Abstract
Indole terpenes have attracted the interests of synthetic chemists due to their complex architectures and potent biological activities. Examples of total syntheses of several indole terpenes were reviewed in this article to honor Professor KC Nicolaou.
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Introduction
The indole diterpenoids constitute a large family natural products which possess interesting architectures and diverse biological activities.1, 2, 3 Among these, the paspaline subclass features a common multi-substituted indole core in conjunction with a tricyclic terpene moiety that features a signature trans-anti-trans 5,6,6-fused ring system (Figure 1).4, 5, 6 This subclass displays a wide variety of biological activities including tremorgenic, antibacterial, antitumor, antiviral and insecticidal activity.7, 8, 9, 10, 11, 12, 13 In the early 1980s we initiated a synthetic program involving the paspaline indole diterpenoids and have over the years achieved a number of total syntheses (Figure 1). In this review, we will present the strategic and tactical evolution of this long-term program, focusing on the construction of the multi-substituted indole cores and the trans-anti-trans 5,6,6-fused ring systems. Of equal importance, we will review two recent total syntheses of indole terpenoids which are structurally related to the systems in which we have engaged. The latter is included, not inappropriately, given the purpose of this review is to honor Professor KC Nicolaou, a friend and previous colleague in the Chemistry Department at the University of Pennsylvania, Philadelphia, PA.
Representative indole terpenes that have been synthetically achieved.
Discussion
The beginning
This synthetic venture began with (−)-paspaline (Figure 1), an architecturally complex indole diterpenoid that was initially disclosed by the Arigoni and co-workers14, 15, 16 in the mid 1960s (Figure 1).
Our synthetic interests concerned not only the disubstituted indole core but equally the trans-fused 5/6 ring system, both of which were challenging structural features from the synthetic perspective. No syntheses of the paspaline-type indole diterpenoids had been achieved at that time. At the outset, we decided to take advantage of a reductive alkylation protocol (1→3),17 that was developed early in our laboratory, to construct the fused pyran moiety (Scheme 1).
The synthesis thus began with bicyclic ketone 4 (Scheme 2), which was derived from enone 1 via a reductive alkylation.17 Nazarov cyclization of the generated diene (5) then led to tricyclic enone 6 which was set up for a key vicinal bifunctional reaction. Exploiting the Trost alkylation protocol from their aphidicolin synthesis,18 the critical trans-fused 5/6 ring system was generated albeit with disfavored diastereoselectivity (trans:cis=0.5:1), the latter likely due to conformational constraints. Notwithstanding this shortcoming, side chain elongation of the trans isomer 7 led to olefin 8. Following an epoxidation-cyclization cascade, the fused pyran ring F of 9 was established, which was further converted to the indolization precursor 10. Optimization of the Gassman indole synthesis19 at this late stage proved challenging due to the substrate structural complexity; nonetheless the first total synthesis of (−)-paspaline was achieved, in a total of 23 steps.20, 21
Strategy evolution: a second-generation formal synthesis
The critical unmet issue in our first generation paspaline synthesis comprised introduction of the vicinal quaternary stereocenters in 7 in a stereocontrolled fashion. Recognizing that the trans-fused 5/6 ring system is higher in strain energy than the cis counterpart, and that the computed trans-fused 6/6 ring system would constitute a thermodynamically more favorable situation, the strategic decision was made on the basis of a 6/6 to 5/6 ring contraction. To this end, a second generation strategy was initiated with the Robinson annulation of (+)-Wieland–Miescher ketone 12 (Scheme 3). The resulting enone 13 was then subjected to Luche conjugate addition22, 23 to establish the C/D trans 6/6 geometry of 14. With the desired trans configuration in hand, a ring contraction sequence successfully led to the desired 5/6 trans ring system (15) as a single diastereomer. Encouraged by this result, we further expanded the reductive alkylation protocol on the late stage intermediate 16. The last two stereocenters were then introduced in a highly stereoselective manner to lead eventually to common advanced olefin intermediate 7, cumulating in a second generation, now formal total synthesis of (−)-paspaline that proceeded with full stereocontrol.24, 25
Development of a unified strategy
Gaining access to the advanced intermediate 15 (Scheme 3) via a second generation strategy not only improved efficiency but also led to a unified strategy to construct the structurally more complex members of the indole diterpenoid family (Scheme 4).
