Seven Steps to Psychoactive Alkaloids

Welcome to this week’s Organic Synthesis Newsletter.

Monday 3^rd February – Sunday 9^th February 2025 | Volume 2, Issue 5

HIGHLIGHT OF THE WEEK
Efficient and Modular Synthesis of Ibogaine and Related Alkaloids

R. N. Iyer, D. Favela, A. Domokos, G. Zhang, A. A. Avanes, S. J. Carter, A. G. Basargin, A. R. Davis, D. J. Tantillo & D. E. Olson*

Nat. Chem. 2025 (DOI: 10.1038/s41557-024-01714-7)

The psychoactive alkaloid ibogaine and its active metabolite noribogaine are reported to have powerful anti-addictive properties, producing long-lasting therapeutic effects across a range of substance use disorders and co-occurring neuropsychiatric diseases such as depression and post-traumatic stress disorder. Here, the authors report a gram-scale, seven-step synthesis of ibogaine from pyridine. Key features of this strategy enabled the synthesis of three additional iboga alkaloids, as well as an enantioselective total synthesis of (+)-ibogaine and the construction of four analogues. Biological testing revealed that the unnatural enantiomer of ibogaine does not produce ibogaine-like effects on cortical neuron growth, while (−)-10-fluoroibogamine exhibits exceptional psychoplastogenic properties and is a potent modulator of the serotonin transporter.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Total Synthesis of DMOA-Derived Meroterpenoids: Achieving Selectivity in the Synthesis of (+)-Berkeleyacetal D and (+)-Peniciacetal I

J. Zhang, X. Luo, J. Zhang & C. Li*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c15205)

Berkeleyacetals, a subfamily of 3,5-dimethylorsellinic acid (DMOA)-derived meroterpenoids, pose substantial synthetic challenges due to their densely functionalized and highly oxidized architectures. Here, the authors present the first total synthesis of this class of DMOA-derived meroterpenoids, specifically (+)-berkeleyacetal D and (+)-peniciacetal I. The approach features a chemoselective deprotonation followed by an intramolecular single-electron transfer (SET) from an enolate to an alkyl bromide, enabling the construction of the 2,3-dihydrofuran ring in berkeleyacetal D, an endo-selective intramolecular Diels–Alder reaction and a solvent-controlled diastereoselective epoxidation.

Convergent Total Synthesis of Aleutianamine

J. P. Tuccinardi & J. L. Wood*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c12946)

The authors describe a convergent total synthesis of the pyrroloiminoquinone natural product aleutianamine that exemplifies a novel paradigm for pyrroloiminoquinone synthesis by hinging upon a convergent intermolecular carbon–carbon bond forming event. Specifically, the coupling of a pyrroloquinone monoketal and a siloxythiophene fragment, each prepared in seven steps from commercially available materials, allows for access to the entire carbon framework of aleutianamine in only eight steps. A variety of intriguing skeletal rearrangements, minimal late-stage redox adjustments, and a carefully choreographed sequence of carbon–nitrogen bond formations then deliver the natural product.

Asymmetric Total Synthesis of Janthinoid A

F. Tang,^† Z.-C. Zhang,^†* Z.-L. Song, Y.-H. Li, Z.-H. Zhou, J.-J. Chen & Z. Yang*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c17480)

The authors report the first asymmetric total synthesis of janthinoid A in 14 steps and without the use of protecting groups. The trans-decalin subunit and the rigid oxabicyclo[3.2.1]octane motif were constructed via an epoxide-initiated cationic π-cyclization reaction and a Fe(ClO₄)₃-mediated oxidative cascade cyclization reaction, respectively.

Iridium-Catalyzed Stereocontrolled C(sp³)–C(sp³) Cross-Coupling of Boronic Esters and Allylic Carbonates Enabled by Boron-to-Zinc Transmetalation

H.-C. Shen & V. K. Aggarwal*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c17931) 🔓

The stereocontrolled C(sp³)–C(sp³) cross-coupling represents a considerable challenge of great contemporary interest. While this has been achieved through the reactions of boronate complexes with π-allyl iridium complexes, such reactions suffered from a limited substrate scope. Here, the authors report that following transmetalation from boronate complexes to organozinc reagents enables previously unreactive substrates to engage in stereocontrolled C(sp³)–C(sp³) cross-coupling. The broader substrate scope has enabled their application to the synthesis of biologically active molecules. The organozinc reagents react through a stereoinvertive coupling pathway with π-allyl iridium complexes, in contrast to reactions with other electrophiles that occur with retention of stereochemistry.

Co-Catalytic Coupling of Alkyl Halides and Alkenes: The Curious Role of Lutidine

R. Hanumanthu,^† P. Sharma,^† A. Ethridge & J. D. Weaver III*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c15812) 🔓

The authors report a dual catalytic activation strategy to access primary, secondary, and tertiary alkyl radicals from alkyl chlorides, bromides, tosylates and trifluoroacetates. While the method relies on visible light and a photocatalyst to facilitate electron transfer, based on reduction potentials, the substrates are not expected to be reduceable; however, in the presence of lutidine they are. Further investigation revealed that lutidine was a precatalyst, ultimately leading to the discovery and use of a lutidinium iodide salt that served as a critical co-catalyst resulting in improved reaction profiles.

