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. Author manuscript; available in PMC: 2026 Jul 28.
Published in final edited form as: Org Lett. 2026 Jul 31;28(30):9707–9711. doi: 10.1021/acs.orglett.6c02545

Directed Heterodimerization: Total Synthesis of (−)-Folicangine, (−)-Voafolidine, (−)-Isovoafolidine, and (−)-Tabernaesine B

Robert-Cristian Raclea †, Mohammad Movassaghi †,*
PMCID: PMC13404208  NIHMSID: NIHMS2192388  PMID: 42467558

Abstract

We report the first total synthesis of heterodimeric aspidosperma–aspidosperma alkaloids (−)-folicangine, (−)-voafolidine, (−)-isovoafolidine and (−)-tabernaesine B. Our biosynthesis-inspired stereoselective directed union of complex fragments derived from (−)-mehranine (northern half) and (−)-deoxoapodine (southern half) provided a methylene-bridged heterodimer, serving as a key precursor to these structurally related bisindole alkaloids. Methylenation of this versatile heterodimeric intermediate resulted in a stereodivergent ring closure to give (−)-tabernaesine B alongside its C7 diastereomer, enabling our stereochemical revision of this alkaloid. The corresponding C2’-hemiaminal alkaloids (−)-voafolidine and (−)-isovoafolidine were obtained via an analogous spirocyclization-reduction sequence from a hydrated derivative of the methylene-bridged heterodimeric precursor. Our biosynthesis-inspired heterodimerization strategy allowed for the assembly of the intricate double hemiaminal alkaloid (−)-folicangine via C8-iminium ion capture by the C2’-hemiaminal of an intermediate en route to (−)-isovoafolidine.

Graphical Abstract

graphic file with name nihms-2192388-f0001.jpg

Aspidosperma alkaloids, characterized by a shared fused pentacyclic core (Figure 1; rings A-E), represent a large family of monoterpene indole alkaloids displaying diverse patterns of peripheral oxidation and substitution.1,2 The structural complexity of these natural products and their biological activity have prompted significant interest over the past decades.3,4,5 More than 50 years ago, the isolation and characterization efforts led by Kunesch and co-workers involving the extraction of leaves from the Voacanga africana tree resulted in the discovery of a fascinating subset of aspidosperma–aspidosperma bisindole alkaloids.6,7 This afforded (−)-folicangine (3), a spirofused doubly methylene-bridged bisindole alkaloid featuring a transannular hemiaminal ether,8,9 with its northern and southern halves resembling the hexacyclic Tabernaemontana alkaloids (−)-mehranine (1)10 and (−)-deoxoapodine (2),11 respectively (Figure 1).2 The same extract also yielded (−)-voafolidine (4), a structurally related hemiaminal with the opposite configuration at the C7-spirocenter.8 Its C7 diastereomer, (−)-isovoafolidine (5), was not initially isolated, but rather prepared through the reduction of (−)-folicangine (3).8 In 2020, Yi and co-workers described the isolation of (−)-voafolidine (4) and (−)-isovoafolidine (5) from the leaves of Tabernaemontana pachysiphon, alongside other new spirofused bisindole alkaloids, including the C2’-enamine (−)-tabernaesine B (7, revised stereochemistry, vide infra).12 Importantly, they demonstrated that (−)-voafolidine (4) and (−)-isovoafolidine (5) displayed moderate cytotoxicity against several human cancer cell lines.12

Figure 1.

Figure 1.

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Representative structures of Voacanga and Tabernaemontana alkaloids.

