Abstract
Increasing effort has been made towards the asymmetric total synthesis of rotenoid natural products owing to their impressive biological and pharmaceutical activities. Here we report the modular asymmetric total synthesis of rotenoid natural products. The concise construction of the cis-fused tetrahydrochromeno[3,4-b]chromene core structure of rotenoids through N-heterocyclic carbene-catalyzed dynamic kinetic resolution is achieved, and a series of annulation products containing rotenoid key structures are rapidly assembled using this method. More importantly, the protocol enables the modular synthesis of a variety of rotenoid natural products in a highly convergent fashion, and the concise asymmetric total synthesis of tephrosin, the first asymmetric total synthesis of 12a-hydroxymunduserone, milletosin, and 12a-hydroxyrotenone, and the formal synthesis of deguelin are accomplished.
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Introduction
Rotenoids are an important class of natural products isolated from Derris and Lonchocarpus species and include a large amount of naturally occurred and structurally related compounds1,2,3. A cis-fused tetrahydrochromeno[3,4-b]chromene core (B and C rings) is featured by quite a lot of rotenoid compounds (Fig. 1), and a variety of biological and pharmacological properties including antibacterial, antiviral, antifungal, anticancer, antiplasmodial, anti-inflammatory, and insecticidal activities have been disclosed4,5,6,7,8,9,10. Particularly, 12a-hydroxymunduserone (1a) shows efficient antitumor activity for HepG2 proliferation11; tephrosin (1b) and deguelin (1e) are potent apoptotic and antiangiogenic reagents against various human cancer cells, such as lung, prostate, head and neck, and stomach cancer cells12,13,14,15; retenone (1f) and 12a-hydroxyrotenone (1d) have impressive inhibitory effect on breast cancer and lung cancer16,17; tephrosin (1b), milletosin (1c), and rotenone (1f) are also important pesticides18,19.
Selected rotenoid natural products with cis-fused core structures. The blue color indicates the same core structure of many rotenoid natural products, and the red atoms show the different substituents of the core structure
Owing to the limited availability of these substances using the isolation method from the corresponding plants, chemical total synthesis of rotenoids has drawn long-term attention from both chemical and medicinal communities. However, to date most of the known reports are semi, formal, and racemic synthesis20,21,22,23,24,25,26,27, and the successful methods of asymmetric total synthesis are still less developed. In this context, the Suh group reported a 12-step enantioselective total synthesis of deguelin (1e) using an iterative pyran-ring formation approach as the key step, and the overall yield of the target was 10.5% (Fig. 2a)28. Recently an elegant six-step (longest linear) synthesis of deguelin (1e) was achieved by the Scheidt group through a chiral thiourea-catalyzed cyclization strategy, and this represents the shortest route of deguelin synthesis (Fig. 2a)29. Starting from resorcine, de Konig and co-workers realized the total synthesis of rotenone (1f) in 2% total yield via 17 steps, and an alkyne-aldehyde coupling, a six-endo hydroarylation, and a Michael addition completed the key ring construction process (Fig. 2a)30. In contrast, the asymmetric total synthesis of hydroxyl group-substituted rotenoids, such as 12a-hydroxymunduserone (1a), tephrosin (1b), milletosin (1c), and 12a-hydroxyrotenone (1d), has been less achieved31. The report from the Winssinger group used chiral epoxide as starting material to produce the final target tephrosin (1b) in 7% yield via five key retro-synthetic steps and seven longest linear steps (Fig. 2a); noteworthy in this report is that deguelin (1e) could also be obtained via one more dehydroxylation step from tephrosin (1b)32. To the best of our knowledge, the enantioselective total synthesis of 12a-hydroxymunduserone (1a), milletosin (1c), 12a-hydroxyrotenone (1d), 1g, and 12a-hydroxyisomillettone (1h) has not been accomplished (Fig. 1).
