Communications
Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201706994 German Edition: DOI: 10.1002/ange.201706994
Natural Products
Divergent Asymmetric Total Synthesis of Mulinane Diterpenoids Yun-Ting Liu, Lin-Ping Li, Jian-Hua Xie,* and Qi-Lin Zhou Abstract: A concise, divergent, asymmetric total syntheses of mulinane diterpenoids has been achieved. Specifically, a new strategy was developed featuring a key intramolecular Friedel– Crafts reaction to construct the chiral fused 5-6-6 tricyclic motif, followed by sequential Birch reduction, conjugate methylation, and homologation/ring-expansion reactions to furnish the desired 5-6-7 tricyclic skeleton bearing five contiguous stereocenters. With this efficient strategy, seven mulinane diterpenoids and two analogues were synthesized via late-stage functional modification or functionalization in 8.6– 20 % overall yields and 11–15 steps.
Terpenoids, which are structurally fascinating molecules with
intriguing biological activities, continue to challenge synthetic chemists with the complexity of their hydrocarbon scaffolds.[1] For example, mulinane diterpenoids, first isolated in 1990 from the Chilean shrub Mulinum crassifolium, are used in traditional folk medicine to treat ailments such as diabetes and bronchial and intestinal disorders.[2] To date, more than thirty mulinane diterpenoids have been isolated and identified from plants in the Apiaceae family (which includes the Azorella, Laretia, and Mulinum genera).[3] These natural products are assumed to share the same biogenic precursor, mulin-11,13-diene (1),[4] and to be generated through various oxygenation reactions[2a] (Figure 1). In preliminary biological studies, mulinane diterpenoids were found to possess a broad range of bioactivities including gastroprotective,[5] antituberculosis,[6] antiplasmodial,[7] and antimicrobial activities.[8] Recently, semisynthetic analogues and biotransformation analogues of mulinane diterpenoids have been found to exhibit higher antituberculosis[9] and gastroprotective activities[10] than their parent diterpenoids. Like the related cyathane diterpenoids,[3] mulinane diterpenoids possess a fused 5-6-7 tricyclic ring system. In plants, both types of diterpenoids are formed from geranylgeranyl diphosphate via cyclization followed by multiple oxidation reactions. Numerous syntheses of cyathane diterpenoids have been reported, but mulinane diterpenoids have received considerably less attention.[3] The reason may be that in addition to the difficulty of constructing the trans,cis-fused 56-7 tricyclic core system with its 1,4-syn-quaternary carbon centers at the ring junctures,[11] installing the contiguous [*] Y.-T. Liu, L.-P. Li, Prof. J.-H. Xie, Prof. Q.-L. Zhou State Key Laboratory and Institute of Elemento-organic Chemistry, College of Chemistry, and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University Tianjin 300071 (China) E-mail: [email protected] Homepage: http://zhou.nankai.edu.cn Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.org/10.1002/anie.201706994.
12708
Figure 1. Biosynthesis and typical examples of mulinane- and cyathane-type diterpenoids.
stereocenters (of which there are at least five, two of which are all-carbon quaternary centers) of mulinane diterpenoids is also challenging. In 2015, Guerrero et al. reported the only known syntheses of mulinane diterpenoids; these investigators used a Robinson annulation and a ring-closing metathesis reaction as the key steps to construct the tricyclic core system, and a diastereoselective anionic oxy-Cope rearrangement was used to establish the relative configuration of the quaternary stereocenter at C8.[12] This elegant strategy afforded four racemic mulinane diterpenoids in 1.9–4.6 % overall yields over 17–19 steps. However, the tricyclic core motif was set up at a late stage, which increased the number of functional group manipulations and thus led to a lengthier synthetic route.[13] Herein, we report the enantioselective construction of the chiral tricyclic core system of mulinane diterpenoids by means of a strategy featuring an intramolecular Friedel–Crafts reaction to set up the chiral fused 5-6-6 tricyclic motif at an early stage and a subsequent homologation/ring-expansion reaction to furnish the desired chiral trans,cis-fused 5-6-7 tricyclic ring system. Using this strategy, we accomplished the first asymmetric total syntheses of mulinane diterpenoids. We are interested in the development of methods for asymmetric catalysis, and we are especially interested in methods for asymmetric hydrogenation of ketones for the synthesis of bioactive natural products.[14] On the basis of our previous work, particularly our recent work on the synthesis of chiral cyclic alcohols with a b-alkyl-substituted tertiary stereocenter by means of asymmetric hydrogenation of tetrasubstituted cyclic enones,[15] we began by addressing the challenges of creating the chiral 5-6-7 tricyclic core of the mulinane diterpenoids. Because they have a carboxylic acid or hydroxy group at C20 and a C13-functionalized sevenmembered ring,[3] we envisaged that mulinane diterpenoids
T 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 12708 –12711
Angewandte
Communications such as the highly oxidized compounds mulinic acid (5) and isomulinic acid (6) could be synthesized from less-oxidized mulinane diterpenoids such as 13-epi-mulinolic acid (3) and mulin-11,13-dien-20-oic acid (4), which would be prepared from 13-epi- mulinolic acid ethyl ester (10), an ethyl ester of 13-epi-mulinolic acid (3) (Scheme 1). Importantly, ethyl ester
Chemie
bonyl)cyclopentenone (14)[18] by selective catalytic hydrogenation of the C=C bond using Ir-(R)-SpiroPAP ((R)-15), a catalyst developed in our laboratory[19] (Scheme 2). How-
Scheme 2. Asymmetric synthesis of tricyclic ester 12.
Scheme 1. The synthetic strategy and retrosynthetic analysis of mulinane diterpenoids.
