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Recent Progress in the Chemistry of Pandanus Alkaloids
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Recent Progress in the Chemistry of Pandanus Alkaloids Mario A. Tana, Hiromitsu Takayamab,* a
Department of Chemistry, College of Science, Research Center for the Natural and Applied Sciences, University of Santo Tomas, Manila, Philippines Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan *Corresponding author: e-mail address: [email protected] b
Contents 1. Introduction 2. New Alkaloids from Pandanus Species 3. Synthetic Studies on the Pandanus Alkaloids 3.1 Synthesis of Pandamarilactone-1 3.2 Synthesis of Pandamarine 3.3 Synthesis of epi-Pandamarilactonine-H 3.4 Synthesis of Dubiusamine-A and its Enantiomer 3.5 Synthesis of Dubiusamine-B 3.6 Synthesis of Dubiusamine-C 3.7 Synthesis of Pandanamine, Norpandamarilactonines, and Pandamarilactonines 3.8 Synthesis of Pandalizine-A and -B 4. Pharmacology of the Pandanus Species 5. Summary References
2 2 12 12 13 14 15 18 19 21 24 25 26 26
Abstract The genus Pandanus (Pandanaceae) is widely distributed in the tropical and subtropical regions. With about 700 species worldwide, three Pandanus species (P. amaryllifolius, P. utilis, and P. dubius) have been investigated and found to contain new alkaloids possessing a pyrrolidinyl-α,β-unsaturated γ-lactone, a γ-butylidene-α-methyl-α,βunsaturated γ-lactam, and/or indolizidine residues. Several total syntheses of Pandanus alkaloids have been accomplished. Several pharmacological studies on Pandanus species, including scientific validations of their antibacterial, antiinflammatory, antidiarrheal, and cytotoxic activities, have been conducted in relation to their traditional folk medicine uses.
The Alkaloids ISSN 1099-4831 https://doi.org/10.1016/bs.alkal.2018.12.001
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2019 Elsevier Inc. All rights reserved.
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1. Introduction Pandanus represents the largest genus among the four genera in the family Pandanaceae.1 Consisting of about 700 species, they are distributed in tropical and subtropical regions, including the Pacific Islands, Malaysian islands, and Australia. Several Pandanus species are medicinal plants that have been used in traditional medicine because they possess pharmacological activities such as antihyperlipidemic,2 antihyperglycemia,3 anticancer,4 antiviral,5 antiinflammatory,6 antimicrobial,7 and antidiarrheal8 activities. The genus Pandanus is also an excellent source of secondary metabolites, including steroids,9 terpenoids,9a,10 flavonoids,11 lignans,12 benzenoids,13 and alkaloids.14 Among these secondary metabolites, the isolation of alkaloids has been emphasized in phytochemical studies on the genus Pandanus, specifically Pandanus amaryllifolius, Pandanus dubius, and Pandanus utilis. A review on Pandanus alkaloids was published in 2008 in Volume 66 of the series The Alkaloids.14 This review offers an update, covering literatures on the identification of new alkaloids and synthetic studies published up to September 2018.
2. New Alkaloids from Pandanus Species As most alkaloids have been identified from the leaves of P. amaryllifolius, the roots were prioritized and given importance in the isolation and identification of alkaloids. A sample of P. amaryllifolius roots collected from the Philippines yielded five new alkaloids named pandamarilactonine-E (1), -F (2), -F N-oxide (3), -G (4), and -H (5) (Fig. 1).15,16 Pandamarilactonine-E (1) is an optically active alkaloid with a molecular formula C18H29NO4 as determined by HR-ESIMS. It contains a 3,5disubstituted γ-butyrolactone unit comprising the upper part where a trans configuration is observed between the H-3 and H-5 methine protons as evidenced by NOE correlation of the characteristic 1H peaks at H-5 (δH 4.50 ppm) and H-21 methyl (δH 1.27 ppm). The presence of a γ-pyrrolidinyl-α-methyl-γ-butyrolactone unit in the lower part was identified by 1D and 2D NMR experiments. The relative stereochemistry at the C-14 and C-15 stereocenters was elucidated on the basis of the observed NOE correlation between H-15 methine (δH 4.43 ppm) with H-14 (δH 2.86 ppm) and H-17 (δH 2.78 ppm) methines, and the NOE correlation between H-17 and H3-20 (δH 1.28 ppm) methyl, indicating a syn
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Fig. 1 Alkaloids from the roots of Pandanus amaryllifolius.
orientation of H-15 and H-17 methine protons. The relative threo configuration was further supported by the observed NOE at H-14 and H3-20 protons. If an erythro configuration is proposed, this NOE correlation will not be observed on the basis of the Dreiding model analysis. The absolute configuration of pandamarilactone-E (1) was finally established to be (3R, 5R, 14R, 15R, 17R) by a stereoselective hydrogenation of synthetically pure dubiusamine-B (6) (Scheme 1) with a threo configuration at the C-14 and C-15 positions.
Scheme 1 Conversion of dubiusamine-B (6) to pandamarilactonine-E (1).
