In this work we have successfully developed a new and reliable synthetic route to obtain a series of novel 3,5-substituted spirocyclohexyl piperidinyl nitroxides. Investigation of the conformations of these compounds by X-ray crystallography and DFT calculations confirmed our hypothesis that, with sufficient additional steric pressure, it is possible to obtain spirocyclohexyl nitroxides that favor closed conformations. As indicated by kinetic decay studies with CW EPR, this conformational biasing significantly increases the stability of spirocyclohexyl nitroxides towards reduction by ascorbate. At the same time, the beneficial extended phase memory times (Tm) exhibited by spirocyclohexyl nitroxides in pulsed EPR are generally preserved despite the introduction of methyl substituents on the nitroxide ring, thereby striking an excellent compromise between reduction stability and extended Tm in these scaffolds. This balance is of great potential utility in nitroxides intended for applications such as biocompatible spin labels, imaging probes or DNP NMR polarization transfer agents.