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Total Synthesis of Securinega Alkaloids (-)-Norsecurinine, (-)Niruroidine and (-)-Flueggine A† Nan Ma†,‡,#,⊥, Yiwu Yao‡,⊥, Bing-Xin Zhao#, Ying Wang#, Wen-Cai Ye†,#,*, Sheng Jiang‡,*

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Received (in XXX, XXX) Xth XXXXXXXXX 201X, Accepted Xth XXXXXXXXX 201X First published on the web Xth XXXXXXXXX 201X DOI: 10.1039/b000000x

A consecutive synthetic strategy was developed toward the total synthesis of securinega alkaloids. (-)-Norsecurinine was concisely assembled by addition of a methoxyallene to a ketone for efficient side-chain installation. Ring-closing metathesis was also utilized as a key step. The first total synthesis of (-)-niruroidine was achieved from (-)-norsecurinine in three steps, while the route to (-)-flueggine A featured a 1,3-dipolar cycloaddition to forge the core structure. The securinega alkaloids are a small family of bridged tetracyclic natural products produced by Securinega, Phyllanthus, Flueggea and other plant genera in the Euphorbiaceae family.1 Some of these plants have been widely used for years in traditional folk medicine in China and the Amazon.2 They show intriguing biological activities, including diuretic, antipyretic, hepatoprotective and GABA receptor antagonist activities.3 Among this family of natural products, securinine (1) and (-)-norsecurinine (2) are the most representative examples (Figure 1). 4,5 Structurally, most securinega alkaloids share a bridged tetracyclic ring system that includes a benzofuranone subunit (rings C and D) and a piperidine or pyrrolidine ring (ring A), and the size of the latter ring defines the securinine and norsecurinine subgroups. Due to the unique structural features and interesting biological properties of the securinega alkaloids, these compounds have drawn significant attention from synthetic chemists, resulting in a number of innovative total syntheses.1a,6,7 Recently, (-)flueggine A (4)8 and (-)-niruroidine (3)9 were isolated from the twigs and leaves of Flueggea virosa by Ye and coworkers (Figure 1) and were found to have unprecedented skeletal structures. The unique structural features of (-)-flueggine A (4) are an isoxazolidine and the 7-oxa-1azabicyclo[3.2.1]octane ring system. Recently, Yang and Li reported the first total synthesis of (-)-flueggine A (4) using ()-norsecurinine (2) and nitrone 6 in a 1,3-dipolar cycloaddition reaction.10 However, it is highly desirable to develop a consecutive synthetic strategy that may be applied to a number of securinega alkaloid family members. To verify its feasibility, we attempted the consecutive synthesis of (-)norsecurinine (2), (-)-niruroidine (3) and (-)-flueggine A (4).

Figure 1. Representative securinega alkaloids.

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Scheme 1. A biomimetic approach to the consecutive synthesis of (-)-norsecurinine (2), (-)-niruroidine (3) and (-)-flueggine A (4).

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Because of the structural similarity of (-)-norsecurinine (2), (-)-niruroidine (3) and (-)-flueggine A (4), and the fact that all three natural products were isolated from plants of the same genus (Flueggea) we considered the possibility that (-)norsecurinine (2) may be an intermediate in the biosynthesis of these alkaloids. As shown in the biosynthetic route (scheme 1), we envisioned that the framework of (-)-niruroidine (3) could be derived from (-)-norsecurinine (2) through rearrangement of the C ring, which may occur in nature. This hypothesis could be verified by the interconversion of (-)niruroidine (3) and (-)-norsecurinine (2). (-)-Flueggine A (4) may be generated through a 1,3-dipolar cycloaddition.

Inspired by the proposed biosynthesis, we devised a ring oxidation-cycloaddition approach for the consecutive synthesis of (-)-norsecurinine (2), (-)-niruroidine (3) and (-)Journal Name, [year], [vol], 00–00 | 1

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yield. The spectral data of the synthetic (-)-niruroidine (3) were identical to those reported for the natural product. 9 50

Scheme 2. Enantioselective synthesis of (-)-norsecurinine (2) and (-)-niruroidine (3). H

O N

N

Boc 9

H

H

O Br

O

1. methoxyallene, n-BuLi,THF, TMEDA

12 N

Mg, THF, 90%

OH O

2. HCl, 70%

10 Boc O H HO

Grubbs's 2nd gen.

