Letter pubs.acs.org/OrgLett
Biomimetic Total Synthesis of Rhodonoids C and D, and Murrayakonine D Aaron J. Day,† Hiu C. Lam,† Christopher J. Sumby, and Jonathan H. George* Department of Chemistry, University of Adelaide, Adelaide, SA 5005, Australia S Supporting Information *
ABSTRACT: A divergent, three-step total synthesis of rhodonoids C and D has been achieved using a biosynthetically inspired, acid-catalyzed cascade cyclization of an epoxychromene that involves the presumed intermediacy of oquinone methides. Application of a similar strategy also allowed synthesis of the alkaloid murrayakonine D.
R
Scheme 1. Proposed Biosynthesis of Rhodonoids C−D
hodonoids C (1) and D (2) (Figure 1) are tetracyclic meroterpenoids isolated from Rhododendron capitatum.1
Figure 1. Rearranged chromene meroterpenoids of interest in this work.
Rhodonoid C (1) has a unique 6/6/6/5 ring system that is structurally similar to murrayakonine D (3), a carbazole alkaloid isolated from the Indian traditional medicinal plant Murraya koenigii.2 Rhodonoid D (2) has a 6/6/5/5 ring system. Compounds 1−3 each possess four stereocenters, but 1 and 2 were isolated as scalemic mixtures (the optical rotation of 3 was not reported). This implies that the biosynthesis of 1 and 2 possibly occurs via predisposed, nonenzymatic cyclizations, which we intended to investigate further using biomimetic synthesis. The biosynthetically related rhodonoids A (4) and B (5) have also been isolated from Rhododendron capitatum3 and were recently synthesized by Tang et al.4 Our proposal for the biogenetic origin of 1 and 2 is outlined in Scheme 1. Chromene 7 is an (unnamed) meroterpenoid previously isolated from Rhododendron anthopogonoides and presumably derived from oxidation of a geranylated derivative of orcinol.5 Epoxidation of the prenyl side chain of 7 could give epoxide 8 (single diastereomer), which could lead to 1 and 2 via acid-catalyzed rearrangements. To be precise, a 6-endo-tet ring opening6 of epoxide 8 (probably via an SN1 mechanism © 2017 American Chemical Society
under acidic conditions) by the electron-rich chromene double bond could give o-quinone methide 9, which could further cyclize via nucleophilic attack of the resultant alcohol back onto the o-quinone methide to give 1 (path a). Alternatively, initial 5-exo-tet ring opening of epoxide 8 (via an SN2 mechanism, with inversion at C-12) could give o-quinone methide 10, and then 2 via a final cyclization (path b). The structure of 2 is similar to that of siccanin (6), a meroterpenoid that has been proposed to be biosynthesized via an analogous rearrangement of an epoxy-chromene.7 However, attempts to achieve a biomimetic synthesis of siccanin by Trost and co-workers failed under acidic conditions, and a radical cyclization strategy was used instead.8 The cascade reactions in Scheme 1 represent novel biomimetic rearrangements of chromene meroterpenoids, Received: March 16, 2017 Published: May 3, 2017 2463
DOI: 10.1021/acs.orglett.7b00779 Org. Lett. 2017, 19, 2463−2465
Letter
Organic Letters
catalyzed rearrangement of the epoxidized form of mahanimbine (12).13 Thus, racemic 12 was synthesized according to the previously published procedures of Knölker et al.14 and then epoxidized with m-CPBA to give 13 in a 61% yield as a 1:1 mixture of diastereomers (Scheme 3). Acid-catalyzed rearrange-
which have previously been dominated by intramolecular photochemical or cationic [2 + 2] cyclizations to give cyclobutane-containing “cyclol” natural products,9 or acidcatalyzed intramolecular [4 + 2] cyclizations to give “citran” natural products.10 We recently reported an unusual intramolecular Diels−Alder reaction of a chromene meroterpenoid in a biomimetic total synthesis of verrubenzospirolactone.11 Our racemic, divergent total synthesis of 1 and 2 (Scheme 2) began with chromene 7, prepared in one step from orcinol and
Scheme 3. Total Synthesis of Murrayakonine D
Scheme 2. Total Synthesis of Rhodonoids C and D
