Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Total Synthesis of the Neoclerodane Diterpene Salvinorin A via an Intramolecular Diels−Alder Strategy Yuzhou Wang and Peter Metz* Fakultät Chemie und Lebensmittelchemie, Organische Chemie I, Technische Universität Dresden, Bergstrasse 66, 01069 Dresden, Germany S Supporting Information *
ABSTRACT: A concise total synthesis of the neoclerodane diterpene salvinorin A from 3-furaldehyde is reported using two highly diastereoselective intramolecular Diels−Alder reactions (IMDA) as the key transformations.
S
Scheme 1. Retrosynthesis of Salvinorin A (1)
alvinorin A (1) was isolated from the leaves of Salvia divinorum, which is a Mexican medicinal plant also used for spiritual practices.1 The diterpene 1 is the most potent naturally occurring hallucinogen in humans known to date, and it is a potent, as well as highly selective κ-opioid receptor (KOR) agonist.2,3 Because of the latter unusual bioactivity, 1 is a promising lead for the therapy of CNS disorders, including depression, pain, and drug addiction.4 The groups of Evans, Hagiwara, and Forsyth have already achieved total syntheses of salvinorin A (1).5 In addition, further studies with the aim of synthesizing 16 and intense work on the semisynthetic generation of analogues by modification of 1 have been carried out.7 Very recently, endeavors to generate designed analogues of 1 by total synthesis led to several compounds that maintain strong KOR agonism.8 We were interested in devising a conceptually novel access to 1 that would also allow the synthesis of novel functional analogues that cannot be derived from the natural product. Scheme 1 illustrates our retrosynthetic analysis of salvinorin A (1). As a crucial precursor for the natural product 1, we chose olefin 2 that was eventually to be converted to 1 by selective oxidation. The cyclohexene moiety of 2 offers the option of using an intramolecular Diels−Alder reaction (IMDA) of triene 3 to establish the tricyclic framework with good stereochemical control.9,10 Triene 3, in turn, might be available by chemoselective carbonyl olefination and epimerization α to the lactone carbonyl group from keto aldehyde 4. This intermediate can be obtained by olefin cleavage from the known bicyclic lactone 5, which, itself, is readily produced by another IMDA as the key transformation (see Scheme 2).6d The original route6d from 3-furaldehyde (6) to the BC building block 5 was further optimized, as depicted in Scheme 2. Thus, Liebeskind coupling11 of vinyl iodide 7 and stannane 8 gave an improved yield of diene 10. Moreover, extending the reaction time for IMDA of the derived acrylate 11 to 3 d resulted in an increased overall yield of cycloadduct 5. © XXXX American Chemical Society
Dihydroxylation of unsaturated lactone 5 gave rise to the diastereomeric diols 12 and 13, the relative configuration of which was elucidated by 2D NMR experiments (Scheme 3). Whereas 12 and 13 showed a significantly different reactivity toward sodium periodate, so that 2 days were required for complete diol cleavage of the mixture, phenyliodine diacetate12 drastically reduced the reaction time to 1.5 h with improved yield. Chemoselective Takai olefination13 of the resulting keto aldehyde 4 provided E vinyl iodide 14 that was subjected to Horner−Wadsworth−Emmons olefination with sodium salt 15.9,13b During this reaction, partial epimerization to give the desired C8 (neoclerodane numbering) epimer 17 was observed. With the aid of DBU, equilibrium between 16 and 17 could be Received: April 28, 2018
A
DOI: 10.1021/acs.orglett.8b01357 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Optimized Preparation of the BC Building Block 5
Scheme 4. Preparation and IMDA of Triene 19
Scheme 3. Conversion of Bicyclic Lactone 5 into Vinyl Iodides 16 and 17
flash chromatography, 21 was isolated in pure form, and 20 was enriched to 84% ds but was still contaminated with small amounts of the C8-epimer 2. The relative configuration of compounds 20 and 21 was rigorously established by 2D NMR measurements, while identification of 2 followed from comparison with the major product obtained from IMDA of triene 3 (see Scheme 5). Presumably, stereoisomers 20 and 21 are formed first via the depicted endo-chair transition states with Scheme 5. Preparation and IMDA of Triene 3
