, , , , ,

*Hat tip to Reed Roberts and Danny Allwood for bringing this paper to my attention via #Chemclub*

Natural product characterization isn’t for the faint of heart. The compounds are often insanely complex, and present in such minute quantities that kilograms of crude material are required just for basic characterization [1].

Determining the stereochemistry of such compounds is no small task, and natural product chemists are some of the few people still routinely performing (a form of) functional group tests.  In particular, secondary alcohols of uncertain chirality are often reacted with enantiomerically pure acyl chlorides (ie. Mosher’s acid chlorides). The resulting diastereomeric esters can then be characterized by NMR, and the structures tracked back to the determine the chirality of the original alcohol.

S-HBTMWhile not prohibitively expensive, Mosher’s acid chlorides are not cheap either, and there’s been a push in recent years to discover catalytic methods capable of doing the same work [2]. A couple of years back the Rychnovsky group published a catalytic acylation based on HBTM, and this week took the reaction from interesting to awesome.

At 4% catalyst loading and 3 equivalents of DIEA and propionic anhydride, they found that secondary alcohols are rapidly esterified—provided the stereochemistry of the alcohol doesn’t match that of the catalyst. The difference is significant enough that stereochemistry can be assigned in about 60 minutes with just TLC, even if the original natural product is not enantiomerically pure [3].

Stereochem TLCLet’s just bask in that for a moment.  Using low molar equivalents of a relatively accessible catalyst (two steps from commercial materials), it’s possible to assign the stereochemistry of secondary alcohols via TLC.  Admittedly the examples given aren’t very complex and a second alcohol would foul the test, but this is still a nice step forward.

[1] According to the math provided in the initial paper, isolating 5.3 mg of GFP required the death and processing of 9375 jellyfish. There’s a distressingly vivid neologism used to describe the jellyfish extracts, “squeezate.”

[2] I caught a talk on this subject at the last CSC from an assistant professor just starting research at St. Francix Xavier university, Derren Derksen. Unfortunately there haven’t published anything yet, though one paper is in press.  EDIT: It’s in the ASAPs.

[3] The example given had an EE of 70%.