Memory of Chirality

Nature

Stereospecific Radical Coupling with a Non-Natural Photodecarboxylase

V. Tseliou,^† L. Kqiku,^† M. Berger, F. Schiel, H. Zhou, G. J. Poelarends & P. Melchiorre*

Nature 2024 (DOI: 10.1038/s41586-024-08004-9)

Photoenzymes are light-powered biocatalysts that typically rely on the excitation of cofactors or unnatural amino acids for their catalytic activities. A notable natural example is the fatty acid photodecarboxylase (FAP), which uses light energy to convert aliphatic carboxylic acids to achiral hydrocarbons. Here, the authors report a way to design a non-natural photodecarboxylase based on the excitation of enzyme-bound catalytic intermediates, instead of relying on cofactor excitation. Iminium ions, transiently generated from enals within the active site of an engineered class I aldolase, can absorb violet light and function as single-electron oxidants. Activation of chiral carboxylic acids, followed by decarboxylation, generates two radicals that undergo stereospecific cross-coupling, yielding products with two stereocenters. Using the appropriate enantiopure chiral substrate, the desired diastereoisomeric product is selectively obtained with complete enantiocontrol. This finding underscores the active site's ability to transfer stereochemical information from the chiral radical precursor into the product, effectively addressing the longstanding problem of rapid racemization of chiral radicals. The resulting “memory of chirality” scenario is a rarity in enantioselective radical chemistry.

Nature Chemistry

Radical-Triggered Translocation of C–C Double Bond and Functional Group

S. Wang,^† X. Luo,^† Y. Wang,^† Z. Liu, Y. Yu, X. Wang, D. Ren, P. Wang, Y.-H. Chen, X. Qi,* H. Yi* & A. Lei*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01633-7)

Multi-site functionalization of molecules provides a powerful approach to access intricate compounds. However, simultaneous functionalization of a reactive site and an inert remote C(sp³ )–H poses a formidable challenge, as chemical reactions conventionally occur at the most active site. In addition, achieving precise control over site selectivity for remote C(sp³ )–H activation presents an additional hurdle. Here, the authors report an alternative modular method for alkene difunctionalization, encompassing radical-triggered translocation of functional groups and remote C(sp³ )–H desaturation via photo/cobalt dual catalysis. By systematically combining radical addition, functional group migration and cobalt-promoted hydrogen atom transfer, the translocation of a carbon–carbon double bond and another functional group with precise site selectivity and remarkable E/Z selectivity has been achieved. This redox-neutral approach shows good compatibility with diverse fluoroalkyl and sulfonyl radical precursors, enabling the migration of benzoyloxy, acetoxy, formyl, cyano and heteroaryl groups.

Stereoselective and Site-Divergent Synthesis of C-Glycosides

S. Xu,^† Y. Ping,^† M. Xu, G. Wu, Y. Ke, R. Miao, X. Qi* & W. Kong*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01629-3)

Carbohydrates play important roles in medicinal chemistry and biochemistry. However, their synthesis relies on specially designed glycosyl donors, which are often unstable and require multi-step synthesis. Furthermore, the catalytic and stereoselective installation of arylated quaternary stereocentres on sugar rings remains a formidable challenge. Here, the authors report a facile and versatile method for the synthesis of diverse C–R (R = (hetero)aryl, alkenyl, alkynyl or alkyl) glycosides from readily available and bench-stable 1-deoxyglycosides. The reaction proceeds under mild conditions and exhibits high stereoselectivity across a broad range of glycosyl units. This protocol can be used to synthesize challenging 2-deoxyglycosides, unprotected glycosides, non-classical glycosides and deuterated glycosides. Catalyst-controlled site-divergent functionalization for the synthesis of carbohydrates containing arylated quaternary stereocentres that are inaccessible by existing methods has also been developed. The synthetic utility is further demonstrated in the synthesis of pharmaceutically relevant molecules and carbohydrates.

