Preparing Pyridines from Pyrimidines

Nature

A Deconstruction-Reconstruction Strategy for Pyrimidine Diversification

B. J. H. Uhlenbruck, C. M. Josephitis, L. de Lescure, R. S. Paton* & A. McNally*

Nature 2024 (DOI: 10.1038/s41586-024-07474-1)

Structure-Activity Relationship (SAR) studies are fundamental to drug and agrochemical development, yet only a few synthetic strategies apply to the nitrogen heteroaromatics frequently encountered in small molecule candidates. Here, the authors present an alternative approach where they convert pyrimidine-containing compounds into various other nitrogen heteroaromatics. Transforming pyrimidines into their corresponding N-arylpyrimidinium salts enables cleavage into a three-carbon iminoenamine building block, used for various heterocycle-forming reactions. This deconstruction-reconstruction sequence diversifies the initial pyrimidine core and enables access to various heterocycles, such as azoles. In effect, this approach allows heterocycle formation on complex molecules, resulting in analogs that would be challenging to obtain by other methods.

Stereoselective Amino Acid Synthesis by Photobiocatalytic Oxidative Coupling

T.-C. Wang, B. K. Mai, Z. Zhang, Z. Bo, J. Li, P. Liu & Y. Yang*

Nature 2024 (DOI: 10.1038/s41586-024-07284-5) 🔓

Photobiocatalysis—where light is used to expand the reactivity of an enzyme—has recently emerged as a powerful strategy to develop chemistries that are new to nature. These systems have shown potential in asymmetric radical reactions that have long eluded small-molecule catalysts. So far, unnatural photobiocatalytic reactions are limited to overall reductive and redox-neutral processes. Here, the authors report photobiocatalytic asymmetric sp³ –sp³ oxidative cross-coupling between organoboron reagents and amino acids. This reaction requires the cooperative use of engineered pyridoxal biocatalysts, photoredox catalysts and an oxidizing agent. The authors repurpose a family of pyridoxal-5′-phosphate-dependent enzymes, threonine aldolases, for the α-C–H functionalization of glycine and α-branched amino acid substrates by a radical mechanism, giving rise to a range of α-tri- and tetrasubstituted non-canonical amino acids possessing up to two contiguous stereocentres. Directed evolution of pyridoxal radical enzymes allowed primary and secondary radical precursors, including benzyl, allyl and alkylboron reagents, to be coupled in an enantio- and diastereocontrolled fashion.

Nature Chemistry

Persistent Organonickel Complexes as General Platforms for Csp²–Csp³ Coupling Reactions

L. P. Dinh, H. F. Starbuck,^‡ T. B. Hamby,^‡ M. J. LaLama, C. Q. He, D. Kalyani* & C. S. Sevov*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01528-7)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2023-kqtm5) 🔓

The importance of constructing Csp² –Csp³ bonds has motivated the development of electrochemical, photochemical and thermal activation methods to reductively couple abundant aryl and alkyl electrophiles. However, these methodologies are limited to couplings of very specific substrate classes and require specialized sets of catalysts and reaction set-ups. Here, the authors show a consolidation of these myriad strategies into a single set of conditions that enable reliable alkyl–aryl couplings, including those that were previously unknown. These reactions rely on the discovery of unusually persistent organonickel complexes that serve as stoichiometric platforms for Csp² –Csp³ coupling. Aryl, heteroaryl or vinyl complexes of Ni can be inexpensively prepared on a multigram scale by mild electroreduction from the corresponding Csp² electrophile. Organonickel complexes can be isolated and stored or telescoped directly to reliably diversify drug-like molecules. Finally, the procedure was miniaturized to micromole scales by integrating soluble battery chemistries as redox initiators, enabling a high-throughput exploration of substrate diversity.

Nature Catalysis

Nickel-Catalysed Enantioselective Alkene Dicarbofunctionalization Enabled by Photochemical Aliphatic C–H Bond Activation

X. Hu, I. Cheng-Sánchez, W. Kong, G. A. Molander & C. Nevado*

Nat. Catal. 2024 (DOI: 10.1038/s41929-024-01153-0) 🔓

The development of novel strategies to rapidly construct complex chiral molecules from readily available feedstocks is a long-term pursuit in the chemistry community. Radical-mediated alkene difunctionalizations represent an excellent platform towards this goal. However, asymmetric versions remain highly challenging, and more importantly, examples featuring simple hydrocarbons as reaction partners are elusive. Here, the authors report an asymmetric three-component alkene dicarbofunctionalization capitalizing on the direct activation of Csp³ –H bonds through the combination of photocatalysed hydrogen atom transfer and nickel catalysis. This protocol provides an efficient platform for installing two vicinal carbon–carbon bonds across alkenes in an atom-economic fashion, providing a wide array of high-value chiral α-aryl/alkenyl carbonyls and phosphonates, as well as 1,1-diarylalkanes from ubiquitous alkane, ether and alcohol feedstocks. This method exhibits operational simplicity, broad substrate scope and excellent regioselectivity, chemoselectivity and enantioselectivity.

