- freely available
Marine Drugs 2010, 8(8), 2395-2416; doi:10.3390/md8082395
Published: 24 August 2010
Abstract: There are several avenues by which promising bioactive natural products can be produced in sufficient quantities to enable lead optimization and medicinal chemistry studies. The total synthesis of natural products is an important, but sometimes difficult, approach and requires the development of innovative synthetic methodologies to simplify the synthesis of complex molecules. Various classes of natural product alkaloids are both common and widely distributed in plants, bacteria, fungi, insects and marine organisms. This mini-review will discuss the scope, mechanistic insights and enantioselectivity aspects of selected examples of recently developed one-pot methods that have been published in 2009 for the synthesis of substituted piperidines, quinolizidines, pyrrolidines, hexahydropyrrolizines, octahydroindolizines and γ-lactams. In addition, progress on the synthesis of β-carboline (manzamine) alkaloids will also be discussed.
The challenging task of developing a drug candidate from a natural source to clinical usage has many obstacles. Toxicity, development of resistance associated with the drug candidate, and providing a sufficient amount of material needed for preclinical and clinical studies, all represent major challenges. Although nature has been generous in providing structurally diverse molecules with varying biological activities, it is not always possible to obtain the required quantities of the desired drug candidate. This lack of material has inspired innovative chemistry that develops new methodologies, catalysts and inventive synthetic routes for the synthesis and modification of natural products.
Our research program has been involved in the isolation and the optimization process of a number of marine alkaloids and peptides. Among the most intriguing is manzamine A (1) with impressive antimalarial activity. A number of chemical stability challenges associated with its chemical modification require significant attention due to the complexity of the structure. This compound can be easily isolated from a marine sponge in good yields . This inspired the development of new one-pot synthetic methodologies and conditions which are applicable to 1 and to other bioactive natural products.
During lead optimization of the manzamine alkaloids, the importance of one-pot methods for scaling certain drug leads became apparent. One-pot reactions are reactions in which two or more bond-forming transformations take place under the same reaction conditions without adding additional reagents or catalysts . These reactions have numerous applications in the field of total synthesis of natural products, particularly in avoiding the costly protection/deprotection processes and purification of intermediates [2–6]. The importance of these reactions to the organic synthesis community is illustrated by the numerous reviews that have discussed different aspects of these reactions [2–11]. Most of these reviews discuss one-pot reactions that were developed during the total synthesis of selected examples of natural products (either as designed or serendipitous developments) such as Nicolaou’s [4–6] and Tietze’s reviews [2,3]. Although outstanding one-pot transformations designed for total synthesis of natural products were highlighted in these reviews, other one-pot transformations designed for other purposes were omitted. Synthesis of heterocycles by one-pot methodologies were discussed in detail in Padwa’s reviews [9,10]. Specific reviews on the construction of alkaloids are not found with the exception of Kobayashi’s review that discussed new methodologies developed for the total synthesis of some select examples of alkaloids .
Due to the growing interest in marine alkaloids, a detailed discussion of select, newly developed one-pot methodologies that have been utilized for the modification of marine alkaloids or the synthesis of common alkaloid moieties emphasizing asymmetric synthesis, are presented here. This mini-review discusses applications, mechanistic insights and enantioselectivity of recently developed one-pot methods that have been published during 2009. Those reports that could be applied in the synthesis of marine alkaloid scaffolds (i.e., alkaloid moieties found in marine alkaloids) are emphasized. This mini-review will also cover our results for the manzamine alkaloids, as well as detailed asymmetric one-pot methods for the synthesis of substituted piperidines, quinolizidines, pyrrolidines, hexahydropyrrolizines, octahydroindolizines and γ-lactams.
2. New One-Pot Methods Used in the Modification of Marine Alkaloids
One-pot reductive amidation of nitroarenes
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 . 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 . 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 . 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 .
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 . 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 3o 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%). 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 3o amine base. A reasonable explanation for this observation is that 5 has two 3o 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 3o 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.
3. New One-Pot Reactions Used in the Asymmetric Construction of Some Important Alkaloid Moieties
3.1. One-pot asymmetric synthesis of substituted piperidines
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). 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 . 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.
