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Total Synthesis of (±)-Lycojaponicumin D and Lycodoline-Type Lycopodium Alkaloids Xian-He Zhao,† Qing Zhang,† Ji-Yuan Du,† Xin-Yun Lu,† Ye-Xing Cao,† Yu-Hua Deng,† and Chun-An Fan*,†,‡ †

State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, 222 Tianshui Nanlu, Lanzhou 730000, China ‡ Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China S Supporting Information *

ABSTRACT: Lycopodium alkaloids with structural diversity and biological significance have been stimulating an increasing interest in the synthetic and medicinal communities, in which inspiration and exploration of their related biogenetic relationship generally constitute one of the major concerns. Driven by the plausible biogenetic entry to lycojaponicumin D as the first member of Lycopodium alkaloids having a structurally unusual C3−C13-linked scaffold, a new connection with lycodoline has been proposed and discovered on the basis of the design of an unprecedented bioinspired tandem fragmentation/Mannich reaction. Initiated by expeditious assembly of bridgehead heterofunctionalization in the [3.3.1] bicyclic system of lycodoline, a novel tandem palladium-mediated oxidative dehydrogenation/hetero-Michael reaction has been developed for the strain-driven formation of the C−heteroatom bond, leading to a new approach to conformationally rigid bridgehead heteroquaternary carbons. The present unified strategy provides a scenario for the divergent total syntheses of nine natural Lycopodium alkaloids and four unnatural C12 epimers, wherein (±)-lycojaponicumin D and six lycodoline-type alkaloids have been synthetically achieved for the first time.

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INTRODUCTION Lycopodium genus plants with nearly 1000 different species are widely distributed all over the world and have a long pharmaceutical history in traditional folk medicine. As one type of bioactive components, Lycopodium alkaloids have been known since the first isolation of lycopodine from Lycopodium complanatum in 1881.1 Significantly among the Lycopodium alkaloids, huperzine A, which was isolated from the club moss Huperzia serrata that is used medicinally in China, is potent in the reversible inhibition of acetylcholinesterase (AChE).2 Structurally, Lycopodium alkaloids are mainly classified into the lycodine group, the lycopodine group, the fawcettimine group, or the phlegmarine group. Because of their architectural diversity and bioactive potentials, Lycopodium alkaloids as an important class of nitrogen-containing natural products have been stimulating a lot of interest in both the synthetic and medicinal communities over the past half century.3 In 2012, a structurally unprecedented Lycopodium alkaloid, lycojaponicumin D (1) (Scheme 1), was isolated from Lycopodium japonicum Thunb. ex Murray by Yu,4 and its stereochemistry was spectroscopically elucidated by NMR and electronic circular dichroism analysis. Despite its slight activity against lipopolysaccharide (LPS)-induced proinflammatory factors in BV2 macrophages, lycojaponicumin D, which possesses a unique 5/7/6/6 tetracyclic skeleton, constitutes the first example of a Lycopodium alkaloid with an unusual C3−C13 linkage. © 2017 American Chemical Society

According to the previous biogenetic connection between lysine and fawcettimine (3) via aza-semipinacol rearrangement of lycodoline (2) (route a),5 a plausible biosynthetic approach from fawcettimine to lycojaponicumin D (route b) was proposed by Yu (Scheme 1), in which sequential transformations involving α-hydroxylation of the carbonyl, retro-aldol reaction, intramolecular Mannich cyclization, and the tertiary C12−H oxidation were described.4 To gain insight into the biogenetic relationship between lycojaponicumin D and lycodoline, exploring an alternative pathway would impact on the synthesis design of these structurally related Lycopodium alkaloids, especially some that are scarce in nature. Stimulated by known biogenesis, as depicted in Scheme 1, a new fragmentation/Mannich cyclization cascade of lycodoline oxide (miyoshianine A, 4) could be conceived to establish an unprecedented chemical connection between lycodoline and lycojaponicumin D (route c). To probe the feasibility of this approach, lycojaponicumin D and lycodoline become two original synthetic targets for a platform centering on the effective and divergent synthesis of a series of Lycopodium alkaloids having intriguing polycyclic architecture. With our above proposal for the bioinspired access to lycojaponicumin D (route c, Scheme 1), the effective synthesis Received: April 1, 2017 Published: April 27, 2017 7095