10, which is similar in structure to the presumed biogenic precursor (1), is also an ideal precursor for the synthesis of mulinane diterpenoids having a hydroxy group at C20, such as 13-epi-mulinol (8), via reduction reactions. Thus, with the advanced “biogenic precursor” 10, various mulinane diterpenoids could be divergently synthesized via late-stage functional modification or functionalization. Stereoselective construction of the three contiguous stereocenters in the five-membered ring of ester 10 was the key to our synthetic strategy because the stereocenters of the seven-membered ring could be generated in subsequent manipulations. We planned to construct these congested contiguous stereocenters from optically active b-isopropyl substituted ketoester (1R,2R)-13 (Scheme 1). The chiral fused 5-6-6 tricyclic motif would be constructed by means of an alkylation, an intramolecular Friedel–Crafts reaction, and a hydrogenation. The resulting tricyclic ester 12 would be converted into ketone 11, which contains five contiguous stereocenters, by means of a two-step process involving a Birch reduction and a conjugate methylation sequence to install the C8-methylated quaternary stereocenter.[16] Regioselective homologation/ring expansion of the ketone 11,[17] followed by a base-promoted elimination and methylation, would afford 10 with a trans,cis-fused 5-6-7 tricyclic ring system in optically active form. We began by attempting to prepare optically active cyclopentanone (1R,2R)-13 from 3-isopropyl-2-(ethoxycarAngew. Chem. Int. Ed. 2017, 56, 12708 –12711
ever, the yield of the desired product was < 20 %, as indicated by GC (see Supporting Information). Therefore, we completely hydrogenated cyclopentenone 14 to afford chiral cyclopentanol (1R,2S,5R)-16,[15] which was then oxidized to ketone (1R,2R)-13 in 85 % yield with > 99 % ee. Alkylation of (1R,2R)-13 with 2-(3’-methoxyphenyl)ethyl iodide afforded C-alkylation product 17 a in 65 % yield, along with a 20 % yield of the undesired O-alkylation product (17 b), which could be converted into (1R,2R)-13 in 85 % yield by treatment with concentrated HCl. Treatment of 17 a with methanesulfonic acid at 0 8C resulted in an intramolecular Friedel–Crafts reaction that provided tricyclic compound 18 in 91 % yield. Compound 18 was hydrogenated over Pd/C to afford transfused tricyclic ester 12 in 99 % yield. Subsequently, we studied the conversion of ester 12 to tricyclic ketone 11, which has five contiguous stereocenters, and we then completed the synthesis of 13-epi-mulinolic acid ethyl ester (10) (Scheme 3). Under Birch reduction conditions,[20] ester 12 was transformed to the corresponding diene, which was then treated with concentrated HCl to generate tricyclic enone 20 (80 % yield). Conjugate methylation of enone 20 with lithium dimethylcuprate (Me2CuLi) generated in situ yielded ketone 11 in 85 % yield. Selective bromination at the C12 of ketone 11 with trimethyl(phenyl)ammonium perbromide (PTAB) gave a-bromo ketone 21 in 97 % yield. The structure and absolute configuration of 21 were determined by X-ray crystallography. Regiospecific ring expansion of 21 with (trimethylsilyl)diazomethane and subsequent treatment with pyridinium 4-toluenesulfonate (PPTS) afforded ketone 22 in 85 % yield. DBU-promoted elimination of HBr and methylation of the ketone with methyl lithium in
T 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
12709
Communications
Scheme 3. Asymmetric synthesis of 13-epi-mulinolic acid ethyl ester 10.
the presence of cerium chloride converted 22 into 13-epimulinolic acid ethyl ester (10) in 71 % yield (over two steps). In this way, we accomplished the asymmetric synthesis of an advanced “biogenic precursor” on a gram scale in 20 % overall yield from cyclopentenone 14 via 11 steps. With 10 in hand, we turned our attention to the asymmetric total synthesis of mulinane diterpenoids via late-stage functional modification or functionalization (Scheme 4). After testing various conditions for hydrolysis of hindered esters, we found that ester 10 could be converted to the corresponding acid, 13-epi-mulinolic acid (3),[21] in 92 % yield by reaction with a large excess of potassium tertbutoxide in dimethyl sulfoxide at 95 8C.[22] The structure and absolute configuration of 3 were determined by X-ray
Angewandte
Chemie
crystallography. Dehydration of 3 in benzene in the presence of catalytic TsOH afforded mulin-11,13-dien-20-oic acid (4)[23] in 90 % yield. Mulinane diterpenoid 4 was then converted to mulinic acid (5)[2a] in 65 % yield via photooxidation (300 W mercury lamp) with tetraphenylporphyrin (TPP, 1 mol %) as a photosensitizer at room temperature according to AdamsQs method.[24] Isomerization of 5 with NoyoriQs rutheniumcatalyzed procedure[25] gave isomulinic acid (6)[2a] in 80 % yield. Furthermore, direct allylic oxidation of 4 with SeO2, followed by reduction with NaBH4, provided 16-hydroxy mulin-11,13-dien-20-oic acid (7)[26] in 91 % yield. Furthermore, direct reduction of the ester group of 10 with LiAlH4 yielded 13-epi-mulinol (8) in 85 % yield. Subsequently, TsOHcatalyzed dehydration of 8 afforded mulin-11,13-dien-20-ol (9)[5b] in 88 % yield. Acetylation of the C20 hydroxy group of 9 yielded 20-hydroxy mulin-11,13-dienyl acetate (24),[27] which is also a naturally occurring mulinane diterpenoid. Thus, we completed the synthesis of seven mulinane diterpenoids from advanced “biogenic precursor” 10. In conclusion, we achieved divergent enantioselective total syntheses of seven mulinane diterpenoids, namely, 13epi-mulinolic acid (3, 12 steps, 18 % overall yield), mulin11,13-dien-20-oic acid (4, 13 steps, 17 % yield), mulinic acid (5, 14 steps, 11 % yield), isomulinic acid (6, 15 steps, 8.6 % yield), 16-hydroxy mulin-11,13-dien-20-oic acid (7, 14 steps, 15 % yield), mulin-11,13-dien-20-ol (9, 13 steps, 15 % yield), and 20-hydroxy mulin-11,13-dienyl acetate (24, 14 steps, 14 % yield), along with two analogues, namely, 13-epi-mulinol (8, 12 steps, 17 % yield) and 13-epi-mulinolic acid ethyl ester (10, 11 steps, 20 % yield), from readily available cyclopentenone 14. Our synthetic strategy involved an iridium-catalyzed asymmetric enone hydrogenation to obtain the chiral starting material, an intramolecular Friedel–Crafts reaction to construct the chiral fused 5-6-6 tricyclic structure, a Birch reduction combined with conjugate methylation to set up the C8-methylated quaternary stereocenter, a homologation/ ring-expansion reaction to furnish the trans,cis-fused 5-6-7 tricyclic ring system, and late-stage functional modification or functionalization to complete the divergent enantioselective syntheses. This work represents the first example of asymmetric syntheses of mulinane diterpenoids and provides an efficient approach to the mulinane diterpenoids as well as to other types of 5-6-7 tricyclic diterpenoids and their analogues.
