Divergent Entry to Gelsedine-Type Alkaloids: Total Syntheses of

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Divergent Entry to Gelsedine-Type Alkaloids: Total Syntheses of (−)-Gelsedilam, (−)-Gelsenicine, (−)-Gelsedine, and (−)-Gelsemoxonine Pingluan Wang,† Yang Gao,† and Dawei Ma*

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State Key Laboratory of Bioorganic & Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China S Supporting Information *

ABSTRACT: The gelsedine-type alkaloids possess a common oxabicyclo[3.2.2]nonane core and spiro-Nmethoxyindolinone moiety along with a diversely functionalized heterocycle embedded in the compact framework. Herein we disclose a divergent entry to gelsedine-type alkaloids that hinges on rapid assembly of the common core by the orchestrated application of an asymmetric Michael addition, a tandem oxidation/aldol cyclization, and a pinacol rearrangement and generation of the structural diversity via a late-stage heterocyclization. The power of this strategy has been demonstrated through very short total syntheses of four gelsedine-type alkaloids: gelsedilam, gelsenicine, gelsedine, and gelsemoxonine.

Figure 1. Three indolinone subclasses of Gelsemium alkaloids.

syntheses7−12 have been reported to date. Of particular note are Fukuyama’s landmark synthesis of gelsemoxonine (6) featuring a divinylcyclopropane−cycloheptadiene rearrangement to assemble the spiro-quaternary center connected to the oxabicyclo[3.2.2]nonane core skeleton8 and Carreira’s elegant synthesis of the same target molecule, wherein a novel ring contraction was utilized to furnish the unique azetidine moiety.9 Very recently, Ferreira and co-workers adopted a catalyzed cycloisomerization strategy to complete the first total synthesis of gelsenicine (4).10 Soon after that, the unified total synthesis of five gelsedine-type alkaloids was achieved by the Fukuyama group from a common intermediate.11 In addition, Zhao published a total synthesis of gelsidilam by means of thiol-mediated conjugate addition-aldol reaction.12 Despite these innovative strategies, efforts toward more efficient routes to this family have been scarce. Moreover, given the fact that the comprehensive biological profiles of these alkaloids remain unclear, we sought to develop a more efficient and divergent synthetic strategy whereby large collections of natural products or unnatural analogues could be rapidly assembled for use as lead compounds or biological probes. Herein we report the successful development of a divergent entry to gelsedine-type alkaloids that culminates in short asymmetric total syntheses of (−)-gelsidilam (5), (−)-gelsenicine (4), (−)-gelsedine (3), and (−)-gelsemoxonine (6) without using protecting groups.

Treating human diseases by means of plant extracts has a rich history in traditional medicine all around the world. Plants from the genus Gelsemium, native to subtropical and tropical Asia and North America, are recognized as poisonous species and have been widely used in traditional Asian medicine to treat skin ulcers, dermatitis, and various ailments for over a thousand years.1 Extensive phytochemical studies on Gelsemium plants have led to the isolation of a series of structurally diverse alkaloids,2 some of which exhibit a variety of promising therapeutic properties, including analgesic, anti-inflammatory, and immunomodulating characteristics in addition to potent antitumor activity.3 Nevertheless, the narrow therapeutic window of these alkaloids limits their clinical use because of the lack of comprehensive biological profiling, which is largely hampered by synthetic accessibility. Among the five known classes of Gelsemium alkaloids, three subfamilies possess a common spiro-indolinone motif, namely, the gelsemine, humantenine, and gelsedine types (Figure 1). The interesting biological activities displayed by Gelsemium alkaloids and their densely packed polycyclic architectures have received great attention from the synthetic community. Notably, tremendous efforts have been devoted to the development of synthetic approaches toward gelsemine (1) (Figure 1), the flagship member of this family, resulting in nine total syntheses4 in the past two decades. Gelsedine-type alkaloids, as the largest subfamily of the Gelsemium alkaloids (>60 members isolated to date), have received relatively less attention,5 and only a handful of semisyntheses6 and total © 2018 American Chemical Society

Received: July 31, 2018 Published: August 30, 2018 11608

DOI: 10.1021/jacs.8b08127 J. Am. Chem. Soc. 2018, 140, 11608−11612

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Journal of the American Chemical Society From a structural standpoint, gelsedine-type alkaloids possess a common oxabicyclo[3.2.2]nonane core and spiroN-methoxyindolinone moiety along with a diversely functionalized heterocycle (e.g., a pyrrolidine, pyrroline, pyrrolidinone, or azetidine ring) embedded in the compact framework (3−6; Figure 1). Our retrosynthetic analysis of these molecules is depicted in Scheme 1. We envisioned that the synthetic

