Totally Synthetic by Paul H. Docherty, 2 February 2009
Total Synthesis of Valerenic Acid
J. Ramharter, J. Mulzer, Org. Lett. 2009, 11, 1151-1153.
Mulzer’s work is somewhat focused on small, complex and (mostly) highly oxidised natural products. Today’s synthesis is that of a GABA receptor modulator, valerenic acid. For the uninitiated, the GABA receptor (γ-aminobutyric acid) is a key component in neurotransmittion, but has a variety of types and subtypes, each responsible for different physical manifestations. I’ll quote Mulzer’s suggestion that it could have a role in ‘panic disorders, hyperactivity, poor motor coordination, learning deficits, spontaneous epileptic seizures…’. Importantly, it’s also a pretty small molecule - 234 gmol-1 - so there’s plenty of room for medicinal chemists to modify the structure.
Mulzer first completes the synthesis in a racemic manner, and then repeats using enantiomerically pure starting materials. In the supporting information, we find that the synthesis is five steps from (R)-glycidol, but in a reasonable yield (32%). A Grubbs I catalysed enyne metathesis completed the cyclopentene with a propenyl sidechain. This diene is perfectly set for a Diels-Alder reaction. Initially, they had planned to do this reaction in an intramolecular fashion, but this approach ultimately failed; they then turned to metal coordination, which following Mulzer’s transitions state (shown below) gave them the product as a single diasteromer.
This pretty-much completed the core of the target, with only a further seven steps required to complete the total synthesis. Most of this is straight forward, but I did like the control of stereochemistry. Reduction of the lactone, and in situ addition of a stabilised Wittig reagent allowed appendage of the sidechain, preserving the allylic stereocenter. Then, use of the Crabtree catalyst in a hydrogen atmosphere delivered the reduction from the desired face. Ultimately, two of these five stereocenters were extraneous, and were removed by oxidation of the alcohol and formation of the more substituted enol triflate. The methyl group was then delivered using a Negishi coupling.
Nice work, as ever…