The design of a novel selective estrogen receptor modulator (SERM) for the potential treatment of uterine leiomyoma is described. 16 (LY2066948-HCl) binds with high affinity to estrogen receptors alpha and beta (ERalpha and ERbeta, respectively) and is a potent uterine antagonist with minimal effects on the ovaries as determined by serum biomarkers and histologic evaluation.

A brief introduction into the chemistry of the CP-molecules is followed by first-generation synthetic sequences toward key building blocks for their total synthesis. Processes for both racemic and enantiomerically enriched bicyclo[4.3.1] ketone 6 or its equivalent are described, and the absolute stereochemistries of the optically enriched intermediates are determined. The efficient route developed to racemic 6 and the ready access to both enantiomers of key building blocks provided the opportunity for the total synthesis of the CP-molecules and determination of their absolute stereochemistry.

Crucial model synthetic and mechanistic studies directed toward the development of methodology for the construction of the maleic anhydride moiety of the CP-molecules are described. Studies directed toward the stereoselective attachment of the upper side chain, culminating in the discovery of long-range stereochemical control, are also discussed. In addition, a first-generation strategy toward the CP-molecules, establishing key intermediate 5 as a "beachhead" from which all future operations would diverge, is also presented. Although this first-gene ration strategy failed to yield the target molecules, the endeavor laid the important groundwork for the next-generation drives toward the CP-molecules.

[formula: see text] The array of challenging structural lineaments embodied in the CP molecules (1 and 2, Figure 1) offers synthetic chemists uncharted realms of exploration and discovery. In this communication, we focus on the chemical hurdies posed by the gamma-hydroxy lactone moiety of these exciting targets. Thus, the examination of the general reactivity of these systems, the development of a novel tandem oxidation sequence to construct the gamma-hydroxy lactone moiety, and the successful construction of the complete polycyclic core of 2 (compound 28, Scheme 5) is enumerated within.

Durch ein Syntheselabyrinth, das zahllose Hindernisse, aber auch etliche verborgene Schätze enthielt, führte der Weg zu den CP-Verbindungen CP-263,114 1 und CP 225,917 2. Deren komplexer Molekülbau und das Vorhandensein einer ganzen Reihe sensibler Funktionalitäten machen die Synthese dieser Verbindungen zu einer großen Herausforderung. Darüber hinaus weisen sie auch interessante biologische Eigenschaften auf. Obwohl die ersten Synthesestrategien trotz sorgfältiger Ausarbeitung und zahlreicher begleitender Modellstudien kurz vorm Erreichen des Ziels in Sackgassen endeten, trugen sie doch durch die dabei gewonnenen Erkenntnisse dazu bei, einen neuen überarbeiteten Ansatz zu entwickeln, der schließlich zum Erfolg führte.

A seven-step cascade reaction-in which selective mesylation, epoxide formation, epoxide lysis, cyclization, reiterative oxidation, and nitrogen-oxygen exchange occur sequentially-facilitates the construction of the maleic anhydride moiety of CP molecules 1 and 2 (>93% yield per step). Unstable intermediates of this reaction sequence were detected, providing evidence for the proposed mechanism and resulting in the discovery of a new chemical entity.

