Sarpagine Alkaloids Research Articles

BiBr3 -Mediated Intramolecular Aza-Prins Cyclization of Aza-Achmatowicz Rearrangement Products: Asymmetric Total Synthesis of Suaveoline and Sarpagine Alkaloids.

An intramolecular aza-Prins cyclization of aza-Achmatowicz rearrangement products was developed in which bismuth tribromide (BiBr3 ) plays a dual role as an efficient Lewis acid and source of the bromide nucleophile. This approach enables the facile construction of highly functionalized 9-azabicyclo[3.3.1]nonanes (9-ABNs), which are valuable synthetic building blocks and a powerful platform for the synthesis of a variety of alkaloid natural products and drug molecules. Suitable substrates for the aza-Prins cyclization include 1,1-disubstituted alkenes, 1,2-disubstituted alkenes, alkynes, and allenes, with good to excellent yields observed. Finally, we showcase the application of this new approach to the enantioselective total synthesis of six indole alkaloids: (-)-suaveoline (1), (-)-norsuaveoline (2), (-)-macrophylline (3), (+)-normacusine B (4), (+)-Na -methyl-16-epipericyclivine (5) and (+)-affinisine (6) in a total of 9-14 steps. This study significantly expands the synthetic utility of the aza-Achmatowicz rearrangement, and the strategy (aza-Achmatowicz/aza-Prins) is expected to be applicable to the total synthesis of other members of the big family of macroline and sarpagine indole alkaloids.

BiBr3‐Mediated Intramolecular Aza‐Prins Cyclization of Aza‐Achmatowicz Rearrangement Products: Asymmetric Total Synthesis of Suaveoline and Sarpagine Alkaloids

AbstractAn intramolecular aza‐Prins cyclization of aza‐Achmatowicz rearrangement products was developed in which bismuth tribromide (BiBr3) plays a dual role as an efficient Lewis acid and source of the bromide nucleophile. This approach enables the facile construction of highly functionalized 9‐azabicyclo[3.3.1]nonanes (9‐ABNs), which are valuable synthetic building blocks and a powerful platform for the synthesis of a variety of alkaloid natural products and drug molecules. Suitable substrates for the aza‐Prins cyclization include 1,1‐disubstituted alkenes, 1,2‐disubstituted alkenes, alkynes, and allenes, with good to excellent yields observed. Finally, we showcase the application of this new approach to the enantioselective total synthesis of six indole alkaloids: (−)‐suaveoline (1), (−)‐norsuaveoline (2), (−)‐macrophylline (3), (+)‐normacusine B (4), (+)‐Na‐methyl‐16‐epipericyclivine (5) and (+)‐affinisine (6) in a total of 9–14 steps. This study significantly expands the synthetic utility of the aza‐Achmatowicz rearrangement, and the strategy (aza‐Achmatowicz/aza‐Prins) is expected to be applicable to the total synthesis of other members of the big family of macroline and sarpagine indole alkaloids.

A Bischler-Napieralski and homo-Mannich sequence enables diversified syntheses of sarpagine alkaloids and analogues

Sarpagine alkaloids offer signicant opportunities in drug discovery, yet the efficient total syntheses and diverse structural modifications of these natural products remain highly challenging due to the architectural complexity. Here we show a homo-Mannich reaction of cyclopropanol with imines generated via a Bischler-Napieralski reaction enables a protecting-group-free, redox economic, four-step access to the tetracyclic sarpagine core from L-tryptophan esters. Based on this advancement, diversified syntheses of sarpagine alkaloids and analogues are achieved in a short synthetic route. The systematic anticancer evaluation indicates that natural products vellosimine and Na-methyl vellosimine possess modest anticancer activity. Intensive structural optimization of these lead molecules and exploration of the structure−activity relationship lead to the identification of analogue 15ai with an allene unit showing a tenfold improvement in anticancer activities. Further mechanism studies indicate compound 15ai exertes antiproliferation effects by inducing ferroptosis, which is an appealing non-apoptotic cell death form that may provide new solutions in future cancer therapies.

Oxidative Coupling Approach to Sarpagine Alkaloids: Total Synthesis of (-)-Trinervine, Vellosimine, (+)-Normacusine B, and (-)-Alstomutinine C.