Scheme 2. Construction of the Key Intermediates 17 and 20

Scheme 1. Retrosynthetic Analysis of Gelsedine-Type Alkaloids

gramine in three steps)16 and dihyropyranone 15 with a variety of organic bases all met with failure, leading to decomposition of both coupling partners in most cases. Exhaustive experiments revealed that inorganic bases drastically promoted the asymmetric Michael addition, providing the desired adduct 16 in 95% yield as a 1:1 diastereoisomeric mixture under the optimized conditions. Careful structural analysis confirmed that the dr value originated from the α-position of the nitro group, which in turn indicated that the chiral center at the anomeric position fully controlled the other newly formed stereocenter. Moving forward, we sought to establish the quaternary stereocenter of the spiro-N-methoxyindolinone via a tandem oxidation/aldol cyclization sequence. A stereochemical question regarding the configuration of the pivotal quaternary center had to be addressed, and two possible transition states (21a and 21b) were envisioned for this key cyclization. We speculated that there would be considerable steric repulsion between the nitro group and the benzene ring in transition state 21b, whereas transition state 21a would be more favorable, leading to the cyclization product with the configuration matching that of the natural products. Furthermore, the stabilizing hydrogen-bonding interactions17 between the nitro group and the hydroxyl group would also favor intermediate 21a. Much to our delight, treatment of Nchlorosuccinimide (NCS) and water allowed for the formation of oxindole through hydrolysis of the corresponding 2chloroindole,18 which underwent a concomitant aldol cyclization to exclusively produce oxabicyclo[3.3.1]nonane 17 as a single isomer in 90% yield. To the best of our knowledge, this

diversity of these natural products could be realized through tetracyclic nitro compound 8 or 9 via a late-stage heterocyclization process. Specifically, gelsemoxonine (6), a unique azetidine-containing alkaloid, could be derived from epoxide 7 through a biomimetic cyclization.13 The pyrrolidine and pyrroline, meanwhile, were expected to be formed by intramolecular condensation and reduction from ethyl ketone 8. Likewise, the pyrrolidinone core in 5 could be accessed by reduction of the nitro group and the alkene in ester 9 followed by lactamization. Compound 8 or 9 was anticipated to be derived from a versatile intermediate 10 by a general strategy of acylation at the α-position of the ketone followed by a series of functional group manipulations. The oxabicyclo[3.2.2]nonane skeleton of 10 could be constructed by a key oxonium ion-induced pinacol rearrangement14 of greatly simplified oxabicyclo[3.3.1]nonane 11. The quaternary stereocenter of the indolinone moiety in 11 could be built through a tandem oxidation/aldol cyclization of tricyclic 12, which would be further divided in half via an asymmetric Michael addition to deliver the two simple known compounds 13 and 14. With the above analysis in mind, we first investigated the asymmetric Michael addition, as shown in Scheme 2. Taking inspiration from Varela’s seminal work,15 we decided to choose (−)-menthol-derived enone 15 (readily accessible from Larabinose in four steps with dr > 98:2) as the Michael acceptor, in the hope of accessing serviceable stereocontrol. Initial attempts to treat indole fragment 13 (easily prepared from 11609

DOI: 10.1021/jacs.8b08127 J. Am. Chem. Soc. 2018, 140, 11608−11612

Communication

Journal of the American Chemical Society

leading to the formation of 23 as a 1:1 diastereomeric mixture. Next, the enol mixture 23 was converted to the corresponding enol triflate 24 under conditions of trifluoromethanesulfonic anhydride (Tf2O) and Hünig’s base. Subsequent reductive removal of the triflate group was achieved by treatment with Pd(PPh3)4 and triethylsilane (Et3SiH)8a to furnish the penultimate α,β-unsaturated methyl ester 25. We found that the base and elevated temperature were essential for the complete epimerization to produce the more thermodynamically stable isomer 25. Finally, the synthetic route was completed by nickel borohydride-mediated reduction of the alkene and the nitro group to give an uncyclized intermediate that delivered enantioenriched (−)-gelsedilam (5) upon heating with silica gel at 40 °C. Overall, 5 was obtained in 24% overall yield in only seven steps from 13 and 15. Our attention then turned to achieving a different late-stage heterocyclization to deliver (−)-gelsenicine (4) and (−)-gelsedine (3) (Scheme 4). One overarching problem to be solved

oxidation/cyclization cascade reaction represents one of the few examples of a ketone aldol reaction of 3-substituted oxindoles.19 It is worth noting that quenching with silica gel and triethylamine was essential for complete epimerization of the nitro group to form the more thermodynamically stable isomer 17, whose absolute configuration and structural assignment were confirmed by X-ray crystallographic analysis (Scheme 2). With ample quantities of 17 in hand, the stage was set to exploit the pivotal pinacol rearrangement. Myriad Lewis and Brønsted acids were evaluated, and we were pleased to find that adding p-toluenesulfonic acid (p-TsOH) to 17 in toluene solution and heating the mixture at reflux successfully effected the oxonium ion-induced pinacol rearrangement20 to give the key intermediate 20 in 54% isolated yield, whose structure was unambiguously determined by X-ray crystallographic analysis. However, this procedure suffered from poor reproducibility, especially at large scales, which affected the ensuing divergent synthesis. After extensive optimization, we ultimately found that heating a mixture of aluminum chloride (AlCl3) and 17 in toluene/Et2O (10:1 v/v) at reflux dramatically promoted the yield (86%) on a 30 mmol scale with excellent reproducibility, providing ketone 20 (8.6 g) in a single pass. The AlCl3/ether complex, mainly used in the fields of olefin polymerization21 and aromatic alkylation,22 was particularly effective for this transformation, presumably because of its mild Lewis acidity, since the employment of AlCl3 alone led to total decompostion of 17. Furthermore, the structurally related Lewis acids Al(OEt)2Cl and Al(OEt)Cl2, possibly produced by heating AlCl3 and ether, were also tested for the crucial pinacol rearrangement. Interestingly, the former kept 17 intact while the latter was able to partially accelerate the transformation. Having achieved rapid assembly of the common tetracyclic scaffold in a highly efficient manner, we were positioned to test the feasibility of the divergent synthesis, and the total synthesis of (−)-gelsidilam was pursued first (Scheme 3). Treatment of 20 with potassium hexamethyldisilazide (KHMDS) and Mander’s reagent23 (methyl cyanoformate) introduced a carbomethoxy group at the α-position of the ketone group in 73% yield. An inconsequential epimerization at the α-position of the nitro group was also observed during the procedure,