Acknowledgements We thank the National Natural Science Foundation of China (No. 21325207, 21532003, and 21421062), and the “111” project (B06005) of the Ministry of Education of China for financial support.
Conflict of interest The authors declare no conflict of interest. Scheme 4. Asymmetric synthesis of mulinane diterpenoids via latestage functional modification or functionalization.
12710
www.angewandte.org
T 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 12708 –12711
Angewandte
Communications Keywords: asymmetric synthesis · diterpenoids · mulinane · natural products · total synthesis How to cite: Angew. Chem. Int. Ed. 2017, 56, 12708 – 12711 Angew. Chem. 2017, 129, 12882 – 12885 [1] For reviews, see: a) T. J. Maimone, P. S. Baran, Nat. Chem. Biol. 2007, 3, 396 – 407; b) M. Bgschleb, S. Dorich, S. Hanessian, D. Tao, K. B. Schenthal, L. E. Overman, Angew. Chem. Int. Ed. 2016, 55, 4156 – 4186; Angew. Chem. 2016, 128, 4226 – 4258. [2] a) L. A. Loyola, G. Morales, B. Rodriguez, J. Jimenez-Barbero, M. C. de la Torre, A. Perales, M. R. Torres, Tetrahedron 1990, 46, 5413 – 5420; b) L. A. Loyola, G. Morales, M. C. de la Torre, B. Rodriguez, Phytochemistry 1990, 29, 3950 – 3951. [3] I. S. Marcos, R. F. Moro, A. Gil-Mesln, D. D&ez in Studies in natural products chemistry, Vol. 48 (Ed.: Atta-ur-Rahman), Elsevier, Amsterdam, 2016, pp. 137 – 207. [4] F. Salgado, C. Areche, B. Sepffllveda, M. J. Simirgiotis, F. C#ceres, C. Quispe, L. Quispe, T. Cano, Pharmacogn. Mag. 2014, 10, 543 – 548. [5] a) C. Areche, B. Sepffllveda, A. S. Martin, O. Garc&a-Beltr#n, M. Simirgiotis, A. CaÇete, Bioorg. Med. Chem. 2014, 12, 6406 – 6413; b) C. Areche, F. Rojas-Alvarez, C. Campos-Briones, C. Lima, E. G. P8rez, B. Sepffllveda, J. Pharm. Pharmacol. 2013, 65, 1231 – 1238. [6] a) G. A. W-chter, S. G. Franzblau, G. Montenegro, E. Suarez, R. H. Fortunato, J. Nat. Prod. 1998, 61, 965 – 968; b) G. M. Molina-Salinas, J. Blrquez, S. Said-Fern#ndez, L. A. Loyola, A. Yam-Puc, P. Becerril-Montes, F. Escalante-Erosa, L. M. PeÇaRodr&guez, Fitoterapia 2010, 81, 219 – 222. [7] L. A. Loyola, J. Blrquez, G. Morales, A. San-Mart&n, J. Darias, N. Flores, A. Gim8nez, Phytochemistry 2004, 65, 1931 – 1935. [8] G. A. W-chter, G. Matooq, J. J. Hoffmann, W. M. Maiese, M. P. Singh, G. Montenegro, B. N. Timmermann, J. Nat. Prod. 1999, 62, 1319 – 1321. [9] a) G. M. Molina-Salinas, J. Blrquez, A. Ardiles, S. Said-Fern#ndez, L. A. Loyola, A. San-Mart&n, I. Gonz#lez-Collado, L. M. PeÇa-Rodr&guez, Fitoterapia 2010, 81, 50 – 54; b) G. M. MolinaSalinas, J. Blrquez, A. Ardiles, S. Said-Fern#ndez, L. A. Loyola, A. Yam-Puc, P. Becerril-Montes, F. Escalante-Erosa, A. SanMart&n, I. Gonz#lez-Collado, L. M. PeÇa-Rodr&guez, Phytochem. Rev. 2010, 9, 271 – 278. [10] B. Sepffllveda, C. Quispe, M. Simirgiotis, O. Garc&a-Beltr#n, C. Areche, Bioorg. Med. Chem. Lett. 2016, 26, 3220 – 3222. [11] The cyathane diterpenoids generally possess a fused 5-6-7 tricyclic core system with 1,4-anti-quaternary carbon centers at the ring junctures and a trans-fused 6-7 ring, and have received intensive synthetic study over the past decades. For reviews, see: a) D. L. Wright, C. R. Whitehead, Org. Prep. Proced. Int. 2000, 32, 307 – 330; b) J. J. A. Enquist, Jr., B. M. Stoltz, Nat. Prod. Rep. 2009, 26, 661 – 680; c) M. Nakada, Chem. Rec. 2014, 14, 641 – 662; For selected recent papers, see: d) S. P. Waters, Y. Tian, Y.M. Li, S. J. Danishefsky, J. Am. Chem. Soc. 2005, 127, 13514 – 13515; e) M. W. B. Pfeiffer, A. J. Phillips, J. Am. Chem. Soc. 2005, 127, 5334 – 5335; f) B. M. Trost, L. Dong, G. M. Schroeder, J. Am. Chem. Soc. 2005, 127, 2844 – 2845; g) B. M. Trost, L. Dong, G. M. Schroeder, J. Am. Chem. Soc. 2005, 127, 10259 – 10268; h) E. DrHge, C. Tominaux, G. Morgant, D. Desma]le, Eur. J. Org. Chem. 2006, 4825 – 4840; i) H. Watanabe, M. Takano, A. Umino, T. Ito, H. Ishikawa, M. Nakada, Org. Lett. 2007, 9, 359 – 362; j) J. A. Enquist, Jr., B. M. Stoltz, Nature 2008, 453, 1228 – 1231; k) K. Kim, J. K. Cha, Angew. Chem. Int. Ed. 2009, 48, 5334 – 5336; Angew. Chem. 2009, 121, 5438 – 5440; l) N. Kanoh, K. Sakanishi, E. Iimori, K. Nishimura, Y. Iwabuchi, Org. Lett. 2011, 13, 2864 – 2867; m) E. Elamparuthi, C. Fellay, M.
