Recent Progress of Selective Monohydrolysis of Symmetric Diesters Satomi Niwayama Graduate School of Engineering Muroran Institute of Technology

Synthesis of Pharmaceuticals with the use of half-esters

Previous examples of monosaponification KOH C 6 H 5 COOC 2 H 5 EtOH C 6 H 5 COOC 2 H 5 Vecchi, A.; Melone, G. H 3 C COOC 2 H 5 r.t. 100hrs H 3 C COOH J. Org. Chem. 1959 , 24 109 (yield unknown) KOH COOC 2 H 5 EtOH COOC 2 H 5 Corey, E. J. Pr Pr J. Am. Chem. Soc. 1952 , 74 , 5897 COOC 2 H 5 r.t. 20 hrs COO H 74.6 % KOH COOC 2 H 5 EtOH COOC 2 H 5 Corey, E. J. C 6 H 5 C 6 H 5 COOC 2 H 5 r.t. 1 .5 hrs J. Am. Chem. Soc. 1952 , 74 , 5897 COO H 98.5 % (as a crude product)

New Selective Monohydrolysis aqueous NaOH or KOH CO 2 R THF or other co-solvent CO 2 H o C H 3 O + CO 2 R CO 2 R R=Me, Et

Comparison to C lassical onditions NaOH/MeOH (1eq.) 10% y ellowish 2 Me H NaOH/MeOH (1eq.) 10% y ellowish r.t. + diester + dicarboxylic acid CO 2 Me H THF/aqueous NaOH (2eq.) o C, 30-60 min. ~quant. white cryst. m.p. 106-107 C (lit. 108-109 C)

Monohydrolysis of Symmetric Diesters MeO 2 C CO Me H O >99% 95% b 79% 1a 5 HO 1b 2b entry 1 3 5a 70% 2a 4 diester product yield (%) a 4b 3b 3a 5b 4a 6 6a 6b CH Ph 7 7a 7b 8 8a 8b 96% 9 9a 9b Yields are isolated yields from silica gel column chromatography based on the amounts of the diesters submitted to the reaction. The yield was diminished due to the slight volatility of .

Potential Mechanism H2O H2O H2O H2O H2O H2O CO 2 R - O C RO H2O H2O H2O H2O H2O Soap-like aggregates prohibit further hydrolysis

Solvent Effects

Effects of Kinds of Co-Solvent

A B or Nu Conformational Preference of the Starting Diesters d + - O H OMe R Me CHO CO 2 SnBu 3 d + anti-Cram a) high pressure or - Nu MeO Cram 82-90 18-10 : J. Am. Chem. Soc. 1990 , 112 , 8598 A B heating or BF . OEt b) i) BF ii) H , Pd/C Yamamoto, Y. ; Nemoto, H.; Kikuchi, R.; Komatsu, H.; Suzuki, I. H

The Conformer of Dimethyl Maleate with the Lowest Energy (MP2/6-31G(d)//B3LYP/6-31G(d)) 72.6o 7.4o 2.850Å 111.2o 8.3o dihedral angles n->* interaction

Experimental Support for the Predominant Conformation by Theoretical Studies

6 . 5 8 2 9 3 1 4 7 K O H C s L i N a r S l v y > ≥ E p h R e c t o 7 K O H C s L i N a R e c t o n m / r : b ( % ) q u M T F , = + d S l v y > ≥ E p h

New Conditions for Monohydrolysis of Linear Diesters 100g $306 ~96% purity ~100% purity More hydrophobic

Recognition of Steric Environment 0 oC 0 oC

Summary A highly efficient, mild, straightforward reaction using co-solvent aqueous base CO 2 R CO 2 H o C H 3 O + CO 2 R CO 2 R R=Me, Et A highly efficient, mild, straightforward reaction using co-solvent-aqueous base at 0 oC was found to produce pure half-esters from symmetric diesters in high yields. This reaction has been licensed by Kishida Chemical Co.Ltd., Japan www.kishida.co.jp