Selected known synthetic routes and our synthetic plan. a Selected asymmetric total syntheses of rotenoid natural products. b Our two-step key retro-synthetic plan. c Modular synthesis of rotenoid natural products
Here we describe a synthetic plan that can not only lead to the concise synthesis of a specific rotenoid natural product, but also can be used as a general approach to rapidly produce a large amount of compounds that belong to rotenoid family. A careful evaluation of the structure of 1a−1f and other rotenoid compounds reveals that, besides the core bicyclic ring structure (B and C rings), in many cases, they share the same substituted A ring and D ring. For instance, the methoxy-substituted D ring of 1a also exists in 1g; a cyclohexenyl ether structure is found in 1b, 1c, and 1e; moreover, a chiral benzocyclopentane unit appears in 1d, 1f, and 1h. On the other side, two methoxy groups at A ring exist in 1a, 1b, 1d, 1e, and 1f; a 1,3-dioxolane moiety occurs in 1c, 1h, and 1g (Fig. 1). These features lead us to the idea that if these natural products can be divided into two pieces (modules), the combination of different pieces will lead to different natural products, thus simplifying the total synthesis of rotenoid family natural products. To make the plan possible, a two-step key retrosynthesis route is proposed and shown in Fig. 2b. The route features first the dynamic kinetic resolution (DKR)-mediated C-C bond formation via asymmetric benzoin reaction, a powerful transformation pioneered by Enders and Suzuki33,34,35,36,37,38,39,40,41,42,43, and then the forge of C-O bond via an SN2 reaction. This plan leads to two units of acetal/aldehyde modules (i.e., A1, A2, and A3) and ketone modules (i.e., B1 and B2) (Fig. 2c). Then as mentioned above, the combination of A1 and B1 will construct 1a (12a-hydroxymunduserone), and similarly, A2 and B1 will lead to 1b (tephrosin), A2 together with B2 will get 1c (milletosin), and so on. Furthermore, using Winssinger’s dehydration method, 1e (deguelin) can be produced from 1b, and 1f (rotenone) can be obtained from 1d. Thus, a large amount of rotenoid type natural products with cis-fused bicyclic core skeletons can be concisely and systematically synthesized using this approach.
Results
Optimization of the reaction conditions
Apparently, the efficiency and stereoselectivities of NHC-catalyzed DKR step are critical for the success of the whole research project. In recent years, the kinetic resolutions of a series of racemates have been achieved via NHC organocatalysis44,45,46,47,48. Particularly, the elegance of NHC-catalyzed DKR processes have been demonstrated by the Scheidt, Johnson, Wang, Chi, Fang, and Biju groups, respectively49,50,51,52,53,54,55,56,57,58. Therefore, to test our hypothesis, we selected racemic 2a as model substrate for further studies (Fig. 3). However, as outlined in Table 1, the optimization of reaction conditions proved a significant challenge mainly arising from the formation of a series of by-products and the enantioselectivity control of the desired benzoin product. For instance, the reaction of 3a under the catalysis of A59,60,61,62 using KOH as the base in THF afforded the desired product 3a in 54% yield with high diastereoselectivity; however, poor enantioselectivity was observed and significant amount of aldol product 3aa was obtained (Table 1, entry 1). Replacing KOH with Et3N or Na2CO3 increased the yield of 3a to an excellent level, but still with low er values (Table 1, entries 2−3). To our delight, decreasing the temperature showed beneficial effect on the reaction (Table 1, entry 4), and catalyst B59,60,61,62 led to a promising 75:25 er of 3a, albeit in a low yield (Table 1, entry 5), and in both cases the formation of 3aa could not be suppressed. Catechol type additives have proved useful for enhancing the stereoselectivities of NHC-catalyzed reactions by Rovis, Chi, and Fang’s works63,64,65,66; therefore, we tested the reaction by introducing additive a1. We were pleased to find that the annulation product 3a was obtained in excellent 90% yield with 83:17 er (Table 1, entry 6). Additive a2 also displayed promotion effect on the results (Table 1, entry 7). Slight promotions of the enantioselectivity were also observed when a3 or a4 was used (78:22 er, 22% yield for a3, and 76:24 er, 44% yield for a4, respectively). Then we found that the use of both a1 and a2 resulted in the formation of 3a with good 90.5:9.5 er, together with small amount of the aldol product (Table 1, entry 8). Under the same conditions, we then surveyed catalysts A, C, D, E, and F59, but unfortunately, no better results were detected (Table 1, entries 9−13). Gladly, we found that the addition of the third additive a3 or a4 and simultaneously increasing the amount of the base could slightly increase the enantioselectivity of the reaction, although one more side product 3ab, formed probably via the dihydroxylation from 3a, was also detected (Table 1, entries 14−15); therefore, we checked the reaction using additives a1−a4, and 93.5:6.5 er of 3a was obtained (Table 1, entry 16). Although the exact role of catechol type additives remains unambiguous, we believe that the hydrogen-bonding network between the OH groups of catechol type additives, the carbonyl groups of substrates, and the OH groups of Breslow intermediates plays a vital role in enhancing the stereoselectivity of the reaction63,64,65,66. Variation of the solvent using toluene proved not beneficial to the reaction (Table 1, entry 17), but CH3CN allowed access to 3a with excellent 95:5 er in 60% yield (Table 1, etnry 18). Under these conditions, using Et3N instead of KOH further increased the enantioselectivity of the reaction, but 3a was isolated in only 30% yield (Table 1, entry 19). To our delight, the use of Cs2CO3 allowed the formation of 3a in good 73% yield with excellent 97:3 er (Table 1, entry 20). Further conditions screening did not lead to better results and therefore the conditions listed in entry 20 (Table 1) were set as the optimal ones.
