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Total Synthesis of Septedine and 7‑Deoxyseptedine Shupeng Zhou,† Rui Guo,† Peng Yang, and Ang Li* State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China

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a concise approach to dihydronavirine, the formal imine reduction product of navirine (1), featuring a gallium-catalyzed cycloisomerization reaction and a Michael/aldol sequence.8a,b Baran and colleagues established a connection between entkaurane diterpenoids and atisine/hetidine type alkaloids, which led to an elegant synthesis of the hetidine skeleton highlighted by a position-selective C−H iodination reaction and an cascade sequence involving azomethine ylide isomerization and Mannich cyclization.3j The Qin group exploited an aza-Prins strategy to effect a bioinspired transformation from an atisine type precursor to the hetidine scaffold.3l,8c Very recently, Ma and Liu disclosed an efficient synthesis of the proposed structure of navirine C featuring a hydrogen atom transfer (HAT) based radical cyclization reaction.3m Septedine (2) is an oxygenated hetidine type alkaloid isolated by Usmanova et al. from Aconitum sepentrionale, the structure of which was determined by X-ray crystallographic analysis.9 Herein, we report the first and asymmetric total synthesis of 2 as well as its 7-deoxy analogue 3. Inspired by our experience with taiwaniaquinoids10 and taiwaniadducts,11 we recognized that the “upper layer” of 2 (Figure 2; highlighted in red) may arise from an abietatriene type precursor12 that could be prepared by using iridiumcatalyzed asymmetric polyene cyclization developed by Carreira and co-workers.13 The “lower layer” (Figure 2; highlighted in blue) was expected to be constructed through Diels−Alder cycloaddition and N,O-ketalization. Functionalized C20 would serve as a key junction of the two “layers”. With these thoughts in mind, we undertook a retrosynthetic analysis of 2 (Figure 2). Disassembly of the oxazolidinopiperidine gave ketoaldehyde 4 as an immediate precursor. Reductive amination of the aldehyde needed to be carefully controlled to prevent the formation of a tertiary amine through over-reduction. Taking advantage of the C15 carbonyl, we may introduce the C7 hydroxy group through directed C−H oxidation.14 Therefore, 4 was traced back to a simplified pentacycle 5. Notably, there were few precedents of oxime directed secondary Csp3−H oxidation using the Baldwin15 or Sanford16 protocol in natural product synthesis, in contrast to various examples of methyl C− H oxidation17 including our recent application in the oridamycin B synthesis.18 Thus, the position selectivity (C7 vs C17) was a concern to us. On the other hand, Schönecker oxidation19 has recently emerged as a powerful method for secondary C−H oxidation.20,21 However, preparation of the 2picolylimine from the sterically hindered ketone precursor

ABSTRACT: Septedine (2) is a hetidine type C20diterpenoid alkaloid bearing an oxygenated heptacyclic scaffold. We have accomplished the first and asymmetric total synthesis of 2 and its 7-deoxy analogue 3. A functionalized tricyclic intermediate was prepared with excellent enantiopurity by using Carreira polyene cyclization. An unusual anionic Diels−Alder reaction was responsible for the construction of the bicyclo[2.2.2]octane. The α-methyl ketone was furnished by iridiumcatalyzed allylic alcohol isomerization. Sanford Csp3−H oxidation was exploited to install the secondary hydroxy group of 2. The oxazolidinopiperidine was assembled by selective reductive amination and spontaneous N,Oketalization at a final stage.

T

he C20-diterpenoid alkaloids are a large family of structurally intricate natural products that display diverse biological activities.1 They have attracted considerable attention from the synthesis community over decades.1b,2 A series of syntheses of members from the atisine,3 hetisine,4 denudatine,5 veatchine,6 and napelline7 subfamilies have been achieved based on the evolution of strategies for constructing fused and bridged ring systems.2b,e From a biogenetic perspective, the hetidine subfamily (Figure 1) can be viewed as a bridge between the atisine and hetisine subfamilies (Figure 1).1a However, the hetidine type alkaloids remain to be conquered by synthetic chemists, despite various efforts toward the synthesis of this subclass.8 Sarpong and co-workers developed

Figure 1. Atisine, hetidine, and hetisine skeletons and selected members (1 and 2) from the hetidine subfamily. © 2018 American Chemical Society

