Skip to main content
NCBI home page
ACS AuthorChoice logoLink to ACS AuthorChoice
. 2024 Feb 19;26(8):1556–1560. doi: 10.1021/acs.orglett.3c04199

Routes to Advanced Intermediates in the Synthesis of Tetracarbocyclic Sesquiterpenoids Daphnenoid A and Artatrovirenols A and B

Jiarui Zong 1, Kirsten E Christensen 1, Jeremy Robertson 1,*
PMCID: PMC10913076  PMID: 38373293

Abstract

graphic file with name ol3c04199_0007.jpg

A short route from dihydrocarvone is described, which led to the tetracarbocyclic core common to artatrovirenol A and B and daphnenoid A. A variant of this route afforded guaia-4,6-dien-3-one (from Enterospermum madagascarensis) and its epimer. From 2-(2-oxoethyl)furan, a 15-step sequence then delivered the complete carbon skeleton and all functionality necessary for daphnenoid A. Key steps in the route include diastereoselective intramolecular oxidopyrylium cycloaddition, oxa-bridge cleavage under “push–pull” conditions, and intramolecular Diels–Alder cycloaddition.

The sesquiterpenes and their oxidized derivatives, the sesquiterpenoids, form a major class of natural products with structures based on 1.5 (sesqui-) C10-monoterpene units, the first established being those of α-santalol1 and farnesol.2 Their wide-ranging biological properties and vast range of structural types have attracted the efforts of synthetic chemists for more than a century, with many of these efforts patterned on biosynthetic speculations.3 Recently, a new caged-ring sesquiterpenoid subclass has emerged in two papers reporting the structures (Figure 1) of artatrovirenols A 1 and B 2 from Artemisia atrovirens,4 and daphnenoid A 3 from Daphne penicillata.5 The same tetracyclic ring system is also found in the prenylated phloroglucinol garcinielliptone enantiomers HG and HH from Garcinia subelliptica.6

Figure 1.

Figure 1

Open in a new tab

Structures of artatrovirenols A 1 and B 2, daphnenoid A 3, and the (biosynthetic) relationship between their core framework 5 and the guaiane framework 4.9

Tetracarbocyclic frameworks are rare in sesquiterpenoids, those containing cyclopropanes excepted; therefore, this new sesquiterpene subclass is of interest not least from a biosynthetic standpoint. Both Chen’s4 and Song’s5 reports associate these novel structures with the guaiane system 4. The new framework 5 can be derived from 4 both conceptually and biosynthetically by connecting the isopropenyl Δ11,12 carbons to C-1 and C-4, respectively. Building on our recent studies of simple guaianes,7 our group set out to explore the synthesis of daphnenoid A based on an intramolecular Diels–Alder (IMDA) cycloaddition or an equivalent process from an appropriate guaianoid precursor. Very recently, Zhu’s group reported the total synthesis of (−)-artatrovirenol A by an unrelated synthetic strategy,8 which has prompted us to disclose our current progress in this area.

Retrosynthetically, it was envisaged that the new ring system would be constructed from enone 7 (Scheme 1) by using a silylation-induced (Mukaiyama) Michael/Michael-type reaction via dienol ether 6. In this scheme, the appropriately configured protected 3°-alcohol in this enone would arise by elimination of the 1,7-oxa bridge in 8, the product of intramolecular oxidopyrylium cycloaddition via 9. Completing the analysis led back to a 2,5-disubstituted furan of general form 10, although it was appreciated that the combination of a furfurylic alcohol, a β,γ-unsaturated ketone, and a methylene flanked by both electron releasing (furan) and electron withdrawing (carbonyl) functionality would render this specific precursor somewhat fragile.

Scheme 1. Retrosynthetic Analysis of Daphnenoid A.

Scheme 1

Open in a new tab

Before embarking on the route outlined above, a preliminary investigation of the viability of the key formal cycloaddition step (cf. 7 → 3) was undertaken (Scheme 2). The known ring-expansion product 11(10) of dihydro-(R)-carvone was alkylated to give 1,4-diketone 12 after ester hydrolysis and decarboxylation. Intramolecular aldol condensation gave a complex mixture of diastereomeric and regioisomeric enones 13, but this was considered to be of no consequence because the thermal silylating conditions11 for the subsequent step were expected to generate some equilibrium concentration of 14,12 the only intermediate capable of undergoing [4 + 2]-cycloaddition at a reasonable rate. In the event, and despite no dienophilic activation,13 the crude reaction product consisted mainly of the desired tetracyclic ketone 15. This ketone was found to be unstable toward purification by chromatography on silica gel; therefore, ketone reduction was carried out, which enabled a pure sample of alcohol 16 to be obtained whose structure was confirmed by single-crystal X-ray diffraction.14

Scheme 2. Model Studies of the IMDA-Equivalent Cycloaddition.

