We have tested a number of synthetic methods for large-scale synthesis of targeted substituted aromatic alkyne (S)-[4-(3-chloro-5-ethynyl-4-fluoro-phenyl)-1-methyl-butyl]-carbamic acid benzyl ester (1). This research resulted in an improved method for the Corey-Fuchs approach to alkyne synthesis from aldehydes. Importantly, we have shown that the use of P(OCH3)(3)/CBr4 in toluene for the synthesis of the dibromo-methylene intermediate (S)-{4-[3-chloro-5-(2,2-dibromo-vinyl)-4-fluoro-phenyl]-1-methyl-butyl}-carbamic acid benzyl ester (5) allows the synthesis of alkyne 1 under conditions that may be amenable for scaling-up. Since this method was developed, multiple batches of alkyne 1, each approaching 100 g in size, have been prepared under process-friendly conditions, as well as multigram batches of other alkynes.

The copper-catalyzed "click" reaction of an azide with an alkyne has become a popular method to build tip 1,4-substituted 1H-1,2,3-triazoles in medicinal chemistry and this approach was used on a laboratory scale during the preparation of novel macrolide 1. However, the manufacture of the key azide component, as well as its subsequent use in the presence of a copper catalyst on a large scale, was associated with potential safety concerns. Therefore, a sequence was developed in which construction of the 1,4-substituted 1H-1,2,3-triazole in 1 was accomplished via cyclocondensation of an alpha,alpha-dichloro tosyl hydrazone with an amine.

We have developed a first generation of hybrid sparsomycin–linezolid compounds into a new family of orally bioavailable biaryloxazolidinones that have activity against both linezolid-susceptible and -resistant Gram-positive bacteria as well as the fastidious Gram-negative bacteria Haemophilus influenzae and Moraxella catarrahalis. The convergent synthesis of these new compounds is detailed.

Delafloxacin is a 6-fluoroquinolone antibiotic which is under development at Rib-X Pharmaceuticals. During initial scale-up runs to prepare delafloxacin, up to 0.43% of a new impurity arose in the penultimate chlorination step. This was identified as a dimeric adduct of delafloxacin. Subsequent application of design of experiments (DoE) led to the identification of the factors responsible for this impurity. Implementation of the knowledge gained from the DoE reproducibly enabled the suppression of this impurity to acceptable levels.

From the X-ray crystal structures of linezolid and the non-selective antibiotic sparsomycin, we have derived a new family of hybrid oxazolidinones. From this initial compound set we have developed a new biaryloxazolidinone scaffold that shows both potent antimicrobial activity as well as selective inhibition of ribosomal translation. The synthesis of these compounds is outlined.

L'invention concerne des procedes de preparation de triazoles. Ces composes sont utiles comme agents anti-infectieux, anti-proliferatifs, anti-inflammatoires et pro-cinetiques.

Isoxazolidines have been synthesized in diastereomeric excess up to 94% via a MgBr2-induced chelation-controlled 1,3-dipolar cycloaddition reaction with N-hydroxyphenylglycinol as a chiral auxiliary. The diastereomerically pure isoxazolidines were further transformed into cyclic and acyclic beta-amino acid derivatives.

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Rutamycin B (2) was synthesized from three principal subunits, spiroketal 75, keto aldehyde 83, and aldehyde 108. First, triol 62 was assembled by Julia coupling of sulfone 56 with aldehyde 58 followed by an acid-catalyzed spiroketalization. The three hydroxyl functions of 62 were successfully differentiated, leading to phosphonate 75. The latter was condensed in a Wadsworth-Emmons reaction with 83, prepared in six steps from (R)-aldehyde 76, to give 92. Coupling of the titanium enolate of 92 with 108 afforded Felkin product 109 with high stereoselectivity in a process that is critically dependent on the presence of the p-methoxybenzyl ether in the aldehyde. Transformation of 109 via aldehyde 116 to vinylboronate 122 was followed by macrocyclization under Suzuki conditions to yield 123. Exhaustive desilylation of the latter yielded rutamycin B.

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.

ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTSynthesis of Epiantillatoxin, a Stereoisomer of the Potent Ichthyotoxin from Lyngbya majusculaJames D. White, Roger Hanselmann, and Duncan J. WardropView Author Information Department of Chemistry, Oregon State University, Corvallis, Oregon 97331-4003 Cite this: J. Am. Chem. Soc. 1999, 121, 5, 1106–1107Publication Date (Web):January 22, 1999Publication History Received18 September 1998Published online22 January 1999Published inissue 1 February 1999https://pubs.acs.org/doi/10.1021/ja983334lhttps://doi.org/10.1021/ja983334lrapid-communicationACS PublicationsCopyright © 1999 American Chemical SocietyRequest reuse permissionsArticle Views924Altmetric-Citations26LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information SUBJECTS:Alcohols,Aldehydes,Chromatography,Mixtures,Organic acids Get e-Alerts

The macrolide rutamycin B containing 17 stereogenic centres and a 26-membered ring was synthesized by a route which features a chelate-controlled, double differentiating aldol reaction and ring closure by means of a vinyl-vinyl coupling.

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.