Scheme 4. Completion of the Divergent Total Syntheses of Gelsedine-Type Alkaloids

Scheme 3. Endgame of the Total Synthesis of (−)-Gelsedilam (5)

was how to introduce a 1-propanoyl group at the α-carbon of the ketone group in 20 in a direct manner. This seemingly simple conversion proved to be remarkably difficult. Indeed, after extensive efforts on direct introduction of the 1-propanoyl motif were met with failure, Fukuyama and co-workers developed a five-step sequence to circumvent this obstacle.8 Not to be deterred, we set out to study the key acylation by changing every conceivable variable, including the base used to deprotonate, the acylation reagent, the solvent, and the temperature. Emerging from this exhaustive study was the finding that treatment of 20 with KHMDS and freshly distilled propionyl cyanide led to 1,3-diketone 26 as a single isomer in 11610

DOI: 10.1021/jacs.8b08127 J. Am. Chem. Soc. 2018, 140, 11608−11612

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Journal of the American Chemical Society 43−55% yield24 after quenching with 1 M HCl. Despite the modest yield, this sequence successfully introduced the requisite acyl unit in a straightforward fashion and validated the critical acylation strategy of our synthetic design. Using a slight modification of the two-step procedure employed in the synthesis of gelsedilam furnished the desired α,β-unsaturated ethyl ketone 28 in 47% yield over two steps, thus setting the stage for the late-stage heterocyclization. Selective reduction of the alkene and nitro group without disturbing the ketone group was accomplished by the combination of NiCl2 and NaBH4 at low temperature, delivering (−)-gelsenicine (4). Overall, 4 was obtained in 6.6% yield in seven steps from 13 and 15. Catalytic hydrogenation of 4 with Adam’s catalyst under a hydrogen atmosphere following the precedent reports11 furnished (−)-gelsedine (3) smoothly. Finally, we further extended our strategy of divergent synthesis to the total synthesis of (−)-gelsemoxonine (6). Starting from advanced intermediate 28, the ensuing epoxidation turned out to be nontrivial because the wellestablished alkaline conditions for α,β-unsaturated carbonyl compounds all suffered from inevitable epimerization of the αposition of the nitro group. After some experimentation, we found that the stereoselective epoxidation of 28 promoted by mCPBA gave epoxide 29 in 56% yield along with 24% recovered 28. Subsequent reduction of the nitro group with zinc powder and acetic acid (AcOH) followed by biomimetic cyclization8a rendered synthetic (−)-gelsemoxonine (6) in 78% yield over two steps. The entire route was completed in 6.6% overall yield in only nine steps from 13 and 15. In brief, we developed and implemented a divergent route to gelsedine-type alkaloids that culminated in the total syntheses of (−)-gelsedilam, (−)-gelsedine, (−)-gelsenicine, and (−)-gelsemoxonine in seven to nine steps from known fragments 13 and 15 without using any protecting groups. These synthetic routes feature a number of key elements, including an asymmetric Michael addition and a tandem oxidation/aldol cyclization for the introduction of the quaternary center in the spiro-N-methoxyindolinone moiety, an unprecedented oxonium ion-induced pinacol rearrangement to construct the common oxabicyclo[3.2.2]nonane core, and a late-stage heterocyclization process for structural diversity. The above endeavor represents the shortest synthetic routes of gelsedine-type alkaloids to date. The versatility of advanced intermediate 20 would facilitate the total synthesis of a diverse set of structurally related alkaloids as well as unnatural analogues, which should accelerate further investigations of pharmacological action and structure−activity relationships.

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Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are grateful to the Chinese Academy of Sciences (supported by the Strategic Priority Research Program, Grants XDB20020200 and QYZDJ-SSW-SLH029) and the National Natural Science Foundation of China (Grants 21132008 and 21831009) for their financial support.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b08127. Experimental procedures and compound characterization (PDF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Dawei Ma: 0000-0002-1721-7551 Author Contributions †

P.W. and Y.G. contributed equally. 11611

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DOI: 10.1021/jacs.8b08127 J. Am. Chem. Soc. 2018, 140, 11608−11612