Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 17, Issue 25, Pages 6964-6972Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201100178
Keywords
asymmetric catalysis; cross-coupling; metathesis; natural products; total synthesis
Categories
Funding
- MPG
- Chemical Genomics Center (CGC Initiative of the MPG)
- Fonds der Chemischen Industrie
- Alexander von Humboldt Foundation
- Association pour la Recherche sur le Cancer
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Iejimalide B (2) is the most promising member of a small family of marine polyene macrolides endowed with remarkably selective activity against human cancer cell lines. As this product, however, is hardly available from the natural sources, a detailed evaluation requires the development of an efficient and practical synthetic approach. This challenge has now been met by adapting the first total synthesis of 2 previously reported by our group to the needs of high material throughput. Redesigning the access routes to the five required building blocks in combination with a careful optimization of the fragment coupling processes provided gram amounts of this valuable compound in a sequence of no more than 16 linear steps with an overall yield of about 7%. Key elements of the successful strategy include: i) three hydrostannylation processes of elaborate terminal alkynes with lower order stannyl cuprates, ii) a Brown allylation, a Noyori transfer hydrogenation, and a Marshall propargylation to set the chiral centers at C9, C17, C22 and C23, and iii) a modified Takai-Utimoto olefination for the preparation of the very labile skipped 1,4-diene flanking the ester group. The assembly process benefited from a particularly mild protocol for the Stille cross-coupling previously developed in this laboratory, which clearly outperformed the alternative Suzuki reaction in terms of yield and scalability. The 24-membered macrocyclic frame was forged by a remarkably selective ring-closing metathesis reaction (RCM), in which two out of the ten double bonds present in the cyclization precursor were selectively activated with the aid of a second-generation Grubbs catalyst.
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