Manzamine alkaloids are a unique class of compounds that contain a complicated ring system coupled with a β-carboline moiety (Figure 1). The first representative of this family is manzamine A (1), which was first isolated by Higa and co-workers in 1986 [11]. This class of alkaloids has shown a wide range of biological activities (antimicrobial, antiparasitic, cytotoxicity, anti-inflammatory and pesticidal) and has also shown activity against HIV-1 and AIDS opportunistic infections [12]. The most potent activity for the manzamine alkaloids appears to be against malaria. Manzamine A (1) and its natural analog 8-hydroxymanzamine A (2) exhibited improved potency against malarial parasites both in vitro and in vivo relative to chloroquine and artemisinin [13]. However, the toxicity associated with high dose schedules limited the development of this class of compounds as new antimalarial drugs.

Since the mechanism of action of manzamine alkaloids as antimalarial agents is not completely clear; several structure activity relationship SAR and optimization studies using 1, 2 or 3 as starting materials have been completed [14–18]. Nitration of 1 yielded 6 and 8 nitromanzamines and after reduction afforded the corresponding aminomanzamines (Scheme 1). Aminomanzamines are not stable, making them unsuitable for further amidation and N-alkylation reactions. However, 20 amide analogs were successfully synthesized in very low yield [15].

Inspired by the instability of aminomanzamines (7 and 8) and by the low yields of the amide derivatives, a one-pot reductive amidation method was developed for the conversion of nitroarenes to the corresponding amides [19]. The reduction of the nitro group generally requires a protic solvent as a carrier of the hydrogen generated in situ. However, the amidation reaction using acyl chloride requires aprotic solvents as well as dry conditions to prevent side reactions with the solvent. In addition, the amidation reaction using acyl chlorides requires basic conditions in which the base will neutralize the hydrochloric acid liberated from the reaction as a by-product. Because of this, a 3^o amine base (triethylamine, Et₃N) was added in the reduction step where equimolecular amounts of acetic acid and zinc are used in addition to the acyl chloride. Once the amine is formed in situ, it immediately reacted with the acyl chloride facilitated by the tertiary amine present. Dimethylformamide DMF was shown to be the best choice of solvent for this reaction (Scheme 2). Using the optimized conditions, several nitroarenes were screened for one-pot conversion to amides. All the reagents were added at once and complete conversion of the starting materials to the corresponding amines and amides was observed with ~60% yield of the amides.

As a validation of this method, a one-pot approach was used for the synthesis of 6-cyclohexamidomanzamine A (9). This amide derivative showed potent antimalarial activity in vitro with an IC₅₀ of 0.032 μM against the D6 clone of Plasmodium falciparum, and was synthesized from 6-aminomanzamine A (7) through the normal amidation pathway with low yield (17%)[15]. Starting with 6-nitromanzamine A (5), and using the optimized one-pot reductive amidation method, the yield of amide analog 9 was increased to 56% relative to 17% (Scheme 3). It was surprising that the reductive amidation of 5 proceeded without the addition of a 3^o amine base. A reasonable explanation for this observation is that 5 has two 3^o amine built-in bases which could possibly facilitate the reductive amidation reaction. To validate this explanation, harmane was nitrated to produce the closely related model compounds, 6- and 8- nitroharmanes. When the optimized one-pot reductive amidation conditions were applied to nitroharmanes without the addition of the Et₃N, no amides were obtained, only aminoharmanes (Scheme 4, Equation 1); However, by adding Et₃N the amide derivatives of harmane were isolated in good yield (60%)(Scheme 4, Equation 2). These experimental results validated the hypothesis regarding the built-in 3^o amine bases in manzamine alkaloids.

Although this method was developed particularly for the modification of manzamine alkaloids, it has clear utility in the synthesis of other alkaloids. The nitration of several biologically active natural products, as well as currently utilized drugs to generate the starting nitro materials for this one-pot reductive amidation method is ongoing. The goal is to show the general and practical applications for this method, as well as generating a library of compounds for further optimization and biological evaluation.

