Skip to main content
NCBI home page
JACS Au logoLink to JACS Au
. 2026 Sep 10;6(9):4903–4909. doi: 10.1021/jacsau.6c01108

Cascade MHAT Radical Cyclopentannulation of Skipped Enyne to Access Highly Functionalized Carbocycles

Santosh J Gharpure 1,*, Simran R Narang 1, Rupali S Chavan 1
PMCID: PMC13625546  PMID: 42819272

Abstract

An iron-mediated metal-hydride hydrogen atom transfer (MHAT) radical cyclization cascade has been developed for the efficient construction of highly functionalized carbocyclic frameworks. This versatile [3+2] cyclopentannulation strategy starting from skipped enynes provides rapid access to a broad range of alkylidene cyclopentanes/cyclopentenes. Termination of this cascade with various radical trapping agents allows efficient construction of annulated products via successive C–H/C–C/C–C/C–X bond (X = C, H, S, Se, Te, I) formation. The method allows an expeditious entry into diquinanes, angular triquinanes with 4 quaternary carbons (3 contiguous) and substituted cyclopentadienes, all amenable to complex carbocycle synthesis.

Keywords: MHAT radical cyclization, cascade annulation, cyclopentane, cyclopentene, diquinane, triquinane, skipped enyne

graphic file with name au6c01108_0006.webp

graphic file with name au6c01108_0005.webp

Carbocyclic frameworks are ubiquitous structural motifs in biologically active natural products, underscoring their central role in medicinal chemistry. In particular, highly functionalized five-membered rings, such as cyclopentene and cyclopentane derivatives, are frequently encountered in natural products and serve as key intermediates in target-oriented synthesis (Scheme A). Despite their significance, constructing cyclopentane frameworks remains a synthetic challenge, often involving lengthy sequences, especially when high functionalization and stereocontrol are required. Consequently, substantial efforts have been directed toward developing efficient synthetic strategies. Most common ways for cyclopentane assembly involve transition-metal-catalyzed [3+2] cycloadditions, and intramolecular radical cyclizations, including electrochemical and photoinduced methods. Recently, MHAT radical coupling has become a powerful tool for C–C, C–H, and C–heteroatom bond formation. , It provides a mild and versatile platform for generating carbon-centered radicals, enabling the formation of strategic C–C bonds in target-directed total synthesis. , Shenvi established MHAT approach to explain the radical mechanism underlying Mukaiyama-type hydrofunctionalization reactions, thereby linking the classic Mukaiyama chemistry of the 1980s with modern reactivity. , While MHAT radical cyclization methods have primarily centered on intramolecular radical cyclizations, annulation strategies that achieve carbocycle formation through intermolecular cyclization remain underexplored. In this context, Pronin and co-workers recently reported an efficient iron-catalyzed annulation strategy based on an MHAT-enabled radical-polar crossover process for the construction of terpenoid frameworks (Scheme B). Furthermore, Vanderwal described a cobalt-catalyzed process for the efficient assembly of complex tetralin architectures, featuring an initial intermolecular radical addition followed by intramolecular cyclization onto an arene (Scheme C). MHAT-mediated radical hydrofunctionalization of isolated olefins has been widely employed to construct polycyclic architectures and in the total synthesis of structurally complex natural products. However, to the best of our knowledge, MHAT-mediated radical [3+2] annulation strategies using enyne for the synthesis of cyclopentanes have not been reported to date. In continuation of our interest in this domain, we report the first MHAT-enabled [3+2] cascade cyclization of skipped enynes for the synthesis of highly functionalized carbocycles. We also demonstrate that the termination of this cascade with various radical trapping agents allows efficient construction of annulated products via successive C–H/C–C/C–C/C–X bond (X = C, H, S, Se, Te, I) formation. We proposed that enyne 1a would first undergo intermolecular radical addition to the acceptor, followed by intramolecular cyclization to deliver the target cyclopentane derivative 3aa. To test this hypothesis, enyne 1a was reacted with acrylonitrile (2a) (3.0 equiv) in the presence of Fe­(acac)3 (1.5 equiv) and PhSiH3 (1.5 equiv) in a 5:1 mixture of ethanol and ethylene glycol at 60 °C under N2 atmosphere. Under these conditions, instead of the formation of product 3aa, the reaction furnished cyclopentane 3a, resulting from an additional trapping of in situ-generated vinyl radical by the acceptor (Table , entry 1). Changing the solvent from ethanol to HFIP increased the yield of cyclopentane 3a but not the cis:trans ratio (3:1) (Table , entry 2). In contrast, replacing the Fe­(acac)3 with Fe­(dibm)3 resulted in a reduced yield of the substituted benzylidene cyclopentane 3a, while the use of Mn­(dpm)3 completely suppressed the product formation (Table , entries 3-4). Likewise, decreasing the loading of Fe­(acac)3 led to diminished yield of product 3a (Table , entries 5-6), so a higher loading of Fe­(acac)3 is required to achieve efficient conversion, given the complexity of both the cascade process and the substrates. Increasing the loading of PhSiH3 to 2.0 equiv further reduced the yield of cyclopentane 3a (Table , entry 7). Next, substituting the reductant with TMDS and PMHS did not improve the reaction efficiency (Table , entries 8-9). Conducting the reaction in THF at 60 °C was also found to be incompetent in improving the yield of cyclopentane 3a (Table , entry 10). In the absence of ethylene glycol, cyclopentane 3a was obtained in lower yield, highlighting its crucial role in promoting efficient radical coupling through enhanced cage collapse (Table , entry 11). Reducing the radical acceptor to 1.0 equiv led to the formation of cyclopentane 3a in lower yield rather than the formation of 3aa (Table , entry 12).

