Barbier allylation using 2-substituted allyl halides in the directed synthesis of natural and bioactive compounds

Authors

  • Uladzimir S. Masiuk Belarusian State University, 4 Niezaliezhnasci Avenue, Minsk 220030, Belarus
  • Iryna V. Mineyeva Belarusian State University, 4 Niezaliezhnasci Avenue, Minsk 220030, Belarus , Research Institute for Physical Chemical Problems, Belarusian State University, 14 Lieningradskaja Street, Minsk 220006, Belarus

Keywords:

allylation reaction, Barbier reaction, allyl halide, aldehyde, organometallic compound, organic synthesis, diastereoselective reaction, natural product
Supporting Agencies
This work was carried out with the financial support of the Ministry of Education of the Republic of Belarus within the framework of the state programme of scientific research «Chemical processes and technologies» for 2026–2030 (assignments «Design and methods for the synthesis of new heterocyclic hybrid molecules with high biological activity potential and drug prototypes», «New polyfunctional 3-hydroxy-2-oxoindoles and heterocyclic compounds based on them with high potential for biological activity for the creation of drug prototypes», «Multi-component and cascade reactions in the synthesis and transformations of small and medium-sized cycles for the modification and synthesis of bioactive heterocyclic compounds promising as drug prototypes»).

Abstract

It is noted that allylation reactions of carbonyl compounds have proven to be a reliable tool in the directed synthesis of natural and bioactive compounds. Among these reactions, Barbier allylation involving 2-substituted functionalised allyl bromides hold a significant place, as they often achieve a high degree of diastereo- and enantioselectivity, providing access to diverse structures and functional groups. This review summarises examples of the use the Barbier allylation of aldehydes as a key step in the synthesis of complex molecules with various types of biological activity. The examples are systematised according to the structure of the aldehydes and the catalytic systems employed.

Author Biographies

  • Uladzimir S. Masiuk, Belarusian State University, 4 Niezaliezhnasci Avenue, Minsk 220030, Belarus

    PhD (chemistry); head of the laboratory of organoelement synthesis, associate professor at the department of organic chemistry, faculty of chemistry

  • Iryna V. Mineyeva, Belarusian State University, 4 Niezaliezhnasci Avenue, Minsk 220030, Belarus, Research Institute for Physical Chemical Problems, Belarusian State University, 14 Lieningradskaja Street, Minsk 220006, Belarus

    doctor of science (chemistry), full professor; professor at the department of organic chemistry, faculty of chemistry, Belarusian State University, and head of the fine organic synthesis sector, Research Institute for Physical Chemical Problems, Belarusian State University

