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 J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b08127 • Publication Date (Web): 30 Aug 2018 Downloaded from http://pubs.acs.org on August 30, 2018

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Journal of the American Chemical Society

Divergent Entry to Gelsedine-type Alkaloids: Total Syntheses of (–)-Gelsedilam, (–)-Gelsenicine, (–)-Gelsedine and (–)Gelsemoxonine Pingluan Wang†, Yang Gao† and Dawei Ma* 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 Supporting Information Placeholder ABSTRACT: The gelsedine-type alkaloids possess an common oxabicyclo[3.2.2]nonane core and spiro-N-methoxy indolinone moiety, along with a diversely functionalized heterocycle embedded in the compact framework. Herein, we disclose a divergent entry to gelsedine-type alkaloids, which hinges on the rapid assembly of the common core by orchestrated application of asymmetric Michael addition, tandem oxidation/aldol cyclization and pinacol rearrangement, and 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.

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 the 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 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 due to the lack of comprehensive biological profiling, which was largely hampered by synthetic accessibility. Among the five known classes of Gelsemium alkaloids, three subfamilies possess a common spiro-indolinone motif, namely, gelseminetype, humantenine-type and gelsedine-type (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 attention5 and only a handful of semi-syntheses6 and total 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 skeleton,8 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 cy-

cloisomerization strategy to complete the first total synthesis of gelsenicine (4).10 Soon after that, unified total synthesis of five gelsedine-type alkaloids was achieved by 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 route to this family have been scarce. Moreover, given the fact that the comprehensive biological profiles of these alkaloids remain unclear, we seek 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, culminating in short, asymmetric total syntheses of (–)-gelsidilam (5), (–)-gelsenicine (4), (–)-gelsedine (3) and (–)-gelsemoxonine (6) without using protecting groups.

Figure 1. The Three Indolinone Subclasses of Gelsemium Alkaloids.

From a structural standpoint, gelsedine-type alkaloids possess a common oxabicyclo[3.2.2]nonane core and spiro-N-methoxy indolinone moiety, along with a diversely functionalized heterocycle (such as pyrrolidine, pyrroline, pyrrolidinone or azetidine ring) embedded in the compact framework (3-6; Figure 1). Our retrosynthetic analysis for these molecules is depicted in Scheme 1. We envisioned that the synthetic 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 lac-

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tamization. Compound 8 or 9 was anticipated to be derived from a versatile intermediate 10 by a general acylation strategy at the αposition of 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 a 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 asymmetric Michael addition to deliver two simple known compounds 13 and 14. Scheme 1. Retrosynthetic Analysis of Gelsedine-type Alkaloids.

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would be more favorable, leading to the cyclization product with the matched configuration to 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 N-chlorosuccinimide (NCS) and water allowed for the formation of oxindole through hydrolysis of the corresponding 2-chloroindole,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 oxidation-cyclization cascade reaction represents one of the few examples of ketone aldol reaction of 3-substituted oxindoles.19 It was worth noting that quenching with silica gel and triethylamine was essential for complete epimerization of nitro group to form the more thermodynamically stable isomer 17, whose absolute configuration and structural assignment was confirmed by X-ray crystallographic analysis (Scheme 2). Scheme 2. Construction of the Key Intermediates 17 and 20. O

Me

Me Me

O

O

MeO N

Me

15

Cs2CO3, Et2O

Me NO2

+

Me

95% dr = 1:1

O O

NCS, H2O THF 13

N OMe

Me

Me

Me

N OMe O H N O O 21a (favor)

Me

Me

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 L-arabinose in four steps, dr> 98:2) as the Michael acceptor, in the hope of accessing serviceable stereocontrol. Initial attempts to treat indole fragment 13 (easily prepared from 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 an 1:1 diastereoisomeric mixture under the optimized condition. Careful structural analysis confirmed that the dr value originated from the α-position of nitro group, which in turn indicated 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-methoxy indolinone via a tandem oxidation and aldol cyclization sequence. A stereochemical question regarding the configuration of the pivotal quaternary center should be addressed and two possible transition states (21a and 21b) were envisioned for this key cyclization. We speculated that there was considerable steric repulsion between the nitro group and the benzene ring in transition state 21b, whereas the transition state 21a

O

O Me

HO

N OMe 17

O NO2

Me O O

O N OMe

O NO2 22a (major)

Me

OMe N

O2N

O

AlCl3 Me toluene Et2O 95 oC

Me

Me

Me

HO

silica gel Et3N 90%

O HO

O

21b (disfavor)

Me O

Me O

O

Me

16 NO2

O

O Me

O

Me

HO

OMe N

O2N 22b (minor)

Me AlCl3 O O

O O

O H

N OMe

N OMe 18

O NO2 19

O NO2

86%

O

ORTEP of 17

ORTEP of 20

O N OMe NO2 20

O

With ample quantities of 17 in hand, the stage was set to exploit the pivotal pinacol rearrangement. Myriad Lewis acid and Brønsted acid were evaluated and we were pleased to find out that adding p-toluenesulfonic acid (p-TsOH) to 17 in toluene solution and heating the mixture at reflux successfully affect 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 the mixture of


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Journal of the American Chemical Society 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. AlCl3/ether complex, mainly used in the field of olefin polymerization21 and aromatic alkylation22, was particularly effective for this transformation, presumably owing to its mild Lewis acidity, since the employment of AlCl3 alone led to total decompostion of 17. Furthermore, structurally related Lewis acid 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. Scheme 3. End Game of the Total Synthesis of (–)-Gelsedilam (5).

