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Totally Synthetic by Paul H. Docherty, 30 August 2009

Total Synthesis of 6-Deoxyerythronolide B


E. M. Stang, M. C. White, Nat. Chem. 2009, 1, 547-551.

DOI: 10.1038/nchem.351

6-deoxyerythronolide B (6-dEB) is a typical polyketide macrolide, as the configuration of the stereocenters is very much the norm. This meant two things: 1) the group could use typical polyketide chemistry to build the stereocenters and 2) this would serve as an excellent example for macrocyclisation chemistry.

The first task, of course, was to build the linear polyketide, unsurprisingly using a route rich in aldol reactions. Working from right to left, the group first used a Myers alkylation to append an allyl group in a stereoselective manner. Two Evans-type boron syn-aldol reactions allowed construction of the central unit, whilst a further Myers alkylation allowed the C-6 stereocenter to be installed along with an aldehyde, ready for the next aldol reaction. This final aldol reaction connected two larger, and quite highly functionalised units with several competing stereochemical interactions. Using standard conditions (see this paper in Tetrahedron) returned a reasonable yield of the product (49%, 7:1 d.r.). However, the group went further, trying to improve the reaction using Ti(Oi-Pr)Cl3.

Reduction of the keto groups and removal of the chiral auxilliary finished the linear precursor. With a free seco-acid, they were ready to build the macrocycle - except for the missing C-13 hydroxyl group, that is needed to form the ester. However performing a stereoselective C-H oxidation and generating the lactone in situ is a goal, on which the group have worked for some time.

They needed to use a huge amount of catalyst in a highly concentrated reaction mixture to isolate product in a near perfect d.r. in 34% yield, along with 45% of recovered starting material. The substrate has been reused in a subsequent run, so the yield could be improved to 56%. Very nice work.

The paper then goes on to discuss the rationale for this stereochemical result, using a rather interesting method. Presuming that the reaction proceeds via a macrocyclic tether, the group using a source of flouride to deactivate this selectivity. The fluoride presumably attacks the catalyst, disrupting the tether, and is evident in the dramatic drop in diastereoselectivity. The suggestion is that it is the conformation of this tether, and the product-like transition-state that account for the stereoselectity. Computational studies suggest a 3 kcal mol-1 preference for the desired stereochemistry. When forming the π-allyl intermediate, this complex can epimerise, with the desired conformation leading to product.

A further three steps were needed to finish this nice total synthesis.