Sojung F. Kim

Saturated heterocycles are found in numerous therapeutics and bioactive natural products and are abundant in many medicinal and agrochemical compound libraries. To access new chemical space and function, many methods for functionalization on the periphery of these structures have been developed. Comparatively fewer methods are known for restructuring their core framework. Herein, we describe a visible light-mediated ring contraction of α-acylated saturated heterocycles. This unconventional transformation is orthogonal to traditional ring contractions, challenging the paradigm for diversification of heterocycles including piperidine, morpholine, thiane, tetrahydropyran, and tetrahydroisoquinoline derivatives. The success of this Norrish type II variant rests on reactivity differences between photoreactive ketone groups in specific chemical environments. This strategy was applied to late-stage remodeling of pharmaceutical derivatives, peptides, and sugars.

Protein aggregation involves the assembly of partially misfolded proteins into oligomeric and higher-order structures that have been associated with several neurodegenerative diseases. However, numerous questions relating to protein aggregation remain unanswered due to the lack of available tools for visualization of these species in living cells. We recently developed a fluorogenic method named aggregation tag (AggTag), and presented the AggTag probe P1, based on a Halo-tag ligand, to report on the aggregation of a protein of interest (POI) in live cells. However, the Halo-tag-based AggTag method only detects the aggregation of one specific POI at a time. In this study, we have expanded the AggTag method by using SNAP-tag technology to enable fluorogenic and biorthogonal detection of the aggregation of two different POIs simultaneously in live cells. A new AggTag probe-P2, based on a SNAP-tag ligand bearing a green solvatochromic fluorophore-was synthesized for this purpose. Using confocal imaging and chemical crosslinking experiments, we confirmed that P2 can also report both on soluble oligomers and on insoluble aggregates of a POI fused with SNAP-tag in live cells. Ultimately, we showed that the orthogonal fluorescence of P1 and P2 allows for simultaneous visualization of two different pathogenic protein aggregates in the same cell.

Under mild blue-light irradiation, α-acylated saturated heterocycles undergo a photomediated one-atom ring contraction that extrudes a heteroatom from the cyclic core. However, for nitrogenous heterocycles, this powerful skeletal edit has been limited to substrates bearing electron-withdrawing substituents on nitrogen. Moreover, the mechanism and wavelength-dependent efficiency of this transformation have remained unclear. In this work, we increased the electron richness of nitrogen in saturated azacycles to improve light absorption and strengthen critical intramolecular hydrogen bonding while enabling the direct installation of the photoreactive handle. As a result, a broadly expanded substrate scope, including underexplored electron-rich substrates and previously unsuccessful heterocycles, has now been achieved. The significantly improved yields and diastereoselectivities have facilitated reaction rate, kinetic isotope effect (KIE), and quenching studies, in addition to the determination of quantum yields. Guided by these studies, we propose a revised ET/PT mechanism for the ring contraction, which is additionally corroborated by computational characterization of the lowest-energy excited states of α-acylated substrates through time-dependent DFT. The efficiency of the ring contraction at wavelengths longer than those strongly absorbed by the substrates was investigated through wavelength-dependent rate measurements, which revealed a red shift of the photochemical action plot relative to substrate absorbance. The elucidated mechanistic and photophysical details effectively rationalize empirical observations, including additive effects, that were previously poorly understood. Our findings not only demonstrate enhanced synthetic utility of the photomediated ring contraction and shed light on mechanistic details but may also offer valuable guidance for understanding wavelength-dependent reactivity for related photochemical systems.

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.