Sarpagine alkaloids are bioactive indole natural products that contain a highly rigid indole-fused 1-azabicyclo[2.2.2]octane, more than 100 members of which have been identified. Herein, a detailed examination of the intramolecular oxidative coupling between a ketone and a Weinreb amide for assembling the complex 1-azabicyclo[2.2.2]octane core structure of sarpagine family alkaloids is described. Precise late-stage manipulations of the ketone and Weinreb amide enable the divergent syntheses of (-)-trinervine, (+)-vellosimine, (+)-normacusine B, and (-)-alstomutinine C. Other notable transformations of the synthesis featured an aza-Achmatowicz/indole cyclization cascade to generate the azabicyclo[3.3.1]nonane structure, a regioselective elimination reaction to form the ethylidene motif embedded in the (+)-vellosimine and (+)-normacusine B structures, and a diastereoselective indole oxidative rearrangement to form the spirooxindole structure in (-)-alstomutinine C.

Oxidative Coupling Approach to Sarpagine Alkaloids: Total Synthesis of (−)‐Trinervine, Vellosimine, (+)‐Normacusine B, and (−)‐Alstomutinine C

AbstractSarpagine alkaloids are bioactive indole natural products that contain a highly rigid indole‐fused 1‐azabicyclo[2.2.2]octane, more than 100 members of which have been identified. Herein, a detailed examination of the intramolecular oxidative coupling between a ketone and a Weinreb amide for assembling the complex 1‐azabicyclo[2.2.2]octane core structure of sarpagine family alkaloids is described. Precise late‐stage manipulations of the ketone and Weinreb amide enable the divergent syntheses of (−)‐trinervine, (+)‐vellosimine, (+)‐normacusine B, and (−)‐alstomutinine C. Other notable transformations of the synthesis featured an aza‐Achmatowicz/indole cyclization cascade to generate the azabicyclo[3.3.1]nonane structure, a regioselective elimination reaction to form the ethylidene motif embedded in the (+)‐vellosimine and (+)‐normacusine B structures, and a diastereoselective indole oxidative rearrangement to form the spirooxindole structure in (−)‐alstomutinine C.

Total Synthesis of Sarpagine Alkaloid (-)-Normacusine B.

An asymmetric total synthesis of the sarpagine alkaloid (-)-normacusine B is presented. Salient features of this synthesis include a photocatalytic nitrogen-centered radical cascade reaction to assemble the tetrahydrocarbolinone skeleton, a titanium-mediated intramolecular amide-alkene coupling to construct the bridged azabicyclo[3.3.1]nonane moiety, and a nickel-catalyzed reductive Heck coupling to assemble the azabicyclo[2.2.2]octane ring system.

Biopatterned Reorganization of Alkaloids Enabled by Ring-Opening Functionalization of Tertiary Amines.

Biosynthetic processes often involve reorganization of one family of natural products to another. Chemical emulation of nature's rearrangement-based structural diversification strategy would enable the conversion of readily available natural products to other value-added secondary metabolites. However, the development of a chemical method that can be universally applied to structurally diverse natural products is nontrivial. Key to the successful reorganization of complex molecules is a versatile and mild bond-cleaving method that correctly places desired functionality, facilitating the target synthesis. Here, we report a ring-opening functionalization of a tertiary amine that can introduce desired functionalities in the context of alkaloids reorganization. The semistability of the difluoromethylated ammonium salt, accessed by the reaction of tertiary amine and in situ generated difluorocarbene, enabled the attack at the α-position by various external nucleophiles. The utility and generality of the method is highlighted by its applications in the transformation of securinega, iboga, and sarpagine alkaloids to neosecurinega, chippiine/dippinine, and vobasine-type bisindole alkaloids, respectively. During the course of these biosynthetically inspired reorganizations, we could explore chemical reactivities of biogenetically relevant precursors.

Asymmetric Total Synthesis of Sarpagine and Koumine Alkaloids

AbstractWe report here a concise, collective, and asymmetric total synthesis of sarpagine alkaloids and biogenetically related koumine alkaloids, which structurally feature a rigid cage scaffold, with L‐tryptophan as the starting material. Two key bridged skeleton‐forming reactions, namely tandem sequential oxidative cyclopropanol ring‐opening cyclization and ketone α‐allenylation, ensure concurrent assembly of the caged sarpagine scaffold and installation of requisite derivative handles. With a common caged intermediate as the branch point, by taking advantage of ketone and allene groups therein, total synthesis of five sarpagine alkaloids (affinisine, normacusine B, trinervine, Na‐methyl‐16‐epipericyclivine, and vellosimine) with various substituents and three koumine alkaloids (koumine, koumimine, and N‐demethylkoumine) with more complex cage scaffolds has been accomplished.

Asymmetric Total Synthesis of Sarpagine and Koumine Alkaloids.