1. Selected Natural Products and Previous Reports on the Synthesis of Carbocycles.

1

Open in a new tab

1. Optimization for Substituted Benzylidene Cyclopentane 3a .

graphic file with name au6c01108_0004.webp

Entry Metal Reagent (equiv) Reductant (equiv) Solvent Yield (%) ,
1 Fe(acac)3 (1.5) PhSiH3 (1.5) EtOH 63
2 Fe(acac) 3 (1.5) PhSiH 3 (1.5) HFIP 70
3 Fe(dibm)3 (0.3) PhSiH3 (1.5) HFIP 5
4 Mn(dpm)3 (0.3) PhSiH3 (1.5) HFIP  
5 Fe(acac)3 (0.3) PhSiH3 (1.5) HFIP 37
6 Fe(acac)3 (1.0) PhSiH3 (1.5) HFIP 50
7 Fe(acac)3 (1.5) PhSiH3 (2.0) HFIP 53
8 Fe(acac)3 (1.5) TMDS (3.0) HFIP 49
9 Fe(acac)3 (1.5) PMHS (3.0) HFIP 57
10 Fe(acac)3 (1.5) PhSiH3 (1.5) EtOH:THF 51
11 Fe(acac)3 (1.5) PhSiH3 (1.5) HFIP 20
12 Fe(acac)3 (1.5) PhSiH3 (1.5) HFIP 25
Open in a new tab
a

cis:trans ratios were measured using crude 1H NMR.

b

The reaction was carried out using 1a (0.320 mmol), 2a (0.960 mmol), metal reagent, and reductant in HFIP (2.0 mL) and (CH2OH)2 (0.4 mL) at room temperature under a N2 atmosphere.

c

Isolated yield.

d

Reaction temperature 60 °C.

e

Without (CH2OH)2.

f

2a (0.320 mmol).