Nature Communications

Deoxytrifluoromethylation/Aromatization of Cyclohexan(en)ones to Access Highly Substituted Trifluoromethyl Arenes

P. Bhattarai, M. K. A. El-Gaber,^‡ S. Koley^‡ & R. A. Altman

Nat. Commun. 2024, 15, 7882 (DOI: 10.1038/s41467-024-52035-9) 🔓

Trifluoromethyl arenes (Ar–CF₃) are amongst the most commonly encountered fluorinated substructures in pharmaceutical, agrochemical, and material sciences. However, methods to access Ar–CF₃ often possess several limitations, including harsh conditions, lack of substrate availability and poor regioselectivity, all of which restrict access to desirable highly functionalized Ar–CF₃-containing compounds. To expand the scope of accessible Ar–CF₃-based molecules, the authors present an orthogonal deoxyfluoroalkylation/aromatization approach that exploits readily accessible and programable cyclohexan(en)one substrates, which undergo a reliable 1,2-addition reaction with the Ruppert-Prakash reagent (TMSCF₃) followed by aromatization to deliver highly functionalized Ar–CF₃ compounds in a one/two-pot sequence.

Journal of the American Chemical Society

Total Synthesis of the Phenylnaphthacenoid Type II Polyketide Antibiotic Formicamycin H via Regioselective Ruthenium-Catalyzed Hydrogen Auto-Transfer [4+2] Cycloaddition

G. Hu,^† R. S. Doerksen,^† B. R. Ambler & M. J. Krische*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c09068)

The first total synthesis of the pentacyclic phenylnaphthacenoid type II polyketide antibiotic formicamycin H is described. A key feature of the synthesis involves the convergent, regioselective assembly of the tetracyclic core via ruthenium-catalyzed α-ketol-benzocyclobutenone [4+2] cycloaddition. Double dehydration of the diol-containing cycloadduct provides an achiral enone, which upon asymmetric nucleophilic epoxidation and further manipulations delivers the penultimate tetracyclic trichloride in enantiomerically enriched form. Subsequent chemo- and atroposelective Suzuki cross-coupling of the tetracyclic trichloride introduces the E-ring to complete the total synthesis. Single-crystal X-ray diffraction analyses of two model compounds suggest that the initially assigned stereochemistry of the axially chiral C6–C7 linkage may require revision.

Chemoenzymatic Oxidation of Labdane and Formal Synthesis of Nimbolide

X. Liu,^† Y. Xu,^† L. Li & J. Li*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c07956)

In nature, basic terpene skeletons are produced and subsequently undergo enzymatic or non-enzymatic oxidative transformations, leading to diverse structural variations. To date, thousands of natural products featuring a variety of oxidation patterns have been isolated solely from the labdane family. This work describes a strategy for the comprehensive introduction of oxidation states into the labdane core by employing a combination of enzyme library screening, directed evolution, and sequential chemical oxidation processes. Furthermore, the functional viability of this chemoenzymatic approach has been showcased by accomplishing a formal synthesis of nimbolide, highlighting its potential for streamlining the synthesis of complex natural products.

Photocatalytic Decarboxylative Alkylation of Cyclic Imine–BF₃ Complexes: A Modular Route to Functionalized Azacycles

K. Bhatt, A. Adili, A. H. Tran, K. M. Elmallah, I. Ghiviriga & D. Seidel*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c08754)

Alkyl radicals generated via an acridine photocatalyzed decarboxylation reaction of feedstock carboxylic acids engage with a range of cyclic imine–BF₃ complexes to provide α-functionalized azacycles in an operationally simple process. A three-component variant of this transformation incorporating [1.1.1]propellane as an additional reaction partner enables the synthesis of valuable bicyclopentane (BCP)-containing azacycles. Reactions exhibit good functional group compatibility, enabling late-stage modification of complex bioactive molecules.

A General Enantioselective α-Alkyl Amino Acid Derivatives Synthesis Enabled by Cobalt-Catalyzed Reductive Addition

C. Zhang, X. Wu, J. Qu & Y. Chen*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c09556)

Enantioenriched unnatural amino acids represent a prevalent motif in organic chemistry with profound applications in biochemistry, medicinal chemistry, and materials science. Herein, the authors report a cobalt-catalyzed aza-Barbier reaction of dehydroglycines with unactivated alkyl halides to afford unnatural α-amino esters with high enantioselectivity. This catalytic reductive alkylative addition protocol circumvents the use of moisture-, air-sensitive organometallic reagents, and stoichiometric chiral auxiliaries, enabling the conversion of a variety of primary, secondary, and even tertiary unactivated alkyl halides to α-alkyl-amino esters under mild conditions, thus leading to broad functional group tolerance.

