Unnatural amino acids (UAAs) are key building blocks with widespread application across several scientific fields. Therefore, it is highly attractive to develop straightforward and simple methodologies capable of granting quick access to these species. Herein we report a light‐mediated protocol for the synthesis of UAA via radical decarboxylative processes. This methodology, which employs readily available and abundant starting materials – such as carboxylic and α‐keto acids – proceeds under very mild reaction conditions and shows a high functional group tolerance. In addition, the products of the radical reaction can be readily derivatized to grant rapid access to complex UAAs.

In radical processes involving Selectfluor®, TEDA 2 + * (N-(chloromethyl)triethylenediamine) is often generated after an electron or fluorine transfer step. This is a highly reactive species that displays different and unique reactivity when compared to Selectfluor®: It can act as a hydrogen atom transfer (HAT), halogen atom transfer (XAT), or aminating reagent, as well as a powerful single electron oxidant. Despite this versatility, the use of TEDA 2 + * in synthetic processes remains highly underexplored. This minireview, which covers recent applications of TEDA 2 + * to promote a wide range of C-heteroatom and CÀ C bond formations, aims to highlight the potential of this interesting species in organic chemistry. Particular attention is paid to mechanistic aspects involving how TEDA 2 + * is generated and the different reactivity patterns that it can display. TEDA 2 + * as Hydrogen Atom Transfer (HAT) ReagentThe direct functionalization of CÀ H bonds is one of the most attractive strategies for preparing synthetically useful chemicals out of abundant and cheap feedstocks. [4] A key challenge in CÀ H functionalizations is to achieve the selective activation of a given CÀ H bond. Hydrogen atom transfer (HAT) reactions represent a powerful strategy to achieve this goal. [5] One of the main applications of TEDA 2 + * in synthetic organic chemistry is its use as a HAT reagent to facilitate the formation of a wide range of C-heteroatom and CÀ C bonds. Although there are no precise measurements of the properties of TEDA 2 + * as a HAT reagent, based on its reactivity and structure, it can be compared to other amine-based HAT reagents, e. g. quinuclidine. This means that it can selectively activate hydridic CÀ H bonds with BDE � 100 kcal/mol. Csp 3 À F Bond FormationIn 2012, Lectka reported one of the first examples of the use of TEDA 2 + * in HAT processes (Scheme 1). [6] This straightforward fluorination methodology, which enabled the formation of CÀ F bonds from aliphatic, allylic or benzylic CÀ H bonds, required a Cu I catalyst, a radical precursor -N-hydroxyphthalimide (NHPI), a phase transfer catalyst (KB(C 6 F 5 ) 4 ), and Selectfluor® to proceed. Although several mechanistic studies were carried out to [a

AdriµnG ómez-Suµrez graduated from the University of Santiago de Compostela in 2009. In 2014 he was awarded his PhD from the University of St. Andrews for his studies on the chemistry of dinuclear gold complexes under the supervision of Prof. Steven P. Nolan. Forp ostdoctoral research he moved to the WWU Münster to work with Prof. Frank Glorius. In 2018 he started his habilitation at the Bergische Universität Wuppertal, under the mentorship of Prof. Stefan F. Kirsch. His research interests include radical chemistry,c atalysis, and photochemistry. Scheme 1. Syntheses of a,b-diamino esters. Scheme 2. Synthesis of C-glyco-a-AAs.

Due to their abundance and readily available synthesis, alcohols provide ideal handles for the selective derivatisation of organic molecules. Radical chemistry offers versatile strategies for the conversion of Csp3−O bonds into a wide range of Csp3−C, Csp3−H, or Csp3−heteroatom bonds. In these reactions, alcohols are readily derivatised with an activator group which can undergo facile mesolysis to generate a primary, secondary, or tertiary open‐shell species that can engage in further transformations. These strategies are particularly effective at overcoming steric limitations associated with nucleophilic substitution pathways. Despite their potential, the use of radical deoxyfunctionalisation reactions as a general strategy for the synthesis of useful and complex molecules remains underutilised. In this Review, we highlight recent advancements in this exciting field in which photocatalysis, transition metal catalysis or electrochemistry are used to initiate the radical processes.

