Rapid Generation Of Molecular Complexity Research Articles

Photoredox/Cu‐Catalyzed Decarboxylative C(sp3)−C(sp3) Coupling to Access C(sp3)‐Rich gem‐Diborylalkanes

Abstractgem‐Diborylalkanes are highly valuable building blocks in organic synthesis and pharmaceutical chemistry due to their ability to participate in multi‐step cross‐coupling transformations, allowing for the rapid generation of molecular complexity. While progress has been made in their synthetic metholodology, the construction of β‐tertiary and C(sp3)‐rich gem‐diborylalkanes remains a synthetic challenge due to substrate limitations and steric hindrance issues. An approach is presented that utilizes synergistic photoredox and copper catalysis to achieve efficient C(sp3)−C(sp3) cross‐coupling of alkyl N‐hydroxyphthalimide esters, which can easily be obtained from alkyl carboxylic acids, with diborylmethyl species, providing a series of C(sp3)‐rich gem‐diborylalkanes with 1°, 2°, and even 3° β positions. Furthermore, this approach can also be applied to complex medicinal compounds and natural products, offering rapid access to molecular complexity and late‐stage functionalization of C(sp3)‐rich drug candidates. Mechanistic experiments revealed that diborylmethyl Cu(I) species participated in both the photoredox process and the key C(sp3)−C(sp3) bond‐forming step.

Photoredox/Cu-Catalyzed Decarboxylative C(sp3)-C(sp3) Coupling to Access C(sp3)-Rich gem-Diborylalkanes.

gem-Diborylalkanes are highly valuable building blocks in organic synthesis and pharmaceutical chemistry due to their ability to participate in multi-step cross-coupling transformations, allowing for the rapid generation of molecular complexity. While progress has been made in their synthetic metholodology, the construction of β-tertiary and C(sp3)-rich gem-diborylalkanes remains a synthetic challenge due to substrate limitations and steric hindrance issues. An approach is presented that utilizes synergistic photoredox and copper catalysis to achieve efficient C(sp3)-C(sp3) cross-coupling of alkyl N-hydroxyphthalimide esters, which can easily be obtained from alkyl carboxylic acids, with diborylmethyl species, providing a series of C(sp3)-rich gem-diborylalkanes with 1°, 2°, and even 3° β positions. Furthermore, this approach can also be applied to complex medicinal compounds and natural products, offering rapid access to molecular complexity and late-stage functionalization of C(sp3)-rich drug candidates. Mechanistic experiments revealed that diborylmethyl Cu(I) species participated in both the photoredox process and the key C(sp3)-C(sp3) bond-forming step.

Silver‐Enabled Cycloaddition of Bicyclobutanes with Isocyanides for the Synthesis of Polysubstituted 3‐Azabicyclo[3.1.1]heptanes

AbstractSynthesis of bicyclic scaffolds has emerged as an important research topic in modern drug development because they can serve as saturated bioisosters to enhance the physicochemical properties and metabolic profiles of drug candidates. Here we report a remarkably simple silver‐enabled strategy to access polysubstituted 3‐azabicyclo[3.1.1]heptanes in a single operation from readily accessible bicyclobutanes (BCBs) and isocyanides. The process is proposed to involve a formal (3+3)/(3+2)/retro‐(3+2) cycloaddition sequence. This novel protocol allows for rapid generation of molecular complexity from simple starting materials, and the products can be easily derivatized, further enriching the BCB cycloaddition chemistry and the growing set of valuable sp3‐rich bicyclic building blocks.

Silver-Enabled Cycloaddition of Bicyclobutanes with Isocyanides for the Synthesis of Polysubstituted 3-Azabicyclo[3.1.1]heptanes.

Synthesis of bicyclic scaffolds has emerged as an important research topic in modern drug development because they can serve as saturated bioisosters to enhance the physicochemical properties and metabolic profiles of drug candidates. Here we report a remarkably simple silver-enabled strategy to access polysubstituted 3-azabicyclo[3.1.1]heptanes in a single operation from readily accessible bicyclobutanes (BCBs) and isocyanides. The process is proposed to involve a formal (3+3)/(3+2)/retro-(3+2) cycloaddition sequence. This novel protocol allows for rapid generation of molecular complexity from simple starting materials, and the products can be easily derivatized, further enriching the BCB cycloaddition chemistry and the growing set of valuable sp3-rich bicyclic building blocks.

Cobalt-Catalyzed Asymmetric Remote Borylation of Alkyl Halides.