N 11 Boc O HO H

DCM, reflux, 96%

NBS, AIBN N CCl4, reflux, 59%

Boc 7 O

1. TFA, DCM then Et3N, DCM O ClCO2CH2CCl3 2. DCC, Reflux, DCM H O O K2CO3, CH2Cl2 OEt N P 96%, 0oC 14 N HO OEt 13 Boc Br 3. NaH, THF (-)-norsecurinine (2) 39% in 3 steps O O 1. NaI, acetone, 60oC

H O

N 2. AgOAc, AcOH 110oC O 60% overall yield O AcO 16 O O Cl3C

N

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Figure 2. Retrosynthetic analysis. Based on the above analysis, we first investigated the synthesis of (-)-norsecurinine (2), as shown in Scheme 2. Weinreb amide 9 was readily prepared from commercially available D-proline (8) via a known operation.11 Weinreb amide 9 was subjected to Grignard reaction with homoallyl magnesium bromide to afford ketone 10 in 90% yield,12 which was treated with methoxyallene13 to afford the corresponding terminal olefin 11 as a single diastereomer. Treatment of olefin 11 with Grubbs’s second generation catalyst14 in DCM furnished cyclohexene 7 in 96% yield. Cyclohexene 7 was converted into the corresponding bromide 13 in 59% yield using NBS and AIBN.15 Subsequent formation of the B ring and introduction of the butenolide unit to 7 involved a three step sequence: (i) TFA-mediated Boc deprotection followed by base-induced nucleophilic substitution, (ii) DCC-mediated acylation of the tertiary alcohol with diethylphosphonoacetic acid, and (iii) intramolecular Horner–Wadsworth–Emmons reaction to furnish (-)-norsecurinine (2).7c The spectral data (1H NMR, 13C NMR, and optical rotation) of the synthetic (-)norsecurinine (2) were consistent with those reported in the literature.5 With (-)-norsecurinine (2) in hand, our next challenge was to open the B ring and construct the framework of (-)niruroidine (3) (Scheme 2). Treatment of (-)-norsecurinine (2) with 2,2,2-trichloroethylchloroformate16 in the presence of potassium carbonate at 0 °C provided 15 in 96% yield as a single diastereomer. The structure was confirmed by X-ray crystallographic analysis.17 Substitution of the chloride with NaI at 60 °C followed by nucleophilic displacement with AgOAc in AcOH afforded intermediate 16 in 60% overall yield. Reductive cleavage of the Troc group with freshly prepared zinc dust in 80% AcOH followed by cyclization afforded the core structure 17 in 78% yield, which was saponified with NaOH to provide (-)-niruroidine (3) in 82%

O

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N OH

82% 17

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(-)-niruroidine (3)

An alternative and perhaps more convenient route has also been developed to convert (-)-norsecurinine (2) to (-)niruroidine (3) (Scheme 3). A variety of Lewis acids were tested to evaluate the nucleophilic substitution of the chloride of 15 with a hydroxy group; AgBF 4 was the most efficient promoter. Thus, treatment with AgBF 4 in acetone and water at 60 °C provided intermediate 18 in 75% yield as a single diastereomer. Following deprotection of the Troc group, compound 18 was treated with freshly prepared zinc dust in 80% AcOH, affording (-)-niruroidine (3) in 51% yield (Scheme 3). Scheme 3. An alternative synthesis of (-)-niruroidine (3).