ACS Catalysis

Ni-Catalyzed Deoxygenative Cross-Coupling of Alcohols with Aryl Chlorides via an Organic Photoredox Process

W. Xiong, T. Kang,* F. Li, H. Liao, Y. Yan, J. Dong, G. Li & D. Xue*

ACS Catal. 2024, ASAP (DOI: 10.1021/acscatal.4c03909)

Cross-electrophile coupling from naturally abundant materials is of significant value in organic synthesis. Herein, the authors established a highly efficient deoxygenative cross-coupling reaction using alcohols and aryl chlorides as coupling partners by merging photoredox and nickel catalysis with a diaryl ketone photocatalyst. This methodology features a broad substrate scope, high functional group tolerance, scale-up synthesis and the late-stage modification of structurally complex natural products and pharmaceuticals, including C-4 alkylated pyridines.

Angewandte Chemie International Edition

Synthesis of Non-canonical Tryptophan Variants via Rh-catalyzed C–H Functionalization of Anilines

J. Z. Huang, V. Y. Ying & M. R. Seyedsayamdost*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202414998)

Previously: ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-7bgzg) 🔓

Tryptophan and its non-canonical variants play critical roles in pharmaceutical molecules and enzymes. Facile access to this privileged class of amino acids from readily available building blocks remains a long-standing challenge. Here, the authors report a regioselective synthesis of non-canonical tryptophans bearing C4-C7 substituents via Rh-catalyzed annulation between structurally diverse tert-butyloxycarbonyl (Boc)-protected anilines and alkynyl chlorides readily prepared from amino acid building blocks. This transformation harnesses Boc-directed C–H metalation and demetalation to afford a wide range of C2-unsubstituted indole products in a redox-neutral fashion. This umpolung approach compared to the classic Larock indole synthesis offers a novel mechanism for heteroarene annulation and will be useful for the synthesis of natural products and drug molecules containing non-canonical tryptophan residues in a highly regioselective manner.

ChemRxiv

Synthesis of Diverse Terpenoid Frameworks via Enzyme-Enabled Abiotic Scaffold Hop

H. Deng, J. Yang, F. Li, J. Li* & H. Renata*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-4kpr3) 🔓

Owing to their structural complexity, target-oriented syntheses of natural products usually requires the design of individualized routes that are tailor-made for the specific targets. As such, route re-design is needed when targets of different skeletal connectivities are considered. Here, the authors report a versatile synthetic strategy that runs counter to this conventional wisdom and allows access to a range of terpenoids with distinct skeletal frameworks from the sesquiterpene lactone sclareolide as the starting material. By viewing a biocatalytically-installed alcohol as an exploitable motif rather than a structural endpoint, a number of abiotic skeletal rearrangements were designed, resulting in significant structural divergence from the original drimane ring system of sclareolide. Using this approach, the syntheses of four terpenoid natural products, namely merosterolic acid B, cochlioquinone B, (+)-daucene and dolasta-1(15),8-diene, were achieved.

Contrasteric Glycosylations of Cotylenol and 1,2-Diols by Virtual Linker Selection

D. W. Snelson,^† S. I. Ting^† & R. A. Shenvi*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-j7c15) 🔓

Many terpene glycosides exhibit contrasteric patterns of 1,2-diol glycosylation in which the more hindered alcohol bears a sugar; protection of the less hindered alcohol only increases steric repulsion. Here, the authors report a method for contrasteric glycosylation using a new sugar-linker that forms a cleavable, 10-membered ring with high efficiency, leading to syntheses of cotylenin E, J, and ISIR-050. Linker selection was aided by DFT calculations of side reactions and stereoselectivity, as well as conformational analysis using autoDFT, a Python script that converts SMILES strings to DFT-optimized conformational ensembles.