Enantioselective functionalization of racemic alkyl halides is an efficient strategy to assemble complex chiral molecules, but remains one of the biggest challenges in organic chemistry. The distant and selective activation of unreactive C-H bonds in alkyl halides has received growing interest as it enables rapid generation of molecular complexity from simple building blocks. Here, we reported a cobalt-catalyzed remote borylation of alkyl (pseudo)halides (alkyl-X, X=I, Br, Cl, OTs) with pinacolborane (HBpin) and presented a robust approach for the generation of valuable chiral secondary organoboronates from racemic alkyl halides. This migration borylation reaction is compatible with primary, secondary, and tertiary bromides, offering direct access to a broad range of alkylboronates. The extension of this catalytic system to the borylation of aryl halides was also demonstrated. Preliminary mechanistic studies revealed that this remote borylation involved a radical reaction pathway.

Cobalt‐Catalyzed Asymmetric Remote Borylation of Alkyl Halides

AbstractEnantioselective functionalization of racemic alkyl halides is an efficient strategy to assemble complex chiral molecules, but remains one of the biggest challenges in organic chemistry. The distant and selective activation of unreactive C−H bonds in alkyl halides has received growing interest as it enables rapid generation of molecular complexity from simple building blocks. Here, we reported a cobalt‐catalyzed remote borylation of alkyl (pseudo)halides (alkyl−X, X=I, Br, Cl, OTs) with pinacolborane (HBpin) and presented a robust approach for the generation of valuable chiral secondary organoboronates from racemic alkyl halides. This migration borylation reaction is compatible with primary, secondary, and tertiary bromides, offering direct access to a broad range of alkylboronates. The extension of this catalytic system to the borylation of aryl halides was also demonstrated. Preliminary mechanistic studies revealed that this remote borylation involved a radical reaction pathway.

Enantioselective Hydroalkenylation and Hydroalkynylation of Alkenes Enabled by a Transient Directing Group: Catalyst Generality through Rigidification.

The catalytic enantioselective synthesis of α-chiral alkenes and alkynes represents a powerful strategy for rapid generation of molecular complexity. Herein, we report a transient directing group (TDG) strategy to facilitate site-selective palladium-catalyzed reductive Heck-type hydroalkenylation and hydroalkynylation of alkenylaldehyes using alkenyl and alkynyl bromides, respectively, allowing for construction of a stereocenter at the δ-position with respect to the aldehyde. Computational studies reveal the dual beneficial roles of rigid TDGs, such as L-tert-leucine, in promoting TDG binding and inducing high levels of enantioselectivity in alkene insertion with a variety of migrating groups.

Enantioselective Hydroalkenylation and Hydroalkynylation of Alkenes Enabled by a Transient Directing Group: Catalyst Generality through Rigidification**

AbstractThe catalytic enantioselective synthesis of α‐chiral alkenes and alkynes represents a powerful strategy for rapid generation of molecular complexity. Herein, we report a transient directing group (TDG) strategy to facilitate site‐selective palladium‐catalyzed reductive Heck‐type hydroalkenylation and hydroalkynylation of alkenylaldehyes using alkenyl and alkynyl bromides, respectively, allowing for construction of a stereocenter at the δ‐position with respect to the aldehyde. Computational studies reveal the dual beneficial roles of rigid TDGs, such as L‐tert‐leucine, in promoting TDG binding and inducing high levels of enantioselectivity in alkene insertion with a variety of migrating groups.

Palladium-Catalyzed Cascade Cyclization/Alkylation of Oxime Ethers: Assembly of 4-Alkylisoxazoles by "Chain-Walking" Strategy.

A reliable and efficient palladium-catalyzed cascade cyclization/alkylation of oxime ethers with unactivated alkenes is described, affording a whole variety of structurally diverse isoxazole derivatives in moderate to good yields with excellent functional group compatibility. Ionic liquid [Aeim]Br not only acts as an environmentally friendly solvent but also acts as an accelerating agent to provide excess bromine source to eliminate bromomethane from oxime ethers. More importantly, the use of "chain-walking" strategy provides a novel methodology in organic synthesis to rapid generation of molecular complexity from readily available starting materials.

Visible-Light-Mediated Three-Component Cascade Sulfonylative Annulation.

Visible-light-promoted cascade radical cyclization for the synthesis of sulfonylated benzimidazo/indolo[2,1-a]iso-quinolin-6(5H)-ones has been reported. The reaction provides transition-metal-free and expeditious access to sulfonylated polyaromatics. The use of sodium metabisulfite as a SO2 surrogate and the rapid generation of molecular complexity using a three-component photochemical protocol are the salient features of this reaction manifold.