We report here a concise, collective, and asymmetric total synthesis of sarpagine alkaloids and biogenetically related koumine alkaloids, which structurally feature a rigid cage scaffold, with L-tryptophan as the starting material. Two key bridged skeleton-forming reactions, namely tandem sequential oxidative cyclopropanol ring-opening cyclization and ketone α-allenylation, ensure concurrent assembly of the caged sarpagine scaffold and installation of requisite derivative handles. With a common caged intermediate as the branch point, by taking advantage of ketone and allene groups therein, total synthesis of five sarpagine alkaloids (affinisine, normacusine B, trinervine, Na -methyl-16-epipericyclivine, and vellosimine) with various substituents and three koumine alkaloids (koumine, koumimine, and N-demethylkoumine) with more complex cage scaffolds has been accomplished.

Macroline, talpinine, and sarpagine alkaloids from Alstonia penangiana. An NMR-based method for differentiating between A. penangiana and A. macrophylla

Fourteen previously undescribed alkaloids comprising two N-1-hydroxymethylmacroline alkaloids, one talpinine-type oxindole acetal, a pair of equilibrating talpinine-type oxindole hemiacetals, eight oxidized derivatives of sarpagine- and akuammiline-type indole alkaloids, in addition to alstochalotine a diastereomer of gelsochalotine recently isolated from Gelsemium elegans, were isolated from the leaf and stem-bark extracts of Alstonia penangiana. The structures and relative configurations of these alkaloids were established using NMR, MS, and in one instance, confirmed by X-ray diffraction analysis. An NMR-based method is described as a useful chemotaxonomic tool for differentiating between A. penangiana and A. macrophylla. Several of the alkaloids isolated showed appreciable growth inhibitory effects when tested against a number of human cancer cell lines.

Studies towards the Synthesis of (+)‐Lochnerine

AbstractThe efforts directed towards the stereoselective synthesis of (+)‐lochnerine, a sarpagine alkaloid is disclosed. The synthesis was designed utilizing an intramolecular catalytic hydroamination of an alkene by an oxazolidine, derived in situ from an unsaturated aldehyde, as the key step. The other key steps of the sequence include substrate‐controlled, Lewis acid promoted C3 allylation to secure the C3/C5 syn‐disubstituted product, Kulinkovich and ring‐closing metathesis reactions.

Gram-Scale Total Synthesis of Sarpagine Alkaloids and Non-Natural Derivatives.

This work describes the total synthesis of three members of the sarpagine alkaloid family and ten non-natural congeners through an improved synthetic sequence, which was designed for gram-scale production of materials suited for structure-activity relationship (SAR) studies. Furthermore, the manuscript details how the synthetic route was used to access the biogenetically completely unrelated Stemona alkaloid parvineostemonine (34), providing a showcase for efficient synthetic design.

Total Synthesis of Parvineostemonine by Structure Pattern Recognition: A Unified Approach to Stemona and Sarpagine Alkaloids.

Through structure pattern recognition based total synthesis we designed a synthesis in which two biogenetically unrelated natural product families (Stemona- and Sarpagine alkaloids) share 50 % of their synthetic sequence. In this report, the efficiency of such a strategic approach is demonstrated in the total synthesis of the Stemona alkaloid parvineostemonine, proceeding through a privileged intermediate that we have previously transformed into biogenetically completely unrelated Sarpagine alkaloids. In addition, we capitalized on the symmetry properties of the privileged intermediate, which was obtained as two regioisomers. After their separation by column chromatography the two regioisomers were converted to the corresponding pair of enantiomers by one transformation. To the best of our knowledge, this feature (conversion of regioisomers to enantiomers) has never been applied to natural product synthesis, and proved to be very valuable, since it allowed to obtain both optical antipodes of parvineostemonine in a single synthetic campaign. This not only enabled the determination of the previously undisclosed absolute configuration of the natural product, but gave 60-200 mg amounts of both enantiomers of the natural product.

Total Syntheses of Vellosimine, N‐Methylvellosimine, and 10‐Methoxyvellosimine and Formal Synthesis of 16‐Epinormacusine B through a [5+2] Cycloaddition

To date, more than 100 members of the sarpagine alkaloid family have been isolated. Their structural variations originate from oxidative transformations of the carboskeleton and the presence of both absolute configurations at the C‐16 atom, which is established in the course of their biosynthesis. More than 40 sarpagine alkaloids belong to the either the 16‐regular or 16‐epi subgroups, depending on the stereochemistry at C‐16. Herein, we report the formal synthesis of 16‐epinormacusine B, a member of the 16‐epi group, by using our well‐established generalized strategy for the total synthesis of these alkaloids. Furthermore, we provide the synthetic details and pitfalls of the asymmetric total syntheses of vellosimine, N‐methylvellosimine, and 10‐methoxyvellosimine, all members of the 16‐regular group.

