Entry to Heterocycles Based on Indium‐Catalyzed Conia‐Ene Reactions: Asymmetric Synthesis of (−)‐Salinosporamide A

Takahashi, Keisuske; Midori, Michiko; Kawano, K.; Ishihara, Jun; Hatakeyama, Susumi

doi:10.1002/ange.200801967

Cited by 99 publications

(22 citation statements)

References 36 publications

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“…[97] The chiral propargyl alcohol 101 [98] was converted in a five-step sequence into diol 102 . Oxidation of 102 and activation of the carboxylic acid thus obtained as an acid chloride followed by condensation with dimethyl 2-(PMB-amino)malonate gave the key precursor 103 .…”

Section: Total Syntheses Of Salinosporamide Amentioning

confidence: 99%

Salinosporamide Natural Products: Potent 20 S Proteasome Inhibitors as Promising Cancer Chemotherapeutics

2010

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Proteasome inhibitors are rapidly evolving as potent treatment options in cancer therapy. One of the most promising drug candidates of this type is salinosporamide A from the bacterium Salinispora tropica. This marine natural product possesses a complex, densely functionalized γ-lactam-β-lactone pharmacophore, which is responsible for its irreversible binding to its target, the β subunit of the 20S proteasome. Salinosporamide A entered phase I clinical trials for the treatment of multiple myeloma only three years after its discovery. The strong biological activity and the challenging structure of this compound have fueled intense academic and industrial research in recent years, which has led to the development of more than ten syntheses, the elucidation of its biosynthetic pathway, and the generation of promising structure-activity relationships and oncological data. Salinosporamide A thus serves as an intriguing example of the successful interplay of modern drug discovery and biomedical research, medicinal chemistry and pharmacology, natural product synthesis and analysis, as well as biosynthesis and bioengineering.

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Section: Total Syntheses Of Salinosporamide Amentioning

confidence: 99%

Salinosporamide Natural Products: Potent 20 S Proteasome Inhibitors as Promising Cancer Chemotherapeutics

2010

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“…:12b [ α ]${{{23\hfill \atop {\rm D}\hfill}}}$ =−73.0 ( c =0.40 in MeOH); lit. :12g [ α ]${{{26\hfill \atop {\rm D}\hfill}}}$ =−76.0 ( c =0.48 in MeOH); lit. :12h [ α ]${{{22\hfill \atop {\rm D}\hfill}}}$ =−75.8 ( c =0.2 in MeOH); IR (film): $\tilde \nu $ =3367, 1824, 1700, 1442, 1385, 1242 cm −1 ; 1 H NMR (500 MHz, C 5 D 5 N): δ =10.62 (s, 1 H), 6.41 (d, J =10.3 Hz, 1 H), 5.91–5.86 (m, 1 H), 4.25 (d, J =8.9 Hz, 1 H), 4.16–4.10 (m, 1 H), 4.05–3.98 (m, 1 H), 3.18 (m, 1 H), 2.89–2.81 (m, 1 H), 2.53–2.44 (m, 1 H), 2.36–2.27 (m, 2 H), 2.07 (s, 3 H), 1.99–1.88 (m, 2 H), 1.74–1.66 (m, 2 H), 1.41–1.33 ppm (m, 1 H); 13 C NMR (125 MHz, C 5 D 5 N): δ =176.4 (C), 169.0 (C), 128.6 (CH), 128.2 (CH), 85.9 (C), 79.9 (C), 70.5 (CH), 45.7 (CH), 42.8 (CH 2 ), 38.8 (CH), 28.5 (CH 2 ), 26.0 (CH 2 ), 24.9 (CH 2 ), 21.3 (CH 2 ), 19.5 ppm (CH 3 ); HRMS (ESI): m / z : calcd for C 15 H 20 35 ClNNaO 4 Na + : 336.0979 [ M +Na] + ; found: 336.0981.…”

Section: Methodsmentioning

confidence: 99%

Total Synthesis of (−)‐Salinosporamide A

Kaiya

Hasegawa

Momose

et al. 2010

Chemistry An Asian Journal

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A detailed description of our second-generation total synthesis of salinosporamide A is presented. Three contiguous stereocenters in the γ-lactam structure seen in the natural product were established by stereoselective functionalization of a D-arabinose scaffold, including an Overman rearrangement to generate a highly congested tetrasubstituted carbon center. One of the definitive reactions in the synthesis was a Lewis acid mediated skeletal rearrangement of a pyranose structure, which enabled the practical conversion of the carbohydrate scaffold to the γ-lactam structure embedded in salinosporamide A. The use of a benzyl ester as a protective group for a sterically hindered carboxylic acid led to a one-pot global deprotection at the end of the synthesis.

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“…[92,95] Eine neuartige Route zum g-Lactamteil von 4 über eine Indium-katalysierte Conia-En-Reaktion [96] im Schlüssel-schritt wurde von Hatakeyama und Mitarbeitern entwickelt (Schema 12). [97] Der chirale Propargylalkohol 101 [98] [99] Eine weitere Methode zum Aufbau das g-Lactamteils von Salinosporamid A (4) publizierten kürzlich Chida et al im Rahmen einer formalen Totalsynthese von 4.…”

Section: Angewandte Chemieunclassified

Salinosporamid‐Naturstoffe: potente Inhibitoren des 20S‐Proteasoms als vielversprechende Krebs‐Chemotherapeutika

Gulder

Moore

2010

Angewandte Chemie

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Proteasominhibitoren entwickeln sich rasch zu potenten Behandlungsoptionen in der Krebstherapie. Einer der vielversprechensten Wirkstoffkandidaten dieses Typs ist das Salinosporamid A aus dem Bakterium Salinispora tropica. Dieser marine Naturstoff hat einen komplexen, dicht funktionalisierten γ‐Lactam‐β‐lacton‐Pharmakophor, der für die irreversible Bindung zum Target, der β‐Untereinheit des 20S‐Proteasoms, verantwortlich ist. Klinische Studien der Phase I zur Behandlung von multiplem Myelom mit Salinosporamid A begannen nur drei Jahre nach dessen Entdeckung. Die starke biologische Aktivität und die faszinierende Struktur dieser Verbindung haben in den letzten Jahren intensive akademische und industrielle Forschungsarbeiten angetrieben, die zur Entwicklung von mehr als zehn Totalsynthesen, der Aufklärung des Biosyntheseweges und der Generierung vielversprechender Informationen zu Struktur‐Aktivitäts‐Beziehungen sowie onkologischer Daten geführt haben. Salinosporamid A ist daher ein faszinierendes Beispiel für das erfolgreiche Zusammenspiel von moderner Wirkstoffsuche und biomedizinischer Forschung, Medizinalchemie and Pharmakologie, Naturstoffanalyse und ‐synthese sowie Biosynthese und Bioengineering.

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Entry to Heterocycles Based on Indium‐Catalyzed Conia‐Ene Reactions: Asymmetric Synthesis of (−)‐Salinosporamide A

Cited by 99 publications

References 36 publications

Salinosporamide Natural Products: Potent 20 S Proteasome Inhibitors as Promising Cancer Chemotherapeutics

Salinosporamide Natural Products: Potent 20 S Proteasome Inhibitors as Promising Cancer Chemotherapeutics

Total Synthesis of (−)‐Salinosporamide A

Salinosporamid‐Naturstoffe: potente Inhibitoren des 20S‐Proteasoms als vielversprechende Krebs‐Chemotherapeutika

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