For the syntheses of (+)-paspalicine and (+)-paspalinine (Scheme 5), the latter being a naturally occurring tremorgen that features a tertiary hydroxyl groups at C(13), we began with the earlier stage construction of the indole system via a Gassman indole protocol to provide common indole 16a (Scheme 5). A Stork hydrazone alkylation26 with advanced intermediate 17 and epoxide 18 proved unexpectantly challenging due to the substrate complexity and the harsh reaction conditions required; pleasingly, conditions were eventually discovered that led to key advanced union intermediate 19, that embodied the full carbon elements of the targeted natural products. Acylation of 19 followed by hydrazone hydrolysis provided enone 20, which in turn was treated with acid to promote an intramolecular trans ketalization that precisely set up the cis pyran geometry of ketal 21. The acetyl group in 21 was then removed by hydrolysis and the derived product subjected to Moffatt oxidation27 to generate ketone 22, wherein the isolated double bond underwent smooth isomerization into the requisite conjugated position upon applying the conditions of Grieco28, 29 to complete the first total synthesis of (+)-paspalicine.30 After extensive experimentation, we were successful in converting (+)-paspalicine to (+)-paspalinine by treatment with selenium dioxide.31
With two additional indole terpenes constructed, we reviewed the overall synthetic program and recognized that the frequently employed Gassman indole synthesis protocol, although playing a major role in the construction of the multi-substituted indole skeletons, the sequence often required at best four to five steps that proceeded in only moderate yield (40–50%). We thus faced the dilemma of employing an early stage coupling to construct a substituted indole core which then had to be carried through the synthetic sequence with considerable care, and then introduced via a late-stage elaboration utilizing complex fragments, at best in moderate to low yield. We thereafter sought to develop a more general strategy that would permit efficient construction (that is, single step) of a multi-substituted indole system that would employ large, late stage union fragments.
Development and validation of a new indole synthetic protocol
Our accumulation of interests and efforts in anion chemistry17, 20, 32, 33, 34 led to the discovery and validation of a two-component indole construction tactic (Scheme 6) which was initiated by bis-metalation of an N-silyl-o-toluidine.35 The resulting dianion was then added to an ester to generate the corresponding ketone, which in turn would undergo an intramolecular aza-Peterson olefination/tautomerization to yield the disubstituted indole in a ‘single flask’.36 With this protocol established, and in conjugation with our previous successful syntheses of (−)-paspaline, (+)-paspalicine and (+)-paspalinine, we devised a blueprint for expanding the two-component ‘one-flask’ indole construction tactic for the considerably more complex indole terpene (−)-penitrem D (Scheme 7). Toward this end we envisioned the use of o-toluidine 23 and lactone 24.
Lactone fragment 24 (Scheme 8) was constructed beginning with the kinetic deprotonation of ketone 25 employing the Whitesell reagent.37 The resulting enol silyl ether 26 was then carried forward via a series of transformations (27→28), including a conjugate addition/oxidation/conjugate addition sequence, that eventually led to the tricyclic lactone 34. In similar fashion to that of the (+)-paspalinine and (+)-paspalicine synthetic ventures, a late-stage Stork hydrazone alkylation protocol was applied on 35 to install the side chain, which in turn was fashioned into the desired cis pyran that eventually permitted elaboration of the highly functionalized tetracyclic core of lactone 24.
To access the required advanced o-toluidine cyclobutane fragment 23, we began with enone 27a (Scheme 9), the enantiomer of an early stage intermediate (27) in the synthesis of lactone 24. A [2+2] photocycloaddition of 27a with methyl acrylate led to 38 with the requisite 6/4 cis ring geometry. A Woodward-Wilds modification of the Robinson annulation38, 39 followed by Semmler-Wolff aromatization40, 41 eventually afforded advanced o-toluidine 23.
With both fragments in hand, we turned to the two-component indole construction (Scheme 10). In situ generation of dianion 41 permitted attack of the carbon-anion on the lactone carbonyl of 24. The resulting union intermediate (42) then underwent an intramolecular aza-Peterson olefination/tautomerization in a finely-tuned binary solvent system that eventually landed the system at the desired multi-substituted indole 43, which comprised the fully elaborated carbon skeleton of penitrem D, remarkably in 81% yield.
With the two-component indole synthesis tactic now demonstrated on highly elaborated late stage substrates, the end game of (−)-penitrem D was at hand. Parikh–Doering oxidation followed by acid treatment permitted equilibration between 44 and 45. Pleasingly, a single treatment with scandium triflate converted the equilibrium mixture to macrocyclic ether 46 via a cascade cyclization in a highly stereoselective fashion (dr>95:5). After an elimination sequence to introduce the exomethylene moiety, the first and to date only total synthesis of architecturally complex indole diterpenoid (−)-penitrem D was achieved in a highly convergent and fully stereocontrolled manner.42, 43
During the (−)-penitrem D synthetic venture, a new indole diterpenoid, (−)-21-isopentenylpaxilline (Scheme 11) appeared in the literature.44 A unified synthetic strategy was thus proposed exploiting our two-component indole construction tactic. Beginning with advanced intermediate 49 employed in the (−)-penitrem D synthesis, a similar side chain introduction sequence led to the highly elaborated lactone 50, which in this case was alkylated with dianion 48.