O

KHMDS NCCOOMe

O N O 2N

TfO

O

_

OMe

N

N

OMe

Tf2O, DIPEA OMe

81%

O N O OMe 2 23

Pd(PPh3)4, DIPEA Et3SiH, DMF, 70 oC

O

O 2N

O

O

20

O OMe

78 oC 73%

HO

80%

O

Scheme 4. Completion of the Divergent Total Syntheses of Gelsedine-type Alkaloids. O N

O OMe

24

study the key acylation by changing every conceivable variable including the base used to deprotonate, the acylation reagent, solvent, and temperature. Emerging from this exhaustive study was the finding that treatment 20 with KHMDS and freshly distilled propionyl cyanide led to 1,3-diketone 26 as a single isomer in 43~55% yield22 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. Employment of a slight modification of the two-step procedure used in synthesis of gelsidilam furnished the desired α,β-unsaturated ethyl ketone 28 in 47% yield over 2 steps, thus setting the stage for the late-stage heterocyclization. Selective reduction of alkene and nitro group without disturbing the ketone group was accomplished by the combination of NiCl2 and NaBH4 under low temperature, delivering (–)gelsenicine (4) in 7 steps and 6.6% overall yield from 13 and 15. Catalytic hydrogenation of 4 with Adam’s catalyst in the hydrogen atmosphere following the precedent reports11 furnished (–)gelsedine (3) smoothly.

O 2N

OMe

O

O

O 25

N O2N

O

NiCl2, NaBH4 _ 10 oC to rt N OMe then silica gel, o rt to 40 C NH O O 67% (_)-gelsedilam (5) 7 steps from known compounds 13 and 15 24% overall yield

KHMDS, NCCOEt _ 78 oC to rt

TfO

O 20

O

O

OMe then 1 N HCl O 43-55%

Tf2O DIPEA N OMe 65% O

O2N 26

O

O

PdCl2(PPh3)2, DIPEA, Et3SiH, DMF N

O

o OMe 70 C, 73%

O O2N O 28

O2N O 27

ORTEP of 5

O

Having achieved rapid assembly of 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 first pursued (Scheme 3). Thus, 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, leading to the formation of 23 as a 1:1 diastereomeric mixture. Next, the enol mixture 23 was converted to 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 penultimate α,β-unsaturated methyl ester 25. We found that the base and elevated temperature were essential for the complete epimerization to produce more thermodynamically stable isomer 25. Finally, the synthetic route was completed by nickel boronhydride-mediated reduction of the alkene and the nitro group to give an uncyclized intermediate, which, delivered enantioenriched (–)gelsedilam (5) upon heating with silica gel at 40 oC in only 7 steps and 24% overall yield from 13 and 15. Our attention was then turned to achieving a different late-stage heterocyclization to deliver (–)-gelsenicine (4) and (–)-gelsedine (3) (Scheme 4). One overarching problem to be solved was how to introduce an 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

NiCl2, NaBH4, _ 78 oC to rt 44%

O N

PtO2/H2 OMe

85%

N O (_)-gelsenicine (4) 7 steps from known compounds 13 and 15 6.6% overall yield

O mCPBA, NaHCO3

O2N O 28 O O O NH2O 30

N

H

N 56% (74% brsm) O OMe

Zn AcOH

O

N OMe O2N 29

EtOH, reflux 78% (2 steps) N OMe

OMe

NH O (_)-gelsedine (3) 8 steps from known compounds 13 and 15 5.6% overall yield

O O

N OMe

O

O O

HO

N H O

OMe

N H (_)-gelsemoxonine (6) 9 steps from known compounds 13 and 15 6.6% overall yield Et

Finally, we further extended our strategy of divergent synthesis to a total synthesis of (–)-gelsemoxonine (6). Starting from advanced intermediate 28, the ensuing epoxidation turned out to be nontrivial because the well-established alkaline conditions for α,βunsaturated carbonyl compound all suffered from inevitable epimerization of the α-position of 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 cy-



clization8a rendered synthetic (–)-gelsemoxonine (6) in 78% yield over two steps and completed the entire route in only 9 steps and 6.6% overall yield from 13 and 15. In brief, we developed and implemented a divergent route to gelsedine-type alkaloids, which culminated in total syntheses of (– )-gelsedilam, (–)-gelsedine, (–)-gelsenicine and (–)gelsemoxonine in 7-9 steps from known fragments 13 and 15 without using any protecting group. These synthetic routes feature a number of key elements, including an asymmetric Michael addition and a tandem oxidation/aldol cyclization for the introduction of quaternary center in spiro-N-methoxy indolinone moiety, an unprecedented oxonium ion-induced pinacol rearrangement to construct the common oxabicyclo[3.2.2]nonane core, and a latestage heterocyclization process for structural diversity. The above endeavor represents the shortest synthetic routes of gelsedine-type alkaloids to date. The versatility of the 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 on pharmacological action and structure-activity relationships.

ASSOCIATED CONTENT Supporting Information. Experimental procedures and compound characterization. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author *[email protected]

Author Contributions †

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

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

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NO2 RO

O

O

7-9 steps

+ N OMe

N

H NH O

O

_

O

( )-gelsedilam

O

O H

N OMe H

H O

H NH O

H

_

O N OMe

N OMe H _

( )-gelsenicine

( )-gelsedine

O

Et

HO

N OMe H O

N H ( )-gelsemoxonine _


Divergent Entry to Gelsedine-Type Alkaloids: Total Syntheses of

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