English

• Voacafricines, monoterpenoid indole alkaloids (MIAs), were isolated from Voacanga Africana by Luo's group in 2018 [1]. Structurally, they were characterized by a complex 6/5/6/5/6/5 hexacyclic fused architecture, comprising of five stereocenters, an uncommon quaternary ammonium cation in the aminal functionality together with a carboxyl anion. Preliminary studies of voacafricines A and B on the biological activity demonstrated their potent ability to inhibit the growth of Staphulococcus aureus and Salmonella typhi, superior to berbrine and fibrauretine, two well-known antibacterial natural products (Fig. 1).

  Figure 1

  

  Figure 1.  Structures of voacafricines and their antibacterial activities.

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  Due to the fascinating chemical structure and intriguing antibacterial activities, voacafricines A and B have attracted much attention from chemists and inspired them to pursue the chemical synthesis and further pharmacological exploration. In 2023, Zhu and co-workers firstly accomplished the total synthesis of voacafricines A and B from readily available intermediates with an organocatalyzed Pictet-Spengler condensation and an intramolecular addition of tertiary amine to oxonium species as the key reactions [2].

  In this work, we developed a concise and direct strategy to achieve the asymmetric synthesis of (-)-voacafricine A from three commercially available starting materials, 5-methoxy tryptamine, 2-oxoglutaric acid and 4-(tert-butyldimethylsiloxy) butanoic acid. The longest linear route was 14 steps, and the overall yield was 5.2%.

  The retrosynthetic analysis of (-)-voacafricine A is shown in Scheme 1. We envisioned that the quaternary ammonium moiety of (-)-voacafricine A could be achieved through intramolecular glycosylation from intermediate A, which might be prepared via Dess-Martin oxidation of intermediate B, followed by deprotection of TBS. The intermediate B could be accessible from intermediate C through simultaneous desulfurization of thiolactam, hydrogenation of carbon-carbon double bond and debenzylation catalyzed by Raney Ni under hydrogen atmosphere. Notably, the asymmetric hydrogenation of carbon-carbon double bond could be achieved via a substrate-controlled process, in which, the carbon-carbon double bond was preferentially attacked by H₂ from the opposite face of -CO₂iPr due to the less steric hindrance. Next, intermediate C could be obtained from intermediate E through elimination of hydroxyl group with DCC and CuCl in toluene, followed by selective conversion of lactam to thiolactam with Lawesson's reagent. We envisioned the effective conversion of lactam to thiolactam might not only allow a quick access to (-)-voacafricine A, but also achieve selective reduction of thiolactam while simultaneously keeping N-Boc and -CO₂iPr intact. The key intermediate E could be readily provided through intermolecular Aldol condensation of lactam F to aldehyde G in the presence of LDA in THF. The tetracyclic lactam F might be synthesized utilizing organocatalytically asymmetric Pictet-Spengler reaction, followed by a tandem lactamization established by She [3], which allowed the smooth conversion of 5-methoxytryptamine H and α-ketoester Ⅰ to 6/5/6/5 tetracyclic skeleton with good yield and enantioselectivity. Finally, intermediate G could be tracked back to commercially available 4-(tert-butyldimethylsiloxy)butanoic acid J through a sequence of functional group manipulations, in which, the construction of the stereocenter could be accomplished by an asymmetric α-alkylation of carbonyl group induced by Evans' chiral auxiliary.

  Scheme 1

  

  Scheme 1.  Retrosynthetic analysis of (-)-voacafricine A (1).

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  The synthesis of (-)-voacafricine A commenced with stereoselective Pictet-Splenger cyclization of commercially available 5-methoxy tryptamine 3 and isopropyl 2-oxopentanedioate 5. It is well known that stereoselective Pictet-Splenger cyclization catalyzed by organocatalysts has been widely applied for the asymmetric synthesis of tetrahydroisoquinolines [4, 5] and tetrahydro-β-carbolines [3, 6-13]. In this work, we employed a cascade asymmetric Pictet-Spengler cyclization and lactamization protocol developed by She [3], which could directly convert tryptamine and α-ketoester to its corresponding tetracyclic lactam with good enantioselectivity.