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O Cl 15

Cl3C

H O

Interestingly, when (-)-niruroidine (3) was subjected to PPh3 and DIAD, (-)-norsecurinine (2) was obtained in 87% yield (Scheme 4). This result supports our hypothesis that this transformation occurs in nature. The proposed mechanism is illustrated in Scheme 4; the initial reaction between Ph3P and DIAD forms betaine II. (-)-Niruroidine (3) reacts with II to This journal is © The Royal Society of Chemistry [year]

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flueggine A (4) (Figure 2). (-)-Flueggine A (4) could be obtained through a 1,3-dipolar cycloaddition from (-)norsecurinine (2) and nitrone 6, which could in turn be generated from (-)-niruroidine (3) via regioselective oxidation and elimination. (-)-Niruroidine (3) could be generated from (-)-norsecurinine (2) through rearrangement of the C ring. Construction of (-)-norsecurinine (2) would require bromination-substitution and annulation of the butenolide from cyclohexenone 7, which may be prepared from inexpensive and commercially available D-proline (8).

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form the intermediate III, followed by cyclization. Subsequent β-elimination affords (-)-norsecurinine (2) with the assistance of base. Scheme 4. Transformation of (-)-niruroidine (3) into (-)norsecurinine (2), with a proposed mechanism. Proposed mech anism. O N CO2i-Pr I O H CO 2i- Pr

N

i-PrO 2C

Ph3P

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N i-Pr O2C

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PP h3 II +

O

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O

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PP h3, DIAD, THF, 87% 0oC then r.t.

OH (-)-nir uroidine (3)

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Notes and references †

N (-)-norsecur inine (2)

With both (-)-norsecurinine (2) and (-)-niruroidine (3) in hand, we were ready to construct nitrone 6 (Scheme 5). Oxidation of (-)-niruroidine (3) with Dess-Martin periodinane followed by reduction with NaBH4 furnished alcohol 20 in 46% yield over two steps. Inversion of the configuration of the hydroxyl group was confirmed by X-ray crystallographic analysis. 18 We found that 20 could be cleanly oxidized to nitrone 6 in 55% yield using Na2WO4/H2O2.19 Finally, nitrone 6 was reacted with (-)-norsecurinine (2) in refluxing toluene to provide (-)-flueggine A (4) in 66% yield through a 1,3dipolar addition (Scheme 5). The optical rotation of the synthetic product ([α] 20D -31.6 (c 0.1, MeOH)) was identical to that reported for natural (-)-flueggine A (4), -31.9 (c 0.25, MeOH). The spectroscopic data (1H NMR and 13C NMR) for the synthetic substance matched the data published for the natural product (see Supporting Information).

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Scheme 5. Enantioselective synthesis of (-)-flueggine A (4). O

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O

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0oC - r.t. , 55%

N OH O

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achieved in 9 steps in 12.5 % overall yield, whereas (-)niruroidine was synthesized in 3 steps and 37 % overall yield from (-)-norsecurinine. (-)-Niruroidine was converted into (-)flueggine A in four steps and 21% overall yield. Notably, we have demonstrated that (-)-niruroidine (3) can be transformed into (-)-norsecurinine (2) in one step, supporting our hypothesis that this transformation occurs in nature. Further application of this strategy for other members of the securinega family of alkaloids is currently under investigation. This work was supported by the Joint Fund of NSFCGuangdong Province (No. U0932004) and the National Natural Science Foundation (Grant No. 21172220 and 20972160).

O

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H

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In summary, (-)-norsecurinine, (-)-niruroidine and (-)flueggine A were synthesized enantioselectively through biomimetic approaches. Starting from commercially available D-proline (8), the total synthesis of (-)-norsecurinine was This journal is © The Royal Society of Chemistry [year]

