BASICITY OF 3-AMINOPROPIONAMIDINE DERIVATIVES IN WATER AND DIMETHYL-SULFOXIDE - IMPLICATION FOR A PIVOTAL STEP IN THE SYNTHESIS OF DISTAMYCIN A ANALOGS

The acid-base properties of eight 3-aminopropionamidine derivatives R( 1)R(2)N(CH2)(2)C(=NH)NR(3)R(4) (1, R(1) = R(2) = R(3) = R(4) = H; 2, R (1) = R(3) = R(4) = H, R(2) = Me; 3, R(1) = R(2) = R(4) = H, R(3) = Me ; 4, R(1) = R(2) = H, R(3) = R(4) = Me; 5, R(1) = Tos, R(2) = R(3) = R (4) = H; 6, R(1) = Tos, R(2) = Me R(3) = R(4) = H; 7, R(1) = Tos, R(2) = R(4) = H, R(3) = Me; 8, R(1) = Tos, R(2) = H, R(3) = R(4) = Me; Tos = 4-toluenesulphonyl) related to the antiviral natural product distam ycin A were investigated in water and dimethyl sulphoxide (DMSO). The measured pK(a) values for the ammonium function in 1-4 in water ranged between 7.48 and 7.73, whereas the corresponding values in DMSO were 9.4 +/- 0.3. The amidinium moiety of these compounds displayed pK(a) v alues in the range 11.4-12.0 and 13.4-13.6 in water and DMSO, respecti vely. The tosylamide group in compounds 5-8 was deprotonated in the ex pected pH region and exhibited pK(a) values between 9.49 and 10.02 in water, but was considerably less acidic in DMSO (14.5 less than or equ al to pK(a) less than or equal to 15.7). The behaviour of the amidiniu m cation of 5-8 in water and DMSO resembled that of 1-4. The measured pK(a) values are discussed and the solvent-induced pK(a) shifts are ex plained in terms of solvent and substituent effects. The observed pK(a ) differences between the ammonium and the amidinium functions in 1-4 render these compounds suitable intermediates in an alternative synthe sis of distamycin A.