Diversifying chemical space of DNA-encoded libraries: synthesis of 2-oxa-1-azaspiro(bicyclo[3.2.0])heptanes on-DNA via visible light-mediated energy transfer catalysis.

Azaspiro[3.3]heptanes are valuable synthetic targets for drug discovery programs. The challenges associated with the preparation and diversification of this moiety as compared to other small, saturated rings have led to limited applications of compounds containing this spirocycle. In this regard, important advances in the field of synthetic photochemistry have exploited the biradical nature of the triplet excited state of 2-isoxazoline-3-carboxylates, engaging these species in intermolecular coupling reactions under visible light irradiation. As a continuation of our program preparing F(sp3)-rich, structurally complex molecules for DNA-encoded library technology (DELT) applications via photocatalysis, we disclose herein the incorporation of unique and densely functionalized 2-oxa-1-azabicyclo[3.2.0]heptanes via [2+2] cycloaddition energy transfer sensitization, providing access to an unexplored library of azaspiro compounds, many of which include additional synthetic handles important for further functionalization of the DNA-conjugated products and for library production.

Sustainable Photoinduced Decarboxylative Chlorination Mediated by Halogen Atom Transfer.

Chlorinated organic backbones constitute important components in existing biologically active chemicals, and they are extraordinary useful intermediates in organic synthesis. Herein, an operationally simple and sustainable halodecarboxylation protocol via halogen-atom transfer (XAT) as a key step is presented. The method merges a metal-free photoredox system with (diacetoxyiodo)benzene (PIDA) as a hypervalent iodine reagent using 1,2-dihaloethanes as halogen sources to afford haloalkanes in an efficient manner. The sustainability of this protocol is highlighted by an important waste recovery protocol as well as by atom economy and carbon efficiency parameters.

Photoinduced Diastereoselective Aminoalkylation of Cubanes.

The unique properties of rigid, nonconjugated hydrocarbons provide many opportunities to design molecular building blocks for a variety of applications, but the development of suitable conditions for alkylation of cubanes is quite challenging. Herein, a photoinduced method for aminoalkylation of cubanes is reported. The benign conditions reported allow the incorporation of a wide variety of (hetero)arylimine reaction partners with broad functional group tolerance and high diastereoselectivity.

Dearomative intermolecular [2 + 2] photocycloaddition for construction of C(sp3)-rich heterospirocycles on-DNA.

DNA-encoded library (DEL) screens have significantly impacted new lead compound identification efforts within drug discovery. An advantage of DELs compared to traditional screening methods is that an exponentially broader chemical space can be effectively screened using only nmol quantities of billions of DNA-tagged, drug-like molecules. The synthesis of DELs containing diverse, sp3-rich spirocycles, an important class of molecules in drug discovery, has not been previously reported. Herein, we demonstrate the synthesis of complex and novel spirocyclic cores via an on-DNA, visible light-mediated intermolecular [2 + 2] cycloaddition of olefins with heterocycles, including indoles, azaindoles, benzofurans, and coumarins. The DNA-tagged exo-methylenecyclobutane substrates were prepared from easily accessible alkyl iodides and styrene derivatives. Broad reactivity with many other DNA-conjugated alkene substrates was observed, including unactivated and activated alkenes, and the process is tolerant of various heterocycles. The cycloaddition was successfully scaled from 10 to 100 nmol without diminished yield, indicative of this reaction's suitability for DNA-encoded library production. Evaluation of DNA compatibility with the developed reaction in a mock-library format showed that the DNA barcode was maintained with high fidelity, with <1% mutated sequences and >99% amplifiable DNA from quantitative polymerase chain reaction (PCR) and next generation sequencing (NGS).

Photochemical Methods Applied to DNA Encoded Library (DEL) Synthesis.