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Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China ‡ Laboratory of Medicinal Chemistry, Guangzhou Institute of Biomedicine and Health, CAS, Guangzhou 510530, PR China # Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, PR China ⊥ These authors contributed equally. Email:[email protected]; [email protected] † Electronic Supplementary Information (ESI) available: Experimental procedures and characterization data for all new compounds described herein, including CIF files for compounds 15 and 20. See DOI: 10.1039/c000000x/ 1 (a) S. M. Weinreb, Nat. Prod. Rep., 2009, 26, 758; (b) V. Snieckus., New York: Academic Press, 1973, pp. 425-506. 2 (a) J. A. Beutler and A. N. Brubaker, Drug Future, 1987, 12, 957; (b) A. K. Nadkarni, in Indian Materia Medica; Popular Prakashan Pvt. Ltd: Bombay, 1976, vol. 1, pp. 1292. 3 (a) H. Weenen, M. H. H. Nkunya, D. H. Bray, L. B. Mwasumbi, L. S. Kinabo, V. A. E. B. Kilimali and J. B. P. A. Wijnberg, Planta Med, 1990, 56, 371; (b) E. Galvez-Ruano, M. H. Aprison, D. H. Robertson and K. B. Lipkowitz, J. Neurosci. Res., 1995, 42, 666. 4 I. Satoda, M. Murayama, J. Tsuji and E. Yoshii, Tetrahedron Lett., 1962, 3, 1199. 5 S. Saito, T. Tanaka, K. Kotera, H. Nakai, N. Sugimoto, Z. Horii, M. Ikeda and Y. Tamura, Chem. Pharm. Bull. (Tokyo), 1965, 13, 786. 6 (a) R. Alibés, M. Ballbé, F. Busqué, P. de March, L. Elias, M. Figueredo and J. Font, Org. Lett., 2004, 6, 1813; (b) G. G. Bardají, M. Cantó, R. n. Alibés, P. Bayón, F. l. Busqué, P. de March, M. Figueredo and J. Font, J. Org. Chem., 2008, 73, 7657; (c) B. Dhudshia, B. F. T. Cooper, C. L. B. Macdonald and A. N. Thadani, Chem. Commun., 2009, 463; (d) A. B. Leduc and M. A. Kerr, Angew. Chem. Int. Ed., 2008, 47, 7945. 7 (a) P. Magnus, J. Rodriguez-Lopez, K. Mulholland and I. Matthews, J. Am. Chem. Soc., 1992, 114, 382; (b) D. González-Gálvez, E. García-García, R. Alibés, P. Bayón, P. de March, M. Figueredo and J. Font, J. Org. Chem., 2009, 74, 6199; (c) G. Han, M. G. LaPorte, J. J. Folmer, K. M. Werner and S. M. Weinreb, J. Org. Chem., 2000, 65, 6293; (d) A. M. ElSohly, D. A. Wespe, T. J. Poore and S. A. Snyder, Angew. Chem. Int. Ed., 2013, 52, 5789.

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B.-X. Zhao, Y. Wang, D.-M. Zhang, R.-W. Jiang, G.-C. Wang, J.-M. Shi, X.-J. Huang, W.-M. Chen, C.-T. Che and W.-C. Ye, Org. Lett., 2011, 13, 3888. For the isolation and structural determination of (-)-niruroidine, please see the supporting information. H. Wei, C. Qiao, G. Liu, Z. Yang and C.-C. Li, Angew. Chem. Int. Ed., 2013, 52, 620. I. Moldvai, G. Dömyei, E. Temesvári-Major and C. Szántay, Org. Prep. Proced. Int., 2007, 39, 503. A. Sathish Reddy and P. Srihari, Tetrahedron Lett., 2012, 53, 5926. R. Pulz, Synlett, 2000, 2000, 1697. (a) G. C. Vougioukalakis and R. H. Grubbs, Chem. Rev., 2009, 110, 1746; (b) A. Fürstner, Angew. Chem. Int. Ed., 2000, 39, 3012. The stereochemistry of the compound 13 could not be determined at this stage. The following cyclization of allylic bromide would be assumed to precede with both SN2 and SN1-like reaction mechanisms: (a) T. Honda, H. Namiki, K. Kaneda, H. Mizutani, Org. Lett., 2004, 6, 87-89; (b) D. González-Gálvez , E. García-García , R. Alibés , P. Bayón , P. de March , M. Figueredo and J. Font, J. Org. Chem., 2009, 74, 6199–6211. P. Magnus, M. Giles, R. Bonnert, G. Johnson, L. McQuire, M. Deluca, A. Merritt, C. S. Kim and N. Vicker, J. Am. Chem. Soc., 1993, 115, 8116. The crystal data were deposited at the Cambridge Crystallographic Data Centre. The deposited number is CCDC 971441. The crystal data were deposited at the Cambridge Crystallographic Data Centre. The deposited number is CCDC 971455. S. Murahashi, H. Mitsui, T. Shiota, T. Tsuda and S. Watanabe, J. Org. Chem., 1990, 55, 1736.