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Journal of the American Chemical Society Scheme 1. Plausible Biogenesis of Lycodoline, Fawcettimine, and Lycojaponicumin D

Scheme 2. Proposed Bridgehead C−H Heteroatom Functionalization

a symmetry-driven cleavage strategy10 featuring a novel bridgehead C−H heterofunctionalization might be applied to an expeditious installation of the functionalized bicyclo[3.3.1] scaffold, which constitutes a privileged core structure in many bioactive natural products. Compared with previously known methods through carbonyl α-deprotonation,11 radical abstraction,12 or nitrene insertion13 of a bicyclic [n.3.1] bridgehead C−H bond, a novel tandem reaction consisting of oxidative β-dehydrogenation of carbonyls (Saegusa−Ito oxidation14) and hetero-Michael addition could be strategically envisaged in our case, wherein a highly strained bridgehead enone

of lycodoline constitutes a central topic for the current study. Lycodoline was originally isolated from Lycopodium annotinum Linn. in 19436 and then structurally elucidated in 1962.7 Notably, total and formal syntheses of lycodoline were only reported in the 1980s by Heathcock8 and Kim,9 respectively. From a synthetic point of view, efficient construction of the bridgehead aza-quaternary carbon of the bicyclo[3.3.1]nonane ring skeleton I (Scheme 2) would be one of the most important issues in the synthesis of lycodoline; a combined stepwise sequence involving enamination, oxidation, and Mannich cyclization was adopted in Heathcock’s synthesis.8 To address this point, 7096

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Journal of the American Chemical Society Scheme 3. Retrosynthetic Analysis

Scheme 4. Synthesis of Pseudosymmetric [3.3.1] Building Blocks

reaction could be postulated to achieve the bridgehead C−H heterofunctionalization. Chemically, the keto and hemiacetal functional groups in synthon C could be installed by keto addition and olefin oxidation from the known bicyclic β,γ-enone building block 15.15 The synthesis, as shown in Scheme 4, commenced with the known 7-methylbicyclo[3.3.1]non-2-en-9-one (15), which was prepared readily on an 80 g scale by a modified three-step, onecolumn process using acrolein and 4-methylcyclohexone.15a Selective allylation of 15 with allylic Grignard reagent at −98 °C (MeOH/liquid N2 bath) predominantly led to the formation of chromatographically separable bishomoallylic alcohol 16, in which the desired diastereoselectivity arises from the preferential facial attack at the less hindered carbonyl plane proximate to the olefin moiety. Subsequently, following a two-step, one-column protocol involving Brown hydroboration−oxidation and 2-iodoxybenzoic acid (IBX) oxidation, bishomoallylic alcohol 16 having sterically biased olefin motifs was smoothly converted to hemiacetal ketone 18a in a combined yield of 52%, in which the regio- and diastereoselectivity observed in the oxidative

intermediate II (Scheme 2) formed in situ would be chemically involved.

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RESULTS AND DISCUSSION According to our analysis mentioned above, as shown in Scheme 3, lycojaponicumin D would be accessed from lycodoline through the proposed bioinspired tandem fragmentation/ Mannich reaction, in which an unprecedented skeletal rearrangement from the 6/6/6/6 fused polycyclic core of lycodoline to the 5/7/6/6 tetracyclic framework of lycojaponicumin D will be involved. Logically, the assembly of fused ring A of lycodoline could be enabled by intramolecular annulation of conformationally rigid tricyclic keto synthon A. With the disconnection of two endocyclic C−N bonds in ring C of synthon A, a simplified synthon B having a functionalized bicyclo[3.3.1] skeleton could be conceived, wherein the reductive amination/cyclization would be convergently used to forge the piperidine unit (ring C) of synthon A. Retrosynthetically, fission of the bridgehead C−X bond in synthon B could introduce pseudosymmetric synthon C, in which a tandem dehydrogenation/hetero-Michael 7097

