Leighton, Tran and Lombardi. Org. Lett., 2008, ASAP. DOI: 10.1021/ol8011869.
A nice little Org Lett, this; basically the story of one key transformation, but let’s look at the target first.Â Manzacidin C would appear to have a fairly interesting biological profile, including Î±-adrenoceptor
blocking, but apparently there hasn’t been enough isolated to be able to assess this fully.Â Ideal territory for a bit of total synthesis action, then – and there’s been quite a few.Â 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 (we’ll come back to the DuBois paper).
This paper is all about the acylhydrazone-enol ether [3+2] cycloaddition developed by the group, which appears to be a cracking way to develop a 1,3-diamine with good stereochemical control.Â 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 + a bit of Zr alkoxide).Â That paper was kinda limited in scope, as the reaction was only intramolecular, with a bit of Thorpe Ingold there to push the kinetics.Â Â However, a few years later, he’d gone intermolecular; however, although the ee’s were impressive, the dr’s weren’t, with the majority around 60:40.
Leighton seems to have improved on that considerably.Â In this case, the yield, dr and ee are all impressive, generating that pyrazolidine ring system with apparent ease.Â However, it must be noted that the reaction isn’t catalytic – they need to use an excess (1.5 eq) of the chiral silane.Â 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.Â As might be expected, the weak N-N bond was ruptured (good word!) using a bit of radical chemistry – using what I’ll always think of as the French reagent. (I realise that the French may have made some other reagents too…).Â The ring was then reformed as the analogous tetrahydropyrimidine, completing the core of the molecule. (No yields were given for the individual steps, but they look to be favourable.)Â This cyclisation was also used in the DuBois paper.
Final functionalisation used a spot of acid of hydrolyse the ester and remove the thiophene-thing (which was required to give the [3+2] enough omph).Â Couple the pyrrole-carboxylic acid – job done, nice work.
Tran, K., Lombardi, P.J., Leighton, J.L. (2008). An Efficient Asymmetric Synthesis of Manzacidin C. Organic Letters DOI: 10.1021/ol8011869