Angew. Chem. Int. Ed. 2017, 56, 12708 –12711
[12] [13] [14]
[15] [16] [17] [18]
[19]
[20] [21] [22] [23] [24] [25] [26] [27]
Chemie
Neuburger, K. Gademann, Angew. Chem. Int. Ed. 2012, 51, 4071 – 4073; Angew. Chem. 2012, 124, 4147 – 4149; n) Y. Kobayakawa, M. Nakada, Angew. Chem. Int. Ed. 2013, 52, 7569 – 7573; Angew. Chem. 2013, 125, 7717 – 7721; o) C. Wang, D. Wang, S.-H. Gao, Org. Lett. 2013, 15, 4402 – 4405; p) K. E. Kim, B. M. Stoltz, Org. Lett. 2016, 18, 5720 – 5723. K. P. Reber, J. Xu, C. A. Guerrero, J. Org. Chem. 2015, 80, 2397 – 2406. The construction of the fused 5-6-7 tricyclic core structures of cyathane diterpenoids also led to lengthier synthetic routes in some cases; see Refs. [3, 11a,b]. For reviews, see: a) J.-H. Xie, Q.-L. Zhou, Aldrichimica Acta 2015, 48, 33 – 40; For selected recent papers, see: b) J.-Q. Chen, J.-H. Xie, D.-H. Bao, S. Liu, Q.-L. Zhou, Org. Lett. 2012, 14, 2714 – 2717; c) C. Liu, J.-H. Xie, Y.-L. Li, J.-Q. Chen, Q.-L. Zhou, Angew. Chem. Int. Ed. 2013, 52, 593 – 596; Angew. Chem. 2013, 125, 621 – 624; d) H. Lin, L.-J. Xiao, M.-J. Zhou, H.-M. Yu, J.-H. Xie, Q.-L. Zhou, Org. Lett. 2016, 18, 1434 – 1437; e) Y. Liu, L.-J. Cheng, H.-T. Yue, W. Che, J.-H. Xie, Q.-L. Zhou, Chem. Sci. 2016, 7, 4725 – 4729; f) L.-Y. Pu, J.-Q. Chen, M.-L. Li, Y. Li, J.-H. Xie, Q.-L. Zhou, Adv. Synth. Catal. 2016, 358, 1229 – 1240; g) X.D. Zuo, S.-M. Guo, R. Yang, J.-H. Xie, Q.-L. Zhou, Chem. Sci. 2017, 8, 6202 – 6206. Y.-T. Liu, J.-Q. Chen, L.-P. Li, X.-Y. Shao, J.-H. Xie, Q.-L. Zhou, Org. Lett. 2017, 19, 3231 – 3234. A. Radha Krishna Murthy, G. S. R. S. Rao, Tetrahedron 1982, 38, 3335 – 3338. V. Dave, E. W. Warnhoff, J. Org. Chem. 1983, 48, 2590 – 2598. 3-Isopropyl-2-(ethoxycarbonyl)cyclopentenone (14) can be synthesized on a gram scale from commercially available 5-methyl4-oxohexanoic acid in 65 % overall yield via two steps according to our previous reported method, see Ref. [15] and Supporting Information. a) J.-H. Xie, X.-Y. Liu, J.-B. Xie, L.-X. Wang, Q.-L. Zhou, Angew. Chem. Int. Ed. 2011, 50, 7329 – 7332; Angew. Chem. 2011, 123, 7467 – 7470; b) J.-H. Xie, X.-Y. Liu, X.-H. Yang, J.-B. Xie, L.-X. Wang, Q.-L. Zhou, Angew. Chem. Int. Ed. 2012, 51, 201 – 203; Angew. Chem. 2012, 124, 205 – 207; c) X.-H. Yang, J.H. Xie, Q.-L. Zhou, Org. Chem. Front. 2014, 1, 190 – 193; d) J.-H. Xie, Q.-L. Zhou, Acta Chim. Sin. 2014, 72, 778 – 797. a) A. L. Wilds, N. A. Nelson, J. Am. Chem. Soc. 1953, 75, 5360 – 5365; b) H. Pellissier, M. Santelli, Org. Prep. Proced. Int. 2002, 34, 609 – 642. L. A. Loyola, J. Borquez, G. Morales, A. San-Martin, Phytochemistry 2000, 53, 961 – 963. a) F. C. Chang, N. F. Wood, Tetrahedron Lett. 1964, 9, 2969 – 2973; b) W. L. Meyer, R. A. Manning, E. Schindler, R. S. Schroeder, D. C. Shew, J. Org. Chem. 1976, 41, 1005 – 1015. L. A. Loyola, J. Borquez, G. Morales, A. San-Martin, Phytochemistry 1997, 44, 649 – 651. W. Adams, O. Cueto, O. DeLucchi, K. Peters, E. Peters, H. G. Von Schnering, J. Am. Chem. Soc. 1981, 103, 5822 – 5828. M. Suzuki, H. Ohtake, Y. Kameya, N. Hamanaka, R. Noyori, J. Org. Chem. 1989, 54, 5292 – 5302. C. Areche, L. A. Loyola, J. Borquez, J. Rovirosa, A. San-Martin, Magn. Reson. Chem. 2008, 46, 765 – 768. The sign of the optical rotation of the synthetic 24 ([a] = @178.6 (c = 0.168, CHCl3)) was found to be opposite to that of natural 24 ([a] =+ 89.28 (c = 0.168, CHCl3)), with the magnitude being approximately two times greater; see Ref. [7].
