Samari-Ω

Science

Reductive Samarium (Electro)catalysis enabled by Sm^III-Alkoxide Protonolysis

E. A. Boyd,^† C. Shin,^† D. J. Charboneau, J. C. Peters* & S. E. Reisman*

Science 2024, 385, 847–853 (DOI: 10.1126/science.adp5777)

Samarium diiodide (SmI₂) is a privileged, single-electron reductant deployed in diverse synthetic settings. However, generalizable methods for catalytic turnover remain elusive because of the well-known challenge associated with cleaving strong Sm^III –O bonds. Prior efforts have focused on the use of highly reactive oxophiles to enable catalyst turnover. However, such approaches give rise to complex catalyst speciation and intrinsically limit the synthetic scope. Herein, the authors leveraged a mild and selective protonolysis strategy to achieve samarium-catalyzed, intermolecular reductive cross-coupling of ketones and acrylates with broad scope. The modularity of the approach allows rational control of selectivity based on solvent, pKa (where Ka is the acid dissociation constant), and the samarium coordination sphere and provides a basis for future developments in catalytic and electrocatalytic lanthanide chemistry.

Nature

Catalytic Asymmetric Synthesis of meta Benzene Isosteres

M. Zhang, M. Chapman, B. R. Sarode, B. Xiong, H. Liang, J. K. Chen, E. Weerapana & J. P. Morken*

Nature 2024 (DOI: 10.1038/s41586-024-07865-4)

Although aromatic rings are common elements in pharmaceutically active compounds, the presence of these motifs brings several liabilities with respect to the developability of a drug. Nonoptimal potency, metabolic stability, solubility and lipophilicity in pharmaceutical compounds can be improved by replacing aromatic rings with non-aromatic isosteric motifs. Moreover, whereas aromatic rings are planar and lack three-dimensionality, the binding pockets of most pharmaceutical targets are chiral. Thus, the stereochemical configuration of the isosteric replacements may offer an added opportunity to improve the affinity of derived ligands for target receptors. A notable impediment to this approach is the lack of simple and scalable catalytic enantioselective syntheses of candidate isosteres from readily available precursors. Here, the authors present a previously unknown palladium-catalysed reaction that converts hydrocarbon-derived precursors to chiral boron-containing nortricyclanes and show that the shape of these nortricyclanes makes them plausible isosteres for meta disubstituted aromatic rings. With chiral catalysts, the Pd-catalysed reaction can be accomplished in an enantioselective fashion and subsequent transformation of the boron group provides access to a broad array of structures. They also show that the incorporation of nortricyclanes into pharmaceutical motifs can result in improved biophysical properties along with stereochemistry-dependent activity.

Nature Communications

Iron-Catalyzed Radical Markovnikov Hydrohalogenation and Hydroazidation of Alkenes

J. Elfert, N. L. Frye, I. Rempel, C. G. Daniliuc & A. Studer*

Nat. Commun. 2024, 15, 7230 (DOI: 10.1038/s41467-024-51706-x) 🔓

The authors report radical hydroazidation and hydrohalogenation of mono-, di- and trisubstituted alkenes through iron catalysis. The alkene moiety that often occurs as a functionality in natural products is readily transformed into useful building blocks through this approach. Commercially available tosylates and α-halogenated esters are used as radical trapping reagents in combination with silanes as reductants. The reported radical Markovnikov hydroazidation, hydrobromination, hydrochlorination, and hydroiodination occur under mild conditions. These hydrofunctionalizations are valuable and practical alternatives to ionic hydrohalogenations with the corresponding mineral acids that have to be run under harsher acidic conditions, which diminishes the functional group tolerance. Good to excellent diastereoselectivities can be obtained for the hydrofunctionalization of cyclic alkenes.

Journal of the American Chemical Society

C3 Selective Hydroxylation of Pyridines via Photochemical Valence Isomerization of Pyridine N-Oxides

C.-Y. Cai, S.-J. Chen, R. R. Merchant, Y. Kanda & T. Qin*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c10057)

The C–H hydroxylation of pyridine’s C3 position is a highly desirable transformation but remains a great challenge due to the inherent electronic properties of this heterocycle, which brings with it difficulties in chemical reactivity and regioselectivity. Herein, the authors present an efficient method for formal C3 selective hydroxylation of pyridines via photochemical valence isomerization of pyridine N-oxides. This metal-free transformation features operational simplicity and compatibility with a diverse array of functional groups, and the resulting hydroxylated products are amenable to further elaboration to synthetically useful building blocks. The synthetic utility of this strategy is further demonstrated in the effective late-stage functionalization of pyridine-containing medicinally relevant molecules and versatile derivatizations of 3-pyridinols.

