Skip to main content
NCBI home page
ACS AuthorChoice logoLink to ACS AuthorChoice
. 2023 Jun 20;25(29):5401–5405. doi: 10.1021/acs.orglett.3c01470

Bioinspired Synthesis of Platensimycin from Natural ent-Kaurenoic Acids

Álvaro Pérez †, José F Quílez del Moral †,*, Alberto Galisteo †, Juan M Amaro ‡, Alejandro F Barrero †,*
PMCID: PMC10391625  PMID: 37338151

Abstract

graphic file with name ol3c01470_0008.jpg

The biomimetic formal synthesis of the antibiotic platensimycin for the treatment of infection by multidrug-resistant bacteria was accomplished starting from either ent-kaurenoic acid or grandiflorenic acid, each of which is a natural compound available in multigram scale from its natural source. Apart from the natural origin of the selected precursors, the keys of the described approach are the long-distance functionalization of ent-kaurenoic acid at C11 and the efficient protocol for the A-ring degradation of the diterpene framework.

The proliferation of antibiotic-resistant bacteria and fungi is proving to be one of the major health issues in developed countries. According to estimates from the Centers for Disease Control and Prevention, >2.8 million people are infected by antibiotic-resistant pathogens each year in the United Sates, resulting in at least 35 000 deaths, a figure that is very similar to that for Europe.1 In this context, the search for new antibiotics presenting new modes of action to fight against resistant bacteria is becoming a pressing global need. In 2006, (−)-platensimycin (PTM), a meroditerpenoid from Streptomyces platensis, was isolated by Merck researchers.2,3 Its activity has been tested against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate S. aureus (VISA), and vancomycin-resistant enterococci (VRE) among others.4,5 Additionally, this substance possesses a unique mode of action as a suppressor of β-ketoacyl-(acyl-carrier protein) synthase II (FabF) engaged in the mechanism of fatty acid biosynthesis.2,3 This unique mode of action, its challenging structural and functional architecture, has attracted the attention of many synthetic chemists, and consequently, a number of synthetic strategies have been developed to complete the synthesis of PTM and analogues.6−16 Furthermore, a fermentation process for producing PTM from S. platensis SB12026 was described.17graphic file with name ol3c01470_0007.jpg

Recent studies have proven that ent-kauran-16α-ol and other ent-kauranes18−22 are involved as intermediates in the PTM tricyclic core biosynthesis. On the basis of this biosynthetic evidence, it was anticipated that natural ent-kaurenoic and grandiflorenic acids contain the structural and stereochemical requirements to eventually afford PTM. Indeed, both compounds include in their structure not only the C17 tricyclic carbon framework of PTM but also the appropriate stereochemistry at C8–C10 and C13. Furthermore, the exocyclic methylene at C16 (together with the C9=C11 bond in the case of grandiflorenic acid) should enable generation of the tetrahydrofuran moiety. Finally, the presence of the carboxylic acid at C4 will be key to the development of a new A-ring degradation protocol that should involve the loss of C4, C18, and C19 (Figure 1).

Figure 1.

Figure 1

Open in a new tab

Evaluation of the structural features of grandiflorenic and ent-kaurenoic acids enabling the synthesis of PTM.

The use of these starting materials will depend on their availability and easy accessibility in multigram quantities. Because both ent-kaurenoic (3) and grandiflorenic (2) acids are commercially available from Sigma Aldrich with expensive prices ranging from 301 € for grandiflorenic acid to 342 € for ent-kaurenoic acid (prices per milligram), the search for suitable natural sources of these compounds constitutes a determining factor for the success of this strategy. In this regard, plants such as Helianthus annuus (sunflower) and Stevia lucida were reported to possess good concentrations of kaurenoic acid (sunflower)23,24 and ent-kaurenoic and grandiflorenic acids (S. lucida).25 In addition, because the worldwide production of sunflower oil in 2022 exceeded 57 million tons,26 the use of the residue of sunflower heads would constitute a nice example of turning agricultural residues into ecological and economic assets.27

The retrosynthetic planning of our work is shown in Scheme 1. The first disconnection, that is, the formation of an amide bond from platensic acid (4) to obtain PTM (1), was described by Nicolaou and co-workers in 2009.16 The synthesis of acid 4 was proposed to occur via the oxidative degradation of the olefin present on the A-ring of 5, which, in turn, will be obtained by oxidative decarboxylation of 6. The generation of 6 from grandiflorenic acid would involve a double regio- and stereoselective hydration to generate the 11,17-diol formation, which after dehydration of the primary alcohol and subsequent acid cyclization would produce the ether bridge present in 6. Moreover, the methylene anti-Markownikoff hydration of kaurenoic acid would enable us to obtain 6 through a long-distance functionalization mediated by lead tetraacetate (LTA). Grandiflorenic acid (2) and ent-kaurenoic acid (3) will be obtained from the aerial parts from S. lucida., and H. annuus heads, respectively.