As part of our group’s long-standing campaign targeting complex aspidosperma alkaloids,10,11,13 we previously developed a biogenesis-inspired fragment assembly leading to methylene-bridged alkaloids (−)-voacinol and (−)-voacandimine C.14 A crucial aspect of this synthesis involved the late-stage D-ring methylenation of an oxidized (−)-deoxoapodine derivative, which was accessed via Polonovski–Potier reaction and subsequent reversible masking of a crude C7–C8-enamine as a versatile C8-aminonitrile.14,15 Following this, we further expanded our insights concerning our (−)-deoxoapodine-derived enamine intermediate, which we found to undergo C7–C8’-dimerization upon chromatographic purification, a process we demonstrated to be reversible in solution.15 More recently, we utilized these findings in the preparation of (−)-deoxoapodine-derived C7-methylenated electrophiles in the first total synthesis of doubly methylene-bridged heterodimeric alkaloids (−)-owerreine and (−)-anhydrovobtusine.16 Notably, these bisindole alkaloids resemble the structure of (−)-tabernaesine B (7), albeit featuring a distinct (−)-beninine-derived northern half.17 Furthermore, our insights regarding the union of sensitive hemiaminal intermediates in the first total synthesis of Hazunta bisindole alkaloids18 prompted us to further refine our late-stage methylenation strategy to allow access to the intricate heterodimeric hemiaminal (−)-folicangine (3) and related alkaloids. Herein, we report the first total synthesis of (−)-folicangine (3), (−)-voafolidine (4), (−)-isovoafolidine (5) and (−)-tabernaesine B (7), allowing our revision of the C7 stereochemistry for alkaloid (−)-7. Our concise and biosynthesis-inspired strategy involved the stereoselective and directed coupling of a variant of (−)-mehranine (1)18 and a C7-substituted derivative of (−)-deoxoapodine (2),14–16 followed by methylenation and spirocyclization of the resulting heterodimer and its hydrated derivative.

Our biosynthesis-inspired retrosynthetic analysis of (−)-folicangine (3) is depicted in Scheme 1.14,16 We proposed that putative N1’-methylene iminium ion 8 could undergo spirocycle closure via C7–C23 bond formation,18 following which the resulting C8-iminium ion would be trapped by the C2’-hydroxyl to afford the hemiaminal ether (−)-folicangine (3). In line with our synthesis of (−)-owerreine and (−)-anhydrovobtusine,16 we anticipated this key spirocyclization step to produce two C7-diastereomeric iminium ions, which could be alternatively reduced at C8 to access (−)-voafolidine (4) and (−)-isovoafolidine (5), respectively. To generate the iminium ion 8, we envisioned the use of aqueous conditions for the N1’-methylenation of heterodimer 9 to ensure the formation of the C2’-hemiaminal. Finally, we postulated that the directed coupling of indolenine (−)-10, a key intermediate in our synthesis of Hazunta alkaloids,18 with an appropriate precursor to C7-methylenated (−)-deoxoapodine-derived iminium ion 11,14–16,19 would yield the methylene-bridged heterodimer 9 as a versatile precursor for the synthesis of alkaloids 3–7.

Scheme 1.

Scheme 1.

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Retrosynthetic analysis of (−)-folicangine (3).

To begin our synthetic campaign, we selected C7-methoxymethyl (−)-deoxoapodine derived enamine (−)-12 as a versatile surrogate for iminium ion 11.15,16 Upon addition of acetic acid (10 equiv) to a dichloroethane–trifluoroethanol (DCE–TFE, 10:1, v/v) solution of enamine (−)-12 and (−)-mehranine-derived indolenine (−)-10 (2.0 equiv), we observed the formation of methylene-bridged heterodimer (−)-9 in 63% yield as a single diastereomer (Scheme 2).20 The C3’ stereochemistry, guided by the C5’-ethyl group,18 was confirmed through 2D ROESY correlations. The use of acetic acid was crucial for the isolation of heterodimer (−)-9, as the use of the stronger trifluoroacetic acid triggered an additional cyclization event. Treatment of methylene-bridged heterodimer (−)-9 with trifluoroacetic acid (5.1 equiv) in dichloromethane furnished tridecacyclic aminal-enamine (−)-13 in 81% yield as a single diastereomer, as supported by 2D ROESY correlations. Prompted by the efficiency of this process, we sought the formation of the corresponding C2’-hemiaminal (−)-14. Indeed, the addition of an aqueous solution of trifluoroacetic acid (4.9 equiv) to a dichloromethane solution of methylene-bridged heterodimer (−)-9 (water–dichloromethane, 1:1) resulted in the formation of aminal-hemiaminal (−)-14 in 84% yield as a mixture of diastereomers (10:1). Flash column chromatography on silica gel provided an analytical sample of the major diastereomer of hemiaminal (−)-14 with the desired C3’ stereocenter as demonstrated by 2D ROESY correlations.20

Scheme 2.

Scheme 2.

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Synthesis and acid-mediated cyclizations of methylene-bridged heterodimer (−)-9. Reagents and conditions: (a) AcOH, TFE, DCE, 23 °C, 0.5 h; (b) TFA, CH2Cl2, 23 °C, 0.5 h; (c) TFA, H2O, CH2Cl2, 23 °C, 1h.

