Skeletal Editing Strategies Driven by Total Synthesis

ConspectusSingle-atom skeletal editing strategies that precisely modify the core frameworks of molecules have the potential to streamline and accelerate organic synthesis by enabling conceptually simple, but otherwise synthetically challenging, retrosynthetic disconnections. In contrast to broader skeletal remodeling and rearrangement strategies, these methodologies more specifically target single-atom changes with high selectivity, even within complex molecules such as natural products or pharmaceuticals. For the past several years, our laboratory has developed several skeletal editing methodologies, including single-atom ring contractions, expansions, and transpositions of both saturated and unsaturated heterocycles, as well as other carbon scaffolds. This Account details the evolution of “skeletal editing logic” within the context of our extensive work on natural product total synthesis.Early work in the Sarpong group leveraged metal-mediated C–C bond cleavage of in situ-generated strained intermediates to accomplish total syntheses of natural products, such as the icetexane diterpenoids and cyathane diterpenes. Continuing our focus on leveraging C–C bond cleavage through “break-it-to-make-it” strategies, we then developed carvone remodeling strategies to access a variety of terpenoids (including longiborneol sesquiterpenoids, phomactins, and xishacorenes) from hydroxylated pinene derivatives. In applying this skeletal remodeling and C–C cleavage framework to alkaloid natural products, such as the preparaherquimides and lycodine-type alkaloids, we recognized that single-atom changes to the saturated nitrogen-containing rings within these natural products would enable the direct conversion between distinct but structurally related natural product families. Thus, we began developing methods that selectively modify the core frameworks of N-heterocycles; this focus led to our work on the deconstructive fluorination and diversification of piperidines and ultimately to our recent body of work on direct, single-atom core framework modifications (single-atom skeletal editing). In the context of saturated heterocycles, we developed photomediated enantioselective ring contractions of α-acylated motifs and reductive ring contractions of cyclic hydroxylamines. For unsaturated heterocycles, we have developed ring contractions of azines (e.g., pyrimidine to pyrazole), 15N isotopic labeling of azines, and phototranspositions of indazoles to benzimidazoles. To direct our focus on reaction development, a cheminformatic analysis of heteroaromatic skeletal edits served to quantitatively inform which transformations would most significantly expand the accessible chemical space. Apart from heterocycles, we also reported single-nitrogen insertion through the reductive amination of carbonyl C–C bonds. Ultimately, the goal of this research is to develop mild and selective skeletal editing methodologies that can be applied to total synthesis and organic synthesis more generally. While recent total syntheses from our group have targeted simplified retrosyntheses through single-atom skeletal editing logic (e.g., daphenylline and harringtonolide), multiple steps were still required to achieve the formal desired “edit”. As such, the continued development of truly single-step, mild, and selective reactions that can edit the cores of highly complex molecules remains highly desirable.