Received: April 6, 2018 Published: June 6, 2018 9025

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the methyl in previous studies13a,11,22) might result in less satisfactory diastereoselectivity of the Friedel−Crafts process. 8 was further traced back to readily available compound 9 and reagents 10 and 11. The synthesis commenced with the preparation of the tricyclic intermediate 7 (Scheme 1). Treatment of Weinreb amide 1223 with Grignard reagent 1324 afforded ketone 9 in 87% yield. Wittig olefination of 9 with the ylide generated from phosphonium salt 1025 and n-BuLi proceeded with good Z/E selectivity (15:1), furnishing trisubstituted alkene 14 in 82% isolated yield. This compound underwent a sequence of desilylation, oxidation, and addition of vinylMgBr (11) to give allylic alcohol 8 as a substrate for Carreira polyene cyclization. Under the standard conditions13a {[Ir(cod)Cl]2, ligand (S)-15, Zn(OTf)2, 22 °C}, we obtained an inseparable mixture of 7 and its regioisomer 16 (2.0:1) in 71% yield.26 The use of an analogous isopropoxy substrate did not improve the regioselectivity. To our delight, the MOM protecting group survived under the acidic conditions, and the Friedel−Crafts annulation turned out to be highly diastereoselective. Interestingly, we detected a small quantity of an ethyl ketone side product, presumably generated through iridium-mediated isomerization of the allylic alcohol 8.27,28 This inspired us to introduce the α-methyl ketone functionality to the bicyclo[2.2.2]octane skeleton using a similar transformation (vide inf ra). MOM deprotection with p-TsOH enabled chromatographic separation of alcohol 17 from its regioisomer. The ee of 17 (measured by HPLC) exceeded 99%. The enantioselective polyene cyclization was reliably performed on decagram scale. We then assembled the doubly bridged tricyclic motif of 2 through an intramolecular Diels−Alder reaction (Scheme 1). Birch reduction of arene 17 with Na/NH3 (l) gave a single regioisomer containing a tetrasubstituted CC bond, and subsequent ketalization in the presence of ethylene glycol and PPTS provided compound 18 in 83% overall yield. Oxidation of this primary alcohol with TPAP/NMO afforded aldehyde 19 in 91% yield, which underwent one-pot vinyllithium addition

Figure 2. Retrosynthetic analysis of septedine.

could be a challenge. The bicyclo[2.2.2]octane moiety of 5 may result from a Diels−Alder reaction; compound 6 was considered a suitable precursor. Further simplification revealed an abietatriene type intermediate 7, which could arise from aryl diene 8 through Carreira polyene cyclization. Acid lability of the MOM group was an obvious concern, and another potential problem was that the larger substituent at C10 (compared with Scheme 1. Construction of the Pentacyclic Core of Septedine

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saturation of the vinyl group (see the SI for details). We then explored the feasibility of the C7−H bond oxidation. The Schönecker approach19−21 was hindered by the failure to prepare the 2-picolylimine from 23. To our delight, condensation of 23 with NH2OMe at 80 °C afforded the corresponding oxime smoothly. However, the vinyl group was not tolerated under the Sanford C−H acetoxylation conditions.16a In contrast, an analogous substrate with an ethyl substituent at C3 performed well in this reaction.32 Thus, we masked the olefin as a cleavable epoxide and subjected compound 24 to the Sanford conditions [Pd(OAc)2, PhI(OAc)2, AcOH/Ac2O, 100 °C, 1 h]. The desired product 25 was obtained in 42% yield (33% recovery of 24) with excellent diastereoselectivity at C7. A small amount of epoxide opening side products were also detected. Exposure of 25 to H5IO6 gave compound 26 in 81% yield. Face-selective α-methylation (tBuOK/MeI)22 of the aldehyde followed by global deprotection [aq. HClO4 (6.0 M)])18 furnished ketoaldehyde 4, the structure of which was verified by X-ray crystallographic analysis (Scheme 2). The completion of the synthesis of 2 and 3 is illustrated in Scheme 3. We prepared compound 27,33 the 7-deoxy analogue

and MOM protection to furnish allylic ether 20 in 71% yield, along with its C20 epimer (14% yield). Exposure of 20 to aq. HCl led to ketal hydrolysis and CC bond migration. Thus, α,β-unsaturated enone 6 was isolated in 75% yield. Using this enone as a precursor, we investigated the Diels−Alder reaction. The silyl dienol ether and dienamine4e,f were first generated from 6. However, the anticipated intramolecular cycloaddition did not occur even at elevated temperature (see the SI). A vinyl ketone substrate was then prepared for a double Michael sequence, which should lead to a formal [4 + 2] product (see the SI). Unfortunately, this substrate decomposed under basic conditions. To our surprise, treatment of 6 with LiHMDS at 0 °C afforded the desired cycloadduct 21 in 77% yield, presumably through an unusual anionic Diels−Alder reaction.29 This interesting reactivity may further be exploited in the construction of similar bridged ring systems of other natural products; the unactivated dienophile and mild conditions would be advantageous. With 21 in hand, we directed our attention to the elaboration of the pentacyclic skeleton (Scheme 2). Compound 22 was Scheme 2. Elaboration of the Pentacyclic Core of Septedine