Total Synthesis of the Norcembranoid Scabrolide B and its Transformation into Sinuscalide C, Ineleganolide, and Horiolide

D. S. Lin, G. Späth, Z. Meng, L. H. E. Wieske, C. Farès & A. Fürstner*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c09467) 🔓

It was recognized only recently that the sister norcembranoids scabrolides A and B have notably different carbotricyclic scaffolds. Therefore, the authors’ previous synthetic route leading to scabrolide A could not be extended to its sibling. Rather, a conceptually new approach had to be devised that relied on a challenging intramolecular alkenylation of a ketone to forge the congested central cycloheptene ring at the bridgehead enone site; the required cyclization precursor was attained by a lanthanide-catalyzed Mukaiyama–Michael addition. The dissonant 1,4-oxygenation pattern was then installed by allylic rearrangement/oxidation of the enone, followed by suprafacial 1,3-transposition. Synthetic scabrolide B was transformed into sinuscalide C by dehydration and into ineleganolide by base-mediated isomerization/oxa-Michael addition, which has potential biosynthetic implications; under basic conditions, the latter compound converts into horiolide by an intricate biomimetic cascade.

Anti-Selective Cyclopropanation of Nonconjugated Alkenes with Diverse Pronucleophiles via Directed Nucleopalladation

H.-Q. Ni, T. M. Alturaifi, W. Rodphon, N. F. Scherschel, S. Yang, F. Wang, I. J. McAlpine,* D. G. Piercey,* P. Liu* & K. M. Engle*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c07039)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2023-b1bdb) 🔓

A facile approach to obtaining densely functionalized cyclopropanes is described. The reaction proceeds under mild conditions via the directed nucleopalladation of nonconjugated alkenes with readily available pronucleophiles and gives excellent yields and good anti-selectivity using I₂ and TBHP as oxidants. Pronucleophiles bearing a diverse collection of electron-withdrawing groups, including −CN, −CO₂R, −COR, −SO₂Ph, −CONHR, and −NO₂, are well tolerated. Internal alkenes, which are generally challenging substrates in other cyclopropanation methods, provide excellent yields and good diastereoselectivity in this methodology, allowing for controlled access to cyclopropanes substituted at all three C atoms. DFT calculations and mechanistic experiments reveal that the major mechanistic pathway involves the initial α-iodination of the nucleophile, followed by anti-carbopalladation and intramolecular C(sp³ )–I oxidative addition. Strain-release-promoted C(sp³ )–C(sp³ ) reductive elimination then furnishes the cyclopropanated product.

Versatile, Modular, and General Strategy for the Synthesis of α-Amino Carbonyls

J. Liu & M. J. Gaunt*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c09434) 🔓

Modulating the basicity of alkylamines is a crucial factor in drug design. Consequently, alkylamines with a proximal amide, ester, or ketone have become privileged features in many pharmaceutical candidates. The impact of α-amino carbonyls has made the development of new methods for their preparation a continuous challenge in synthesis. Here, the authors describe a practical strategy that provides a modular and programmable synthesis of a wide range of α-amino carbonyls. The generality of this process is made possible by an extremely mild method to generate carbamoyl radicals, proceeding via a Lewis acid-visible-light-mediated Norrish type-I fragmentation of a tailored carboxamide reagent and intercepted through addition to in situ generated unbiased imines. Aside from the reaction’s broad scope in each component, its capacity to draw on plentiful and diversely populated amine and carbonyl feedstocks is showcased through a two-dimensional array synthesis that is used to construct a library of novel, assay-ready, α-amino amides.

Rh(I)-Catalyzed Regio- and Enantioselective Ring Opening of Vinyl Cyclopropanes

S. J. Webster, L. B. Balázs, F. W. Goetzke, V. Stojalnikova, K. Liu, K. E. Christensen, H. W. Mackenzie & S. P. Fletcher*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c09490) 🔓

The authors describe a Rh(I) catalyzed asymmetric ring opening of racemic vinyl cyclopropanes using aryl boronic acids as C-nucleophiles. When ferrocene-based chiral bisphosphines are used as ligands, the products are obtained with regioselectivities typically 99:1 and e.e.’s generally between 88–96%. A wide range of aryl boronic acids can be used, and the products can be converted into a variety of targets. Preliminary mechanistic studies indicate that Zn(OTf)₂ plays a significant role in the reaction by promoting rhodium-ligand complex formation and accelerating the reaction.

