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Issue 44, 2017
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Total synthesis of 7-des-O-pivaloyl-7-O-benzylbryostatin 10

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Abstract

The first total synthesis of a derivative of a 20-deoxybryostatin, namely 7-des-O-pivaloyl-7-O-benzylbryostatin 10 is described. Preliminary studies demonstrated that the modified Julia reactions of 2-benzothiazolylsulfones corresponding to the C17–C27 fragment with aldehydes corresponding to the C1–C16 fragment, provided an efficient and stereoselective assembly of advanced intermediates with the (E)-16,17-double-bond. The synthesis of the C1–C16 fragment was then modified so that the C1 acid was present as its allyl ester before the Julia coupling. A more efficient synthesis of the C17–C27 sulfone was developed in which a key step was the bismuth mediated coupling of an allylic bromide with an aldehyde in the presence of an acrylate moiety in the allylic bromide. A scalable synthesis of an advanced macrolide was completed using the modified Julia reaction followed by selective deprotection and macrolactonisation. The final stages of the synthesis required selective hydroxyl deprotection and the introduction of the sensitive C19–C21 unsaturated keto-ester functionality. Unexpected selectivities were observed during studies of the hydroxyl group deprotections. In particular, cleavage of tri-isopropylsilyl ethers of the exocyclic primary allylic alcohols was observed in the presence of the triethylsilyl ether of the secondary alcohol at C19. Model studies helped in the design of the methods used to introduce the C19–C21 keto-ester functionality and led to the completion of a total synthesis of a close analogue of bryostatin 10 in which a benzyloxy group rather than the pivaloyloxy group was present at C7.

Graphical abstract: Total synthesis of 7-des-O-pivaloyl-7-O-benzylbryostatin 10

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Publication details

The article was received on 25 Aug 2017, accepted on 27 Oct 2017 and first published on 27 Oct 2017


Article type: Paper
DOI: 10.1039/C7OB02129A
Citation: Org. Biomol. Chem., 2017,15, 9497-9526
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    Total synthesis of 7-des-O-pivaloyl-7-O-benzylbryostatin 10

    A. P. Green, S. Hardy, A. T. L. Lee and E. J. Thomas, Org. Biomol. Chem., 2017, 15, 9497
    DOI: 10.1039/C7OB02129A

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