Carreira, Weiss. ACIEE, 2011, EarlyView. 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. Anyone read the IUPAC Gold Book last night?) – adding up regardless of maths to one hell of a synthetic challenge. And there’s even some token biological activity to aim for – this bad-boy 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 it 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 PIs like Erick Carriera neglect the scientific process… Lets just hope that it was high-yielding and amenable to scale! A bit of mono-protection of this C2 symmetric intermediate, followed by enol triflation gave them a partner for a rather neat B-alkyl Suzuki cross-coupling, appending the silyl-protected propanol side-chain. Unfortunately this reaction require the use of Triphenylarsine – not the most pleasent of additives – required 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 to two Claisen rearrangements. The first is perhaps the more obvious – the alkenes are sitting the perfect place to be tickled with a little heat to encourage carbon-carbon bond formation, 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 neat 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 stunning yield in this challenging system.
With the medium ring closed, the (one-man) group were 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 de-BOCing the amine with TFA was enough to enough to prompt imine formation, and completion of the final ring. Removal of final protecting group completed the synthesis – one that cleverly balances new methods with classical techniques.