Palladium-Catalyzed Enantioselective Stereodivergent Desymmetrization of Cyclic 1,4-Allyldiboronates

H. Liang, L. D. Battistoni, S. Tcyrulnikov, C. Allais, R. A. Singer & J. P. Morken*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c16020)

In the presence of a chiral palladium-based catalyst, 1,4-diboryl-2-alkenes undergo enantioselective cross-coupling that results in desymmetrization of the substrate structure. Depending on the reaction conditions and the choice of ligand, the process can occur with cis- or trans- selectivity, allowing for the construction of differentially substituted chiral carbocycles in an enantiomerically enriched fashion.

Synthesis, Characterization, and Catalytic Activity of Ni(0)(DQ)dtbbpy, an Air-Stable, Bifunctional Red-Light-Sensitive Precatalyst

J. Li, P. Wang, B. Bai, Y. Xiao, Y.-F. Wan, Y. Yan, F. Li, G. Song, G. Li, C. Wang, X.-P. Zhang, J. Dong, T. Kang & D. Xue*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c14533)

Despite a well-established and growing body of work on nickel(0) precatalysts, the potential of nickel(0) complexes as bifunctional precatalysts remains underexplored. In this study, the authors synthesized, characterized, and evaluated the catalytic activity of Ni(0)(DQ)dtbbpy, a bifunctional, red-light-sensitive and air-stable nickel(0) complex. Owing to its unique photophysical properties, it effectively catalyzed the etherification and amination of aryl bromides under 620–630 nm light irradiation, functioning as both a photocatalyst and an active metal catalyst.

Electrocatalytic Alkene Hydrogenation/Deuteration

F. Bu,^† Y. Deng,^† L. Lu,^† Y. Li, W. Song, Z. Yang, X. Luo, X. Dong, R. Yi, D. Yang, S. Wang, A. Lei* & W. Li*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c14320)

The authors demonstrate a universal method for the electrocatalytic hydrogenation and deuteration of alkenes with modified electrodes under ambient temperature. The key M-H/M-D species for alkene reduction were generated from the electrolysis of H₂O/D₂O on modified electrodes, avoiding the usage of H₂ and D₂. Mono-, di-, tri-, and tetra-substituted alkenes, electron-donating/-withdrawing alkenes, those with easily reducible functional groups, and complicated natural products and drugs were all hydrogenated and deuterated in excellent yields (85 examples, yields up to 99%).

ORGANIC PROCESS RESEARCH & DEVELOPMENT
Development of a Scalable Synthesis of Casdatifan (AB521), a Potent, Selective, Clinical-Stage Inhibitor of HIF-2α

C. Hardman, A. K. Mailyan, G. Mata, J. W. Beatty, S. L. Drew, J. Fournier, J. Kalisiak, B. R. Rosen, M. Epplin, B. Gal, K. Yu, Z. Wang, K. Haelsig, A. Tran, M. R. Leleti, J. P. Powers & K. V. Lawson*

Org. Process Res. Dev. 2025, ASAP (DOI: 10.1021/acs.oprd.4c00497)

Casdatifan (AB521) is a potent and selective inhibitor of HIF-2α, currently under clinical evaluation for the treatment of clear cell renal cell carcinoma (ccRCC). Here, the authors report the development of a scalable synthesis of casdatifan, which was used to support its preclinical characterization and the initiation of phase 1 clinical studies. A convergent approach to assembling the tetracyclic scaffold and the development of efficient routes to key intermediates enabled the successful delivery of material to meet clinical development timelines. Crucial to the efficiency of the synthesis was the strategic design of synthetic routes that leverage a combination of substrate and catalyst control to set each of the 5 stereocenters found in the molecule with exquisite selectivity.

ANGEWANDTE CHEMIE INTERNATIONAL EDITION
Cationic, Iodine(III)-Mediated and Directed Diastereoselective Oxidation of Inert C–H Bonds in Cyclic Hydrocarbons

N. G.-Simonian,^† B. R. Brutiu,^† D. Kaiser & N. Maulide*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202421872)

Over the past three decades, the functionalization of unactivated C–H bonds has become a workhorse of synthesis. In the field of C–H bond oxygenation, most established methods hinge on single-electron reactivity, encountering challenges pertaining to regio- and/or stereocontrol. Herein, the authors describe a conceptually distinct strategy relying on the unique features of carbocation chemistry. This iodine(III)-mediated method achieves the diastereoselective oxygenation of remote C–H bonds at traditionally unreactive sites and enables late-stage functionalization at steroidal frameworks as well as an unusual chirality relay.