Synthesis of Sarpagine Alkaloids

Key words alkaloids - cycloaddition - Fischer indole synthesis - ring expansion

Enantioselective, Protecting‐Group‐Free Total Synthesis of Sarpagine Alkaloids—A Generalized Approach

A generalized synthetic access to sarpagine alkaloids through a joint synthetic sequence has been accomplished. Its applicability is showcased by the enantioselective total syntheses of vellosimine (1), N-methylvellosimine (3), and 10-methoxyvellosimine (8). The synthetic sequence is concise (eight steps) from known compound 13, and requires no protecting groups. The indole heterocycle was introduced in the last step. This strategy allows access to sarpagine alkaloids through a shared synthetic route leading to precursor 10, which we term "privileged intermediate". Starting from this intermediate, all sarpagine alkaloids can be synthesized using phenylhydrazines with different substitution patterns (15-17). Our approach brings about the advantage, that synthesis optimization only needs to be performed once for many natural products. The key features of the synthesis are a [5+2]-cycloaddition and a ring enlargement.

Bioactive indole alkaloids isolated from Alstonia angustifolia

A new sarpagine-type indole alkaloid (1), together with nine known alkaloids (2 – 9), were isolated from the stems of Alstonia angustifolia Wall. ex A. DC. (Apocynaceae) collected in South Vietnam. Compounds 1 – 10 were evaluated for their NF-κB (p65) inhibitory activities against HT-29 cells in an ELISA assay. The new sarpagine alkaloid (1), was found to show significant NF-κB inhibitory activity (ED50= 1.2 µM). Furthermore, all the isolates (1 – 10) were tested in vitro for their antileishmanial activity, and compounds (1 – 4, 6, 8 – 10) were found to show leishmaniacidal activities.

Bioactive indole alkaloids isolated from Alstonia angustifolia

Bioassay-guided fractionation was conducted on a CHCl3-soluble extract of the stem bark of Alstonia angustifolia (Apocynaceae) collected in Vietnam using the HT-29 human colon cancer cell line, and led to the isolation of a new sarpagine-type indole alkaloid (1), together with nine known alkaloids, including four macroline-derived alkaloids (2–5), a sarpagine-type alkaloid (6), and four macroline-pleiocarpamine bisindole alkaloids (7–10). The structure of the new compound (1) was determined on the basis of spectroscopic data interpretation. Compounds 1–10 were evaluated in vitro for their NF-κB (p65) inhibitory activity against the Hela cells in an ELISA assay. The new sarpagine alkaloid, N(4)-methyltalpinine (1), was found to show significant NF-κB inhibitory activity (ED50=1.2μM). Furthermore, all the isolates (1–10) were evaluated in vitro for their antileishmanial activity, and compounds (1–4, 6 and 8–10) exhibited leishmaniacidal activity against promastigotes of Leishmania mexicana.

Regiospecific, enantiospecific total synthesis of C-19 methyl substituted sarpagine alkaloids dihydroperaksine-17-al and dihydroperaksine.

The optically active tetracyclic ketone 8 was converted into the pentacylic core 14 of the C-19 methyl substituted N(a)-H sarpagine and ajmaline alkaloids via a critical haloboration reaction. The ketone 14 was then employed in the total synthesis of 19(S),20(R)-dihydroperaksine-17-al (1) and 19(S),20(R)-dihydroperaksine (2). The key regioselective hydroboration and controlled oxidation-epimerization sequence developed in this approach should provide a general method to functionalize the C(20)-C(21) double bond in the ajmaline-related indole alkaloids.

Synthesis of bridged azabicyclic structures via ring-closing olefin metathesis.

A new strategy for the facile synthesis of azabicyclo[m.n.1]alkenes (m = 3-5; n = 3, 2) has been developed that involves the ring-closing metathesis (RCM) reaction of cis-2,6-dialkenyl-N-acyl piperidine derivatives. The requisite 2,6-dialkenylpiperidines may be readily prepared in six steps starting from glutarimide (11) or three steps from 4-methoxypyridine (25). In one example that establishes the practical utility of the procedure, the functionalized 8-azabicyclo[3.2.1]octane 32, which is a potential intermediate for the syntheses of various tropane alkaloids, was prepared. Additionally, a new route for the construction of the bridged tetrahydro-beta-carboline ring system 5 has been developed that features the ring-closing metathesis of the enyne 45 to construct the bridging ring in 46. This concise route to 46 also features a potentially general and useful procedure for the one-step preparation of a terminal alkyne from an ester function. Selective oxidation of the vinyl group in 46 afforded the unsaturated aldehyde 47, which may serve as a useful intermediate in syntheses of several Sarpagine alkaloids.