Biomimetic Polyene Cyclisations

Nature

The Catalytic Asymmetric Polyene Cyclization of Homofarnesol to Ambrox

N. Luo,^† M. Turberg,^† M. Leutzsch, B. Mitschke, S. Brunen, V. N. Wakchaure, N. Nöthling, M. Schelwies, R. Pelzer & B. List*

Nature 2024 (DOI: 10.1038/s41586-024-07757-7) 🔓

Polyene cyclizations are among the most complex and challenging transformations in biology. In a single reaction step, multiple carbon–carbon bonds, ring systems and stereogenic centres are constituted from simple, acyclic precursors. Simultaneously achieving this kind of precise control over product distribution and stereochemistry poses a formidable task for chemists. In particular, the polyene cyclization of (3E,7E)-homofarnesol to the valuable naturally occurring ambergris odorant (−)-ambrox is recognized as a longstanding challenge in chemical synthesis. Here, the authors report a diastereoselective and enantioselective synthesis of (−)-ambrox and the sesquiterpene lactone natural product (+)-sclareolide by a catalytic asymmetric polyene cyclization by using a highly Brønsted-acidic and confined imidodiphosphorimidate catalyst in the presence of fluorinated alcohols. Several experiments, including deuterium-labelling studies, suggest that the reaction predominantly proceeds through a concerted pathway in line with the Stork–Eschenmoser hypothesis. Mechanistic studies show the importance of the enzyme-like microenvironment of the imidodiphosphorimidate catalyst for attaining exceptionally high selectivities, previously thought to be achievable only in enzyme-catalysed polyene cyclizations.

Journal of the American Chemical Society

A Radical Strategy for the Alkylation of Amides with Alkyl Halides by Merging Boryl Radical-Mediated Halogen-Atom Transfer and Copper Catalysis

Z. Zhang, L. Poletti & D. Leonori*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c05487)

Amide alkylation is a fundamental process in organic chemistry. However, the low nucleophilicity of amides means that divergent coupling with alkyl electrophiles is often not achievable. To circumvent this reactivity challenge, individual amine synthesis followed by amidation with standard coupling agents is generally required. Herein, the authors demonstrate a radical solution to this challenge by using an amine–borane complex and copper catalysis under oxidative conditions. While borohydride reagents are generally used as reducing agents in ionic chemistry, their conversion into amine-ligated boryl radicals diverts their reactivity toward halogen-atom transfer. This enables the conversion of alkyl halides into the corresponding alkyl radicals for amide functionalization via copper catalysis. The process is applicable to the N-alkylation of primary amides employing unactivated alkyl iodides and bromides, and it was also showcased in the late-state functionalization of both complex amide- and halide-containing drugs.

A General Three-Component Alkyl Petasis Boron–Mannich Reaction

C. Hu, J. Tsien, S.-J. Chen, M. Kong, R. R. Merchant, Y. Kanda & T. Qin*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c05940)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-647cr) 🔓

Aryl amines are one of the most common moieties in biologically active molecules, and approximately 37% of drug candidates contain aromatic amines. Recent advancements in medicinal chemistry, coined “escaping from flatland”, have led to a greater focus on accessing highly functionalized C (sp³ )-rich amines to improve the physicochemical and pharmacokinetic properties of compounds. This article presents a modular and operationally straightforward three-component alkyl Petasis boron–Mannich (APBM) reaction that utilizes ubiquitous starting materials, including amines, aldehydes, and alkyl boronates. By adaptation of this transformation to high-throughput experimentation (HTE), it offers rapid access to an array of diverse C(sp³ )-rich complex amines, amenable for rapid identification of drug candidates.

