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Totally Synthetic by Paul H. Docherty, 23 June 2009

Total Synthesis of Gloeosporone


J. Trenkle, T. F. Jamison, Angew. Chem. Int. Ed. 2009, 48, 5366-5368.

DOI: 10.1002/anie.200902079

When a target has been made as many times as gloeosporone by Seebach, Fürstner, Schreiber, Ley and Holmes, it’s a good idea to come along with something new. Thankfully, Tim Jamison has got such interest in macrocycles, and an impressive creativity with them - as demonstrated in his total synthesis of acutiphycin, covered here back in 2006. He’s moved on from the ene-type cyclisation used in that synthesis to perform a Ni-catalysed epoxide opening.

In the fragment construction phase, a Jacobsen hydrolytic kinetic resolution (HKR) allowed asymmetric construction of an octeneal. This stereocenter is a bit too remote to direct alkylation of the aldehyde, so Jamison used diamylzinc and a trans-cyclohexane-1,2-diamine to provide very high d.r. in good yield (citing Yoshioka). A coupling with an alkynyl acid provided the cyclisation precursor in short order.

The cyclisation chemistry was developed by Jamison initially to perform smaller cyclisations, in which he suggests that the initial process is ligation of Ni to the epoxide, then association of the alkyne and an exo-dig ring closure. That mechanism is supported by the short ‘tether’ between the alkyne and epoxide - which is necessarily far longer when closing a macrocycle. Jamison probed this effect by varying the macrocycle size and the position of the ester moiety along the chain. The ester is key to the reaction, and might initially ligate the Ni, holding it in a position where both the alkyne and epoxide can interact. However, a problem eventuated: to get a decent yield, they needed to use a stoichiometric amount of the nickel catalyst including that smelly cyclooctadiene and tributylphosphine.

The missing tetrahydrofuran was constructed with a very interesting method. That furan was put in by closing an alcohol onto a 1,2-diketone - so we need to install a further ketone, adjacent to that currently present. That presents a huge regioselectivity problem, but using Bredereck’s reagent resultet in fantastic selectivity (see this paper in JOC).

Rather than the usual ozonolytic cleavage of the freshly installed exocyclic olefin, Jamison used Rose-Bengal to make singlet from triplet oxygen. This induces [2+2] cycloaddition with the olefin to give a strained peroxide, which performs a retro-[2+2] cycloaddition to yield the desired ketone. An interesting total synthesis and some very useful methods!