Scheme 1. Retrosynthetic Analysis of PTM.

Scheme 1

Open in a new tab

As mentioned above, the availability of starting materials from inexpensive and accessible natural sources represents a crucial feature of our strategy. For this reason, we started by developing an appropriate procedure for the extraction of ent-kaurenoic acid from sunflower heads (Barrero et al., 2023, unpublished results). On the contrary, acids from aerial parts of S. lucida were obtained via Soxhlet extraction and fractionation following Amaro’s procedure.25

Once we had multigram quantities of our starting materials in hand, we decided to study the key step of A-ring degradation using the product of hydrogenation of ent-kaurenoic acid (7) as a simple model. Thus, the synthetic procedure started with the reduction of ent-kaurenoic acid by catalytic hydrogenation to afford 7 in 75% yield (Scheme 2).28 Oxidative decarboxylation of 7 with lead tetraacetate29,30 afforded a variable mixture of acetylated compound 8 and regioisomers 9a–c. Treatment of this mixture with p-toluenesulfonic acid caused both acetic acid elimination and olefin isomerization to afford only the desired tetrasubstituted olefin 9c in 91% yield in two steps. A-Ring opening was accomplished by bubbling ozone through a solution of 9c in dichloromethane at 0 °C to furnish diketone 10 in 82% yield. The intramolecular aldolic condensation of 10 provided pentacyclic methyl ketone 11 (Scheme 2). It is noteworthy that exposure of 11 to ozone caused the opening of the cyclopentene ring to afford, after esterification, ketoester 12 in 85% yield. As required, two carbon atoms were lost during the process, which should involve degradation of the initially formed α-diketone. A proposed mechanism for rationalizing this transformation is shown in the Supporting Information. Finally, α,β-unsaturated ketone 13 was obtained via treating 12 with phenyl selenium chloride in EtOAc and subsequent elimination of the corresponding selenoxide generated after the addition of H2O2 [83% yield (Scheme 2)].

Scheme 2. ent-Kaurenoic Acid A-Ring Degradation Model.

Scheme 2

Open in a new tab

Once the appropriate experimental conditions for the A-ring degradation were found, we focused our efforts on developing a strategy for the construction of the furan ring in PTM using the methyl esters of ent-kaurenoic and grandiflorenic acids as starting materials (see Schemes 4 and 5). The two parallel approaches starting from each one of these precursors converged in the generation of furan derivative 6 (Scheme 3).

Scheme 4. Selective Double Hydroboration–Oxidation of 6.

Scheme 4

Open in a new tab

Scheme 5. Synthesis of Methyl Platensinoate (4a).

Scheme 5

Open in a new tab

Scheme 3. Ether Ring Synthesis.

Scheme 3

Open in a new tab

Starting from the methyl ester of ent-kaurenoic acid (3a), our first approach to PTM began with the regio- and stereoselective hydration by the most accessible α face of the olefin present in 3a using BH3 in THF as a hydroborating agent and H2O2/KOH as an oxidant. Primary alcohol 14 was thus obtained in 74% yield. The required oxygenation at C11 was accomplished by treating 14 with LTA in refluxing cyclohexane31−33 to produce 15 in a remarkable 75% yield, improving the result reported by McAlles and McCrindle32 for this transformation. This good yield is the result of the spatial proximity of C17-hydroxyl to H11β.

Trimethylsilyl iodide-mediated opening of cyclic ether 15 produced, after acetylation of the resulting unstable iodo alcohol 16, primary iodide 17 and starting 15 in 40% and 43% yields, respectively, in a one-pot reaction. Additionally, we obtained a minor product (18) in 13% yield with a double bond at C11, as a result of the secondary hydroxyl group elimination. It should be noted that the presence of 15 derives from cyclization of the intermediate iodo alcohol and not from an unaltered starting material. Iodine elimination of 17 with DBU produced exocyclic olefin 19 in 81% yield, along with minor proportions of cyclic ether 15 (6% yield). Hydrolysis of acetate 19(34) and subsequent treatment of the corresponding alcohol with TFA caused the desired regioselective cyclization to generate targeted furan derivative 20 in a combined 91% yield. Finally, treatment of 20 with lithium iodide in collidine at reflux afforded acid 6(35) in 87% yield (Scheme 3).