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Pandamarilactonine-F (2) has the same molecular formula as 1. Spectroscopic analysis indicated that 2 had almost the same structure as 1. The relative erythro configuration at C-14 and C-15 in the pyrrolidinyl-γbutyrolactone moiety was deduced by comparison of the chemical shifts and coupling constants with those of previously isolated alkaloids, pandamarilactonines-A to -D. In accordance with that, the relative stereochemistry of (3R*, 5R*, 14R*, 15S*, 17R*) for 2 was proposed. The molecular formula of pandamarilactonine-F N-oxide (3) denotes an additional oxygen atom compared to alkaloids 1 and 2. Its polar nature in chromatography and the downfield-shifted signals of H-9 (δ 3.57, δ 3.33), H-11 (δ 3.65, δ 3.16), H-14 (δ 3.42) and H-15 (δ 5.47) further indicate that it is an N-oxide of alkaloid 1 or 2. The structure of pandamarilactonine-F N-oxide (3) was established by the m-CPBA oxidation of natural 2. The spectroscopic data of the semisynthetic product were in complete agreement with the natural compound. Pandamarilactonine-G (4) was established to contain pyrrolidinone moiety in its lower part on the basis of 2D NMR analysis. Its structure and (3R, 5R) absolute configuration were unambiguously elucidated via the condensation of 2-pyrrolidinone (7) and iodo-γ-butyrolactone 8, which was prepared from butyrolactone alcohol 9 (Scheme 2).
Scheme 2 Synthesis of pandamarilactonine-G (4).
Pandamarilactonine-H (5) has a Z-configured γ-butylidene-α-methylα,β-unsaturated butyrolactone unit in the upper part as shown by the characteristic NMR signals at δH 6.98 (1H, dd, J ¼ 1.6, 0.9 Hz, H-4), 5.15 (1H, t, J ¼ 8.0 Hz, H-6), 1.99 ppm (3H, d, J ¼ 0.9 Hz, H3-17); δC 171.1 (C-2), 129.1 (C-3), 137.7 (C-4), 148.5 (C-5), 114.1 (C-6), 10.5 ppm (C-17), in addition to the strong UV absorption at 275 nm.16
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A methyl 2-(pyrrolidin-2-yl)acetate functionality in the lower part was established by 1D and 2D NMR experiments. Alkaloid 5 was isolated as diastereomeric mixture with 5a (Fig. 1) having an E-configured γ-butylideneα-methyl-α,β-unsaturated butyrolactone unit. The enantiomers of compounds 5 and 5a were synthesized (vide infra) in diastereomerically and enantiomerically pure forms and the absolute configuration of 14S was established. The presence of a methyl 2-(pyrrolidin-2-yl)acetate indicates a new type of structure in Pandanus alkaloids. The biogenesis (Scheme 3) of pandamarilactonine-H (5) was postulated to involve a condensation reaction of N-(3-carboxypropyl)-GABA (10) and 4-hydroxy-4-methylglutamic acid (11) to form an amine 12. A series of reactions including decarboxylation, transamination, dehydration, and cyclization would furnish an iminium ion 13. A Mannich type reaction involving the addition of methyl acetate (or acetyl-CoA) to the iminium ion 13 would finally yield pandamarilactonine-H (5).17
Scheme 3 Plausible biogenesis of pandamarilactonine-H (5).
Phytochemical investigation of P. amaryllifolius leaves collected in Taiwan afforded the new alkaloids N-acetylnorpandamarilactonine-A (14),17 and -B (15)17; norpandamarilactonine-C (16)18 and -D (17)18; pandalizine-A (18),17 -B (19),17 -C (20),18 -D (21),18 and -E (22)18; pandanusine-A (23)18 and -B (24)18; pandamarilactone-2 (25)17 and -3 (26)17; (5E)-pandamarilactonine-32 (27)17; pandanmenyamine (28)17; and pandalactonine (29)17 (Fig. 2). N-acetylnorpandamarilactonines-A (14) and -B (15) contain an acetyl pyrrolidinyl-α,β-unsaturated γ-lactone moiety. The pyrrolidinylα,β-unsaturated γ-lactone group was resolved on the basis of 1D and 2D
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Fig. 2 New alkaloids from the leaves of Pandanus amaryllifolius.
NMR experiments and by comparison with known norpandamarilactonineB.19 The acetyl group attached to the N atom was established from IR (1643 cm1) and 13C NMR data and by comparison with N-acetylpyrrolidine. The absolute stereochemistry of 14 and 15 was determined on the basis of
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calculated electronic circular dichroism (ECD) at the B3LYP/6-311++G (2d,2p)//BY3Yp/6-31++G(dd) level using the Gaussian 9.0 program. Comparison of the experimental ECD data with the calculated ECD, 14 showed a positive Cotton effect (CE) at λmax 228 nm and negative CEs at 208 and 255 nm. Similarly, comparison of the experimental ECD with the calculated ECD, 15 showed positive CEs at 236 and 276 nm and a negative CE at 209 nm. These data suggested that 14 and 15 are epimers and were assigned an absolute configuration of (5R, 8R) for N-acetylnorpandamarilactonine-A (14) and (5R, 8S) for N-acetylnorpandamarilactonine-B (15). Norpandamarilactonines-C (16) and -D (17) were isolated as a mixture in 9:10 ratio.18 The spectral data were similar to those of 14 and 15 indicating a formamide group instead of an acetamide. Norpandamarilactonine-C (16) was elucidated to contain an N-formylpyrrolidinyl-α,β-unsaturated γ-lactone moiety with (5R, 6R) absolute configuration. Norpandamarilactonine-D (17) contains an N-formylpyrrolidinyl-α,β-unsaturated γ-lactone moiety with (5R, 6S) absolute configuration. Structure characterization of pandalizine-A (18) suggested the presence of an α-methyl-α,β-unsaturated γ-lactam fused to a tetrahydropyridine ring.18 Pandalizine-A (18) was established to be 2-methyl-6,7dihydroindolizin-3(5H)-one. Pandalizine-B (19) was elucidated to be 8a-methoxy-2-methyl-6,7,8,8a-tetrahydroindolizin-3(5H)-one. The absolute stereochemistry of R at C-8a was determined on the basis of the observed positive CEs at λmax 246 and 350 nm and a negative CE at 300 nm, which were similar to those of the calculated ECD spectrum of 8aR enantiomer. Structure elucidation of pandalizine-C (20) established the presence of fused piperidine and α-methyl-α,β-unsaturated γ-lactam moieties with a hydroxyl group at C-8a position. The C-8aR absolute stereochemistry was determined by comparing the experimental ECD with the calculated ECD for both 8aR and 8aS enantiomers. A positive CE at 211 nm and negative CEs at 187, 223, and 288 nm data were consistent with the 8aR enantiomer. Pandalizine-D (21) and pandalizine-E (22) were elucidated to have similar structures to pandalizine-C (20) with an additional hydroxyl group at C-8 for 21 and at C-7 for 22. The 8aS configuration of 21 was assigned based on a similar skeleton pattern with pandalizine-B (19) and -C (20). The experimental ECD for pandalizine-D (21) also demonstrated a positive CE at λmax 204 nm and negative CEs at 186, 247, and 283 nm, similar to the calculated ECD for an 8R, 8aS enantiomer, indicating an absolute stereochemistry of (8R, 8aS). On the other hand, the absolute stereochemistry of (7R, 8aR) was elucidated for pandalizine-E (22) based on ECD and vibrational circular dichroism (VCD) experiments.
