Carboxylic activation with DPPA

Tertiary alcohols are converted directly to azides using NaN3/ Sulfuric Acid or HN3/Boro Trifluoride or TUanium(IV) Chloride (eq 5), and the carboxylic acid to acyl azide transformation (often en route to Curtius rearrangements to isocyanates) occurs with DPPA or via activation with DMF/Thionyl Chloride. ... 

The first methods for aza-annulation with a-amido-derived acrylate reagents, such as 344, involved activation of the carboxylic acid toward acylation through the use of DPPA (eq. 69).42 Efficient aza-annulation of 104 and 109 generated the corresponding amino acid derivatives 345 and 346. 

Other activating groups for carboxylic acids, such as 1-hydroxybenzotriazole (hobt) <89TL2897> or diphenylphosphorylazide (DPPA) <90TL6469>, have also been used with good success to give (45), (46) or (47) (Equations (15), (16), and (17), respectively). 

Some of the more innovative and creative aspects of peptide chemistry have centered around the peptide bond-forming reaction. Because of the asymmetric center adjacent to the carboxylic acid carbonyl group, the superficially simple operation of amide formation has required study, unparalleled in detail, to avoid racemization. While racemization can usually be limited to less than 1% there is still no universally infallible reaction technique and the advantages of having several good methods at one s disposal is well known to every peptide organic chemist. Presently, in our laboratory, we prefer to first use the MCA method employing isobutyl chloroformate with one equivalent of a relatively weak base such as N-methylmorpholine in tetrahydrofuran. If this proves unsatisfactory we then resort to a method from one of the series A, DCCl-HOBT, ED Cl, WRK, or one of the active ester methods such as OSU, OPCP, or ONP. Soon, we may find it appropriate to add the BBDQ, NCA, SPY, and DPPA methods to this list for reasons outlined below. 

In 1982, Hamada and Shioiri reported that carboxylic acids could be directly employed as acyl donors in the Schollkopf reaction via in situ activation (presumably via a mixed anhydride or azidocarbonyl species) using diphenyl phosphorazidate (DPPA). Thus reaction of a mixture of carboxylic acid, isocyanide, DPP A, and potassium carbonate in DMF afforded the anticipated oxazole product in good yield cf, 14 + 15 —> 16). Notably, this reaction was compatible with iV-protected a-amino acid starting materials and proceeded with minimal epimerization. Although diethyl phosphorocyanidate (DEPC) has found similar use in... 

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