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Totally Synthetic by Paul H. Docherty, 29 June 2008

Total Synthesis of Manzacidin C


K. Tan, P. J. Lombardi, J. Leighton, Org. Lett. 2008, 10, 3165-3167.

DOI: 10.1021/ol8011869

A nice paper in Org. Lett., basically the story of one key transformation, but let’s look at the target first. Manzacidin C would appear to have a fairly interesting biological profile, including α-adrenoceptor
blocking, but apparently there hasn’t been enough isolated to run more trials. An ideal territory for total synthesis - and there has been quite a few. There’s a good OBC paper reviewing the state of play as of the end of last year, but the most important work has been done by Ohfune and DuBois.

This paper is all about the acylhydrazone-enol ether [3+2] cycloaddition developed by the group, which is an astonishing method for the construction of 1,3-diamines with good stereochemical control. Initial work on an asymmetric approach to the reaction was published by Jun Kobayashi back in 2002, where he used a chiral Lewis Acid to promote the reaction (BINOL and a Zr alkoxide as catalyst). That paper was somewhat limited in scope, as the reaction was only intramolecular, with the Thorpe Ingold effect to push the kinetics.  However, a few years later, he published an intermolecular reaction. However, although the ees were impressive, the drs weren’t, with the majority around 60:40.

Leighton seems to have improved on that considerably. In this case, the yield, dr and ee are all impressive, generating that pyrazolidine ring system with apparent ease. However, it must be noted that the reaction isn’t catalytic - they need to use an excess (1.5 eq) of the chiral silane. They don’t get to recover it either - but they do get a good return of the pseudoephedrine precursor.

With the key functionality in place, it was time to cleave the hydrozine. As might be expected, the weak N-N bond was cleaved using SmI2 promoted radical chemistry. The ring was then reformed as the analogous tetrahydropyrimidine, completing the core of the molecule. This cyclisation was also used in the DuBois paper.

Final functionalisation used an acid to hydrolyse the ester and remove the thiophene (which was required to perform the [3+2] cycloaddition). Couple the pyrrole-carboxylic acid - job done, nice total synthesis!