Sylvaticin
Donohoe, Harris, Burrows and Parker. JACS, 2006, ASAP. DOI: 10.1021/ja0660148.
Oxidation action in this latest JACS from Tim Donohoe, completing the first synthesis of sylvaticin, a potent antitumor agent and nanomolar cytotoxicity target. The focus is, of course, the THF rings, lying four carbons apart, and with neighbouring hydroxyls. Their route hinges upon an interesting oxidative cyclisation, developed within the group and detailed in a previous methodology paper.
The fun begins with the synthesis of the cyclisation substrate, with the bulk of the work done by a pair of AD reaction performed on a commercially avaliable tetraene. Although the yield for this reaction was low, that can be attributed to the isomeric nature of the starting material. Clevage of the alkene was also low-yielding, but recycling the tetraol biproduct increased this, allowing Wittig olefination and completion of the cyclisation precursor.
Cyclisation, as completed in the previous paper, resulted in a excellent yield of the desired product (the notes mention use of cinammic cinnamic acid as reducing agent – taking Os(VIII) to Os(VI) via dihydroxylation). Creation of the more complex sidechain was completed in six step and reasonable yield, allowing Grubbs II appendage to the related alkene, and completion of the natural product after diimide reduction and deprotection. A great showcase for a top THF-ilysing reaction.
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Nice synthesis! I particularly like to see that much confidence placed in the cross-metathesis reaction to couple together two reasonably complex fragments… although the fact that you have to use 4 equivalents of one of them is a bit of a downer.
Shame no-one knows how to spell cinnamic these days…
off topic: I was surprized to hear from one of the students this saying “…after my compound was deBOCed…”, deBOCed = deprotection of Boc group…damn, yea lets come up with extra verbs here…deTBSed, deBOMed, deALLOCed
aaa
[...] Somewhat similar in structure to silvaticin, blogged here back in October, intricatetraol is an interesting C2 symmetric bis-THF. This feature lead to a somewhat unsurprising disconnection along the axis of symmetry, to reveal a dimerisation metathesis and reduction strategy. As dull as that might be, the rest of the synthesis was a whole lot more exciting, if based predominately on epoxidation/opening. However, it’s quite the master-class, so lets look at the epoxidation strategy at a whole. As you can see, the SM is trans,trans-farnesyl acetate, which might actually be the biological SM too. [...]
[...] isn’t the first poly-THF we’ve examined at Tot. Syn., but it is the most complex (see sylvaticin back in 2006 for the other example). To the casual eye, the molecule looks deceptively symmetrical, but it [...]