DNA-encoded library technology (DELT) is a new screening modality that allows efficient, cost-effective, and rapid identification of small molecules with potential biological activity. This emerging technique represents an enormous advancement that, in combination with other technologies such as high-throughput screening (HTS), fragment-based lead generation, and structure-based drug design, has the potential to transform how drug discovery is carried out. DELT is a hybrid technique in which chemically synthesized compounds are linked to unique genetic tags (or "barcodes") that contain readable information. In this way, millions to billions of building blocks (BBs) attached on-DNA via split-and-pool synthesis can be evaluated against a biological target in a single experiment. Polymerase chain reaction (PCR) amplification and next-generation sequencing (NGS) analysis of the unique sequence of oligonucleotides in the DNA tag are used to identify those ligands with high affinity for the target. This innovative fusion of genetic and chemical technologies was conceived in 1992 by Brenner and Lerner (Proc. Natl. Acad. Sci. 1992, 89, 5381-5383) and is under accelerated development with the implementation of new synthetic techniques and protocols that are compatible with DNA. In fact, reaction compatibility is a key parameter to increasing the chances of identification of a drug target ligand, and a central focus has been the development of new transformations and the transition to robust protocols for on-DNA synthesis. Because the sole use of the DNA tag is as an amplifiable identification barcode, its structural integrity during a new chemical process is mandatory. As such, the use of these sensitive, polyfunctional biological molecules as substrates typically requires aqueous solutions within defined pH and temperature ranges, which is considered a notable challenge in DEL synthesis.Using low-energy visible light as the driving force to promote chemical transformations represents an attractive alternative to classical synthetic methods, and it is an important and well-established synthetic tool for forging chemical bonds in a unique way via radical intermediates. Recent advances in the field of photocatalysis are extraordinary, and this powerful research arena is still under continuous development. Several applications taking advantage of the mild reaction conditions of photoinduced transformations have been directed toward DEL synthesis, allowing the expansion of chemical space available for the evaluation of new building blocks on-DNA. There are no doubts that visible-light-driven reactions have become one of the most powerful approaches for DELT, given the easy way they provide to construct new bonds and the challenges to achieve equal success via classical protocols.Key characteristics of photocatalytic synthesis include the short reaction times and efficiency, which translate into retention of DNA integrity. In this Account, we describe recent advances in the photoinduced diversification of building blocks prepared on-DNA, highlighting the amenability of the techniques employed for preserving the genetic structure of the molecules. We demonstrate with recent research from our group the applicability of photocatalysis to the field and include in the summary a table containing all the photoinduced methods reported to date for DELT, demonstrating their key aspects such as scope, applications, and DNA compatibilities. With this information, practitioners are provided with compelling reasons for developing/choosing photocatalytic methods for DELT applications.

1,2-Radical Shifts in Photoinduced Synthetic Organic Transformations: A Guide to the Reactivity of Useful Radical Synthons.

The exploration of 1,2-radical shift (RS) mechanisms in photoinduced organic reactions has provided efficient routes for the generation of important radical synthons in many chemical transformations. In this Review, the basic concepts involved in the traditional 1,2-spin-center shift (SCS) mechanisms in recently reported studies are discussed. In addition, other useful 1,2-RSs are addressed, such as those proceeding through 1,2-group migrations in carbohydrate chemistry, via 1,2-boron shifts, and by the generation of α-amino radicals. The discussion begins with a general overview of the basic aspects of 1,2-RS mechanisms, followed by a demonstration of their applicability in photoinduced transformations. The sections that follow are organized according to the mechanisms operating in combination with the 1,2-radical migration event. This contribution is not a comprehensive review but rather aims to provide an understanding of the topic, focused on the more recent advances in the field, and establishes a definition for the nomenclature that has been used to describe such mechanisms.

On-DNA Hydroalkylation to Introduce Diverse Bicyclo[1.1.1]pentanes and Abundant Alkyls via Halogen Atom Transfer.

DNA-encoded libraries have proven their tremendous value in the identification of new lead compounds for drug discovery. To access libraries in new chemical space, many methods have emerged to transpose traditional mol-scale reactivity to nmol-scale, on-DNA chemistry. However, procedures to access libraries with a greater fraction of C(sp3) content are still limited, and the need to "escape from flatland" more readily on-DNA remains. Herein, we report a Giese addition to install highly functionalized bicyclo[1.1.1]pentanes (BCPs) using tricyclo[1.1.1.01,3]pentane (TCP) as a radical linchpin, as well as other diverse alkyl groups, on-DNA from the corresponding organohalides as non-stabilized radical precursors. Telescoped procedures allow extension of the substrate pool by at least an order of magnitude to ubiquitous alcohols and carboxylic acids, allowing us to "upcycle" these abundant feedstocks to afford non-traditional libraries with different physicochemical properties for the small-molecule products (i.e., non-peptide libraries with acids). This approach is amenable to library production, as a DNA damage assessment revealed good PCR amplifiability and only 6% mutated sequences for a full-length DNA tag.

Synthesis of α-Fluorinated Areneacetates through Photoredox/Copper Dual Catalysis.

The development of mild and practical conditions for the fluoroalkylation of arenes is an ongoing challenge in chemical organic synthesis. Herein, we report a metallaphotoredox method for the preparation of fluoroalkyl arenes based on the synergistic combination of Ir/Cu dual catalysis from boronic acids. The mild conditions allow broad functional group tolerance, including substrates containing aldehydes, free phenols, and N-Boc-protected amines. Mechanistic investigations support a process proceeding via photoredox/copper dual catalysis.