Manuscript received: July 10, 2017 Accepted manuscript online: August 13, 2017 Version of record online: September 1, 2017
T 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
12711
Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201706994 German Edition: DOI: 10.1002/ange.201706994
Natural Products
Divergent Asymmetric Total Synthesis of Mulinane Diterpenoids Yun-Ting Liu, Lin-Ping Li, Jian-Hua Xie,* and Qi-Lin Zhou Abstract: A concise, divergent, asymmetric total syntheses of mulinane diterpenoids has been achieved. Specifically, a new strategy was developed featuring a key intramolecular Friedel– Crafts reaction to construct the chiral fused 5-6-6 tricyclic motif, followed by sequential Birch reduction, conjugate methylation, and homologation/ring-expansion reactions to furnish the desired 5-6-7 tricyclic skeleton bearing five contiguous stereocenters. With this efficient strategy, seven mulinane diterpenoids and two analogues were synthesized via late-stage functional modification or functionalization in 8.6– 20 % overall yields and 11–15 steps.
Terpenoids, which are structurally fascinating molecules with
intriguing biological activities, continue to challenge synthetic chemists with the complexity of their hydrocarbon scaffolds.[1] For example, mulinane diterpenoids, first isolated in 1990 from the Chilean shrub Mulinum crassifolium, are used in traditional folk medicine to treat ailments such as diabetes and bronchial and intestinal disorders.[2] To date, more than thirty mulinane diterpenoids have been isolated and identified from plants in the Apiaceae family (which includes the Azorella, Laretia, and Mulinum genera).[3] These natural products are assumed to share the same biogenic precursor, mulin-11,13-diene (1),[4] and to be generated through various oxygenation reactions[2a] (Figure 1). In preliminary biological studies, mulinane diterpenoids were found to possess a broad range of bioactivities including gastroprotective,[5] antituberculosis,[6] antiplasmodial,[7] and antimicrobial activities.[8] Recently, semisynthetic analogues and biotransformation analogues of mulinane diterpenoids have been found to exhibit higher antituberculosis[9] and gastroprotective activities[10] than their parent diterpenoids. Like the related cyathane diterpenoids,[3] mulinane diterpenoids possess a fused 5-6-7 tricyclic ring system. In plants, both types of diterpenoids are formed from geranylgeranyl diphosphate via cyclization followed by multiple oxidation reactions. Numerous syntheses of cyathane diterpenoids have been reported, but mulinane diterpenoids have received considerably less attention.[3] The reason may be that in addition to the difficulty of constructing the trans,cis-fused 56-7 tricyclic core system with its 1,4-syn-quaternary carbon centers at the ring junctures,[11] installing the contiguous [*] Y.-T. Liu, L.-P. Li, Prof. J.-H. Xie, Prof. Q.-L. Zhou State Key Laboratory and Institute of Elemento-organic Chemistry, College of Chemistry, and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University Tianjin 300071 (China) E-mail: [email protected] Homepage: http://zhou.nankai.edu.cn Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.org/10.1002/anie.201706994.
12708
Figure 1. Biosynthesis and typical examples of mulinane- and cyathane-type diterpenoids.
stereocenters (of which there are at least five, two of which are all-carbon quaternary centers) of mulinane diterpenoids is also challenging. In 2015, Guerrero et al. reported the only known syntheses of mulinane diterpenoids; these investigators used a Robinson annulation and a ring-closing metathesis reaction as the key steps to construct the tricyclic core system, and a diastereoselective anionic oxy-Cope rearrangement was used to establish the relative configuration of the quaternary stereocenter at C8.[12] This elegant strategy afforded four racemic mulinane diterpenoids in 1.9–4.6 % overall yields over 17–19 steps. However, the tricyclic core motif was set up at a late stage, which increased the number of functional group manipulations and thus led to a lengthier synthetic route.[13] Herein, we report the enantioselective construction of the chiral tricyclic core system of mulinane diterpenoids by means of a strategy featuring an intramolecular Friedel–Crafts reaction to set up the chiral fused 5-6-6 tricyclic motif at an early stage and a subsequent homologation/ring-expansion reaction to furnish the desired chiral trans,cis-fused 5-6-7 tricyclic ring system. Using this strategy, we accomplished the first asymmetric total syntheses of mulinane diterpenoids. We are interested in the development of methods for asymmetric catalysis, and we are especially interested in methods for asymmetric hydrogenation of ketones for the synthesis of bioactive natural products.[14] On the basis of our previous work, particularly our recent work on the synthesis of chiral cyclic alcohols with a b-alkyl-substituted tertiary stereocenter by means of asymmetric hydrogenation of tetrasubstituted cyclic enones,[15] we began by addressing the challenges of creating the chiral 5-6-7 tricyclic core of the mulinane diterpenoids. Because they have a carboxylic acid or hydroxy group at C20 and a C13-functionalized sevenmembered ring,[3] we envisaged that mulinane diterpenoids
T 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 12708 –12711
Angewandte
Communications such as the highly oxidized compounds mulinic acid (5) and isomulinic acid (6) could be synthesized from less-oxidized mulinane diterpenoids such as 13-epi-mulinolic acid (3) and mulin-11,13-dien-20-oic acid (4), which would be prepared from 13-epi- mulinolic acid ethyl ester (10), an ethyl ester of 13-epi-mulinolic acid (3) (Scheme 1). Importantly, ethyl ester
Chemie
bonyl)cyclopentenone (14)[18] by selective catalytic hydrogenation of the C=C bond using Ir-(R)-SpiroPAP ((R)-15), a catalyst developed in our laboratory[19] (Scheme 2). How-
Scheme 2. Asymmetric synthesis of tricyclic ester 12.
Scheme 1. The synthetic strategy and retrosynthetic analysis of mulinane diterpenoids.