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Journal of the American Chemical Society

bicyclo[4.3.1]dec-1-en-3-one (17.7 kcal/mol) is lower than that of either bicyclo[3.2.1]oct-1-en-3-one (32.3 kcal/mol) or bicyclo[3.3.1]non-1-en-3-one (21.3 kcal/mol).17c Significantly, it could be seen from the above results that the existence of some extent of bridgehead strain is crucial for the subsequent heteroMichael addition in this tandem reaction. Having developed this key bridgehead heterofunctionalization, we then focused our attention on the total synthesis of lycodoline (Scheme 5a). According to our proposed retrosynthetic analysis (Scheme 3), 18a was subjected to the standard conditions for tandem oxidative dehydrogenation/heteroMichael reaction, and the bridgehead C−H-functionalized products 19a, α-19a′, and β-19a′, which could be readily separated by column chromatography, were supplied on a gram scale in 17% (1.3:1 dr), 23%, and 12% yield, respectively. To introduce the pendant amine chain, reductive amination of hemiacetal 19a in the presence of 3-aminopropanol under mild conditions (NaBH3CN, CF3CO2H, MeOH/H2O, 30 °C) was performed. Surprisingly, an unexpected piperidine-containing tricyclic product, 21, was obtained in 80% yield, and its relative configuration was unambiguously confirmed by X-ray crystallographic analysis.16 Notably, analogous reactivity of α-19a′ and β-19a′ under the above conditions was observed, leading to the formation of 21 in 85% yield. To gain insight into the above tandem reductive amination/ bridgehead aminolysis reaction f hemiacetal 19a and hemiacetal silyl ether α-19a′/β-19a′, preliminary control experiments were performed as shown in Scheme 6. Mechanistically, the inertness of 19c under the control conditions rules out the pathway of preferential intermolecular aminolysis, showing the necessity of its intramolecular fashion. Compared with the mild conversion of 19d to aza-annulated tricyclic product 22 in 80% yield, the negative result in the case using 19i demonstrates that the presence of the bridgehead acetate group is crucial for the current mild intramolecular aminolysis. In view of these facts, this unusual tandem transformation could probably be rationalized by the initial reductive amination and subsequent intramolecular bridgehead aminolysis,18b,c,22 wherein acid-promoted direct aza annulation of the bridgehead tertiary alcohol ester might proceed through the transition state TS-2 because of the intrinsic leaving ability of the bridgehead acetate group, which was partially accelerated by the favorable hyperconjugation effect in the [3.3.1] bicyclic system. After installation of the crucial bridgehead aza-quaternary center in 21, a combined protocol involving Oppenauer oxidation, aldol condensation, and reductive hydrogenation was conducted under Heathcock’s conditions,8 completing the total synthesis of (±)-lycodoline (2) in 75% yield on a gram scale. The stereochemistry of 2 was clearly confirmed by X-ray crystallographic analysis.16 To explore the feasibility of the bioinspired synthesis of lycojaponicumin D (1) from lycodoline (2), as shown in Scheme 5b, a thermodynamically favored α-hydroxylation first yielded (±)-lycoposerramine G (5),23 and then a sequential oxidation of the amine with H2O2 smoothly gave (±)-miyoshianine A (4)24 (also known as (±)-lycoposeramine F23). With the precursor 4 in hand, our proposed tandem fragmentation/ Mannich cyclization was then probed by using various electrophilic activating reagents (e.g., carbonyl anhydrides, sulfonyl anhydride, sulfonyl chloride, and Lewis acids),25−27 but disappointingly, no positive results were obtained for this transformation. To improve the driving force for N−O bond cleavage, triphosgene as an equivalent of chloroformyl was

