A very nice synthesis of this popular target, (-)-terpestacin, from Prof. Barry Trost’s group at Stanford University. The synthesis demonstrates a very clever use of 1,2-cyclopentadione as its enol ether form, which is embedded in the molecule in installing two different side-chains. In addition, the synthesis also features several selectivity challenges, which have been overcome in creative ways.
The key reaction early on involves a Pd-AAA (Pd-Asymmetric Allylation Alkylation)-Claisen rearrangement sequence to install a quarternary center stereoselectively with a chiral ligand. This was followed by a protection of the resulting primary alcohol in one pot in 95% yield and 88-96% ee. The product was then subjected to Saegusa oxidation with Pd(OAc)2 and Sakurai allylation with MgBr2-Et2O to give back the enol ether. This was the first time the alpha-carbonyl cyclopentenone of this type was used as a Michael accepter in a Sakurai-type reaction. Upon a few functional group manipulations, they arrived at key intermediate allylic bromide below.
- Grubbs’ 2nd generation catalyst was found to be best.
- The condition required to give the highest chemo-selectivity to afford the desired ring size (15-membered) instead of any other combinations was when the catalyst loading was 10 mol% in benzene at rt.
- The allylic OH is required to effect the 15-membered formation.
- When the OH is protected or the when the reaction was performed at higher temp, the reaction did not give any 15-membered ring.
- Even with all these prerequisites, the 15-membered carbocycle was only formed in modest 35-44%.
The OPMB was then deprotected, followed by another Pd-AAA and Claisen sequence to give the fully-substituted cyclopenten-1,2-dione enol ether, which was protected again as OPMB, together with the protection of the allylic alcohol as acetate ester. In the next step, the 1,2-disubstituted alkene had to be oxidatively cleaved without disturbing other tri-substituted alkenes, which is normally more reactive toward oxidation. The restricted rotation of the tri-substituted alkenes in the macrocycle is believed to give some bias against them, preventing them from being oxidized easily. Based on this reasoning, the 1,2-disubstituted alkene in the side chain should react more readily.
They found that the Sharpless AD-mix alpha worked well to provide the diol chemoselectively. Upon oxidative cleavage with periodate, and reduction with sodium borohydride of the resulting aldehyde in the presence of ketone, they obtained the desired primary alcohol. From there the acetate ester cleavage with LiOH, followed by PMB deprotection with MgBr2-Et2O/DMS then afforded them the natural product (-)-terpestacin.
This is quite an impressive synthesis, with a clever use of the 1,2-cyclopentane-dione. The authors also demonstrated that several selectivity issues could be overcome with careful planning and genuine creativity.
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