Indoles to Meta-Aminoaryl Nicotinates for Late-Stage Conjugation
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ARTICLE https://doi.org/10.1038/s41467-020-19610-2 OPEN Nature-inspired remodeling of (aza)indoles to meta-aminoaryl nicotinates for late-stage conjugation of vitamin B3 to (hetero)arylamines ✉ Begur Vasanthkumar Varun 1,2, Kannan Vaithegi 1,2, Sihyeong Yi 1 & Seung Bum Park 1 Despite the availability of numerous routes to substituted nicotinates based on the Bohlmann–Rahtz pyridine synthesis, the existing methods have several limitations, such as 1234567890():,; the inevitable ortho-substitutions and the inability to conjugate vitamin B3 to other phar- maceutical agents. Inspired by the biosynthesis of nicotinic acid (a form of vitamin B3) from tryptophan, we herein report the development of a strategy for the synthesis of meta-ami- noaryl nicotinates from 3-formyl(aza)indoles. Our strategy is mechanistically different from the reported routes and involves the transformation of (aza)indole scaffolds into substituted meta-aminobiaryl scaffolds via Aldol-type addition and intramolecular cyclization followed by C–N bond cleavage and re-aromatization. Unlike previous synthetic routes, this biomimetic method utilizes propiolates as enamine precursors and thus allows access to ortho-unsub- stituted nicotinates. In addition, the synthetic feasibility toward the halo-/boronic ester- substituted aminobiaryls clearly differentiates the present strategy from other cross-coupling strategies. Most importantly, our method enables the late-stage conjugation of bioactive (hetero)arylamines with nicotinates and nicotinamides and allows access to the previously unexplored chemical space for biomedical research. 1 CRI Center for Chemical Proteomics, Department of Chemistry, Seoul National University, Seoul 08826, Republic of Korea. 2These authors contributed ✉ equally: Begur Vasanthkumar Varun, Kannan Vaithegi. email: [email protected] NATURE COMMUNICATIONS | (2020) 11:6308 | https://doi.org/10.1038/s41467-020-19610-2 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-19610-2 ecent remarkable advancements in drug discovery have In this sequence, there are also several MCR (multicomponent inspired the development of synthetic strategies aiming for reaction) approaches developed for synthesis of polysubstituted R 33,35–38 the incorporation of bioactive skeletal features into newly pyridines sharing nicotinate/nicotinamide scaffold . However, synthesized molecules, as exemplified by late-stage functionali- the Bohlmann–Rahtz pyridine synthesis and its variants employ zation1,2, diversity-oriented synthesis (DOS)3,4, biology-oriented dicarbonyl compounds as enamine precursors and propargyl synthesis (BIOS)5, and bioconjugation reactions6,7. The key ske- ketones or α,β-unsaturated carbonyls as the Michael acceptors, and letal features of natural and synthetic bioactive compounds have therefore inevitably produce ortho-substituted nicotinates. To over- been recognized as privileged structures with high biological come this limitation, we carried out a careful analysis of the vitamin 8,9 relevance and the incorporation of such structures into mole- B3 biosynthetic process, which inspired us to design a strategy cular frameworks has been an important criterion for harnessing involving the conjugation of nicotinates with (hetero)arylamines their biological activities10,11. Therefore, the development of from simple (aza)indoles (Fig. 1d). This unparalleled biosynthetic = synthetic pathways for the incorporation of privileged structures process involves an enzymatic C2 C3 bond cleavage of the trypto- into bioactive molecules, especially at the later stages of synthesis, phan indole ring to produce N-formyl kynurenine, an important may reveal bioactivities by expanding the chemical space toward structural intermediate that can be subsequently transformed into a unexplored biological applications via skeletal functionalization. nicotinic acid, which is also a precursor to other forms of vitamin 20,21 For example, Wang et al. recently demonstrated the enhanced B3 . To simulate the formation of N-formyl kynurenine con- pharmacological effects (synergistic effects) of the products taining the aniline moiety released from the indole unit of trypto- obtained by the incorporation of the skeletal features of clopi- phan in the vitamin B3 biosynthetic process, we hypothesized the dogrel (antiplatelet drug) into SC-560 (COX-1 inhibitor) via skeletal remodeling of 3-formyl(aza)indole which allows the robust triazene-based cycloaddition, which showed that the conjugation synthesis of meta-aminoaryl nicotinates with unfunctionalized C2 of key skeletal features of drug moieties might induce synergistic and C6 positions via aldol-type addition/dehydration and intramo- effects12. On