With reliable access to methylene-bridged heterodimer (−)-9 and its hydrated derivative (−)-14, we proceeded to apply our biosynthesis-inspired spirocyclization strategy (Scheme 1). Initially, we employed methylenating conditions used in our synthesis of (−)-owerreine and (−)-anhydrovobtusine.16 Namely, subjection of indolenine-enamine (−)-9 to Eschenmoser’s salt (3 equiv) and excess formic acid (73 equiv) in DCE, followed by in situ C8-reduction using sodium triacetoxyborohydride, resulted in the isolation of (−)-tabernaesine B (7) in 30% yield along with (−)-7-epi-tabernaesine B (6) in 11% yield (Scheme 3). Our 1H and 13C NMR data for (−)-tabernaesine B (7), as well as our optical rotation data [observed [α]d24 = −388 (c = 0.37, MeOH); lit. [α]d25 = −389 (c = 0.10, MeOH)12] were in agreement with the isolation report. Our 2D NOESY analysis revealed correlations between the C22 and C4 signals, as well as a set of correlations linking C23 and C19 via the α-C8-methine, which allowed us to assign the C7 configuration as (R) for (−)-tabernaesine B (7). Furthermore, the (−)-7-epi-tabernaesine B (6) revealed 2D ROESY correlations between the C23 and C4 signals consistent with a C7-(S) configuration. Whereas the isolation report provided a C7-(S) configuration for (−)-tabernaesine B,12 our access to both C7 diastereomers of this alkaloid combined with their detailed 2D ROESY analysis prompts our revision of the C7 stereochemistry of the naturally occurring (−)-tabernaesine B (7) as C7-(R) as shown in Scheme 3.

Scheme 3.

Scheme 3.

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Synthesis and stereochemical reassignment of (−)-tabernaesine B (7) and (−)-7-epi-tabernaesine B (6). Reagents and conditions: (a) Eschenmoser’s salt, formic acid, DCE, 23 °C, 5.5 h; NaBH(OAc)3, 0 to 23 °C, 0.5 h.

We next focused on the synthesis of the C2’-hemiaminal members of this heterodimeric aspidosperma–aspidosperma alkaloid family. Importantly, we harnessed the acid-mediated reversible piperidine ring opening of aminal (−)-14 followed by N1’-methylenation under aqueous conditions.18 Under optimal conditions, the addition of excess formalin (340 equiv) and acetic acid (100 equiv) to a solution of aminal (−)-14 in TFE afforded a mixture of C7-diastereomeric intermediates 15. Treatment of the mixture of intermediates 15 with sodium triacetoxyborohydride led to C8-reduction, providing (−)-voafolidine (4) and (−)-isovoafolidine (5) in 97% yield as a mixture of diastereomers (1:6, respectively, Scheme 4). Flash column chromatography on silica gel afforded analytical samples of (−)-voafolidine (4) and (−)-isovoafolidine (5) in 8.7% and 74% yield, respectively. The optical rotation data for our synthetic sample of (−)-voafolidine (4) [observed [α]57824 = −318 (c = 0.12, CHCl3); lit. [α]578 = −300 (c = 1.0, CHCl3)8], as well as our 1H and 13C NMR data were in agreement with available literature values.21 Additionally, we provide an expanded set of 1H NMR resonances (43 vs 12 original assignments) and revise three 13C NMR resonances.20 The C7-(S) configuration and the preservation of the C3’ stereocenter were established using 2D ROESY correlations. Similarly, our optical rotation data for (−)-isovoafolidine (5) [observed [α]57824 = −623(c = 0.25, CHCl3); lit. [α]578 = −642 (c 1.0, CHCl3)8], our expanded 1H NMR data set (42 vs 12 original assignments)20 and our 13C NMR data (one revised resonance) agreed with literature data.21 The C7-(R) configuration and the C3’ stereochemistry were secured via 2D ROESY analysis.20

Scheme 4.

Scheme 4.

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Synthesis of (−)-folicangine (3), (−)-voafolidine (4) and (−)-isovoafolidine (5). Reagents and conditions: (a) CH2O (37% wt. in H2O), AcOH, TFE, 23 °C, 0.5 h; (b) TMSCN, H2O, HFIP, 0 to 23 °C, 0.75 h; AgBF4, DTBMP, THF, 23 °C, 1h; (c) NaBH(OAc)3, AcOH, DCE, 0 to 23 °C, 0.5 h, 97% (1:6 dr) combined yield before further chromatography.