Piperidine containing alkaloids are common in marine environments [20–22]. Although there have been several synthetic methods [23–25] reported for construction of this moiety, stereoselectivity remains a challenging task especially when three or more stereogenic centers or quaternary substituted carbons are present. The Shi group developed a novel cascade approach for the stereoselective synthesis of the piperidine moiety, based on their development of an intermolecular cross-double-Michael addition between α, β-unsaturated carbonyl compounds and nitroalkenes, facilitated by amines as Lewis bases (LB)[26]. Allylic nitro products are generated in the process via the β-elimination of the LB (Figure 2). The new cascade reaction encouraged Shi’s group to extend the cascade by involving an activated electrophilic intermediate for the construction of nitrogen containing heterocycles with two or more stereogenic centers.

Based on their previous results, which showed that the addition of the amine to nitroalkene is fast, they proposed a one-pot cascade approach for the asymmetric synthesis of the piperidine moiety [27]. They postulated that adduct A (Figure 3), the addition product of the amine with nitroalkene, was suitable for Michael addition type reaction with an activated carbonyl to generate adduct B. Ring closure then provides the substituted piperidine motif in a one-pot approach with the generation of three stereogenic centers. To validate this proposed one-pot cascade sequence, nitrostyrene was allowed to react with methyl vinyl ketone (MVK) in the presence of a primary amine (Scheme 5). Being a complex mixture with many possible side reactions (i.e., Baylis-Hillman reaction), it was surprising that substituted piperidines, 13a and 13b, were obtained in excellent yields and good diastereoselectivities with no side products. Solvent optimization of these one-pot conditions showed that THF gave the best yields with good diastereoselectivities (97%, dr = 7:1 for 13a; 85%, dr = 15:1 for 13b). The formation of 13 confirmed the formation of adduct B (Figure 3), which was trapped by a sequential Henry-aldol cyclization. Although three stereogenic centers were generated in piperidine 13 only two C-4 diastereoisomers were obtained, of which the cis isomer of C-3 nitro and C-4 hydroxy groups was the major product.

This one-pot reaction was compatible with a variety of nitroalkenes, amines and activated carbonyls. Different aryl and alkyl substituted nitroalkenes generated variation at the C-2 position. Moreover, both alkyl and aryl ketones were suitable for this cascade one-pot process giving different choices of substitutes on the C-4 position. Substituents on C-5 were possible through α-substituted enones, while β-substituted enones delivered variation at the C-6 position only when ammonia was used. It is interesting that only C-4 isomers were obtained in all cases.

The aza-Michael adduct B (Figure 3) was not observed in reaction NMR studies; moreover, the piperidine products were stable under strong basic conditions. These results strongly suggested that the irreversible Henry-aldol cyclization was the rate determining step, which accounts for the piperidine diastereoselectivity through the chair transition state. With the formation of the C-2 stereogenic center during the amine conjugate addition, it is possible that the stereochemistry of the final piperidine product could be selectively induced by chiral amines through its involvement in the spatial arrangement of the chair transition state. In this case, a new stereogenic center on the exocyclic C-7 will be introduced on the piperidine product, which may result in the formation of four diastereoisomers. To investigate this proposed chirality induction, arylethanamines 14a–c were applied in the one-pot piperidine synthesis and as expected, piperidines 15a–c were obtained in good yields (Scheme 6). The results showed excellent diastereoselectivity of the C-4 position in 15a and 15b with dr > 10:1. In addition, modest chirality induction by the C-7 position was observed with dr = 4:1.

X-ray analysis of the piperidine crystals revealed that the exocyclic C-7 adopted a staggered conformation with respect to the ring. Moreover, the chemical shifts of the C-8 and C-9 carbons were significantly shifted upfield in an anti-parallel position relative to the nitrogen lone pair electrons. This data suggest that the N1-C7 σ-bond rotation was restricted. Based on these results, a Henry-aldol cyclization chair transition state was proposed in Figure 4. The N-1 nitrogen lone pair electrons were placed in the axial position and the preferred staggered N1-C7 conformation could be achieved when the small group on C-7 was placed anti (axial orientation) to the N-1 nitrogen lone pair. Three syn-pentane interactions were expected in this staggered conformation (as shown in Figure 4); however, placement of the small group on C-7 anti to the lone pair will minimize these interactions. This proposed transition state was consistent with experimental observations. Also, the stability of this transition state could be influenced by the n-σ* electronic interaction between the nitrogen lone pair and the exocyclic axial small group.

