2. I think that a lot of people, myself included, think of RaNi as quite an exciting and unselective reagent, but actually desulfurisation can be done even in the presence of numerous double bonds. A neat application of this can be found in Stotter's formal synthesis of juvenile hormone I, a popular target of the late 60s and 70s, via Corey's intermediate. The way the group uses the same starting material to make two building blocks which are then reunited is cool, and conceptually quite similar to what Woodward did for erythromycin:
1. Despite appearing online back in July it's still in the ASAPs (DOI: ). This methodology has proved surprisingly popular and contributed to the synthesis of good number of natural products in the decades following the untimely demise of RBW. The review was written by a former Woodward postdoc who worked on the erythromycin project, Dale E. Ward.
I'd be very surprised if we see a Nobel Prize award to a synthetic organic chemist any time soon. The total synthesis/general organic crowd never seem very high up . As in the very first post in this series, Woodward interestingly didn't use the opportunity given him to lecture on the work that actually won him the prize, instead choosing to speak on his entirely new and unpublished work on cephalosporin C. I think Woodward entirely deserved his Nobel prize, which he gained through an unbelievable pertinacity where chemical problems and puzzles were concerned, as well as the willingness to take on daunting challenges. Woodward's chemical legacy was enviable and it's telling that no conversation or book on classic synthesis can fail to cover such masterpieces as his work on reserpine, strychnine, chlorophyll and B12. That aside, I've heard numerous chemists talk about his contributions to other Nobel Prize winning work, so I thought it might be interesting to write a post on this.
Coming just a year before his own Nobel Prize, in my opinion Woodward was a major contributor to Konrad Bloch's elucidation of the biosynthetic pathways surrounding the production of cholesterol, even appearing on the seminal paper reporting the now well -known cascade cyclisation of squalene. Even people who don't know much steroid chemistry (and I definitely put myself in this catergory) are probably aware of the beautiful (and much imitated) cationic cascade sequence used by nature to assemble that instantly recognisable tetracyclic ring system.
For its time I think this synthesis was amazing accomplishment; only 25 years earlier did Woodward himself describe the erythromycin problem as 'quite hopelessly complex'. Unfortunately, Woodward didn't live to see his synthetic plan come to fruition due to his untimely death some two years before the completion of the project. In his stead Kishi oversaw the completion of the target as it acknowledged as such:
As Hoffman's featuring in this citation was for his part in the Woodward-Hoffmann rules, I think it's fair to say that if Woodward were alive, the chance of his sharing in this prize would have been good. He featured on the classic 1963 paper with Hoffmann that first defined the rules as they're known today, and much of the inspiration for them came from observations made during work towards the total synthesis of Vitamin B12 carried out by Woodward and Eschenmoser. Few would debate this one, and I think it's fair to say that Woodward only missed out here by dying too young, as Nobel prizes are only award posthumously if the recipient dies after the announcement is made.
Woodward was a member of the highly elite few; organic chemists who won Nobel prizes not for a specific reaction, discovery, or work with a particular element but for simple mastery of organic chemistry - theory, synthesis, methodology, structural determination, biochemistry - the list goes on. The elegant citation for his prize summed this up nicely:
Compare Woodward's and Corey's syntheses, with their cyclic precursors, resolutions and huge lists of coauthors to, for example, the recent , accomplished entirely using acyclic stereocontrol by a single coworker. I wonder what we'll be doing in another 30 years...
During the optimisation of the previous step, Woodward discovered a new isomeric ring system, which he named the phlorins, where the aromaticity of the system had been disrupted by removal of one of the annulene double bonds. The first instance of this system characterised was as an intermediate in the above sequence, which although not usually isolated, could be obtained as the dihydrobromide salt by modification of the reaction conditions. Although, obviously a number of tautomers are possible for these systems, this one seemed to exist only in a single form, and was quite stable considering the general ease of gaining aromaticity. The reason for this, which is discussed at length in paper during the initial retrosynthesis, is what Woodward referred to as ‘peripheral overcrowding’. As I’ve tried to highlight in the phlorin below, the large meso propionate substituent clashes with the two ester groups on the nearby pyrroles. In tautomers where the meso carbon is sp3 hybridised then this strain is relieved as the subtituents can avoid each other to an extent. Conversely, this strain is exacerbated when this carbon is sp2 as all three substituents are forced to be coplanar, and this effect disfavours isomers where this the case. It is worth noting that although these compounds are stable enough to isolate and characterise, oxidation can still be effected using fairly mild oxidants such as the quinones DDQ and chloranil, or even molecular oxygen.
I hadn't planned to cover this synthesis, Woodward's last, so early in this series, but as a review on the use of thiopyrans as templates in polypropionate syntheses was recently published in Chem. Commun. it seems timely to mention it now. Woodward once said in a talk at CIBA in India that
3. Woodward's synthesis of quinine has generated a vast amount of discussion related to its validity. To start with, the paper was titled 'The Total Synthesis of Quinine', although in modern parlance it was only a formal total synthesis via some earlier work by Rabe. The main objection voiced was that Rabe did not publish experimental information for the steps in question, and Woodward never repeated them. This lead some chemists, particularly Gilbert Stork, who claimed (rightfully) the first stereoselective synthesis of quinine, to dispute the fact that Woodward's work constituted a synthesis of the natural product at all. For a brilliant account of the debate, and some interesting historical information then there's a FREE Angewandte paper by Seeman that's well worth reading (). Another, non-free Angewandte paper published the following year by Williams titled 'Rabe Rest in Peace' contained a detailed analysis of Rabe's work and ultimately was able to successfully reproduce the steps in question, confirming the validity of Woodward's claim to a (formal) synthesis (). The fact that two Angewandte papers have been published on this topic in the past 5 years shows just how hot the debate has been.
The quote itself most likely comes from a remark made by Woodward during a lecture he gave in London in 1968 on his progress towards the synthesis of vitamin B12. I'm probably not going to do a Woodward Wednesdays post on the B12 synthesis any time soon for reasons of time (as much as anything), but to give some context to the quote, a partial retrosynthesis is shown below. Woodward disconnected the molecule into eastern (B/C) and western domains (A/D), and set out to synthesise the western domain from the tricyclic indoline shown. Although B12 would be a daunting molecule to synthesis even diastereoselectively today, Woodward's aim was in fact to devise a route to the target in its natural, enantioenriched form—which in the 1960s meant either a dip in the chiral pool, or a resolution. Although the group was able to develop a route to either enantiomer of the slightly later intermediate XXXVII, starting from (+)- or (-)-camphor, for the final sequence they found that it was in fact more efficient to instead use a resolution of the earlier indoline, accomplished by derivatisation with (S)-α-phenylethyl isocyanate and separation of the resulting diastereomers.