Derek Lowe has a recent post entitled "Another Funny-Looking Structure Comes Through". He cites a recent medchem article in which the following acetal sub-structure appears in a promising drug candidate (blue component below). His point is that orally taken drugs have to survive acid (green below) encountered in the stomach, and acetals are famously sensitive to hydrolysis (red below). But if X=NH2, compound "G-5555" is apparently stable to acids. So I pose the question here; why? This reminded me of some work we did a few years ago on herbicides containing such an acetal substructure, where one diastereoisomer was very unstable to hydrolysis (and hence did not have the lifetime required of a herbicide) whereas the other diastereomer was far less labile and hence more suitable., Crystal structures (below) revealed that the two C-O bond lengths of the labile form were very unequal in length (Δ0.043Å), whereas the stable form had two equal C-O lengths (1.408Å, Δ=0.0Å).Time for calculations. A model (X=R=H) for the hydrolysis was constructed as above in which proton transfer from an acid (ethanoic) is achieved via a cyclic 8-ring transition state and which includes a continuum solvent field as ωB97XD/6-311G(d,p)/SCRF=water and one explicit water in the proton relay. The IRC looks thus: This shows that the first event is protonation of an oxygen, closely followed by cleavage of the associated C-O bond, and ending with deprotonation of the erstwhile water molecule. The value of ΔG‡298 is 38.2 kcal/mol (38.4 in relative total energy). Although rather high for a facile thermal reaction (perhaps the 8-ring TS is a bit too strained; possibly adding a second active water molecule to form a 10-ring might lead to a lower barrier?), we are more interested in the effect upon this barrier of group X (Table below).
- C.O. Ndubaku, J.J. Crawford, J. Drobnick, I. Aliagas, D. Campbell, P. Dong, L.M. Dornan, S. Duron, J. Epler, L. Gazzard, C.E. Heise, K.P. Hoeflich, D. Jakubiak, H. La, W. Lee, B. Lin, J.P. Lyssikatos, J. Maksimoska, R. Marmorstein, L.J. Murray, T. O’Brien, A. Oh, S. Ramaswamy, W. Wang, X. Zhao, Y. Zhong, E. Blackwood, and J. Rudolph, " Design of Selective PAK1 Inhibitor G-5555: Improving Properties by Employing an Unorthodox Low-p K a Polar Moiety ", ACS Med. Chem. Lett., vol. 6, pp. 1241-1246, 2015. http://dx.doi.org/10.1021/acsmedchemlett.5b00398
- P. Camilleri, D. Munro, K. Weaver, D.J. Williams, H.S. Rzepa, and A.M.Z. Slawin, "Isoxazolinyldioxepins. Part 1. Structure–reactivity studies of the hydrolysis of oxazolinyldioxepin derivatives", J. Chem. Soc., Perkin Trans. 2, pp. 1265-1269, 1989. http://dx.doi.org/10.1039/P29890001265
- P. Camilleri, D. Munro, K. Weaver, D.J. Williams, H.S. Rzepa, and A.M.Z. Slawin, "Isoxazolinyldioxepins. Part 1. Structure–reactivity studies of the hydrolysis of oxazolinyldioxepin derivatives", J. Chem. Soc., Perkin Trans. 2, pp. 1929-1933, 1989. http://dx.doi.org/10.1039/P29890001929