Scheme 3. Completion of the Synthesis of 7-Deoxyseptedine and Septedine

delivered smoothly through a sequence of MOM deprotection, Dess−Martin oxidation, and Wittig methylenation. The more hindered carbonyl was unreactive under the Wittig conditions. Chemoselective oxidation with SeO2/t-BuOOH furnished a pair of allylic alcohols (1.7:1 dr at C15), which were subjected to iridium-catalyzed isomerization.27,28 [Ir(cod)(PMePh2)2]PF630 caused substrate decomposition at elevated temperature. Crabtree catalyst (activated by H2) was found to be a suitable promoter for the isomerization;28a we obtained α-methyl ketone 23 in 68% yield, along with its C16 epimer (22% yield).31 The use of more reactive Pfaltz catalyst28a containing a BArF− counterion resulted in lowered diastereoselectivity (1.2:1 dr). Upon treatment with LiHMDS, the undesired 16-epi-23 was converted into a mixture of 23 and 16-epi-23 in a ratio of 1.5:1. Interestingly, under the heterogeneous hydrogenation conditions (H2, Pd/C), isomerization products were also observed, despite moderate C16 diastereoselectivity and

of 4, as a model substrate to investigate the reductive amination with ethanolamine (28). The use of NaBH(OAc)3 or NaBH3CN resulted in complete over-reduction to generate the undesired tertiary amine. Selective reduction of the aldehyde with NaBH4 followed by mesylation of the resultant alcohol afforded a neopentyl mesylate that, unfortunately, was resistant to nucleophilic substitution. The different reactivity of the carbonyl groups inspired us to develop a one-pot, sequential protocol to address the problem of the selective reductive amination. Condensation of 27 with 28 formed an 9027

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aldimine intermediate 29, which was observed by 1H NMR. Selective reduction of the imine with NaBH4 followed by instantaneous cyclization gave diol 30. In a neat form, 30 spontaneously underwent N,O-ketalization to render 7deoxyseptedine (3) as a single C20 diastereomer in 76% yield. The X-ray crystallographic analysis unambiously confirmed the outcome of the above sequence (Scheme 3). Similarly, compound 4 was converted into septedine (2) in 68% yield by using this protocol. The structure of 2 was corroborated by X-ray crystallographic analysis of its derivative 31 that was prepared through 3,5-dinitrobenzoylation (Scheme 3). In summary, we have accomplished the first and asymmetric total synthesis of septedine (2) and 7-deoxyseptedine (3). The recognition of the “upper layer” of the hetidine skeleton as an abietane type structure formed the strategic basis of the synthesis. The key steps included Carreira polyene cyclization, anionic Diels−Alder cycloaddition, allylic alcohol isomerization, and Sanford Csp3−H acetoxylation. An efficient sequence was developed for the late-stage construction of the oxazolidinopiperidine moiety. This work paves the way for the enantioselective synthesis of a broad range of hetidine type C20-diterpenoid alkaloids and may facilitate the biological studies of this fascinating class.



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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b03712.



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Experimental procedures and spectroscopic data of compounds, NMR spectra of compounds (PDF) CIF files (ZIP)

AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Ang Li: 0000-0002-8808-0636 Author Contributions †

S.Z. and R.G. contributed equally.

Notes

The authors declare no competing financial interest.



ACKNOWLEDGMENTS This paper is dedicated to Professor Feng-Peng Wang. We thank Prof. Dawei Ma, Dr. David Edmonds, Lianchao Liu, and Deliang Zhang for discussions, and Xiaoli Bao and Lingling Li from the Instrumental Analysis Center of Shanghai Jiao Tong University for X-ray crystallographic analysis. Financial support was provided by the National Natural Science Foundation of China (21525209, 21621002, 21772225, and 21761142003), the Chinese Academy of Sciences (Strategic Priority Research Program XDB20000000 and Key Research Program of Frontier Sciences QYZDB-SSW-SLH040), Shanghai Science and Technology Commission (15JC1400400 and 17XD1404600), the National Program for Support of Top-Notch Young Professionals of China, and the K. C. Wong Education Foundation. 9028