the other hand, despite the existing limitations13,14, lecular cyclization followed by simultaneous re-aromatization and much effort has been directed at the synthesis of antibody-drug C–N bond cleavage (Fig. 1eandSupplementaryFig.1). – conjugates through the covalent conjugation of small molecules Actually, highly regioselective direct C H arylation at the C3- to biomacromolecules. However, the late-stage covalent con- position of substituted pyridines are possible (Fig. 1f)39,40,only – – jugation of therapeutic agents to other bioactive small molecules, when pyridines contain electron-withdrawing groups ( NO2, CN, such as vitamins, amino acids, and sugars, has not been well –F, and –Cl) or directing group (carboximide). In addition, these explored6,7. methods cannot be employed to conjugate functional aromatics In-line with our continuous efforts to develop synthetic routes like arylamines to pyridines. Furthermore, a retrosynthetic analysis for privileged substructure-based DOS (pDOS) strategies and of the cross-coupling-based routes to ortho-nicotinated arylamines thereby increase molecular diversity10,15–17, we aimed to establish also revealed serious limitations, including long synthetic routes, a methodological concept for the late-stage modification of var- limited substrate scope due to the poor accessibility of corre- ious small molecules with biologically-relevant substructures, sponding boronic esters, and apparent competitive side reactions such as vitamins. In particular, we focused on vitamin B3, also (Fig. 1g). In fact, halogen (Br, I)- as well as boronic ester- known as niacin or nicotinic acid, because of its simple structure substituted products, which could be valuable substrates for further and high biological relevance18–21. Nicotinates and nicotinamide diversification, proved impossible to access, thereby placing serious are pharmaceutical surrogates of nicotinic acid22, and are used as constraints on transition metal-based cross-coupling strategies. dietary supplements to treat pellagra and other vitamin B3 defi- This proposed biomimetic strategy allowed the transformation of ciencies20–22 in addition to being the key ingredients of numerous (aza)indole scaffolds to the meta-amino(hetero)aryl nicotinates in cosmetics and rubefacient creams22–25. Other classes of nicotinate good yields and featured a broad substrate scope with limited side drugs include vasodilators, estrogen, androgen (Testosterone reactions while offering unique access to halogen/boronic ester- nicotinate), opioid analgesic and cough suppressants (Nicoco- substituted (hetero)arylamines conjugated to vitamin B3 along with deine), anti-inflammatory agents (Morniflumate), and hypolipi- robust conjugation of arylamines and nicotinate pharmaceuticals demic agents (Fig. 1a)18,19,22. On the other hand, (hetero) (Fig. 1h). This unique transformation involves the sequential arylamines are key structural units that are found in numerous reactions of different intermediates generated in the one-pot pharmaceuticals and feature a wide bioactivity range, as exem- strategy and almost exclusively yields a single major product at the plified by their antipyretic, analgesic, anesthetic, antiviral, anti- end of the final step. Although a number of research groups have bacterial, and anticancer activities (Fig. 1b)2,26,27. To the best of attempted indole ring transformations to aminoaryl pyrazoles or our knowledge, coupling reactions for connecting nicotinates to other fused ring scaffolds17,41–43, in this work, we show the robust arylamines have not yet been reported. Although the Suzuki– biomimetic remodeling of (aza)indoles to the vitamin B3 scaffolds Miyaura cross-coupling reaction is a standard protocol for con- conjugated to (hetero)arylamines as the last-stage transformation. structing C(sp2)–C(sp2) bonds from halogenated arylamines and appropriate arylboronic acids, this reaction has yet to be successfully applied to simple and/or electron-deficient pyridine Results boronic acids, which includes nicotinate or nicotinamide scaf- Reaction optimization and substrate scope. We initially inves- fold28–30. tigated our hypothesis (shown in Fig. 1e) for the remodeling of 3- Because of the importance of the nicotinate moiety, numerous formylindoles with the readily available β-aminoacrylate; how- methods have been developed for its synthesis. Since the pioneering ever, the reaction did not proceed efficiently (<10% conversion, synthesis of 2-methylnicotinate by Dornow and Baumgarten in see Supplementary Figs. 1 and 3). Therefore, we postulated the 1939 using β-alkoxyacrolein acetal and β-aminocrotonate31,the in situ generation of β-aminoacrylate from the corresponding – 32 Bohlmann Rahtz synthesis , which employs substituted enamines propiolates with NH4OAc, which is known