The route from grandiflorenic acid started with the double regio- and selective hydroboration of the olefinic bonds of methyl gradiflorenate (2a) to give diol 21. The selectivity of this double hydration process is noteworthy, especially if we considered that the diol obtained after a stepwise hydroboration is 21b, the C11 epimer of diol 21. To rationalize this facial selectivity, it is proposed that the BH3/THF reagent initially binds selectively by the α face to the exocyclic olefin to produce an alkylborane complex (I), which evolves toward cyclic dialkylborane II after an intramolecular hydroboration of the C9=C11 bond by the β face (Scheme 4).

Once we obtained diol 21, selective dehydration of the primary alcohol was tried using Grieco’s dehydration procedure.36 Via this process, pyran derivative 15 was again formed, most likely due to the spatial proximity of the hydroxyl groups, which tends to collapse toward the stable six-membered heterocyclic ring via a SN2 displacement of the corresponding seleno intermediate. Although at this point cyclic ether 15 is an intermediate in the kaurenic acid approach to furan derivative 6, we geared our efforts toward establishing an alternative route to target 6.

Our new approach from diol 21 involved some protecting group manipulation. Thus, selective acetylation of the primary alcohol of 21 was accomplished using acetyl chloride at −78 °C to afford acetate 22 in 79% yield. The secondary alcohol was then protected with methoxymethyl chloride (MOMCl) to give 23 in 96% yield. Alkaline deprotection of the acetate group led to primary alcohol 24, which was now successfully eliminated following Grieco’s protocol33 to furnish olefin 25 (69% yield, two steps). Finally, furan derivative 20 was produced in 97% yield by treating 25 with TFA, after a one-pot deprotection–cyclization process.

Once we succeeded in making our two approaches converge in tetrahydrofuran derivative 6, our next goal was to apply to 6 the A-ring degradation experimental conditions that were optimized with the reduced derivative of kaurenoic acid (7) (Scheme 2). Following the procedure detailed above, the decarboxylation of carboxylic acid 6 was conducted using lead tetraacetate. The resulting reaction mixture was then reacted with pTsOH to obtain olefin 5 in low yields. Gratifyingly, when the mentioned crude was treated with molecular iodine, the desired tetrasubstituted 5 was obtained in 78% yield over two steps. Ozonolysis led to A-ring cleavage, affording diketone 26 in 85% yield (Scheme 5). Intramolecular aldol condensation of compound 26 with potassium hydroxide in ethanol provided enone 27 in 69% yield. Ozonolysis of 27 caused, as previously described, the loss of two carbon atoms and the generation of methyl ester 28 after methylation with trimethylsilyl diazomethane of the corresponding acid (63% yield, two steps). Finally, the dehydrogenation of 28 to produce methyl platensinoate (4a) was accomplished in 83% yield using the same PhSeCl/H2O2 protocol previously described in the model study.

Because compound 4a constitutes an intermediate in the PTM synthesis described by Nicolaou in 2009,16 the herein described synthetic approach constitutes a formal enantioselective synthesis of PTM. It should be noted that the spectroscopic data of our methyl platensinoate (4a) match completely those described by Nicolau et al. for the same product.

In conclusion, we have investigated two approaches to 4a, resulting in the formal bioinspired synthesis of PTM, a multidrug-resistant antibiotic possessing a unique mode of action as a suppressor of fatty acid biosynthesis in bacteria. The use of renewable starting materials was essential in our strategies. The use of ent-kaurenoic acid present in sunflowers, whose oil worldwide production in 2020 exceeded 55 million tons, features the harnessing of agricultural residues to produce value-added chemicals. Also key in our strategies was the unprecedented protocol described for the A-ring degradation of kaurene diterpenoids, which additionally enabled the required loss of three carbon atoms for the synthesis of methyl platensinoate. Additionally, the long-distance functionalization at C11 in the first approach, as well as the double hydroboration–oxidation in the second, also stands out as a key step. All in all, our synthetic route competes favorably with other synthetic approaches, resulting in fact in one of the shortest sequences to this natural product.37 Finally, our protocol is flexible enough to be applicable to the synthesis of other PTM analogues in the search for more active antibiotics.