Enabling Cyclization Strategies through Carbonyl-Ylide-Mediated Synthesis of Malonate Enol Ethers.

Malonate enol ethers are afforded in one step by condensation of cyclic ketones with α-diazomalonates under [CpRu(CH3CN)3][BArF] catalysis. The dual reactivity of these 2-vinyloxymalonates can be used to expand the classical range of cyclizations derived from carbonyl ylide intermediates.

Four-Component Photoredox-Mediated Azidoalkoxy-trifluoromethylation of Alkenes.

We report herein an efficient four-component photoredox-catalyzed reaction. Under the optimized conditions using [Ru(bpy)3(PF6)2] as the photocatalyst, a wide range of terminal and internal alkenes can efficiently undergo azidoalkoxy-trifluoromethylation in the presence of Umemoto's reagent, carbonyl compound, and TMSN3, giving rise to original and highly complex molecules in a single operation.

Chiral phosphoric acid-catalyzed enantioselective construction of structurally diverse benzothiazolopyrimidines.

A highly efficient catalytic enantioselective [4+2] cycloaddition was developed between 2-benzothiazolimines and enecarbamates. A wide range of benzothiazolopyrimidines bearing three contiguous stereogenic centers was obtained in high to excellent yields and with excellent diastereo- and enantioselectivities (d.r. > 98 : 2 and up to >99% ee). Furthermore, this chiral phosphoric acid-catalyzed strategy was scalable and enabled access to a new class of optically pure Lewis base isothiourea derivatives.

Catalyst-free cycloaddition of 1,3-diene-1-carbamates with azodicarboxylates: A rapid click reaction.

Novel click reactions are of continued interest in many scientific research areas and applications. Herein, we report a novel practical, catalyst-free, azo-Diels-Alder reaction between dienecarbamates and azodicarboxylates exhibiting a remarkable functional group tolerance. The availability of starting materials, mild reaction conditions, chemoselectivity and scalability make this cycloaddition a viable supplement to the other reactions in "click" chemistry.

Highly Diastereo- and Enantioselective Synthesis of Cyclohepta[b]indoles by Chiral-Phosphoric-Acid-Catalyzed (4+3) Cycloaddition.

A highly enantio- and diastereoselective formal (4+3) cycloaddition of 1,3-diene-1-carbamates with 3-indolylmethanols in the presence of a chiral phosphoric acid catalyst is reported. The approach described herein provides efficient access to 6-aminotetrahydrocyclohepta[b]indoles in good yields with mostly complete diastereoselectivity and excellent levels of enantioselectivity (>98:2 dr and up to 98 % ee). Mild reaction conditions, facile scale-up, and versatile derivatization highlight the practicality of this methodology. A mechanistic study suggests that cycloaddition occurs in a stepwise fashion, after the formation of an ion pair between the chiral catalytic phosphate and the intermediate carbocation.

Stereoselectivity Switch in the Trapping of Polar Organometallics with Andersen's Reagent-Access to Highly Stereoenriched Transformable Biphenyls.

The trapping of racemic polar carbometallic species with (-)-menthyl ( SS)- p-toluenesulfinate (Andersen's reagent) typically proceeds with a very low level of resolution. In this paper, we describe a strategy that allows access to highly atropo-enriched and functionalizable biphenyls by means of Andersen's reagent under kinetic resolution conditions. In particular, useful enantiopure 2-iodobiphenyls could be obtained and were employed in a challenging hypervalent iodine-catalyzed oxidation reaction.

Asymmetric α-Sulfonyl- and α-Phosphoryl-Oxylation of Ketones by a Chiral Hypervalent Iodine(III).

An enantioselective direct oxygenation of propiophenone derivatives mediated by a catalytic or stoichiometric amount of new chiral non-C2-symmetric iodoarenes(III) is reported. The reaction gives an easy entry to optically active α-sulfonyl- and α-phosphoryl oxyketones in respectable yields and enantioselectivities.

Photoredox-Catalyzed Three-Component Tandem Process: An Assembly of Complex Trifluoromethylated Phthalans and Isoindolines.

A novel photoredox-mediated tandem three-component process afforded a wide variety of CF3-containing phthalans and isoindolines in respectable yields and with moderate to excellent diastereoselectivity.

Visible-Light Photoredox-Catalyzed Coupling Reaction of Azoles with α-Carbamoyl Sulfides.

A simple, straightforward strategy for the synthesis of N-substituted azoles is reported that involves a visible-light photoredox-catalyzed coupling reaction of azoles with α-carbamoyl sulfides. A variety of heterocyclic units, including pyrazoles, benzopyrazoles, benzoimidazoles, and purines, can be efficiently incorporated under mild reaction conditions in respectable yields.