Acid- and Base-Stable Esters: A New Protecting Group for Carboxylic Acids

Abstract

An acid- and base-stable protecting group for carboxylic acids is described. The esters of (2,6-dichloro-4-methoxyphenyl)(2,4-dichlorophenyl)methanol are stable to Brønsted and Lewis acids, Brønsted bases, and a wide variety of nucleophiles; however, the esters can be conveniently deprotected by a solvolytic displacement reaction with 20% trifluoroacetic acid.

Key words

acid-stable ester - base-stable ester - carboxylic acid protecting group - chlorodiphenylmethyl esters

References

• 1 Dini C. Curr. Top. Med. Chem.  2005,  5:  1221 
• 2a Kurosu M. Narayanasamy P. Crick DC. Heterocycles  2007,  72:  339 
• 2b Kurosu M. Mahapatra S. Narayanasamy P. Crick DC. Tetrahedron Lett.  2007,  48:  799 
• 2c Kurosu M. Biswas K. Crick DC. Org. Lett.  2007,  9:  1141 
• 2d Kurosu M. Crick DC. Tetrahedron Lett.  2006,  47:  5325 
• 3a Handbook of Reagents for Organic Synthesis: Activating Agents and Protecting Groups   Pearson AJ. Roush WR. Wiley; New York: 1999. 
• 3b Greene TW. Wuts PGM. Protective Groups in Organic Synthesis   3rd ed.:  Wiley & Sons; New York: 1999. 

4

The nucleophilicity of diphenylmethanol may be increased due to: 1) introduction of the methoxy group at the 4-posi­-tion, and 2) stereoelectronic effects of the chloro substituents on the aromatic rings.

5

50% regeneration of 3d was observed with 1 N aq NaOH at 50 °C for one hour.

6

No deuterium exchange at the α-position of the esters upon quenching with CD₃OD and aldol reactions with benzaldehyde were observed.

7

The -CO-O- linkage and the ether methine proton showed a deviation of 20.2° out of a preferential common plane.

8

We have synthesized a variety of esters with N-protected
d- or l-amino acids. Significant separation of signals for a diastereomeric mixture of esters at the α-position of the carbonyl group is observed in the ¹H NMR spectra; however, so far no separation of the diastereomers of 4d has been observed on TLC. These characteristics may be applied to the determination of the stereochemistry of unknown
α-chiral carboxylic acids by using optically pure 3d. The synthesis of (+)-3d and (-)-3d will be reported elsewhere.