References

  1. Haym I, Brimble MA. The Kulinkovich hydroxycyclopropanation reaction in natural product synthesis. Organic & Biomolecular Chemistry. 2012;10(38):7649 –7665. DOI: 10.1039/C2OB26082D.
  2. Cai X, Liang W, Dai M. Total syntheses via cyclopropanols. Tetrahedron. 2019;75(2):193 –208. DOI: 10.1016/j.tet.2018.11.026.
  3. Masiuk US, Kozyrkov YuYu, Mineyeva IV. Synthesis of α,β-unsaturated aldehydes with an (E )-trisubstituted double bond via ring opening of cyclopropanols. Russian Journal of Organic Chemistry. 2021;57(10):1563 –1574. DOI: 10.1134/S1070428021100018.
  4. Masiuk US, Mineyeva IV, Kananovich DG. Highly diastereoselective chelation-controlled 1,3-anti-allylation of (S )-3-(methoxymethyl)hexanal enabled by hydrate of scandium triflate. Symmetry. 2021;13(3):470. DOI: 10.3390/sym13030470.
  5. Masiuk US, Faletrov YaV, Kananovich DG, Mineyeva IV. Stereodivergent assembly of 2,6-cis- and -trans-tetrahydropyrans via base-mediated oxa-Michael cyclization: the key role of the TMEDA additive. The Journal of Organic Chemistry. 2023;88(1):355 –370. DOI: 10.1021/acs.joc.2c02382.
  6. Yamamoto Y, Asao N. Selective reactions using allylic metals. Chemical Reviews. 1993;93(6):2207–2293. DOI: 10.1021/cr00022a010.
  7. Li C-J. Aqueous Barbier – Grignard type reaction: scope, mechanism, and synthetic applications. Tetrahedron. 1996;52(16):5643 –5668. DOI: 10.1016/0040-4020(95)01056-4.
  8. Postigo A, Nudelman NS. Synthetically useful metal-mediated radical transformations in water and aqueous media. Coordination Chemistry Reviews. 2011;255(23 –24):2991–3030. DOI: 10.1016/j.ccr.2011.07.015.
  9. Mondal B, Roy UK. Making and breaking of Zn – C bonds in the cases of allyl and propargyl organozincs. Tetrahedron. 2021;90:132169. DOI: 10.1016/j.tet.2021.132169.
  10. Petrides S, Georgiades SN. Stereocontrolled Barbier reactions for generation of homoallylic alcohols: new applications in the synthesis of natural products. Trends in Organic Chemistry [Internet]. 2022 [cited 2026 January 10];23:1–32. Available from: https://www.researchgate.net/publication/369305661_Stereocontrolled_Barbier_reactions_for_generation_of_homoallylic_alcohols_New_applications_in_the_synthesis_of_natural_products#full-text.
  11. Mushtaq A, Zahoor AF, Ahmad MN, Khan SG, Akhter N, Nazeer U, et al. Accessing the synthesis of natural products and their analogues enabled by the Barbier reaction: a review. RSC Advances. 2024;14(45):33536 −33567. DOI: 10.1039/D4RA05646A.
  12. Zhang N, Samanta SR, Rosen BM, Percec V. Single electron transfer in radical ion and radical-mediated organic, materials and polymer synthesis. Chemical Reviews. 2014;114(11):5848 –5958. DOI: 10.1021/cr400689s.
  13. Domini CE, Álvarez MB, Silbestri GF, Cravotto G, Cintas P. Merging metallic catalysts and sonication: a periodic table overview. Catalysts. 2017;7(4):121. DOI: 10.3390/catal7040121.
  14. Podlech J, Maier TC. Indium in organic synthesis. Synthesis. 2003;2003(5):633 – 655. DOI: 10.1055/s-2003-38064.
  15. Ma K, Yin X, Dai M. Total syntheses of bisdehydroneostemoninine and bisdehydrostemoninine by catalytic carbonylative spirolactonization. Angewandte Chemie International Edition. 2018;57(46):15209 –15212. DOI: 10.1002/anie.201809114.
  16. Baranov MS, Kaskova ZM, Gritсenko R, Postikova SG, Ivashkin PE, Kislukhin AA, et al. Synthesis of panal terpenoid core. Synlett. 2017;28(5):583 –588. DOI: 10.1055/s-0036-1588104.