10, which is similar in structure to the presumed biogenic precursor (1), is also an ideal precursor for the synthesis of mulinane diterpenoids having a hydroxy group at C20, such as 13-epi-mulinol (8), via reduction reactions. Thus, with the advanced “biogenic precursor” 10, various mulinane diterpenoids could be divergently synthesized via late-stage functional modification or functionalization. Stereoselective construction of the three contiguous stereocenters in the five-membered ring of ester 10 was the key to our synthetic strategy because the stereocenters of the seven-membered ring could be generated in subsequent manipulations. We planned to construct these congested contiguous stereocenters from optically active b-isopropyl substituted ketoester (1R,2R)-13 (Scheme 1). The chiral fused 5-6-6 tricyclic motif would be constructed by means of an alkylation, an intramolecular Friedel–Crafts reaction, and a hydrogenation. The resulting tricyclic ester 12 would be converted into ketone 11, which contains five contiguous stereocenters, by means of a two-step process involving a Birch reduction and a conjugate methylation sequence to install the C8-methylated quaternary stereocenter.[16] Regioselective homologation/ring expansion of the ketone 11,[17] followed by a base-promoted elimination and methylation, would afford 10 with a trans,cis-fused 5-6-7 tricyclic ring system in optically active form. We began by attempting to prepare optically active cyclopentanone (1R,2R)-13 from 3-isopropyl-2-(ethoxycarAngew. Chem. Int. Ed. 2017, 56, 12708 –12711
ever, the yield of the desired product was < 20 %, as indicated by GC (see Supporting Information). Therefore, we completely hydrogenated cyclopentenone 14 to afford chiral cyclopentanol (1R,2S,5R)-16,[15] which was then oxidized to ketone (1R,2R)-13 in 85 % yield with > 99 % ee. Alkylation of (1R,2R)-13 with 2-(3’-methoxyphenyl)ethyl iodide afforded C-alkylation product 17 a in 65 % yield, along with a 20 % yield of the undesired O-alkylation product (17 b), which could be converted into (1R,2R)-13 in 85 % yield by treatment with concentrated HCl. Treatment of 17 a with methanesulfonic acid at 0 8C resulted in an intramolecular Friedel–Crafts reaction that provided tricyclic compound 18 in 91 % yield. Compound 18 was hydrogenated over Pd/C to afford transfused tricyclic ester 12 in 99 % yield. Subsequently, we studied the conversion of ester 12 to tricyclic ketone 11, which has five contiguous stereocenters, and we then completed the synthesis of 13-epi-mulinolic acid ethyl ester (10) (Scheme 3). Under Birch reduction conditions,[20] ester 12 was transformed to the corresponding diene, which was then treated with concentrated HCl to generate tricyclic enone 20 (80 % yield). Conjugate methylation of enone 20 with lithium dimethylcuprate (Me2CuLi) generated in situ yielded ketone 11 in 85 % yield. Selective bromination at the C12 of ketone 11 with trimethyl(phenyl)ammonium perbromide (PTAB) gave a-bromo ketone 21 in 97 % yield. The structure and absolute configuration of 21 were determined by X-ray crystallography. Regiospecific ring expansion of 21 with (trimethylsilyl)diazomethane and subsequent treatment with pyridinium 4-toluenesulfonate (PPTS) afforded ketone 22 in 85 % yield. DBU-promoted elimination of HBr and methylation of the ketone with methyl lithium in
T 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
12709
Communications
Scheme 3. Asymmetric synthesis of 13-epi-mulinolic acid ethyl ester 10.
the presence of cerium chloride converted 22 into 13-epimulinolic acid ethyl ester (10) in 71 % yield (over two steps). In this way, we accomplished the asymmetric synthesis of an advanced “biogenic precursor” on a gram scale in 20 % overall yield from cyclopentenone 14 via 11 steps. With 10 in hand, we turned our attention to the asymmetric total synthesis of mulinane diterpenoids via late-stage functional modification or functionalization (Scheme 4). After testing various conditions for hydrolysis of hindered esters, we found that ester 10 could be converted to the corresponding acid, 13-epi-mulinolic acid (3),[21] in 92 % yield by reaction with a large excess of potassium tertbutoxide in dimethyl sulfoxide at 95 8C.[22] The structure and absolute configuration of 3 were determined by X-ray
Angewandte
Chemie
crystallography. Dehydration of 3 in benzene in the presence of catalytic TsOH afforded mulin-11,13-dien-20-oic acid (4)[23] in 90 % yield. Mulinane diterpenoid 4 was then converted to mulinic acid (5)[2a] in 65 % yield via photooxidation (300 W mercury lamp) with tetraphenylporphyrin (TPP, 1 mol %) as a photosensitizer at room temperature according to AdamsQs method.[24] Isomerization of 5 with NoyoriQs rutheniumcatalyzed procedure[25] gave isomulinic acid (6)[2a] in 80 % yield. Furthermore, direct allylic oxidation of 4 with SeO2, followed by reduction with NaBH4, provided 16-hydroxy mulin-11,13-dien-20-oic acid (7)[26] in 91 % yield. Furthermore, direct reduction of the ester group of 10 with LiAlH4 yielded 13-epi-mulinol (8) in 85 % yield. Subsequently, TsOHcatalyzed dehydration of 8 afforded mulin-11,13-dien-20-ol (9)[5b] in 88 % yield. Acetylation of the C20 hydroxy group of 9 yielded 20-hydroxy mulin-11,13-dienyl acetate (24),[27] which is also a naturally occurring mulinane diterpenoid. Thus, we completed the synthesis of seven mulinane diterpenoids from advanced “biogenic precursor” 10. In conclusion, we achieved divergent enantioselective total syntheses of seven mulinane diterpenoids, namely, 13epi-mulinolic acid (3, 12 steps, 18 % overall yield), mulin11,13-dien-20-oic acid (4, 13 steps, 17 % yield), mulinic acid (5, 14 steps, 11 % yield), isomulinic acid (6, 15 steps, 8.6 % yield), 16-hydroxy mulin-11,13-dien-20-oic acid (7, 14 steps, 15 % yield), mulin-11,13-dien-20-ol (9, 13 steps, 15 % yield), and 20-hydroxy mulin-11,13-dienyl acetate (24, 14 steps, 14 % yield), along with two analogues, namely, 13-epi-mulinol (8, 12 steps, 17 % yield) and 13-epi-mulinolic acid ethyl ester (10, 11 steps, 20 % yield), from readily available cyclopentenone 14. Our synthetic strategy involved an iridium-catalyzed asymmetric enone hydrogenation to obtain the chiral starting material, an intramolecular Friedel–Crafts reaction to construct the chiral fused 5-6-6 tricyclic structure, a Birch reduction combined with conjugate methylation to set up the C8-methylated quaternary stereocenter, a homologation/ ring-expansion reaction to furnish the trans,cis-fused 5-6-7 tricyclic ring system, and late-stage functional modification or functionalization to complete the divergent enantioselective syntheses. This work represents the first example of asymmetric syntheses of mulinane diterpenoids and provides an efficient approach to the mulinane diterpenoids as well as to other types of 5-6-7 tricyclic diterpenoids and their analogues.