formation of major water-soluble triol intermediate 17 was unambiguously confirmed by X-ray crystallographic analysis.16 With pseudosymmetric hemiacetal ketone 18a in hand, as proposed in Scheme 2, the bridgehead C−H heterofunctionalization of the [3.3.1] bicyclic ring system, involving a highly strained bicyclo[3.3.1] bridgehead enone intermediate, was then pursued. As is known, unisolable bicyclo[3.3.1] bridgehead enones were experimentally proposed by House in 1978.17 In the earlier studies, these bridgehead enones were mainly prepared in situ by elimination or Wittig reaction under basic conditions.18 Inspired by Saegusa−Ito oxidation for the enone synthesis,14 as shown in Table 1, a tandem oxidative dehydrogenation/oxa-Michael reaction of the silyl enol ether of 18a, which was individually prepared with TMSCl and potassium bis(trimethylsilyl)amide (KHMDS), was explored in the presence of stoichiometric amounts of freshly prepared Pd(OAc)2 in anhydrous CH3CN as the solvent at 60 °C.19,20 Pleasingly, the desired bridgehead acetate-functionalized products 19a′ and 19a (19a′/19a = 67:33; entry 1) were afforded in 52% combined yield over the two steps. To our knowledge, there has been no report on the application of Saegusa−Ito oxidation in the construction of highly strained bridgehead [3.3.1] bicyclic enone systems. Importantly, an interesting strain-driven conjugate addition17,18,21 was observed in this unprecedented tandem reaction, providing a new perspective for direct assembly of the bridgehead heteroquaternary center in bicyclo[3.3.1] building blocks. To initially probe the generality of this tandem reaction, three additional examples using substituted bicyclo[3.3.1]nonan3-ones with cyclic or acyclic C9-bridging linkers (e.g., 1,3-dioxolanyl, tetrahydrofuranyl, and chloroamide pendant groups) were performed under standard conditions, and the expected bridgehead-oxygen-containing products 19b−d (Table 1, entries 2−4) were obtained, albeit in moderate yields (35−46%). In addition to the above oxa functionalization in the bridgehead system (entries 1−4), the possibility of aza functionalization using bridged ketone 18e with an acyclic secondary amide group was also examined, and interestingly, the tricyclic nitrogen-containing product 19e (entry 5), which might result from a competitive intramolecular conjugate addition of the amide group instead of acetate anion, was obtained, but in a lower yield (22%). Notably, in contrast to the result employing acyclic tertiary carbamate 18d (entry 4), the reaction of cyclic carbamate 18f under the optimal conditions unexpectedly gave tetracyclic aza-functionalized product 19f (entry 6) in 46% yield. According to the structural assignment of 19f, which was unambiguously determined by X-ray crystallographic analysis,16 an unusual process consisting of aza-conjugate addition of an in situ-formed bridgehead enone intermediate and a subsequent carbamate acyl migration might be involved in TS-1 for this case. After preliminary investigations of the reactivity in the [3.3.1] bicyclic system, the influence of the bridged ring size on this key tandem reaction was then considered. When ketone 18g with a [3.2.1] ring skeleton was subjected to the standard conditions, the tandem oxidative dehydrogenation/oxa-Michael reaction could proceed to deliver the oxa-addition product 19g in a modest yield of 13% (Table 1, entry 7), to some extent demonstrating an unfavorable oxidative dehydrogenation resulting from the increasing strain energy in the smaller [3.2.1] bridgehead enone system. Surprisingly, when ketone 18h having a larger [4.3.1] ring skeleton was employed as the substrate, the chemically stable bridgehead enone 19h, instead of the expected oxa-conjugate adduct, was isolated in 59% yield (entry 8). Apparently, this result is mostly consistent with the fact that the strain energy of 7098