  17. Takamura H, Kikuchi T, Endo N, Fukuda Y, Kadota I. Total synthesis of sarcophytonolide H and isosarcophytonolide D: structural revision of isosarcophytonolide D and structure – antifouling activity relationship of sarcophytonolide H. Organic Letters. 2016;18(9):2110 –2113. DOI: 10.1021/acs.orglett.6b00737.
  18. Takamura H, Kikuchi T, Iwamoto K, Nakao E, Harada N, Otsu T, et al. Unified total synthesis, stereostructural elucidation, and biological evaluation of sarcophytonolides. The Journal of Organic Chemistry. 2018;83(18):11028 –11056. DOI: 10.1021/acs.joc.8b01634.
  19. Carrër A, Turban S, Provost N, Caliez A, Lamarche G, Zanirato G, et al. Juniperanol: first total synthesis and evaluation in type 2 diabetes disease. Bioorganic Chemistry. 2019;92:103243. DOI: 10.1016/j.bioorg.2019.103243.
  20. Green AP, Hardy S, Lee ATL, Thomas E J. Total synthesis of 7-des-O-pivaloyl-7-O-benzylbryostatin 10. Organic & Biomolecular Chemistry. 2017;15(44):9497– 9526. DOI: 10.1039/C7OB02129A.
  21. Gallego-Jara J, Lozano-Terol G, Sola-Martínez RA, Cánovas-Díaz M, de Diego Puente T. A compressive review about Taxol: history and future challenges. Molecules. 2020;25(24):5986. DOI: 10.3390/molecules25245986.
  22. Liu W, Patouret R, Barluenga S, Plank M, Loewith R, Winssinger N. Identification of a covalent importin-5 inhibitor, goyazensolide, from a collective synthesis of furanoheliangolides. ACS Central Science. 2021;7(6):954 – 962. DOI: 10.1021/acscentsci.1c00056.
  23. Yokokawa H, Ishizawa S, Saito K, Meguro Y, Kuwahara S, Enomoto M. Total synthesis of aculenes B and D. European Journal of Organic Chemistry. 2023;26(6):e202201482. DOI: 10.1002/ejoc.202201482.
  24. He H-W, Chi Y, Chen C-Y, Wang F-Y, Wang J-X, Xu D, et al. Synthesis and structure – activity relationship studies of nicotlactone analogues as anti-TMV agents. Synthesis. 2022;54(16):3642–3650. DOI: 10.1055/a-1814-9637.
  25. Hubert JG, Furkert DP, Brimble MA. Preparation of cis-γ-hydroxycarvone derivatives for synthesis of sesterterpenoid natural products: total synthesis of phorbin A. The Journal of Organic Chemistry. 2015;80(4):2231–2239. DOI: 10.1021/jo502748s.
  26. Zhang W, Yao H, Yu J, Zhang Z, Tong R. Total syntheses of sesterterpenoid ansellones A and B, and phorbadione. Angewandte Chemie International Edition. 2017;56(17):4787– 4791. DOI: 10.1002/anie.201701879.
  27. Gandamana DA, Wang B, Tejo C, Bolte B, Gagosz F, Chiba S. Alkyl ethers as traceless hydride donors in Brønsted acid catalyzed intramolecular hydrogen atom transfer. Angewandte Chemie International Edition. 2018;57(21):6181– 6185. DOI: 10.1002/anie.201801953.
  28. Manoni F, Rumo C, Li L, Harran PG. Unconventional fragment usage enables a concise total synthesis of (–)-callyspongiolide. Journal of the American Chemical Society. 2018;140(4):1280 –1284. DOI: 10.1021/jacs.7b13591.
  29. Kargbo RB, Cook GR. Stereoselective indium-mediated allylation reactions. Current Organic Chemistry. 2007;11(15):1287–1309. DOI: 10.2174/138527207782023139.
  30. Wang L, Zhang K, Wang Y, Li W, Chen M, Zhang J. Enantioselective synthesis of isoxazolines enabled by palladium-catalyzed carboetherification of alkenyl oximes. Angewandte Chemie International Edition. 2020;59(11):4421– 4427. DOI: 10.1002/anie.201912408.