Visible-Light-Promoted Enantioselective α-Amidation of Aldehydes by Harnessing Organo-Iron Dual Catalysis

S. Hore,^† J. Jeong,^† D. Kim & S. Chang*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c07884)

The strategic integration of organocatalysis with transition-metal catalysis to achieve otherwise unattainable stereoselective transformations may serve as a powerful synthetic tool. Herein, the authors present a synthetically versatile α-amidation of aldehydes by leveraging dual iron and chiral enamine catalysis in an enantioselective manner (up to >99:1 e.r.). Experimental and computational studies have led to the proposal of a new mechanistic platform, wherein visible-light-promoted LMCT generates [Fe(II)Cl₃^– ], which effectively activates dioxazolones to form an iron-acylnitrenoid radical that inserts into chiral enamine intermediates.

Molecular Editing of Ketones through N-Heterocyclic Carbene and Photo Dual Catalysis

Q.-Z. Li,^† M.-H. He,^† R. Zeng, Y.-Y. Lei, Z.-Y. Yu, M. Jiang, X. Zhang & J.-L. Li*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c08163)

The molecular editing of ketones represents an appealing strategy due to its ability to maximize the structural diversity of ketone compounds in a straightforward manner. However, developing efficient methods for the arbitrary modification of ketonic molecules, particularly those integrated within complex skeletons, remains a significant challenge. Herein, the authors present a unique strategy for ketone recasting that involves radical acylation of pre-functionalized ketones facilitated by N-heterocyclic carbene and photo dual catalysis. This protocol features excellent substrate tolerance and can be applied to the convergent synthesis and late-stage functionalization of structurally complex bioactive ketones.

Manganese Complexes with Consecutive Mn(IV) → Mn(III) Excitation for Versatile Photoredox Catalysis

T. Huang, P. Du, X. Cheng & Y.-M. Lin*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c07084)

Manganese complexes stand out as promising candidates for photocatalyst design, attributed to their eco- and biocompatibility, versatile valence states, and capability for facilitating multiple electronic excitations. However, several intrinsic constraints, such as inadequate visible light response and short excited-state lifetimes, hinder effective photoinduced electron transfer and impede photoredox activation of substrates. To overcome this obstacle, the authors have developed a class of manganese complexes featuring boron-incorporated N-heterocyclic carbene ligands. These complexes enable prolonged excited-state durations encapsulating both Mn(IV) and Mn(III) oxidation stages, with lifetimes reaching microseconds for Mn(IV) and nanoseconds for Mn(III), concurrently exhibiting robust redox capabilities. They efficiently catalyze direct, site-selective cross-couplings between diverse arenes and aryl bromides, at a low catalyst loading of 0.5 mol %. Their proficiency spans an extensive array of substrates including both highly electron-rich and electron-deficient molecules, which underscore the superior performance of these manganese complexes in tackling intricate transformations. Furthermore, the versatility of these complexes is further highlighted by their successful applications in various photochemical transformations, encompassing reductive cross-couplings for the formation of C–P, C–B, C–S and C–Se bonds, alongside oxidative couplings for creating C–N bonds.

Enantioselective Nitrene Transfer to Hydrocinnamyl Alcohols and Allylic Alcohols Enabled by Systematic Exploration of the Structure of Ion-Paired Rhodium Catalysts

N. J. Hodson, S. Takano, A. Fanourakis & R. J. Phipps*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c07117) 🔓

This work describes highly enantioselective nitrene transfer to hydrocinnamyl alcohols (benzylic C–H amination) and allylic alcohols (aziridination) using ion-paired Rh (II,II) complexes based on anionic variants of Du Bois’ esp ligand that are associated with cinchona alkaloid-derived chiral cations. Directed by a substrate hydroxyl group, the authors’ previous work with these complexes had not been able to achieve high enantioselectivity on these most useful short-chain compounds; however, they overcame this challenge through a combination of catalyst design and modified conditions. A hypothesis that modulation of the linker between the anionic sulfonate group and the central arene spacer might provide a better fit for shorter chain length substrates led to the development of a new biaryl-containing scaffold, which has allowed a broad scope for both substrate classes to be realized for the first time. Furthermore, the authors describe a systematic structural “knockout” study on the cinchona alkaloid-derived chiral cation to elucidate which features are crucial for high enantioinduction. De novo synthesis of modified scaffolds led to the surprising finding that for high e.e, the quinoline nitrogen of the alkaloid is crucial, although its location within the heterocycle could be varied, even leading to a superior catalyst. The free hydroxyl is also crucial and should possess the naturally occurring diastereomeric configuration of the alkaloid.

