their use in a study of Nod1 stimulation.

A convenient approach towards the synthesis of orthogonally protected chiral bis-α-amino acids (OPBAAs) is described. The key transformations include: (1) a highly stereoselective conjugation (alkylation) of the Schöllkopf bis-lactim ethers and oxazolidinyl alkyl halides to build a backbone skeleton; and (2) our orthogonal protection strategy. A series of enantiopure OPBAAs bearing a variety of alkyl chain as a spacer; two stereogenic centers; and three protecting groups were prepared as examples. These versatile molecules were applied to the synthesis of biologically interesting di- or tri-peptide analogues, including chiral iE-meso-DAP and A-iE-meso-DAP, for the study of Nod1 activation in the innate immune response.

Asymmetric synthesis of α-methyl-α-amino acids via diastereoselective alkylation of (1S)-(+)-3-carene derived tricyclic iminolactone.

A novel carene-based alanine-equivalent tricyclic iminolactone 16 has been synthesized via stereoselective dihydroxylation of the double bond, IBX oxidation of the secondary alcohol, esterification of the tertiary alcohol, deprotection of the resulting ester, and subsequent cyclization from commercially available (1S)-(+)-3-carene in 79% overall yield. The iminolactone 16 demonstrated high reactivity toward alkylation with a wide range of electrophiles at room temperature under phase-transfer catalysis conditions. The alkylated products were produced with excellent diastereoselectivities (>98% de) in good isolated yields (86-94%). High yields (83-91%) of optically pure (S)-α-methyl-α-substituted-α-amino acids were obtained by basic hydrolysis of the dialkylated iminolactones with the recovery of the chiral auxiliary 15 (78-87%).

In Vitro Activity of 2-methoxy-1,4-naphthoquinone and Stigmasta-7,22-diene-3ß-ol from Impatiens balsamina L. against Multiple Antibiotic-Resistant Helicobacter pylori.

Infection with Helicobacter pylori is strongly associated with gastric cancer and gastric adenocarcinoma. WHO classified H. pylori as a group 1 carcinogen in 1994. Impatiens balsamina L. has been used as indigenous medicine in Asia for the treatment of rheumatism, fractures and fingernail inflammation. In this study, we isolated anti-H. pylori compounds from this plant and investigated their anti- and bactericidal activity. Compounds of 2-methoxy-1,4-naphthoquinone (MeONQ) and stigmasta-7,22-diene-3ß-ol (spinasterol) were isolated from the pods and roots/stems/leaves of I. balsamina L., respectively. The minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) for MeONQ were in the ranges of 0.156-0.625 and 0.313-0.625 µg mL(-1), respectively, and in the ranges of 20-80 µg mL(-1) both of MICs and MBCs for spinasterol against antibiotic (clarithromycin, metronidazole and levofloxacin) resistant H. pylori. Notably, the activity of MeONQ was equivalent to that of amoxicillin (AMX). The bactericidal H. pylori action of MeONQ was dose-dependent. Furthermore, the activity of MeONQ was not influenced by the environmental pH values (4-8) and demonstrated good thermal (121°C for 15 min) stability. MeONQ abounds in the I. balsamina L. pod at the level of 4.39% (w/w db). In conclusion, MeONQ exhibits strong potential to be developed as a candidate agent for the eradication of H. pylori infection.

Asymmetric synthesis of alpha-amino acids: preparation and alkylation of monocyclic iminolactones derived from alpha-methyl trans-cinnamaldehyde.

Two novel chiral monocyclic iminolactones 14a and 14b have been prepared. The chiral auxiliary 12 was obtained from alpha-methyl-trans-cinnamaldehyde through reduction, methylation, Sharpless asymmetric dihydroxylation, and oxidation in 87% overall yield. Esterification of compound 12 with the respective protected amino acids followed by deprotection and cyclization provided the corresponding iminolactones, each in 82% overall yield. Alkylation of the iminolactone 14a afforded the alpha-methyl-alpha,alpha-disubstituted products 15 and 16 in good yields (78-99%) and excellent diastereoselectivity (de >98%). Alkylations of the iminolactone 14b furnished the alpha-benzyl-alpha,alpha-disubstituted products 15a, 16b, 17, and 18 in good yields (51-86%) but moderate diastereoselectivities (43-56%). When HMPA or DMPU was used as a cosolvent, the rate of alkylation of the iminolactone 14b was accelerated with improved yields (56-99%) and diastereoselectivities (50-83%). Hydrolysis of the dialkylated iminolactones yielded the alpha,alpha-disubstituted alpha-amino acids in good yields (80-98%) and high enantiomeric excesses (98-99%) with good recovery of compound 12 (83-92%).

Impact of language anxiety and self-efficacy on accessing Internet sites.

Language interface plays a critical role as the foundation of communication. Possessing greater fluency in the host language can lead to increased opportunities for interaction with host members. This research is to examine the impact of language and Internet usage anxiety and self-efficacy on the intended uses of Internet sites, respectively. By the same token, whether Internet/language self-efficacy would mediate the effects of Internet/language anxiety on the intention of the Internet site use is also examined. A valid sample of 368 undergraduates was tested in this study. The path analysis results mostly supported the model tested. The results display that the anxiety of language and Internet use have significantly influenced self-efficacy of Internet use and language, respectively. Anxiety about language and Internet use have also significantly influenced the intention to use Internet sites individually. Furthermore, language self-efficacy has significantly influenced the intention to use Internet sites, but Internet self-efficacy has not. The implications are discussed at the end of the paper.