Abstract
Alkenes are indispensable feedstocks in chemistry. Functionalization at both carbons of the alkene—1,2-difunctionalization—is part of chemistry curricula worldwide1. Although difunctionalization at distal positions has been reported2,3,4, it typically relies on designer substrates featuring directing groups and/or stabilizing features, all of which determine the ultimate site of bond formation5,6,7. Here we introduce a method for the direct 1,3-difunctionalization of alkenes, based on a concept termed ‘charge relocation’, which enables stereodivergent access to 1,3-difunctionalized products of either syn- or anti-configuration from unactivated alkenes, without the need for directing groups or stabilizing features. The usefulness of the approach is demonstrated in the synthesis of the pulmonary toxin 4-ipomeanol and its derivatives.
Similar content being viewed by others
Main
Alkene functionalization reactions are a staple of every undergraduate programme in chemistry and can be broadly divided into two families: (1) transformations that result in either temporary (for example, olefin metathesis) or permanent (for example, ozonolysis) C=C bond cleavage and (2) reactions resulting in products that maintain the original C–C σ-bond connectivity1,8. Among the latter, the broad family of 1,2-difunctionalization reactions9,10 ranges from classical halogenation to sophisticated transition-metal-catalysed processes11,12,13, and the nascent field of remote functionalization has emerged as a way of redirecting reactivity towards a distal position, away from the initial reactive site2,3,4,14,15,16,17,18,19,20. Indeed, a number of methods for alkene 1,3-difunctionalization using transition-metal catalysis have emerged in the literature. Such methods (Fig. 1a) invariably rely on a mechanistic handle to achieve regioselectivity: a directing group or ‘stopper’ (such as an arene ring that provides a benzylic resting point for the catalyst) must be embedded in the substrate, primarily because of the pronounced tendency of C(sp3)–M species to engage in β-hydride (β-H) elimination, resulting in the generation of Heck products5,6,7,21,22. Similarly, an extensive body of research on Friedel–Crafts-type reactions of alkenes is known (Fig. 1b)23. Primarily, reactions of acylium ions have been shown to afford the products of 1,2-difunctionalization, with product distribution often highly dependent on the nature of substrate, reagent and solvent (Fig. 1b, top). Intriguingly, Friedel–Crafts-type reactions of alkenes have also been found to enable remote functionalization of alkenes (Fig. 1b, bottom); such transformations, however, invariably suffer from undefined selectivity—often giving mixtures of 1,2- and 1,3-functionalization products24,25,26,27—or are possible only under substrate control or on specialized substrates28,29,30. Thus, although the corresponding reactivity, at its core that of the Friedel–Crafts reaction, has been explored, little is known about the factors governing the selectivity or predictability of such transformations, and the direct and general 1,3-difunctionalization of unactivated and unfunctionalized alkenes remains an unmet challenge.
a, Current paradigm for the distal functionalization of alkenes, relying on directing-group-mediated metal catalysis. b, Friedel–Crafts-type reactions of alkenes generally provide mixtures of products—which depend on the substrate, reagent and solvent—with selectivity observed only with specialized substrates. c, This work: stereodivergent, reagent-controlled 1,3-difunctionalization of alkenes through charge relocation. DG, directing group; Bpin, pinacol boronate.
We present such a difunctionalization of unactivated alkenes under simple conditions, through which olefins are converted into products in which functionalization has occurred with generality at positions 1 and 3 (Fig. 1c). We achieved this by adapting electrophilic addition to alkenes as the basis for a general, predictable and highly selective strategy termed ‘charge relocation’—a synthetic logic in which incipient or localized charge at a given atom relocates to a defined position through a series of hydride shifts.
