Gademann, Bonazzi, GÃ¼ttinger, Zemp and Kuta. ACIEE, 2007, EarlyView. DOI: 10.1002/anie.200703134.
I’ll start by admitting that when I saw this structure in the Angewandte EarlyView list of abstracts I though “great, aldols and wittigs…” and moved on to the next article. I was partially correct, in that there are certainly aldol reactions in this paper, but there’s a whole lot more too. Gademann starts by talking about “selectivity or pRB tumor suppressor inactivated, immortalized cells”, which means little to me, so I’m glad he goes on to explain that this means “apoptosis in such tumor cell lines in picomolar concentrations, and, remarkably, induce only growth arrest in normal cells”. Now that’s a biological activity profile worth considering.
The synthesis is also rather sweet, starting with the left-hand dihydropyranone fragment. This was constructed via a DHP, developed in a Jacobsen Cr-mediated AHDA:
Nice result! But the stereochemistry wasn’t quite right – the acetal center needed inverting. Simple treatment of this with acidic IPA did the job… They then lost the TES group with a bit of TBAF, and hydrozirconated to give them the coupling partner for a little Negishi action with a vinyl dibromide. Interestingly, adding a substoichiometric amount DiBAL-H to the reaction gave the best result… A second Negishi coupling provide the required trisubstituted double bond, and also “isomerized” to the cis- configuration. This interesting result is discussed here and here by Negishi himself, but the exact mechanism at play is still unconfirmed.
Now for the other partner, a bit of Evans aldol chemistry. Rather than Evan’s own oxazolidinone, they used the Seebach DIOZ auxiliary, which they recommend due to it’s propensity for crystalline products and higher selectivities. One alkylation and two aldols later, they had their vinyl iodide and were set for the final coupling – a sweet sp2-sp3 Suzuki, completing the carbon skeleton of the natural product in great yield. A bit of deprotection, and they were there. Nice!
FUWBLKXIWLBGHS-SPHGEHAYBQ VFHNTFNIMUIGLU-LEMHNUOUBV QPHOYKZYKMOFQP-HZPDHXFCBY
CEYICUHJZXKDSF-KGLIPLIRBU OFBLDHGLZHJKQU-QUZIXLBSBZ XQKBCWFPCLBWQE-LHMACSPOBV