- Concise total syntheses of (±)-Strychnine and (±)-Akuammicine
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Concise total syntheses of Strychnos alkaloids strychnine (1) and akuammicine (2) have been realized in 13 and 6 operations, respectively. Key steps include (1) the vinylogous Mannich reaction; (2) a novel, sequential one-pot spirocyclization/intramolecular aza-Baylis-Hillman reaction; and (3) a Heck cyclization. The synthesis of 1 proceeds via the Wieland-Gumlich aldehyde (26).
- Sirasani, Gopal,Paul, Tapas,Dougherty, William,Kassel, Scott,Andrade, Rodrigo B.
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- Flow thermolysis rearrangements in the indole alkaloid series: Strictamine and akuammicine derivatives. The absolute configurations of ngouniensine and epi-ngouniensine
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Flow thermolysis of strictamine (1) generated two of the predictable rearrangement products, resulting from [1,5]-sigmatropic shifts: akuammicine (2) and indolenine 9. Besides formation of these two compounds, a quite different pathway gave rise to a novel rearrangement leading to indole 6, with the framework of the natural alkaloid ngouniensine (19). Rearrangement to the ngouniensine skeleton became the major pathway when the akuammicine derivatives 10, 12, and 17 were submitted to thermolysis, generating compounds 11, 13 + 15, and 18, respectively. These results allowed us to assign the absolute configuration of (-)-ngouniensine (19) (3R,20R) and that of (-)-epingouniensine ((-)-21) (3R,20S).
- Hugel, Georgette,Royer, Daniel,Le Men-Olivier, Louisette,Richard, Bernard,Jacquier, Marie-Jose,Levy, Jean
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- Syntheses of Strychnos- and Aspidospermatan-Type Alkaloids. 6. Total Syntheses of (+/-)-Echitamidine, (+/-)-Alstogustine, (+/-)-19-epi-Alstogustine, and (+/-)-Akuammicine
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19-Oxodihydroakuammicine was obtained in a three-pot sequence, in 25percent overall yield based on a new condensation-sigmatropic rearrangement sequence.Reductions and quaternization reactions furnished the title compounds.
- Kuehne, Martin E.,Xu, Feng,Brook, Christopher S.
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- Synthesis of tetracyclic spiroindolines by an interrupted Bischler-Napieralski reaction: total synthesis of akuammicine
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Judicious substrate design allows interruption of the classical Bischler-Napieralski reaction, providing access to a range of diversely substituted tetracyclic spiroindolines. These complex polycyclic scaffolds are valuable building blocks for the construction of indole alkaloids, as showcased in a concise total synthesis of (±)-akuammicine.
- Faltracco, Matteo,Ruijter, Eelco
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p. 9641 - 9644
(2021/12/01)
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- Catalytic Asymmetric Alkynylation of 3,4-Dihydro-β-carbolinium Ions Enables Collective Total Syntheses of Indole Alkaloids
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Chiral tetrahydro-β-carboline (THβC) is not only a prevailing structural feature of many natural alkaloids but also a versatile synthetic precursor for a vast array of monoterpenoid indole alkaloids. Asymmetric synthesis of C1-alkynyl THβCs remains rarely explored and challenging. Herein, we describe the development of two complementary approaches for the catalytic asymmetric alkynylation of 3,4-dihydro-β-carbolinium ions with up to 96 % yield and 99 % ee. The utility of chiral C1-alkynyl THβCs was demonstrated by the collective total syntheses of seven indole alkaloids: harmicine, eburnamonine, desethyleburnamonine, larutensine, geissoschizol, geissochizine, and akuammicine.
- Liang, Lixin,Zhou, Shiqiang,Zhang, Wei,Tong, Rongbiao
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supporting information
p. 25135 - 25142
(2021/10/23)
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- Enantioselective Syntheses of Strychnos and Chelidonium Alkaloids through Regio- and Stereocontrolled Cooperative Catalysis
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We describe enantioselective syntheses of strychnos and chelidonium alkaloids. In the first case, indole acetic acid esters were established as excellent partner nucleophiles for enantioselective cooperative isothiourea/Pd catalyzed α-alkylation. This provides products containing indole-bearing stereocenters in high yield and with excellent levels of enantioinduction in a manner that is notably independent of the N-substituent. This led to concise syntheses of (?)-akuammicine and (?)-strychnine. In the second case, the poor performance of ortho-substituted cinnamyl electrophiles in the enantioselective cooperative isothiourea/Ir catalyzed α-alkylation was overcome by appropriate substituent choice, leading to enantioselective syntheses of (+)-chelidonine, (+)-norchelidonine, and (+)-chelamine.