Pleasingly, the second example of our two-component indole construction tactic could be altered slightly to form indole 52. Negishi cycloalkylation45 followed by late stage elaboration then led to the first total synthesis of (−)-21-isopentenylpaxilline.46, 47
The nodulisporic acids
In the late 1990s to the early 2000s, a series of indole terpenoids with a novel scaffold, namely the nodulisporic acids A−F (Figure 2), were discovered at the Merck Research Laboratory and found to possess potent insecticidal activities.48, 49, 50, 51, 52 These novel indole diterpenes embodied a highly strained, electron-rich indole or indoline ring system, the latter of which proved air sensitive, and in several cases the benzylic-homoallylic secondary hydroxyl group at C-24 was found to be extremely labile to very mild acid (that is, even unstable to the inherent dienoic acid moiety!).51 Continuing with our long-standing interest in the indole diterpenes, we initiated a synthetic campaign towards the nodulisporic acid family of molecules.
Representative structures of nodulisporic acids.
Total synthesis of (+)-nodulisporic acid F and (−)-nodulisporic acid D
At the outset we selected the structurally less complex member, (+)-nodulisporic acid F (Scheme 12), to employ our two-component indole construction tactic with aniline 55 and lactone 56.
The lactone fragment (for example, 56) not surprisingly required significant synthetic effort, the major obstacle being construction of the vicinal stereocenters, in a highly efficient manner, that are embedded in the 5/6 trans ring system. A new synthetic route to such systems was thus envisioned again beginning with (+)-Wieland−Miescher ketone (Scheme 13). Dissolving metal reduction of 57 followed by capture of the resulting enolate employing trimethylsilyl chloride (TMSCl)/Et3N led to 59, which was then subjected to an aldol reaction taking advantage of the remarkable ‘aqueous formalin’ protocol introduced by Kobayashi53, 54 to result in β-hydroxyl ketone 60 in 70% yield! We note this effective transformation was employed by Nicolaou and Li in their synthesis of (−)-anominine and (+)-tubingensin A (vide infra). Next a Gribble-Saksena-Evans reduction55, 56, 57 was used to achieve the requisite stereoselective introduction of the C-7 hydroxyl in ketone 61 after some minor modifications including acid hydrolysis of the ketal and TBS protection of the diol. Subsequent triflation and Stille carbonylation58 then provided enal 63. Application of a Koga alkylation59, 60 intended to establish the requisite stereochemical relationship of the vicinal quaternary centers surprisingly led unexpectantly with reversal of the predicted stereogenicity at C-4. To correct the stereochemistry, an epimerization/lactonization sequence of 65 was required, initiated with a Pinnick oxidation.61 The resulting acid was then transformed to methyl ester 65a with TMS-CHN2. Upon ozonolysis, the terminal double bond of 65a was cleaved to an aldehyde which in turn was treated with DBU to establish the correct stereogenicity at C-4. Sodium borohydride reduction of aldehyde 65b followed by lactonization completed the construction of the key advanced lactone 67. Notably, the synthetic route to lactone 67 was developed into a scalable synthetic route starting from (+)-Wieland−Miescher ketone.62
With 56 now in hand, another example of our two-component indole construction tactic was successfully executed employing 56 and o-toluidine 55 (Scheme 14). Following a cyclization sequence involving 69 via mesylation/cyclization, we arrived at the desired indole core 70. A late stage Suzuki-Miyaura cross coupling63 and deprotection then completed the first total synthesis of (+)-nodulisporic acid F.64, 65
Advancing to (−)-nodulisporic acid D, a second representative member of the nodulisporic acid family of indole diterpenes alkaloids, we recognized that the harsh anionic conditions of the two-component indole construction tactic would likely lead to decomposition regardless of attempts at optimizations (Scheme 15).