  The detailed synthesis is described in Scheme 2. Initially, esterification of 2-oxoglutaric acid 4 in the presence of i-PrOH and p-TsOH in refluxing toluene generated isopropyl 2-oxopentanedioate 5 in 91% yield. Following She's protocol [3], asymmetric Pictet-Spengler reaction between 5-methoxy tryptamine 3 and isopropyl 2-oxopentanedioate 5 was conducted with a 1, 1′-bi-2-naphthol (BINOL)-derived chiral phosphoric acid as catalyst and 4 Å MS as additive in refluxing toluene, followed by a cascade lactamization to directly yield tetracyclic lactam 6 (6/5/6/5 tetracyclic scaffold) with 95% yield and 63% ee. The ee value of compound 6 was determined by chiral HPLC (Chiral MS(2)5u, 2 mL/min, 25 ℃, hexane: i-PrOH = 30:70), and the configuration was identified as S by electronic circular dichroism (ECD), which was consistent with natural product (Fig. 2). Protection of the indole nitrogen atom with Boc₂O in the presence of Et₃N and DMAP in THF provided the key tetracyclic lactam intermediate 7 in 87% yield (Scheme 2).

  Scheme 2

  

  Scheme 2.  Synthesis of key tetracyclic lactam intermediate 7.

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  Figure 2

  

  Figure 2.  Electronic circular dichroism (ECD) of compound 6.

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  The synthesis of compound 12, another precursor for aldol condensation, is detailed in Scheme 3. In the synthetic route, asymmetric α-alkylation of carbonyl group induced by Evans' chiral auxiliary was the key transformation, which enabled the formation of the important stereocenter with high diastereoselectivity. Reaction of 4-(tert-butyldimethylsiloxy)butanoic acid 8 with Evans' chiral auxiliary 9 ((S)−4-benzyl-2-oxazolidinone) in the presence Et₃ N, LiCl and trimethylacetyl chloride in THF generated compound 10 in 86% yield [14, 15], which underwent a following α-alkylation with BOMCl in the presence of LiHMDS in THF to provide compound 11 in 81% yield with excellent diastereoselectivity [16, 17]. Reduction of compound 11 using DIBAL-H in THF readily yielded the desired aldehyde 12 in 72% yield. Compound 12 was unstable and easily oxidized to carboxylic acid while open to air, therefore it must be prepared freshly and purified by flash column chromatography just before use.

  Scheme 3

  

  Scheme 3.  Synthesis of aldehyde 12.

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  The final synthesis of (-)-voacafricine A is depicted in Scheme 4. Aldol condensation of tetracyclic lactam 7 with aldehyde 12 was conducted in the presence of LDA in THF at −78 ℃ [18, 19]. In this step, we predominantly obtained two compounds 13a (23%) and 13b (47%), which were presumably the two anti-stereoisomers and could be conveniently separated by column chromatography. Then, dehydration of compounds 13a and 13b was carried out in the presence of DCC and CuCl in refluxing toluene separately. To our delight, compounds 13a and 13b were converted to identical α, β-unsaturated lactam 14. The configuration of the carbon-carbon double bond in compound 14 was assigned as Z through NOESY experiment. The stereochemical process was shown in Scheme 5. Initially, it was well known that Aldol condensation occurred via six-member transition state. The transition state (Ⅰ) was more stable, because the substituent of aldehyde 12 was at the equatorial bond, which resulted in the formation of anti-products 13a and 13b, predominantly. Subsequently, compounds 13a and 13b underwent a E2 elimination to be both converted into compound (Z)−14. It should also be noted that, during the Aldol condensation, the Boc group on the indole nitrogen atom proved to be essential for the successful transformation. It was found that the aldol condensation did not occur in the absence of a protective group on indole nitrogen, whereas self-condensation of lactam 7 took place if the protective group was not bulky enough, such as MOM or Ts.

  Scheme 4

  

  Scheme 4.  Synthesis of natural product (-)-voacafricine A (1).

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  Scheme 5

  

  Scheme 5.  Stereochemical analysis during Aldol condensation and subsequent E2 elimination.