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Structure elucidation of pandanusine-A (23) disclosed the presence of a piperidine ring and an α-methyl-γ-lactam moiety linked together in a diazaspirocyclic ring at C-5 position.18 A new dihydrofurocoumarin was also isolated from P. tectorius called pandanusin A, its name is almost similar with that of alkaloid 23.20 The absolute stereochemistry at C-5 was elucidated by J-based configuration analysis and ECD prediction. The conformation was analyzed by the observed3 JH-6/C-4 (3.0 and 6.1 Hz) in the HMBC spectrum. Then, by comparison of experimental ECD data with those of calculated ECD at the B3LYP/6-31 + G* level using the Gaussian 9.0 software which yielded a positive CE at 224 nm and negative CEs at 256 and 279 nm for S configuration, on the contrary, a negative CE at 224 nm and positive CEs at 256 and 279 nm for R configuration, the absolute configuration at C-5 in 23 was determined to be S. The same functional moieties were elucidated in pandanusine-B (24) on the basis of spectral analysis and comparison of NMR data of 23 and 24. One major difference in the structure was the presence of an ethylbenzene attached to the nitrogen of the piperidine ring. The absolute stereochemistry of S at C-5 of 24 was disclosed on the basis of similarity of experimental CD data to those of pandanusine-A (23). Pandamarilactone-2 (25) has a piperidine ring linked to a γ-butylideneα,β-unsaturated γ-lactone moiety and an α-methyl-α,β-unsaturated γ-lactone moiety. Its structure was determined by comparison of NMR data with those of previously isolated pandamarilactone-121 and pandamarilactonine-C.22 The E configuration at Δ5,6 position was established on the basis of NOE correlation between H-4 and H-7 protons. Pandamarilactone-3 (26) has a Z-configured γ-butylidene-α,β-unsaturated γ-lactone in the upper part. The lower part is composed of a spirostructure that includes a piperidine ring and an α-methyl-α,β-unsaturated γ-lactam moiety. The structure and NMR data of (5E)-pandamarilactonine-32 (27) are similar to those of previously isolated pandamarilactone-3221 containing a γ-butylidene-α,β-unsaturated γ-lactone and a 5-methylene-2-cyclopentenone annulated to a piperidine ring. An E Δ5,6 configuration was confirmed on the absence of an NOE correlation at H-4 and H-6, in contrast to the Z-configuration of pandamarilactone-32. Pandanmenyamine (28) has a γ-butylidene-α-methyl-α,β-unsaturated γ-butyrolactone with a Z configuration at Δ5,6 position as determined by NOESY and comparison with the previously isolated pandamarilactam-3y.17,23 Moreover, an N-acetyl fragment was deduced to be linked
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to the butylidene unit as evidenced by HMBC correlation of the H2-9 proton of the butylidene and the C-11 carbonyl of the amide group. Pandalactonine (29) possesses similar NMR data to the previously isolated pandamarilactonine-A24 having a γ-butylidene-α,β-unsaturated butyrolactone at the upper part. In contrast to pandamarilactonine-A, the lower part in pandalactonine (29) is composed of a fused tricyclic ring structure with spirolactone and pyrrolo[1,2-c]oxazole units as indicated by an additional oxygen atom and the HMBC correlation between H-9 and C-15. NOESY and NOE experiments enabled the disclosure of the relative configuration of 29 as (9R*, 14R*, 15S*). The fused tricyclic ring system in pandalactonine (29) represents a new type of Pandanus alkaloid. A plausible biogenetic pathway for the alkaloids isolated from the leaves of P. amaryllifolius from Taiwan is presented in Scheme 4.17 Condensation of 4hydroxy-4-methylglutamic acid (11) and γ-aminobutyric acid (GABA) yields an amine 30, which undergoes decarboxylation, transamination, dehydration, reduction, and cyclization forming the bicyclic amine 31, and will eventually led to form pandalizines-A to -E (18–22). The formation of pandanmenyamine (28) involved an amine 33 from the condensation of 11 and
Scheme 4 Proposed biosynthesis of new alkaloids from the leaves of Pandanus amaryllifolius.
