Chelating Picolinaldehyde Hydrazone Amides as Protecting Groups for Carboxylic Acids: Orthogonal Reactivities of Hydrazone Amides and Esters in Hydrolysis.

We report a chelating hydrazone amide as a protecting group for carboxylic acids. Unlike most esters, 2-picolinaldehyde hydrazone amides are stable under acidic or basic hydrolytic conditions. However, hydrazone amides can be easily converted to the corresponding carboxylic acids via Ni-mediated hydrolysis. Orthogonal reactivities of the hydrazone amides and representative protecting groups were verified by control experiments and peptide synthesis, demonstrating that chelating hydrazone amides are highly useful protecting groups.

Site-Selective Acylations of α- and ß-Hydroxyamides in Complex Molecules: Application of Template-Driven Acylation to Disaccharides and a Glycopeptide.

Site-selective acylations of α-and ß-hydroxyamides in complex polyols are described. The combination of a pyridine aldoxime ester and Zn(OTf)2 facilitates the acylation of two types of N-glycolyl disaccharides, namely, Gal-GlcNGc and Neu5Gc-Gal, both of which are partial structures of polysaccharides responsible for biological actions, with highly site-selective modifications achieved. Furthermore, biotinylation, one of the most important techniques in chemical biology, is used to site-selectively acylate the ß-hydroxyl group in a glycopeptide.

Site-Selective Esterifications of Polyol ß-Hydroxyamides and Applications to Serine-Selective Glycopeptide Modifications.

The site-selective acylations of ß-hydroxyamides in the presence of other hydroxyl groups are described. Central to the success of this modification is the metal-template-driven acylation using pyridine ketoxime esters as acylating reagents in combination with CuOTf. This strategy enables ß-hydroxyl groups to be site-selectively acylated in various derivatives, including sterically hindered secondary ß-alcohol. The utility of this methodology is showcased by the serine-selective modification of a glycopeptide with unprotected sugar.

Enantioselective Bromolactonization of Trisubstituted Olefinic Acids Catalyzed by Chiral Pyridyl Phosphoramides.

Enantioselective bromolactonization of trisubstituted olefinic acids producing synthetically useful chiral lactones with two contiguous asymmetric centers has remained mainly unexplored except for the 6-exo cyclization mode. In this work, the 5-exo- and 6-endo modes of bromocyclization of trisubstituted olefinic acids were enabled for the first time using N-bromosuccinimide and a pyridyl phosphoramide catalyst. The utility of the resulting bromolactones was demonstrated by transformations harnessing reactive alkyl bromide moieties without losing stereochemical information. Optimization studies and control experiments revealed that the basicity of pyridine moieties and presence of N-H protons in the phosphoramide species strongly affected both the reactivity and enantioselectivity parameters.

Metal Template Assisted Proximal Arrangement of a Nucleophile and an Electrophile: Site-Selective Acylation of α-Hydroxyamides in Polyols.

Site-selective acylation of α-hydroxyl groups in amides has been achieved in the presence of other primary hydroxyl groups with intrinsic high reactivity. In this methodology, a relatively stable pyridine aldoxime ester was exploited as an acyl donor to suppress undesired acylation. The catalytic activation of a pyridine aldoxime ester with a Lewis acid produced a cationic complex, which preferentially attracted the Lewis basic α-hydroxyamide via a template effect, to thus facilitate o-acylation.

Chiral Pyridinium Phosphoramide as a Dual Brønsted Acid Catalyst for Enantioselective Diels-Alder Reaction.

Chiral pyridinium phosphoramide 1·HX was designed to be a new class of chiral Brønsted acid catalyst in which both the pyridinium proton and the adjacent imide-like proton activated by the electron-withdrawing pyridinium moiety could work cooperatively as strong dual proton donors. The potential of 1·HX was shown in the enantioselective Diels-Alder reactions of 1-amino dienes with various dienophiles including N-unsubstituted maleimide, which has yet to be successfully used in an asymmetric Diels-Alder reaction.

Pd(II)-catalyzed allylic C-H amination for the preparation of 1,2- and 1,3-cyclic ureas.

A general synthesis of 1,2- and 1,3-cyclic ureas is accomplished by intramolecular allylic C-H amination employing Pd(TFA)2/bis-sulfoxide as a catalyst. By careful modification of substrates and catalyst, a variety of 1,2-cyclic ureas are accessible from not previously employed terminal olefins substituted in allylic or vinylic positions. Furthermore, MS4A is found to be an effective additive for the synthesis of 1,3-cyclic ureas in good yields and excellent diastereoselectivities.