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  Subsequently, lactam 14 was reacted with the Lawesson's reagent in refluxing toluene to afford thiolactam 15 in 66% yield. The reaction time should be controlled strictly for < 0.5 h, otherwise, the yield would decrease dramatically. Afterwards, deprotection of the Boc group in compound 15 was performed. It was worth mentioning that the removal of Boc group was extremely difficult due to the congested environment around it. Moreover, it was well documented that 1, 2, 3, 4-tetrahydro-β-carboline was easily racemized under acidic condition via the cleavage and the reformation of C(1)-N(2) bond [20]. In this regard, we initiated the reaction under basic conditions (CH₃ONa, LiOH, NaOH) and neutral conditions (TMSOTf/2, 6-lutidine, ZnBr₂), but all attempts turned out to be unsuccessful for the transformation. Several weak acidic conditions were in turn surveyed (HCl/MeOH, CH₃COOH, p-TsOH), and only starting material was recovered in all cases. TFA proved to be effective to remove the Boc group. As anticipated, the reaction proceeded quickly in TFA solution accompanied by a complete epimerization of 1, 2, 3, 4-tetrahydro-β-carboline (Scheme 6). However, the rate of epimerization was found to be decreasing accordingly with lowering the concentration of TFA. Eventually, we performed the deprotection of compound 15 in a mixture of TFA and CH₂Cl₂ in a ratio of 1:8 (v/v) to provide the desired compound 16 successfully after treatment by aqueous ammonia without any epimerization.

  Scheme 6

  

  Scheme 6.  Epimerization of 1,2,3,4-tetrahydro-β-carboline under acidic condition.

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  The resulting hydroxyl group in compound 16 was protected by TBSCl to deliver compound 17 in 95% yield. Then, the one-pot desulfurization of thiolactam, stereoselective hydrogenation of carbon-carbon double bond and debenzylation was accomplished upon exposure of compound 17 to Raney Ni under hydrogen atmosphere, resulting in the formation of compound 18 in 66% yield with a tiny amount of diastereomeric impurity based on its ¹³C NMR. The excellent facial selectivity was owing to the steric hinderance exerted by isopropyl ester, which made the attack of H₂ to carbon-carbon double bond preferentially from the opposite face of ester group (Scheme 7) [10].

  Scheme 7

  

  Scheme 7.  Substrate-controlled stereoselective hydrogenation of carbon-carbon double bond.

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  Finally, oxidation of compound 18 afforded aldehyde 19 under Dess-Martin conditions, which was directly converted to hemiacetal 20 after desilylation with TBAF. Compound 20 was a pair of inseparable diastereomers (dr = 2:1), and was previously reported to be too unstable to be separated [2]. Nevertheless, hemiacetal 20 was readily isolated by column chromatography in this work and its structure was able to be fully characterized by ¹H NMR and ¹³C NMR spectra. With hemiacetal 20 in hand, we then focused on the investigation of the ultimate construction of the cagelike skeleton. At first, the reported method was employed [2], but it did not work in our study, which was presumably due to the difference of the ester group. Since the exact synthetic approaches to access quaternary aminal ammonium functionality remains substantially limited in literatures, we turned our attention to the typical aminal synthetic methods or the well-established glycosylation reactions, which basically involved Brønsted acid- (Table 1, entries 1 and 2) and Lewis acid- (entries 3–7) mediated synthesis. Eventually, Vorbürggen reaction [21-29], a ribosylation reaction generally used for the synthesis of nucleoside analogues, proved to be applicable in our work, which afforded (-)-voacafricine A in a yield of 64% from intermediate 20 after the ensuing hydrolysis by LiOH (entry 8). To the best of our knowledge, this represented the first example of intramolecular Vorbürggen reaction in synthesizing quaternary ammonium salt. Finally, (-)-voacafricine A was successfully prepared through 14 longest linear steps in 5.2% overall yield. Its ¹H and ¹³C NMR spectra were well in agreement with natural product reported in literatures [1, 2].