smoothly established without material loss, which enabled complete conversion of 16 into 17 prior to the IMDA step, facilitated by the good chromatographic separation of these two isomers. Before proceeding with vinyl iodide 17, we briefly looked into the IMDA of triene 19 featuring a cis relationship between diene and dienophile (Scheme 4).14 If cycloadduct 20 would be efficiently available, a late-stage epimerization at C85a,c,d could be used in an alternative access to diterpene 1. Stille coupling15 of 16 with vinylstannane 18 led to triene 19 in high yield. Heating 19 for 5 d in toluene (sealed tube) with small amounts of 2,6-di-tert-butyl-4-methylphenol (BHT) to 200 °C furnished a mixture of diastereomeric cycloadducts 20, 2, and 21. After B
DOI: 10.1021/acs.orglett.8b01357 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
the sterically less hindered face gave rise to diol 23 that was converted by silylation with TESCl predominantly (86:14) to the regioisomer 24, next to small amounts of the isomeric TES ether at the C1 hydroxyl group. Following Ley−Griffith oxidation18,5d of this mixture and flash chromatography, ketone 25 was isolated as a single regio- and diastereomer in 72% yield from diol 23. Desilylation of 25 with TBAF buffered with acetic acid proceeded uneventfully to give 2-epi-salvinorin B (26)5b nearly quantitatively. The final Mitsunobu inversion of 26 with acetic acid to afford salvinorin A (1) in high yield was already reported by the Hagiwara group.5b However, Hagiwara et al. used a large excess of acetic acid, triphenylphosphine, and diisopropyl azodicarboxylate, which complicates product isolation. After varying the nature of the phosphine and the azodicarboxylate, as well as testing different quantities of the reagents, we found that using the conditions listed in Scheme 6 reliably led to very good results. Thus, the target molecule 1 was isolated in 81% yield next to 18% of 2-epi-119 formed by a competing activation of acetic acid. In conclusion, we accomplished a total synthesis of salvinorin A (1) by application of two highly diastereoselective intramolecular Diels−Alder reactions as the key transformations. Commencing with 3-furaldehyde (6), 18 steps were required, which constitutes one of the shortest routes to diterpene 1. Transition to enantioselective synthesis is easy, as the (S) configured propargylation product of 6, the direct precursor to (S)-7, is known5a and can also be obtained in a single step with high enantiomeric purity through kinetic resolution of the racemic mixture by Sharpless asymmetric epoxidation.20,21 Direct catalytic asymmetric propargylation of 6, further streamlining of the synthetic sequence, and preparation of designed analogues of 1 are currently under investigation.
equatorial orientation of the furyl substituent either on a boatlike16 (left) or a chairlike folded δ-lactone (right), respectively. Subsequently, thermal C8 epimerization17 of 20 leads to the formation of isomer 2. Since the diastereoselectivity of the IMDA step was only ca. 2:1, this approach with triene 19 was abandoned, and we focused on the utilization of the readily available vinyl iodide 17. Triene 3 was efficiently prepared by Stille coupling of 17 with vinylstannane 18 (see Scheme 5). As anticipated,9 IMDA of 3 with a trans relationship between diene and dienophile turned out to be highly diastereoselective in the required sense. After variation of the solvent, temperature, and amount of BHT, the conditions given in Scheme 5 were found to be optimal. Thus, upon heating triene 3 for 3.5 d in chlorobenzene (sealed tube) with 1.2 equiv of BHT to 200 °C, the desired diastereomer 2 was isolated by flash chromatography in 66% yield (94% ds) next to 25% recovered starting material 3. Cycloadduct 2 is probably formed via the depicted endo-chair transition state, and the minor diastereomer 22 arises from the corresponding exo-chair transition state. The relative configuration of both compounds 2 and 22 was unambiguously elucidated by 2D NMR experiments, while the minor product 20, most likely resulting from thermal C8 epimerization of 2,17 was identified by comparison with the major IMDA product derived from triene 19 (see Scheme 4). The remaining steps of our synthesis of salvinorin A (1) are illustrated in Scheme 6. Dihydroxylation of cyclohexene 2 from Scheme 6. Completion of the Total Synthesis of Diterpene 1
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01357. Experimental procedures, spectroscopic data, and 1H and 13 C NMR spectra (PDF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Peter Metz: 0000-0002-0592-9850 Notes
The authors declare no competing financial interest.