Synthesis of Highly Congested Tertiary Alcohols via the [3,3] Radical Deconstruction of Breslow Intermediates.

Pericyclic processes such as [3,3]-sigmatropic rearrangements leading to the rapid generation of molecular complexity constitute highly valuable tools in organic synthesis. Herein, we report the formation of particularly hindered tertiary alcohols via rearrangement of Breslow intermediates formed in situ from readily available N-allyl thiazolium salts and benzaldehyde derivatives. Experimental mechanistic studies performed suggest that the reaction proceeds via a close radical pair which recombine in a regio- and diastereoselective manner, formally leading to [3,3]-rearranged products.

Biomimetic Diels–Alder Reactions in Natural Product Synthesis: A Personal Retrospect

AbstractNature has been recognized for her super capability of constructing complex molecules with remarkable efficiency and elegancy. Among nature’s versatile synthetic toolkits, Diels–Alder reaction is particularly attractive since it allows for rapid generation of molecular complexity from simple precursors. For natural products biosynthetically formed through Diels–Alder reactions, the most straightforward way to access them should build on biomimetic Diels–Alder reactions. However, the implementation of biomimetic Diels–Alder reactions in a laboratory setting may encounter considerable challenges, particularly for those suffering from complicated reactivity and selectivity issues. Indeed, the translation of a biosynthetic hypothesis into a real biomimetic synthesis entails the orchestrated combination of nature’s inspiration and chemist’s rational design. In this Account, we will briefly summarize our recent progress on the application of biomimetic Diels–Alder reactions in natural product synthesis. As shown in the discussed stories, rational manipulation of the structures of biosynthetic precursors plays a crucial role for the successful implementation of biomimetic Diels–Alder reactions.1 Introduction2 Biomimetic Synthesis of Rossinone B3 Biomimetic Synthesis of Homodimericin A4 Biomimetic Synthesis of Polycyclic and Dimeric Xanthanolides5 Biomimetic Synthesis of Periconiasins and Pericoannosins6 Biomimetic Synthesis of Merocyctochalasans7 Conclusion and Outlook

A Widely Applicable Dual Catalytic System for Cross-Electrophile Coupling Enabled by Mechanistic Studies.

A dual catalytic system for cross-electrophile coupling reactions between aryl halides and alkyl halides that features a Ni catalyst, a Co cocatalyst, and a mild homogeneous reductant is described. Mechanistic studies indicate that the Ni catalyst activates the aryl halide, while the Co cocatalyst activates the alkyl halide. This allows the system to be rationally optimized for a variety of substrate classes by simply modifying the loadings of the Ni and Co catalysts based on the reaction product profile. For example, the coupling of aryl bromides and aryl iodides with alkyl bromides, alkyl iodides, and benzyl chlorides is demonstrated using the same Ni and Co catalysts under similar reaction conditions but with different optimal catalyst loadings in each case. Our system is tolerant of numerous functional groups and is capable of coupling heteroaryl halides, di-ortho-substituted aryl halides, pharmaceutically relevant druglike aryl halides, and a diverse range of alkyl halides. Additionally, the dual catalytic platform facilitates a series of selective one-pot three-component cross-electrophile coupling reactions of bromo(iodo)arenes with two distinct alkyl halides. This demonstrates the unique level of control that the platform provides and enables the rapid generation of molecular complexity. The system can be readily utilized for a wide range of applications as all reaction components are commercially available, the reaction is scalable, and toxic amide-based solvents are not required. It is anticipated that this strategy, as well as the underlying mechanistic framework, will be generalizable to other cross-electrophile coupling reactions.

Biomimetic Synthetic Studies on the Bruceol Family of Meroterpenoid Natural Products.

A biomimetic approach to total synthesis can offer several benefits, including the development of cascade reactions for the rapid generation of molecular complexity, and guidance in the structure revision of old natural products and the anticipation of new ones. Herein, we describe how a biomimetic synthesis of bruceol, a pentacyclic meroterpenoid, led to the anticipation, isolation, and synthesis of isobruceol. The key step in the synthesis of both bruceol and isobruceol was an intramolecular hetero-Diels-Alder reaction of an o-quinone methide that was formed by dearomatization of an electron-rich chromene. The synthesis of an elusive biosynthetic intermediate also allowed a concise synthesis of eriobrucinol via a photochemical [2 + 2] cycloaddition. Furthermore, some speculation on the biosynthesis of prenylated bruceol derivatives inspired the development of a Claisen/Cope/Diels-Alder cascade reaction. We also report the generation of halogenated bruceol derivatives and the synthesis of several protobruceol natural products using singlet oxygen ene reactions.