Complementary photoelectrocatalytic approach by Q. Lu and co-workers: ChemRxiv (DOI: 10.26434/chemrxiv-2024-vz46b) 🔓

Journal of the American Chemical Society

Palladium-Catalyzed Remote Hydrosulfonamidation of Alkenes: Access to Primary N-Alkyl Sulfamides by the SuFEx Reaction

C. Hou,^‡ Z. Liu,^‡ L. Gan, W. Fan, L. Huang, P. Chen, Z. Huang & G. Liu*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c03283)

The authors report a remote hydrosulfonamidation (HSA) of alkenes using palladium catalysis, where N-fluoro-N-(fluoro-sulfonyl)-carbamate with a sulfur(VI) fluoride moiety is demonstrated as a good amidation reagent. The anti-Markovnikov HSA reaction of terminal alkenes and the remote HSA of internal alkenes are achieved to efficiently yield primary N-alkyl-N-(fluorosulfonyl)-carbamates. The generated N-alkyl products exhibit a unique reactivity of sulfur(VI) fluorides, which can be directly transferred to N-alkyl sulfamides or amines via the sulfur(VI) fluoride exchange reaction, thereby streamlining their synthesis.

Angewandte Chemie International Edition

Total Synthesis of Lissodendoric Acid A

F. M. Ippoliti,^‡ L. G. Wonilowicz,^‡ N. J. Adamson, E. R. Darzi, J. S. Donaldson, D. J. Nasrallah, M. M. Mehta, A. V. Kelleghan, K.N. Houk & N. K. Garg*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202406676)

The authors describe a full account of their synthetic strategy leading to the first total synthesis of the manzamine alkaloid lissodendoric acid A. These efforts demonstrate that strained cyclic allenes are valuable synthetic building blocks and can be employed efficiently in total synthesis.

Related publication from N. K. Garg and co-workers: Science, 2023, 379, 261–269 (DOI: 10.1126/science.ade0032).

ß-Phenethylamine Synthesis via Latent Dual Electrophilicity of N-Pyridinium Aziridines

S. Samanta, P. Biswas, B. O'Bannon & D. C Powers*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202406335) 🔓

ß-Phenethylamines are widely represented in biologically and pharmacologically active organic small molecules. Here, the authors introduce N-pyridinium aziridines as latent dual electrophiles for the synthesis of ß-phenethylamines. Bromide-promoted ring opening generates ß-halopyridinium amines. Selective Ni-catalyzed C–C cross-coupling between organozinc nucleophiles and the benzylic C–Br electrophile affords a diverse family of ß-functionalized phenethylaminopyridinium salts, and coupling is stereoconvergent in the presence of chiral ligands. Subsequent Ni-catalyzed reductive N–N bond activation within the ß-functionalized phenethylamino-pyridinium salts furnishes the products of formal olefin carboamination. Other reductive N–N cleavage reactions are demonstrated to provide access to free primary amines, alkylated amines, heterocycles, and products derived from N-centered radical chemistry.

Alkene 1,3-Difluorination via Transient Oxonium Intermediates

A. C. Dean, E. H. Randle, A. J. D. Lacey, G. A. M. Giorio, S. Doobary, B. D. Cons & A. Lennox*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202404666) 🔓

The 1,3-difunctionalization of unactivated alkenes is an under-explored transformation that leads to moieties that are otherwise challenging to prepare. Herein, the authors report a hypervalent iodine-mediated 1,3-difluorination of homoallylic (aryl) ethers to give unreported 1,3-difluoro-4-oxy groups with moderate to excellent diastereoselectivity. The transformation proceeds through a different mode of reactivity for 1,3-difunctionalization, in which a regioselective addition of fluoride opens a transiently formed oxonium intermediate to rearrange an alkyl chain. The optimized protocol is scalable and shown to proceed well with a variety of functional groups and substitution on the alkenyl chain, hence providing ready access to this fluorinated, conformationally controlled moiety.

ChemRxiv

Enantioconvergent Carbenoid Insertion into Carbon−Boron Bonds

Q. Xie, T. H. Tugwell, J. Li, P. Liu* & G. Dong*

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

Boron-mediated homologation can potentially access almost any kind of chiral centers from readily available boronates via asymmetric carbenoid insertion, followed by versatile transformations of the carbon−boron bonds. However, the current asymmetric boron homologation strategies exhibit limitations, and enantioselective insertion of diversely substituted carbenoids remains challenging. Here, the authors report an enantioconvergent approach for direct insertion of carbon-, oxygen-, nitrogen-, sulfur-, and silicon-substituted carbenoids into carbon−boron bonds. The excellent enantioselectivity is enabled by a new class of chiral oxazaborolidines derived from inexpensive α-amino esters. Computational studies revealed that the non-C2-symmetric oxazaborolidine features a puckered geometry and the cooperative effects of multiple substituents create an asymmetric environment for effective enantioinduction. This method is scalable, and each chiral center can be independently controlled by the chiral oxazaborolidine without being influenced by nearby stereocenters.