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Journal of the American Chemical Society Table 1. Scope of the Key Tandem Oxidative Dehydrogenation/Hetero-Michael Reactiona

a Unless otherwise noted, reactions of TMS enol ethers of 18a−h, which were individually obtained in the presence of KHMDS (3.0 equiv) and TMSCl (3.0 equiv) in THF at 0 °C (for 18a) or at −78 °C (for 18b−h), were performed with freshly prepared Pd(OAc)2 (1.5 equiv) in freshly distilled CH3CN at 60 °C. bOverall yields of the isolated products starting from the ketone. cYields based on the recovered starting material are given in parentheses. dFollowed by the deprotection of N-Boc using CF3CO2H. eThe structure of 19f was established by X-ray crystallographic analysis. f With the remaining starting material (ca. 10%), another structurally undetermined major byproduct was isolated.

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Journal of the American Chemical Society Scheme 5. Total Synthesis of Lycopodium Alkaloids

anticipated to introduce a highly reactive leaving group formed in situ. Upon treatment of β-amino alcohol N-oxide 4 with triphosgene and NEt3 in CH2Cl2 at 25 °C, gratifyingly, the first total synthesis of (±)-lycojaponicumin D (1) could be achieved in 44% yield, and its structure was clearly elucidated by X-ray crystallographic analysis.16 Significantly, this bioinspired

transformation involving a skeletal rearrangement offers a new connection between the 6/6/6/6 fused framework of lycodoline and the 5/7/6/6 tetracyclic skeleton of lycojaponicumin D, wherein an unprecedented tandem protocol involving intermediates III−V mainly consists of sequential chemoselective chloroformylation, regioselective fragmentation controlled by a 7100

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by X-ray crystallographic analysis, was produced in 40% total yield,16 wherein the hydroxy-directed stereospecific Si−H reduction might be involved in the formation of (±)-12-epiflabelliformine (13). Stimulated by the possible biogenetic assumption from lycodoline to fawcettimine via a rearrangement proposed by Inubushi in 1966 (Scheme 1),5 the possibility of such an azasemipinacol rearrangement was explored experimentally.37 Upon treatment of lycodoline with a series of Brønsted and Lewis acids,25 no desired rearrangement product was detected, partially showing the negative influence of the decreased migratory aptitude of the C−C bond adjacent to the electronically deactivated aliphatic amine moiety of lycodoline under acidic conditions. Besides, attempts at in situ introduction of the hydroxyl leaving group using various electrophilic reagents (e.g., acyl, sulfonyl, and phosphoryl chlorides and anhydrides) were also performed under basic conditions,25 and disappointingly, there was still no positive result for the proposed aza-semipinacol rearrangement. Among the above attempts at this rearrangement, notably an unexpected N,O-bisacylation/ring-opening chlorination of lycodoline occurred in the presence of oxalyl chloride and NaH in CH2Cl2, affording morpholindione-containing tetracyclic chloride 23, which was structurally characterized by X-ray crystallographic analysis.16 This nonrearrangeable transformation might give a clue that electronic deactivation of the conformationally rigid convex nitrogen atom of lycodoline, competitively caused by reaction with electrophilic reagents being used for installing an oxygen leaving group, might to some extent retard the proposed aza-semipinacol rearrangement. In contrast to this observation, when lycodoline was subjected to similar conditions using triphosgene instead of oxalyl chloride, the hydroxy elimination occurred preferentially to give (±)-anhydrolycodoline (9) as a major undesired product.