Synthesis of Z-gem-Cl,CF₃-Substituted Alkenes by Stereoselective Cross-Metathesis and the Role of Disubstituted Mo Alkylidenes

Q. Liu,^† C. Qin,^† J. Wan,^† B. K. Mai,^† X. Z. Sui, H. Kobayashi, H. Zahedian, P. Liu* & A. H. Hoveyda*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c06071)

Stereochemically defined organofluorine compounds are central to drug discovery and development. Here, the authors present a catalytic cross-metathesis method for the synthesis of Z-trisubstituted olefins that contain a Cl- and a CF₃-bound carbon terminus. Notably, the process is stereoselective, which is in contrast to the existing stereoretentive strategies that also involve a trisubstituted olefin as starting material. Reactions are catalyzed by a Mo monoaryloxide pyrrolide alkylidene, involve a trisubstituted alkene and gem-Cl,CF₃-substituted alkene, and are fully Z-selective. Catalytic cross-coupling can be used to convert the C–Cl bond of the trisubstituted olefin to C–B, C–D, and different C–C bonds. Experimental and computational (DFT) data show that in some instances a disubstituted alkylidene is formed and then transformed to a more active complex. In other cases, the Cl,CF₃-disubstituted alkylidene is a direct participant in a catalytic cycle.

Stereoselective Construction of Multifunctional C-Glycosides Enabled by Nickel-Catalyzed Tandem Borylation/Glycosylation

X. Wu,^† S. Li,^† L. Chen, S. Ma, B. Ma, L. Song & D. Qian*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c05485)

Stereochemically pure saccharides have indispensable roles in fields ranging from medicinal chemistry to materials science and organic synthesis. However, the development of a simple, stereoselective, and efficient glycosylation protocol to access α- and β-C-glycosides (particularly 2-deoxy entities) remains a persistent challenge. Existing studies have primarily focused on C1 modification of carbohydrates and transformation of glycosyl radical precursors. Here, the authors innovate by harnessing the in situ generated glycosyl-Ni species to achieve one-pot borylation and glycosylation in a cascade manner, which is enabled by an earth-abundant nickel-catalyzed carboboration of readily accessible glycals without any ligand. This work reveals the potential for the development of a modular and multifunctional glycosylation platform to facilitate the simultaneous introduction of C–C and C–B bonds at the stereogenic center of saccharides, a largely unexploited research area. Preliminary experimental and computational studies indicate that the endocyclic O and the C3 group play important roles in stereoselectively forging glycosidic bonds. As a result, a diverse range of C–R (R = alkyl, aryl, and alkenyl) and 2-deoxygenated glycosides bearing modifiable boron groups could be rapidly made with excellent stereocontrol and exhibit remarkable functional group tolerance. The synthetic potential is underscored in the late-stage glycosylation of natural products and commercial drugs as well as the facile preparation of various rare sugars, bioactive conjugates, and key intermediates to prorocentin, phomonol, and aspergillide A.

Angewandte Chemie International Edition

Total Synthesis of (+)-Kalmanol

T. Ma, Y. Ma, B. Li & Y. Jia*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202407215)

Kalmanol, the flagship member of the kalmane diterpene family, possesses a complex and highly oxidized 5/5/8/5 tetracyclic skeleton with nine contiguous stereocenters and exhibits significant analgesic effects and cardiotoxic properties. The authors have achieved the efficient total synthesis of (+)-kalmanol in 22 steps with 2.3% yield. The synthesis featured a Rh-catalyzed [5+2+1] cycloaddition reaction to construct 5/5/8 tricyclic skeleton, and a meticulously designed sequence of stereoselective oxidations of the 5/5/8/5 tetracyclic skeleton.