Scheme 2

Open in a new tab

Adapting this route to incorporate the C-15 methyl group required for the complete sesquiterpene skeleton was not achieved. Although a suitable substrate 19 was prepared from the same keto-ester 11, attempts to access the [4 + 2]-cycloadduct failed, and the only tractable result was alkene isomerization to deliver known15 dienones 20 (a sesquiterpenoid from Enterospermum madagascarensis)16 and 21.

It was concluded that the dienophile in the C-15 methyl-bearing enone would require electronic activation, and so, the route outlined in Scheme 1 was initiated. The first phase of the synthesis proceeded smoothly, with little in the five steps17−19 to hydroxypyrone 26 (Scheme 3) requiring comment. The anti-crotylation20 product (S2, see Supporting Information) derived from aldehyde 22 was targeted in order to allow the two substituents in the projected cycloadduct to be both cis and exo-disposed,21 thus easing the course of the cycloaddition. The use of classical methods for initiating formation and cycloaddition of the oxidopyrylium derived from 26 were unproductive or inefficient; however, Suga’s mild conditions using Boc-anhydride to activate the hydroxyl group, in combination with triethylamine as catalyst,22 produced the separable diastereomeric exo-cycloadducts 27 and 28 in ∼80% combined yield. In this reaction, the major isomer is that expected from Sammes’ studies of related reactions.23 Conjugate addition of lithium dimethylcuprate to the more exposed α-face of the enone, followed by desilylation and oxidation, afforded tricyclic diketone 30, from which it was envisaged that mild treatment with basic or Lewis acidic reagents would induce enone formation with cleavage of the C-1–O bond (→ 31). In the event, no reagent combinations were able to achieve this elimination, presumably because any ring-opening remained hidden by rapid reclosure of the so-formed 3°-alcohol.

Scheme 3. Oxidopyrylium Cycloaddition and Elimination of the 1,7-Oxa Bridge.

Scheme 3

Open in a new tab

Taking inspiration from Mascareñas’ “push–pull” approach to oxa-bridge cleavage in related structures,24 the steps from cycloadduct 27 were reordered to enable the two ketones (in 32) to be distinguished. Thus, the “pushing” silyl enol ether functionality was introduced prior to methyl 1,4-addition, and then, the Lewis acidic “pulling” conditions were applied to so-formed 33 with the inclusion of acetic anhydride to capture liberated 3°-alcohol and prevent its recyclization. This was effective, and the acetoxy enedione 34 was accessed in readiness for the proposed IMDA-equivalent step. Again, forward progress was thwarted since all attempts to effect cycloaddition using variants of the conditions used for the formation of tetracycle 15 led to decomposition. Here, reaction mixtures usually developed a purple coloration that was attributed to azulene formation by acetate elimination and aerial oxidation.

To obviate the need to add activating reagents for the IMDA cycloaddition and reduce the likelihood of azulene formation, a preformed diene component was targeted and the oxidation state of the substrate was lowered (Scheme 4). First, the C-8 ketone was reduced, and the resulting alcohol acetylated during the β-elimination step to form the enone (→ 35). Luche reduction of the C-3 ketone then gave cyclopentenol 36. For the dehydration step, Burgess reagent was chosen based on its preference for a syn-elimination mechanism;25 from this, a major cyclopentadiene regioisomer 37 was obtained. Once more, the incorrect placement of the diene was not envisaged to be problematic and, indeed, heating this substrate in toluene (in a pressure tube) initiated clean IMDA cycloaddition, with the tetracyclic cycloadduct 38 this time being perfectly stable toward chromatographic purification.

Scheme 4. Completion of the Tetracyclic Core and Progress towards Daphnenoid A.