Scheme 6. Control Experiments for Bridgehead Aminolysis

stereoelectronic effect, keto−enol tautomerization, and regioselective Mannich cyclization. With the completion of the above bioinspired conversion, the divergent syntheses of a series of structurally relevant lycodoline-type alkaloids were also implemented starting from lycodoline. As shown in Scheme 5c, N-oxidation of the amine using m-chloroperoxybenzoic acid (m-CPBA) and kinetically controlled α-hydroxylation of the ketone using sterically bulky Davis’ oxaziridine were conducted to deliver (±)-obscurumine A (6)28 in 85% yield and the crystallographically determined (±)-serratezomine C (7)16,29 in 90% yield (brsm), respectively. Subsequent Swern oxidation of 7 gave a 76% yield of (±)-huperzine O (8),30 which could not be obtained by direct oxidation of lycodoline using SeO2 (Riley oxidation).31 In order to further access C12 epimers of lycodoline-type alkaloids, a two-step protocol involving alcohol dehydration and olefin hydration was adopted to reverse the configuration of the tertiary C12−OH in lycodoline. Following SOCl2-mediated elimination of the tertiary hydroxy group of lycodoline under basic conditions, (±)-anhydrolycodoline (9)32 was smoothly obtained in 97% yield. Subsequent Co(II)-promoted Mukaiyama hydration33 of 9 led to the first synthesis of (±)-12-epilycodoline (10)34 in 43% yield along with chromatographically separable (±)-lycodoline (2) in 17% yield. The relative configuration of 10 was confirmed by X-ray crystallographic analysis.16 Further amine N-oxidation of 10 using m-CPBA resulted in the formation of previously proposed (±)-12-epilycodoline N-oxide (11)35 in 85% yield. It is noteworthy that the distinct discrepancies in the NMR spectra between the reported 12-epilycodoline N-oxide and our synthetic sample (11) imply the necessity of structural reassignment for the original natural sample. Interestingly, it was found that the originally reported spectral data for 12-epilycodoline N-oxide are entirely consistent with those of (±)-obscurumine A (6) obtained above as a diastereomeric congener, offering its structural revision for the first time. Additionally, to improve the diastereoselectivity in the aforementioned olefin hydration of 9, Mukaiyama hydration mediated by Mn(acac)236 followed by oxidation with m-CPBA afforded the unexpected product (±)-4-hydroxy-12epilycodoline N-oxide (12) in 53% overall yield. With the hydration protocol using Mn(acac)3 instead of Mn(acac)2, followed by oxidation, an unusual oxidative product, (±)-12-epiflabelliformine N-oxide (14), whose structure was determined

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CONCLUSION Driven by the total synthesis of lycojaponicumin D, a bioinspired synthetic strategy featuring an unprecedented tandem fragmentation/Mannich reaction starting from lycodoline has been explored, in which the unique skeletal rearrangement opens a new connection between the 6/6/6/6 and 5/7/6/6 tetracyclic ring systems. Focusing on effective assembly of bridgehead heteroatom functionalization in the [3.3.1] bicyclic system of lycodoline, we have developed a novel tandem palladiummediated oxidative dehydrogenation/hetero-Michael reaction wherein the strain-driven construction of the bridgehead heteroquaternary carbon through conjugate addition of in situformed bridgehead enones offers a new opportunity for the development of tandem reactions based on Saegusa−Ito oxidation. The present studies led to the total synthesis of nine natural Lycopodium alkaloids as well as four unnatural C12 epimers. New syntheses of (±)-lycodoline (2) (eight steps starting from the known compound 15, 15% yield) and (±)-anhydrolycodoline (9) (nine steps, 14% yield) are reported. Moreover, the syntheses of (±)-lycojaponicumin D (1) (11 steps, 5% yield) and six lycodoline-type alkaloids, (±)-lycoposerramine G (5) (nine steps, 13% yield), (±)-miyoshianine A (4) (10 steps, 13% yield), (±)-obscurumine A (6) (nine steps, 13% yield), (±)-serratezomine C (7) (nine steps, 4% yield), (±)-huperzine O (8) (10 steps, 3% yield), and (±)-12epilycodoline (10) (10 steps, 6% yield), are reported for the first time. These divergent syntheses centralized by lycodoline not only strategically provide a new scenario for the synthetic chemistry of topologically related Lycopodium alkaloids but also chemically shed light on their biogenetic relevance. 7101

