Asymmetric Total Synthesis of Yuzurimine-Type Daphniphyllum Alkaloid (+)-Caldaphnidine J
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ARTICLE https://doi.org/10.1038/s41467-020-17350-x OPEN Asymmetric total synthesis of yuzurimine-type Daphniphyllum alkaloid (+)-caldaphnidine J Lian-Dong Guo 1, Yan Zhang 1,2, Jingping Hu 1,2, Chengqing Ning 1, Heyifei Fu1, Yuye Chen 1 & ✉ Jing Xu 1 Ever since Hirata’s report of yuzurimine in 1966, nearly fifty yuzurimine-type alkaloids have been isolated, which formed the largest subfamily of the Daphniphyllum alkaloids. Despite 1234567890():,; extensive synthetic studies towards this synthetically challenging and biologically intriguing family, no total synthesis of any yuzurimine-type alkaloids has been achieved to date. Here, the first enantioselective total synthesis of (+)-caldaphnidine J, a highly complex yuzurimine- type Daphniphyllum alkaloid, is described. Key transformations of this approach include a highly regioselective Pd-catalyzed hydroformylation, a samarium(II)-mediated pinacol cou- pling, and a one-pot Swern oxidation/ketene dithioacetal Prins reaction. Our approach paves the way for the synthesis of other yuzurimine-type alkaloids and related natural products. 1 Shenzhen Grubbs Institute and Department of Chemistry and Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and ✉ Technology, 518055 Shenzhen, China. 2These authors contributed equally: Yan Zhang, Jingping Hu. email: [email protected] NATURE COMMUNICATIONS | (2020) 11:3538 | https://doi.org/10.1038/s41467-020-17350-x | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-17350-x O he plant family of genus Daphniphyllum has produced a O wide range of complex caged natural products—the O O T 1–4 H Daphniphyllum alkaloids . Owing to their challenging H H OH chemical structures and interesting biological profiles (such as H 5,6 anticarcinogenic, neurotrophic, and anti-HIV activity) , these N N N OAc alkaloids have drawn much attention from the synthetic AcO 1,3,4 fi community . Depending on the taxonomy, the diversi ed Common skeleton of H H structures of the Daphniphyllum alkaloids can be categorized into Yuzurimine-type alkaloids Caldaphnidine J Yuzurimine 13–35 subfamilies1,4,7. To date, about 20 elegant total syntheses of the Daphniphyllum alkaloids, from seven subfamilies, have been O O O – reported by the research groups of Heathcock8 15, Carreira16, O O O – 17 20 21,22 23 24 25 H H H H Li , Smith , Hanessian , Fukuyama/Yokoshima , Zhai , H H OH Dixon26, Qiu27, Gao28, and Sarpong29,30 groups, respectively. H Moreover, our group has recently accomplished the asymmetric O 31 32 N O N OAc N total syntheses of himalensine A , dapholdhamine B , and H HO 33 caldaphnidine O . However, despite extensive synthetic stu- H H H 34–48 — dies , total synthesis of yuzurimine-type alkaloids the largest Daphcalycine Daphnezomine J Yunnandaphnine E subfamily of the Daphniphyllum alkaloids—has not been achieved so far. Fig. 1 Yuzurimine-type Daphniphyllum alkaloids. Our target molecule, Since the milestone achievement by Hirata in 196649, nearly 50 caldaphnidine J, are highlighted in color, which posed a formidable synthetic yuzurimine-type alkaloids were isolated, which account for challenge for accessing its total synthesis. almost one-sixth of all known Daphniphyllum alkaloids to date. It is recognized that the members of this subfamily share a unique, O O O highly complex and caged hexacyclic skeleton (Fig. 1). Caldaph- O nidine J, our target molecule, was isolated by the Yue group in H H Ni(0)-mediated 50 2008 . It possesses a hexacyclic scaffold with six contiguous reductive coupling Br H stereogenic centers, two quaternary centers, and an α,β,γ,δ- N unsaturated carboxylic ester thus signifying a formidable syn- N thetic challenge. Following our long-lasting interest in the H 31–33,51,52 H synthesis of the Daphniphyllum alkaloids , we now wish (+)–Caldaphnidine J 1 to report an asymmetric total synthesis of yuzurimine-type alkaloid, (+)-caldaphnidine J. Our approach is featured with a Ketene dithioacetal Prins reaction Pd-catalyzed regioselective hydroformylation that furnishes the critical aldehyde motif, and the construction of the 5/5 bicyclic S S system using a SmI2-promoted pinacol coupling and a one-pot OBn OBn Enyne acetal Swern oxidation/ketene dithioacetal Prins reaction. Other notable O Ring Nazarov O attempts toward the 7/5 bicycle in our target molecule are also cleavage carbocyclization OH H discussed. Ts N Results N N CH(OMe)2 Retrosynthetic analysis. As shown in Fig. 2, our retrosynthetic Ts Ts H 4 3 2 analysis indicates that (+)-caldaphnidine J could be converted from the intermediate 1 via Ni(0)-mediated reductive coupling Fig. 2 Retrosynthetic analysis of (+)-caldaphnidine J. The key reaction53. It was further envisioned that a ketene dithioacetal disconnections include