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Home > Indole Alkaloid Synthesis Facilitated by Photoredox Catalytic Radical Cascade Reactions
Indole Alkaloid Synthesis Facilitated by Photoredox Catalytic Radical Cascade Reactions
Xiao-Yu Liu and Yong Qin
1.INTRODUCTION
Indole alkaloids belong to one of the largest families of secondary metabolites created by nature.1 As a unique category of these molecules, the monoterpene indole alkaloids biogenetically originate from tryptamine and secologanin (Figure 1).2 Condensation of these two fragments via an enzymatic Pictet−Spengler reaction affords strictosidine; diversification of the latter common intermediate results in over 40 structural types and more than 3000 members of monoterpene indole alkaloids.1 Of particular note, many of these compounds exhibit a wide range of bioactivities, and molecules such as reserpine (antihypertensive), vincamine (nootropic), quinine (antimalaria), and vinblastine/vincristine (antitumor) have been used as important drugs.
Due to their significant biological profiles and intricate structures, various monoterpene indole alkaloids have long challenged synthetic chemists. Such synthetic campaigns could be traced back to as early as the 1950s, when Woodward and co-workers first conquered strychnine4 and reserpine.5 Since then, the structural diversity and complexity of monoterpene indole alkaloids have made them important testing grounds for synthetic methodologies and tactics.6 Traditionally, many elegant approaches were documented but were only suitable for the synthesis of individual molecules or small groups of molecules from this natural product family. However, efficient access to large collections of complex indole alkaloids is always desirable and would call for a breakthrough in developing innovative synthetic methods and strategies.
Visible-light-mediated photoredox chemistry has been an active research field in the most recent decade and offers chemists new opportunities to form chemical bonds.7 Never- theless, these single electron transfer (SET) processes have only begun to benefit natural product total synthesis,8,9 and they were mostly employed to realize single transformations. Design of visible light photoinduced radical cascade reactions to facilitate multiple bond-forming events in one pot would allow chemists to assemble the cores of natural products as well as to achieve their total synthesis in highly efficient fashion.
Stemming from a long-standing interest in the synthesis of intriguing indole alkaloids,10,11 our group recently developed a new photoredox catalytic radical cascade strategy that led to the asymmetric total synthesis of a collection of monoterpene indole alkaloids.12−16 As illustrated in Scheme 1, treating the sulfonamide substrate A with base and photocatalyst under the irradiation of blue light-emitting diodes (LEDs) generated a key nitrogen-centered radical B, which could be subsequently involved in further bond-forming events. Specifically, we designed three types of radical cascade pathways [intra-/ intramolecular, intra-/intermolecular, and intra-/inter-/intra- molecular] and realized facile construction of the aspidosper- ma (type I, via C), tetrahydrocarbolinone (type II, via D), and corynanthe (type III, via E) core structures. While some of the obtained compounds already possessed the frameworks of indole alkaloids, the versatile functionalities in these cores could be manipulated to access more alkaloid types. As a result, harnessing the three types of photocatalytic radical cascades as key reactions allowed the asymmetric total synthesis of 42 monoterpene indole alkaloids belonging to 7 structural types.12−16 This Account summarizes the radical cascade methodologies developed in our laboratory and their applications in natural product total synthesis.
2.TYPE I RADICAL CASCADE AND ITS APPLICATIONS IN TOTAL SYNTHESIS
2.1.Development of the Type I Radical Cascade Reaction
Bearing in mind the idea of developing a radical cascade approach to indole-alkaloid skeletons, we initiated our studies with the preparation of chiral substrate 4 (Scheme 2) from tert- butyl methyl malonate (1) and o-nitrocinnamic aldehyde (2). The organocatalytic asymmetric Michael addition of commer- cially available 1 to 2 followed by decarboxylation yielded chiral aldehyde ester 3 (96% ee),17 which was readily conducted on a 500 g scale in our laboratory. Compound 3 was then converted to 4 in three steps. By subjecting sulfonamide 4 to various non-photoredox conditions, we observed the cyclization product (tetrahydroquinoline 5) or oxidation product (pyridinone 6) or no reaction. Generation of tetrahydroquinoline 5 was, not surprisingly, the result of a C− N bond formation between the aniline nitrogen and the electron-deficient α-carbon of the enamide functionality. To reach the desired indoline product, a C−N bond formation at the β-position of the enamide was required. Classical methods for the generation of nitrogen-centered radicals18 from N− heteroatom bonds or directly from N−H bonds under harsh oxidative conditions were neither economic nor environ- mentally benign, which also proved to be unsuitable for our substrate. After much experimentation, we were delighted to isolate the tetracyclic product 7a (41% yield) along with tricycles 8 (6% yield) and 9 (35% yield) in the reaction of 4 with Ir(dtbbpy)(ppy)2PF6 and Et3N under the irradiation of blue LEDs.