- Fyfe, James W. B.,Hutchings-Goetz, Luke S.,Snaddon, Thomas N.,Yang, Chao
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p. 17556 - 17564
(2020/08/14)
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- Total Synthesis of Strychnine
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The total synthesis of the flagship Strychnos indole alkaloid, strychnine, has been accomplished. The developed synthetic sequence features a novel vinylogous 1,4-addition, a challenging iodinium salt mediated silyl enol ether arylation, a palladium-catalyzed Heck reaction, and a streamlined late-stage conversion to strychnine. Furthermore, an application of asymmetric counterion-directed catalysis (ACDC) in the context of target-oriented organic synthesis has been rendered access to an optically active material. The synthetic sequence described herein represents the most concise entry to optically active strychnine to date.
- Lee, Geun Seok,Namkoong, Gil,Park, Jisook,Chen, David Y.-K.
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p. 16189 - 16193
(2017/11/21)
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- Reaction of Donor-Acceptor Cyclobutanes with Indoles: A General Protocol for the Formal Total Synthesis of (±)-Strychnine and the Total Synthesis of (±)-Akuammicine
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A ligand-promoted catalytic [4+2] annulation reaction using indole derivatives and donor-acceptor (D-A) cyclobutanes is reported, thus providing an efficient and atom-economical access to versatile cyclohexa-fused indolines with excellent levels of diastereoselectivity and a broad substrate scope. In the presence of a chiral SaBOX ligand, excellent enantioselectivity was realized with up to 94 % ee. This novel synthetic method is applied as a general protocol for the total synthesis of (±)-akuammicine and the formal total synthesis of (±)-strychnine from the same common-core scaffold.
- Feng, Liang-Wen,Ren, Hai,Xiong, Hu,Wang, Pan,Wang, Lijia,Tang, Yong
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p. 3055 - 3058
(2017/03/13)
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- A sequential cycloaddition strategy for the synthesis of Alsmaphorazine B traces a path through a family of Alstonia alkaloids
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Driven by a new biogenetic hypothesis, the first total synthesis of alsmaphorazine B and several related indole alkaloids has been achieved. Numerous early approaches proved unsuccessful owing to unproductive side reactivity; nevertheless, they provided important clues that guided the evolution of our strategy. Critical to our success was a major improvement in our Zincke aldehyde cycloaddition strategy, which permitted the efficient gram-scale synthesis of akuammicine. The sequential chemoselective oxidations of akuammicine leading up to the key oxidative rearrangement also yielded several biogenetically related indole alkaloids en route to alsmaphorazine B.
- Hong, Allen Y.,Vanderwal, Christopher D.
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p. 4160 - 4171
(2017/06/29)
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- Biomimetic total syntheses of (-)-leucoridines A and C through the dimerization of (-)-dihydrovalparicine
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Concise biomimetic syntheses of the Strychnos-Strychnos-type bis-indole alkaloids (-)-leucoridine A (1) and C (2) were accomplished through the biomimetic dimerization of (-)-dihydrovalparicine (3). En route to 3, the known alkaloids (+)-geissoschizoline (8) and (-)-dehydrogeissoschizoline (10) were also prepared. DFT calculations were employed to elucidate the mechanism, which favors a stepwise aza-Michael/spirocyclization sequence over the alternate hetero-Diels-Alder cycloaddition reaction. Concise biomimetic syntheses of the Strychnos-Strychnos-type bis-indole alkaloids (-)-leucoridine A and C were accomplished through the biomimetic dimerization of (-)-dihydrovalparicine. DFT calculations were used to elucidate the mechanism, which favors a stepwise aza-Michael/spirocyclization sequence over the alternate hetero-Diels-Alder cycloaddition reaction.
- Kokkonda, Praveen,Brown, Keaon R.,Seguin, Trevor J.,Wheeler, Steven E.,Vaddypally, Shivaiah,Zdilla, Michael J.,Andrade, Rodrigo B.
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supporting information
p. 12632 - 12635
(2015/10/28)
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- Total syntheses of (-)-alstolucines A, B, and F, (-)-echitamidine, and (-)-N-demethylalstogucine
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Abstract The first enantioselective total syntheses of (-)-alstolucinces A, B, and F, (-)-echitamidine, and (-)-N-demethylalstogucine are reported. This article details the development of our first- and second-generation approaches toward the ABCE tetracyclic core of the strychnos alkaloids and the application thereof to the aforementioned targets. Key steps involve our sequential one-pot biscyclization method that constructs the C and E rings of the tetracyclic core and Rawal's application of the intramolecular Heck reaction to secure the pentacyclic framework common amongst all targets.
- Teijaro, Christiana N.,Zhao, Senzhi,Kokkonda, Praveen,Andrade, Rodrigo B.
