Saturday, June 23, 2012

Trauner's Synthesis of the Hydrindane Substructure of Retigeranic Acid A

We have previously discussed synthetic strategies to access functionalized hydrindane structures in the context of the preparation of building blocks for steroid total synthesis. Hydrindanes also constitute substructural skeletal fragments of related natural products including limonoids and sesterpenoids. A popular synthetic target within the latter class of natural products is retigeranic acid (structure shown below). This complex pentacyclic terpenoid has been synthesized previously by the laboratories of Corey, Paquette, Hudlicky and Wender. Quite recently (JOC ASAP), Dirk Trauner's group in Germany described a new synthetic protocol to generate hydrindanes that might be useful for the synthesis of various sesterpenoids (including retigeranic acid) and derivatives thereof. The route exhibits a high level of stereocontrol and features a fascinating hydrogenation step that results in an unexpected stereochemical outcome.
The forward synthesis begins from the Hajos-Parrish diketone (2) which is accessed in enantiopure form by implementation of the Hajos-Parrish-Eder-Sauer-Wiechert (H-P-E-S-W) reaction. Nine subsequent operations are then required to advance to the silyl enol ether (3). The highly linear nature of the conversion of 2 into 3 is a shortcoming of the Trauner hydrindane synthesis. Nonetheless, 3 undergoes Saegusa oxidation and conjugate addition to secure the hydrindanone 4 in good yield and as a single diastereomer.
Interestingly, hydrogenation of the olefin 4 under standard palladium on carbon conditions afforded the ketone 5 containing the (R)-configuration at the isopropyl-substituted cyclopentanone carbon position. The authors postulate that the epimerization is the result of palladium-catalyzed isomerization of the isopropenyl group to the more highly substituted olefin prior to reduction. The unexpected result was confirmed by an X-ray crystal structure analysis. Deoxygenation of the ketone 5 is then achieved by palladium-catalyzed reduction of the corresponding enol triflate to deliver the cyclopentene 6. Finally, straightforward hydrogenation and acetal cleavage generates the trans-hydrindane building block 7 which contains the intact substructure of the sesterpenoid natural product retigeranic acid A. Notably, intermediate 7 has been converted into retigeranic acid A twice previously (here and here). The authors comment, with regard to the 'stereochemical serendipity' in the conversion of 4 into 5, that this work "emphasizes the importance of meticulous product analysis, even with seemingly straightforward reactions."

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