Platensimycin Pt. VI… return of the bacterium…
Lee, Kim, Jang, Choi and Chung. ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200800568.
Yep, you all know about platensimycin, and half of you have probably worked on / are working on syntheses of this ‘popular’ target. Eun Lee hasn’t bothered with a full total synthesis, instead satisfying a neat formal of the right-hand ‘cage’ motif. Key to this was the optimisation of a substrate for a rhodium catalysed carbonyl-ylide cycloaddition.
They suggest that they knew that a terminal olefin would have the incorrect electronic configuration to lead to the desired product in the [3+2] before attempting the chemistry. However, they did the reaction anyway, and ended out with a cracking yield of the wrong isomer and only a trace of the desired. Playing with the HOMO coefficient by using a vinyl halide in place of the terminal olefin allowed the chemistry to proceed in a tasty 83% yield, with small amounts of the competing products. They then had to remove the extraneous halide – using hypophosphite.
All the optimisation of this reaction was performed on racemic material – but their synthesis of enantiopure substrate was quite nice. They took (S)-propylene oxide and opened it with the enolate of isopropyl cyanoacetate. This of course leaves a free hydroxyl anion, which closes onto the isopropyl ester to give the gamma-lactone – a reaction I did not so long ago with dimethyl malonate. It’s trickier than you might imagine… They then went one-further, and alkylated in-situ with iodoallyl iodide to give the desired product in pretty decent yield (and what appears to be 5:1 d.r.). Transformation of this into the key substrate was straight forward.
However, transformation of the cyclisation product into the formal synthesis intermediate was more challanging. An HWE olefination onto the ketone gave an enone in good yield, but reduction of said enone was apparently trying – an hydrosilylation and hydrolysis of the silyl enol ether was required. A few more steps took them to the desired intermediate – but in which synthesis? Did I miss that reference?
Kim, C.H., Jang, K.P., Choi, S.Y., Chung, Y.K., Lee, E. (2008). A Carbonyl Ylide Cycloaddition Approach to Platensimycin. Angewandte Chemie International Edition DOI: 10.1002/anie.200800568
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