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Totally Synthetic by Paul H. Docherty, 30 October 2011

Total Synthesis of Daphmanidin E


M. E. Weiss, E. M. Carreira, Angew. Chem. Int. Ed. 2011, 50, 11501-11505.

DOI: 10.1002/anie.201104681

Now that’s a busy polycyclic ring-system! Three five-membered rings, two six-membered rings and one seven (depending, of course, on how one counts the ring sizes) - adding up regardless of maths to one great synthetic challenge. And there’s even some token biological activity to aim for - this complex compound has some moderate vasorelexant acitivity next to rat aorta. (When the paper mentions ‘moderate’ activity, we can be pretty sure it does very little indeed…) But who knows - perhaps one of it’s derivatives or intermediates could be more biologically interesting.

What we’re interested in is of course the synthesis - and it’s a one-man job in this case. That man by the fumehood is Matthias Weiss, and he started the chemoenzymatic or chromatographic separation of a diethyl succinate derivative. With no Supporting Information to hand, I’m unsure how he went about that - it’s always a disappointment when leading principal investigators like Erick Carriera neglect the scientific process… Let's just hope that it was high-yielding and amenable to scale! Mono-protection of this C2 symmetric intermediate, followed by formation of the enol triflate gave them a partner for an interesting alkyl Suzuki cross-coupling, appending the silyl-protected propanol side-chain. Unfortunately this reaction requires the use of Triphenylarsine - not the most pleasent of additives - to suppress reductive detriflation.

The product was then treated with an array of Group-13 organometallics, firstly diastereoselectively hydroborating the alkene, and then reducing virtually everything to give a triol product in excellent yield. What I like about this procedure is the apparent simplicity in functional group transformation. A few steps manipulating protecting groups lead them to an intermedate that was O-alkylated with the corresponding tosylate then took them to the precursor of two Claisen rearrangements. The first is perhaps the more obvious - the alkenes placed in the right way to encourage carbon-carbon bond formation upon heating, and diastereoselective formation of a congested tertiary - tertiary system. Next, they treated the resulting ketone with base and 18-crown-6 to O-alkylate again, this time with allyl bromide. Again, heating was used to simulate rearrangement, neatly forming the quaternary centre in three steps.

Eight steps further on (including a Henry condensation and a stereoselective methylation), and the team were ready for a spectacular formation of the octahydroazulene domain. Working from an alkyl iodide and looking for coupling with the cyclopentenone, the group had a lot of possible conditions to consider. However, what they went forward with was rather unusual - a cobaloxime-mediated Heck cyclization, requiring irradiation to proceed in good yield. Carreria states that this method development will be published in another paper, but I haven’t seen anything just yet. Looks very interesting though - and delivers a astonishing yield in this challenging system.

With the medium ring closed, the (one-man) group was pretty close to the finish. An intramolecular aldol codensation was used to install the remaining cyclopentene (requiring two reaction cycles to achieve a 77% yield), whilst deprotection of the amine with TFA was enough to prompt imine formation, and completion of the final ring. Removal of final protecting groups completed the synthesis - one that cleverly balances new methods with classical techniques.