ment of 13 using p-TsOH in CH2Cl2 gave a chromatogaphically inseparable 7.4:1 mixture of 3 and the undesired ketone 14. From this mixture, pure 3 was obtained in 33% overall yield by washing the crude solid with cold MeOH to remove the more soluble byproduct 14. Spectral data for 3 correlated fully with published data for the natural product, and the structure was proven beyond doubt using single crystal X-ray crystallography.15 Despite extensive efforts, we have not isolated any products with a rhodonoid D-type ring system from acid-catalyzed rearrangements of 13. Furthermore, no natural products in the murrayakonine family with a rhodonoid D skeleton have been found in Murraya koenigii, despite the isolation of over 70 carbazole natural products from this plant. A possible explanation for this is the differing reactivity of epoxides 8 and 13 under acidic conditions due to the decreased nucleophilicity of the chromene alkene of 13 (with a carbazole as the electron-donating group at C-1) compared to that of 8 (with a free phenol as the electron-donating group at C-1, and the ability to form an o-quinone methide). This decreased nucleophilicity would lead to a slower 5-exo-tet, SN2 ring opening (path b in Scheme 1) of epoxide 13 compared to epoxide 8. However, the rates of 6-endo-tet cyclization (path a in Scheme 1) of 8 and 13 should be similar due to the increased SN1 character of this reaction. In conclusion, we have synthesized two polyclic meroterpenoids, rhodonoids C and D, in three steps from simple, commercially available starting materials. The key step is a divergent, acid-catalyzed rearrangement of a common epoxychromene intermediate that is directly inspired by our biosynthetic hypothesis. The predisposed selectivity of this cascade reaction suggests that rhodonoids C and D could be formed nonenzymatically in nature. A similar biomimetic cascade reaction was also used in a synthesis of a carbazole natural product, murrayakonine D.
citral according to the procedure of Hsung and co-workers.12 Epoxidation of 7 with m-CPBA gave 8 in 51% yield as an inseparable 1:1 mixture of diastereomers. We then screened various conditions for the cascade cyclization of 8 to give 1 and 2, alongside the undesired ketone byproduct 11 that is formed via a formal 1,2-hydride shift (see the Supporting Information for a detailed table of reaction conditions). Our optimal conditions involved the exposure of 8 to 1 equiv of SnCl4 in CHCl3 at −60 °C for 30 min, which gave a 32% yield of 1, 5% of 2, and 21% of 11. In this reaction, the maximum combined yield of 1 and 2 from 8 is just 50%, as only one of the two diastereomers of 8 has the correct relative configuration (9S*12R*) to undergo the desired cascade cyclizations (as shown in Scheme 1). The other diastereomer (9S*12S*) of 8 is presumably the main source of the undesired ketone byproduct 11. In order to probe this hypothesis further, epoxide 8 was treated with only 0.5 equiv of SnCl4 in CHCl3 at −60 °C and the reaction was quenched after roughly 50% consumption of starting material (TLC analysis). This gave 22% of 1, 3% of 2, and 8% of 11, along with 39% of recovered 8 as a 3.3:1 mixture of diastereomers, presumably in favor of the less reactive (9S*12S*) diastereomer. Reaction of this 3.3:1 mixture of epoxides under our standard conditions (SnCl4 in CHCl3 at −60 °C) then gave 13% of 1, 0% of 2, and 32% of 11. The use of protic acids in the biomimetic rearrangement of epoxide 8 gave slightly lower overall yields of 1 and 2. For example, the use of p-TsOH in CHCl3 at room temperature gave 1 (21%), 2 (2%), and 11 (5%). We attempted to improve the yield of 2 by employing basic reagents that might promote 5-exo-tet, SN2 ring opening of 8 via deprotonation of the free phenol, but no reaction was observed under these conditions. Clearly, the cascade reaction requires activation of epoxide 8 by protonation or coordination to a Lewis acid, and the formation of 1 is inherently favored over 2 under these conditions. Murrayakonine D (3) has a similar ring system to rhodonoid C (1), and it could be formed in nature by an analogous acid 2464
DOI: 10.1021/acs.orglett.7b00779 Org. Lett. 2017, 19, 2463−2465
Letter
Organic Letters
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(14) Hesse, R.; Gruner, K. K.; Kataeva, O.; Schmidt, A. W.; Knölker, H.-J. Chem. - Eur. J. 2013, 19, 14098. (15) CCDC 1538308 (3) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00779. Experimental procedures and full characterization data for all compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Jonathan H. George: 0000-0002-7330-2160 Author Contributions †
A.J.D. and H.C.L. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the Australian Research Council for financial support (Discovery Project, DP160103393).