Construction of Vicinal Quaternary Centers via Ru-Catalyzed Enantiospecific Allylic Substitution with Lithium Ester Enolates

S. M. Papidocha & E. M. Carreira*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c07690) 🔓

The installation of vicinal quaternary centers with absolute stereocontrol constitutes a considerable challenge in organic synthesis. Herein, the authors introduce a novel [Cp*Ru(MeCN)₃]PF₆/phenoxythiazoline catalyst system that achieves enantiospecific allylic substitution of tertiary carbonates with α,α-disubstituted lithium ester enolates to give products containing vicinal quaternary centers. Noteworthy features include the direct use of nonstabilized ester enolates, a class of nucleophiles which has rarely been used in transition metal-catalyzed allylic substitution reactions. The approach is demonstrated for a broad scope of tertiary electrophiles as well as ester enolates and accomplishes stereoretentive substitution with excellent conservation of e.e. (89–99%) and branched/linear regioselectivities (up to 40:1).

ACS Catalysis

Atomic Carbon Equivalent: Design and Application to Diversity-Generating Skeletal Editing from Indoles to 3-Functionalized Quinolines

F.-P. Wu, J. L. Tyler, C. G. Daniliuc & F. Glorius*

ACS Catal. 2024, ASAP (DOI: 10.1021/acscatal.4c03868)

Atomic carbon and its corresponding masked analogues are exceedingly underexplored intermediates in synthesis. Despite this, these reagents possess inimitable reactivity such as the ability to directly insert carbon atoms into aromatic frameworks while simultaneously generating an additional bond at the carbon center to further diversify the structure. Herein, the authors report the design of the orthogonally reactive atomic carbon equivalent Cl-DADO and demonstrate its application to the molecular editing of indole and pyrrole, accessing linchpin-containing ring-expanded heterocycles that can be subsequently derivatized. The value of this approach and the broad applicability of this reagent are highlighted by the late-stage skeletal editing of numerous natural products and drug molecules.

Angewandte Chemie International Edition

An Aza-Prilezhaev-Based Method Inverts Regioselectivity in Stereospecific Alkene 1,2-Aminohydroxylations

W. Tu, J. J. Farndon, C. M. Robertson & J. Bower*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202409836)

Under acidic conditions (TFA) and in the presence of water, BocNHOTs promotes stereospecific 1,2-aminohydroxylations of alkenes. The processes involve intermolecular aza-Prilezhaev aziridination followed by stereospecific S_N2 opening by water. This reagent combination provides regiochemical outcomes that are opposite to, or more selective than those observed using epoxidation initiated 1,2-aminohydroxylation protocols. Replacement of water by other nucleophiles allows 1,2-amino(thio)etherification, diamination, aminoazidation and aminofluorination reactions. Intramolecular processes are also feasible, including unusual variants that evoke azabicyclobutane-like reactivity.

ChemRxiv

Accessing Sulfonamides via Formal SO₂ Insertion into C–N Bonds

M. Kim, C. E. Obertone, C. B. Kelly,* C. A. Reiher,* C. Grosanu, J. C. Robertson & M. D. Levin*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-vj26z) 🔓

Functional group interconversions of abundant substructures that accommodate the often-complex molecular architectures seen in pharmaceuticals are particularly sought after by medicinal chemists as a means to enable both lead optimization and library diversification. Here, the authors report a conceptually new strategy that enables net SO₂-insertion into the C–N bond of primary amines, enabling the direct synthesis of primary sulfonamides without pre-activation and effectively inverting the nitrogen’s properties (acidity, hydrogen bonding, etc.). The key to realizing this overall transformation is the implementation of an anomeric amide as a dual-function reagent which both serves to cleave the initial C–N bond and deliver a nitrogen atom to the product after SO₂ incorporation. The process tolerates a wide array of functionalities and can be run in an automated fashion thus allowing libraries of amines to be viable progenitors to highly desirable sulfonamides. Mechanistic studies support an isodiazene radical chain mechanism that generates an intermediate sulfinate which reacts with the anomeric amide to forge the S–N bond. As a proof of concept, the protocol was used to conduct a high-throughput library diversification campaign, was applied to the synthesis and modification of approved active pharmaceutical ingredients and was used to enable a net CO-to-SO₂ “isosteric replacement” approach.