Well aware that classical electrophilic additions to double bonds hinge on immediate interception of an (incipient) positive charge by a nucleophile23, we became intrigued by the mode of electrophilic addition to a double bond in the absence of a suitable nucleophilic species. Over the course of these investigations we eventually found that the treatment of cyclohexene with an acylium cation carrying non-nucleophilic hexafluoroantimonate as the counter anion, generated in situ from acyl chloride and silver hexafluoroantimonate, swiftly and selectively formed a product of 1,3-hydroxyacylation following hydrolytic work-up (Fig. 2a; see Supplementary Information for additional conditions surveyed during optimization of reaction conditions). Notably, the success of the reaction was found to rely heavily on the nature of the halophilic reagent, with only silver hexafluoroantimonate providing a high yield of 19 whereas other silver salts or Lewis acids gave low levels of conversion to the desired product. Most interestingly, this reaction not only resulted in 1,3-difunctionalization but it did so with exclusive selectivity for the syn-products over a range of different unactivated alkenes, as depicted in Fig. 2.
a, 1,3-Hydroacylation of cyclohexene. b, Scope of syn-alcohols. c, Comparison with transition-metal catalysis. All yields in the table of optimization correspond to nuclear magnetic resonance yields using 1,3,5-trimethoxybenzene as an internal standard. All products were obtained at greater than 20:1 d.r. and regioisomeric ratio (r.r.), unless otherwise mentioned. All yields correspond to isolated material. See Supplementary Information for further details and additional scope entries. *The reported yields correspond to averages over three runs. In cases in which competing pathways led to the observation of enone byproducts in the crude mixtures, the following percentages were observed: a37, b24, c30. Additional substrate scope is presented in Extended Data Fig. 1 and Supplementary Information.
Following this finding we turned to investigate the scope of this transformation (Fig. 2b), initially using a phenyl-substituted acylium ion. Our survey of linear alkenes, inherently lacking the ability to form diastereomeric products, showed high yields for a range of chain lengths (1 and 2). Appended functional groups were also found to be tolerated, with substrates bearing a trifluoroacetate (3) or phthalimide (4) providing the desired products at good yield. Importantly, 4-phenyl-1-butene—a substrate bearing potential bias due to the presence of a benzylic position—afforded exclusively the product 1,3-difunctionalization (5) with the benzylic site remaining untouched.
As highlighted above, the reaction with cyclohexene was found to deliver exclusively the product of syn-hydroxyacylation (6), a fact proven to be true for a large variety of arene-substituted acylium ions regardless of electronic or steric properties (7–17). The same stereochemical outcome was observed for a cyclopentene-derived ketoalcohol (18), as well as for products resulting from the addition of aliphatic acylium ions (19–24). Notably, an acryloyl-derived acylium ion also provided the desired product of syn-hydroxyacylation (25), as did those bearing heteroaromatic groups (26 and 27). Finally, when norbornene was employed, the intermediately formed, positively charged species underwent rearrangement (presumably via a non-classical carbocation), affording crystalline 28.
Figure 2c shows a comparison of this method with previously reported approaches to alkene 1,3-difunctionalization, relying on substrate rather than reagent control. Indeed, when a fully unbiased alkene (1-nonene) was subjected to established, transition-metal-catalysed protocols using either nickel or palladium catalysis, no products of 1,3-difunctionalization were obtained—rather, products of Heck coupling or non-specific decomposition were observed (see Supplementary Information for details on these reactions). By contrast, the protocol presented herein—as shown above—provided the product of 1,3-difunctionalization (2) at 64% isolated yield.