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N-acetyl-GABA (32), which then undergoes cyclization, deamination, reduction, transamination, and reduction reactions. N-acetylnorpandamarilactonines (14 and 15) are formed from the cyclization of 28. Condensation of 11 and N-carboxypropyl-GABA (34) forms an amine 35. Condensation of 35 and another molecule of 11 yields amine 36, which undergoes a reaction sequence including dehydration, decarboxylation, cyclization, and oxidation at C-9 to form pandalactonine (29). Apart from P. amaryllifolius, two other species were found to contain alkaloids. Purification of the crude base of P. dubius collected in the Philippines led to the identification of dubiusamine-A (37) and -B (6) (Fig. 3).25 Dubiusamine-A (37) was identified as a saturated symmetrical amine whose structure is similar to that of pandanamine.26 An α-methyl-γ-butyl-γbutyrolactone unit with an anti relationship between C-3 and C-5 methine protons was evidenced by NOE analysis. A minor diastereomer, dubiusamine-C (38),25,27 was also identified, which had a syn relationship between C-3 and C-5 methine protons. Several total syntheses (vide infra) resulted in the characterization of dubiusamine-A (37) and the determination of its absolute configuration as (3R, 5R). Dubiusamine-B (6) has a 3,5disubstituted γ-butyrolactone with an anti relationship between C-3 and C-5 methine protons in the upper part. The lower part is composed of a pyrrolidinyl-substituted α-methyl-α,β-unsaturated γ-butyrolactone with a threo configuration at C-14 and C-15 positions. The (3R, 5R, 14R, 15R) absolute configuration of dubiusamine-B (6) was unambiguously confirmed by its asymmetric total synthesis (vide infra). An Egyptian shrub, P. utilis, was investigated to yield two novel indolizidine alkaloids, pandalisine-A (39) and -B (40) (Fig. 4).28 Pandalisine-A (39) has an α-methylbutenolide that is connected to the indolizidine moiety at C-50 and C-8 positions, as evidenced by HMBC 0 experiments. An E configuration for Δ5 ,8 was also elucidated on the basis
Fig. 3 New alkaloids isolated from Pandanus dubius.
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Fig. 4 Novel indolizidine alkaloids from Pandanus utilis. 0
0
of the observed NOESY cross peaks of H2-1/H-4 and H-4 /H-9. The absolute configuration of R at C-9 was determined on the basis of experimental CD and calculated ECD data. The experimental CD showed a positive CE at 290 nm and a negative CE at 240 nm, consistent with the calculated ECD data for 9R configuration. Pandalisine-B (40) has similar functional moieties to pandalisine-A (39) except for the Z-configuration 0 of the C-5 /C-8 double bond. The configuration of R at C-9 was also observed on the basis of similar experimental CD and calculated ECD patterns to a 9R configuration. A plausible biogenetic pathway (Scheme 5)28 for
Scheme 5 Plausible biogenesis of novel indolizidine alkaloids.
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39 and 40 has been described as follows. Condensation followed by reduction of N-carboxypropyl-GABA (34) and 4-hydroxy-4-methylglutamic acid (11) yields amine 35, which undergoes a series of reactions including cyclization, decarboxylation, transamination, and dehydration to afford pandalisine-A (39) and -B (40). Most of the Pandanus alkaloids found in early studies feature a γ-butylidene-α-methyl-α,β-unsaturated γ-lactam, a γ-butylidene-αmethyl-α,β-unsaturated γ-lactone, and/or a pyrrolidinyl-substituted α,βunsaturated γ-lactone residue. It is noteworthy that new alkaloids such as pandalizine-A to -E (18–22) and pandalisine-A (39) and -B (40), possess an indolizidine core in their molecules.
3. Synthetic Studies on the Pandanus Alkaloids 3.1 Synthesis of Pandamarilactone-1 Pandamarilactone-1 (41) was isolated from the leaves of P. amaryllifolius in optically active form in 1993.21 It consists of a spirostructure with a piperidine ring linked to a γ-butylidene-α,β-unsaturated γ-lactone moiety and an α-methyl-α,β-unsaturated γ-lactone moiety. Its first total synthesis was accomplished in 2014, which features the oxidation of symmetrical furan derivative 46 with singlet oxygen.29 Substrate 46 for the key reaction was prepared as follows. The acetylide generated from 5-chloro-1pentyne was coupled with TMS-acetol (hydroxyacetone) and then treated with AgNO3–SiO2 to give furan derivative 42, which was then transformed into cyanopropyl-substituted furan 43 by a substitution reaction. Cyanopropyl-substituted furan 43 thus obtained was converted into furan carbaldehyde 44 and aminobutyl-substituted furan 45 under different reductive conditions. Condensation of 44 and 45 by reductive amination and protection of the resultant secondary amine with Boc afforded symmetrical difuran 46. Finally, 46 was subjected to 1O2mediated furan oxidation in the presence of rose Bengal followed by deprotection of Boc with TMSBr to give bis(methoxybutenolide) 47, which was then treated with H2SO4/CH2Cl2 under vigorous stirring to yield ()-pandamarilactone-1 (41) in 12% yield via spiro-N,O acetal formation and elimination of methanol. In this reaction a mixture of pandamarilactonines-A to -D were also obtained when 47 was treated with H2SO4 (Scheme 6).29
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Scheme 6 Synthesis of pandamarilactone-1 (41).
3.2 Synthesis of Pandamarine ()-Pandamarine (48) is the first alkaloid isolated from Pandanus plants.30 Its structure, which is composed of diazaspiro[4.5] and 5-butylidenepyrrol-2 (5H)-one units, was determined by X-ray diffraction. The first total synthesis of this alkaloid was accomplished in 2015 (Scheme 7),31 although the strategy is similar to that of the synthesis of pandamarilactone-1 (41) (vide supra). Commercially available 5-hexynenitrile was condensed with hydroxyacetone to give alkynyldiol 49, which was converted into cyanopropyl-substituted furan 43 by treatment with AgNO3. Compound
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Scheme 7 Synthesis of pandamarine (48).