Cobalt-Hydride Catalyzed Alkene-Carboxylate Transposition (ACT) of Allyl Carboxylates via 1,2-Radical Migration (RaM)

G. Zhao,* A. Khosravi, S. Sharma, D. G. Musaev* & M.-Y. Ngai*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-glz1z) 🔓

The Alkene-Carboxylate Transposition (ACT) of allyl carboxylates is one of the most atom-economic and synthetically reliable transformations in organic chemistry. Classic ACT transformations, including 3,3-sigmatropic rearrangement and transition metal-catalyzed allylic rearrangement, typically yield 1,2-alkene/1,3-acyloxy shifted products through a two-electron process. However, position-altered ACT to produce distinct 1,3-alkene/1,2-acyloxy shifted products has remained elusive. Here, the authors report the first cobalt-hydride catalyzed ACT of allyl carboxylates, enabling access to these unprecedented 1,3-alkene/1,2-acyloxy shifted products via a 1,2-radical migration (RaM) strategy. This transformation demonstrates broad functional group tolerance, is suitable for late-stage modification of complex molecules, and is amenable to gram-scale synthesis.

Facile Generation of ortho-Quinodimethanes Toward Polycyclic Compounds

K. Inagaki, Y. Onozawa, Y. Fukuhara, D. Yokogawa, K. Muto* & J. Yamaguchi*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-dnf75) 🔓

The Diels–Alder reaction is a cornerstone of organic synthesis, enabling the construction of complex molecular architectures through the cycloaddition of a diene and a dienophile. Among the various dienes employed in this reaction, ortho-quinodimethane stands out as an exceptionally powerful intermediate due to its high reactivity, making it particularly effective for constructing benzo-fused polycyclic skeletons. Although this method has been widely applied in total synthesis, the requirement for the laborious preparation of its precursors remains a significant challenge. This study presents a solution through a conceptually distinct palladium-catalyzed generation of ortho-quinodimethane via a multicomponent assembly reaction of 2-vinylbromoarenes, diazo species, and carbon nucleophiles bearing a dienophile moiety. The synthetic applications of this ortho-quinodimethane generation method are demonstrated through the synthesis of a range of polycyclic compounds, including a natural product, highlighting the convergent and diversity-generating nature of this reaction.

Chem

Pyridine-Boryl Radical-Catalyzed [3π+2σ] Cycloaddition for the Synthesis of Pyridine Bioisosteres

Y. Liu, S. Lin, Z. Ding, Y. Li, Y.-J. Tang, J.-H. Xue, Q. Li, P. Li* & H. Wang*

Chem 2024, Online Now (DOI: 10.1016/j.chempr.2024.08.010)

Previously: ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-n3wlw) 🔓

The utilization of C(sp³ )-rich three-dimensional (3D) scaffolds as bioisosteres for pyridine presents formidable challenges as these scaffolds must accurately replicate the spatial stereochemistry and basicity of pyridine. Herein, the authors disclose a pyridine-boryl radical-catalyzed [3π+2σ] cycloaddition reaction of vinyl azides with bicyclo[1.1.0]butanes (BCBs). This reaction offers an efficient and metal-free synthesis of unprecedented 2-azabicyclo[3.1.1]heptenes, which serve as potential bioisosteres of 1,3,5-trisubstituted pyridines.

Chemical Science

Deprotective Lossen Rearrangement: A Direct and General Transformation of Nms-Amides to Unsymmetrical Ureas

P. Spieß, J. Brześkiewicz & N. Maulide*

Chem. Sci. 2024, Accepted (DOI: 10.1039/D4SC04974H) 🔓

Ureas stand out as potent pharmacophores in drug development, rendering them a prime focus for synthesis. Herein, the authors present an appealing entry point for urea synthesis from protected amines (Nms-amides) and relying on a Lossen-type rearrangement process as an elegant example of deprotective functionalisation. The method developed exhibits an exceptionally broad tolerance towards various protected amines, encompassing numerous drug derivatives, and delivers high reaction yields.

That’s all for this issue! Have a great week and we’ll see you next Monday.