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Total Synthesis of Securinega Alkaloids (-)-Norsecurinine, (-)Niruroidine and (-)-Flueggine A† Nan Ma†,‡,#,⊥, Yiwu Yao‡,⊥, Bing-Xin Zhao#, Ying Wang#, Wen-Cai Ye†,#,*, Sheng Jiang‡,*

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Received (in XXX, XXX) Xth XXXXXXXXX 201X, Accepted Xth XXXXXXXXX 201X First published on the web Xth XXXXXXXXX 201X DOI: 10.1039/b000000x

A consecutive synthetic strategy was developed toward the total synthesis of securinega alkaloids. (-)-Norsecurinine was concisely assembled by addition of a methoxyallene to a ketone for efficient side-chain installation. Ring-closing metathesis was also utilized as a key step. The first total synthesis of (-)-niruroidine was achieved from (-)-norsecurinine in three steps, while the route to (-)-flueggine A featured a 1,3-dipolar cycloaddition to forge the core structure. The securinega alkaloids are a small family of bridged tetracyclic natural products produced by Securinega, Phyllanthus, Flueggea and other plant genera in the Euphorbiaceae family. 1 Some of these plants have been widely used for years in traditional folk medicine in China and the Amazon.2 They show intriguing biological activities, including diuretic, antipyretic, hepatoprotective and GABA receptor antagonist activities. 3 Among this family of natural products, securinine (1) and (-)-norsecurinine (2) are the most representative examples (Figure 1).4,5 Structurally, most securinega alkaloids share a bridged tetracyclic ring system that includes a benzofuranone subunit (rings C and D) and a piperidine or pyrrolidine ring (ring A), and the size of the latter ring defines the securinine and norsecurinine subgroups. Due to the unique structural features and interesting biological properties of the securinega alkaloids, these compounds have drawn significant attention from synthetic chemists, resulting in a number of innovative total syntheses. 1a,6,7 Recently, (-)flueggine A (4)8 and (-)-niruroidine (3)9 were isolated from the twigs and leaves of Flueggea virosa by Ye and coworkers (Figure 1) and were found to have unprecedented skeletal structures. The unique structural features of (-)-flueggine A (4) are an isoxazolidine and the 7-oxa-1-azabicyclo[3.2.1]octane ring system. Recently, Yang and Li reported the first total synthesis of (-)-flueggine A (4) using (-)-norsecurinine (2) and nitrone 6 in a 1,3-dipolar cycloaddition reaction.10 However, it is highly desirable to develop a consecutive synthetic strategy that may be applied to a number of securinega alkaloid family members. To verify its feasibility, we attempted the consecutive synthesis of (-)-norsecurinine (2), (-)-niruroidine (3) and (-)-flueggine A (4).

Figure 1. Representative securinega alkaloids.

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Scheme 1. A biomimetic approach to the consecutive synthesis of (-)-norsecurinine (2), (-)-niruroidine (3) and (-)-flueggine A (4).

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Because of the structural similarity of (-)-norsecurinine (2), (-)-niruroidine (3) and (-)-flueggine A (4), and the fact that all three natural products were isolated from plants of the same genus (Flueggea) we considered the possibility that (-)norsecurinine (2) may be an intermediate in the biosynthesis of these alkaloids. As shown in the biosynthetic route (scheme 1), we envisioned that the framework of (-)-niruroidine (3) could be derived from (-)-norsecurinine (2) through rearrangement of the C ring, which may occur in nature. This hypothesis could be verified by the interconversion of (-)niruroidine (3) and (-)-norsecurinine (2). (-)-Flueggine A (4) may be generated through a 1,3-dipolar cycloaddition.

