HATU

Description

HATU, first prepared by Louis A. Carpino in 1993, is widely used in carboxylic acid amidation reactions. It acts as a facilitator of amide bond generation by activating the carboxyl group.

Chemical properties

White crystalline to off-white powder

The Uses of HATU

HATU is a peptide coupling reagent.

The Uses of HATU

To a solution of the acid (5.00 g, 32.0 mmol) in ACN (22.9 mL) was added TEA (9.82 mL, 70.5 mmol) followed by HATU (12.8 g, 33.6 mmol). The mixture was stirred at RT for 15 min, after which time the dark clear mixture was treated with the amine (3.44 g, 35.2 mmol). The reaction mixture was stirred at RT for 18 h. The mixture was diluted with EtOAc (100 mL) and washed with 1N HCl (2 x 100 mL), sat. NaCl (5 x 100 mL), dried (Na2SO4), and concentrated. The resulting crude orange solid was adsorbed onto a plug of silica gel and purified by chromatography (0-25% EtOAc/heptane) to provide the product as a yellow liquid. [5.050 g, 79%]

The Uses of HATU

HATU[148893-10-1] is a coupling reagent and used as an additive in peptide synthesis. It is also involved efficiently to speed up the coupling process and reduces the loss of chiral integrity.
Reagent for: Synthesis of Aurora A kinase inhibitors, HPLC assay to determine D- and L- acid enantiomers in human plasma, Amide bond formation reactions.
Catalyst for: Selective acylation, Selecocyclization-oxidation deselenation sequence.

What are the applications of Application

HATU is a peptide coupling reagent

Synthesis

The synthesis of HATU is as follows:The resulting residue treated with 2-Methoxycarbonylamino-3-methyl-butyric acid (60 mg, 0.343 mmol) and HATU (130 mg, 0.343 mmol), suspended in DMF (3 mL) and cooled to 0° C. DIPEA (0.272 mL, 1.56 mmol) was added dropwise. After stirring for 4 h, NaOH (5M in H2O, 0.300 mL, 1.5 mmol) was added. This mixture was stirred for 3 h then diluted with EtOAc and washed with 1 M LiOH (2*) then brine. The organic phase was dried over MgSO4, filtered and concentrated. The crude residue was then purified by HPLC to afford the title compound (53 mg, 44%).

Mechanism

The reaction mechanism of HATU is shown below in three steps.
(1) The base deprotonates the carboxylic acid. The resulting carboxylic acid anion attacks the electron deficient carbon atom of the HATU.
(2) The generated HOAt anion reacts with the newly formed activated carboxylic acid-derived intermediate to form an OAt activated ester.
(3) The amine reacts with the OAt-activated ester to form the amide pdt.