Asymmetric Total Synthesis of Euphordraculoate A and Pedrolide

C. Tu, Y. Yang, Y. Jiang, Y. Hao, Z. Wang, S. Fu, S. Qin & B. Liu*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202409997)

The authors report the asymmetric total syntheses of two rearranged tigliane diterpenoids, euphordraculoate A and pedrolide. A reductive dihydroxylation cascade and Nazarov cyclization were performed to generate euphordraculoate A, which was subjected to a cascade of Eu-promoted dienyl enolization, intramolecular Diels-Alder reaction and enol-ketone tautomerization to afford pedrolide, a pathway consistent with their proposal for the biogenesis of pedrolide

ChemRxiv

Tailoring Unstrained Pyrrolidines via Reductive C–N Bond Cleavage with Lewis Acid and Photoredox Catalysis

M. Hirao,^† K. Aida,^† T. Saitoh, T, Yamamoto, Y. Einaga, E. Ota,* & J. Yamaguchi*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-q5f3h) 🔓

Skeletal remodeling of unstrained azacycles such as pyrrolidine remains a formidable challenge in synthetic chemistry. To achieve such remodeling, continuous development of the cleavage of inert C–N bonds is essential. In this study, the authors introduce an effective strategy for the reductive cleavage of C–N bond in N-benzoyl pyrrolidine, leveraging a combination of Lewis acid and photoredox catalysis. This method involves single-electron transfer to the amide, followed by site-selective cleavage at C2–N bond. Cyclic voltammetry and NMR studies demonstrated that the Lewis acid is crucial for promoting the single-electron transfer from the photoredox catalyst to the amide carbonyl group. This protocol is widely applicable to various pyrrolidine-containing molecules and enables inert C–N bond cleavage including C–C bond formation via intermolecular radical addition. Furthermore, the current protocol successfully converts pyrrolidines to aziridines, γ-lactones, and tetrahydrofurans, demonstrating the potential to expand synthetic strategies in skeletal remodeling.

Xanthopinacol Boronate: A Robust, Photochemically Assembled and Cleavable Boronic Ester for Orthogonal Chemistry

D. M. Heard,^† M. C. Lessard^† & D. G. Hall*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-r809t) 🔓

Organoboronic acids impact numerous fields of application from organic synthesis to materials science and drug discovery. However, their highly polar nature makes them challenging to handle, purify, and characterize. Boronic esters help overcome these issues, and pinacol esters (Bpin) have become the dominant boronic acid surrogate in organic synthesis. Despite its popularity, Bpin is not without drawbacks as it is intrinsically reversible in the presence of water or alcohols, which may cause issues of premature release leading to losses during reactions and purification. This reversibility complicates the hydrolytic regeneration of free boronic acids, which often requires additional steps to destroy the pinacol by-product. Although other boronyl protecting groups exist, their cleavage to afford the boronic acid tends to require harsh pH conditions. To address these issues, the authors developed xanthopinacol boronates (Bxpin), a robust protecting group for boronic acids with excellent orthogonality in various chemical reactions and mild irreversible removal. Xpin boronates can be obtained directly by irradiation of a mixture of free boronic acid and xanthone with UV light, causing an in-situ dimerization of xanthone to the required xanthopinacol.

Diastereoselective Dearomative 1,3-Dipolar Cycloaddition of Bicyclobutanes with Pyridinium Ylides: A Modular Approach to Multisubstituted Azabicyclo[3.1.1]heptanes

K. Dhake,^† K. Woelk,^† L. Krueckl, F. Alberts, J. Mutter, M. Pohl, G. Thomas, M. Sharma, J. Bjornerud-Brown, N. P. Fernandez, N. Schley & D. Leitch*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-59vs5) 🔓

The authors describe a formal 1,3-dipolar cycloaddition between bicyclobutanes and pyridinium ylides to form azabicycloheptanes via diastereoselective pyridine dearomatization. Microscale highthroughput experimentation led to identification of conditions affording high yield and stereoselectivity without the need for catalysis. These reactions proceed using as-received reagents and solvents under ambient atmosphere. The resulting ring-fused azabicyclo[3.1.1]heptanes have diverse synthetic handles for further transformations, making them potentially valuable scaffolds for the design of Csp³ -rich drug candidates. They also demonstrate a diastereoselective photochemical skeletal rearrangement to give a 1,1,3,3-tetrasubstitued cyclobutane.