  31. Imai T, Nishida S. A mild and convenient Barbier-type allylation of aldehydes to homoallylic alcohols via iodide ion promoted stannylation of allylic bromides and chlorides with tin(II) chloride. Synthesis. 1993;1993(4):395 –399. DOI: 10.1055/s-1993-25871.
  32. Houllemare D, Outurquin F, Paulmier C. Synthesis of homoallylic (but-3-enylic) alcohols from aldehydes with allylic chlorides, tin(II) chloride and potassium iodide in water. Journal of the Chemical Society, Perkin Transactions 1. 1997;26(11):1629 –1636. DOI: 10.1039/A608487G.
  33. Campbell CD, Greenaway RL, Holton OT, Walker PR, Chapman HA, Russell CA, et al. Ynamide carbopalladation: a flexible route to mono-, bi- and tricyclic azacycles. Chemistry – A European Journal. 2015;21(36):12627–12639. DOI: 10.1002/chem.201501710.
  34. Hu X, Musacchio AJ, Shen X, Tao Y, Maimone TJ. Allylative approaches to the synthesis of complex guaianolide sesquiterpenes from Apiaceae and Asteraceae. Journal of the American Chemical Society. 2019;141(37):14904 –14915. DOI: 10.1021/jacs.9b08001.
  35. Feng J, Lei X, Guo Z, Tang Y. Total synthesis of homodimericin A. Angewandte Chemie International Edition. 2017;56(27):7895 –7899. DOI: 10.1002/anie.201702893.
  36. Joung S, Kim R, Lee H-Y. Total synthesis of (–)-phorbaketal A. Organic Letters. 2017;19(14):3903 –3906. DOI: 10.1021/acs.orglett.7b01797.
  37. Zhang Y, Guo Q, Sun X, Lu J, Cao Y, Pu Q, et al. Total synthesis of bryostatin 8 using an organosilane-based strategy. Angewandte Chemie International Edition. 2018;57(4):942– 946. DOI: 10.1002/anie.201711452.
  38. Maguire R J, Mulzer J, Bats J W. 1,4-Asymmetric induction in the Nozaki – Hiyama reaction. Tetrahedron Letters. 1996;37(31):5487–5490. DOI: 10.1016/0040-4039(96)01161-6.
  39. Maguire R J, Mulzer J, Bats J W. 1,4-Asymmetric induction in the chromium(II)- and indium-mediated coupling of allyl bromides to aldehydes. The Journal of Оrganic Сhemistry. 1996;61(20):6936 – 6940. DOI: 10.1021/jo960986o.
  40. Hargaden GC, McManus HA, Cozzi PG, Guiry PJ. The application of bis(oxazoline) ligands in the catalytic enantioselective methallylation of aldehydes. Organic & Biomolecular Сhemistry. 2007;5(5):763 –766. DOI: 10.1039/B618516A.
  41. Zhang Z, Huang J, Ma B, Kishi Y. Further improvement on sulfonamide-based ligand for catalytic asymmetric 2-haloallylation and allylation. Organic Letters. 2008;10(14):3073 –3076. DOI: 10.1021/ol801093p.
  42. Deng Q-H, Wadepohl H, Gade LH. The synthesis of a new class of chiral pincer ligands and their applications in enantioselective catalytic fluorinations and the Nozaki – Hiyama – Kishi reaction. Chemistry – A European Journal. 2011;17(52):14922–14928. DOI: 10.1002/chem.201102375.
  43. Nagata A, Akagi Y, Masoud SS, Yamanaka M, Kittaka A, Uesugi M, et al. Stereoselective synthesis of four calcitriol lactone diastereomers at C23 and C25. The Journal of Оrganic Сhemistry. 2019;84(12):7630 –7641. DOI: 10.1021/acs.joc.9b00403.
  44. Inoue M, Suzuki T, Nakada M. Asymmetric catalysis of Nozaki – Hiyama allylation and methallylation with a new tridentate bis(oxazolinyl)carbazole ligand. Journal of the American Chemical Society. 2003;125(5):1140 –1141. DOI: 10.1021/ja021243p.
  45. Zhu S, Wu Y. Synthesis and configuration of neomaclafungin A. Chemistry – An Asian Journal. 2017;12(17):2211–2215. DOI: 10.1002/asia.201700950.