Obviously, not only an unusual reactivity between two nucleophilic amine and enamine groups (in 4) but also an impressive radical cascade reaction (product 7a) was achieved in the aforementioned photocatalytic transformation. With the initial results, we next screened the reaction conditions and found that the radical cascade of 4 proceeded smoothly to produce 7a in 70% yield (>50:1 dr) using Ir(dtbbpy)- (ppy)2PF6 (0.5 mol %; dtbbpy = 4,4′-bis(di-t-butyl)-2,2′- bipyridine; ppy = 2-phenylpyridine) and KHCO3 in degassed THF with irradiation of 5 W blue LEDs. In addition to 4, a series of substrates were designed and synthesized to examine the generality of this intra-/intramolecular radical cascade reaction. As depicted in Figure 2,12 substrates possessing either electron-rich or electron-deficient double/triple bonds teth- ered to the enamide nitrogen atom were suitable for the cascade reaction, furnishing the corresponding products (e.g., selected examples 7b−e) with fused pyrrolidine or piperidine rings in moderate to high yields and high to excellent dr values. Exceptionally, the adduct 7f with a more flexible azepane unit was generated with a lower dr value (2.5:1). Of note, this cascade reaction proved to be robust and worked without loss of yield and diastereoselectivity in aqueous THF (product 7a). A proposed catalytic cycle for the photoredox radical cascade reaction is shown in Scheme 3A. Initially, deprotona- tion of the N−H bond in 10 took place in the presence of base to generate anion I. The photoexcited IrIII complex then oxidized I (via SET) and produced nitrogen-centered radical II, triggering subsequent cascade cyclization to yield carbon radical III. After SET reduction of radical III with the reductive state IrII complex, the resultant anion IV could be converted into product 7 via protonation. Regeneration of the ground-state IrIII photocatalyst completed the catalytic cycle.
Concerning the observed stereoselectivity of the radical cascade, formation of a cis relationship between H2 and H7 via transition state TS-I was realized in a substrate-controlled fashion (Scheme 3B).12 The resulting amide nitrogen- associated carbon radical might adopt two transition states, TS-IIa and TS-IIb, which acted as controllable switches for the subsequent reactions. The N-atom in TS-IIa had no contribution to enhancing the nucleophilicity of the adjacent carbon radical due to donation of the nitrogen lone pair electrons to the carbonyl moiety in the characteristic amide functionality. On the other hand, unfavorable steric repulsion between the Ts-protected indoline group and the radical acceptor in TS-IIa also inhibited occurrence of the ensuing reaction. By contrast, the key two-center, three-electron interaction in TS-IIb greatly contributed to enhancing the radical stability, nucleophilicity, and selectivity.19 First, because of the greater stability, the sufficient lifetime of the carbon radical enabled subsequent bond formations especially in intermolecular manners (type II and III cascades). Second, twisting of the amide bond in TS-IIb restored the electron- donating ability of the N-atom to the carbon radical, thus increasing the radical nucleophilicity. Furthermore, attack of the carbon radical to the intramolecular acceptors (or intermolecular ones in type II and III cascades) exclusively from the bottom face of the piperidinone ring led to complete stereocontrol at C3.