Ultrasound-assisted green one-pot synthesis of linked bis-heterocycle peptidomimetics via IMCR/post-transformation/tandem strategy

The sequential aligning of two eco-friendly and powerful tools for the synthesis of peptidomimetics resulted in the rapid generation of molecular complexity in target molecules. We herein report a versatile IMCR/post-transformation/tandem synthetic strategy that emphasizes the special role of orthogonal bifunctional reagents in isocyanide based multicomponent reactions (IMCR) to generate a synthetic platform for subsequent heterocyclization reactions. This is the first one-pot synthesis of a 2,5-diketopiperazine linked to a 1,4-disubstituted 1,2,3-triazole. The Ugi-4CR/lactamization/click sequence is facile, mild, atom-economical, and green. The present work contributes to the green and one-pot synthesis of bis-heterocycle peptidomimetics and design of new bioactive molecules.

Rapid Generation of Molecular Complexity by Chemical Synthesis: Highly Efficient Total Synthesis of Hexacyclic Alkaloid (-)-Chaetominine and Its Biosynthetic Implications.

The efficiency becomes a key issue in today's natural product total synthesis. While biomimetic synthesis is one of the most elegant strategies to achieve synthetic efficiency and thus to approach the ideal synthesis, most biogenetic pathways are unknown or unconfirmed. In this account, we demonstrate, through the shortest and also the most efficient asymmetric total syntheses of the hexacyclic alkaloid (-)-chaetominine to date, that on the basis of biogenetic thinking, one can develop quite efficient bio-inspired total synthesis, which in turn serves to suggest and chemically validate plausible biosynthetic routes for the natural product. The synthetic strategy thus developed is also inspiring for the development of other synthetic methods and efficient total synthesis of other natural products.

Radical cascade reactions triggered by single electron transfer

The rapid generation of molecular complexity from simple starting materials is of paramount importance in synthetic chemistry. The unique combination of high reactivity and high selectivity often associated with open-shell intermediates makes radical chemistry ideal for cascade reactions, in which simple substrates undergo a series of processes involving bond formation (and bond cleavage) to give complex, high-value products. Crucially, radical cascade reactions can greatly diminish the time, cost and amount of waste associated with complex target synthesis. Recent exciting advances in the field of radical chemistry initiated by single electron transfer (SET) have led to a considerable upward shift in our ability to design powerful new cascade reactions. This Review highlights recent advances in the development of radical cascades, triggered by SET processes, that deliver molecular constructs of importance in medicine and biology. This Review considers cascade reactions initiated by single electron transfer. Open-shell intermediates are highly reactive but undergo reactions with high selectivity. They are thus ideal intermediates in cascade reactions that generate complex, high-value products from simple starting materials

Enantioselective cyclizations and cyclization cascades of samarium ketyl radicals.

The rapid generation of molecular complexity from simple starting materials is a key challenge in synthesis. Enantioselective radical cyclization cascades have the potential to deliver complex, densely packed, polycyclic architectures, with control of three-dimensional shape, in one step. Unfortunately, carrying out reactions with radicals in an enantiocontrolled fashion remains challenging due to their high reactivity. This is particularly the case for reactions of radicals generated using the classical reagent, SmI2. Here, we demonstrate that enantioselective SmI2-mediated radical cyclizations and cascades that exploit a simple, recyclable chiral ligand can convert symmetrical ketoesters to complex carbocyclic products bearing multiple stereocentres with high enantio- and diastereocontrol. A computational study has been used to probe the origin of the enantioselectivity. Our studies suggest that many processes that rely on SmI2 can be rendered enantioselective by the design of suitable ligands.

Cyclisations Catalysed by Bismuth(III) Triflate

Cyclisation reactions have always drawn the attention of organic chemists in pursuit of methods for the selective construction of natural‐product‐like polycyclic compounds. The search for new and efficient ring‐forming reactions has witnessed growing interest, resulting in the design of many elegant synthetic strategies and the discovery of useful methodologies. In this context, cycloisomerisation reactions are very attractive, because they allow for the rapid generation of molecular complexity with use of a low loading of a promoter, thus limiting waste production. The search for sustainable and more efficient catalytic systems remains challenging. Relatively nontoxic and inexpensive bismuth(III) salts are of particular interest for catalytic organic synthesis. More specifically, the highly active triflate salt is known to be noncorrosive and easy to handle. This microreview focuses on cyclisation reactions assisted by bismuth(III) triflate catalysis.

ChemInform Abstract: Enantioselective Polyene Cyclizations

AbstractReview: [50 refs.