With the optimized conditions established, we next investigated the scope and generality of this reaction. Enyne derivatives 1b-d bearing electron-donating substituents underwent radical cyclization to afford the cyclopentanes 3b-d in good yield with moderate cis:trans selectivity. Additionally, structurally diverse enynes 1e-g, bearing a trimethylsilyl group and heterocyclic moieties such as thiophene and indole too, participated in this transformation delivering cyclopentanes 3e-g with improved diastereoselectivity. The scope of the cascade annulation was further evaluated with various radical acceptors. Enyne 1h, containing an unsubstituted aromatic ring, under the optimized conditions, furnished the corresponding disubstituted arylidene cyclopentanes 3h and 3i in good yields. Moreover, methyl acrylate (2b) and methyl vinyl ketone (2c) were also compatible acceptors, affording cyclopentane 3j-k in good yield and with exceptionally high selectivity for 3g and 3k, possibly due to the stability of the in situ generated vinyl radical (Scheme A). The geometry of the major isomer was confirmed by NOE experiments on 3f and 3g. When an enyne 1i bearing a strongly electron-withdrawing cyanide group at the para-position of the aromatic ring was subjected to the reaction with acrylonitrile (2a), the transformation deviated from the expected outcome, resulting exclusively in the formation of substituted benzylidene cyclopentane 4a in moderate yield. Similarly, replacement of acrylonitrile with dimethyl acrylamide (2d) as the acceptor furnished the substituted benzylidene cyclopentane 4b, highlighting the crucial role of the electronic properties of the acceptor and the enyne derivative in determining the reaction outcome. Treatment of enyne 1h with the alkyne-based acceptor (2e) did not afford the anticipated cyclopentene 4c, instead yielding a complex mixture (Scheme B). This is likely due to the higher reactivity of the enyne relative to the acceptor, leading to rapid, unselective radical reactions. In contrast, the ester-substituted enyne 1j-k exhibited a greater propensity to undergo the desired [3+2] cyclization, providing the corresponding cyclized products 4d-e, albeit in low yield (Scheme C). Encouraged by these results, we next explored the use of cyclic acceptors to access cyclopentannulated bicyclic carbocycles (Scheme D). Gratifyingly, when cyclopentenone (2f) was employed as the radical acceptor under the standard conditions with enyne derivative 1h, the reaction proceeded smoothly to afford the desired diquinane 4f in good yield. Enynes 1 bearing a broad range of substitution patterns were well tolerated under the optimized conditions, affording the corresponding diquinanes 4g-k in moderate yields with good geometric selectivity and exceptionally high selectivity for the indole-substituted enyne 1g. Moderate yields were generally obtained due to the complexity of the cascade process and competing side reactions, including alkene reduction. In the case of a cyclic acceptor, the trans geometry was formed predominantly, likely due to the steric effects of the cyclic acceptor, which favor formation of the fused bicyclic framework with substituents oriented on the opposite face. When cyclohexanone (2g) was reacted with enyne 1h, it resulted in an inseparable mixture of products. In contrast, cyclic lactones 2h and coumarins 2i participated effectively, providing the cyclopentannulated products 4m-n in good yield. The trans-geometry of the alkylidene moiety of the major isomer was established by NOE of 4i, 4k and 4m and single-crystal X-ray analysis of 4h. To demonstrate the potential of this strategy, we envisioned that terminating the cascade with various trapping agents would enable the formation of diverse C–X bonds. In particular, vinyl sulfides, selenides, and organotellurium compounds are an important class of motifs found in bioactive molecules and serve as valuable synthetic building blocks. Accordingly, we subjected enyne derivative 1h with acrylonitrile (2a) (1.5 equiv) and iodine 5a (3.0 equiv) in the presence of Fe­(acac)3 (1.5 equiv), PhSiH3 (2.0 equiv) in HFIP and ethylene glycol at room temperature. To our delight, we observed the formation of the desired cyclopentane derivative 6a in good yield, albeit with low cis:trans ratio. It is pertinent to mention that the formation of C-X bonds through MHAT cascade radical cyclization has not been explored. Acceptors, namely phenyl disulfide (5b), phenyl diselenide (5c), and phenyl ditelluride (5d) were all found to participate well in the radical cyclization with enyne 1h, delivering the corresponding cyclopentane derivatives 6b–d in satisfactory yields. In contrast, di-tert-butyl disulfide (5e) afforded only 6e′ in moderate yield, likely because steric hindrance from the tert-butyl groups or higher S–S bond dissociation energy hinders trapping of the vinyl radical intermediate (Scheme A). This outcome is interesting as the product 6e′ could not be accessed through the straightforward reaction of skipped enyne 1h and acrylonitrile (2a) (cf. Scheme A).

2. Scope for the Synthesis of Cyclopentanes, Cyclopentenes and Diquinanes .

2

Open in a new tab

a cis:trans ratio in parentheses was measured using 1H NMR of the crude reaction mixture.

3. Trapping with Different Radical Acceptors, Plausible Mechanism, Gram-Scale Synthesis and Postfunctionalization .

3

Open in a new tab

a cis:trans ratio in parentheses was measured using 1H NMR of the crude reaction mixture.

The plausible reaction mechanism involves the addition of hydrogen to enyne 1 under MHAT conditions to generate tertiary radical intermediate II, which adds to acceptor 2, followed by 5-exo-dig cyclization to furnish the alkylidene radical intermediate III (Scheme B). ,, At this stage, the reaction proceeds through two competing pathways. In one pathway, alkylidene radical III undergoes single-electron reduction by the Fe­(II) species to give intermediate IV, which, upon protonation by the solvent, delivers monosubstituted alkylidene 4. Alternatively, alkylidene radical III can undergo a second Michael addition to acceptor 2 and form the intermediate V. Subsequent single-electron reduction of intermediate V by the Fe­(II) complex yields intermediate VI, followed by protonation, which affords the cyclopentane 3.

A gram-scale reaction of enyne 1j with cyclopentenone under the standard conditions delivered 4k in good yield, highlighting the practicality of the protocol (Scheme C). To assess the utility of the protocol, ketoester 4k was alkylated with 4-bromobutene to afford 7, which upon treatment under MHAT conditions, underwent 5-exo-trig cyclization to give angular triquinane 8 as a 1:1 mixture of diastereomers at the Me-bearing carbon (Scheme D). We envisioned that the synthesis of another quaternary centre would be challenging and would also obviate the diastereoselectivity problem. Cyclopentannulated product 4k was converted to prenylated derivative 9, which, under MHAT conditions, underwent intramolecular cyclisation to afford angular triquinane 10 in good yield. This three-step strategy to angularly fused, natural product-like triquinanes is one of the shortest synthetic routes to these moieties and underscores the versatility and robustness of the developed strategy. In a similar vein, isomerisation of alkylidene olefin moiety in bicyclic keto ester derivative 4k′ with DBU resulted in the thermodynamically more stable product 4k. Chemoselective reduction of ketone 4k′ with sodium borohydride resulted in the formation of the corresponding alcohol 11 in excellent yield, albeit with low diastereoselectivity (Scheme E). Furthermore, the methodology was extended to the construction of a cyclopentadiene motif 12, achieved by treating cyclopentene derivative 4d with sodium hydride in THF (Scheme F). Finally, the diastereomeric mixture of cyclopentane derivative 3h was efficiently converted into a single isomer 13 upon treatment with DBU, further highlighting the synthetic flexibility of this approach (Scheme G).