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Angewandte ChemieVolume 111, Issue 4 p. 532-535 Zuschrift Ein außergewöhnlicher Zugang zur anellierten Maleinsäureanhydrid-Einheit der CP-Moleküle K. C. Nicolaou, K. C. Nicolaou kcn@scripps.edu Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+ 1) 619-784-2469 (und) Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USASearch for more papers by this authorPhil S. Baran, Phil S. Baran Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+ 1) 619-784-2469 (und) Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USASearch for more papers by this authorRolf Jautelat, Rolf Jautelat Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+ 1) 619-784-2469 (und) Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USASearch for more papers by this authorYun He, Yun He Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+ 1) 619-784-2469 (und) Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USASearch for more papers by this authorKin Chiu Fong, Kin Chiu Fong Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+ 1) 619-784-2469 (und) Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USASearch for more papers by this authorHa-Soon Choi, Ha-Soon Choi Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+ 1) 619-784-2469 (und) Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USASearch for more papers by this authorWon Hyung Yoon, Won Hyung Yoon Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+ 1) 619-784-2469 (und) Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USASearch for more papers by this authorYong-Li Zhong, Yong-Li Zhong Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+ 1) 619-784-2469 (und) Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USASearch for more papers by this author K. C. Nicolaou, K. C. Nicolaou kcn@scripps.edu Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+ 1) 619-784-2469 (und) Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USASearch for more papers by this authorPhil S. Baran, Phil S. Baran Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+ 1) 619-784-2469 (und) Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USASearch for more papers by this authorRolf Jautelat, Rolf Jautelat Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+ 1) 619-784-2469 (und) Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USASearch for more papers by this authorYun He, Yun He Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+ 1) 619-784-2469 (und) Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USASearch for more papers by this authorKin Chiu Fong, Kin Chiu Fong Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+ 1) 619-784-2469 (und) Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USASearch for more papers by this authorHa-Soon Choi, Ha-Soon Choi Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+ 1) 619-784-2469 (und) Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USASearch for more papers by this authorWon Hyung Yoon, Won Hyung Yoon Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+ 1) 619-784-2469 (und) Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USASearch for more papers by this authorYong-Li Zhong, Yong-Li Zhong Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+ 1) 619-784-2469 (und) Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USASearch for more papers by this author First published: February 15, 1999 https://doi.org/10.1002/(SICI)1521-3757(19990215)111:4<532::AID-ANGE532>3.0.CO;2-QCitations: 14AboutPDF 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 onFacebookTwitterLinked InRedditWechat Abstract Sieben auf einen Streich! Ein chemisches tapferes Schneiderlein – d. h. eine siebenstufige Kaskadenreaktion – ermöglicht den Aufbau der Maleinsäureanhydrid-Einheit der CP-Verbindungen 1 und 2 (>93 % Ausbeute für jede Stufe). Instabile Zwischenstufen dieser Reaktionssequenz konnten nachgewiesen werden, wodurch der vorgeschlagene Mechanismus belegt und neue chemische Spezies nachgewiesen wurden. Citing Literature Volume111, Issue4February 15, 1999Pages 532-535 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

Durch ein Syntheselabyrinth, das zahllose Hindernisse, aber auch etliche verborgene Schätze enthielt, führte der Weg zu den CP-Verbindungen CP-263,114 1 und CP 225,917 2. Deren komplexer Molekülbau und das Vorhandensein einer ganzen Reihe sensibler Funktionalitäten machen die Synthese dieser Verbindungen zu einer großen Herausforderung. Darüber hinaus weisen sie auch interessante biologische Eigenschaften auf. Obwohl die ersten Synthesestrategien trotz sorgfältiger Ausarbeitung und zahlreicher begleitender Modellstudien kurz vorm Erreichen des Ziels in Sackgassen endeten, trugen sie doch durch die dabei gewonnenen Erkenntnisse dazu bei, einen neuen überarbeiteten Ansatz zu entwickeln, der schließlich zum Erfolg führte.

[formula: see text] A mild and reliable one-pot protocol for the elaboration of sterically demanding carboxylic acids into alpha-diazoketones via acyl mesylates has been developed. Aside from delineating the reaction parameters which render this strategy quite general for hindered carboxylic acids, we have directly proven the existence of the fleeting acyl mesylate group as the reactive species in these reactions and shed light onto the differing mechanisms which are operative in the activation of hindered and simple carboxylic acids with methanesulfonyl chloride.

A synthetic labyrinth endowed with countless obstacles, yet filled with numerous hidden treasures, had to be overcome to reach the CP molecules CP-263,114 (1) and CP-225,917 (2). Their complex molecular frameworks coupled with the array of sensitive functionalities present amount to a formidable synthetic challenge. Moreover, these compounds possess interesting biological properties. Although the first synthetic strategies ended before the goals were achieved, in spite of careful preparation and numerous model studies, enough information was gathered en route to enable a revised approach to be formulated, which finally culminated in success.

Einfaches Umlagern der allylischen Doppelbindung in Verbindungen des Typs 1 liefert selektiv die cis‐Endiine 2. Bei der Cycloaromatisierung von 2 entstehen reaktive Diradikale, die den Zwischenstufen des Zerfalls der natürlichen Endiin‐Antitumor/Antibiotica gleichen. R1 = CH2SO2Ph.magnified image