43 was then converted into furan carbaldehyde 44 and aminobutylsubstituted furan 46, which were used in the reductive amination to furnish symmetrical difuran 50. Difuran 50 having a protecting group-free amine was then subjected to a series of operations, that is, oxidation with singlet oxygen generated by methylene blue (MB) and visible light, addition of MB and Me2S, and addition of aqueous ammonia, to form intermediate 51. Finally, removal of the volatile contaminants from the reaction mixture ˚) followed by addition of TFA in CHCl3 containing molecular sieves (4 A afforded ()-pandamarine (48) in 30% overall yield from the difuran 50.
3.3 Synthesis of epi-Pandamarilactonine-H epi-Pandamarilactonine-H (52) was synthesized in the course of the structure elucidation of pandamarilactonine-H (5) (vide supra).16 4-Iodobutylenesubstituted butyrolactone 56 which corresponds to the upper fragment of alkaloid 5, was prepared according to the protocol developed for the synthesis of pandamarilactonine-C and -D.22 Another fragment, i.e., methyl
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pyrrolidinylacetate 55, was synthesized from D-proline. The Arndt–Eistert reaction of the mixed anhydride prepared from Cbz-protected D-proline 53 yielded α-diazoketone 54. A Wolff rearrangement homologation reaction of 54 followed by hydrogenolysis afforded the methyl pyrrolidinylacetate 55. Condensation of a 3:2 (Z/E) mixture of 56 and 55 using Ag2CO3 in CH3CN gave the alkaloid 52 and its E-diastereomer 57, both having the 14R configuration. Comparison of the optical rotation of synthetic 52 {[α]21 D +62 (c. 0.07, CHCl3)} with that of natural pandamarilactonine-H (5) {[α]24 D 43 (c. 0.04, CHCl3)} established the 14S absolute configuration of natural alkaloid 5 (Scheme 8).
Scheme 8 Synthesis of epi-pandamarilactonine-H (52).
3.4 Synthesis of Dubiusamine-A and its Enantiomer Three asymmetric syntheses have been reported for dubiusamine-A (37). The first asymmetric total synthesis utilized a proline-catalyzed asymmetric α-aminoxylation as the key step.25 Thus, a three-step reaction that included the α-aminoxylation of aldehyde 58 with nitrosobenzene in the presence of L-proline, followed by Horner–Emmons reaction, and the O–N bond cleavage utilizing CuSO4 in MeOH, afforded highly enantioselectively ester 59 with 99% ee. The R configuration on the stereocenter of 59 was deduced on the basis of a well-established mechanism for the proline-catalyzed α-aminoxylation. Ester 59 underwent subsequent hydrogenation, cyclization, diastereoselective α-methylation, and deprotection to form the butyrolactone alcohol 9. The Mitsunobu
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reaction of 9 using 2-nitrobenzenesulfonamide gave amine 60. The second Mitsunobu reaction of 9 with 60 and the subsequent deprotection produced enantiomerically and diastereomerically pure dubiusamine-A (37) (Scheme 9). Comparison of the spectroscopic data and optical rotation of the synthetic and natural products led to the establishment of the (3R, 5R) absolute configuration.
Scheme 9 Synthesis of dubiusamine-A (37) using proline-catalyzed α-aminoxylation.
The second approach for the synthesis of dubiusamine-A (37) involved a one-pot conversion of cis,cis-1,3-cyclooctadiene (61) into oxabicyclononenol 62 with >99% ee by a sequential photooxygenation and deMeQAc-catalyzed Toste–Kornblum–DeLaMare rearrangement.32 PhI(OH)OTs (HTIB)-mediated oxidative fragmentation of 62 in the presence of Na2H2PO42H2O afforded unsaturated butyrolactone 63 without loss of enantiomeric integrity. Unsaturated butyrolactone 63 was subjected to hydrogenation and TBS-protection to yield butyrolactone 64. Further reactions of 64, including diastereoselective α-methylation, the Mitsunobu reaction, and deprotection, afforded dubiusamine-A (37) (Scheme 10). The spectroscopic data, including the optical rotation, are in complete agreement with those of the natural product.
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Scheme 10 Synthesis of dubiusamine-A (37) using HTIB-promoted oxidative fragmentation.
The synthesis of ent-dubiusamine-A (65) was carried out via a palladiumcatalyzed asymmetric allylic alkylation reaction.33 A nucleophile generated from N,N-diphenylpropionamide and LiHMDS was reacted with allylphosphate 66 in the presence of palladium catalyst (5 mol% Pd(OAc)2) and phosphine ligand 67 to afford alkylated product 68 with high enantioselectivity (er 96:4). Iodolactonization of 68 followed by deiodination using n-Bu3SnH/Et3B and debenzylation gave butyrolactone 69 exhibiting negative optical rotation. Thus, the formal total synthesis of the enantiomer of natural dubiusamine-A was completed (Scheme 11).
Scheme 11 Synthesis of ent-dubiusamine-A (65) using Pd-catalyzed allylic alkylation.