Inspired by the proposed biosynthesis, we devised a ring oxidation-cycloaddition approach for the consecutive synthesis of (-)-norsecurinine (2), (-)-niruroidine (3) and (-)Journal Name, [year], [vol], 00–00 | 1

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Figure 2. Retrosynthetic analysis. Based on the above analysis, we first investigated the synthesis of (-)-norsecurinine (2), as shown in Scheme 2. Weinreb amide 9 was readily prepared from commercially available D-proline (8) via a known operation. 11 Weinreb amide 9 was subjected to Grignard reaction with homoallyl magnesium bromide to afford ketone 10 in 90% yield, 12 which was treated with methoxyallene13 to afford the corresponding terminal olefin 11 as a single diastereomer. Treatment of olefin 11 with Grubbs’s second generation catalyst 14 in DCM furnished cyclohexene 7 in 96% yield. Cyclohexene 7 was converted into the corresponding bromide 13 in 59% yield using NBS and AIBN.15 Subsequent formation of the B ring and introduction of the butenolide unit to 7 involved a three step sequence: (i) TFA-mediated Boc deprotection followed by base-induced nucleophilic substitution, (ii) DCC-mediated acylation of the tertiary alcohol with diethylphosphonoacetic acid, and (iii) intramolecular Horner–Wadsworth–Emmons reaction to furnish (-)-norsecurinine (2).7c The spectral data (1H NMR, 13C NMR, and optical rotation) of the synthetic (-)norsecurinine (2) were consistent with those reported in the literature.5 With (-)-norsecurinine (2) in hand, our next challenge was to open the B ring and construct the framework of (-)niruroidine (3) (Scheme 2). Treatment of (-)-norsecurinine (2) with 2,2,2-trichloroethylchloroformate 16 in the presence of potassium carbonate at 0 °C provided 15 in 96% yield as a single diastereomer. The structure was confirmed by X-ray crystallographic analysis. 17 Substitution of the chloride with NaI at 60 °C followed by nucleophilic displacement with AgOAc in AcOH afforded intermediate 16 in 60% overall yield. Reductive cleavage of the Troc group with freshly prepared zinc dust in 80% AcOH followed by cyclization afforded the core structure 17 in 78% yield, which was saponified with NaOH to provide (-)-niruroidine (3) in 82%

yield. The spectral data of the synthetic (-)-niruroidine (3) were identical to those reported for the natural product. 9 50

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Scheme 2. Enantioselective synthesis of (-)-norsecurinine (2) and (-)-niruroidine (3).

An alternative and perhaps more convenient route has also been developed to convert (-)-norsecurinine (2) to (-)niruroidine (3) (Scheme 3). A variety of Lewis acids were tested to evaluate the nucleophilic substitution of the chloride of 15 with a hydroxy group; AgBF 4 was the most efficient promoter. Thus, treatment with AgBF 4 in acetone and water at 60 °C provided intermediate 18 in 75% yield as a single diastereomer. Following deprotection of the Troc group, compound 18 was treated with freshly prepared zinc dust in 80% AcOH, affording (-)-niruroidine (3) in 51% yield (Scheme 3). Scheme 3. An alternative synthesis of (-)-niruroidine (3).

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Interestingly, when (-)-niruroidine (3) was subjected to PPh3 and DIAD, (-)-norsecurinine (2) was obtained in 87% yield (Scheme 4). This result supports our hypothesis that this transformation occurs in nature. The proposed mechanism is illustrated in Scheme 4; the initial reaction between Ph 3P and DIAD forms betaine II. (-)-Niruroidine (3) reacts with II to This journal is © The Royal Society of Chemistry [year]

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flueggine A (4) (Figure 2). (-)-Flueggine A (4) could be obtained through a 1,3-dipolar cycloaddition from (-)norsecurinine (2) and nitrone 6, which could in turn be generated from (-)-niruroidine (3) via regioselective oxidation and elimination. (-)-Niruroidine (3) could be generated from (-)-norsecurinine (2) through rearrangement of the C ring. Construction of (-)-norsecurinine (2) would require bromination-substitution and annulation of the butenolide from cyclohexenone 7, which may be prepared from inexpensive and commercially available D-proline (8).