In summary, we have developed an efficient Fe-mediated protocol for constructing carbocyclic frameworks via a sequential intermolecular–intramolecular radical cyclization cascade. The methodology is operationally simple, readily scalable, and employs easily accessible starting materials while exhibiting broad functional-group tolerance. The developed method enables the formation of diverse C–X bonds (X = S, Se, Te, I) through a cascade process involving interception of vinyl radicals by suitable acceptors. These transformations are challenging to achieve using conventional methods. The strategy was further extended to the synthesis of angular triquinane frameworks, representing one of the shortest routes from readily available starting materials. Such motifs are commonly found in complex natural products but are typically accessible only through lengthy synthetic sequences.

Supplementary Material

au6c01108_si_001.pdf (7.5MB, pdf)

Acknowledgments

We thank ANRF, New Delhi, India, Cohizon Life Sciences Limited and S. H. Kelkar & Co. Ltd. (Keva) for financial support. We thank Mr. Darshan Mhatre for the X-ray facility of the Department of Chemistry, IIT Bombay for collecting the crystallographic data and IRCC, IIT Bombay for funding central facilities. We are grateful for the award of a Prime Minister’s Research Fellowship (PMRF) to S.R.N.

Glossary

Abbreviations

THF

tetrahydrofuran

DMF

dimethylformamide

HFIP

1,1,1,3,3,3-hexafluoroisopropanol

TLC

thin layer chromatography

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.6c01108.

  • Experimental details (PDF)

The manuscript was written through the contributions of all authors. All authors have approved the final version of the manuscript.

The authors declare no competing financial interest.