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3.5 Synthesis of Dubiusamine-B The unambiguous determination of the structure including the absolute configuration of dubiusamine-B (6) was achieved by total synthesis (Scheme 12).25 Iodo-γ-butyrolactone 8 having the (3R, 5R) absolute configuration was prepared from butyrolactone alcohol 9 (Scheme 9). The lower part, composed of a pyrrolidinyl-substituted α-methyl-α,βunsaturated γ-butyrolactone with a threo configuration, was prepared from D-prolinol (70). Thus, N-protected D-prolinol was subjected to oxidation and vinylation reactions to give diastereomeric adducts 71 and 72. To elucidate the stereochemistry at the newly generated stereogenic centers, both adducts were converted into their oxazolidone derivatives 73 and 74, respectively. Measurement of the3 JH-1,H-7a coupling constant and the NOE correlation between H-7a and H-1 in 73 and 74 confirmed the presence of an erythro configuration for adduct 71 and a threo configuration for adduct 72. After removal of the protecting group in 72, the resulting amine
Scheme 12 Synthesis of dubiusamine-B (6).
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was condensed with iodo-γ-butyrolactone 8 utilizing Ag2CO3 to form adduct 75. Esterification using methacrylic anhydride and ring-closing metathesis using Grubb’s II catalyst afforded dubiusamine-B (6), whose spectroscopic data and optical rotation, are in complete agreement with the natural product.
3.6 Synthesis of Dubiusamine-C Dubiusamine-C (38) is a minor alkaloid isolated as a diastereomeric mixture with dubiusamine-A (37) from P. dubius.25 NOE experiments showed a syn relationship between the H-3 and H-5 methine protons of 38, in contrast to the anti configuration of the methine protons of 37. To elucidate the stereostructure of 38, a racemic total synthesis was carried out.27 1,5Pentanediol was subjected to a series of reactions that included partial oxidation and vinylation to form compound 76. Subsequent esterification, ring-closing metathesis, and stereoselective hydrogenation of 76 afforded butyrolactone 77. NOE analysis of 77 revealed the desired syn configuration for the H-3 and H-5 methine protons. The Mitsunobu reaction of 77 with 2-nitrobenzenesulfonamide afforded aminopropylbutyrolactone 78. The second Mitsunobu reaction of 77 and 78 gave the symmetrical amine 79. Removal of the Ns group completed the synthesis of dubiusamine-C (39) (Scheme 13).
Scheme 13 Racemic total synthesis of dubiusamine-C (38).
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An asymmetric total synthesis of dubiusamine-C (38) was reported, which utilized a diastereoselective bromolactonization with potassium bromide and Oxone as the key step.34 Initially, according to the Evans protocol, compound 80 was methylated using NaHMDS and MeI and then subjected to the removal of the chiral auxiliary to yield chiral pentenoic acid 81. A cis-selective bromolactonization using KBr/ Oxone in AcOEt provided bromolactone 82 with 77/23 dr. After separation by column chromatography, the major cis-diastereomer 82 was subjected to alkyl–allyl coupling using allyltributyltin, and this was followed by hydroboration-oxidation to afford butyrolactone alcohol 83. According to a known procedure that involved coupling of 83 and its Ns-derivative using the Mitsunobu reaction and N-deprotection, the total synthesis of (+)-dubiusamine-C (38) was accomplished in 36% overall yield (Scheme 14).
Scheme 14 Asymmetric total synthesis of dubiusamine-C (38).
A formal synthesis of dubiusamine-C (38) was also reported using 35 D-mannose as the starting material. Lactone 84, a D-mannose-derived chiral molecule, was treated with 60% AcOH and then refluxed with I2/PPh3/imidazole to afford ethenylbutyrolactone 85. Cross metathesis of butyrolactone 85 and 3-butenol afforded the butyrolactonediol 86. A series of Mitsunobu reactions gave symmetrical alkenylbutyrolactone 87. Reduction followed by deprotection of the amine group successfully generated dubiusamine-C (38) (Scheme 15).
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Scheme 15 Formal synthesis of dubiusamine-C (38).
3.7 Synthesis of Pandanamine, Norpandamarilactonines, and Pandamarilactonines The synthesis of the known alkaloids pandanamine, pandamarilactonines, and norpandamarilactonines have been reported in three separate papers. Pandanamine (88) was postulated to be a precursor of pandamarilactonines24 and later isolated as a natural product from P. amaryllifolius,26 thereby, supporting the proposed biogenetic pathway for various Pandanus alkaloids. It is a symmetrical amine containing γ-butylidene-α-methyl-α,βunsaturated γ-lactone moieties. Pandamarilactonine-A to -D contain the γ-butylidene-α-methyl-α,β-unsaturated γ-lactone in the upper part and the pyrrolidinyl-substituted α,β-unsaturated γ-lactone in the lower part. The C-14 and C-15 positions of the pyrrolidinyl α,β-unsaturated γ-lactone may have a threo configuration as described in pandamarilactonine-A (89) and -C (90) (see Scheme 17), or an erythro configuration, as exhibited by pandamarilactonine-B (91) and -D (92).22 The C-5 and C-6 positions of the γ-butylidene-α,β-unsaturated γ-lactone maybe in the Z configuration (89 and 91) or the E configuration (90 and 92).22 Norpandamarilactonine-A (93) and -B (94) were isolated in 2001 containing the pyrrolidinyl-substituted α,β-unsaturated γ-butyrolactone structure with the threo configuration for 93 and the erythro configuration for 94.
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The synthesis of pandanamine (88) was accomplished via a basepromoted 5-exo-dig selective cyclization of bis(oct-2-en-4-ynoic) derivative 95.36 Compound 95 was prepared as follows. Propargyl alcohol 96 was converted into ether 97 in a three-step process. The Sonogashira coupling of 97 and pent-4-yn-1-ol (98) gave alkyne 99. This was followed by a Mitsunobu reaction with Boc-protected nosylamine and the removal of the protecting group to afford amide 100. Amide 100 was allowed to react with iodide 101 to afford dialkylated alkyne 102. Then, compound 102 was converted to the desired bis(oct-2-en-4-ynoic) derivative 95, which underwent selective cyclization using Et3N and removal of the amino protecting group to provide the desired pandanamine (88) (Scheme 16).