■ ■
ACKNOWLEDGMENTS This work was supported by the Deutsche Forschungsgemeinschaft (No. ME 776/20-2). REFERENCES
(1) (a) Ortega, A.; Blount, J. F.; Manchand, P. S. J. Chem. Soc., Perkin Trans. 1 1982, 2505−2508. (b) Valdes, L. J., III; Butler, W. M.; Hatfield, G. M.; Paul, A. G.; Koreeda, M. J. Org. Chem. 1984, 49, 4716−4720. (2) Roth, B. L.; Baner, K.; Westkaemper, R.; Siebert, D.; Rice, K. C.; Steinberg, S.; Ernsberger, P.; Rothman, R. B. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 11934−11939. C
DOI: 10.1021/acs.orglett.8b01357 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters (3) (a) Cunningham, C. W.; Rothman, R. B.; Prisinzano, T. E. Pharmacol. Rev. 2011, 63, 316−347. (b) Butelman, E. R.; Kreek, M. J. Front. Pharmacol. 2015, 6, 190. (c) Cruz, A.; Domingos, S.; Gallardo, E.; Martinho, A. Phytochemistry 2017, 137, 9−14. (d) Roach, J. J.; Shenvi, R. A. Bioorg. Med. Chem. Lett. 2018, 28, 1436−1445. (4) (a) Fajemiroye, J. O.; Prabhakar, P. R.; da Cunha, L. C.; Costa, E. A.; Zjawiony, J. K. Eur. J. Pharmacol. 2017, 800, 96−106. (b) Paton, K. F.; Kumar, N.; Crowley, R. S.; Harper, J. L.; Prisinzano, T. E.; Kivell, B. M. Eur. J. Pain 2017, 21, 1039−1050. (c) Coffeen, U.; Canseco-Alba, A.; Simón-Arceo, K.; Almanza, A.; Mercado, F.; León-Olea, M.; Pellicer, F. Eur. J. Pain 2018, 22, 311−318. (d) Ewald, A. W. M.; Bosch, P. J.; Culverhouse, A.; Crowley, R. S.; Neuenswander, B.; Prisinzano, T. E.; Kivell, B. M. Psychopharmacology 2017, 234, 2499− 2514. (e) Zhou, Y.; Crowley, R.; Prisinzano, T.; Kreek, M. J. Neurosci. Lett. 2018, 673, 19−23. (5) (a) Scheerer, J. R.; Lawrence, J. F.; Wang, G. C.; Evans, D. A. J. Am. Chem. Soc. 2007, 129, 8968−8969. (b) Nozawa, M.; Suka, Y.; Hoshi, T.; Suzuki, T.; Hagiwara, H. Org. Lett. 2008, 10, 1365−1368. (c) Hagiwara, H.; Suka, Y.; Nojima, T.; Hoshi, T.; Suzuki, T. Tetrahedron 2009, 65, 4820−4825. (d) Line, N. J.; Burns, A. C.; Butler, S. C.; Casbohm, J.; Forsyth, C. J. Chem. - Eur. J. 2016, 22, 17983− 17986. (6) (a) Lingham, A. R.; Hügel, H. M.; Rook, T. J. Aust. J. Chem. 2006, 59, 340−348. (b) Bergman, Y. E.; Mulder, R.; Perlmutter, P. J. Org. Chem. 2009, 74, 2589−2591. (c) Lanfranchi, D. A.; Bour, C.; Hanquet, G. Eur. J. Org. Chem. 2011, 2818−2826. (d) Wang, Y.; Rogachev, V.; Wolter, M.; Gruner, M.; Jäger, A.; Metz, P. Eur. J. Org. Chem. 2014, 4083−4088. (7) (a) Lovell, K. M.; Prevatt-Smith, K. M.; Lozama, A.; Prisinzano, T. E. Top. Curr. Chem. 2011, 299, 