Acknowledgments

Financial support for this work was provided by Ministerio de Economía y Competitividad, PID2019-106222RB-C32/SRA (State Research Agency, 10.13039/501100011033). Funding for open access charge: Universidad de Granada/CBUA.

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.3c01470.

  • Copies of 1H and 13C{1H} NMR and two-dimensional spectra of the obtained compounds (PDF)

  • FAIR data, including the primary NMR FID files, for compounds 2–15 and 17–28 (ZIP)

The authors declare no competing financial interest.

Supplementary Material

ol3c01470_si_001.pdf (7.7MB, pdf)
ol3c01470_si_002.zip (228.9MB, zip)

References

  1. Centers for Disease Control and Prevention . https://www.cdc.gov/drugresistance/national-estimates.html (accessed 2023-03-16).
  2. Wang J.; Soisson S. M.; Young K.; Shoop W.; Kodali S.; Galgoci A.; Painter R.; Parthasarathy G.; Tang Y. S.; Cummings R.; Ha S.; Dorso K.; Motyl M.; Jayasuriya H.; Ondeyka J.; Herath K.; Zhang C.; Hernandez L.; Allocco J.; Basilio Á.; Tormo J. R.; Genilloud O.; Vicente F.; Pelaez F.; Colwell L.; Lee S. H.; Michael B.; Felcetto T.; Gill C.; Silver L. L.; Hermes J. D.; Bartizal K.; Barrett J.; Schmatz D.; Becker J. W.; Cully D.; Singh S. B. Platensimycin Is a Selective FabF Inhibitor with Potent Antibiotic Properties. Nature 2006, 441, 358–361. 10.1038/nature04784. [DOI] [PubMed] [Google Scholar]
  3. Rudolf J. D.; Dong L.-B.; Shen B. Platensimycin and Platencin: Inspirations for Chemistry, Biology, Enzymology, and Medicine. Biochem. Pharmacol. 2017, 133, 139–151. 10.1016/j.bcp.2016.11.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Peterson R. M.; Huang T.; Rudolf J. D.; Smanski M. J.; Shen B. Mechanisms of Self-Resistance in the Platensimycin- and Platencin-Producing Streptomyces platensis MA7327 and MA7339 Strains. Chem. Biol. 2014, 21, 389–397. 10.1016/j.chembiol.2014.01.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Allahverdiyev A. M.; Bagirova M.; Abamor E. S.; Ates S. C.; Cakir Koc R.; Miraloglu M.; Elcicek S.; Yaman S.; Unal G. The Use of Platensimycin and Platencin to Fight Antibiotic Resistance. Infect. Drug Resist. 2013, 6, 99–114. 10.2147/IDR.S25076. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Qiu L.; Wen Z.; Li Y.; Tian K.; Deng Y.; Shen B.; Duan Y.; Huang Y. Stereoselective Functionalization of Platensimycin and Platencin by Sulfa-Michael/Aldol Reactions. Org. Biomol. Chem. 2019, 17, 4261–4272. 10.1039/C9OB00324J. [DOI] [PubMed] [Google Scholar]
  7. Deng Y.; Kang D.; Shi J.; Zhou W.; Sun A.; Ju J.; Zhu X.; Shen B.; Duan Y.; Huang Y. The Semi-Synthesis, Biological Evaluation and Docking Analysis of the Oxime, Hydrazine and Hydrazide Derivatives of Platensimycin. Med. Chem. Comm. 2018, 9, 789–794. 10.1039/C8MD00081F. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Deng Y.; Weng X.; Li Y.; Su M.; Wen Z.; Ji X.; Ren N.; Shen B.; Duan Y.; Huang Y. Late-Stage Functionalization of Platensimycin Leading to Multiple Analogues with Improved Antibacterial Activity in Vitro and in Vivo. J. Med. Chem. 2019, 62, 6682–6693. 10.1021/acs.jmedchem.9b00616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Krauß J.; Plesch E.; Clausen S.; Bracher F. Short and Efficient Synthesis of Alkyl-and Aryl-Ortho-Hydroxy-Anilides and Their Antibiotic Activity. Sci. Pharm. 2014, 82, 501–517. 10.3797/scipharm.1401-19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Moraes F. C.; Alvarenga E. S.; Amorim K. B.; Demuner A. J.; Pereira-Flores M. E. Novel Platensimycin Derivatives with Herbicidal Activity. Pest Manag. Sci. 2016, 72, 580–584. 10.1002/ps.4028. [DOI] [PubMed] [Google Scholar]