Scheme 16 Synthesis of pandanamine (88).
Adopting the reductive intramolecular aza-Michael-type addition as the key step, the synthesis of pandamarilactonine-A to -D, norpandamarilactonine-A and -B, and pandanamine was accomplished using 3-methylfuran-2 (5H)-one (104).37 Initially, butane-1,4-diol was converted to aldehyde 103, which was then reacted with 104 to obtain alcohol 105. Via a two-step process, compound 105 was converted into butylidenebutyrolactone 106 in 57:43 E/Z ratio, and this was converted into azidobutenolide
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derivative 107 using sodium azide. The conversion of 107 into norpandamarilactonine-A (93) and norpandamarilactonine-B (94) was introduced via a triphenylphosphine-induced reductive regioselective intramolecular aza-Michael-type addition to the exocyclic activated double bond (Scheme 17). Coupling of the norpandamarilactonine mixture with iodobutenolide 108 in the presence of silver carbonate gave the pandamarilactonine-A to -D in a 4:4:1:1 ratio, respectively. Treatment of the pandamarilactonine mixture with silica gel gave pandanamine (88).
Scheme 17 Synthesis of pandamarilactonines (72–75), pandanamine (88), and norpandamarilactonines (93–94).
In an attempt to perform the asymmetric synthesis of pandamarilactonineB, an unexpected syn-diastereoselective vinylogous Mannich reaction (VMR) between (Rs)-N-tert-butanesulfinimine 109 and 3-methyl-2-(tertbutyldimethylsilyloxy)furan (111) was observed. Thus, the asymmetric total synthesis of ()-pandamarilactonine-A (89) was accomplished in a
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three-pot reaction (Scheme 18).38 Initially, compound 110 was prepared by the CuSO4-mediated coupling of 4-chlorobutanal and (Rs)tert-butanesulfinamide 109. VMR of 110 and 3-methyl-2-(tert-butyldimethylsilyloxy)furan (111) resulted in the formation of two separable isomers, syn-112 and anti-113, in 95:5 syn:anti ratio. The syn-112 isomer was treated with HCl and K2CO3/NaI and iodobutenolide 108 (Z/E 9:1) to yield pandamarilactonine-A (89), -C (90), and -B (91) in 77:13:11 ratio, respectively. Attempts to separate 89 and 90 proved to be difficult. An 87:13 by 1H NMR and an 89:11 ratio by HPLC (compound 89:90) were determined. The optical rotation of 89 with 12% amount of 90 was [α]D 87.2 (c. 0.12, CHCl3). The enantiomeric excess of the synthetic 89 was determined to be 95.5% by chiral HPLC.
Scheme 18 Synthesis of ()-pandamarilactonine-A (89).
3.8 Synthesis of Pandalizine-A and -B The new alkaloids pandalizines-A (18) and -B (19) contain an indolizidine core and are designated as a new class of alkaloids from the genus Pandanus. The synthesis of these new alkaloids utilized an unprotected primary furylalkylamine that underwent photooxygenation.39 Specifically, a 4-(4methylfuran-2-yl)butan-1-amine (114) was subjected to photooxygenation using methylene blue (MB) as photosensitizer to afford intermediate
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compound 20 as a biogenetic precursor, as proposed by Tsai et al.17 This compound was later isolated from P. amaryllifolius as a natural product named pandalizine-C (20) in 2017.18 Further treatment of 20 with TFA in CHCl3 will eventually lead to pandalizine-A (18), whereas treatment with TFA in MeOH gave pandalizine-B (19) (Scheme 19).
Scheme 19 Synthesis of pandalizine-A (18) and pandalizine-B (19).
4. Pharmacology of the Pandanus Species Investigation of antibacterial activity using the microwell assay for known alkaloids pandamarilactone-1, pandamarilactone-32, pandamarilactonine-A and pandamarilactonine-B revealed that pandamarilactonine-A exhibited a minimum inhibitory concentration of 15.6 μg/mL and minimum bactericidal concentration of 31.25 μg/mL against Pseudomonas aeruginosa ATCC 27853.7 All alkaloids showed weak to no activity against Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 25923. Although there is a limited data on the biological activities of the Pandanus alkaloids, several pharmacological studies were conducted on the extracts of various Pandanus species. The methanolic extract of P. odoratissimus showed significant antiinflammatory activity at a dose of 100mg/kg in carrageenan-induced acute (68%) and formalin-induced chronic (64.2%) paw edema in rats.6 In vitro investigation of the ethanolic extract of P. amaryllifolius using cell cycle progression analysis, the Annexin V assay, and TUNEL assay showed that it mediated mitochondrial activated apoptosis pathways in MDA-MB-231 breast cancer cells. The proposed mechanism in the induction of apoptosis involved the up regulation of the tumor
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suppressor protein p53 and the downregulation of the inhibitor of apoptosis protein XIAP.4 P. foetidus leaf extracts, including the methanol, petroleum ether, chloroform, and aqueous fractions, were investigated for their antidiarrheal activity and cytotoxicity.8 The extract showed antidiarrheal activity, reducing the number of defecations and maintaining stool consistency. The methanol and chloroform fractions reduced the castor oil induced enteropooling and fluid accumulation, whereas the aqueous fraction reduced gastrointestinal motility. The brine shrimp assay for cytotoxicity showed that the chloroform extract gave an LC50 of 106.97 μg/mL.