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REFERENCES
(1) Liao, H.-B.; Huang, G.-H.; Yu, M.-H.; Lei, C.; Hou, A.-J. J. Org. Chem. 2017, 82, 1632. (2) Nalli, Y.; Khajuria, V.; Gupta, S.; Arora, P.; Riyaz-Ul-Hassan, S.; Ahmed, Z.; Ali, A. Org. Biomol. Chem. 2016, 14, 3322. (3) Liao, H.-B.; Lei, C.; Gao, L.-X.; Li, J.-Y.; Li, J.; Hou, A.-J. Org. Lett. 2015, 17, 5040. (4) Wu, H.; Hsung, R. P.; Tang, Y. J. Org. Chem. 2017, 82, 1545. (5) Iwata, N.; Kitanaka, S. Chem. Pharm. Bull. 2011, 59, 1409. (6) The cyclization of epoxide 8 via path a is formally classified by Baldwin as 6-endo-tet, and that convention is maintained in this work; see: (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734. However, Alabugin has recently suggested that this mode of cyclic closure onto epoxides be classified as 6-exo-tet; see: (b) Alabugin, I. V.; Gilmore, K. Chem. Commun. 2013, 49, 11246. Alternatively, Jamison has suggested the use of “fused 6-endo-tet”, see: (c) Vilotijevic, I.; Jamison, T. F. Mar. Drugs 2010, 8, 763. (7) Hirai, K.; Nozoe, S.; Tsuda, K.; Iitaka, Y.; Ishibashi, K.; Shirasaka, M. Tetrahedron Lett. 1967, 8, 2177. (8) (a) Trost, B. M.; Shen, H. C.; Surivet, J.-P. Angew. Chem., Int. Ed. 2003, 42, 3943. (b) Trost, B. M.; Shen, H. C.; Surivet, J.-P. J. Am. Chem. Soc. 2004, 126, 12565. (9) For the pioneering example of an intramolecular photochemical [2 + 2] cycloaddition of a chromene, see: (a) Crombie, L.; Ponsford, R.; Shani, A.; Yagnitinsky, B.; Mechoulam, R. Tetrahedron Lett. 1968, 9, 5771. For further examples of intramolecular photochemical and cationic [2 + 2] cycloadditions of chromenes, see: (b) Kurdyumov, A. V.; Hsung, R. P.; Ihlen, K.; Wang, J. Org. Lett. 2003, 5, 3935. (c) Yeom, H.-S.; Li, H.; Tang, Y.; Hsung, R. P. Org. Lett. 2013, 15, 3130 and references therein. (10) For the seminal example of the biomimetic synthesis of “citran” natural products, see: Begley, M. J.; Crombie, L.; Slack, D. A.; Whiting, D. A. J. Chem. Soc., Perkin Trans. 1 1977, 2402. (11) Lam, H. C.; Pepper, H. P.; Sumby, C. J.; George, J. H. Angew. Chem., Int. Ed. 2017, 56, ASAP. DOI: 10.1002/anie.201700114. (12) Luo, G. Y.; Wu, H.; Tang, Y.; Li, H.; Yeom, H. S.; Yang, K.; Hsung, R. P. Synthesis 2015, 47, 2713. (13) Mahanimbine (9) has been isolated as a racemate; see: Furukawa, H.; Wu, T.-S.; Ohta, T.; Kuoh, C.-S. Chem. Pharm. Bull. 1985, 33, 4132. 2465
DOI: 10.1021/acs.orglett.7b00779 Org. Lett. 2017, 19, 2463−2465