Phototransposition of Indazoles to Benzimidazoles: Tautomer-Dependent Reactivity, Wavelength Dependence, and Continuous Flow Studies

G. L. Bartholomew, S. F. Kim,^‡ Y. Oyamada,^‡ F. Sbordone, J. A. Carroll, J. E. Jurczyk, C. S. Yeung,* C. Barner-Kowollik* & R. Sarpong*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202423803)

The authors report a detailed investigation of the photomediated transformation of indazoles to benzimidazoles through a nitrogen-carbon transposition. The 2H-tautomer of indazole absorbs light more strongly than the 1H-tautomer at longer wavelengths and this improved absorbance profile was leveraged to develop a general system for the conversion of N2-derivatized indazoles (prepared from the corresponding 1H-indazoles) to benzimidazoles in up to 98% yield. Investigation of the substrate scope revealed a strong correlation between reaction yield and electron density at N2 of the indazole substrate, and a continuous flow protocol was established that enables the phototransposition on preparative scale.

meta-Hydroxylation of Pyridines, Quinolines, and Isoquinolines Using Dearomatized Intermediates

D. Bhattacharya & A. Studer*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202423512)

Recently, the regioselective introduction of various functionalities at the meta-position of azines, utilizing readily accessible dearomatized intermediates, has emerged as a highly attractive approach. Along these lines, the meta-hydroxylation of azines is an appealing but challenging transformation due to the inherent electronic nature of these heterocycles. Herein, the authors report a meta-selective hydroxylation of pyridines, quinolines and isoquinolines through easily accessible oxazinoaza-arene intermediates.

CHEMRXIV
Cu-Controlled Enantiodivergent Pd-Catalyzed Stille Cross-Coupling Reactions

G. Ralph, A. R. Santha, N. B. Agyemang, X. Ma, D. W. Zuschlag, B. Murray & M. R. Biscoe*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-mj57m) 🔓

The authors report an enantiodivergent Pd-catalyzed cross-coupling reaction between unactivated enantioenriched alkylcarbastannatrane nucleophiles and aryl electrophiles in which the stereochemical course of the reaction is dictated by the inclusion or omission of a Cu(I) co-transmetalating agent. Use of a new electron-deficient biarylphosphine ligand (MaPhos) is required to promote the previously unreported stereoinvertive transmetalation pathway for unactivated secondary alkylstannanes. When a Cu(I) salt is included as a co-transmetalating agent, the stereochemical course of the reaction changes from stereoinvertive to stereoretentive. Thus, both enantiomers of the cross-coupling product can be accessed in high enantiopurity using a single achiral ligand.

ORGANIC LETTERS
Unified Hydrogen Atom Transfer Approach To Construct Vicinal Functionality

J. J. Chang, M. Kumar, M. Okamoto, E. S. Vergara-Pimentel & D. K. Kim*

Org. Lett. 2025, ASAP (DOI: 10.1021/acs.orglett.4c04767)

Due to their prevalence in pharmaceuticals and natural products, vicinally functionalized motifs are highly sought-after. Traditionally, these fragments are synthesized from alkene precursors via oxidation reactions. However, complementary syntheses via a C–C bond-forming approach are underexplored. Herein, the authors disclose a unified approach for accessing these motifs by acetal reagents made from affordable, prefunctionalized starting materials. The wide applicability of this methodology has been demonstrated with a variety of complex substrates and the coupled products can be employed in one-pot cyclizations to synthesize a variety of lactones.

CHEMICAL SOCIETY REVIEWS
Reaction Development: A Student's Checklist

J. L. Tyler,* D. Trauner* & F. Glorius*

Chem. Soc. Rev. 2025, Advance Article (DOI: 10.1039/D4CS01046A)

So you’ve discovered a reaction. But how do you turn this new discovery into a fully-fledged program that maximises the potential of your novel transformation? Herein, the authors provide a student's checklist to serve as a helpful guide for synthesis development, allowing you to thoroughly investigate the chemistry in question while ensuring that no key aspect of the project is overlooked. A wide variety of the most illuminating synthetic and spectroscopic techniques will be summarised, in conjunction with literature examples and insights, to provide sound justifications for their implementation towards the goal of developing new reactions.

OUTSIDE OF SYNTHESIS, INSIDE OF SCIENCE
A Real Powerhouse

🔬 A real powerhouse. Nature have just released their selection of the best science images in January, featuring a video of a human bone cancer cell with three nuclei (in blue, likely a result of failed cellular division), actin cytoskeleton (in red) and a network of mitochondria (in yellow) moving purposefully around the cell.

💊 The supplement of youth. A recent study published in Nature Aging on the effects of supplements and exercise in 700 over-70s found that a combination of omega-3, vitamin D and exercise over a three-year period reduced biological ageing by 3–4 months. These results complement previous gerontological studies, which found that omega-3 reduced rate of infections by up to 13% and rate of falls by 10% vs. those who didn’t take the supplement.