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Totally Synthetic by Paul H. Docherty, 18 August 2010

Total Synthesis of Manzamine A


T. Toma, Y. Kita, T. Fukuyama, J. Am. Chem. Soc. 2010, 132, 10233-10235.

DOI: 10.1021/ja103721s

Besides prior syntheses by Martin and Winkler, I’m actually a kind of surprised that there haven’t been many more efforts in this direction, as manzamine A is an interesting target. As usual, I’ll quote the authors with respect to biological activity: ‘cytotoxic, antibacterial, antimalarial, insecticidal, anti-inflammatory and anti-HIV’ activity are the headline - you need any more?! And that ring system is something special - two medium rings and a strained 6,6,5 core with a tryptamine-derived unit.

Going back to our first class in retrosynthesis, you’ll remember that cyclohexene = Diels Alder, and Fukuyama doesn’t disappoint. Working with a molecule related to Danishefsky’s diene (with an alkynyl pendant chain), a Diels-Alder with a readily avaliable chiral butenolide completed the cyclohexene, providing two new stereocenters in excellent yield. Unfortunately, the endo/exo selectivity wasn’t amazing, with a 2:1 ratio in their favour, but a 65% yield of their desired product is still pretty respectable. Over the next few steps, the acetoxylactone was broken apart to reveal a pair of alcohols - one remained protected, whereas the other was used to build the fifteen-member ring.

To build the remaining 5,8-system, the group needed to append a small chiral fragment first, which they constructed in great yield by an asymmetric zinc addition. The protocol referenced is a sole-author paper by Nugent from back in ’99. The group completed this small fragment by first introducing a carbamate group, and then displacing the primary alcohol with iodine.

With both fragments in hand, they performed a pair of deprotonation / alkylation sequences to produce a quaternary centre with great control of stereochemistry. Considering that there are quite a few functional groups lying around, the control of reaction is really quite impressive. Even more impressive is that they apparently isolated only one stereoisomer; control derives entirely (and unsurprisingly) from facial selectivity - which is also presumably what controls the third step in this sequence, a nice epoxidation.

With this done, it was time to turn the allylic carbonate into a dihydropyrrole. Firstly, the acid and amine perform a dehydration, creating an intermediate which undergoes a [3,3] sigmatropic rearrangement to give the product, neatly transferring the carbonate stereochemistry across the double bond, forming an intermediate isocyanate. After a bit of experimentation, the group then found conditions to close the C-ring and form the required imine.

Another alkylation appended a greasy chain for creation of the D-ring and a RCM completes that eight-member ring. However, the A ring is still incomplete, so it’s interesting to see how Fukuyama went about it. Firstly, an oxidation takes the ethanol group up to the aldehyde. Then, in a protocol that must smell bad, thiophenol and caesium carbonate were used to remove the nosyl protection group, forming the imine concomitantly, which was reduced with a hydride. And in a very nice yield!

The RCM did the business, and the remaining silyl group was removed the alcohol oxidised to the aldehyde. This allowed for coupling of the tryptamine group using a modified Pictet-Spengler reaction, and completion of the target in only a few more steps.

It’s hardly a short synthesis, but the target is a phenomenal challenge, so hats off to the intrepid trio who managed this.