3.2. One-pot organo-catalytic synthesis of quinolizidine derivatives
An elegant one-pot method was developed recently by Franzen and Fisher  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 . 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.
3.4. One-pot diastereoselective synthesis of γ-lactams
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. (Scheme 16, Equation 1). A mechanistic study was not published until 1983 when Cushman studied the electronic and steric effects on the stereochemical outcome . 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 , 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  (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 . 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.
In this mini-review, we have highlighted a number of one-pot asymmetric methodologies developed for the synthesis of important alkaloid moieties. One-pot reactions are highly practical and ideal for scaling drug leads to gram scale and greater. The manzamine alkaloids are still providing inspiration for new chemistry in which one-pot methodologies are being developed and will be discussed in separate reports. We anticipate a greater application of these methods and similar methodologies in the field of total synthesis of marine alkaloids and have highlighted the possible route to the schulzenine alkaloids. Two or more methodologies could be combined to design a complete synthesis of a particular target. The alkaloid moieties highlighted in this mini-review (i.e., substituted piperidines, quinolizidines, pyrrolidines, hexahydropyrrolizines, octahydroindolizines and γ-lactams) are common within the alkaloid family. Although there are many methods for the synthesis of these moieties, the development of one-pot methodologies to obtain high yields with a high degree of enantioselectivity will provide numerous opportunities for the synthetic community.
The authors would like to thank DOD, NIAID and the NIH National Center for Research Resources project, Grant Numbers 5P20RR021929, C06 RR-14503-01 for the financial support. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. A.E.W. gratefully thanks The Ministry of Higher Education of Egypt for a predoctoral fellowship.
- Samples Availability: Available from the authors.
- Peng, J; Rao, KV; Choo, YM; Hamann, MT. Manzamine alkaloids. In Modern Alkaloids; Fattorusso, E, Taglialatela-Scafati, O, Eds.; Wiley-VCH Verlag GmbH & Co. KgaA: Weinheim, Germany, 2007; pp. 189–232.
- Tietze, LF. Domino reactions in organic synthesis. Chem. Rev 1996, 96, 115–136, doi:10.1021/cr950027e. 11848746
- Tietze, LF; Beifuss, U. Sequential transformations in organic chemistry: A synthetic strategy with a future. Angew. Chem. Int. Ed. Engl 1993, 32, 131–163, doi:10.1002/anie.199301313.
- Nicolaou, KC; Montagnon, T; Snyder, SA. Tandem reactions, cascade sequences, and biomimetic strategies in total synthesis. Chem. Commun 2003, 5, 551–564.
- Nicolaou, KC; Edmonds, DJ; Bulger, PG. Cascade reactions in total synthesis. Angew. Chem. Int. Ed. Engl 2006, 45, 7134–7186, doi:10.1002/anie.200601872. 17075967
- Nicolaou, KC; Chen, SJ. The art of total synthesis through cascade reactions. Chem. Soc. Rev 2009, 38, 2993–3009, doi:10.1039/b903290h. 19847336
- Pellissier, H. Asymmetric domino reactions. Part A: reactions based on the use of chiral auxiliaries. Tetrahedron 2006, 62, 1619–1665, doi:10.1016/j.tet.2005.10.040.
- Pellissier, H. Asymmetric domino reactions. Part B: reactions based on the use of chiral catalysts and biocatalysts. Tetrahedron 2006, 62, 2143–2173, doi:10.1016/j.tet.2005.10.041.
- Padwa, A. Domino reactions of rhodium(ii) carbenoids for alkaloid synthesis. Chem. Soc. Rev 2009, 38, 3072–3081, doi:10.1039/b816701j. 19847342
- Padwa, A; Bur, SK. The domino way to heterocycles. Tetrahedron 2007, 63, 5341–5378, doi:10.1016/j.tet.2007.03.158. 17940591
- Kibayashi, C. Development of new synthetic methods and its applications to total synthesis of nitrogen-containing bioactive natural products. Chem. Pharm. Bull 2005, 53, 1375–1386, doi:10.1248/cpb.53.1375. 16272717
- Sakai, R; Higa, T; Jefford, CW; Bernardinelli, G. Manzamine A, a novel antitumor alkaloid from a sponge. J. Am. Chem. Soc 1986, 108, 6404–6405, doi:10.1021/ja00280a055.
