New Protecting Group; Di-tert-butylisobutylsilyl (BIBS)

Although process chemists try to avoid using protecting groups, occasionally they have to be used in the manufacture of complex multifunctional molecules. The books by Wuts and Greene (Protecting Groups in Organic Synthesis, 4th Ed, Wiley-Interscience, NY, 2007) and Kocienski (Protecting Groups, 3rd Ed, Thieme Stuttgart, 2005) are very useful compilations of the types of groups, and methods for their attachment and removal. Many types of silyl groups are listed ranging from the relatively labile TMS to the relatively robust TBDPS, but the tri-tert-butylsilyl group is rarely used because it is difficult to prepare in quantity, difficult to attach even to an OH group, and resistant to cleavage.

Now the group of Corey at Harvard (Org Lett, 2011, 13(15), 4120-3) has introduced the BIBS (di-tert-butylisobutylsilyl) group which is useful for protecting acidic hydroxyl groups such as phenols. BIBS groups are much more stable than TBS, TIPS and TBDPS, but are cleaved with tetrabutylammonium fluoride in THF.  BIBS groups are stable to silica gel chromatography and to acidic washing at pH 3-9, though this will need to be checked for individual compounds particularly if scaling up, where extended times could ensue.

Carboxylic acids also form BIBS esters which are stable to chromatography. Primary amines are protected as mono-BIBS derivatives by treatment with BIBSOTf and triethylamine in DCM at RT. Secondary amines are protected as BIBS-carbamates using the same reagents with additional carbon dioxide (1 at).

In a footnote it is mentioned that the reagent preparation has been scaled up at Gelest Inc and that BIBS-OTf is commercially available from that company.