Model system used for reaction optimization. Conditions used for optimization of the catalyst, base, additive, solvent, and temperature can be found in Table 1
Synthesis of rotenoid analogues via dynamic kinetic resolution
Having found the suitable conditions for our plan using the model reaction, we then further evaluated the substrate scope and limitation of this NHC-catalyzed DKR process to evaluate the synthetic potential of producing rotenoid analogues. Pleasingly, different substituents and substitution patterns on the both aryl rings having electron-withdrawing and electron-donating groups were all tolerated (Fig. 4). For instance, introduction of electron-withdrawing Cl, Br, or F group into the formyl aryl units of substrates showed little effect on the outcomes, delivering the corresponding products in good yields with up to 94.5:5.5 er (Figs. 4, 3 b–d). Similarly, substrates equipped with electron-donating Me or OMe group at the aromatic aldehyde moieties performed well, allowing access to 3e and 3f with 91:9 and 96:4 er, respectively (Figs. 4, 3 e, f). Substrate diversity was further evaluated by the installation of substituents into both formyl aryl rings and aromatic ketones. To our delight, when R1 was electron-donating Me and R2 was electron-withdrawing Cl group, the reaction occurred smoothly, with 3k obtained in 77% yield with 94:6 er (Figs. 4, 3 k). Moreover, the combinations of electron-withdrawing R1 such as Cl or Br with electron-donating R2 such as OMe were also tolerated under the optimal conditions, with good er values gotten for 3l and 3m (Figs. 4, 3 l, m). Finally, dimethyl-substituted substrate 2n was also tested, and the corresponding product 3n was formed in 71% yield with 93.5:6.5 er (Figs. 4, 3 n). The absolute configuration of the annulation products was determined via the X-ray single crystal structure analysis of 3b (Supplementary Data 1 and Supplementary Table 1), and the cis-fused bicyclic ring skeleton was unambiguously confirmed.
Substrate scope. Reaction conditions: 2 (0.1 mmol), NHC (20 mol%), Cs2CO3 (1.5 equiv), a1 (0.5 equiv), a2 (0.5 equiv), a3 (0.5 equiv), a4 (0.5 equiv), CH3CN (1 mL), argon protection
Synthesis of related natural products via dynamic kinetic resolution
Having successfully developed a protocol for the rapid asymmetric construction of the rotenoid core structure and evaluated the generality of this method, we then commenced to test its power in the modular total synthesis of related natural products. 12a-Hydroxymunduserone (1a), tephrosin (1b), milletosin (1c), and 12a-hydroxyrotenone (1d) were selected for further investigation. As has been demonstrated in Fig. 2c, these natural products can be derived from three aldehyde modules (A1, A2, and A3) and two ketone modules (B1 and B2). So at the first stage we need to get all modules ready for the synthesis of the final natural products. As listed in Fig. 5a, A1 could be easily obtained via one-step protection from commercially available 2-hydroxy-4-methoxybenzaldehyde in quantitative yield. Furthermore, A2 was synthesized from 2,4-dihydroxybenzaldehyde via a two-step method (Fig. 5b). To simplify the synthesis of A3, we envisioned the making of A3 in its racemic form, and the later DKR process would produce the corresponding chiral natural product 1d in a stereodivergent fashion together with its epimer. Thus, the bromination of isoprene led to dibromide 5, and the following annulation with 1,3-cyclohexadione afforded cyclic enone 6. Reaction of 6 with ethyl formate with the assistance of microwave and the subsequent oxidation delivered hydroxybenzaldehyde 8. Then after protection A3 was gotten in 33% total yield (Fig. 5c).
Synthesis of aldehyde modules and ketone modules. a Synthesis of module A1. b Synthesis of module A2. c Synthesis of module A3. d Synthesis of module B1. e Synthesis of module B2
Then the second stage is to make ketone modules B1 and B2. Starting from 3,4-dimethoxyphenol, acid 9 was formed in 76% yield via substitution. Then the PPA-catalyzed Friedel-Crafts reaction afforded ketone 10, and after α-hydroxylation, 11 was generated. Protection of 11 using Tf2O provided B1 in 89% yield (Fig. 5d). Using the similar method, module B2 could also be furnished in 48% total yield from sesamol (Fig. 5e).