  Table 1

  

  Table 1.  Condition optimization for the synthesis of quaternary ammonium salt.^a

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  Entry	Conditions	Yield (%)
  1	TFA, CH2Cl2 (1:8, v/v), 12 hb	− e
  2	p-TsOH·H2O, toluene, 12 hb	n. r.f
  3	TMSOTf, CH2Cl2, 1 hb	- e
  4	BF3·OEt2, CH2Cl2, 1 hb	- e
  5	TMSOTf, CH2Cl2, 1 hc	- e
  6	SnCl4, CH2Cl2, 1 hc	- e
  7	TMSOTf, CH3CN, 1 hc	- e
  8	BSAd, TMSOTf, CH3CN, then LiOH, THF/H2Oc	64
  a All the reactions were performed on a 20 mg scale. b The reactant was compound 20. c The reactant was compound 21. d BSA was N,O-bis(trimethylsilyl)acetamide. e Reactions were messy and not isolated. f n. r. represented no reaction.

  In conclusion, we have accomplished an asymmetric total synthesis of (-)-voacafricine A in 5.2% overall yield over 14 longest linear steps from commercially available starting materials (5-methoxy tryptamine, 2-oxoglutaric acid and 4-(tert-butyldimethylsiloxy) butanoic acid). The synthetic protocol enabled concise and facile access to (-)-voacafricine A, which features the following key transformations: (a) Stereoselective Pictet-Spengler reaction of 5-methoxy tryptamine with isopropyl 2-oxopentanedioate catalyzed by a BINOL-derived chiral phosphoric acid catalyst followed by a cascade lactamization to furnish functionalized tetracyclic lactam and the first quaternary chiral carbon center; (b) Asymmetric α-alkylation of carbonyl group in the presence of Evans' chiral auxiliary to establish the second stereocenter with excellent diastereoselectivity; (c) Conversion of lactam to thiolactam with Lawesson's reagent to facilitate the one-pot transformations of reductive desulfurization of thiolactam, stereoselective hydrogenation of carbon-carbon double bond along with debenzylation using Raney Ni, in which, the third chiral center was created; (d) Employment of Vorbürggen reaction for the first time in an intramolecular manner to successfully construct the quaternary ammonium cation and the final cagelike skeleton.

  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  CRediT authorship contribution statement

  Xuan Pan: Writing – original draft, Methodology, Investigation. Tao Sheng: Investigation. Zhanzhu Liu: Writing – review & editing, Supervision, Resources, Project administration, Funding acquisition, Conceptualization.

  Acknowledgments

  This work was supported by Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, CAMS Innovation Fund for Medical Sciences (CIFMS, No. 2022-I2M-3–002).

  Supplementary materials

  Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2025.110913.

  
  
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• 

  Figure 1  Structures of voacafricines and their antibacterial activities.

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  Scheme 1  Retrosynthetic analysis of (-)-voacafricine A (1).

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  Scheme 2  Synthesis of key tetracyclic lactam intermediate 7.

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  Figure 2  Electronic circular dichroism (ECD) of compound 6.

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  Scheme 3  Synthesis of aldehyde 12.

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  Scheme 4  Synthesis of natural product (-)-voacafricine A (1).

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  Scheme 5  Stereochemical analysis during Aldol condensation and subsequent E2 elimination.

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  Scheme 6  Epimerization of 1,2,3,4-tetrahydro-β-carboline under acidic condition.

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  Scheme 7  Substrate-controlled stereoselective hydrogenation of carbon-carbon double bond.

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  Table 1.  Condition optimization for the synthesis of quaternary ammonium salt.^a

  Entry	Conditions	Yield (%)
  1	TFA, CH2Cl2 (1:8, v/v), 12 hb	− e
  2	p-TsOH·H2O, toluene, 12 hb	n. r.f
  3	TMSOTf, CH2Cl2, 1 hb	- e
  4	BF3·OEt2, CH2Cl2, 1 hb	- e
  5	TMSOTf, CH2Cl2, 1 hc	- e
  6	SnCl4, CH2Cl2, 1 hc	- e
  7	TMSOTf, CH3CN, 1 hc	- e
  8	BSAd, TMSOTf, CH3CN, then LiOH, THF/H2Oc	64
  a All the reactions were performed on a 20 mg scale. b The reactant was compound 20. c The reactant was compound 21. d BSA was N,O-bis(trimethylsilyl)acetamide. e Reactions were messy and not isolated. f n. r. represented no reaction.

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