Scheme 4

Open in a new tab

From this point, a potential end-sequence to daphnenoid A was projected: (i) double deacetylation, (ii) oxidation of the C-8 alcohol to the required enone, and (iii) formation of the C-3 carbonyl group by either hydroboration/oxidation or Wacker oxidation. In practice, methanolysis of triester 38 gave pentacyclic lactone 39, similar in structure to artatrovirenol A. Heating this lactone with triethylamine in methanol established an equilibrium with diol 40, allowing a sample of the latter to be separated. An attempt to access the C-8–C-10 enone directly with IBX26 led to decomposition, but under milder conditions, ketone 41 was formed, which is currently our most advanced intermediate en route to daphnenoid A.27,28

The synthetic chemistry summarized in Schemes 3 and 4 comprises a 15-step sequence to tetracyclic intermediate 38, from which some redox adjustments remain necessary to reach daphnenoid A. It is, however, conceivable that a variant of the route to form compound 15 (Scheme 2) could deliver the complete carbon skeleton more quickly, from which chemical and enzymatic C–H hydroxylation29 would then offer access to this interesting class of tetracarbocyclic sesquiterpenoids and their analogues. Efforts to that end are ongoing in our laboratories.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.3c04199.

  • Experimental procedures, characterization data, copies of 1H and 13C NMR spectra for all compounds, and crystallographic details (PDF)

Author Contributions

All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.

Supplementary Material

ol3c04199_si_001.pdf (7.7MB, pdf)