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p. 1547 - 1556
(2015/06/02)
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- Synthesis and biological evaluation of pentacyclic strychnos alkaloids as selective modulators of the ABCC10 (MRP7) efflux pump
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The selective modulation of ATP-binding cassette (ABC) efflux pumps overexpressed in multidrug resistant cancers (MDR) and attendant resensitization to chemotherapeutic agents represent a promising strategy for treating cancer. We have synthesized four novel pentacyclic Strychnos alkaloids alstolucines B (2), F (3), and A (5) and N-demethylalstogucine (4), in addition to known Strychnos alkaloid echitamidine (16), and we evaluated compounds 1-5 in biochemical assays with ABCC10 and P-glycoprotein (P-gp). Alstolucines B (2) and F (3) inhibited ABCC10 ATPase activity at 12.5 μM without affecting P-gp function; moreover, they resensitized ABCC10-transfected cell lines to paclitaxel at 10 μM. Altogether, the alstolucines represent promising lead candidates in the development of modulators of ABCC10 for MDR cancers overexpressing this pump.
- Teijaro, Christiana N.,Munagala, Surendrachary,Zhao, Senzhi,Sirasani, Gopal,Kokkonda, Praveen,Malofeeva, Ekaterina V.,Hopper-Borge, Elizabeth,Andrade, Rodrigo B.
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p. 10383 - 10390
(2015/02/19)
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- Collective synthesis of natural products by means of organocascade catalysis
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Organic chemists are now able to synthesize small quantities of almost any known natural product, given sufficient time, resources and effort. However, translation of the academic successes in total synthesis to the large-scale construction of complex natural products and the development of large collections of biologically relevant molecules present significant challenges to synthetic chemists. Here we show that the application of two nature-inspired techniques, namely organocascade catalysis and collective natural product synthesis, can facilitate the preparation of useful quantities of a range of structurally diverse natural products from a common molecular scaffold. The power of this concept has been demonstrated through the expedient, asymmetric total syntheses of six well-known alkaloid natural products: strychnine, aspidospermidine, vincadifformine, akuammicine, kopsanone and kopsinine.
- Jones, Spencer B.,Simmons, Bryon,Mastracchio, Anthony,MacMillan, David W. C.
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p. 183 - 188
(2012/05/20)
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- Biogenetically inspired approach to the Strychnos alkaloids. Concise syntheses of (±)-akuammicine and (±)-strychnine
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A linear synthesis of the indole alkaloid (±)-akuammicine (2) was completed by a novel sequence of reactions requiring only 10 steps from commercially available starting materials. The approach features a tandem vinylogous Mannich addition and an intramol
- Ito,Clark,Mortimore,Goh,Martin
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p. 8003 - 8010
(2007/10/03)
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- A general synthetic entry to Strychnos alkaloids of the curan type via a common 3a-(2-nitrophenyl)hexahydroindol-4-one intermediate. Total syntheses of (±)- and (-)-tubifolidine, (±)-akuammicine, (±)-19,20-dihydroakuammicine, (±)-norfluorocurarine, (±)-ec
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A general strategy for the synthesis of pentacyclic Strychnos alkaloids with the curan skeleton has been developed. It utilizes 3a-(2-nitrophenyl)hexahydroindol-4-one (23), which was prepared from 2-allyl-2-(2-nitrophenyl)-1,3-cyclohexanedione (15), as th
- Bonjoch, Josep,Solé, Daniel,García-Rubio, Silvina,Bosch, Joan
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p. 7230 - 7240
(2007/10/03)
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- A new solution for the construction of the piperidine ring of Strychnos alkaloids from 3a-(o-nitrophenyl)hexahydroindol-4-ones. Total syntheses of (±)-tubifolidine, (±)-dihydroakuammicine, and (±)-akuammicine
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Alkylation of cis-3a-(o-nitrophenyl)hexahydroindol-4-one 1 with 1-iodo- 4-(trimethylsilyl)-2-butyne followed by BF3·Et2O-promoted cyclization of the resulting propargylic silane 2 afforded the tricyclic vinylidene ketone 3, which was further converted to the Strychnos alkaloids tubifolidine, 19,20-dihydroakuammicine, and akuammicine.
- Sole, Daniel,Bonjoch, Josep,Garcia-Rubio, Silvina,Suriol, Ramon,Bosch, Joan
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p. 5213 - 5216
(2007/10/03)
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- The aza-Cope-Mannich approach to Strychnos alkaloids. Short stereocontrolled total syntheses of (±)-dehydrotubifoline and (±)-akuammicine
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A direct approach for the total synthesis of Strychnos alkaloids has been developed. The key strategic element is the aza-Cope-Mannich rearrangement (Scheme II) of formaldiminium ions derived from azabicyclo[3.2.1]octanols 5 (Scheme I). This reorganizatio
- Angle, Steven R.,Fevig, John M.,Knight, Steven D.,Marquis Jr., Robert W.,Overman, Larry E.
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p. 3966 - 3976
(2007/10/02)
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