Acknowledgements We thank the National Natural Science Foundation of China (No. 21325207, 21532003, and 21421062), and the “111” project (B06005) of the Ministry of Education of China for financial support.
Conflict of interest The authors declare no conflict of interest. Scheme 4. Asymmetric synthesis of mulinane diterpenoids via latestage functional modification or functionalization.
12710
www.angewandte.org
T 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 12708 –12711
Angewandte
Communications Keywords: asymmetric synthesis · diterpenoids · mulinane · natural products · total synthesis How to cite: Angew. Chem. Int. Ed. 2017, 56, 12708 – 12711 Angew. Chem. 2017, 129, 12882 – 12885 [1] For reviews, see: a) T. J. Maimone, P. S. Baran, Nat. Chem. Biol. 2007, 3, 396 – 407; b) M. Bgschleb, S. Dorich, S. Hanessian, D. Tao, K. B. Schenthal, L. E. Overman, Angew. Chem. Int. Ed. 2016, 55, 4156 – 4186; Angew. Chem. 2016, 128, 4226 – 4258. [2] a) L. A. Loyola, G. Morales, B. Rodriguez, J. Jimenez-Barbero, M. C. de la Torre, A. Perales, M. R. Torres, Tetrahedron 1990, 46, 5413 – 5420; b) L. A. Loyola, G. Morales, M. C. de la Torre, B. Rodriguez, Phytochemistry 1990, 29, 3950 – 3951. [3] I. S. Marcos, R. F. Moro, A. Gil-Mesln, D. D&ez in Studies in natural products chemistry, Vol. 48 (Ed.: Atta-ur-Rahman), Elsevier, Amsterdam, 2016, pp. 137 – 207. [4] F. Salgado, C. Areche, B. Sepffllveda, M. J. Simirgiotis, F. C#ceres, C. Quispe, L. Quispe, T. Cano, Pharmacogn. Mag. 2014, 10, 543 – 548. [5] a) C. Areche, B. Sepffllveda, A. S. Martin, O. Garc&a-Beltr#n, M. Simirgiotis, A. CaÇete, Bioorg. Med. Chem. 2014, 12, 6406 – 6413; b) C. Areche, F. Rojas-Alvarez, C. Campos-Briones, C. Lima, E. G. P8rez, B. Sepffllveda, J. Pharm. Pharmacol. 2013, 65, 1231 – 1238. [6] a) G. A. W-chter, S. G. Franzblau, G. Montenegro, E. Suarez, R. H. Fortunato, J. Nat. Prod. 1998, 61, 965 – 968; b) G. M. Molina-Salinas, J. Blrquez, S. Said-Fern#ndez, L. A. Loyola, A. Yam-Puc, P. Becerril-Montes, F. Escalante-Erosa, L. M. PeÇaRodr&guez, Fitoterapia 2010, 81, 219 – 222. [7] L. A. Loyola, J. Blrquez, G. Morales, A. San-Mart&n, J. Darias, N. Flores, A. Gim8nez, Phytochemistry 2004, 65, 1931 – 1935. [8] G. A. W-chter, G. Matooq, J. J. Hoffmann, W. M. Maiese, M. P. Singh, G. Montenegro, B. N. Timmermann, J. Nat. Prod. 1999, 62, 1319 – 1321. [9] a) G. M. Molina-Salinas, J. Blrquez, A. Ardiles, S. Said-Fern#ndez, L. A. Loyola, A. San-Mart&n, I. Gonz#lez-Collado, L. M. PeÇa-Rodr&guez, Fitoterapia 2010, 81, 50 – 54; b) G. M. MolinaSalinas, J. Blrquez, A. Ardiles, S. Said-Fern#ndez, L. A. Loyola, A. Yam-Puc, P. Becerril-Montes, F. Escalante-Erosa, A. SanMart&n, I. Gonz#lez-Collado, L. M. PeÇa-Rodr&guez, Phytochem. Rev. 2010, 9, 271 – 278. [10] B. Sepffllveda, C. Quispe, M. Simirgiotis, O. Garc&a-Beltr#n, C. Areche, Bioorg. Med. Chem. Lett. 2016, 26, 3220 – 3222. [11] The cyathane diterpenoids generally possess a fused 5-6-7 tricyclic core system with 1,4-anti-quaternary carbon centers at the ring junctures and a trans-fused 6-7 ring, and have received intensive synthetic study over the past decades. For reviews, see: a) D. L. Wright, C. R. Whitehead, Org. Prep. Proced. Int. 2000, 32, 307 – 330; b) J. J. A. Enquist, Jr., B. M. Stoltz, Nat. Prod. Rep. 2009, 26, 661 – 680; c) M. Nakada, Chem. Rec. 2014, 14, 641 – 662; For selected recent papers, see: d) S. P. Waters, Y. Tian, Y.M. Li, S. J. Danishefsky, J. Am. Chem. Soc. 2005, 127, 13514 – 13515; e) M. W. B. Pfeiffer, A. J. Phillips, J. Am. Chem. Soc. 2005, 127, 5334 – 5335; f) B. M. Trost, L. Dong, G. M. Schroeder, J. Am. Chem. Soc. 2005, 127, 2844 – 2845; g) B. M. Trost, L. Dong, G. M. Schroeder, J. Am. Chem. Soc. 2005, 127, 10259 – 10268; h) E. DrHge, C. Tominaux, G. Morgant, D. Desma]le, Eur. J. Org. Chem. 2006, 4825 – 4840; i) H. Watanabe, M. Takano, A. Umino, T. Ito, H. Ishikawa, M. Nakada, Org. Lett. 2007, 9, 359 – 362; j) J. A. Enquist, Jr., B. M. Stoltz, Nature 2008, 453, 1228 – 1231; k) K. Kim, J. K. Cha, Angew. Chem. Int. Ed. 2009, 48, 5334 – 5336; Angew. Chem. 2009, 121, 5438 – 5440; l) N. Kanoh, K. Sakanishi, E. Iimori, K. Nishimura, Y. Iwabuchi, Org. Lett. 2011, 13, 2864 – 2867; m) E. Elamparuthi, C. Fellay, M.