References

  1. Semmler F. W. Zur Kenntnis der Bestandteile Ätherischer Öle. (Konstitution der α-Santalol- und α-Santalen-Reihe: Die Konstitution der Sesquiterpenalkohole und Sesquiterpene.). Ber. 1910, 43, 1893–1898. 10.1002/cber.191004302121. [DOI] [Google Scholar]
  2. Kerschbaum M. Über den Aliphatischen Sesquiterpen-Alkohol Farnesol. Ber. 1913, 46, 1732–1737. 10.1002/cber.19130460274. [DOI] [Google Scholar]
  3. Selected reviews:; a Degenhardt J.; Köllner T. G.; Gershenzon J. Monoterpene and Sesquiterpene Synthases and the Origin of Terpene Skeletal Diversity in Plants. Phytochem 2009, 70, 1621–1637. 10.1016/j.phytochem.2009.07.030. [DOI] [PubMed] [Google Scholar]; b Fraga B. M. Natural Sesquiterpenoids. Nat. Prod. Rep. 2013, 30, 1226–1264. 10.1039/c3np70047j. [DOI] [PubMed] [Google Scholar]; c Chadwick M.; Trewin H.; Gawthrop F.; Wagstaff C. Sesquiterpenoids Lactones: Benefits to Plants and People. Int. J. Mol. Sci. 2013, 14, 12780–12805. 10.3390/ijms140612780. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Zhang X.; Zheng M.; Fu A.; Li Q.; Chen C.; Zhu H.; Zhang Y. Natural Sesquiterpenoids, Diterpenoids, Sesterterpenoids, and Triterpenoids with Intriguing Structures from 2017 to 2022. Chin. J. Chem. 2023, 41, 3115–3132. 10.1002/cjoc.202300275. [DOI] [Google Scholar]; e Kourgiantaki M.; Bagkavou G. G.; Stathakis C. I.; Zografos A. L. Selective Preparative ‘Oxidase Phase’ in Sesquiterpenoids: the Radical Approach. Org. Chem. Front. 2023, 10, 2095–2114. 10.1039/D3QO00314K. [DOI] [Google Scholar]
  4. Su L.-H.; Geng C.-A.; Li T.-Z.; Ma Y.-B.; Huang X.-Y.; Zhang X.-M.; Chen J.-J. Artatrovirenols A and B: Two Cagelike Sesquiterpenoids from Artemisia atrovirens. J. Org. Chem. 2020, 85, 13466–13471. 10.1021/acs.joc.0c01491. [DOI] [PubMed] [Google Scholar]
  5. Zhao P.; Li Z.-Y.; Qin S.-Y.; Xin B.-S.; Liu Y.-Y.; Lin B.; Yao G.-D.; Huang X.-X.; Song S.-J. Three Unusual Sesquiterpenes with Distinctive Ring Skeletons from Daphne penicillata Uncovered by Molecular Networking Strategies. J. Org. Chem. 2021, 86, 15298–15306. 10.1021/acs.joc.1c01880. [DOI] [PubMed] [Google Scholar]
  6. Liaw C.-C.; Chang J.-L.; Wang B.-W.; Chen P.-L.; Weng J.-R.; Lin K.-W.; Lin C.-N. Discovering a Racemate Polycyclic Prenylated Acylphloroglucinol with Unprecedented Skeleton by an ESI-LCMS Analytical Approach. Org. Lett. 2019, 21, 857–861. 10.1021/acs.orglett.8b03445. [DOI] [PubMed] [Google Scholar]
  7. a Zhang X.Evolved P450 Mutants as General Oxidation Catalysts for Target Synthesis via Early-/Late-Stage Hydroxylation. DPhil Thesis, University of Oxford, 2022. [Google Scholar]; b Zong J.; Robertson J. An Enantiospecific Synthesis of 5-epi-α-Bulnesene. Molecules 2023, 28, 3900. 10.3390/molecules28093900. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Lavernhe R.; Domke P.; Wang Q.; Zhu J. Enantioselective Total Synthesis of (−)-Artatrovirenol A. J. Am. Chem. Soc. 2023, 145, 24408–24415. 10.1021/jacs.3c09683. [DOI] [PubMed] [Google Scholar]
  9. The C-14 and C-15 methyl group numbering follows refs (4) and (5).
  10. Rüthi F.; Schröder F. Total Synthesis of (−)-Rotundone and (−)-epi-Rotundone from Monoterpene Precursors. Helv. Chim. Acta 2020, 103, e2000129. 10.1002/hlca.202000129. [DOI] [Google Scholar]
  11. a Danishefsky S.; Kitahara T. A Useful Diene for the Diels–Alder Reaction. J. Am. Chem. Soc. 1974, 96, 7807–7808. 10.1021/ja00832a031. [DOI] [Google Scholar]; b Ihara M.; Fukumoto K. Syntheses of Polycyclic Natural Products Employing the Intramolecular Double Michael Reaction. Angew. Chem., Int. Ed. 1993, 32, 1010–1022. 10.1002/anie.199310101. [DOI] [Google Scholar]
  12. Via reversible enolization and reprotonation steps combined with rapid [1,5]-hydrogen shifts in cyclopentadienyl intermediates; cf.; Snowden R. L. The Intramolecular Diels–Alder Reactions of (E)- and (Z)-Methyl 5-[2-methyl-4-(trimethylsilyloxy)-2,4-cyclopentadienyl]-2-pentenoate. A Stereoselective Synthesis of (±)-Sativene. Tetrahedron 1986, 42, 3277–3290. 10.1016/S0040-4020(01)87392-0. [DOI] [Google Scholar]
  13. Maimone T. J.; Voica A.-F.; Baran P. S. A Concise Approach to Vinigrol. Angew. Chem., Int. Ed. 2008, 47, 3054–3056. 10.1002/anie.200800167. [DOI] [PubMed] [Google Scholar]
  14. Low temperature single crystal X-ray diffraction data were collected using a (Rigaku) Oxford Diffraction SuperNova diffractometer. Raw frame data were reduced using CrysAlisPro and the structures were solved using Superflip.; a Palatinus L.; Chapuis G. SUPERFLIP – a Computer Program for the Solution of Crystal Structures by Charge Flipping in Arbitrary Dimensions. J. Appl. Crystallogr. 2007, 40, 786–790. 10.1107/S0021889807029238. [DOI] [Google Scholar]; b Parois P.; Cooper R. I.; Thompson A. L. Crystal Structures of Increasingly Large Molecules: Meeting the Challenges with CRYSTALS Software. Chem. Cent. J. 2015, 9, 30. 10.1186/s13065-015-0105-4. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Cooper R. I.; Thompson A. L.; Watkin D. J. CRYSTALS Enhancements: Dealing with Hydrogen Atoms in Refinement. J. Appl. Crystallogr. 2010, 43, 1100–1107. 10.1107/S0021889810025598. [DOI] [Google Scholar]