2.2.Total Synthesis of the Eburnane Alkaloids
Inspired by the development of an intra-/intramolecular radical cascade for preparing indole-alkaloid-like skeletons, we sought to investigate its applications in natural product total synthesis. The eburnane indole alkaloids (Figure 3) are a group of structurally diverse molecules featuring a common pentacyclic core (e.g., 11−13) and an all-carbon quaternary center at C20.20,21 Functionalizations at the terminal C18 as well as further cyclizations may result in more variants of these natural products (e.g., 14−17). In this context, the C18 unfunctionalized eburnane alkaloids were envisaged to be synthesized from 18a (R = H), while various C18 function- alized counterparts could be derived from 18b (R = OPG). In turn, the versatile tetracyclic intermediate 18a,b with a crucial C20 quaternary stereogenic center would be accessible by the photocatalytic type I radical cascade of precursor 19a,b.
According to the synthetic plan, preparation of the C18 unfunctionalized eburnane alkaloids was examined using sulfonamide 20 as a starting material (Scheme 4).12 To evaluate the potential applications of a new synthetic methodology, especially in natural product total synthesis, an important criterion is whether it could be scaled up without loss of efficacy. Gratifyingly, the designed radical cascade reaction of 20 was easily performed on a decagram scale under photocatalytic conditions,12 where the solvent MeCN was found to be superior to THF, giving the bis-cyclization products 21a and 21b (81% overall yield, 2:3 dr). As most C18 unfunctionalized eburnane alkaloids possess a β-Et substituent at C20, the corresponding intermediate 21b with a β-Et group was used for further manipulations. On one hand, three steps of functional group transformations converted 21b into acetal. Reduction of the amide group in 22 to the corresponding amine followed by treatment with TFA afforded (+)-eburna- menine (23) in 80% overall yield. Subsequent hydration of the C16−C17 double bond delivered (−)-eburnamine (11) and (+)-isoeburnamine (12); oxidation of the resultant hydroxyl group with pyridinium dichromate (PDC) gave (+)-eburna- monine (24). The intermediate 22 was also used for the synthesis of (−)-vallesamidine (26). Establishing the remain- ing five-membered carbocycle in 26 relied on a SmI2-mediated reductive cyclization of the aldehyde to the C2 of indole. On the other hand, subjecting 21b to a four-step sequence produced amino alcohol 27. The latter underwent oxidation/ cyclization/oxidation to generate lactam 28, which was finally converted into (−)-vincamine (13) according to a literature method.
Employing precursor 29 with a C18-OBn group for the radical cascade reaction under the standard photoredox conditions smoothly furnished the tetracyclic product 30 as a pair of inseparable diastereomers (Scheme 4).14 Both isomers were used for accessing eburnane indole alkaloids with C18 functionalities. Specifically, the diastereomeric mixture of 30 was converted to separable 31a and 31b by three steps. Treatment of the minor 31a with HCl/MeOH at reflux forged a new lactam ring with simultaneous removal of the benzyl radical acceptors, respectively. Again, the stereochemical outcomes of the newly formed stereocenters (C2 and C3) were excellently controlled in all of the products.
Total Synthesis of the Akuammiline Alkaloids (−)-Strictamine and (−)-Rhazinoline
Strictamine and its associated akuammiline alkaloids (43−45, Figure 5) are structurally unique natural products possessing a group, which was followed by Dess−Martin periodinane (DMP) oxidation of the resultant primary alcohol, leading to aldehyde 32. A SmI2-mediated radical cyclization of 32 with subsequent Barton deoxygenation generated (−)-strempelio- pine (15). Meanwhile, starting from 31b, formation of a hemiaminal with ensuing deprotection of the benzyl group yielded (−)-eburnaminol (14); the latter was treated with HCl to give (+)-larutenine (33). On the other hand, first removal of the benzyl group in 31b, followed by oxidation and cyclization in the presence of Bz2O2, furnished tetrahydropyran 34. Exposure of 34 to di-isobutyl aluminum hydride (DIBAL-H) at 0 °C completed the synthesis of (−)-terengganensine B (16). Moreover, the radical cascade product (30) underwent a five-step transformation to provide access to the diallyl product. Ring-closing metathesis (RCM) of 35 with Grubbs’ II catalyst delivered 36 (82% yield); the latter was further converted to (−)-terengganensine A (17) based on the method developed by Zhu and colleagues.
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