In subsequent investigations we found that, if the final work-up was preceded by treatment with dimethyl sulfoxide (DMSO)31, the corresponding products of anti-hydroxyacylation were obtained with excellent stereoselectivity (29–37, typically over 20:1 diastereomeric ratio (d.r.); Fig. 3), thus enabling flexible access to either isomer in a stereodivergent manner32,33,34,35,36,37. Replacement of the hydrolytic work-up by the addition of other nucleophilic sources such as chloride (38), bromide (39) or iodide (40) resulted in anti-halogenated products. Interestingly (Fig. 3), interception with amides such as N,N-dimethylacetamide or -formamide resulted in the isolation of anti-acyloxy-acylated products (41 and 42) whereas—even more intriguingly—the addition of the stable aminoxyl radical TEMPO provided anti-OTMP product 43 at high yield. Importantly, when the addition of DMSO was followed by treatment with triethylamine, the products of a 1,3-ketoacylation reaction were obtained (44–49). This is a process that, to the best of our knowledge, has no precedent in the literature and converts simple alkenes directly to 1,4-dicarbonyls37,38,39,40.
a, Selected example of syn-selective hydroxyacylation in contrast to anti-configured product 29. b, Scope of anti-selective 1,3-hydroxyacylation, achieved by the addition of DMSO at 35 °C and quenching with tetrabutylammonium bromide at room temperature. c, Additional 1,3-difunctionalization reactions using other nucleophiles—tetrabutylammonium halides, dimethylacetamide, dimethylformamide or TEMPO—at 35 °C. d, 1,4-Dicarbonyl synthesis through Kornblum-type oxidation, employing DMSO at 35 °C, followed by NEt3 at room temperature. All products were obtained at greater than 20:1 d.r. and 20:1 r.r., unless otherwise mentioned (Supplementary Information). *The reported yields correspond to averages over three runs. In cases in which competing pathways led to observation of enone byproducts in the crude mixtures, the following percentages were observed: a5, b10, c11.
Aiming to showcase the synthetic prowess of this facile, yet powerful, 1,3-alkene difunctionalization, we explored potential synthetic applications. We selected 4-ipomeanol (50), a model pulmonary pretoxin with activity for protein binding (N-acetyl cysteine and N-acetyl lysine)41,42, the reported synthesis of which is a multistep endeavour (Fig. 4a; five steps from diethyl furan-3,4-dicarboxylate)43. Alkene 1,3-difunctionalization, as presented here, instead enables the one-step synthesis of this compound (as well as the known phenyl-analogue 51 and other derivatives (52 and 53 (ref. 44)) from inexpensive 1-butene in a straightforward manner.
a, Synthesis of 4-ipomeanol and other biologically active molecules43. b, Proposed mechanism of 1,3-alkene difunctionalization, involving charge relocation. c, Mechanistic investigations support the hypothesis that nascency of the charge does not affect the constitution of the obtained product (Supplementary Information). d, Complete stereocontrol for the formation of a 1,2,3-trisubstituted cyclohexane.
From a mechanistic point of view (Fig. 4b) we believe that the 1,3-difunctionalizations presented above rely on a rapid isomerization event. This converts, under thermodynamic control, what would be the first intermediate of electrophilic addition23,24,27, the β-keto cation, into the rearranged, cyclic oxocarbenium ion rac-I45,46,47,48,49,50—with the formation of rac-I constituting a locking event to prevent further isomerization and non-selective product formation. This common intermediate is then intercepted either in hydrolytic fashion at the carbonyl (affording the syn-configured products) or through invertive displacement at the secondary sp3-centre C3 with other nucleophiles, resulting in the formation of the anti-configured products described above.
The concept of charge relocation is best illustrated by the mechanistic experiments depicted in Fig. 4c. We established that, regardless of where the carbocation is initially formed (by bromide abstraction), the overwhelming majority of the material is converted into the expected 1,3-difunctionalized target: the carbocation was drawn to the γ position independently of its nascent state.
The reactions of more complex substrates also proved interesting. When 1-methylcyclohexene, a trisubstituted alkene, was used, the all-syn-hydroxyketone 54 was obtained as a single diastereomer (see X-ray structure to the right; Fig. 4d). This stereochemical outcome is probably governed by the preferred equatorial orientation of the only substituent not bound within a ring, the methyl group (Fig. 4d).
Data availability
All data are available in the manuscript or Supplementary Information.
