To study the structural determinants required for protein kinase C (PKC) activation by indolactam V (ILV) for purposes of arriving at simpler versions of this PKC activator, four simplified analogues of ILV (4a–c and 14a) were synthesized. These analogues contain a benzene ring in place of the indole group of ILV and were designed for synthesis because molecular modeling studies revealed these simplified structures to possess readily accessible [ILV]-sofa-like conformations, thus mimicking the literature-reported bioactive conformation of ILV. During the course of designing these analogues, a more rigorous conformational search program (SysSearch) was developed to analyze the highly functionalized nine-membered lactam ring system present in ILV. The results of the molecular modeling studies using the SysSearch program on which the design of these analogues was based were confirmed by 2-D NMR and X-ray studies. The compounds of this series were constructed by use of the Mitsunobu reaction to generate the unique nine-membered lactam ring present in these structures. Two routes to compound 4a are presented, one of which utilizes the amino acid building blocks, L-valine and L-phenylalanine, to fix the stereochemistry of its two asymmetric centers. The biological studies reveal that these new analogues fail to modulate PKC activity, and thus they exclude the possibility that a benzene ring can serve as a surrogate of the indole ring of ILV. The present work therefore indicates that the nine-membered lactam ring moiety of ILV in an [ILV]sofa conformation is not a sufficient structural determinant for PKC activation.