Deoxycyanation of Alkyl Alcohols

C. Hümpel,^† J. Chen,^† W. L. Lyon, R. E. McNamee & D. W. C. MacMillan*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-t33vn) 🔓

Cyano groups represent an important class of functional motifs in medicinal chemistry given their synthetic versatility and capacity to engage in essential interactions with biological targets. However, the synthesis of sterically hindered alkyl nitriles using non-toxic reagents remains challenging. Traditional methods often rely on toxic cyanide sources and suffer from limited substrate scope. Herein, the authors report a photoredox catalyzed, metal-free deoxycyanation of alkyl alcohols that allows rapid access to a wide array of 1º, 2º, and 3º cyanides using non-toxic cyanide reagents.

β-Selective 2-Deoxy- and 2,6-Dideoxyglucosylations Catalyzed by Bis-Thioureas

P. D. Beyer,^† M. M. Nielsen,^† E. N. Picazo & E. N. Jacobsen*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-7414b) 🔓

The authors present methods for β-selective 2-deoxy and 2,6-dideoxyglucosylations of natural products, carbohydrates, and amino acids using bis-thiourea hydrogen-bond-donor catalysts. Disarming ester protecting groups were necessary to counter the high reactivity of 2-deoxyglycosyl electrophiles toward non-stereospecific S_N1 pathways. Alcohol and phenol nucleophiles with both base- and acid-sensitive functionalities were compatible with the catalytic protocol, enabling access to a wide array of 2-deoxy-β-O-glucosides.

Site- and Enantioselective Allylic and Propargylic C-H Oxidation enabled by Copper-Based Biomimetic Catalysis

H. Zhang,^† Y. Zhou,^† T. Yang,^† J. Wu, P. Chen, Z. Lin* & G. Liu*

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

Methods for the direct, enantioselective oxidation of C(sp³ )–H bonds in organic molecules will revolutionize the preparation of chiral alcohols and their derivatives, which are important moieties in natural products, pharmaceuticals and agrochemicals. Enzymatic catalysis, which employs key metal oxides to facilitate efficient hydrogen atom abstraction, has evolved as a highly selective approach for C-H oxidation in biological systems. Despite its effectiveness, reproducing this function and achieving high stereoselectivity in biomimetic catalysts has proven to be a daunting task. Here, the authors present a copper-based mimetic catalytic system that achieves highly efficient asymmetric sp³ C-H oxidation with the C-H substrates as the limiting reagent. An unprecedent Cu(II)-bound tert-butoxy radical is responsible for the site-selective C–H bond cleavage, which resembles the active site of copper-based enzymes for C–H oxidation. The developed allylic and propargylic C-H oxidation reactions have been successfully accomplished with good functional group compatibility and exceptionally high site- and enantioselectivity, and this method is applicable for the late-stage oxidation of bioactive compounds.

Mechanistic Exploration of N-Heterocyclic Carbene Boranes as the Hydrogen Atom Transfer Reagent in Selective Hydrodefluorination Reactions

A. K. Jaiswal, B. B. Skjelstad, S. Maeda* & C.-Y. D. Huang*

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

In the modern era of organic synthesis, mechanisms centering on radical intermediates have become increasingly impactful in unlocking novel reactivity. Among all, hydrogen atom transfer (HAT) represents one of the most fundamental chemical reaction steps and has found applications in designing practical transformations. Herein, the authors present a detailed case study on selective hydrodefluorination of trifluoromethylarenes utilizing N-heterocyclic carbene boranes (NHC-boranes) as the HAT donor. Under the optimal conditions featuring an acridine-based photocatalyst, complete selectivity for mono-hydrodefluorination was achieved across a wide array of substrates. Comprehensive mechanistic studies combining experimental and computational approaches disproved a chain process involving a fluorine atom transfer but rather pointed to a HAT non-chain mechanism, where the key step involves the difluorobenzylic radical abstracting a hydrogen atom from the NHC-borane to generate a boryl radical in a polarity-matched fashion. Evaluation of a selection of Lewis base-ligated boranes revealed molecular descriptors critical to the outcomes of this reaction, and a classification model is built to explain the structure-reactivity relationship and how various elementary steps can be influenced.