141−185. (b) Sherwood, A. M.; Crowley, R. S.; Paton, K. F.; Biggerstaff, A.; Neuenswander, B.; Day, V. W.; Kivell, B. M.; Prisinzano, T. E. J. Med. Chem. 2017, 60, 3866− 3878. (8) (a) Roach, J. J.; Sasano, Y.; Schmid, C. L.; Zaidi, S.; Katritch, V.; Stevens, R. C.; Bohn, L. M.; Shenvi, R. A. ACS Cent. Sci. 2017, 3, 1329−1336. (b) Sherwood, A. M.; Williamson, S. E.; Crowley, R. S.; Abbott, L. M.; Day, V. W.; Prisinzano, T. E. Org. Lett. 2017, 19, 5414− 5417. (c) Hirasawa, S.; Cho, M.; Brust, T. F.; Roach, J. J.; Bohn, L. M.; Shenvi, R. A. Bioorg. Med. Chem. Lett. 2018, 28, in press (DOI: DOI: 10.1016/j.bmcl.2018.01.055). (9) Ihara, M.; Katsumata, A.; Egashira, M.; Suzuki, S.; Tokunaga, Y.; Fukumoto, K. J. Org. Chem. 1995, 60, 5560−5566. (10) (a) Tanner, D.; Ascic, E. In Comprehensive Organic Synthesis, 2nd Edition; Knochel, P., Molander, G. A., Eds.; Elsevier B.V.: Amsterdam, 2014; Vol. 5, pp 466−517. (b) Heravi, M. M.; Vavsari, V. F. RSC Adv. 2015, 5, 50890−50912. (11) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748−2749. (12) Nicolaou, K. C.; Adsool, V. A.; Hale, C. R. H. Org. Lett. 2010, 12, 1552−1555. (13) (a) Kruger, A. W.; Meyers, A. I. Tetrahedron Lett. 2001, 42, 4301−4304. (b) Balskus, E. P.; Jacobsen, E. N. Science 2007, 317, 1736−1740. (14) Appendino, G.; Hoflack, J.; De Clercq, P. J.; Chiari, G.; Calleri, M. Tetrahedron 1988, 44, 4605−4618. (15) Heravi, M. M.; Hashemi, E.; Azimian, F. Tetrahedron 2014, 70, 7−21. (16) Munro, T. A.; Duncan, K. K.; Staples, R. J.; Xu, W.; Liu-Chen, L.-Y.; Béguin, C.; Carlezon, W. A., Jr.; Cohen, B. M. Beilstein J. Org. Chem. 2007, 3, 1, DOI: 1. (17) Ma, Z.; Deng, G.; Dai, R.; Xu, W.; Liu-Chen, L.-Y.; Lee, D. Y. W. Tetrahedron Lett. 2010, 51, 5480−5482. (18) (a) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem. Soc., Chem. Commun. 1987, 1625−1627. (b) Griffith, W. P.; Ley, S. V. Aldrichimica Acta 1990, 23, 13−19. (19) Harding, W. W.; Schmidt, M.; Tidgewell, K.; Kannan, P.; Holden, K. G.; Gilmour, B.; Navarro, H.; Rothman, R. B.; Prisinzano, T. E. J. Nat. Prod. 2006, 69, 107−112.
(20) (S)-1-(Furan-3-yl)but-3-yn-1-ol was isolated in 44% yield with 99% ee after kinetic resolution of the racemic substrate using 1 equiv Ti(Oi-Pr)4, 1.2 equiv (−)-DIPT, 0.65 equiv TBHP, CH2Cl2, −30 °C to −21 °C (Wang, Y.; Metz, P. unpublished). (21) (a) Kusakabe, M.; Kitano, Y.; Kobayashi, Y.; Sato, F. J. Org. Chem. 1989, 54, 2085−2091. (b) Pommier, A.; Stepanenko, V.; Jarowicki, K.; Kocienski, P. J. J. Org. Chem. 2003, 68, 4008−4013.
D
DOI: 10.1021/acs.orglett.8b01357 Org. Lett. XXXX, XXX, XXX−XXX
