Lowering Lipophilicity by Adding Carbon: AzaSpiroHeptanes, a logD Lowering Twist

We have conducted an analysis of azaspiro3.3heptanes used as replacements for morpholines, piperidines, and piperazines in a medicinal chemistry context. In most cases, introducing a spirocyclic center lowered the measured logD 7.4 of the corresponding molecules by as much as -1.0 relative to the more usual heterocycle. This may seem counterintuitive, as the net change in the molecule is the addition of a single carbon atom, but it may be rationalized in terms of increased basicity. An exception to this was found with N-linked 2-azaspiro3.3heptane, where logD 7.4 increased by as much as +0.5, consistent with the addition of carbon. During our investigation, we also concluded that azaspiro3.3heptanes are most likely not suitable bioisosteres for morpholines, piperidines, and piperazines, when not used as terminal groups, due to significant changes in their geometry.