Our mechanistic rationale for the conversion of aminal (−)-14 to alkaloids (−)-voafolidine (4) and (−)-isovoafolidine (5) involves C8-aminal opening of tridecacycle (−)-14, N1’-methylenation and C23 leaving group ionization to give our originally planned N1’methylene iminium ion 8 (Scheme 1), which can undergo spirocyclization via C7–C23 bond formation followed by solvolysis of the C8-iminium ion to give a mixture of hemiaminals 15. To prepare the double hemiaminal ether (−)-folicangine (3), we sought to replace the final C8-reduction step with a sequence involving aminonitrile formation and ionization.14 In this regard, treatment of the mixture of diastereomeric hemiaminals 15 (~1:6, C7-(S):C7-(R)) with trimethylsilyl cyanide (15 equiv) and water (22 equiv) in HFIP, followed by exposure of the resulting C8-aminonitriles to silver tetrafluoroborate (0.92 equiv) in the presence of 2,6-di-tert-butyl-4-methylpyridine (DTMBP, 1.9 equiv) in THF provided (−)-folicangine (3) in 63% yield from aminal (−)-14 (Scheme 4). Our expanded 1H NMR data set (41 vs 13 original assignments), our 13C NMR data with eight revised resonances,20 and our optical rotation data for (−)-folicangine (3) [observed [α]57824 = −264(c = 0.19, CHCl3); lit. [α]578 = −271 (c = 1.0, CHCl3)8] were in good agreement with literature data.21 The C7-(R) configuration, as well as the relative configurations at the C8 and C3’ stereocenters, were determined through analysis of 2D ROESY correlations. Notably, products derived from the minor C7-(S) diastereomer of hemiaminal 15 were not identified under these conditions, likely due to competing degradation in the absence of C2’-hydroxyl capture of the corresponding C8-iminium ion. As a final stereochemical checkpoint, we demonstrated the structural relationship between the three C7-(R) spirocycles of this alkaloid family through chemical derivatization.20 In the event, treatment of (−)-folicangine (3) with sodium borohydride in methanol provided (−)-isovoafolidine (5) in 99% yield, while heating a solution of (−)-isovoafolidine (5) in formic acid led to dehydration to afford (−)-tabernaesine B (7) in 41% yield.

In summary, we have accomplished the first total synthesis of (−)-folicangine (3), (−)-voafolidine (4), (−)-isovoafolidine (5) and (−)-tabernaesine B (7), leading to our C7-stereochemical revision of the latter bisindole alkaloid. Our approach to these heterodimeric doubly methylene-bridged spirocycles involved the preparation of a methylene-bridged heterodimer (−)-9, a plausible biogenetic precursor to these alkaloids, by a directed stereoselective coupling of the required mehranine-derived northern half (−)-10 and the deoxoapodine-derived southern half (−)-12. Methylenation of heterodimer (−)-9 using Eschenmoser’s salt afforded C2’-enamines (−)-tabernaesine B (7) and its C7 diastereomer (−)-6 in 30% and 11% yield, respectively. Furthermore, a formalin-mediated spirocyclization of aminal (−)-14, a hydrated derivative of heterodimer (−)-9, followed by reduction, provided access to C2’-hemiaminal alkaloids (−)-voafolidine (3) and (−)-isovoafolidine (4) in 7.3% and 62% from heterodimer (−)-9. Under optimal conditions, interception of the corresponding C8-iminium ion of hemiaminals 15 by the C2’-hydroxyl afforded the hemiaminal ether (−)-folicangine (3) in 53% yield from (−)-9. The success of this concise strategy for the total synthesis of alkaloids 3–7 relied on our biosynthesis-inspired directed assembly of methylene-bridged heterodimer (−)-9 followed by controlled manipulation of intricate intermediates.

Supplementary Material

Movassaghi-Folicangine-SIPP

The Supporting Information is available free of charge.

Experimental procedures, spectroscopic data, and copies of 1H, and 13C NMR spectra (PDF)

ACKNOWLEDGMENTS

We thank Dr. In-Soo Myeong and Dr. Taylor Pinto, members of the Movassaghi group, for helpful discussions.

Funding Sources

We are grateful for financial support by NIH-NIGMS (R35GM141963).

Footnotes

The authors declare no competing financial interest.

REFERENCES

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Supplementary Materials

Movassaghi-Folicangine-SIPP
NIHMS2192388-supplement-Movassaghi-Folicangine-SIPP.pdf (5.7MB, pdf)

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