  46. Kim J H, Kim I, Song Y, Kim MJ, Kim S. Asymmetric total synthesis of (+)-neooxazolomycin using a chirality-transfer strategy. Angewandte Chemie International Edition. 2019;58(32):11018 –11022. DOI: 10.1002/anie.201906158.
  47. Ota K, Miyaoka H. Total synthesis of marine sesquiterpenoid sinularianin B and 8-episinularianin B. Heterocycles. 2015;90(1):442– 461. DOI: 10.3987/COM-14-S(K)42.
  48. Green AP, Hardy S, Thomas E J. Synthetic approaches to the C11 – C27 fragments of bryostatins. Organic & Biomolecular Chemistry. 2017;15(44):9475 – 9496. DOI: 10.1039/C7OB02127E.
  49. Kwon MS, Sim SH, Chung YK, Lee E. Synthetic studies on soft coral norcembranolides: total synthesis of (+)-10-epigyrosanolide E. Tetrahedron. 2011;67(52):10179 –10185. DOI: 10.1016/j.tet.2011.09.011.
  50. Kimura K, Usuki T. Synthesis of (1Z )-deacylcnicin. Tetrahedron Letters. 2022;107:154102. DOI: 10.1016/j.tetlet.2022.154102.
  51. Hu X, Xu S, Maimone TJ. A double allylation strategy for gram-scale guaianolide production: total synthesis of (+)-mikanokryptin. Angewandte Chemie International Edition. 2017;56(6):1624 –1628. DOI: 10.1002/anie.201611078.
  52. Hanessian S, Park H, Yang R-Y. Zinc-mediated allylation of N-protected α-amino aldehydes in aqueous solution. Stereoselective synthesis of Phe-Phe hydroxyethylene dipeptide isosteres. Synlett. 1997;1997(4):351–352. DOI: 10.1055/s-1997-803.
  53. Steurer S, Podlech J. Indium-induced addition of bromomethylacrylates to phthaloyl-protected amino aldehydes. Synthesis. 2002;2002(7):945 – 950. DOI: 10.1055/s-2002-28503.
  54. Wang D, Hou M, Ji Y, Gao S. Total synthesis of scholarisine K and alstolactine A. Organic Letters. 2017;19(7):1922–1925. DOI: 10.1021/acs.orglett.7b00722.
  55. Vibhute AM, Tamai H, Logviniuk D, Jones PG, Fridman M, Werz DB. Azide-functionalized derivatives of the virulence-associated sugar pseudaminic acid: chiral pool synthesis and labeling of bacteria. Chemistry – A European Journal. 2021;27(41):10595 –10600. DOI: 10.1002/chem.202100443.
  56. Liu H, Zhang Y, Wei R, Andolina G, Li X. Total synthesis of Pseudomonas aeruginosa 1244 pilin glycan via de novo synthesis of pseudaminic acid. Journal of the American Chemical Society. 2017;139(38):13420 –13428. DOI: 10.1021/jacs.7b06055.
  57. Pan C-F, Zhang Z-H, Sun G-J, Wang Z-Y. Concise symmetric synthesis of (5R)-6-hydroxy-3,8-dioxabicyclo[3.2.1]octane derivatives. Organic Letters. 2004;6(18):3059 –3061. DOI: 10.1021/ol049008u.
  58. Moral JA, Moon S-J, Rodriguez-Torres S, Minehan TG. A sequential indium-mediated aldehyde allylation/palladium-catalyzed cross-coupling reaction in the synthesis of 2-deoxy-β-C-aryl glycosides. Organic Letters. 2009;11(16):3734 –3737. DOI: 10.1021/ol901353f.
  59. Dhanjee H, Minehan TG. Indium-mediated allylation of aldehydes, ketones and sulfonimines with 2-(alkoxy)allyl bromides. Tetrahedron Letters. 2010;51(42):5609 –5612. DOI: 10.1016/j.tetlet.2010.08.064.
  60. Mineyeva IV. Synthesis of (2S )-4-methyl- and (2S )-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-carbaldehydes as precursors to C22 – C27 fragments of fijianolides and their synthetic analogs. Russian Journal of Organic Chemistry. 2018;54(9):1341–1349. DOI: 10.1134/S1070428018090130.