To validate the importance of this n-σ* electronic interaction in the chirality enhancement, the methyl group was replaced in the chiral amine with a carboxylate group which is less bulky and would produce a stronger n-σ* interaction. As expected, the reaction of the amino esters 16a, b with enone 12a and nitroarene 10a yielded the corresponding piperidine products in moderate yields (Scheme 7). Interestingly, piperidines 17a, b were obtained in their diastereomerically pure form. Complete chirality induction was achieved through control via exocyclic asymmetry. This new one-pot method opens the door for the asymmetric synthesis of several natural products that contain a piperidine moiety.

An elegant one-pot method was developed recently by Franzen and Fisher [28] for the asymmetric synthesis of substituted quinolizidines. This moiety is widely represented in several alkaloids isolated from plants, ants and marine organisms. Their retrosynthetic analysis for the indolo[2,3a]quinolizidine skeleton is highlighted in Figure 5. They postulated that the stereogenic center 11b could be generated through the asymmetric acyliminium ion cyclization of the imine (19). This imine could be obtained from the aldehyde precursor 20, in which the aldehyde is apparently the adduct of an enantioselective Michael addition.

This retro-analysis required the addition of an activated amide 22 to the unsaturated aldehyde 21, which has not yet been reported in the literature. To accomplish their synthetic plan, they optimized the enantioselective Michael addition of cinnamic aldehyde 23 and an activated indol substituted amide 22, using different proline derivatives as organocatalysts (Figure 6), exploring different solvents, temperatures, as well as various acids needed for the cyclization step of the acyliminium ion (Scheme 8). Dichloromethane (DCM) was the solvent of choice and yielded compounds 24a and 24b with full conversion at room temperature, but with low enantioselectivity (88% ee). The enantioselectivity was increased to 94% by lowering the temperature to 3 °C, while further cooling (−20 °C) resulted in only 5% conversion. The proline derivative (S)-A showed the best selectivity, B was less selective and less active, while C and D were inactive for this reaction. When TFA was used in the acid-catalyzed cyclization of the acyliminium ion, the indoloquinolidine products were obtained nonselectively as a 1:1 mixture. However, some selectivity of 24a over 24b was observed when HCl was used. It was also noted that cooling down the reaction mixture prior to the addition of HCl increased the selectivity up to 85:15. The optimized conditions are highlighted in Scheme 8.

This one-pot, two step method was applied to several aromatic α, β-unsaturated aldehydes with good to excellent enantioselectivity. The indolyl moiety of 22 was replaced with an electron-rich phenyl group, which should give direct access to the benzo[a]quinolizidine skeleton. The reaction between 23 and the activated amide 25, in the presence of the organocatalyst A, and subsequent addition of HCl, delivered the benzo[a]quinolizidines 26a and 26b with good to high enantioselectivity (Scheme 9). It was noted that the formation of the benzo[a]quinolizidine moiety required stronger acidic conditions (40 mol%) relative to the indolo[2,3a]quinolizidine (20 mol%). This is explained by the poorer nucleophilicity of the phenyl ring compared to the 3-indolyl moiety.

The absolute configuration of one of the benzo[a]quinolizidine derivatives was established by X-ray analysis as 2R,3S,11bS, which provided important mechanistic insight (Scheme 10). The aryl groups in the catalyst will shield the Re face of the iminium intermediate 27, which will help to establish the S configuration on C-2 through the unshielded Si face. Intramolecular imine formation with epimerization of the stereochemically labile stereogenic center at C-3 will establish the more thermodynamically stable 2R,3S-trans configuration of the intermediate imine 28. This acyliminium ion undergoes an electrophilic aromatic substitution with the aromatic moiety to give quinolizidine products.