References
Clayden, J., Greeves, N. & Warren S. Organic Chemistry (Oxford Univ. Press, 2012).
Vasseur, A., Bruffaerts, J. & Marek, I. Remote functionalization through alkene isomerization. Nat. Chem. 8, 209–219 (2016).
Massad, I. et al. Stereoselective synthesis through remote functionalization. Nat. Synth. 1, 37–48 (2022).
Delcamp, J. H. & White, M. C. Sequential hydrocarbon functionalization: allylic C-H oxidation/vinylic C–H arylation. J. Am. Chem. Soc. 128, 15076–15077 (2006).
Wang, W. et al. Migratory arylboration of unactivated alkenes enabled by nickel catalysis. Angew. Chem. Int. Ed. 58, 4612–4616 (2019).
Li, Y., Wu, D., Cheng, H.-G. & Yin, G. Difunctionalization of alkenes involving metal migration. Angew. Chem. Int. Ed. 59, 7990–8003 (2020).
Han, C. et al. Palladium-catalyzed remote 1,n-arylamination of unactivated terminal alkenes. ACS Catal. 9, 4196–4202 (2019).
Thompson, R. C., Swan, S. H., Moore, C. J. & vom Saal, F. S. Our plastic age. Phil. Trans. R. Soc. Lond. B Biol. Sci. 364, 1973–1976 (2009).
Trost, B. M. Transition metal templates for selectivity in organic synthesis. Pure Appl. Chem. 53, 2357–2370 (1981).
Tsuji, J. Catalytic reactions via π-allylpalladium complexes. Pure Appl. Chem. 54, 197–206 (1982).
Beller, M., Seayad, J., Tillack, A. & Jiao, H. Catalytic Markovnikov and anti-Markovnikov functionalization of alkenes and alkynes: recent developments and trends. Angew. Chem. Int. Ed. 43, 3368–3398 (2004).
Werner, E. W., Mei, T.-S., Burckle, A. J. & Sigman, M. S. Enantioselective Heck arylations of acyclic alkenyl alcohols using a redox-relay strategy. Science 338, 1455–1458 (2012).
Jensen, K. H. & Sigman, M. S. Mechanistic approaches to palladium-catalyzed alkene difunctionalization reactions. Org. Biomol. Chem. 6, 4083–4088 (2008).
Zhang, F.-G. et al. Remote fluorination and fluoroalkyl(thiol)ation reactions. Chem. Eur. J. 26, 15378–15396 (2020).
Bruffaerts, J., Pierrot, D. & Marek, I. Zirconocene-assisted remote cleavage of C–C and C–O bonds: application to acyclic stereodefined metalated hydrocarbons. Org. Biomol. Chem. 14, 10325–10330 (2016).
Sommer, H., Juliá-Hernández, F., Martin, R. & Marek, I. Walking metals for remote functionalization. ACS Cent. Sci. 4, 153–165 (2018).
Vasseur, A., Perrin, L., Eisensteinc, O. & Marek, I. Remote functionalization of hydrocarbons with reversibility enhanced stereocontrol. Chem. Sci. 6, 2770–2776 (2015).
Morcillo, S. P. et al. Photoinduced remote functionalization of amides and amines using electrophilic nitrogen radicals. Angew. Chem. Int. Ed. 57, 12945–12949 (2018).
Zhao, Y. & Ge, S. Synergistic hydrocobaltation and borylcobaltation enable regioselective migratory triborylation of unactivated alkenes. Angew. Chem. Int. Ed. 61, e202116133 (2022).
Kong, W. et al. Base-modulated 1,3-regio- and stereoselective carboboration of cyclohexenes. Angew. Chem. Int. Ed. 62, e202308041 (2023).
Li, W., Boon, J. K. & Zhao, Y. Nickel-catalyzed difunctionalization of allyl moieties using organoboronic acids and halides with divergent regioselectivities. Chem. Sci. 9, 600–607 (2018).
