Agelastatin A Pt. 3

Du Bois, Wehn. ACIEE, 2009, EarlyView. DOI: 10.1002/anie.200806292. 

Our third visit to this tightly functionalised little molecule (one – Trost, two – Tanaka, Yoshimitsu), that sterotetrad certainly brings in the players.  I’m not going to go into the biology (hit up the Tanaka post for that), so let get straight into the synthesis.  Du Bois kicks off with an opening of an optically active, bicyclic lactam (2-Azabicyclo[2.2.1]hept-5-en-3-one) – which is commercially available, but not exactly cheap.  Good thing the synthesis is so short…  Protection, reductive ring-opening and sulfamate formation give us the SM for the first scheme – a (very) catalytic aziridination, returning cracking diastereomeric control.  That’s no real suprise, as the intramolecular tether isn’t very long, so forming a cis-ring junction would be heavily disfavoured.  However, the next reaction is more impressive (from a selectivity standpoint), as azide attack occurs with an 9:1 preference for their desired position.  More about that selectivity in this paper.

With all four stereocenters now inplace about the core, it was time to start building the rest of the tetracyclic ring system.  First-off was getting rid of that tether – done nicely by using the inherent reactivity of sulfamates.  Thinking about sulfonates (highly reactive, good leaving groups) versus sulfonamides (bastard, bastard protecting groups ¹), it’s clear why displacement occurs at the desired position to give the desired phenyl selenide.

Moving on, elimination of the selenide gives the exo-methylene, whilst a Staudinger reduction gave them a carabamate in the end.  Lastly, a Paal-Knorr pyrrole synthesis allowed construction of the lower ring.  Of course, they’ve now destroyed a stereocenter, but that situation was quickly resolved by doing an oxidative cleavage of the alkene.  The intermediate ketone was then attacked by intramolecular cyclisation, providing the N,O acetal as a single stereoisomer.  The final ring was then installed using a bit of base (and a rather exotic alcohol… Du Bois uses this in preference to t-BuOH as it’s easier to keep dry.  Good knowledge.), leaving a literature bromination to complete the target.  Nice work.

[1] I had to remove a tosyl group from an aniline recently – hadda use 20 equivs. of sodium naphthalimide to get complete deprotection.  Grrr…

PS.  Look at the top of the blog post.  Below the title structure, next the PDF icon – the ChemDraw icon links to my schemes in CDX format.  Might be useful sometime…