Letter pubs.acs.org/OrgLett
Asymmetric Total Synthesis of (−)-Aspidophylline A Taimin Wang,† Xiaoguang Duan,† Hua Zhao,‡ Shengxian Zhai,† Cheng Tao,† Huifei Wang,‡ Yun Li,† Bin Cheng,† and Hongbin Zhai*,†,‡,§ †
The State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China ‡ Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen 518055, China § Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China S Supporting Information *
ABSTRACT: An asymmetric total synthesis of (−)-aspidophylline A has been accomplished. The key transformations include an asymmetric hydride transfer hydrogenation of an α,β-acetylenic ketone and a cationic gold(I)-catalyzed 6-exo-dig cyclization involving an alkynylindole/aminal formation cascade, which enables stereoselective establishment of the requisite quaternary carbon center.
T
molecule of aspidophylline A consists of a peculiar furoindoline unit as well as a unique polysubstituted cyclohexane backbone with five contiguous stereogenic centers. The remarkable structural features of (−)-aspidophylline A, coupled with its notable bioactivities, have rendered it an attractive target molecule for the synthetic community.8 In 2011, the first breakthrough in the total synthesis of (±)-aspidophylline A came from the group of Garg, who exploited a Heck cyclization to assemble the [3.3.1]-bicyclic scaffold as well as an elegant late-stage interrupted Fischer indole cyclization.9 In 2013, Shi and co-workers reported an approach to the pentacyclic core of aspidophylline that featured an intramolecular azidoalkoxylation of an enecarbamate and a ruthenium-catalyzed atom-transfer cyclization.10 In 2014, Ma11 and Zhu12 disclosed back-to-back their novel total syntheses of (±)-aspidophylline A: the former featured an intramolecular oxidative coupling reaction for assemblage of the furoindoline ring system,11 and the latter involved a 1,3-cyclohexanedione desymmetrization and an oxidative azidoalkoxylation as key transformations.12 Recently, the first enantioselective total synthesis of (−)-aspidophylline A was reported by Garg, utilizing a Trost desymmetrization and a gold-mediated cyclization.3c Almost at the same time, the group of Yang completed an asymmetric route to this complex natural product that used a highly enantioselective indole allylic alkylation/ iminium cyclization cascade reaction.13 In connection with our continued interest in the total synthesis of indole alkaloids,14
he akuammiline alkaloids are a highly diverse and ubiquitous family of intricate indole alkaloids, more than 30 of which have been isolated and characterized so far.1 Preliminary studies have indicated that these natural products possess a wide range of biological activities. 1 Several representative akuammiline alkaloids are outlined in Figure 1,
Figure 1. Representative akuammiline alkaloids.
and their intriguing structural complexity poses particular synthetic challenges.2−6 Aspidophylline A (2), a member of the akuammiline alkaloids isolated from Malayan Kopsia Singapurensis by Kam a decade ago, showed promising activity in reversing drug resistance in resistant human KB nasopharyngeal cancer cells.7 Structurally, the intricate pentacyclic cagelike © 2017 American Chemical Society
Received: February 14, 2017 Published: March 23, 2017 1650
DOI: 10.1021/acs.orglett.7b00448 Org. Lett. 2017, 19, 1650−1653
Letter
Organic Letters here we report an asymmetric total synthesis of (−)-aspidophylline A that takes advantage of a cationic gold(I)-catalyzed 6-exo-dig cyclization of alkynylindole/aminal formation cascade, which enables efficient assembly of the unique polycyclic system and stereoselective establishment of the requisite quaternary carbon center.15 Our retrosynthetic analysis of the asymmetric total synthesis of (−)-aspidophylline A is delineated in Scheme 1. The bridged
Scheme 2. Synthesis of Propargyl Alcohol 15
Scheme 1. Retrosynthetic Analysis of (−)-Aspidophylline A
developed by Wang and co-workers.19 Gratefully, desilylation of the terminal alkyne followed by treatment with Ph3PAuCl in the presence of AgSbF6 as cocatalyst resulted in the cyclization product 16, which was directly subjected to 2,6-lutidine and TMSOTf to effect the tetrahydrofuran ring-opening reaction in the same pot.12,20 With compound 9 in hand, we focused our attention on C−N bond formation. As an initial attempt, direct azidation of compound 9 itself by CAN and NaN3 turned out to be disappointing, giving 18 in a very low yield. Compound 18 was separable by SiO2 column chromatography, and X-ray crystallographic analysis of (±)-18 confirmed that the stereogenic centers had been installed as required;21 but in this case, the TMS group of compound 9 was hardly removable at low temperatures. In contrast, if the reaction temperature was increased, inferior stereoselectivity was observed and more of the byproducts were generated. In an alternative attempt, the desired product 19 was formed through prior desilylation in the presence of PPTS followed by treatment with CAN (Scheme 3). Because of the weak acidity of the reaction mixture,