a Ni(0)-mediated reductive coupling reaction, a – Prins reaction54 57 would form the cyclopentene moiety in 1, ketene dithioacetal Prins reaction, an enyne acetal Nazarov carbocyclization while compound 2 might be produced from the enyne acetal 3 via and a ring cleavage strategy. a carbocyclization cascade58. Lastly, compound 3 could be syn- thesized via a facile ring cleavage from the readily available chiral 33 the acetal motifs in compound 9 returned only messy mixtures. It building block, tricyclic ketone 4 . was postulated that the desired cyclization was prevented by the steric bulk at C-8 (caldaphnidine J numbering). Initial synthetic studies toward the 7/5 ring system. The first On the other hand, aldol condensation of 5 yielded solely stage of our investigation focused on the critical 7/5 ring scaffold cyclopentene 11, but not cycloheptenone 12 possessing the assembly (Fig. 3). The treatment of the known tricycle 433 with desired seven-membered ring (Fig. 3). Instead, selective reduction MeMgBr in the presence of CeCl3 was followed by an oxidative of the aldehyde motif in 5 followed by an Appel reaction afforded cleavage of the intermediate diol producing dicarbonyl 5. Sub- the corresponding alkyl iodide, which then underwent an sequently, 5 was subjected to Wittig conditions to yield the enol intramolecular alkylation upon treatment with LDA yielding methyl ether, which was then transformed into acetal 6. Fol- the desired tricycle 13 in 69% overall yield. Inspired by Smith’s lowing Stang’s protocol59, ketone motif in 6 was converted into impressive work21,22, it was envisioned that a carbonylative Stille an enol triflate, which was then treated with pyridine affording coupling reaction followed by a Nazarov cyclization would alkyne 7. Subsequent Sonogashira coupling yielded enyne acetal elaborate the desired bicycle 8. While ketone 13 is quite similar to 3. Inspired by Saá’s impressive Nazarov carbocyclization cas- Smith’s substrates21,22, in our hands all of the deprotonation cade58, enyne acetal 3 was treated with Brønsted acids such as attempts failed resulting in no reaction at negative and • TFA or HBF4 OEt2. However, none of the desired hydro- decomposition events at elevated temperatures. It is quite possible azulenone 8 was detected. Alternatively, attempting to use a that the corresponding enol triflate 14 is unstable by introducing formic acid-promoted cyclization60,61 between the thioalkyne and increased ring strain to the 6/6/7 tricyclic system. 2 NATURE COMMUNICATIONS | (2020) 11:3538 | https://doi.org/10.1038/s41467-020-17350-x | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-17350-x ARTICLE OBn OBn OBn OBn OBn 3) NaBH4 O 3) K CO 4) I2, PPh3 Carbonylative 2 3 H H H H O DMSO 5) LDA O OTf Stille coupling Nazarov 8 Ts N O 100 °C 69% Ts N Ts N Ts N 95% N H Ts H H H 12 (0%) 11 (95%) 13 14 15 OBn OBn OBn OBn O O O 1) MeMgBr, CeCl + – 5) PhNTf , KHMDS 3 3) CH3OCH2PPh3 Cl , 2 OH 2) Pb(OAc) 6) Pyridine, 70 °C 4 KHMDS OMe OMe OMe OMe 91% for 2 steps 4) p-TsOH, CH(OMe)3, 89% for 2 steps MeOH/CH Cl , N N O 2 2 N N 72% (2 steps) Ts Ts Ts Ts (±)–4, known 56 7 7) Bromoethene Pd(PPh 3)2Cl2, CuI, TEA, 50% OBn OBn 7) nBuLi, THF, −78 °C; OBn S-p-Tol Di-p-tolyl disulfide, O MeI,THF O 8) TFA or BnO H H 8) HCOOH −78 °C, 92% HBF4•OEt2 S 8 O 8 OMe O OMe Ts N 100 °C Ts N N N H 10 Ts 9 H 8 Ts 3 Fig. 3 Initial studies towards the 7/5 ring system. Bn benzyl, KHMDS potassium bis(trimethylsilyl)amide, LDA lithium diisopropylamide, Tf trifluoromethanesulfonyl, TFA trifluoroacetic acid, TEA triethylamine, Ts toluenesulfonyl. Total synthesis of (+)-caldaphnidine J. The fruitless synthetic explored. There are only a handful of examples reported in an attempts toward the 7/5 bicyclic ring scaffold forced us to use the intermolecular manner54–57. Inspired by these investigations, it similar strategy to the total synthesis of caldaphnidine O33.As was envisaged that oxidation of the hydroxyl at C-15 would depicted in Fig. 4, treatment of ketone 4 with AllylMgBr in the produce the corresponding ketone motif, and the following presence of CeCl3 furnished a diol intermediate, which was ketene dithioacetal Prins-type reaction should form the crucial subjected to a Pb(IV)-mediated oxidative cleavage. A follow-up C–C bond thus constructing the desired pentacycle. To our β γ NaBH4 reduction yielded a somewhat unstable , -unsaturated delight, subjecting diol 25 to a TFAA/DMSO-mediated Swern ketone 16, which was immediately subjected to iodination pro- oxidation triggered the desired cyclization of the dithioacetal ducing alkyl iodide 17. Subsequently, treating 17 with LDA ketene onto a newly formed ketone moiety. The ultimate product triggered an intramolecular alkylation to afford α-vinyl functio- 26 was then formed by 1,2-addition of dimethyl sulfide onto the nalized ketones 18a (minor, 25%) and 18b (major, 50%).