The great diastereoselectivity observed in the acid catalyzed cyclization could be explained based on the reaction conditions. Considering the synthesis of indoloquinolizidines 24a and 24b (Scheme 11), the major isomer was 24a with the indolyl moiety in an axial orientation. Although the formation of 24a resembles a higher energy product, reaction via the transition state I (Scheme 11) is under kinetic control (−78 °C), owing to less steric hindrance from the equatorial α protons relative to the theromodynamic equatorial product.

As a possible application of this one-pot method in the total synthesis of biologically active marine alkaloids, the tricyclic core of schulzenine alkaloids could be easily constructed using Franzen and Fisher’s method (Figure 7). Schulzenine alkaloids were recently isolated from the marine sponge Penares schulzei [29]. Schulzenine A–C inhibits α-glucosidase with IC₅₀ values of 48–170 nM. Figure 8 represents the proposed one-pot reaction that could be used for the synthesis of the tricyclic core of schulzenine alkaloids.

Recently, organocatalysis has been widely used in asymmetric synthesis due to its operational simplicity, low toxicity and ready availability compared to metal catalyzed reactions [30]. Maruoka and coworkers have used an organocatalyst of type (S)-34 for one-pot construction of pyrrolidine, hexahydropyrrolizine and octahydroindolizine moieties with a high degree of stereoselectivity [31]. These core structures are commonly found in plant and marine alkaloids (Figure 9)[32,33]. Their organocatalytic based retro-synthetic analysis is presented in Scheme 12.

The key strategy is based on the asymmetric conjugate addition of the Schiff base of glycine ester 32 to α, β-unsaturated carbonyl compound 33 catalyzed by the chiral phase transfer organocatalyst (S)-34a–c. The organocatalytic Michael addition of 32 to 33 should deliver the adduct 31 in enantiomerically pure form. This adduct can then undergo intramolecular reductive amination facilitated by the Hantzsch ester to yield the pyrrolidine derivative 30 as an intermediate. Acetal hydrolysis followed by another intramolecular reductive amination of the intermediate 30 will furnish a bicyclic hexahydropyrrolizine skeleton.

First, the asymmetric addition of the glycine derivative 32 to methyl vinyl ketone (MVK), under the influence of an organocatalyst of type 34 (Scheme 13), was examined. Optimization of the reaction between 32 and MVK with K₂CO₃ and 10 mol% of CsCl at 0 °C gave the conjugate adduct 35. This revealed that Et₂O and the organocatalyst (S)-34b gave the best yield (85%), as well as the best diastereoselectivity (94% ee). Subsequently, optimization of the intramolecular reductive amination of 35 with the Hantzsch ester for the synthesis of the substituted pyrrolidine 36 was studied. The optimization process revealed that the Hantzsch ester (2 eq.) and trifloroacetic acid (1 eq.) in aqueous EtOH at 60 °C were the best conditions to build up the 2,5-disubstituted cis-pyrrolidine 36 stereospecifically in 84% yield.

Next, the synthesis of the octahydroindolizine skeleton 39 using their optimized conditions (Scheme 14) was performed. Asymmetric conjugate addition of the glycine ester 32 to the enone 37 (2 eq.) and K₂CO₃ (5 eq.) under the influence of chiral phase transfer catalyst (S)-34b and CsCl in Et₂O at 0 °C for 15 h gave the conjugate adduct 38 in 88% yield with 94% ee. Hantzsch ester mediated intramolecular reductive amination with subsequent acetal hydrolysis, followed by reductive amination, was effective to deliver the octahydroindolizine core 39 in 70% yield. The whole reaction sequence was done in a one-pot approach and performed without any difficulty by sequential addition of the reagents to afford 39 in 48% overall yield.

Hexahydropyrrolizine 42 was also obtained by the same optimized conditions (Scheme 15). The asymmetric conjugate addition of 32 to the enone 40 using their optimized conditions yielded adduct 41 in 85% yield with 90% ee. It was noted that the enantioselectivity was slightly decreased by switching the cyclic acetal moiety of 38 to a 1,3-dioxolane (78% yield, 86% ee). The hexahydropyrrolizine skeleton 42 was then delivered in 55% yield by the action of Hantzsch ester mediated intramolecular reductive amination. The one-pot reaction was also possible with an overall yield of 31%.