  61. Gintner M, Denner C, Schmölzer C, Fischer M, Frühauf P, Kählig H, et al. Synthesis of 3-deoxy-2-uloses via the indium-mediated allylation reaction. Monatshefte für Chemie – Chemical Monthly. 2019;150(5):849 – 860. DOI: 10.1007/s00706-019-02438-y.
  62. Riedl B, Schmid W. A concise route to access C-glycosidic tetrazolyl analogues of Kdo as bioisosteres. Carbohydrate Research. 2018;456:30 –34. DOI: 10.1016/j.carres.2017.12.006.
  63. Mineyeva IV. Allylation of (R)-2,3-O-cyclohexylideneglyceraldehyde with methyl 3-(bromomethyl)but-3-enoate. Methyl 3-{(2S )-2-[(2R)-1,4-dioxaspiro[4.5]dec-2-yl]-2-hydroxyethyl}but-3-enoate as a convenient universal building block for the synthesis of key fragments of bioactive compounds. Russian Journal of Organic Chemistry. 2019;55(8):1112–1123. DOI: 10.1134/S1070428019080098.
  64. Mineyeva IV. Synthesis of the mealworm Tenebrio molitor L. pheromone. Russian Journal of Organic Chemistry. 2020;56(6):994 –1000. DOI: 10.1134/S1070428020060056.
  65. Varanchuk VV, Mineyeva IV. Allylation of (R)-2,3-O-cyclohexylideneglyceraldehyde with 2-substituted allylstannanes. Application in the synthesis of natural compounds. Russian Journal of Organic Chemistry. 2025;61(4):602– 615. DOI: 10.1134/S1070428025600792.
  66. Mineyeva IV. Synthesis of principal building blocks of amphidinolides of the G and H families. Russian Journal of Organic Chemistry. 2025;61(4):587– 601. DOI: 10.1134/S1070428025600809.
  67. Минеева ИВ. Применение метил-(2Е )-5-(бромметил)гекса-2,5-диеноата в реакциях аллилирования альдегидов различного структурного типа. В: Ивашкевич ОА, Воробьева ТН, Артемьев М В, Аршанский ЕЯ, Василевская ЕИ, Кунцевич ЗС и др., редакторы. Свиридовские чтения. Выпуск 21. Минск: СтройМедиаПроект; 2025. с. 96 –115.
  68. Kumar BS, Mishra GP, Rao BV. Synthesis of some carbahexopyranoses using Mn/CrCl3 mediated domino reactions and ring closing metathesis. Tetrahedron. 2016;72(15):1838 –1849. DOI: 10.1016/j.tet.2016.02.044.

Downloads

Additional Files

Published

2026-08-19

Issue

No. 1 (2026): Journal of the Belarusian State University. Chemistry

Section

Original Articles

License

Copyright (c) 2026 Journal of the Belarusian State University. Chemistry

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

The authors who are published in this journal agree to the following:

  1. The authors retain copyright on the work and provide the journal with the right of first publication of the work on condition of license Creative Commons Attribution-NonCommercial. 4.0 International (CC BY-NC 4.0).
  2. The authors retain the right to enter into certain contractual agreements relating to the non-exclusive distribution of the published version of the work (e.g. post it on the institutional repository, publication in the book), with the reference to its original publication in this journal.
  3. The authors have the right to post their work on the Internet (e.g. on the institutional store or personal website) prior to and during the review process, conducted by the journal, as this may lead to a productive discussion and a large number of references to this work. (See The Effect of Open Access.)

How to Cite

[1]
Masiuk, U.S. and Mineyeva, I.V. 2026. Barbier allylation using 2-substituted allyl halides in the directed synthesis of natural and bioactive compounds. Journal of the Belarusian State University. Chemistry. 1 (Aug. 2026), 14–34. DOI:https://doi.org/10.33581/2520-257X-2026-1-%p.