A robust and scalable Cu-I-catalyzed diastereoselective vinylation of an aliphatic aldehyde was developed to enable clinical supply of investigational Mcl-1 inhibitors in our oncology pipeline. Through process design and impurity control, a telescoped process consisting of a benzotriazole salt break and diastereoselective vinylation was developed. This process eliminated the need to perform distillation operations, improved reaction performance and efficiency, and was successfully scaled to >100 kg.

The ipso nitration of aryl boronic acid derivatives has been developed using fuming nitric acid as the nitrating agent. This facile procedure provides efficient and chemoselective access to a variety of aromatic nitro compounds. While several activating agents and nitro sources have been reported in the literature for this synthetically useful transformation, this report demonstrates that these processes likely generate a common active reagent, anhydrous HNO3. Kinetic and mechanistic studies have revealed that the reaction order in HNO3 is >2 and indicate that the •NO2 radical is the active species.

During development of a radical benzylic bromination, observation of polymerized byproducts and variation in isolated yields warranted an in-depth mechanistic investigation to ensure process understanding and robustness. In situ kinetic studies using multinuclear CryoFree NMR spectroscopy revealed molecular bromine to be the active brominating species and variable time normalization analysis allowed accurate determination of the order of each reagent in this process. These kinetic studies allowed for accurate reaction modeling and were used to demonstrate that adoption of a simple procedural change ensured reliability and reproducibility during manufacturing.

The development and kilogram-scale demonstration of an improved process for the synthesis of the epoxyketone warhead of carfilzomib is described. Critical to the success of this process was: (1) development of a scalable asymmetric epoxidation protocol; (2) identification of a crystalline intermediate with improved physical properties for isolation; (3) discovery and optimization of epimerization conditions to set the target stereochemistry; and (4) introduction of a seeded-bed coaddition crystallization to facilitate isolation of the final low-melting target. The results of kilogram-scale demonstration runs are shared, including details of a continuous process for the safe execution of an exothermic Barbier-type Grignard process.

An operationally efficient CDI mediated tandem coupling and cyclization reaction to generate [1,2,4]triazolo[4,3-a]pyridines has been reported. The reaction conditions and scope were investigated, and the methodology was demonstrated in batch mode as well as in a continuous process.

AbstractA CDI mediated coupling of 2‐pyridylhydrazines and carboxylic acids followed by cyclization reaction to generate [1,2,4]triazolo[4,3‐a]pyridines is reported.

AbstractA convenient Raney cobalt‐catalyzed hydrogenation of a variety of heterocyclic ketoximes to form primary amines in good selectivity under mild conditions is presented.

A process to access heteroaromatic primary amines from the corresponding heteroaromatic ketones has been developed. A broad range of previously reported methods to convert ketones to primary amines was examined on heterocyclic ketones without success, including Leuckart-Wallach conditions, borane reductions, and transitionmetal-catalyzed hydrogenations. Unique among the catalysts examined, Raney cobalt produced the desired primary heterocyclic amine. Raney cobalt hydrogenation of structurally varied heterocyclic ketoximes was demonstrated to form primary amines in good selectivity under mild conditions, and the products are easily isolated in high yield. Additionally, this is the first report of a systematic evaluation of the capabilities of Raney cobalt as an oxime hydrogenation catalyst.

Two new, reliable syntheses of a pyrido[2,3-d]-pyrimidine inhibitor of the CXCR3 receptor are described. A nine-step synthesis of the CXCR3 inhibitor (1) from 2-aminonicotinic acid was demonstrated on a multikilogram scale and incorporates a classic resolution to deliver the enantioenriched active pharmaceutical ingredient (API). A second synthesis of the CXCR3 inhibitor starts from (+)-(d)-Boc alanine and 2-chloronicotinic acid and utilizes a Goldberg coupling. This second synthesis, performed on a gram scale, intersects the former route at a common intermediate thereby completing a formal synthesis of the enantioenriched API in higher overall yield without the need for a resolution.

Heteroarenes are important structural moieties in many chemical industry fields. A highly efficient Pd/Cu-catalyzed C-H arylation method for a range of heterocycles has been discovered. It was found that the key to the success of this transformation is a combination of a palladium catalyst and a well-defined copper cocatalyst. The efficiency and low loadings of catalyst (0.25 mol %) and cocatalyst (1 mol %) together with the mild reaction conditions demonstrate this method to be practically useful and mechanistically interesting.

A highly efficient palladium/copper catalyzed C-H arylation method for a range of heterocycles has been investigated. It turned out that the key step of this transformation is a combination of a palladium catalyst and the copper cocatalyst Cu(Xanthphos)I. The efficiency and low loadings of the catalyst (0.25 mol%) and the cocatalyst (1 mol%) in combination with practical reaction conditions demonstrate the utility of this method.

Angewandte ChemieVolume 118, Issue 8 p. 1270-1274 Zuschrift Chemoselective Amide Ligations by Decarboxylative Condensations of N-Alkylhydroxylamines and α-Ketoacids† Jeffrey W. Bode Prof. Dr., bode@chem.ucsb.edu Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, USA, Fax: (+1) 805-893-4120Search for more papers by this authorRyan M. Fox, Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, USA, Fax: (+1) 805-893-4120Search for more papers by this authorKyle D. Baucom, Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, USA, Fax: (+1) 805-893-4120Search for more papers by this author Jeffrey W. Bode Prof. Dr., bode@chem.ucsb.edu Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, USA, Fax: (+1) 805-893-4120Search for more papers by this authorRyan M. Fox, Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, USA, Fax: (+1) 805-893-4120Search for more papers by this authorKyle D. Baucom, Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, USA, Fax: (+1) 805-893-4120Search for more papers by this author First published: 06 February 2006 https://doi.org/10.1002/ange.200503991Citations: 90 † This work was supported by the Donors of the Petroleum Research Fund (administered by the American Chemical Society), the Camille and Henry Dreyfus Foundation (New Faculty Award to J.W.B.), and the University of California. K.D.B. was a 2005 DeWolfe Summer Undergraduate Fellow. We are grateful to Joshua Garretson for preliminary efforts. Read the full textAboutPDF ToolsRequest permissionAdd to favorites ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat Abstract Ganz ohne Additiv: Die chemoselektive Ligation zwischen N-Alkylhydroxylaminen und α-Ketosäuren unter Bildung einer Amidbindung erfordert keine Reagentien und hat als einzige Begleitprodukte Wasser und Kohlendioxid. Nicht geschützte Peptidsubstrate werden dabei nicht epimerisiert, was dem Prozess Potenzial als neuartige chemoselektive Ligation zur Synthese von Peptiden und komplexen Materialien verleiht. Citing Literature Supporting Information Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2001/2006/z503991_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume118, Issue8February 13, 2006Pages 1270-1274 This is the German version of Angewandte Chemie. Note for articles published since 1962: Do not cite this version alone. Take me to the International Edition version with citable page numbers, DOI, and citation export. We apologize for the inconvenience. RelatedInformation