References

  1. a Kumar K., Waldmann H.. Synthesis of Natural Product Inspired Compound Collections. Angew. Chem. Int. Ed. 2009;48:3224–3242. doi: 10.1002/anie.200803437. [DOI] [PubMed] [Google Scholar]; b Hu Y.-J., Li L.-X., Han J.-C., Min L., Li C.-C.. Recent Advances in the Total Synthesis of Natural Products Containing Eight-Membered Carbocycles (2009–2019) Chem. Rev. 2020;120:5910–5953. doi: 10.1021/acs.chemrev.0c00045. [DOI] [PubMed] [Google Scholar]
  2. a Suzuki M., Yanagisawa A., Noyori R.. Prostaglandin Synthesis. 10. An Extremely Short Way to Prostaglandins. J. Am. Chem. Soc. 1985;107:3348–3349. doi: 10.1021/ja00297a051. [DOI] [Google Scholar]; b Meinwald J., Jones T. H.. Synthesis and Stereochemistry of Chrysomelidial and Plagiolactone. J. Am. Chem. Soc. 1978;100:1883–1886. doi: 10.1021/ja00474a038. [DOI] [Google Scholar]; c Roach B., Eisner T., Meinwald J.. Defense Mechanisms of Arthropods. 83. α- and β-Necrodol, Novel Terpenes from a Carrion Beetle (Necrodes surinamensis, Silphidae, Coleoptera) J. Org. Chem. 1990;55:4047–4051. doi: 10.1021/jo00300a020. [DOI] [Google Scholar]; d Arnold L. A., Naasz R., Minnaard A. J., Feringa B. L.. Catalytic Enantioselective Synthesis of Prostaglandin E1 Methyl Ester Using a Tandem 1,4-Addition-Aldol Reaction to a Cyclopenten-3,5-dione Monoacetal. J. Am. Chem. Soc. 2001;123:5841–5842. doi: 10.1021/ja015900+. [DOI] [PubMed] [Google Scholar]; e Helmboldt H., Köhler D., Hiersemann M.. Synthesis of the Norjatrophane Diterpene (−)-15-Acetyl-3-propionyl- 17-norcharaciol. Org. Lett. 2006;8:1573–1576. doi: 10.1021/ol060115t. [DOI] [PubMed] [Google Scholar]; f Schnabel C., Hiersemann M.. Total Synthesis of Jatrophane Diterpenes from Euphorbia characias. Org. Lett. 2009;11:2555–2558. doi: 10.1021/ol900819u. [DOI] [PubMed] [Google Scholar]; g Malinowski J. T., Sharpe R. J., Johnson J. S.. Enantioselective Synthesis of Pactamycin, a Complex Antitumor Antibiotic. Science. 2013;340:180–182. doi: 10.1126/science.1234756. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. a Hudlicky T., Price J. D.. Anionic Approaches to the Construction of Cyclopentanoids. Chem. Rev. 1989;89:1467–1486. doi: 10.1021/cr00097a004. [DOI] [Google Scholar]; b Tanino K., Tomata Y., Shiina Y., Miyashita M.. A Novel Cyclopentene Annulation Method Based on Conjugate Addition Reactions of α-Cyano Carbanion Species. Eur. J. Org. Chem. 2006;2006:328–334. doi: 10.1002/ejoc.200500759. [DOI] [Google Scholar]; c Arteaga J. F., Diéguez H. R., González-Delgado J. A., Quílez del Moral J. F., Barrero A. F.. Control of the Regio- and Diastereoselectivity for the Preparation of Highly Functionalized Terpenic Cyclopentanes through Radical Cyclization. Eur. J. Org. Chem. 2011;2011:5002–5005. doi: 10.1002/ejoc.201100400. [DOI] [Google Scholar]; d Parr B., Davies H. M. L.. Highly Stereoselective Synthesis of Cyclopentanes bearing four Stereocentres by a Rhodium Carbene-Initiated Domino Sequence. Nat. Commun. 2014;5:4455. doi: 10.1038/ncomms5455. [DOI] [PMC free article] [PubMed] [Google Scholar]; e Li S., Zhang P. P., Li Y. H., Lu S. M., Gong J. X., Yang Z.. Diastereoselective Synthesis of Diquinanes and Triquinanes Bearing Vicinal Quaternary Carbon Stereocenters from Acyclic Allene-based Precursors via a Cascade Reaction. Org. Lett. 2017;19:4416–4419. doi: 10.1021/acs.orglett.7b01733. [DOI] [PubMed] [Google Scholar]; f Xuan J., Studer A.. Radical Cascade Cyclization of 1,n-Enynes and Diynes for the Synthesis of Carbocycles and Heterocycles. Chem. Soc. Rev. 2017;46:4329–4346. doi: 10.1039/C6CS00912C. [DOI] [PubMed] [Google Scholar]; g Matsuo K., Yoshitake T., Yamaguchi E., Itoh A.. Photoinduced Atom Transfer Radical Addition/Cyclization Reaction between Alkynes or Alkenes with Unsaturated α-Halogenated Carbonyls. Molecules. 2021;26:6781. doi: 10.3390/molecules26226781. [DOI] [PMC free article] [PubMed] [Google Scholar]; h Guan Z., Zhu S., Ye Y., Li X., Liu Y., Wang P., Zhang H., Huang Z., Lei A.. Synthesis of Cyclopentene Derivatives via Electrochemically Induced Intermolecular Selective (3+2) Annulation. Angew. Chem. Int. Ed. 2022;61:e202207059. doi: 10.1002/anie.202207059. [DOI] [PubMed] [Google Scholar]; i Miguélez R., Barrio P., González J. M.. Recent Advances in the Catalytic Synthesis of the Cyclopentene Core. Chem. Rec. 2023;23:e202300254. doi: 10.1002/tcr.202300254. [DOI] [PubMed] [Google Scholar]; j Samkian A. E., Poonswat K., Virgil S. C., Stoltz B. M.. A Modular Cyclopentene Annulation. Org. Lett. 2025;27:5876–5879. doi: 10.1021/acs.orglett.5c01750. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. a Mukaiyama T., Kato K.. Iron­(III) Complex Catalyzed Nitrosation of Terminal and 1,2-Disubstituted Olefins with Butyl Nitrite and Phenylsilane. Chem. Lett. 1992;21:1137–1140. doi: 10.1246/cl.1992.1137. [DOI] [Google Scholar]; b Iwasaki K., Wan K. K., Oppedisano A., Crossley S. W. M., Shenvi R. A.. Simple, Chemoselective Hydrogenation with Thermodynamic Stereocontrol. J. Am. Chem. Soc. 2014;136:1300–1303. doi: 10.1021/ja412342g. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Lo J. C., Kim D., Pan C.-M., Edwards J. T., Yabe Y., Gui J., Qin T., Gutiérrez S., Giacoboni J., Smith M. W., Holland P. L., Baran P. S.. Fe-Catalyzed C–C Bond Construction from Olefins via Radicals. J. Am. Chem. Soc. 2017;139:2484–2503. doi: 10.1021/jacs.6b13155. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Crossley S. W. M., Barabé F., Shenvi R. A.. Simple, Chemoselective, Catalytic Olefin Isomerization. J. Am. Chem. Soc. 2014;136:16788–16791. doi: 10.1021/ja5105602. [DOI] [PMC free article] [PubMed] [Google Scholar]; e Lo J. C., Yabe Y., Baran P. S.. A Practical and Catalytic Reductive Olefin Coupling. J. Am. Chem. Soc. 2014;136:1304–1307. doi: 10.1021/ja4117632. [DOI] [PMC free article] [PubMed] [Google Scholar]; f Saladrigas M., Bosch C., Saborit G. V., Bonjoch J., Bradshaw B.. Radical Cyclization of Alkene-Tethered Ketones Initiated by Hydrogen-Atom Transfer. Angew. Chem. Int. Ed. 2018;57:182–186. doi: 10.1002/anie.201709659. [DOI] [PubMed] [Google Scholar]; g Saladrigas M., Loren G., Bonjoch J., Bradshaw B.. Hydrogen Atom Transfer (HAT)-Triggered Iron-Catalyzed Intra- and Intermolecular Coupling of Alkenes with Hydrazones: Access to Complex Amines. ACS Catal. 2018;8:11699–11703. doi: 10.1021/acscatal.8b03794. [DOI] [Google Scholar]; h Wu B., Zhu R.. Radical Philicity Inversion in Co- and Fe-Catalyzed Hydrogen-Atom-Transfer-Initiated Cyclizations of Unsaturated Acylsilanes. ACS Catal. 2020;10:510–515. doi: 10.1021/acscatal.9b04774. [DOI] [Google Scholar]
  5. a Barker T. J., Boger D. L.. Fe­(III)/NaBH4-Mediated Free Radical Hydrofluorination of Unactivated Alkenes. J. Am. Chem. Soc. 2012;134:13588. doi: 10.1021/ja3063716. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Lo J. C., Gui J., Yabe Y., Pan C.-M., Baran P. S.. Functionalized Olefin Cross-Coupling to Construct Carbon–Carbon Bonds. Nature. 2014;516:343–348. doi: 10.1038/nature14006. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Crossley S. W. M., Obradors C., Martinez R. M., Shenvi R. A.. Mn-, Fe-, and Co-Catalyzed Radical Hydrofunctionalizations of Olefins. Chem. Rev. 2016;116:8912–9000. doi: 10.1021/acs.chemrev.6b00334. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Lo J. C., Kim D., Pan C.-M., Edwards J. T., Yabe Y., Gui J., Qin T., Gutiérrez S., Giacoboni J., Smith M. W., Holland P. L., Baran P. S.. Fe-Catalyzed C–C Bond Construction from Olefins via Radicals. J. Am. Chem. Soc. 2017;139:2484–2503. doi: 10.1021/jacs.6b13155. [DOI] [PMC free article] [PubMed] [Google Scholar]; e Green S. A., Crossley S. W. M., Matos J. L. M., Vásquez-Céspedes S., Shevick S. L., Shenvi R. A.. The High Chemofidelity of Metal-Catalyzed Hydrogen Atom Transfer. Acc. Chem. Res. 2018;51:2628–2640. doi: 10.1021/acs.accounts.8b00337. [DOI] [PMC free article] [PubMed] [Google Scholar]; f Shevick S. L., Wilson C. V., Kotesova S., Kim D., Holland P. L., Shenvi R. A.. Catalytic Hydrogen Atom Transfer to Alkenes: A Roadmap for Metal Hydrides and Radicals. Chem. Sci. 2020;11:12401–12422. doi: 10.1039/D0SC04112B. [DOI] [PMC free article] [PubMed] [Google Scholar]; g Shelke Y. G., Dhal S.. Recent advances in applications of metal hydride hydrogen atom transfer for natural product synthesis. Org. Biomol. Chem. 2026;24:38. doi: 10.1039/D5OB01671A. [DOI] [PubMed] [Google Scholar]; h Barnes G. L., Rerick A. L., Baran P. S.. Radical Retrosynthesis of Natural Products Enabled by Iron-Based Reductive Olefin Coupling. Angew. Chem. Novit. 2026;2:e70017. doi: 10.1002/anov.70017. [DOI] [Google Scholar]
  6. a Xia X. F., He W., Zhang G. W., Wang D.. Iron-Catalyzed Reductive Cyclization Reaction of 1,6-Enynes for the Synthesis of 3-acylbenzofurans and Thiophenes . Org. Chem. Front. 2019;6:342–346. doi: 10.1039/C8QO01190G. [DOI] [Google Scholar]; b Zhao M., He W., Zou L.-H., Wang D., Sun T.-Y., Xia X.-F.. Iron-Catalyzed Hydrogen Atom Transfer Induced Cyclization of 1,6-Enynes for the Synthesis of Ketoximes: a Combined Experimental and Computational Study. Org. Chem. Front. 2021;8:643–652. doi: 10.1039/D0QO01341B. [DOI] [Google Scholar]; c Hazra S., Patel M., Saha J.. Radical Carbocyclization Intercepted Reductive C– C Bond Formation Between 1, n-Enynes or Dienes and Electron-Poor Olefins/Alkynes. Adv. Synth. Catal. 2024;366:4688. doi: 10.1002/adsc.202400503. [DOI] [Google Scholar]
  7. a Thomas W. P., Schatz D. J., George D. T., Pronin S. V.. A Radical-Polar Crossover Annulation to Access Terpenoid Motifs. J. Am. Chem. Soc. 2019;141:12246. doi: 10.1021/jacs.9b07346. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Thomas W. P., Pronin S. V.. A Concise Enantioselective Approach to Quassinoids. J. Am. Chem. Soc. 2022;144:118. doi: 10.1021/jacs.1c12283. [DOI] [PMC free article] [PubMed] [Google Scholar]; c George D. T., Kuenstner E. J., Pronin S. V.. A Concise Approach to Paxilline Indole Diterpenes. J. Am. Chem. Soc. 2015;137:15410–15413. doi: 10.1021/jacs.5b11129. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Godfrey N. A., Schatz D. J., Pronin S. V.. Twelve-Step Asymmetric Synthesis of (−)-Nodulisporic Acid C. J. Am. Chem. Soc. 2018;140:12770–12774. doi: 10.1021/jacs.8b09965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Johnson L. K., Barnes G. L., Fernandez S. A., Vanderwal C. D.. Hydrogen-Atom-Transfer-Initiated Radical/Polar Crossover Annulation Cascade for Expedient Access to Complex Tetralins. Angew. Chem. Int. Ed. 2023;62:e202303228. doi: 10.1002/anie.202303228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. a Gharpure S. J., Chavan R. S., Ardhapure A. V.. Iron-Catalyzed Reductive Cyclization of Alkenyl Vinylogous Carbonates for Stereoselective Synthesis of Substituted Tetrahydrofurans, Tetrahydropyrans, and Chromans. Adv. Synth. Catal. 2022;364:3094. doi: 10.1002/adsc.202200629. [DOI] [Google Scholar]; b Gharpure S. J., Chavan R. S., Narang S. R.. Iron-Mediated Hydrogen Atom Transfer Radical Cyclization of Alkenyl Indoles and Pyrroles gives their Fused Derivatives: Total Synthesis of Bruceolline E and H. Org. Lett. 2024;26:4583. doi: 10.1021/acs.orglett.4c00032. [DOI] [PubMed] [Google Scholar]; c Gharpure S. J., Chavan R. S., Fartade D. J.. Iron-Mediated Segment Coupling of Alkenols with Acceptors via C–C Radical Translocation and Remote Oxidative 1, 5/6-Hydrogen Atom Transfer. Org. Lett. 2024;26:9920. doi: 10.1021/acs.orglett.4c03749. [DOI] [PubMed] [Google Scholar]; d Gharpure S. J., Narang S. R., Chavan R. S.. MHAT-Enabled Cascade Radical Annulation to Access N-fused Indoles and Pyrroles. Chem. Commun. 2025;61:8423–8426. doi: 10.1039/D5CC01615K. [DOI] [PubMed] [Google Scholar]; e Gharpure S. J., Narang S. R., Chavan R. S., Dessai G. V.. Synthesis of 1,2-N/O-Heterocycles via Metal Hydride Hydrogen Atom Transfer Radical Cyclization on Vinylogous N-Alkoxycarbamates. Adv. Synth. Catal. 2026;368:e70320. doi: 10.1002/adsc.70320. [DOI] [Google Scholar]
  10. CCDC 2549815 (4h) contain the supplementary crystallographic data for this paper. This data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.
  11. a Mugesh G., Du Mont W. W., Sies H.. Chemistry of Biologically Important Synthetic Organoselenium Compounds. Chem. Rev. 2001;101:2125–2179. doi: 10.1021/cr000426w. [DOI] [PubMed] [Google Scholar]; b Pasquini S., Mugnaini C., Tintori C., Botta M., Trejos A., Arvela R. K., Larhed M., Witvrouw M., Michiels M., Christ F., Debyser Z., Corelli F.. Investigations on the 4-Quinolone-3-carboxylic Acid Motif. 1. Synthesis and Structure–Activity Relationship of a Class of Human Immunodeficiency Virus type 1 Integrase Inhibitors. J. Med. Chem. 2008;51:5125–5129. doi: 10.1021/jm8003784. [DOI] [PubMed] [Google Scholar]; c Mukherjee N., Chatterjee T.. Recyclable Iodine-Catalyzed Oxidative C–H Chalcogenation of 1,1-Diarylethenes in Water: Green Synthesis of Trisubstituted Vinyl Sulfides and Selenides. Green Chem. 2023;25:8798–8807. doi: 10.1039/D3GC02999A. [DOI] [Google Scholar]; d Bellé L. P., Bitencourt P. E. R., Abdalla F. H., Guerra R. B., Funchal C., Moretto M. B.. An In Vitro Comparison of a New Vinyl Chalcogenide and Sodium Selenate on Adenosine Deaminase Activity of Human Leukocytes. Chem.