- Rao, KV; Kasanah, N; Wahyuono, S; Tekwani, BL; Schinazi, RF; Hamann, MT. Three new manzamine alkaloids from a common Indonesian sponge and their activity against infectious and tropical parasitic diseases. J. Nat. Prod 2004, 67, 1314–1318, doi:10.1021/np0400095. 15332848
- Peng, J; Kudrimoti, S; Prasanna, S; Odde, S; Doerksen, RJ; Pennaka, HK; Choo, Y; Rao, KV; Tekwani, BL; Madgula, V; Khan, SI; Wang, B; Mayer, AMS; Jacob, MR; Tu, LC; Gertsch, J; Hamann, MT. Structure-activity relationship and mechanism of action studies of manzamine analogues for the control of neuroinflammation and cerebral infections. J. Med. Chem 2010, 53, 61–76, doi:10.1021/jm900672t. 20017491
- Wahba, AE; Peng, J; Kudrimoti, S; Tekwani, BL; Hamann, MT. Structure activity relationship studies of manzamine A: amidation of positions 6 and 8 of the β-carboline moiety. Bioorg. Med. Chem 2009, 17, 7775–7782, doi:10.1016/j.bmc.2009.09.026. 19833520
- Shilabin, AG; Kasanah, N; Tekwani, BL; Hamann, MT. Kinetic studies and bioactivity of potential manzamine prodrugs. J. Nat. Prod 2008, 71, 1218–1221, doi:10.1021/np800163u. 18598080
- El Sayed, KA; Khalil, AA; Yousaf, M; Labadie, G; Kumar, GM; Franzblau, SG; Mayer, AMS; Avery, MA; Hamann, MT. Semisynthetic studies on the manzamine alkaloids. J. Nat. Prod 2008, 71, 300–308, doi:10.1021/np0703702. 18198837
- Ibrahim, MA; Shilabin, AG; Prasanna, S; Jacob, M; Khan, SI; Doerksen, RJ; Hamann, MT. 2-Methyl modifications and SAR studies of manzamine A. Bioorg. Med. Chem 2008, 16, 6702–6706, doi:10.1016/j.bmc.2008.05.079. 18595720
- Wahba, AE; Peng, J; Hamann, MT. Reductive amidation of nitroarenes: a practical approach for the amidation of natural products. Tetrahedron Lett 2009, 50, 3901–3904, doi:10.1016/j.tetlet.2009.04.061.
- De Oliveira, JHHL; Nascimento, AM; Kossuga, MH; Cavalcanti, BC; Pessoa, CO; Moraes, MO; Macedo, ML; Ferreira, AG; Hajdu, E; Pinheiro, US; Berlinck, RGS. Cytotoxic alkylpiperidine alkaloids from the Brazilian marine sponge pachychalina alcaloidifera. J. Nat. Prod 2007, 70, 538–543, doi:10.1021/np060450q. 17346073
- Matsunaga, S; Miyata, Y; van Soest, RWM; Fusetani, N. Tetradehydrohalicyclamine A and 22-hydroxyhalicyclamine A, new cytotoxic bis-piperidine alkaloids from a marine sponge amphimedon sp. J. Nat. Prod 2004, 67, 1758–1760, doi:10.1021/np049824a. 15497958
- Ishiguro, Y; Kubota, T; Ishiuchi, K; Fromont, J; Kobayashi, J. Plakoridine C, a novel piperidine alkaloid from an Okinawan marine sponge Plakortis sp. Tetrahedron Lett 2009, 50, 3202–3204, doi:10.1016/j.tetlet.2009.01.135.
- Escolano, C; Amat, M; Bosch, J. Chiral Oxazolopiperidone Lactams: Versatile Intermediates for the Enantioselective Synthesis of Piperidine-Containing Natural Products. Chem. Eur. J 2006, 12, 8198–8207, doi:10.1002/chem.200600813. 16991186
- Felpin, F; Lebreton, J. Recent advances in the total synthesis of piperidine and pyrrolidine natural alkaloids with ring-closing metathesis as a key step. Eur. J. Org. Chem 2003, 2003, 3693–3712, doi:10.1002/ejoc.200300193.