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Soc. 1994, 116, 9009. (b) Inoue, M.; Sato, T.; Hirama, M. J. Am. Chem. Soc. 2003, 125, 10772. (c) Ghosh, A. K.; Xi, K. Angew. Chem., Int. Ed. 2009, 48, 5372. (d) Sullivan, B.; Carrera, I.; Drouin, M.; Hudlicky, T. Angew. Chem., Int. Ed. 2009, 48, 4229. (e) Malinowski, J. T.; Sharpe, R. J.; Johnson, J. S. Science 2013, 340, 180. (f) Nagatomo, M.; Koshimizu, M.; Masuda, K.; Tabuchi, T.; Urabe, D.; Inoue, M. J. Am. Chem. Soc. 2014, 136, 5916. (g) Ren, W.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2014, 53, 1818. (h) Du, J.-Y.; Zeng, C.; Han, X.-J.; Qu, H.; Zhao, X.-H.; An, X.-T.; Fan, C.-A. J. Am. Chem. Soc. 2015, 137, 4267. (11) (a) Siegel, D. R.; Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128, 1048. (b) Simpkins, N. S. Chem. Commun. 2013, 49, 1042. (12) Winkler, J. D.; Hong, B.-C. Tetrahedron Lett. 1995, 36, 683. (13) (a) Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510. (b) Huters, A. D.; Quasdorf, K. W.; Styduhar, E. D.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 15797. (c) Lescot, C.; Darses, B.; Collet, F.; Retailleau, P.; Dauban, P. J. Org. Chem. 2012, 77, 7232. (14) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011. (15) (a) Appleton, R. A.; Baggaley, K. H.; Egan, S. C.; Davies, J. M.; Graham, S. H.; Lewis, D. O. J. Chem. Soc. C 1968, 2032. (b) Zhang, C.; Hu, X.-H.; Wang, Y.-H.; Zheng, Z.; Xu, J.; Hu, X.-P. J. Am. Chem. Soc. 2012, 134, 9585. (16) The relative configuration was determined by X-ray crystallographic analysis. CCDC 1539340 (17), CCDC 1539341 (19f), CCDC 1539342 (21), CCDC 1539343 (synthetic lycodoline), CCDC 1539344 (synthetic lycojaponicumin D), CCDC 1539345 (synthetic serratezomine C), CCDC 1539346 (synthetic 12-epilycodoline), CCDC 1539347 (12-epi-flabelliformine N-oxide), and CCDC 1539348 (23) contain the crystallographic data for this paper. The data can be obtained free of charge via the Internet at www.ccdc.cam.ac.uk/data_request/cif. (17) (a) House, H. O.; Kleschick, W. A.; Zaiko, E. J. J. Org. Chem. 1978, 43, 3653. (b) House, H. O.; Sieloff, R. F.; Lee, T. V.; DeTar, M. B. J. Org. Chem. 1980, 45, 1800. (c) House, H. O.; Haack, J. L.; McDaniel, W. C.; VanDerveer, D. J. Org. Chem. 1983, 48, 1643. (d) Campbell, K. A.; House, H. O.; Surber, B. W.; Trahanovsky, W. S. J. Org. Chem. 1987, 52, 2474. (18) (a) Bestmann, H. J.; Schade, G. Tetrahedron Lett. 1982, 23, 3543. (b) Kraus, G. A.; Hon, Y.-S. J. Am. Chem. Soc. 1985, 107, 4341. (c) Kraus, G. A.; Hon, Y.-S. Heterocycles 1987, 25, 377. (d) Kraus, G. A.; Hon, Y.-S.; Thomas, P. J.; Laramay, S.; Liras, S.; Hanson, J. Chem. Rev. 1989, 89, 1591. (19) For the fresh preparation of Pd(OAc)2, see: Berry, J. F.; Cotton, F. A.; Ibragimov, S.; Murillo, C. A.; Timmons, D. J.; Fricke, K. A. Inorg. Synth. 