-Biol. Interact. 2011;189:141–145. doi: 10.1016/j.cbi.2010.12.010. [DOI] [PubMed] [Google Scholar]; e Zigman-Hoffman E., Sredni B., Meilik B., Naparstek E., Tartakovsky B.. Tellurium Compound Provides Pro-Apoptotic Signaling in Drug Resistant Multiple Myeloma. Leuk. Lymphoma. 2021;62:1146–1156. doi: 10.1080/10428194.2020.1858292. [DOI] [PubMed] [Google Scholar]; f Duan L., Liu T., Chen T.. Near-Infrared Laser-Triggered Drug Release in a Tellurium Nanosystem for Simultaneous Chemo-Photothermal Cancer Therapy. Biomater. Sci. 2021;9:1767–1778. doi: 10.1039/D0BM01811B. [DOI] [PubMed] [Google Scholar]
  12. a Mehta G., Srikrishna A.. Synthesis of Polyquinane Natural Products: An Update. Chem. Rev. 1997;97:671–720. doi: 10.1021/cr9403650. [DOI] [PubMed] [Google Scholar]; b Annis G. D., Paquette L. A.. Total Synthesis of (±)-Pentalenene. J. Am. Chem. Soc. 1982;104:4504–4506. doi: 10.1021/ja00380a041. [DOI] [Google Scholar]; c DeLoach J. A., Crimmins M. T.. Intramolecular Photocycloadditions-Cyclobutane Fragmentation: Total Synthesis of (±)-Pentalenene, (±)-Pentalenic Acid, and (±)-Deoxypentalenic Acid. J. Am. Chem. Soc. 1986;108:800–806. doi: 10.1021/ja00264a037. [DOI] [Google Scholar]; d Mehta G., Rao K. S.. General Transannulation Approach to Angular Triquinanes. Total Syntheses of (±)-Pentalenene and (±)-epi-Pentalenene. J. Am. Chem. Soc. 1986;108:8015–8021. doi: 10.1021/ja00285a023. [DOI] [Google Scholar]; e Schore N. E., Rowley E. G.. Diastereofacial selectivity in Intramolecular Pauson-Khand Cycloaddition: Highly Stereoselective Synthesis of Pentalenene. J. Am. Chem. Soc. 1988;110:5224–5225. doi: 10.1021/ja00223a069. [DOI] [Google Scholar]; f Wang X., Liu D., Cheng Y.. Advances in the Total Synthesis of Angular Triquinane-Type Natural Products. Molecules. 2025;30:3956. doi: 10.3390/molecules30193956. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. a Leggans E. K., Barker T. J., Duncan K. K., Boger D. L.. Iron­(III)/NaBH4-Mediated Additions to Unactivated Alkenes: Synthesis of Novel 20′-Vinblastine Analogues. Org. Lett. 2012;14:1428–1431. doi: 10.1021/ol300173v. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Wille U.. Radical Cascades Initiated by Intermolecular Radical Addition to Alkynes and Related Triple Bond Systems. Chem. Rev. 2013;113:813–853. doi: 10.1021/cr100359d. [DOI] [PubMed] [Google Scholar]; c Meena S. A., Sharma P., Verma A. K.. Stereoselective Synthesis of Difunctionalized Succinimides from aza-1, 6-Enynes by Radical Cascade Reaction. Chem. Commun. 2023;59:7271. doi: 10.1039/D3CC01391J. [DOI] [PubMed] [Google Scholar]; d Li Z., Zeng G., He Y., Zhou S., Chen J., Chen Z., Chen J., Lv N.. Markovnikov Hydrochlorination of Unactivated Alkenes with FeCl3 via a HAT/XAT Sequence. Org. Lett. 2024;26:4813–4817. doi: 10.1021/acs.orglett.4c01647. [DOI] [PubMed] [Google Scholar]; e Zhu S., Jia L., Cheng Q., Han Y., Sun Q., Yu H., Chen X., Hou H.. Dispersion-Induced Cooperative Hydrogen Atom Transfer for Radical Iodoalkylation. Chem. Commun. 2024;60:10772. doi: 10.1039/D4CC03908D. [DOI] [PubMed] [Google Scholar]; f Li J.-Y., Liu X., Liu Z.-P., Liu H.-C., Tao S.-C., Zhu S., Zheng Y.-L.. Iron-Catalyzed Markovnikov-Selective Radical Hydrochalcogenation of Unactivated Alkenes. ACS Catal. 2025;15:14–22. doi: 10.1021/acscatal.4c06770. [DOI] [Google Scholar]; g Liao Y.-Z., Ruan B.-Q., Hu H.-Y., Cheng H., Wang B.-Q., Pan F.. Iron-Catalyzed Radical Hydrothiolation of gem-Difluoroalkenes. Org. Lett. 2025;27:9293–9298. doi: 10.1021/acs.orglett.5c02890. [DOI] [PubMed] [Google Scholar]; h Meena S. A., Thakur D., Panda D., Ranjan R., Verma A. K.. Visible Light Promoted Metal and Oxidant-Free Stereoselective Synthesis of Functionalized Succinimides from aza-1, 6-Enynes. RSC Sustain. 2025;3:592. doi: 10.1039/D4SU00753K. [DOI] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

au6c01108_si_001.pdf (7.5MB, pdf)

Articles from JACS Au are provided here courtesy of American Chemical Society

RESOURCES