- Laschat, S; Dickner, T. Stereoselective synthesis of piperidines. Synthesis 2000, 2000, 1781–1813, doi:10.1055/s-2000-8218.
- Sun, X; Sengupta, S; Petersen, JL; Wang, H; Lewis, JP; Shi, X. Intermolecular cross-double-Michael addition between nitro and carbonyl activated olefins as a new approach in C-C bond formation. Org. Lett 2007, 9, 4495–4498, doi:10.1021/ol702059x. 17910465
- Chen, Y; Zhong, C; Petersen, JL; Akhmedov, NG; Shi, X. One-pot asymmetric synthesis of substituted piperidines by exocyclic chirality induction. Org. Lett 2009, 11, 2333–2336, doi:10.1021/ol900708d. 19438199
- Franzen, J; Fisher, A. Asymmetric alkaloid synthesis: a one-pot organocatalytic reaction to quinolizidine derivatives. Angew. Chem. Int. Ed. Engl 2009, 48, 787–791, doi:10.1002/anie.200805130. 19090516
- Takada, K; Uehara, T; Nakao, Y; Matsunaga, S; van Soest, RW; Fusetani, N. Schulzeines A-C, new α-glucosidase inhibitors from the marine sponge penares schulzei. J. Am. Chem. Soc 2004, 126, 187–193, doi:10.1021/ja037368r. 14709083
- Enders, D; Grondal, C; Huttl, ARM. Asymmetric organocatalytic domino reactions. Angew. Chem. Int. Ed. Engl 2007, 46, 1570–1581, doi:10.1002/anie.200603129. 17225236
- Wang, Y; Kumano, T; Kano, T; Maruoka, K. Organocatalytic approach to enantioselective one-pot synthesis of pyrrolidine, hexahydropyrrolizine, and octahydroindolizine core structures. Org. Lett 2009, 11, 2027–2029, doi:10.1021/ol900477x. 19348468
- El-Naggar, M; Piggott, AM; Capon, RJ. Bistellettazines A-C and Bistellettazole A: New Terpenyl-Pyrrolizidine and Terpenyl-Imidazole Alkaloids from a Southern Australian Marine Sponge, Stelletta sp. Org. Lett 2008, 10, 4247–4250, doi:10.1021/ol8016512. 18781811
- Biard, JF; Guyot, S; Roussakis, C; Verbist, JF; Vercauteren, J; Weber, JF; Boukef, K. Lepadiformine, a new marine cytotoxic alkaloid from Clavelina lepadiformis Mueller. Tetrahedron Lett 1994, 35, 2691–2694, doi:10.1016/S0040-4039(00)77007-9.
- Castagnoli, NJ. N-Acylenamines from oxazolines. New route to 2-acetamidogylcals. J. Org. Chem 1969, 34, 3187–3189, doi:10.1021/jo01262a081. 5811404
- Cushman, M; Abbaspour, A; Gupta, YP. Total synthesis of (±)-14-epicorynoline, (±)-corynoline, and (±)-6-oxocorynoline. J. Am. Chem. Soc 1983, 105, 2873–2879, doi:10.1021/ja00347a057.
- Masse, CE; Ng, PY; Fukase, Y; Sanchez-Rosello, M; Shaw, JT. Divergent Structural Complexity from a Linear Reaction Sequence: Synthesis of Fused and Spirobicyclic γ-Lactams from Common Synthetic Precursors. J. Comb. Chem 2006, 8, 293–296, doi:10.1021/cc050153o. 16676997
- Wei, J; Shaw, JT. Diastereoselective Synthesis of γ-Lactams by a One-Pot, Four-Component Reaction. Org. Lett 2007, 9, 4077–4080, doi:10.1021/ol701911u. 17760458
- Tang, Y; Fettinger, JC; Shaw, JT. One-Step Synthesis of Complex Nitrogen Heterocycles from Imines and Alkyl-Substituted Maleic Anhydrides. Org. Lett 2009, 11, 3802–3805, doi:10.1021/ol901018k. 19708695
© 2010 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).