Synthesis of Reserpine by Robert B. Woodward (1956)

This inaugural Woodward Wednesdays post will discuss the subject of Woodward's 1965 chemistry Nobel Prize lecture - work culminating in the synthesis of (+)-cephalosporin C.[1] It was difficult to choose a synthesis to open the series with, as a lot of Woodward's papers are, quite rightly, considered classics and have been dissected elsewhere. Woodward's synthesis of strychnine, for example, crops up in a of , has a and is discussed at length in Nicolaou's Classics in Total Synthesis (Chapter 2) as well as T. Hud's Way of Synthesis (pages 803-808) and probably many other places besides; I'm not sure I can add much there that hasn't already been said! Woodward's reserpine synthesis, one of my top five syntheses of all time, is (unfortunately?) also covered in a similarly comprehensive fashion.[2] Strangely, the cephalosporin synthesis remains much less well known, despite containing some excellent chemistry and a few 'Woodwardian' steps.

THE TOTAL SYNTHESIS OF RESERPINE - Journal of the …

THE TOTAL SYNTHESIS OF RESERPINE

Total synthesis of Reserpine: - UW-Madison Chemistry

The two major challenges posed by the vitamin B12 structure were the novelty of the ligand chromophore and the stereochemical complexity of the ligand’s periphery. Woodward’s main focus was the latter. This led him to create a great synthesis of the so-called “Harvard component” —the part of the B12 molecule that is the most complex and contains rings A and D. This synthesis, both in design and execution, appears today as the apotheosis of all that constituted the Woodwardian art and science in natural products total synthesis. Forever in the history of chemistry it will also remain connected with that creative insight of Woodward that eventually grew into the message of the Woodward-Hoffmann rules, changing the way organic chemists think about the reactivity of organic molecules.

Synthetic scheme for total synthesis of Reserpine ..

As Woodward began to tackle the synthesis of more and more complicated biologically important natural products, he ultimately chose to attack vitamin B12. At Harvard this work started in 1961 and gradually evolved into a unique collaboration between Woodward’s group and the group of Eschenmoser at ETH. This work culminated in the announcement by Woodward of the total synthesis of cobyric acid (1973).

Total Synthesis of Reserpine - R.B. Woodward - YouTube
a simplified route to a key intermediate in the total synthesis of reserpine

“The Total Synthesis of Reserpine,” in Tetrahedron ..

Yes, that synthesis is absolutely first rate. Not sure how I can justify a blog post on it yet, but I’ll find a way. The synthesis of the decalin core is highly Woodwardian (and extremely reminiscent of Woodward’s tactics for reserpine, at least at the beginning).

1 May 2006 The spectacular first total synthesis of reserpine was achieved by R.B

Total Synthesis of the Reserpine

Reserpine is an indole alkaloid isolated in 1952 from the extract of or ‘Indian snake root’, a popular plant in traditional Indian medicine used as a sedative and antipyretic, and reportedly taken by Mahatma Gandhi himself. It's also enjoyed some attention from Western doctors as an antihypertensive and antipsychotic, notably being the first ever drug to successfully demonstrate antidepressant properties in a randomized placebo-controlled trial (although it’s rarely used nowadays because of its numerous side effects, which are as varied as they are unpleasant). Its structure was solved in just 3 years (a remarkably short period for the pre-NMR era) and, when it was finally reported in the summer of 1955, Woodward immediately set to work. By the end of 1956, just a year later, he was able to report a detailed series of studies culminating in the landmark first total synthesis of the natural product, again pushing forward the complexity limit at which synthetic chemists could operate. In the years that followed, reserpine became a classic target, worked on by some of the greatest chemists of the past 50 years.[1] In fact, it remains a popular molecule to this day, as indicated by a new total synthesis reported just a month or so ago by Jacobsen and co-workers, ().

This work culminated in the announcement by Woodward of the total synthesis of ..

The total synthesis of reserpine

Following Woodward’s pioneering synthesis of reserpine (2), subsequent syntheses of 2 and related yohimbinoid natural products have appeared in the literature. However, because many of these syntheses adopted a strategy that is similar to the Woodward approach, they were also plagued with a stereoselectivity problem (or in some cases, a regioselectivity issue) in installing the C(3) center, which had to be corrected to obtain the desired diastereomer. In 1989, Stork reported an inventive solution to the reserpine C(3) problem, that took advantage of the ionization of an intermediate aminonitrile (i.e., 3, )., The subtleties in stereocontrol in the Pictet-Spengler reaction afforded by aminonitriles allowed Stork to selectively access the undesired as well as the desired C(3) epimer necessary for the total synthesis of reserpine. While the Stork approach sets the foundation to address the C(3) problem, it remained unclear whether this tactic could be extended to the synthesis of other yohimbinoid natural products given the significant influence of the indole nucleophile on the diastereoselectivity of the Pictet-Spengler ring closure from an aminonitrile as discovered in our own work (vide infra). A general solution to this problem would yield a strategy for the preparation of the yohimbinoid alkaloids, given that structures in this class vary in the substitution about the indole moiety (see 4-13, ), and include several members that are epimeric at C(3).,,,,, Herein, we disclose our efforts toward a general synthesis of the D/E cis-fused members of the yohimbinoid alkaloid family (i.e., 8-13, ). This approach is showcased in the first total syntheses of the C(3) epimeric natural products venenatine (9) and alstovenine (12) in racemic form.,,,,,