Basnet, P. et al. Ni-catalyzed regioselective β,δ-diarylation of unactivated olefins in ketimines via ligand-enabled contraction of transient nickellacycles: rapid access to remotely diarylated ketones. J. Am. Chem. Soc. 140, 7782–7786 (2018).
Groves, J. K. The Friedel–Crafts acylation of alkenes. Chem. Soc. Rev. 1, 73–97 (1972).
Valko, J. T. & Wolinsky, J. Acylation-cycloalkylation. reaction of phenylacetyl chloride with cyclohexene. J. Org. Chem. 44, 1502–1508 (1979).
Gao, S., Gao, X., Yang, Z. & Zhang, F. Process research and impurity control strategy of esketamine. Org. Process Res. Dev. 24, 555–566 (2020).
Wang, Z. Comprehensive Organic Name Reactions and Reagents (Wiley, 2010).
Friess, S. L. & Pinson, R. Jr. A rearrangement in the Nenitzescu reaction of cycloheptene with acetyl chloride and aluminum chloride. J. Am. Chem. Soc. 73, 3512–3514 (1951).
Ahmad, M. S., Baddeley, G., Heaton, B. G. & Rasburn, J. W. Vinyl ethers from the reaction of decalin with Friedel–Crafts acylating agents. Proc. Chem. Soc. 395 (1959).
Lyall, C. L. et al. Lewis C–H functionalization of sp3 centers with aluminum: a computational and mechanistic study of the Baddeley reaction of decalin. J. Am. Chem. Soc. 136, 13745–13753 (2014).
Baddeley, G., Heaton, B. G. & Rasburn, J. W. The interaction of decalin and Friedel–Crafts acetylating agent. Part II. J. Chem. Soc. 4713–4719 (1960).
Zong, Y. et al. Enantioselective total syntheses of manginoids A and C and guignardones A and C. Angew. Chem. Int. Ed. 60, 15286–15290 (2021).
DeHovitz, J. S. et al. Static to inducibly dynamic stereocontrol: the convergent use of racemic β-substituted ketones. Science 369, 1113–1118 (2020).
Krautwald, S., Schafroth, M. A., Sarlah, D. & Carreira, E. M. Stereodivergent α-allylation of linear aldehydes with dual iridium and amine catalysis. J. Am. Chem. Soc. 136, 3020–3023 (2014).
Schafroth, M. A., Zuccarello, G., Krautwald, S., Sarlah, D. & Carreira, E. M. Stereodivergent total synthesis of Δ9-tetrahydrocannabinols. Angew. Chem. Int. Ed. 53, 13898–13901 (2014).
Krautwald, S. & Carreira, E. M. Stereodivergence in asymmetric catalysis. J. Am. Chem. Soc. 139, 5627–5639 (2017).
Zhou, Q., Chin, M., Fu, Y., Liu, P. & Yang, Y. Stereodivergent atom-transfer radical cyclization by engineered cytochromes P450. Science 374, 1612–1616 (2021).
Kaldre, D., Klose, I. & Maulide, N. Stereodivergent synthesis of 1,4-dicarbonyls by traceless charge-accelerated sulfonium rearrangement. Science 361, 664–667 (2018).
Kaiser, D., Teskey, C. J., Adler, P. & Maulide, N. Chemoselective intermolecular cross-enolate-type coupling of amides. J. Am. Chem. Soc. 139, 16040–16043 (2017).
DeMartino, M. P., Chen, K. & Baran, P. S. Intermolecular enolate heterocoupling: scope, mechanism, and application. J. Am. Chem. Soc. 130, 11546–11560 (2008).
Parida, K. N., Pathe, G. K., Maksymenko, S. & Szpilman, A. M. Cross-coupling of dissimilar ketone enolates via enolonium species to afford non-symmetrical 1,4-diketones. Beilstein J. Org. Chem. 14, 992–997 (2018).