2014, 36, 171. (20) The reaction of the silyl enol ether of 18a (0.2 mmol) using a substoichiometric amount of Pd(OAc)2 (0.04 mmol) under O2 (balloon pressure) in the presence of NaOAc (0.3 mmol) as the nucleophile in CH3CN at 60 °C was also examined, but no desired bridgehead acetatefunctionalized product was observed within 24 h, and most of the starting material remained. For catalytic variants of the Saegusa−Ito oxidation, see: (a) Theissen, R. J. J. Org. Chem. 1971, 36, 752. (b) Larock, R. C.; Hightower, T. R.; Kraus, G. A.; Hahn, P.; Zheng, D. Tetrahedron Lett. 1995, 36, 2423. (c) Yu, J.-Q.; Wu, H.-C.; Corey, E. J. Org. Lett. 2005, 7, 1415. (d) Tokunaga, M.; Harada, S.; Iwasawa, T.; Obora, Y.; Tsuji, Y. Tetrahedron Lett. 2007, 48, 6860. (e) Zhu, J.; Liu, J.; Ma, R.; Xie, H.; Li, J.; Jiang, H.; Wang, W. Adv. Synth. Catal. 2009, 351, 1229. (f) Liu, J.; Zhu, J.; Jiang, H.; Wang, W.; Li, J. Chem. - Asian J. 2009, 4, 1712. (g) Muzart, J. Eur. J. Org. Chem. 2010, 2010, 3779. (h) Diao, T.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133, 14566. (i) Lu, Y.; Nguyen, P. L.; Lévaray, N.; Lebel, H. J. Org. Chem. 2013, 78, 776. (j) Chen, Y.; Romaire, J. P.; Newhouse, T. R. J. Am. Chem. Soc. 2015, 137, 5875. (k) Chen, Y.; Turlik, A.; Newhouse, T. R. J. Am. Chem. Soc. 2016, 138, 1166. (l) Iosub, A. V.; Stahl, S. S. ACS Catal. 2016, 6, 8201. (21) (a) Fawcett, F. S. Chem. Rev. 1950, 47, 219. (b) Köbrich, G. Angew. Chem., Int. Ed. Engl. 1973, 12, 464. (c) Buchanan, G. L. Chem. Soc. Rev. 1974, 3, 41. (d) Keese, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 528. (e) Warner, P. M. Chem. Rev. 1989, 89, 1067. (f) Szeimies, G. In Reactive Intermediates; Abramovitch, R. A., Ed.; Plenum Press: New York, 1983; Vol. 3, p 299. (g) Bear, B. R.; Sparks, S. M.; Shea, K. J. Angew. Chem., Int. Ed. 2001, 40, 820. (h) Wilson, M. R.; Taylor, R. E. Angew.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b03280. Experimental procedures and spectral data (PDF) Crystallographic data for 17 (CIF) Crystallographic data for 19f (CIF) Crystallographic data for 21 (CIF) Crystallographic data for synthetic (±)-lycodoline (CIF) Crystallographic data for synthetic (±)-lycojaponicumin D (CIF) Crystallographic data for synthetic (±)-serratezomine C (CIF) Crystallographic data for synthetic (±)-12-epilycodoline (CIF) Crystallographic data for (±)-12-epi-flabelliformine N-oxide (CIF) Crystallographic data for 23 (CIF)

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Chun-An Fan: 0000-0003-4837-3394 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support from NSFC (21572083, 21322201, 21290180), FRFCU (lzujbky-2015-48, lzujbky-2016ct02, lzujbky-2016-ct07), PCSIRT (IRT_15R28), the 111 Project of MOE (111-2-17), and the Chang Jiang Scholars Program (C.-A.F.). We thank Prof. Shi-Shan Yu and Dr. XiaoJing Wang (Institute of Materia Medica, CAMS and PUMC) and Prof. Quan-Xiang Wu (Lanzhou University) for their helpful discussions on the spectral analysis of lycojaponicumin D.

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REFERENCES

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