piperidine ring of (−)-aspidophylline A could possibly be assembled by [Ni(cod)2]-mediated cyclization of compound 7, which would be accessible from azide 8 by a series of functional group interconversions that would install the α,β-unsaturated ester moiety. In a key synthetic step, 8 could be constructed via azidoalkoxylation from the tricycle 9 which, in turn, could be generated from a gold-catalyzed cyclization of the alkynylindole 10. Compound 10, with the desired stereochemical configuration, could be obtained through an asymmetric hydridetransfer hydrogenation from the alkynyl ketone 11. Compound 11 could be prepared from the Weinreb amide 12, which would be available from known tryptophol 13 via intermolecular alkenylation of indole at C2. As outlined in Scheme 2, our synthesis commenced from the known tryptophol 13,16 which was subjected to direct C−H functionalization via a palladium-catalyzed alkenylation to afford the desired unsaturated amide 12 in 50% yield.17 Hydrogenation of 12 followed by treatment with (trimethylsilyl)ethynyllithium furnished ethynyl ketone 11. Asymmetric carbonyl reduction of ketone 11 was then explored. First, the Corey−Bakshi−Shibata reduction conditions were examined, delivering 15 in moderate yield and only 38% ee. Much to our delight, asymmetric reduction was achieved by hydride-transfer hydrogenation catalyzed by [RuCl(p-cymene){(S,S)-TsDPEN}],18 thus providing the corresponding propargyl alcohol 15 in up to 91% yield and in 96.8% ee. Notably, the newly formed stereocenter determines all the remaining stereochemistry based upon substrate control. We next investigated the gold(I)-catalyzed hydroarylation, a key transformation for the synthesis, by following the protocol
Scheme 3. Synthesis of Compound 19
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DOI: 10.1021/acs.orglett.7b00448 Org. Lett. 2017, 19, 1650−1653
Letter
Organic Letters azidoalkoxylation, desilylation, and tetrahydrofuran ring formation all occurred in a one pot fashion. Intramolecular azidoalkoxylation took place at 0 °C; after 17 was completely consumed, the reaction mixture was warmed to 30 °C and stirred at this temperature for 24 h, leading to the expected secondary alcohol 19 with high stereoselectivity (dr >20:1).10,12,22 With the tetracycle 19 secured, we turned our attention toward installing the α,β-unsaturated ester. TBS-protection of allylic alcohol and reduction of the azide under Staudinger conditions followed by nosylation furnished sulfonamide 20 in a good overall yield (76%, three steps). Compound 20 was subjected to hydroboration followed by oxidative workup to produce a primary alcohol, which was converted into aldehyde 21 by IBX oxidation in 61% yield over two steps. In order to generate unsaturated aldehyde 22 in a single step, a variety of reaction conditions were examined. We were finally delighted to find that treatment of 21 with TBAF directly furnished the desired elimination product 22 in 91% yield.23 Then, Pinnick oxidation followed by reaction with freshly prepared CH2N2 led to ester 23 (Scheme 4).
Scheme 5. Completion of the Total Synthesis of (−)-Aspidophylline
Scheme 4. Synthesis of Unsaturated Ester 23
cationic gold(I)-catalyzed 6-exo-dig cyclization involving an alkynylindole/aminal formation cascade reaction followed by an intramolecular azidoalkoxylation of 17, which was utilized to construct the desired challenging tetracyclic framework of (−)-aspidophylline A with high stereoselectivity. Further applications of this cascade reaction to the total synthesis of other related akuammiline alkaloids is under investigation in our group and will be reported in due course.
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00448. Crystallographic data for (±)-18 (CIF) Experimental details; NMR data; HPLC traces (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected].
With α,β-unsaturated ester 23 in hand, we entered the final stages of the total synthesis of (−)-aspidophylline A (Scheme 5). Nosyl deprotection with thiophenol/K2CO3 furnished the corresponding amine, which underwent an N-alkylation with (Z)-1-bromo-2-iodo-2-butene (24) without purification, providing 7 in 73% yield over two steps. N-Formylation of 7 under the standard conditions proceeded uneventfully to form 25 in 90% yield. The piperidine ring of (−)-aspidophylline A was installed through [Ni(cod)2]-mediated cyclization of the vinyl iodide 25, which led to the pentacycle 26 in 68% yield (dr = 5:1).11,14c,24 Finally, deprotection of 26 with TMSOTf delivered the akuammiline alkaloid (−)-aspidophylline A in 92% yield (over 100 mg obtained in a single batch), and the synthetic sample displayed spectral (HRMS, 1H and 13C NMR) and physical (optical rotation) properties in agreement with those reported in the literature.7a In summary, we have developed a concise strategy for the synthesis of (−)-aspidophylline A. The key transformations include an asymmetric hydride-transfer hydrogenation and a
ORCID
Hongbin Zhai: 0000-0003-2198-1357 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the NSFC (21272105, 21672017, 21290183, 21472072), Shenzhen Science and Technology Innovation Committee (JCYJ20150529153646078, JSGG20160229150510483), Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT: IRT_15R28), and “111” Program of MOE for financial support.
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