We therefore committed to an alternative tactic to construct the indole core of the nodulisporic acids, while retaining the strategy of a late-stage large-fragment union. With our increasing involvement in transition metal mediated transformations,64, 66, 67, 68, 69, 70, 71 we turned attention to the elegant indole synthetic protocol developed by Barluenga72, 73 (Scheme 16). Considering our complex substrate setting including the functional group sensitives, we reasoned that this adventure could provide an excellent opportunity to develop further the Barluenga indole construction method. To this end, (−)-nodulisporic acid D was dissected from the retrosynthetic perspective to chloroaniline 72 and vinyl triflate 73.
The requisite tertiary stereocenter residing on chloroaniline 72 was envisioned to be introduced via an Enders asymmetric alkylation74 employing hydrazone 75 (Scheme 17). Further structural modification followed by a Stille-Kelly cyclization75, 76, 77 provided access to the requisite advanced chloroaniline 72, pleasingly with high enantiopurity due to the Enders protocol. Of equally importance, our previous designed synthetic sequence to intermediate enal 63 (employed in the nodulisporic acid F synthetic venture) permitted major progress in overcoming our long-standing difficulty in constructing the 5/6 trans-fused ring system in 65c (Scheme 18). The key new tactic here was twofold. A fine-tuned vinyl cuprate 1,4-addition with excellent facial selectivity generated enolate intermediate 63a. Release of the enolate with methyllithium permitted a kinetic controlled alkylation from the bottom face to provide the desired stereoselectivity, thus setting the critical trans stereochemical relationship in an efficient manner. Upon minor modification involving ring closing metathesis,78, 79, 80, 81 neopentyl aldehyde 64a was then smoothly converted to tricyclic ketone 65c, that now comprised the core trans-anti-trans 5,6,6-fused ring system. Subsequent modifications led to advanced vinyl triflate 73.
With both fragments 72 and 73 for (−)-nodulisporic acid D in hand, we were in position to explore their union. Pleasingly a combination of the Buchwald third generation RuPhos precatalyst82, 83, 84 in the presence of cesium carbonate (Scheme 19) permitted the palladium mediated cascade involving amination/enamine cyclization to deliver indole nucleus 76 in 69% yield, with the sensitive aldehyde group intact! With core structure 77 in hand, Horner–Wadsworth–Emmons olefination85, 86 successfully led to side chain installation. Here we believed the neighboring acetate group participates in delivering the Horner–Wadsworth–Emmons reagent via an intramolecular fashion. Subsequent treatment of 78 with LiOH in H2O/THF/methanol then led to the first total synthesis of (−)-nodulisporic acid D.87 Currently, we are progressing on the total synthesis of the structurally more complex members in the nodulisporic acids family, including acids C and A; progress with this venture will be reported in due course.
Two recent elegant total syntheses of indole diterpenoids
In 2012, Kuwahara from Tohoku University achieved a remarkable total synthesis of (+)-paspalinine (Scheme 20).88 Strategically, the critical stereochemical relationship of the vicinal quaternary stereocenters of 80 was beautifully secured via the Simmons−Smith cyclopropanation of 81, with the substituted indole core 79 constructed via a Corey−Stille union and oxidative cyclization tactic.
Beginning with (+)-Wieland–Miescher ketone, sequential transformations led to phosphonate 83 (Scheme 21), which in turn was transformed via an intramolecular Horner–Wadsworth–Emmons olefination to enone 81. A substrate controlled stereoselective reduction with L-Selectride then furnished alcohol 84, the hydroxyl group of which directed a Simmons−Smith cyclopropanation that after oxidation led to 85 as a single diastereomer. Regioselective cyclopropane ring opening, followed by triflation next set up the angular methyl and the vinyl triflate groups in 80, which was subjected to cross coupling with aryl stannane 87 exploiting the Corey modified Stille coupling protocol89 to provide union fragment 88. A highly interesting oxidative cyclization mediated by palladium (II) trifluoroacetate then permitted construction of the indole core in 79. Installation of the allyl carbonate group by deprotonation of 79 under thermodynamic conditions in turn permitted a Tsuji’s palladium-catalyzed allylation90 that provided enone 90. Subsequent modifications, including cross metathesis with 1,1-dimethylallyl alcohol, followed by Sharpless asymmetric dihydroxylation, furnished triol 91, which was subjected to an acid promoted cyclization and then oxidized to ketal 93 following deprotection to complete a formal synthesis of (+)-paspalicine. Interestingly, treatment of 93 under selenolation/oxidation conditions (unprecedented in our synthesis of (+)-paspalinine) provided the critical tertiary hydroxyl group and, after deprotection, led to the total synthesis of (+)-paspalinine.
