Synthesis of Reserpine by Robert B. Woodward (1956)

All 5 total syntheses to date have used a Diels–Alder reaction to form the molecule's fused bicyclo[2.2.2]octane ring system. The reaction has also featured prominently in approaches by Baran, Trauner, Nicolaou, Chen, Movin, Sorensen and others.[2]

9: Strategies in Reserpine Synthesis - Chemistry …

Complete schematic view of the 1956 Reserpine's synthesis performed by Robert B. Woodward

Woodward’s group reported the first synthesis of Reserpine in 1956 (J

Interestingly, despite the hugely varied interests and specializations of the groups involved, all five of the successful total syntheses reported to date have constructed the molecule’s prominent bicyclo[2.2.2]octane ring system using the venerable Diels–Alder reaction (often in conjunction with the similarly tried-and-true tactic of oxidative dearomatization to establish the diene). That said, the number of Diels–Alder variants employed is impressive, and you could almost imagine giving a short lecture course on the reaction using nothing but examples from synthetic studies on maoecrystal V. I’ve tried to illustrate the variety below.

The Stork Synthesis of (-)-Reserpine - Organic chemistry

From the outset of this campaign, Woodward was said to have regarded the synthesis of reserpine as a problem in stereochemistry, and here is a near-perfect solution that establishes, in just four steps, all five contiguous sterocentres around the E-ring. Despite some rather low yields, tens of grams of the required tetracyclic intermediate could still be obtained using this chemistry.

Reserpine has also been described as inhibiting catecholamine synthesis by blocking the uptake of dopamine into the storage vesicle.

Reserpine synthesis pdf | qunhzeq | Flickr

and (2000)A formal synthesis of reserpine: hydrindane approach to the Woodward’s ring-E precursor. In: Journal of Chemical Society: Perkin Transactions 1 . pp. 1399-1404.

Total synthesis of Reserpine: Reference: Woodward, R

Woodward’s synthesis began with a reaction that he had been fascinated by since the very beginning of his studies in chemistry: the diene synthesis, or as it’s now known, the Diels-Alder reaction. At the age of just 25 he published a paper on its mechanism in JACS (as the sole author), and he’d also recently applied it successfully to the arena of steroid chemistry where it had been the first step of his successful 1952 formal synthesis of cortisone and cholesterol. Here, benzoquinone was used as the dienophile, and freshly prepared vinylacrylic acid as the diene, and the reaction was conducted on grand scale. From the full paper (emphasis mine):

A catalytic, enantioselective synthesis of (+)-reserpine is reported

However, comparison of reserpine effects on sleep with those induced by precursors and blockers of serotonin, and by monoamine oxidase inhibitors suggests that the loss of SW sleep may have resulted from depletion of serotonin, whereas acceleration of the REM cycle may have been caused by a compensatory increase in its rate of synthesis.

The total synthesis of reserpine - ScienceDirect

Sharp eyed readers will note that a large part of this synthesis is adapted from the Zakarian group's previously reported total synthesis of racemic maoecrystal V from back in 2013, and in fact it reuses the same intramolecular Diels–Alder key step to construct the fused furanobicyclo[2.2.2]octane ring system: