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Totally Synthetic by Paul H. Docherty, 15 March 2007

Total Synthesis of Attenol A


T. E. La Cruz, S. D. Rychnosvsky, J. Org. Chem. 2007, 72, 2602-2611.

DOI: 10.1021/jo0626459

You have to love full papers, and this synthesis by Scott Rychnovsky benefits greatly from the space for explanation. They could easily have contracted the publication to a letter or communication, but so much would have been lost. Anyway, on with the science; the target - Attenol A - contains that most annoying of features, a non-anomerically stabilised spiroketal. So making that ring system was going to need a special touch, and Rychnovsky decided to apply a reductive cyclisation to it. The molecule has again been a popular target, with previous syntheses by Uemura, Enders and Eustache.

Interestingly, their route to the cyclisation precursor was also a sort of spiro-acetal - actually an ortho ester (I hate that nomenclature…). They tried to make this at first with a complex cyclic enol with a pendant sidechain. However, the addition was ineffective, returning only a 35% yield, with the mass balance predominantly decomposition. However, a move to a less complex thioketene acetal was effective:

As can be seen from the brief retroanalysis, synthesis of the thioketene acetal was relatively straight-forward, starting from a chiral DHP. Cyclisation this time was far more efficient, and took only a few more transformations to deliver the cyclisation precursor. This required Lews acid mediated opening of the orthoester in the least hindered position, trapping with TMSCN, and conversation to a phosphate ester.

Treatment of this with LiDBB gave a cracking yield of the desired non-anomeric spiroacetal - which they rationalised with a bit of stereoelectronics and molecular modeling, which predict that formation of the axial alkyl-lithium species shown below is preferred. This may then follow two paths to the two products, either retention or inversion of configuration by electrophilic substitution; however, the inversion pathway would presumably to be far less facile. The other possibility, shown in the paper, was formation of the less favoured equatorial alkyllithium species, which would lead to the minor anomerically stabilised product via the same SEret mechanism.