We turn next to the elegant synthetic venture of the total syntheses of (−)-anominine and (+)-tubingensin A by Nicolaou and Li in 2012 (Scheme 22).91 These two indole diterpenes, isolated from Aspergillus sp., possess significant biologic activities including anticancer, antiviral and antiinsectant.92, 93, 94, 95 Strategically, tricyclic ketone 113 served as the cornerstone of this synthetic venture, constructed from enone 114 via a stereoselective cyclization of 116. A convergent approach would then permit Grignard addition to the aldehyde derived from 112 to furnish 111 that would nicely serve as a common advanced intermediate for both (−)-anominine and (+)-tubingensin A.
Beginning with enantiomerically enriched enone 115 (Scheme 23), a Robinson annulation/oxidation sequence led to bicyclic enone 114, which was then converted to iodide 116. Following a strategic cyclization via facial selective radical addition (for example, a Ueno-Stork radical cyclization)96, 97, 98 led to tricyclic ketone 113 as a single diastereomer after treatment with HCl in ethanol. Generation of the kinetic enol silyl ether, followed by the previously described remarkable Kobayashi aldol reaction with ‘aqueous’ formaldehyde, provided alcohol 112 which was converted to aldehyde 117. Subsequent Grignard addition led to the union fragment 111 in both excellent yield and diastereoselectivity considering the complex structural setting. Continuing with common advanced intermediate 111, minor modifications yielded indole 119 which in turn was transformed to diene 120 via a Grignard addition/acetylation/Tsuji reduction99 sequence. Cross metathesis employing the Hoveyda-Grubbs II catalyst with 2-methyl-2-butene followed by DIBAL reduction completed the total synthesis of (−)-anominine in a highly concise manner. In conjugation with this venture, the secondary hydroxyl group of common advanced intermediate 111 was eliminated to provide diene 121, which was then subjected to CuOTf that led to a remarkable intramolecular 6π-electrocyclization/aromatization sequence to provide the multi-substituted carbazole core (122) of (+)-tubingensin A. Employing a similar Grignard addition/acetylation/Tsuji reduction sequence as employed for (−)-anominine, the derived olefin 123 was subjected to cross metathesis and deprotection to complete the total synthesis of (+)-tubingensin A.
Summary
The total synthesis of architecturally complex indole containing natural products clearly remains an attractive venue for the practitioners of complex molecule synthesis. Strategic and tactical evolution will continue to be influenced by the development of new synthetic methods. Although there will never be an absolute finish line in the race to more concise synthetic strategies, a worthy total synthesis will be reached either by unique insight into the architectural structural features leading to the target or by the imaginative development of new synthetic methods and tactics involving novel chemistry. Congratulations to Professor KC Nicolaou in this regard!
Retrosynthetic analysis of (−)-paspaline.
First generation total synthesis of (−)-paspaline.
Second generation synthesis of (−)-paspaline.
Development of a unified strategy.
Total syntheses of (+)-paspalicine and (+)-paspalinine.
Two-component indole construction tactic.
Retrosynthetic analysis of (−)-penitrem D.
Synthesis of lactone 24 fragment.
Synthesis of aniline 23 fragment.
Key union transformation and late stage elaboration of (−)-penitrem D.
Total synthesis of (−)-21-isopentenylpaxilline.
Retrosynthetic analysis of (+)-nodulisporic acid F.
Synthesis of lactone 56 fragment.
Key union transformation and late stage elaboration of (+)-nodulisporic acid F.
Potential decomposition pathway of the dianion.
Retrosynthetic analysis of (−)-nodulisporic acid D.
Synthesis of western hemisphere 72.
Synthesis of eastern hemisphere 73.
Key union transformation and late stage elaboration of (−)-nodulisporic acid D.
Retrosynthetic analysis of (+)-paspalinine.
Total synthesis of (+)-paspalinine and formal synthesis of (+)-paspalicine.
Retrosynthetic analyses of (−)-anominine and (+)-tubingensin A.
Total syntheses of (−)-anominine and (+)-tubingensin A.
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Acknowledgements
It is a pleasure to acknowledge the long-term support of the above investigations in our laboratory to the National Institute of Health (National Institute of Neurology, Communicative Disorders and Stroke and National Institute of General Medical Science) through Grants 18254 and 29028, respectively, and to the Merck Research Laboratory and to Bristol-Myers Squibb Pharmaceutical Research Institute.
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Zou, Y., Smith, A. Total synthesis of architecturally complex indole terpenoids: strategic and tactical evolution. J Antibiot 71, 185–204 (2018). https://doi.org/10.1038/ja.2017.94
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DOI: https://doi.org/10.1038/ja.2017.94