Christian, M. C. et al. 4-Ipomeanol: a novel investigational new drug for lung cancer. J. Natl. Cancer Inst. 81, 1133–1143 (1989).
Parkinson, O. T., Teitelbaum, A. M., Whittington, D., Kelly, E. J. & Rettie, A. E. Species differences in microsomal oxidation and glucuronidation of 4-ipomeanol: relationship to rarget organ toxicity. Drug Metab. Dispos. 44, 1598–1602 (2016).
Boyd, M. R., Wilson, B. J. & Harris, T. M. Confirmation by chemical synthesis of the structure of 4-ipomeanol, a lung-toxic metabolite of the sweet potato, Ipomoea batatas. Nat. New Biol. 236, 158–159 (1972).
Desai, D., Chang, L. & Amin, S. Synthesis and bioassay of 4-ipomeanol analogs as potential chemopreventive agents against 4-(methylnitrosamino)–1-(3-pyridyl)–1-butanone (NNK)-induced tumorigenicity in A/J mice. Cancer Lett. 108, 263–270 (1996).
Lubinskaya, O. V., Shashkov, A. S., Chertkov, V. A. & Smit, W. A. Facile synthesis of cyclic carboxonium salts by acylation of alkenes. Synthesis 11, 742–745 (1976).
Olah, G. A., Kuhn, S. J., Tolgyesi, W. S. & Baker, E. B. Stable carbonium ions. II. 1aOxocarbonium1b(acylium) tetrafluoroborates, hexafluorophosphates, hexafluoroantimonates and hexafluoroarsenates. Structure and chemical reactivity of acyl fluoride: Lewis acid fluoride complexes1c. J. Am. Chem. Soc. 84, 2733–2740 (1962).
Cresswell, A. J., Davies, S. G., Roberts, P. M. & Thomson, J. E. Beyond the Balz–Schiemann reaction: the utility of tetrafluoroborates and boron trifluoride as nucleophilic fluoride sources. Chem. Rev. 115, 566–611 (2015).
Gockel, S. N., Buchanan, T. L. & Hull, K. L. Cu-catalyzed three-component carboamination of alkenes. J. Am. Chem. Soc. 143, 6019–6020 (2021).
Lubinskaya, O. V. et al. Formation of carboxonium salts in the acylation of alkenes by acylium salts and some problems of the mechanism of acylation. Russ. Chem. Bull. 27, 343–351 (1978).
Buchanan, T. L., Gockel, S. N., Veatch, A. M., Wang, Y.-N. & Hull, K. L. Copper-catalyzed three-component alkene carbofunctionalization: C–N, C–O, and C–C bond formation from a single reaction platform. Org. Lett. 23, 4538–4542 (2021).
Acknowledgements
We thank A. Roller (University of Vienna) for X-ray crystallographic structure determination. We thank P. S. Grant, C. R. Gonçalves and N. Gillaizeau-Simonian for helpful discussions. This work has been supported by the Austrian Academy of Sciences (DOC Fellowship to B.R.B.) and the European Research Council (CoG VINCAT to N.M.). We thank the University of Vienna for generous support.
Author information
Authors and Affiliations
Contributions
N.M. designed and directed the project. B.R.B., G.I., M.R. and D.K. performed and analysed the experiments. B.R.B., G.I., D.K. and N.M. cowrote the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature thanks the anonymous reviewers for their contribution to the peer review of this work. Peer reviewer reports are available.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended data figures and tables
Extended Data Fig. 1 Additional products of syn-selective 1,3-hydroxyacylation.
*Percentages of observed enone by-products in the crude mixtures (see the Supplementary Information for additional details).
Supplementary information
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Brutiu, B.R., Iannelli, G., Riomet, M. et al. Stereodivergent 1,3-difunctionalization of alkenes by charge relocation. Nature 626, 92–97 (2024). https://doi.org/10.1038/s41586-023-06938-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41586-023-06938-0
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.