The cycloaddition of imines with succinic anhydride in a one-pot approach to construct the γ-lactam moiety in high yield was first reported three decades ago by Castagnoli et al. [34](Scheme 16, Equation 1). A mechanistic study was not published until 1983 when Cushman studied the electronic and steric effects on the stereochemical outcome [35]. A low yield was obtained when phenyl substituted succinic anhydride was used instead of succinic anhydride (Scheme 16, Equation 2). Also, variations in the structure of the succinic anhydride were not explored in detail in this methodology. Due to the wide abundance of the γ-lactam moiety in natural products and potential drug leads, the Shaw group has extensively studied the effect of substituents on the iminolysis of succinic anhydride derivatives. In their first report, Shaw and coworkers demonstrated the importance of electronic factors on the reactivity of phenylsuccinic anhydride when reacted with the imines derived from benzaldehyde and o-bromobenzaldehyde [36], demonstrating that the electron withdrawing groups in the phenyl ring give excellent yields (>90%)(Scheme 16, Equation 3). Following this yield improvement, Shaw and coworkers reported that sulfur-substituted succinic anhydrides also gave excellent yields (90%) and showed the highest diastereoselectivity (anti diastereoisomer) when reacted with different imines [37] (Scheme 16, Equation 4).

In the case of the iminolysis of maleic anhydride, a possible zwitterionic enolate intermediate could be generated through a prototropic shift which provides allylic stabilization. To validate this, Shaw and coworkers studied the cyclization of several polycyclic imines with maleic anhydride derivatives (Figure 10) as a new one-pot synthesis of complex nitrogen heterocycles [38]. Thus, the reaction of the imine 45 with maleic anhydride derivative 46 formed intermediate 47, which could isomerize to 48. Attack of the α- or γ-positions of the dienolate would lead to products 49a or 49b (Scheme 17).

Tetrahydrophthalic anhydride 44b reacted with several imines through path A to give the formal cycloaddition products with high diastereoselectivity (anti configuration) and acceptable yields (Scheme 18, Equations 1 and 2). It was interesting that the diastereoselectivity of the reaction of 44b with 43b was reversed when triethylamine and triethylammonium hydrochloride were present in the reaction mixture. Methyl and dimethyl-substituted anhydrides did not react with several imines; however, an exomethylene-substituted lactam was obtained in good yield (59%) with excellent diastereoselectivity (>95:5 anti:syn) when imine 43b was used (Scheme 18, Equation 3). Acyclic imines derived from aromatic aldehydes were less reactive relative to cyclic imines.

Although the ¹H-NMR spectrum of the products obtained from the reaction of cyclopentane-fused maleic anhydride 44a with several imines initially appeared to be consistent with the anticipated adduct, X-ray crystallographic analysis revealed the products to be N,O-acetals (Scheme 19). Mixing the anhydride 44a with the imines 43a and 43b at room temperature yielded an immediate precipitate of N,O-acetals 53 and 54 in 78% and 71% yields respectively. No γ-lactam products were produced upon further heating.

A completely different reaction manifold was observed in the reaction of ketimine 43c with the maleic anhydride derivative 44c (Scheme 20). A new γ-lactam product was obtained. The mechanism of formation of this new product is outlined in Scheme 20. A Prototropic shift of acylated imine 55 will yield the enamide carboxylic acid 56, which is setup for an intramolecular Michael-type addition of the enamide to the unsaturated acid to deliver a new lactam 58 through enamide 57.

Anhydrides 44d and 44b reacted similarly with ketimine 43c to produce new γ-lactam products 59 and 60, in yields of 74% and 59% respectively (Scheme 21). In the case of the spiro γ-lactam 60, a 50:50 mixture of diastereoisomers was obtained after 15 min of reaction time. Continued heating of 60 under the reaction conditions shifted the diastereoselectivity to a 70:30 mixture, favoring the anti isomer. Product 61 was obtained in 72% yield when anhydride 44a was reacted with ketimine 43c. No stereoselectivity was observed in this case.