5. Summary This review covers the literature on Pandanus alkaloids published between April 2008 and September 2018. Three Pandanus species (P. amaryllifolius, P. utilis, and P. dubius) were found to contain new alkaloids. A total of 26 new alkaloids were identified, which contained γ-butylidene-αmethyl-α,β-unsaturated γ-lactam, γ-butylidene-α-methyl-α,β-unsaturated γ-lactone, pyrrolidinyl-substituted α,β-unsaturated γ-lactone, and/or indolizidine core residues. The interesting structures of the Pandanus alkaloids have prompted synthetic studies by various research groups. These include known Pandanus alkaloids (pandamarine, pandamarilactone-1, pandanamine, pandamarilactonine-A to -D) as well as the newly isolated alkaloids dubiusamine-A and -B and pandalizine-A and -B. The use of Pandanus species in traditional folk medicine have also encouraged several pharmacological studies that include the scientific validation of their antibacterial, antiinflammatory, antidiarrheal, and cytotoxic activities. Given the large number of Pandanus species distributed worldwide, it is expected that new alkaloids will be studied in the future and that these Pandanus species would be excellent sources of biologically active secondary metabolites.
References 1. Vaughan, R. E.; Wiehe, P. O. Bot. J. Linn. Soc. 1953, 55, 1–33. 2. Zhang, X.; Wu, C.; Wu, H.; Sheng, L.; Su, Y.; Zhang, X.; Luan, H.; Sun, G.; Sun, X.; Tian, Y.; Ji, Y.; Guo, P.; Xu, X. PLoS One 2013, 8, e61922. 3. Sasidharan, S.; Sumathi, V.; Jegathambigai, N. R.; Latha, L. Y. Nat. Prod. Res. 2011, 25, 1982–1987. 4. Chong, H. Z.; Yeap, S. K.; Rahmat, A.; Akim, A.; Alitheen, N. B.; Othman, F.; Gwendoline-Ee, C. L. BMC Complementary Altern. Med. 2012, 12, 134. 5. Ooi, L. S.; Sun, S. S.; Ooi, V. E. Int. J. Biochem. Cell Biol. 2004, 36, 1440–1446. 6. Londonkar, R.; Kamble, A.; Reddy, V. C. Int. J. Pharmacol. 2010, 6, 311–314.
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7. Laluces, H. M.; Nakayama, A.; Nonato, M. G.; dela Cruz, T. E.; Tan, M. A. J. Appl. Pharm. Sci. 2015, 5, 151–153. 8. Islam, A. M.; Uddin, M. E.; Chowdhury, M. A.; Rahman, M. M.; Habib, M. R.; Rahman, M. A. Am. J. Biomed. Sci. 2013, 5, 208–216. 9. (a) Lo, I.-W.; Cheng, Y.-B.; Haung, C.-C.; Hwang, T.-L.; Wu, C.-C.; Liou, J.-R.; Hou, M.-F.; Yuan, S.-S.; Chang, F.-R.; Wu, Y.-C. Nat. Prod. Commun. 2016, 11, 173–176; (b) Hoa, N. T.; Dien, P. H.; Quang, D. N. Res. J. Phytochem. 2014, 8, 52–56. 10. Tan, M. A.; Takayama, H.; Aimi, N.; Kitajima, M.; Franzblau, S. G.; Nonato, M. G. J. Nat. Med. 2008, 62, 232–235. 11. Zhang, X.; Guo, P.; Sun, G.; Chen, S.; Yang, M.; Fu, N.; Wu, H.; Xu, X. J. Med. Plants Res. 2012, 6, 2622–2626. 12. Tan, M. A.; Nonato, M. G.; Kogure, N.; Kitajima, M.; Takayama, H. Biochem. Syst. Ecol. 2012, 40, 4–5. 13. Suzuki, R.; Kan, S.; Sugita, Y.; Shirataki, Y. Chem. Pharm. Bull. 2017, 65, 1191–1194. 14. Nonato, M. G.; Takayama, H.; Garson, M. J. In The Alkaloids, Vol. 66, Cordell, G. A. Ed.; Academic Press: New York, 2008; pp 215–249. 15. Tan, M. A.; Kitajima, M.; Kogure, N.; Nonato, M. G.; Takayama, H. Tetrahedron Lett. 2010, 51, 4143–4146. 16. Tan, M. A.; Kitajima, M.; Kogure, N.; Nonato, M. G.; Takayama, H. J. Nat. Prod. 2010, 73, 1453–1455. 17. Tsai, Y.-C.; Yu, M.-L.; El-Shazly, M.; Beerhues, L.; Cheng, Y.-B.; Chen, L.-C.; Hwang, T.-L.; Chen, H.-F.; Chung, Y.-M.; Hou, M.-F.; Wu, Y.-C.; Chang, F.-R. J. Nat. Prod. 2015, 78, 2346–2354. 18. Cheng, Y.-B.; Hu, H.-C.; Tsai, Y.-C.; Chen, S.-L.; El-Shazly, M.; Nonato, M. G.; Wu, Y.-C.; Chang, F.-R. Tetrahedron 2017, 73, 3423–3429. 19. Takayama, H.; Ichikawa, T.; Kitajima, M.; Nonato, M. G.; Aimi, N. J. Nat. Prod. 2001, 64, 1224–1225. 20. Nguyen, T.; Le, T.; Minh, P.; Dat, B.; Pham, N.; Do, T.; Nguyen, D.; Mai, T. Nat. Prod. Res. 2016, 30, 2389–2395. 21. Nonato, M. G.; Garson, M. J.; Truscott, R. J. W.; Carver, J. A. Phytochemistry 1993, 34, 1159–1163. 22. Takayama, H.; