The bacterial ribosomal decoding region of the aminoacyl-tRNA site (A-site) is one of the most validated target RNAs for antibiotic agents. Although natural aminoglycosides are well-characterized A-site binding ligands, high off-target effects and the growing emergence of bacterial resistance against aminoglycosides limit their clinical use. To circumvent these concerns with the aminoglycoside family, non-aminoglycoside A-site binding ligands have great potential as novel antibiotics against bacterial infections. This work describes a new class of small heterocyclic ligands based on the 2-amino-5,6,7-trimethyl-1,8-naphthyridine (ATMND) structure for the bacterial (Escherichia coli) A-site. ATMND possessing an aminoethyl side chain is found to strongly and selectively bind to the internal loop of the A-site (K-d=0.44m; pH7.0, I=0.06m, 5 degrees C). Significantly, this ligand shows the tightest binding reported to date among non-aminoglycoside ligands. The binding study based on the thermodynamics and molecular modelling reveals key molecular interactions of ATMND-C-2-NH2 for high affinity to the A-site. This ligand is also demonstrated to be applicable to the fluorescence indicator displacement assay for assessing ligand/A-site interactions.

Note from the Editor: When I was editing Tetsuo Nozoe's autobiography Seventy Years in Organic Chemistry in the late 1980s, I realized that the history of Japanese organic chemistry was not too well known in countries other than Japan. I urged Professor Nozoe to include the historical context of his life in his writings, and I was absolutely delighted that he did so. I also suggested that he publish a “Riko Majima Family Tree in Chemistry.” Majima was not only Nozoe's professor but, as detailed in Nozoe's autobiography and elsewhere in the literature, the father figure of Japanese organic chemistry. Nozoe was reluctant because to single-out some chemical academics but not others in such a public manner could—would—prove embarrassing. But faithful to his profession, the obligations to history prevailed and Nozoe's autobiography contains the Majima Family Tree. We now skip ahead 25 years where we are immersed in the publication of the Nozoe Autograph Books (see: http://www.tcr.wiley-vch.de/nozoe and this introductory essay: J. I. Seeman, Chem. Rec. 2012, 12, 517–531). I find myself once again an editor studying in the life and legacies of Riko Majima and Tetsuo Nozoe. The “repeating experiences” of history have been felt once again!22 For an interesting discussion of the repeating and also cumulative nature in the study of history, see the discussion by Mark C. Eilliot in: N. Heller, The New Yorker 2013, http://www.newyorker.com/reporting/2013/05/20/130520fa_fact_heller, accessed May 21, 2013. JIS thanks Roald Hoffmann for bringing this publication to his attention. I asked Professors Ichiro Murata, Shô Itô, and Toyonobu Asao (who are Professor Nozoe's students and biographers) to follow Professor Nozoe's lead and provide his Family Tree in Chemistry. What follows is a reproduction of the Majima Family Tree as provided by Professor Nozoe along with the next generation Family Tree, that being the students of Tetsuo Nozoe's students who themselves became illustrious professors. —Jeffrey I. Seeman Guest Editor University of Richmond Richmond, Virginia 23173, USA E-mail: jseeman@richmond.edu

A nostalgic memoir of the author-then a young organic chemist-is disclosed. He describes his experience in colleges, in Canadian and American post-doctoral life, and in the earlier days thereafter of his long career in Sendai and Tokushima. He tries to emphasize the importance of determination, taking chance, diligence, patience, and gratitude in chemistry as well as in one's life.

The Mitsunobu reaction is a well-established fundamental reaction and has been applied widely in organic synthesis. In the Mitsunobu reaction, a unique dehydration occurs between alcohols and various Brønsted-Lowry ac ids (HA) u t i l i z ing a comb ina t ion o f d ie thy l azodicarboxylate (DEAD) triphenylphosphine (TPP) (Scheme 1).1,2) Organic chemists have enjoyed these advantages of the Mitsunobu reaction in organic synthesis. However, the reaction has a serious limitation (the so-called “the restriction of pKa”); the acidic hydrogen in HA has to have a pKa of less than 11 for the reaction to proceed satisfactorily. If HA has a pKa higher than 11, the yield of RA is considerably lower, and with HA having a pKa higher than 13, the desired reaction does not occur (for example: Scheme 3).1, 2, 4) In order to overcome “the restriction of pKa”, we have developed new Mitsunobu reagents and applied them to organic synthesis.5) In this article, we would like to describe the results.

The 1,1′-(azodicarbonyl)dipiperidine (ADDP)-tributylphosphine (TBP) system was developed as a new institute of the Mitsunobu reagent. The new system activates nitrogen or carbon nucleophiles, known to be innert or poorly reactive with the Mitsunobu reagent. to react with alcohols satisfactorily forming C-N or C-C bonds. The inversion of stereogenic carbinyl carbons was confirmed in the acylaltion reaction of two sec-alcohols.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Cyanomethylenetrimethylphosphorane (CMMP) reacted with esters, lactones, N-Boc lactam, and cyclic imide to give the corresponding Wittig products in excellent yield.

(−)-Antimycin A3b, the antipode of natural antibiotic antimycin A3b, was synthesized utilizing the asymmetric aza-Claisen rearrangement.

Cyanomethylenetrimethylphosphorane (CMMP), a new Mitsunobu reagent developed recently by the authors, mediated the alkylation of arylmethyl phenyl sulfones with primary and secondary alcohols quite efficiently. Utilizing 3-((phenylsulfonyl)methyl)pyridine, theonelladine D, a unique pyridine alkaloid, was synthesized in excellent yield.

Some new Mitsunobu reagents, especially N,N,N′,N′-tetramethylazodicarboxamide (TMAD)-tributylphosphine (TBP) and cyanomethylenetrimethylphosphorane (CMMP), mediated the direct transformation of primary and secondary alcohols into the corresponding nitriles in the presence of acetone cyanohydrin. This type of cyanation process can convert 3β-cholestanol to 3α-cyanocholestane in high yield with complete Walden inversion.

The combination of 4,7-dimethyl-3,5,7-hexahydro-1,2,4,7-tetrazocin-3,8-dione (DHTD) and tributylphosphine (TBP) was found to mediate successfully C-N bond formation between N-methyltosylamide, a typical N-nucleophile, and several alcohols of different structural types. The unique feature of this combination is that it activates the reaction of sec-alcohols at room temperature.

The Mitsunobu reaction, a popular alkylation reaction utilizing the redox system between diethyl azodicarboxylate and triphenylphosphine, has a shortcoming that it can only be applied satisfactorily to a nucleophile (HA) of pK(a) less than 11. In order to overcome the limitation, we introduced several combinations of azodicarboxamides (TIPA, ADDP; TMAD, and DHTD) and tributylphosphine. In our continual search for new Versatile reagents, we found cyanomethylenetrialkylphosphorane (CMBP, CMMP) was capable of mediating the alkylation of various HA of larger pK(a) than 11. Utilizing these reagents, the efficient alkylation of N-, C-, and O-nucleophiles, such as tosylamides, active methylene compounds, alcohols, and carboxylic acid was accomplished. The results are presented along with their synthetic application.

p-Toluenesulfonamide, which is known to form phosphine imides under Mitsunobu conditions, was shown to be alkylated in the presence of cyanomethylenetributylphsphorane to give N-substituted sulfonamides in excellent yields. The reaction can be applied to the synthesis of symmetrical and unsymmetrical N,N-disubstituted amides. When coupled with the desulfurization reactions, the reaction provides a new versatile synthetic route to primary and secondary amines from ammonia.

Cyanomethylenetributylphosphorane was shown to mediate the dehydrocyclization of diols and amino alcohols to give the corresponding 6-membered O- and N-heterocycles in 90% or better yields. Using the reaction as a key step, (+)-α-skytanthine, a unique mono terpene alkaloid, was synthesized stereoselectively.

Intermolecular reaction of two active methine compounds with primary or secondary alcohols in the presence of new Mitsunobu-type reagents afforded alkylation products in excellent (with primary alcohols) to fair yields (with secondary alcohol) except one case. It demonstrates that the new reagents, especially cyanomethylene-trimethylphosphorane, are excellent mediators for this type of alkylation. The double alkylation of an active methylene compound with diols under similar conditions gave cyclization products in good to excellent yields.

Four secondary alcohols of different steric environment reacted with five carboxylic acids of different acidity in the presence of N,N,N′,N′-tetramethylazodicarboxamide and tributylphosphine to give the corresponding epi-esters in better yield than with diethyl azodicarboxylate-triphenylphosphine in most cases. Of special merit is the combination of the new reagent system with p-methoxybenzoic acid to achieve complete inversion of sterically congested secondary alcohols.

When treated with Lewis acids, 2- or 3-vinyl- or -phenylsiloxyaminoacetals generated the corresponding imines or iminium ions which in turn underwent smooth intramolecular amidoalkylation to afford anti-1,2- or -1,3-aminoalcohol derivatives in very high chemical yields and excellent diastereomeric ratios. Applying the reaction, Z-allo-L-threonine and (±)-N-ethoxycarbonyl-anti-γ-hydroxynorvaline were successfully synthesized.

The efficiency of three azodicarboxylic acid derivatives and a stabilized phosphorane in the Mitsunobu type CC bond formation was compared utilizing the reactions of three nucleophiles of different pKa′S and several alcohols of different structure types. The study established the characteristics of each reagent. The synthesis of two insect pheromone analogs was accomplished effectively using these homologation reactions.

N,N,N′,N′-Tetramethylazodicarboxamide, TMAD, was found to be more versatile in the Mitsunobu reaction than traditional diethyl azodicarboxylate or recently developed 1,1′-(azodicarbonyl)dipiperidine, when used in combination with tributylphosphine in benzene. The usefulness of the reagent was demonstrated by the highly efficient two-step synthesis of benzylcrotylamine from N-benzyltrifluoroacetamide.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.