Novel E-configured coumarin-based merocyanines were efficiently synthesized by a one-pot, three-component Sonogashira coupling-Michael addition starting from triflyl coumarins, terminal alkynes and secondary amines. The photophysical properties of the synthesized yellow to orange merocyanines were studied by UV/Vis and fluorescence spectroscopy and rationalized by Hammett-Taft correlations and DFT and TD-DFT calculations. Most compounds were only weakly fluorescent in solution; however, two compounds were investigated in more detail with respect to their aggregation behavior. The system for R =H and NR =pyrrolidinyl shows aggregation induced emission at a water content of 40-60 % in methanol, while the chromophore with R =p-Me NC H and NR =morpholinyl displays considerable aggregation induced emission enhancement with a concomitant redshift at increasing water contents in THF.

The selective activation of a given C−H bond in complex molecules possessing bonds of similar polarity and strength remains one of the foremost challenges in hydrogen atom transfer (HAT) catalysis. Herein, we present the combination of photoredox and HAT catalysis with an oxophilic boron-based catalyst to achieve the chemoselective abstraction of α-hydroxy C−H bonds in β-amino alcohols. This enables us to access α-amino ketyl radicals, which are exploited for the direct synthesis of γ-oxo-δamino esters�a prominent scaffold in biologically active molecules.

Herein we present a highly efficient, light-mediated, deoxygenative protocol to access g-oxo-a-amino acid derivatives. This radical methodology employs photoredox catalysis, in combination with triphenylphosphine, to generate acyl radicals from readily available (hetero)aromatic and vinylic carboxylic acids. This approach allows for the straightforward synthesis of g-oxo-aamino acids bearing a wide range of functional groups (e.g. Cl, CN, furan, thiophene, Bpin) in synthetically useful yields (~ 60% average yield). To further highlight the utility of the methodology, several deprotection and derivatization reactions were carried out.

Triple-negative breast cancer (TNBC), representing the most aggressive form of breast cancer with currently no targeted therapy available, is characterized by an inflammatory and hypoxic tumor microenvironment. To date, a broad spectrum of anti-tumor activities has been reported for phenanthroindolizidine alkaloids (PAs), however, their mode of action in TNBC remains elusive. Thus, we investigated six naturally occurring PAs extracted from the plant Tylophora ovata: O-methyltylophorinidine (1) and its five derivatives tylophorinidine (2), tylophoridicine E (3), 2-demethoxytylophorine (4), tylophoridicine D (5), and anhydrodehydrotylophorinidine (6). In comparison to natural (1) and for more-in depth studies, we also utilized a sample of synthetic O-methyltylophorinidine (1s). Our results indicate a remarkably effective blockade of nuclear factor kappa B (NFκB) within 2 h for compounds (1) and (1s) (IC50 = 17.1 ± 2.0 nM and 3.3 ± 0.2 nM) that is different from its effect on cell viability within 24 h (IC50 = 13.6 ± 0.4 nM and 4.2 ± 1 nM). Furthermore, NFκB inhibition data for the additional five analogues indicate a structure–activity relationship (SAR). Mechanistically, NFκB is significantly blocked through the stabilization of its inhibitor protein kappa B alpha (IκBα) under normoxic as well as hypoxic conditions. To better mimic the TNBC microenvironment in vitro, we established a 3D co-culture by combining the human TNBC cell line MDA-MB-231 with primary murine cancer-associated fibroblasts (CAF) and type I collagen. Compound (1) demonstrates superiority against the therapeutic gold standard paclitaxel by diminishing spheroid growth by 40% at 100 nM. The anti-proliferative effect of (1s) is distinct from paclitaxel in that it arrests the cell cycle at the G0/G1 state, thereby mediating a time-dependent delay in cell cycle progression. Furthermore, (1s) inhibited invasion of TNBC monoculture spheroids into a matrigel®-based environment at 10 nM. In conclusion, PAs serve as promising agents with presumably multiple target sites to combat inflammatory and hypoxia-driven cancer, such as TNBC, with a different mode of action than the currently applied chemotherapeutic drugs.