Having gotten all modules in hand, we could carry out the final stage to make natural products 1a−1d. To our delight, and as illustrated in Fig. 6a, the SN2 reaction between A1 and B1 allowed the smooth conjunction of two modules through C-O bond formation, then after deprotection, rac-15 was liberated. The NHC-catalyzed intramolecular annulation of rac-15 under the standard conditions proceeded smoothly, affording natural product 12a-Hydroxymunduserone (1a) in 58% isolated yield with 95.5:4.5 er (7 linear steps, 21% overall yield). Subsequently, the final total synthesis of tephrosin (1b) was achieved through the combination of A2 and B1, followed by the DKR-mediated annulation under slightly modified conditions (86.5:13.5 er, seven linear steps, 28% overall yield) (Fig. 6b). Similarly, the merger of A2 and B2 produced rac-17, which could undergo smooth C−C bond formation to release milletosin (1c) in 60% yield with 94.5:5.5 er (eight linear steps, 24% overall yield) (Fig. 6c). To our pleasure, 12a-hydroxyrotenone (1d) could also be obtained using this modular synthetic method with 99:1 er (8 linear steps, 10% overall yield), together with its separable epimer (Fig. 6d). We found that recrystallization could be used to further increase the er values of the products (Fig. 6b, c). It’s also worthwhile to mention that using Winssinger’s dehydroxylation method32, the formal synthesis of 1e (deguelin) could also be realized from 1b. Compared to the prior arts of rotenoid asymmetric total synthesis28,29,30,31,32, this strategy can achieve the target molecules using comparable or less steps, and can dramatically improve the total yields of the corresponding natural products. More importantly, this method could render the modular synthesis of a variety of rotenoid natural products using a systematic approach, which will absolutely improve the efficiency of producing these biologically important substances and assist the related medicinal research.
Total synthesis of rotenoid nature products. a Synthesis of 12a-hydroxymunduserone (1a). b Synthesis of tephrosin (1b). c Synthesis of milletosin (1c). d Synthesis of 12a-hydroxyrotenone (1d)
Discussion
In summary, we have successfully developed an N-heterocyclic carbene-catalyzed dynamic kinetic resolution process to achieve the rapid construction of rotenoid cis-fused tetrahydrochromeno[3,4-b]chromene core structures, and the method was proved compatible to a series of substituents with different electronic properties. More importantly, this protocol could enable the production of various rotenoid natural products via a systematic and modular approach. Using this strategy, we accomplished the concise total synthsis of tephrosin, the first enantioselective total synthesis of 12a-hydroxymunduserone, milletosin, and 12a-hydroxyrotenone, and the formal synthesis of deguelin.
Methods
Typical procedure for the preparation of substrate
See Supplementary Methods and Supplementary Figure 1.
Typical procedure for the benzoin reaction
See Supplementary Methods and Supplementary Figure 2.
Total synthesis of natural product 12a-hydroxymunduserone (1a)
See Supplementary Methods, Supplementary Figure 3 and Supplementary Table 2.
Total synthesis of natural product tephrosin (1b)
See Supplementary Methods, Supplementary Figures 4–6 and Supplementary Table 3.
Total synthesis of natural product milletosin (1c)
See Supplementary Methods, Supplementary Figures 7–9 and Supplementary Table 4.
Total synthesis of natural product 12a-hydroxyrotenone (1d)
See Supplementary Methods, Supplementary Figures 10–12 and Supplementary Table 5.
1H NMR and 13C NMR spectra of substrates and products
See Supplementary Figures 13–40.
HPLC spectra of products
See Supplementary Figures 41–54.
1H NMR and 13C NMR spectra of synthetic natural products
See Supplementary Figures 55–71.
HPLC spectra of synthetic natural products
See Supplementary Figures 71–77.
Crystallography
The CIF for compound 3b is available in Supplementary Data 1. Crystal data and structure refinement are shown in Supplementary Table 1.
Data availability
Data for the crystal structures reported in this paper have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under the deposition numbers CCDC 1819861. Copies of these data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif. All other data supporting the findings of this study, including compound characterization, are available within the paper and its Supplementary Information files, or from the corresponding authors on request.
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Acknowledgements
This work was supported by National Natural Science Foundation of China (21871260, 21502192, 21402199), the strategic priority research program of the Chinese Academy of Sciences (XDB20000000), and China Postdoctoral Science Foundation (2018M630734).
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X.F. designed the experiment. S.P. conducted most of the experiments. X.F. and S.Y. wrote the manuscript. S.P. and S.Y. prepared the Supplementary Information. M.M. tested the single crystal structure. G.Z. helped in catalyst synthesis. W.X. and S.Y. contributed to discussions.
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Perveen, S., Yang, S., Meng, M. et al. Asymmetric total synthesis of rotenoids via organocatalyzed dynamic kinetic resolution. Commun Chem 2, 8 (2019). https://doi.org/10.1038/s42004-019-0110-y
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DOI: https://doi.org/10.1038/s42004-019-0110-y
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