Chemical Science

Modular Synthesis of α-Branched Secondary Alkylamines via Visible-Light-Mediated Carbonyl Alkylative Amination

M. A. Smith, R. J. D. Kang, R. Kumar, B. Roya & M. J. Gaunt*

Chem. Sci. 2024, Accepted (DOI: 10.1039/D4SC03916E) 🔓

The development of methods for the assembly of secondary α-alkyl amines remains a central challenge to chemical synthesis because of their critical importance in modulating the physical properties of biologically active molecules. Despite decades of intensive research, chemists still rely on selective N-alkylation and carbonyl reductive amination to make most amine products. Here, the authors report the further evolution of a carbonyl alkylative amination process that, for the first time, brings together primary amines, aldehydes and alkyl iodides in a visible-light-mediated multicomponent coupling reaction for the synthesis of a wide range of α-branched secondary alkylamines. In addition to exploring the tolerance and limitations in each reaction component, they also report preliminary applications to the telescoped synthesis of α-branched N-heterocycles and an N-alkylation protocol that is selective for primary over cyclic secondary amines.

Organic Letters

Total Synthesis of (−)-Flueggeacosine C

L. Liu, T. L. Olson & J. L. Wood*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c02516)

The authors describe a total synthesis of the heterodimeric securinega alkaloid (−)-flueggeacosine C. The convergent synthetic strategy is based on a Liebeskind–Srogl cross-coupling reaction that combines a benzoquinolizidine fragment with a securinine-type alkaloid. An acyloxy nitroso ring-expansion was employed as the key step in accessing a benzoquinolizidine, and a novel intramolecular Diels–Alder reaction of an allenic acid-containing pyridone expeditiously delivers the skeleton of the securinine-type fragment. Finally, a Cu-catalyzed hydroboration-oxidation sequence was employed to regio- and diastereoselectively introduce the secondary alcohol found in (−)-flueggeacosine C.

Synthesis of Tanshinone IIA and Related Terpenes via a C–H Functionalization Strategy

N. Tucker, L. H. Britt & H. K. Grover*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c02438)

The total synthesis of tanshinone IIA and related bioactive diterpenes isolated from the Chinese plant Salvia miltiorrhiza was completed from a common tetralin building block. The synthetic route highlights a 3,4-disubstituted furan synthesis and various regioselective C–H functionalization reactions, including a Pd catalyzed iodination and an Ir catalyzed borylation, along with an intramolecular stanna-Brook type reaction to construct the ortho-quninone ring of the target molecule.

Journal of Organic Chemistry

Tetrachloromaxamycins: Divergent Total Synthesis and Initial Assessments

P. Qin,^† M. J. Moore,^† S. Jung, T. Fukazawa, N. Yamasaki, S. Chatterjee, Z.-C. Wu & D. L. Boger*

J. Org. Chem. 2024, ASAP (DOI: 10.1021/acs.joc.4c01927)

Divergent total syntheses of binding pocket and peripherally modified tetrachlorovancomycins, a non-native synthetic glycopeptide, and their evaluation are disclosed. Central to the approach is the synthesis of a single late-stage intermediate that bears a residue 4 thioamide ([Ψ[C(═S)NH]Tpg⁴ ]-tetrachlorovancomycin, LLS 15 steps, 14% overall) as a precursor to either of two key pocket modifications and their pairing with any combination of two peripheral modifications conducted without protecting groups. A stereochemical simplification achieved by the addition of two aryl chlorides removes two synthetically challenging atropisomer centers in native glycopeptides and streamlines the synthesis. The approach provided [Ψ[C(═S)NH]Tpg⁴ ]-tetrachlorovancomycin from which [Ψ[C(═N)NH]Tpg⁴ ]-tetrachlorovancomycin and [Ψ(CH₂NH)Tpg⁴ ]-tetrachlorovancomycin were prepared in a single-step and bear binding pocket modifications that convey dual ᴅ-Ala-ᴅ-Ala/ᴅ-Lac ligand binding to overcome vancomycin resistance. The newest maxamycin members are disclosed, bearing two additional peripheral modifications that introduce two independent synergistic MOAs that do not rely on native ligand binding for activity. Ligand binding properties of pocket-modified tetrachlorovancomycins, antibacterial activity of a key compound series, and PK assessments of two tetrachloromaxamycins are reported.

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