  15. a Chikamatsu H.; Maeda M.; Nakazaki M. Structure of Torilin. Tetrahedron 1969, 25, 4751–4765. 10.1016/S0040-4020(01)83016-7. [DOI] [PubMed] [Google Scholar]; b Hirota H.; Tanahashi Y.; Takahashi T. Structure of a Guaioxide-type Sesquiterpene from “San-shion”. Bull. Chem. Soc. Jpn. 1980, 53, 785–788. 10.1246/bcsj.53.785. [DOI] [Google Scholar]; c Blay G.; Garcia B.; Molina E.; Pedro J. R. Total Syntheses of Four Stereoisomers of 4α-Hydroxy-1β,7β-peroxy-10βH-guaia-5-ene. Org. Lett. 2005, 7, 3291–3294. 10.1021/ol0511023. [DOI] [PubMed] [Google Scholar]
  16. Raharivelomanana P.; Bianchini J. P.; Ramanoelina A. R. P.; Rasoharahona J. R. E.; Chatel F.; Faure R. Structures of Cadinane- and Guaiane-type Sesquiterpenoids from Enterospermum madagascariensis (Baill.) Homolle. Magn. Reson. Chem. 2005, 43, 1049–1052. 10.1002/mrc.1705. [DOI] [PubMed] [Google Scholar]
  17. Aldehyde 22:Hashmi A. S. K.; Wölfle M. Gold Catalysis: Benzannellation versus Alkylidenecyclopentenone Synthesis. Tetrahedron 2009, 65, 9021–9029. 10.1016/j.tet.2009.08.074. [DOI] [Google Scholar]
  18. Tsuda T.; Yoshida T.; Saegusa T. Generation of [α-(Alkoxycarbonyl)vinyl]aluminum and Aluminum Allenolates by the Hydroalumination of α,β-Acetylenic Carbonyl Compounds and their Reaction with Carbonyl Compounds. J. Org. Chem. 1988, 53, 1037–1040. 10.1021/jo00240a020. [DOI] [Google Scholar]
  19. Lefebvre Y. Oxidation of Furans – 1. Synthesis of 6-Hydroxy-2H-pyran-3(6H)-ones. Tetrahedron Lett. 1972, 13, 133–136. 10.1016/S0040-4039(01)84259-3. [DOI] [Google Scholar]
  20. Fürstner A.; Shi N. Nozaki–Hiyama–Kishi Reactions Catalytic in Chromium. J. Am. Chem. Soc. 1996, 118, 12349–12357. 10.1021/ja9625236. [DOI] [Google Scholar]
  21. With respect to the forming cis-fused 5,5-oxabicyclic substructure in the expected major cycloadduct.
  22. Toda Y.; Shimizu M.; Iwai T.; Suga H. Triethylamine Enables Catalytic Generation of Oxidopyrylium Ylides for [5 + 2] Cycloadditions with Alkenes: An Efficient Entry to 8-Oxabicyclo[3.2.1]octane Frameworks. Adv. Synth. Catal. 2018, 360, 2377–2381. 10.1002/adsc.201800290. [DOI] [Google Scholar]
  23. a Sammes P. G.; Street L. J. Intramolecular Cycloadditions with Oxidopyrylium Ylides. J. Chem. Soc., Chem. Commun. 1982, 1056–1057. 10.1039/c39820001056. [DOI] [Google Scholar]; b Sammes P. G.; Street L. J. Total Synthesis of (±)-β-Bulnesene, (±)-Cryptofauronol, (±)-Fauronyl Acetate, and (±)-Valeranone. J. Chem. Soc., Chem. Commun. 1983, 666–668. 10.1039/C39830000666. [DOI] [Google Scholar]
  24. Rodríguez J. R.; Castedo L.; Mascareñas J. L. Tandem Organolithium Addition/Oxa-Bridge Opening of 8-Oxa[3.2.1]bicyclic Pyrone-Alkene Adducts. Synthesis 2000, 2000, 980–984. 10.1055/s-2000-6299. [DOI] [Google Scholar]
  25. Burgess E. M.; Penton H. R.; Taylor E. A. Thermal Reactions of Alkyl N-Carbomethoxysulfamate Esters. J. Org. Chem. 1973, 38, 26–31. 10.1021/jo00941a006. [DOI] [Google Scholar]
  26. Nicolaou K. C.; Zhong Y.-L.; Baran P. S. A New Method for the One-Step Synthesis of α,β-Unsaturated Carbonyl Systems from Saturated Alcohols and Carbonyl Compounds. J. Am. Chem. Soc. 2000, 122, 7596–7597. 10.1021/ja001825b. [DOI] [Google Scholar]
  27. An attempt to effect enone formation using the procedure reported in ref (28) led to the isolation of the hydromethylation product 42, although the scale of the reaction was too small to obtain sufficiently pure product for definitive assignment of its structure. See the Supporting Information for details.graphic file with name ol3c04199_0006.jpg
  28. Diao T.; Stahl S. S. Synthesis of Cyclic Enones via Direct Palladium-Catalyzed Aerobic Dehydrogenation of Ketones. J. Am. Chem. Soc. 2011, 133, 14566–14569. 10.1021/ja206575j. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Harwood L. A.; Xiong Z.; Christensen K. E.; Wang R.; Wong L. L.; Robertson J. Selective P450BM3 Hydroxylation of Cyclobutylamine and Bicyclo[1.1.1]pentylamine Derivatives: Underpinning Synthetic Chemistry for Drug Discovery. J. Am. Chem. Soc. 2023, 145, 27767–27773. 10.1021/jacs.3c10542. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

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

Supplementary Materials

ol3c04199_si_001.pdf (7.7MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Articles from Organic Letters are provided here courtesy of American Chemical Society

RESOURCES