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Journal of the American Chemical Society Baran, P. S. Angew. Chem., Int. Ed. 2013, 52, 9019. (b) Song, L.; Zhu, G.; Liu, Y.; Liu, B.; Qin, S. J. Am. Chem. Soc. 2015, 137, 13706. (13) (a) Schafroth, M. A.; Sarlah, D.; Krautwald, S.; Carreira, E. M. J. Am. Chem. Soc. 2012, 134, 20276. (b) Jeker, O. F.; Kravina, A. G.; Carreira, E. M. Angew. Chem., Int. Ed. 2013, 52, 12166. (14) For reviews of C−H oxidation strategies in natural product synthesis, see: (a) Newhouse, T.; Baran, P. S. Angew. Chem., Int. Ed. 2011, 50, 3362. (b) Qiu, Y.; Gao, S. Nat. Prod. Rep. 2016, 33, 562. (c) Tao, P.; Jia, Y. Sci. China: Chem. 2016, 59, 1109. (15) (a) Baldwin, J. E.; Najera, C.; Yus, M. J. Chem. Soc., Chem. Commun. 1985, 126. (b) Baldwin, J. E.; Jones, R. H.; Najera, C.; Yus, M. Tetrahedron 1985, 41, 699. (16) (a) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 9542. (b) Neufeldt, S. R.; Sanford, M. S. Org. Lett. 2010, 12, 532. (17) (a) Bore, L.; Honda, T.; Gribble, G. W. J. Org. Chem. 2000, 65, 6278. (b) Zhu, C.; Tang, P.; Yu, B. J. Am. Chem. Soc. 2008, 130, 5872. (c) Siler, D. A.; Mighion, J. D.; Sorensen, E. J. Angew. Chem., Int. Ed. 2014, 53, 5332. (d) Sharpe, R. J.; Johnson, J. S. J. Am. Chem. Soc. 2015, 137, 4968. (e) Sharpe, R. J.; Johnson, J. S. J. Org. Chem. 2015, 80, 9740. (18) Meng, Z.; Yu, H.; Li, L.; Tao, W.; Chen, H.; Wan, M.; Yang, P.; Edmonds, D.; Zhong, J.; Li, A. Nat. Commun. 2015, 6, 6096. (19) Schönecker, B.; Zheldakova, T.; Liu, Y.; Kötteritzsch, M.; Günther, W.; Görls, H. Angew. Chem., Int. Ed. 2003, 42, 3240. (20) (a) Giannis, A.; Heretsch, P.; Sarli, V.; Stößel, A. Angew. Chem., Int. Ed. 2009, 48, 7911. (b) Fortner, K. C.; Kato, D.; Tanaka, Y.; Shair, M. D. J. Am. Chem. Soc. 2010, 132, 275. (21) (a) See, Y. Y.; Herrmann, A. T.; Aihara, Y.; Baran, P. S. J. Am. Chem. Soc. 2015, 137, 13776. (b) Trammell, R.; See, Y. Y.; Herrmann, A. T.; Xie, N.; Díaz, D. E.; Siegler, M. A.; Baran, P. S.; Garcia-Bosch, I. J. Org. Chem. 2017, 82, 7887. (22) Zhou, S.; Chen, H.; Luo, Y.; Zhang, W.; Li, A. Angew. Chem., Int. Ed. 2015, 54, 6878. (23) Silva, F.; Sawicki, M.; Gouverneur, V. Org. Lett. 2006, 8, 5417. (24) Tauh, P.; Fallis, A. G. J. Org. Chem. 1999, 64, 6960. (25) Corey, E. J.; Liu, K. J. Am. Chem. Soc. 1997, 119, 9929. (26) Carreira and co-workers also observed a 2:1 ratio for the para and ortho products when a meta-substituted anisole substrate was used. (27) Uma, R.; Crévisy, C.; Grée, R. Chem. Rev. 2003, 103, 27. (28) (a) Mantilli, L.; Mazet, C. Tetrahedron Lett. 2009, 50, 4141. (b) Li, H.; Mazet, C. Acc. Chem. Res. 2016, 49, 1232. (29) (a) Okamura, H.; Iwagawa, T.; Nakatani, M. Tetrahedron Lett. 1995, 36, 5939. (b) Okamura, H.; Nagaike, H.; Iwagawa, T.; Nakatani, M. Tetrahedron Lett. 2000, 41, 8317. (30) Baudry, D.; Ephritikhine, M.; Felkin, H. Nouv. J. Chim. 1978, 2, 355. (31) The dr of the allylic alcohols was inconsequential to the efficiency and diastereoselectivity of the isomerization. (32) The C−H acetoxylation reaction proceeded smoothly with another more elaborated mesylate substrate as well. See the SI for details. (33) Compound 27 was prepared from 24 through a sequence of epoxide cleavage, α-methylation of the resultant aldehyde, and hydrolysis of the oxime. See the SI for details.

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