Organic Process Research & Development

Synthesis of Lenacapavir Sodium: Active Pharmaceutical Ingredient Process Development and Scale-up

A. M. Wagner,* S. A. Bonderoff, S. Chang, J. Deignan, M. M. Esanum, H. V. Huynh, T. Niu, V. Ngo, B. M. O’Keefe, J. Phoenix, T. J. Rainey, B. J. Roberts, J. Shen, C. Stewart, A. L. Vandehey, S. A. Wolckenhauer, C. Y. Wong & B. H. Yarmuch

Org. Process Res. Dev. 2024, ASAP (DOI: 10.1021/acs.oprd.4c00242)

Lenacapavir sodium (GS-6207-02) is a first-in-class HIV capsid inhibitor. Process development of the four-step final assembly of lenacapavir sodium from four synthetic intermediates is described here. A bis-bromopyridine core is sequentially subjected to an alkynylation, an amide coupling with a chiral pyrazole carboxylic acid, and a Suzuki cross-coupling with an indazole boronic ester. The final step is a telescoped bis-methanesulfonylation and hydrolysis to yield the API. This report highlights experimental work on the final assembly sequence to establish robust processing conditions, minimize process mass intensity, control impurity formation, understand impurity purge, and enable large-scale manufacturing of lenacapavir sodium.

For a follow-up manuscript describing the synthesis of their pyrazole starting material, see: Org. Process Res. Dev. 2024, ASAP (DOI: 10.1021/acs.oprd.4c00235).

Organic Letters

Sacrificial Anode-Free Electrochemical Cross-Electrophile Coupling of 1,3-Diol Derivatives to Form Aliphatic and Aryl Cyclopropanes

N. Hirbawi,^† E. T. A. Raffman,^† J. R. Pedroarena, T. M. McGinnis & E. R. Jarvo*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c02022) 🔓

Cross-electrophile coupling reactions that forge C(sp³ )–C(sp³ ) bonds are strategic methods for the synthesis of molecules with high F(sp³ ), yet very few employ electrochemical conditions as the necessary reductant. Herein, the authors report an electrochemical intramolecular cross-electrophile coupling reaction of 1,3-diol derivatives to access aliphatic and aryl cyclopropanes, including spirocyclic and fused bicyclic cyclopropanes. The scalable electrochemical cross-electrophile coupling (eXEC) reaction employs a nonsacrificial anode in an undivided cell.

Organoselenium-Catalyzed Enantioselective Synthesis of 2-Oxazolidinones from Alkenes

C. C. Cunningham,^† J. L. Panger,^† M. Lupi & S. E. Denmark*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c02377)

An operationally simple method for generating enantioenriched 2-oxazolidinones from N-Boc amines and mono- or trans-disubstituted alkenes via chiral organoselenium catalysis is described. Critical to the success of the transformation was the inclusion of triisopropylsilyl chloride (TIPSCl), likely because it sequestered fluoride generated by the oxidant (N-fluorocollidinium tetrafluoroborate) throughout the reaction and suppressed side reactivity. The scope of both the amine and alkene substrates was explored, generating a variety of 2-oxazolidinones in modest to high yields with high enantioselectivities.

Journal of Organic Chemistry

Total Synthesis of (−)-Fasicularin

Y. Takatori & H. Fuwa*

J. Org. Chem. 2024, ASAP (DOI: 10.1021/acs.joc.4c01447)

Asymmetric total synthesis of (−)-fasicularin was achieved in nine steps from a commercially available inexpensive material, by leveraging (1) an aryl radical-mediated, copper-catalyzed Sonogashira-type cross-coupling, (2) a Au-catalyzed tandem intramolecular alkyne hydroamination/iminium formation/intramolecular allylation, and (3) a tandem hydrogenation/hydrogenolysis/intramolecular reductive amination as key transformations.

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