Angew. Chem. Int. Ed. 2017, 56, 12708 –12711
[12] [13] [14]
[15] [16] [17] [18]
[19]
[20] [21] [22] [23] [24] [25] [26] [27]
Chemie
Neuburger, K. Gademann, Angew. Chem. Int. Ed. 2012, 51, 4071 – 4073; Angew. Chem. 2012, 124, 4147 – 4149; n) Y. Kobayakawa, M. Nakada, Angew. Chem. Int. Ed. 2013, 52, 7569 – 7573; Angew. Chem. 2013, 125, 7717 – 7721; o) C. Wang, D. Wang, S.-H. Gao, Org. Lett. 2013, 15, 4402 – 4405; p) K. E. Kim, B. M. Stoltz, Org. Lett. 2016, 18, 5720 – 5723. K. P. Reber, J. Xu, C. A. Guerrero, J. Org. Chem. 2015, 80, 2397 – 2406. The construction of the fused 5-6-7 tricyclic core structures of cyathane diterpenoids also led to lengthier synthetic routes in some cases; see Refs. [3, 11a,b]. For reviews, see: a) J.-H. Xie, Q.-L. Zhou, Aldrichimica Acta 2015, 48, 33 – 40; For selected recent papers, see: b) J.-Q. Chen, J.-H. Xie, D.-H. Bao, S. Liu, Q.-L. Zhou, Org. Lett. 2012, 14, 2714 – 2717; c) C. Liu, J.-H. Xie, Y.-L. Li, J.-Q. Chen, Q.-L. Zhou, Angew. Chem. Int. Ed. 2013, 52, 593 – 596; Angew. Chem. 2013, 125, 621 – 624; d) H. Lin, L.-J. Xiao, M.-J. Zhou, H.-M. Yu, J.-H. Xie, Q.-L. Zhou, Org. Lett. 2016, 18, 1434 – 1437; e) Y. Liu, L.-J. Cheng, H.-T. Yue, W. Che, J.-H. Xie, Q.-L. Zhou, Chem. Sci. 2016, 7, 4725 – 4729; f) L.-Y. Pu, J.-Q. Chen, M.-L. Li, Y. Li, J.-H. Xie, Q.-L. Zhou, Adv. Synth. Catal. 2016, 358, 1229 – 1240; g) X.D. Zuo, S.-M. Guo, R. Yang, J.-H. Xie, Q.-L. Zhou, Chem. Sci. 2017, 8, 6202 – 6206. Y.-T. Liu, J.-Q. Chen, L.-P. Li, X.-Y. Shao, J.-H. Xie, Q.-L. Zhou, Org. Lett. 2017, 19, 3231 – 3234. A. Radha Krishna Murthy, G. S. R. S. Rao, Tetrahedron 1982, 38, 3335 – 3338. V. Dave, E. W. Warnhoff, J. Org. Chem. 1983, 48, 2590 – 2598. 3-Isopropyl-2-(ethoxycarbonyl)cyclopentenone (14) can be synthesized on a gram scale from commercially available 5-methyl4-oxohexanoic acid in 65 % overall yield via two steps according to our previous reported method, see Ref. [15] and Supporting Information. a) J.-H. Xie, X.-Y. Liu, J.-B. Xie, L.-X. Wang, Q.-L. Zhou, Angew. Chem. Int. Ed. 2011, 50, 7329 – 7332; Angew. Chem. 2011, 123, 7467 – 7470; b) J.-H. Xie, X.-Y. Liu, X.-H. Yang, J.-B. Xie, L.-X. Wang, Q.-L. Zhou, Angew. Chem. Int. Ed. 2012, 51, 201 – 203; Angew. Chem. 2012, 124, 205 – 207; c) X.-H. Yang, J.H. Xie, Q.-L. Zhou, Org. Chem. Front. 2014, 1, 190 – 193; d) J.-H. Xie, Q.-L. Zhou, Acta Chim. Sin. 2014, 72, 778 – 797. a) A. L. Wilds, N. A. Nelson, J. Am. Chem. Soc. 1953, 75, 5360 – 5365; b) H. Pellissier, M. Santelli, Org. Prep. Proced. Int. 2002, 34, 609 – 642. L. A. Loyola, J. Borquez, G. Morales, A. San-Martin, Phytochemistry 2000, 53, 961 – 963. a) F. C. Chang, N. F. Wood, Tetrahedron Lett. 1964, 9, 2969 – 2973; b) W. L. Meyer, R. A. Manning, E. Schindler, R. S. Schroeder, D. C. Shew, J. Org. Chem. 1976, 41, 1005 – 1015. L. A. Loyola, J. Borquez, G. Morales, A. San-Martin, Phytochemistry 1997, 44, 649 – 651. W. Adams, O. Cueto, O. DeLucchi, K. Peters, E. Peters, H. G. Von Schnering, J. Am. Chem. Soc. 1981, 103, 5822 – 5828. M. Suzuki, H. Ohtake, Y. Kameya, N. Hamanaka, R. Noyori, J. Org. Chem. 1989, 54, 5292 – 5302. C. Areche, L. A. Loyola, J. Borquez, J. Rovirosa, A. San-Martin, Magn. Reson. Chem. 2008, 46, 765 – 768. The sign of the optical rotation of the synthetic 24 ([a] = @178.6 (c = 0.168, CHCl3)) was found to be opposite to that of natural 24 ([a] =+ 89.28 (c = 0.168, CHCl3)), with the magnitude being approximately two times greater; see Ref. [7].
Manuscript received: July 10, 2017 Accepted manuscript online: August 13, 2017 Version of record online: September 1, 2017
T 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
12711
