Zakarian and Stivala. JACS, 2008, ASAP. DOI: 10.1021/ja800435j.
What a beast of a molecule! This ‘un’s been around for a while, though, and has several synthesis to it’s credit – most notably that of Kishi. With a target this size, we’ve got to start with a thorough retrosynthesis. Splitting the molecule in half, separating the two polycyclic systems, the unification was planned via an alkylation of an aldehyde, which could be reoxidised for formation of the A-ring imine. RCM could then be used to complete the macrocycle.
The BCD- dispiroketal would be generated from a 1,4-diketone, built from two fragments unified in a sp2-sp3 Suzuki coupling. The other fragment, which would contain the AGEF system, was built in a more stepwise manner; the A ring from a Staudinger reduction of an azide and cyclisation onto a ketone. The G ring was installed via an intramolecular aldol, with the key quaternary stereocenter generated in a Ireland-Claisen rearrangement. The rearrangement precursor (an unsaturated ester) is easily deconstructed into an alcohol partner stemming from D-ribose, and an acid partner built using an auxiliary-controlled alkylation.
You’re probably thinking “damn, that’s a lot of work” (or at least I did) – but a good chunk of the fragment synthesis was presented in other papers leading up to this synthesis. The manipulation of D-ribose and construction of the G ring is in a Tet Lett paper from last year, and the BCD dispiroketal was presented in an Org Lett then too. I think it’s worth a quick look at that paper, as the results from the spiroketalisation reaction is interesting. Both Kishi and Inoue/Hirama used similar chemistry to build this system (in which the desired product contains double anomeric stabilisation), but got different results, attributed to silyation of the C-15 hydroxyl in Kishi’s case. However, Zakarian also noticed that the two groups used different solvent systems, and so he tried a variety of solvents, removing the protecting groups in MeOH, and then continuing the reaction in a second solvent. The effect this had is startling – with non-polar solvents favouring the desired product far more than sticking with methanol.
Construction of the other large fragment was examined more thoroughly in this JACS paper. With the key cyclisation precursor produced by the means suggested in the retrosynthesis, they were ready for a bit of Ireland anion-accelerated rearrangement action. They treated the unsaturated ester with a chiral Koga-type chiral lithium amide, resulting in a Z-enolate, which was trapped as the trimethylsilyl ketene acetal. Warming to RT, this then underwent the crucial 3,3-sigmatropic rearrangment, leaving the desired quaternary centre in excellent yield.
Reductive cleavage of the new double bond and deprotection of the PMB group left a pair of primary alcohols, which after Swern oxidation performed a sweet regioselective dehydrating aldol to give the desired G-ring.
With the bulk of the two main fragments complete, their next task was to unify, using a distinctly old-school lithium/halogen exchange, and addition into an aldehyde partner. The alcohol product was then reoxidised to a ketone, essential for later imine formation. Before that, though, they needed to complete the macrocycle with a bit of Grubbs. Although this reaction didn’t go badly, it’s of no real surprise that more than one product was formed, if one considered the degree of unsaturation. Normally this wouldn’t be the kind of scheme I’d bother drawing, but I have a particular liking for the structure of the biproduct – it’s just nice!
With the macrocycle complete, it was time to form the EF ketal, removing the benzylidene ketal with LiBF4 in wet IPA – apparently conditions attributed to Lipshutz – and causing spontaneous cyclisation onto the C-25 ketone. And as I said in the preamble, the A ring was finally installed by cyclising a free amine (generated by displacement of a tosylate with azide, and then Staudinger reduction) onto a ketone – but requiring quite harsh conditions, also used by Kishi in his synthesis.
Perhaps not filled to the brim with new chemistry, this paper is still an awesome piece of work completed by an amazingly small team!
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