  11. Nicolaou K. C.; Li A.; Edmonds D. J. Total Synthesis of Platensimycin. Angew. Chem., Int. Ed. 2006, 45, 7086–7090. 10.1002/anie.200603892. [DOI] [PubMed] [Google Scholar]
  12. Eey S. T. C.; Lear M. J. Total Synthesis of (-)-Platensimycin by Advancing Oxocarbenium- and Iminium-Mediated Catalytic Methods. Chem. Eur. J. 2014, 20, 11556–11573. 10.1002/chem.201400131. [DOI] [PubMed] [Google Scholar]
  13. Ghosh A. K.; Xi K. Total Synthesis of (-)-Platensimycin, a Novel Antibacterial Agent. J. Org. Chem. 2009, 74, 1163–1170. 10.1021/jo802261f. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Wright D. L.; van Heyst M. D.; Oblak E. Z. Oxabicyclic Building Blocks as Key Intermediates in the Synthesis of the Natural Products (-)-Platensimycin and (+)-Frondosin A. Strateg. Tactics Org. Synth. 2014, 10, 155–181. 10.1016/B978-0-12-417185-5.00007-7. [DOI] [Google Scholar]
  15. Zou Y.; Chen C. H.; Taylor C. D.; Foxman B. M.; Snider B. B. Formal Synthesis of (±)-Platensimycin. Org. Lett. 2007, 9, 1825–1828. 10.1021/ol070563g. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Nicolaou K. C.; Li A.; Edmonds D. J.; Tria G. S.; Ellery S. P. Total Synthesis of Platensimycin and Related Natural Products. J. Am. Chem. Soc. 2009, 131, 16905–16918. 10.1021/ja9068003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Shi J.; Pan J.; Liu L.; Yang D.; Lu S.; Zhu X.; Shen B.; Duan Y.; Huang Y. Titer Improvement and Pilot-Scale Production of Platensimycin from Streptomyces platensis SB12026. J. Ind. Microbiol. Biotechnol. 2016, 43, 1027–1035. 10.1007/s10295-016-1769-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Dong L.-B.; Zhang X.; Rudolf J. D.; Deng M.-R.; Kalkreuter E.; Cepeda A. J.; Renata H.; Shen B. Cryptic and Stereospecific Hydroxylation, Oxidation, and Reduction in Platensimycin and Platencin Biosynthesis. J. Am. Chem. Soc. 2019, 141, 4043–4050. 10.1021/jacs.8b13452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Dong L.-B.; Liu Y. C.; Cepeda A. J.; Kalkreuter E.; Deng M. R.; Rudolf J. D.; Chang C.; Joachimiak A.; Phillips G. N.; Shen B. Characterization and Crystal Structure of a Nonheme Diiron Monooxygenase Involved in Platensimycin and Platencin Biosynthesis. J. Am. Chem. Soc. 2019, 141, 12406–12412. 10.1021/jacs.9b06183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Zhang X.; King-Smith E.; Dong L.-B.; Yang L. C.; Rudolf J. D.; Shen B.; Renata H. Divergent Synthesis of Complex Ent-Kauranes, Ent-Atisanes and Ent-Trachylobanes via a Hybrid Oxidative Approach. chemRxiv 2020, 10.26434/chemrxiv.7663112.v2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Rudolf J. D.; Dong L.-B.; Zhang X.; Renata H.; Shen B. Cytochrome P450-Catalyzed Hydroxylation Initiating Ether Formation in Platensimycin Biosynthesis. J. Am. Chem. Soc. 2018, 140, 12349–12353. 10.1021/jacs.8b08012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Rudolf J. D.; Dong L.-B.; Manoogian K.; Shen B. Biosynthetic Origin of the Ether Ring in Platensimycin. J. Am. Chem. Soc. 2016, 138, 16711–16721. 10.1021/jacs.6b09818. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mitscher L. A.; Rao G. S. R.; Veysoglu T.; Drake S.; Haas T. Isolation and identification of trachyloban-19-oic and (-)-kaur-16-en-oic acids as antimicrobial agents from the prairie sunflower, Helianthus annuus. J. Nat. Prod. 1983, 46, 745–746. 10.1021/np50029a024. [DOI] [PubMed] [Google Scholar]