Combinatorial synthesis of an oligosaccharide library by using beta-bromoglycoside-mediated iterative glycosylation of selenoglycosides: rapid expansion of molecular diversity with simple building blocks.

A new method for constructing an oligosaccharide library composed of structurally defined oligosaccharides is presented based on an iterative glycosylation of selenoglycosides. Treatment of 2-acyl-protected selenoglycosides with bromine selectively generates beta-bromoglycosides, which serve as glycosyl cation equivalents in the oligosaccharide synthesis. Thus, the coupling of the bromoglycosides with another selenoglycoside affords the corresponding glycosylated selenoglycosides, which can be directly used to next glycosylation. The iteration of this sequence allows the synthesis of a variety of oligosaccharides including an elicitor active heptasaccharide. A characteristic feature of the iterative glycosylation is that glycosyl donors and acceptors with the same anomeric reactivity can be selectively coupled by activation of the glycosyl donor prior to coupling with the glycosyl acceptor. Therefore, same selenoglycosides can be used for both the glycosyl donors and the acceptors. This feature has been exemplified by a construction of an oligosaccharide library directed to elicitor-active oligosaccharides. The library composed of stereochemically defined oligoglucosides with considerable structural diversity can be constructed starting from simple selenoglycosides.

Diastereoselective synthesis of all stereoisomers of beta-methoxytyrosine, a component of papuamides.

beta-Methoxytyrosine (beta-OMeTyr) is a stereoundefined component of papuamides A and B, novel cyclodepsipeptides, with anti-HIV and cytotoxic activities. For structural determination and total synthesis of papuamides, all stereoisomers of beta-OMeTyr were stereoselectively prepared from (S)- and (R)-serine, respectively.

Electrochemistry of chalcogenoglycosides. Rational design of iterative glycosylation based on reactivity control of glycosyl donors and acceptors by oxidation potentials.

Electrochemical properties of various para-substituted phenylthio-, phenylseleno-, and phenyltelluroglucopyranosides bearing acetyl, benzoyl, and benzyl protecting groups have been investigated to estimate the reactivity of chalcogenoglycosides toward electrochemical glycosylations. The oxidation potential of the chalcogenoglycosides shows good correlation with the ionization potential of chalcogen atoms, and decreases in the order thio-, seleno-, and telluroglycosides. It is also affected by the para-substituents, and the substitution effect correlates very well with the HOMO energy of para-substituted benzenechalcogenol and with the Hammett sigma p + value. Electrochemical glycosylation of telluroglycosides has been examined, and it was found that the use of an undivided cell is more effective than the use of a divided cell. Selective activation of the chalcogenoglycosides in bulk electrolysis based on their oxidation potentials has been examined, and the relative reactivity of the telluroglycosides can be estimated from their oxidation potentials. However, the relative reactivity of selenoglycosides in the preparative glycosylation was rather insensitive to the oxidation potential values.

Studies on fertilization in the teleost IV. Effects of aphidicolin and camptothecin on chromosome formation in fertilized medaka eggs.

To clarify the mechanisms of fish fertilization, the effects of inhibitors of DNA polymerase-alpha and DNA topoisomerases on nuclear behavior before and after fertilization were examined in eggs of the medaka, Oryzias latipes. Eggs underwent the fertilization process from sperm penetration to karyogamy of pronuclei, even when inseminated and incubated in the continuous presence of aphidicolin (DNA polymerase alpha inhibitor), camptothecin (DNA topoisomerase I inhibitor), etoposide, or beta-lapachone (DNA topoisomerase II inhibitor). However, continuous treatment with aphidicolin or camptothecin during fertilization inhibited the formation of sister chromosomes that were normally separated into blastomeres at the time of the subsequent cleavage. Sister chromosome formation appeared concomitantly with an increase in histone H1 kinase activity at the end of DNA synthesis, 30 min post insemination. However, non-activated eggs that were inseminated in saline containing anesthetic MS222 and aphidicolin had high levels of histone H1 kinase and MAP kinase activities, and transformation of the penetrated sperm nucleus to metaphase chromosomes occurred even in the presence of aphidicolin or camptothecin. The male chromosomes were normally separated into two anaphase chromosome masses upon egg activation. These results suggest that DNA polymerase alpha or DNA topoisomerase I, but not DNA topoisomerase II, may be required for the process by which the mitotic interphase nucleus transforms to separable metaphase chromosomes while the activity of MAP kinase is low, unlike the situation in meiotic division, during which MAP kinase activity is high and DNA replication is not required.