Back to Basics: The Scientific Method

It’s refreshing to see the scientific method applied to research chemistry.  I enjoy reading data tables in Organic Letters to see how switching a variable of a reaction resulted in a certain desired effect.  How wonderful is it to read about 11 entries of Edisonian science (i.e. 11 examples of how the chemistry doesn’t work) followed by the one excellent result (hopefully >95% yield, >20:1 de, 99% ee)?  This sort of research is the basis for good science. 

I came across an example of the scientific method—actual proof that altering one variable at a time will (eventually) give you the desired outcome.  Check out the work recently reported by Ishikawa and co-workers (Org. Process Res. Dev. 2008, 12, 596–602).   The group, which hails from Meiji Seika Kaisha in Japan, was attempting to optimize their synthesis of target CP4715, which has demonstrated excellent cardioprotective efficacy in initial in vivo screenings.

One of their routes to CP4715 involved reductive amination of the ketone below.  After examining several different ammonia sources and reducing conditions, the group ultimately decided on catalytic hydrogenation in the presence of ammonium hydroxide (for literature examples see: Tetrahedron Lett. 2001, 42, 4257 or Org. Lett. 2002, 4, 2055).  The problem Ishikawa’s group encountered was formation of the secondary amine as an unwanted contaminant.  Recall that garden-variety catalytic hydrogenations are typically done in methanol or ethanol.  In using methanol, they detected 23% of the secondary amine by HPLC.  By switching the solvent system to 1:1 1,4-dioxane/methanol, they detected 15% of the contaminant.  Ultimately, byproduct formation was mitigated by using 1,4-dioxane to give 8% of the unwanted material.  The now residual secondary amine was removed by selective crystallization.

Sadly, the 2008 baseball season is over for Red Sox fans.  My guess is that there’ll be several changes in the upcoming days/weeks.  With Ramirez gone, I’m assuming the Sox will probably clean house to make more room in their checkbook: Varitek (if he doesn’t settle for a lesser paycheck); Crisp; Wakefield; Schilling; Colon; Timlin.  Though, I will throw up a red flag.  As the Yankees have proven time and time again, you cannot buy a World Series.  That said, I read a rumor this morning that the Sox are eyeing Jake Peavy…that’s going to be expensive.

P.S. Just submitted my abstract for the Spring ACS meeting!  Who wants to go out for drinks?