Cooperative Phosphine-Photoredox Catalysis Enables N–H Activation of Azoles for Intermolecular Olefin Hydroamination

K. Sedillo, F. Fan, R. R. Knowles* & A. G. Doyle*

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

Catalytic intermolecular olefin hydroamination is an enabling synthetic strategy that offers direct and atom-economical access to a variety of nitrogen-containing compounds from abundant feedstocks. However, despite numerous advances in catalyst design and reaction development, hydroamination of N–H azoles with unactivated olefins remains an unsolved problem in synthesis. The authors report a dual phosphine and photoredox catalytic protocol for the hydroamination of numerous structurally diverse and medicinally relevant N–H azoles with unactivated olefins. Hydroamination proceeds with high anti-Markovnikov regioselectivity and N-site selectivity. The mild conditions and high functional group tolerance of the reaction permit the rapid construction of molecular complexity and late-stage functionalization of bioactive compounds. N–H bond activation is proposed to proceed via polar addition of the N–H heterocycle to a phosphine radical cation, followed by P–N α-scission from a phosphoranyl radical intermediate. Reactivity and N-site selectivity are classified by heterocycle N–H BDFE and nitrogen-centered radical (NCR) spin density, respectively, which can serve as a useful predictive aid in extending the reaction to unseen azoles.

C1-4 Alkylation of Aryl Bromides with Light Alkanes enabled by Metallaphotocatalysis in Flow

A. Pulcinella, P. C. Tiwari, A. Luridiana, K. Yamazaki, D. Mazzarella, A. K. Sadhoe, A. I. Alfano, E. H. Tiekink, T. A. Hamlin* & T. Noël*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-7mk1c) 🔓

The homologous series of gaseous C1-4 alkanes represents one of the most abundant sources of short alkyl fragments. However, their application in synthetic organic chemistry is exceedingly rare due to the challenging C–H bond cleavage, which typically demands high temperatures and pressures, thereby limiting their utility in the construction of complex organic molecules. In particular, the formation of Csp² –Csp³ bonds is crucial for constructing biologically active molecules, including pharmaceuticals and agrochemicals. In this study, the authors present the previously elusive coupling between gaseous alkanes and (hetero)aryl bromides, achieved through a combination of Hydrogen Atom Transfer (HAT) photocatalysis and nickel-catalyzed cross coupling at room temperature. Utilizing flow technology allowed the authors to conduct this novel coupling reaction with reduced reaction times and in a scalable fashion, rendering it practical for widespread adoption in both academia and industry.

Total Synthesis Facilitates in vitro Reconstitution of SgvP, the C–S Bond Forming P450 in Griseoviridin Biosynthesis

C. N. Stout & H. Renata*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-jt6g5) 🔓

Griseoviridin is a group A streptogramin natural product from Streptomyces with broad-spectrum antibacterial activity. A hybrid polyketide-non-ribosomal peptide, it comprises a 23-membered macrocycle, an embedded oxazole motif, and a macro-lactone with a unique ene-thiol linkage. Recent analysis of the griseoviridin biosynthetic gene cluster implicated SgvP, a cytochrome P450 monooxygenase, in late-stage installation of the critical C–S bond. While genetic and crystallographic experiments provided indirect evidence to support this hypothesis, the exact function of SgvP has never been confirmed bio-chemically. Herein, the authors report a convergent total synthesis of pre-griseoviridin, the putative substrate of P450 SgvP and precursor to griseoviridin. The strategy features concise and rapid assembly of two fragments joined via sequential peptide coupling and Stille macrocyclization. Access to pre-griseoviridin then enabled in vitro validation of SgvP as the C–S bond forming P450 during griseoviridin biosynthesis, culminating in a 9-step chemoenzymatic synthesis of griseoviridin.

Organic Letters

Palladium-Catalyzed Denitrative Synthesis of Aryl Nitriles from Nitroarenes and Organocyanides

K. Iizumi,^‡ H. Tanaka,^‡ K. Muto & J. Yamaguchi*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c01118)

A denitrative cyanation of nitroarenes using organocyanides and a palladium catalyst was developed. The key for this reaction was the utilization of an aminoacetonitrile as a cyano source to avoid the generation of stoichiometric metal- and halogen-containing chemical waste. A wide range of nitroarenes, including heteroarenes and pharmaceutical molecules, can be converted into aryl nitriles.

SuFEx-Enabled Direct Deoxy-Diversification of Alcohols

A. S. Odoh, C. Keeler & B. Kim*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c01016)

The authors introduce a new use of sulfonyl fluoride as a bifunctional reagent that facilitates the one-step deoxy-diversification of complex alcohol libraries. The reaction design features a Sulfur(VI) Fluoride Exchange (SuFEx) mediated activation of alcohols and fluoride-induced activation of silicon-bound nucleophiles. This method enables the direct conversion of alcoholic C–O bonds in complex molecules into diverse analogues via C–C, C–N, C–Cl, and C–Br bond formation while suppressing any elimination side-products.

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