Haplophytine

Fukuyama, Tokuyam, Ueda, Satoh, Matsumoto, Sugimoto. ACIEE, 2009, ASAP. DOI:10.1002/anie.200902192. 

And it’s done.  It took almost as long to finish as it took Wiley to finally put it online (are they using dial-up modems?), but it’s finally here, after many (as yet) unsuccessful attempts [Corey, Padwa, Nicolaou].  Unfortunately, its difficult to know exactly what were the more challenging issues, as this is a very compact communication – we’re gonna have to wait even longer for the full paper.  However, we can marvel at the more obvious successes.

The basic strategy was simple – split the molecule in two about the obvious single bond.  This presentsaspidophytine, and another bit (that’s the technical term – honest…).  As aspidophytine has been covered, lets start with the other bit, a ‘bicyclo[3.3.1]skeleton that includes bridged ketone and aminal functionalities‘.  The group were able to garner some insight into it’s synthesis from some isolation studies, but first they had built much of the carbon skeleton.  Perhaps the most difficult feature was completed at the start of the synthesis – a chiral quaternary center.  For this they dug into an unfairly buried Tet. Lett. by d’Angelo, using a chiral amine to form a imine intermediate of that ketone.  Then, conjugate addition to an acrylate allowed highly enantioselective C-C bond formation in good yield.  Of course, a quantitative amounts of chiral amine were required, but it’s relatively inexpensive, and easy to recover after hydrolysis.

It was quite a few steps to the next scheme – an enolisation and ozonolysis of the resulting cyclopentene allowed opening of the 5-membered ring, whilst the thio-ester was easily alkylated with a pendant amine.  This allowed construction of an eleven-membered cyclic-amine macrocycle, which they cunningly used to form three smaller rings.  The key to this was a highly diastereoselective Mannich reaction, and the mandatory Overman reference (this is an alkaloid synthesis, afterall…).  [As a brief aid - the acid removes the ketal, freeing the ketone.  Then the thiophenol removed the nosyl protecting group, reading the molecule for Mannich reaction under acidic conditions - the silica.  The ethyl ester was removed in the course of this (probably the pot-carb), so TMS-diazomethane was used to re-esterify.]

Moving next to the other half of the target, a relatively simple indole was elaborated to a dihydro-beta-carboline using efficient if routine chemistry.  A Noyori asymmetric
reduction was used to reduce the carboline across the imine, providing asymmetry in high e.e.  Addition of NIS to this system caused iodation at the indole C-3 postion, and indolenine formation. Treatment of this with silver triflate caused a Friedel-Crafts alkylation, generating the highly congested quaternary center in a 2.4(ish):1 d.r.  Now, the Friedel–Crafts alkylation might be due some new teeth and a hip-replacement op at 132 years old, but that’s a neat job.  Note the use of a mesyl group as a phenol protecting group!

A few steps on, and the original stereocenters been torn-asunder; however, a little mCPBA epoxidises the probably-quite-activated-sorta-bis-enamine thing, allowing rearrangement of the 5,6,6-system into the desired bicyclo[3.3.1], as expected.  I’ve shown the product in two representations – one similar to it’s direct precursor in the mechanism, and the other that used by the authors.

Coupling of the two fragments is nice, but I’m just going to direct you here, as this is a (rather complex and impressive, but still…) Fischer Indole Synthesis. Which you should all know anyway…  So the last scheme is a rather late-stage lactonisation, done in a rather interesting way; basic hydrolysis of the ester, and then lactone formation using potassium
ferricyanide.  If that’s ringing bells, that cause this is lifted directly from Corey’s synthesis of Aspidophytine.  If the chemistry works…

And that’s more-or-less the theme here – no particularly new chemistry, but the world gains 4.2 mg of the target.  Given how much effort has gone in from some particularly successful groups, only to be met with failure, this is an astonishing achievement.  But bring on the full paper!