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form the intermediate III, followed by cyclization. Subsequent β-elimination affords (-)-norsecurinine (2) with the assistance of base. Scheme 4. Transformation of (-)-niruroidine (3) into (-)norsecurinine (2), with a proposed mechanism.

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achieved in 9 steps in 12.5 % overall yield, whereas (-)niruroidine was synthesized in 3 steps and 37 % overall yield from (-)-norsecurinine. (-)-Niruroidine was converted into (-)flueggine A in four steps and 21% overall yield. Notably, we have demonstrated that (-)-niruroidine (3) can be transformed into (-)-norsecurinine (2) in one step, supporting our hypothesis that this transformation occurs in nature. Further application of this strategy for other members of the securinega family of alkaloids is currently under investigation. This work was supported by the Joint Fund of NSFCGuangdong Province (No. U0932004) and the National Natural Science Foundation (Grant No. 21172220 and 20972160).

Notes and references †

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With both (-)-norsecurinine (2) and (-)-niruroidine (3) in hand, we were ready to construct nitrone 6 (Scheme 5). Oxidation of (-)-niruroidine (3) with Dess-Martin periodinane followed by reduction with NaBH 4 furnished alcohol 20 in 46% yield over two steps. Inversion of the configuration of the hydroxyl group was confirmed by X-ray crystallographic analysis. 18 We found that 20 could be cleanly oxidized to nitrone 6 in 55% yield using Na 2WO4/H2O2.19 Finally, nitrone 6 was reacted with (-)-norsecurinine (2) in refluxing toluene to provide (-)-flueggine A (4) in 66% yield through a 1,3dipolar addition (Scheme 5). The optical rotation of the synthetic product ([α] 20D -31.6 (c 0.1, MeOH)) was identical to that reported for natural (-)-flueggine A (4), -31.9 (c 0.25, MeOH). The spectroscopic data ( 1H NMR and 13C NMR) for the synthetic substance matched the data published for the natural product (see Supporting Information).

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Scheme 5. Enantioselective synthesis of (-)-flueggine A (4). 65

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In summary, (-)-norsecurinine, (-)-niruroidine and (-)flueggine A were synthesized enantioselectively through biomimetic approaches. Starting from commercially available D-proline (8), the total synthesis of (-)-norsecurinine was This journal is © The Royal Society of Chemistry [year]

Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China ‡ Laboratory of Medicinal Chemistry, Guangzhou Institute of Biomedicine and Health, CAS, Guangzhou 510530, PR China # Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, PR China ⊥ These authors contributed equally. Email:[email protected]; [email protected] † Electronic Supplementary Information (ESI) available: Experimental procedures and characterization data for all new compounds described herein, including CIF files for compounds 15 and 20. See DOI: 10.1039/c000000x/ 1 (a) S. M. Weinreb, Nat. Prod. Rep., 2009, 26, 758; (b) V. Snieckus., New York: Academic Press, 1973, pp. 425-506. 2 (a) J. A. Beutler and A. N. Brubaker, Drug Future, 1987, 12, 957; (b) A. K. Nadkarni, in Indian Materia Medica; Popular Prakashan Pvt. Ltd: Bombay, 1976, vol. 1, pp. 1292. 3 (a) H. Weenen, M. H. H. Nkunya, D. H. Bray, L. B. Mwasumbi, L. S. Kinabo, V. A. E. B. Kilimali and J. B. P. A. Wijnberg, Planta Med, 1990, 56, 371; (b) E. Galvez-Ruano, M. H. Aprison, D. H. Robertson and K. B. Lipkowitz, J. Neurosci. Res., 1995, 42, 666. 4 I. Satoda, M. Murayama, J. Tsuji and E. Yoshii, Tetrahedron Lett., 1962, 3, 1199. 5 S. Saito, T. Tanaka, K. Kotera, H. Nakai, N. Sugimoto, Z. Horii, M. Ikeda and Y. Tamura, Chem. Pharm. Bull. (Tokyo), 1965, 13, 786. 6 (a) R. Alibés, M. Ballbé, F. Busqué, P. de March, L. Elias, M. Figueredo and J. Font, Org. Lett., 2004, 6, 1813; b G G ardaj ant n ib s a n us u de arch Figueredo and J. Font, J. Org. Chem., 2008, 73, 7657; (c) B. Dhudshia, B. F. T. Cooper, C. L. B. Macdonald and A. N. Thadani, Chem. Commun., 2009, 463; (d) A. B. Leduc and M. A. Kerr, Angew. Chem. Int. Ed., 2008, 47, 7945. 7 (a) P. Magnus, J. Rodriguez-Lopez, K. Mulholland and I. Matthews, J. Am. Chem. Soc., 1992, 114, 382; (b Gon e -G ve Garc a-Garc a ib s a n de arch igueredo and J. Font, J. Org. Chem., 2009, 74, 6199; (c) G. Han, M. G. LaPorte, J. J. Folmer, K. M. Werner and S. M. Weinreb, J. Org. Chem., 2000, 65, 6293; (d) A. M. ElSohly, D. A. Wespe, T. J. Poore and S. A. Snyder, Angew. Chem. Int. Ed., 2013, 52, 5789. 8 B.-X. Zhao, Y. Wang, D.-M. Zhang, R.-W. Jiang, G.-C. Wang, J.-M. Shi, X.-J. Huang, W.-M. Chen, C.-T. Che and W.-C. Ye, Org. Lett., 2011, 13, 3888.

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For the isolation and structural determination of (-)-niruroidine, please see the supporting information. H. Wei, C. Qiao, G. Liu, Z. Yang and C.-C. Li, Angew. Chem. Int. Ed., 2013, 52, 620. I. Moldvai, G. Dömyei, E. Temesvári-Major and C. Szántay, Org. Prep. Proced. Int., 2007, 39, 503. A. Sathish Reddy and P. Srihari, Tetrahedron Lett., 2012, 53, 5926. R. Pulz, Synlett, 2000, 2000, 1697. (a) G. C. Vougioukalakis and R. H. Grubbs, Chem. Rev., 2009, 110, 1746; (b) A. Fürstner, Angew. Chem. Int. Ed., 2000, 39, 3012. The stereochemistry of the compound 13 could not be determined at this stage. The following cyclization of allylic bromide would be assumed to precede with both SN2 and SN1-like reaction mechanisms: (a) T. Honda, H. Namiki, K. Kaneda, H. Mizutani, Org. Lett., 2004, 6, 87-89; (b) D. González-Gálvez , E. García-García , R. Alibés , P. Bayón , P. de March , M. Figueredo and J. Font, J. Org. Chem., 2009, 74, 6199–6211. P. Magnus, M. Giles, R. Bonnert, G. Johnson, L. McQuire, M. Deluca, A. Merritt, C. S. Kim and N. Vicker, J. Am. Chem. Soc., 1993, 115, 8116. The crystal data were deposited at the Cambridge Crystallographic Data Centre. The deposited number is CCDC 971441. The crystal data were deposited at the Cambridge Crystallographic Data Centre. The deposited number is CCDC 971455. S. Murahashi, H. Mitsui, T. Shiota, T. Tsuda and S. Watanabe, J. Org. Chem., 1990, 55, 1736.

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DOI: 10.1039/C4CC02575J

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Total synthesis of securinega alkaloids (-)-norsecurinine, (-)-niruroidine and (-)-flueggine A.

A consecutive synthetic strategy was developed toward the total synthesis of securinega alkaloids. (-)-Norsecurinine was concisely assembled by additi...
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