  24. Ungur N.; Grinco M.; Kulciţki V.; Barba A.; Bîzîcci T.; Vlad P. F. Isolation of Ent-Kaur-16-En-19-Oic and Ent-Trachiloban-19-Oic Acids from the Sunflower Helianthus Annuus L. Dry Waste. Chem. J. Mold. 2008, 3, 105–108. 10.19261/cjm.2008.03(2).01. [DOI] [Google Scholar]
  25. Amaro-Luis J. M. An Ent-Kaurenolide from Stevia Lucida. Phytochemistry 1993, 32, 1611–1613. 10.1016/0031-9422(93)85190-3. [DOI] [Google Scholar]
  26. Sunflower Production by Country | World Agricultural Production 2022/2023. http://www.worldagriculturalproduction.com/crops/sunflower.aspx (accessed 2023-03-16).
  27. Santana-Méridas O.; González-Coloma A.; Sánchez-Vioque R. Agricultural Residues as a Source of Bioactive Natural Products. Phytochem. Rev. 2012, 11, 447–466. 10.1007/s11101-012-9266-0. [DOI] [Google Scholar]
  28. Although in previous reports (see ref (21)) the reduction of 3 was reported to give only one stereoisomer, in our hands, this reaction afforded a 3.1 mixture of epimers in which 7 was the major one.
  29. Jensen N. P.; Johnson W. S. A Three-Step Synthesis of Fichtelite from Abietic Acid. J. Org. Chem. 1967, 32, 2045–2046. 10.1021/jo01281a097. [DOI] [Google Scholar]
  30. Komissarova N. G.; Belenkova N. G.; Shitikova O. V.; Spirikhin L. V.; Yunusov M. S. Oxidative Decarboxylation of Triterpene C-28 Acids of Lupane Series. Nat. Prod. Commun. 2008, 3, 1569–1574. 10.1177/1934578X0800301002. [DOI] [Google Scholar]
  31. Lewis N. J.; MacMillan J. Terpenoids. Part 8. Partial syntheses of ent-11β-, 12α-, and 12β-hydroxykaur-16-en-19-oic acids from grandiflorenic acid. J. Chem. Soc., Perkin Trans. 1980, 11, 1270–1278. 10.1039/P19800001270. [DOI] [Google Scholar]
  32. Mcalees A. J.; McCrindle R. Ring C Functionalized Diterpenoids. Part I. The Hypoiodite Reaction as a Route to Ring C Functionalized Kauranes and Phyllocladanes. Can. J. Chem. 1. 1973, 51, 4103–4104. 10.1139/v73-614. [DOI] [Google Scholar]
  33. Node M.; Kajimoto T.; Fujita E.; Fuji K. Regioselective Hydroxylation in the C Ring of Ent-Kaurene; Syntheses of Ent-11a-Hydroxykaurene and Ent-11a-Hydroxykauren-15-One. Bull. Inst. Chem. Res., Kyoto Univ. 1987, 65, 129–133. [Google Scholar]
  34. Bohlmann F.; Zdero C.; Hoffmann E.; Mahanta P. M.; Dorner W. Phytochemistry 1978, 17, 1917–1922. 10.1016/S0031-9422(00)88733-6. [DOI] [Google Scholar]
  35. Fraga B. M.; Gonzalez P.; Guillermo R.; Hernandez M. G. The Formation of an Ent-11α,16α-Epoxykaurane of Biosynthetic Significance by Gibberella fujikuroi. Nat. Prod. Lett. 1996, 8, 257–262. 10.1080/10575639608044904. [DOI] [Google Scholar]
  36. Grieco P. A.; Gilman S.; Nishizawa M. Organoselenium Chemistry. A Facile One-Step Synthesis of Alkyl Aryl Selenides from Alcohols. J. Org. Chem. 1976, 41, 1485–1486. 10.1021/jo00870a052. [DOI] [Google Scholar]
  37. For a compilation of the reported syntheses of platensymicin, see:; Trajkovic M.; Ferjancic Z.; Saicic R. N.; Bihelovic F. Chem. Eur. J. 2019, 25, 4340–4344. 10.1002/chem.201900497. [DOI] [PubMed] [Google Scholar]; and references cited therein

Associated Data

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

Supplementary Materials

ol3c01470_si_001.pdf (7.7MB, pdf)
ol3c01470_si_002.zip (228.9MB, zip)

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