Azadirachtin Pt. II
In this part of the discussion, I’m going to cover the synthesis of the more complex fragment from the retrosynthesis given in the previous post, that of the decalin fragment. The subunit is certainly a challenge all by itself, containing ten contiguous stereocenters, and complex oxygenation. Most of the work on this fragment was referenced back to previous papers by the group, and from what I read, most of the information is in this Perkin 1, and this Tetrahedron paper.
Their synthesis of this portion is well envisaged, starting with generation of four stereocenters from an IMDA. Importantly, the endo/exo control comes from their use of a silane precursor, which gave them the endo product in a 5:2 ratio. Without this functional group, the ratio was reduced to 1:7, so was fairly important.
It was also the control element in the next transformation, an intramolecular aldol, which created a further three stereocenters with good control. The desired diastereoisomer was received in a reasonable yield, along with a further 10% of the methyl ketal, which was converted to the hemiketal easily. The silyl group was transformed into the required hydroxyl with retention of stereochemistry using mercuridesilylation, (a modified Tamao-Flemming oxidation) – a reaction on my brown-trousers shortlist…
Also noteworthy in the Perkin 1 paper was the chain reduction of an aldehyde by formation of the corresponding silyl enol-ether and ozonolysis. Such a simple method, it must have been done before – but this is the first time I’ve seen it.
In the same paper, they then took this advance racemic intermediate and did a resolution to get the desired enantiomer – but I can’t tell if this is what they did to complete the total synthesis – any ideas?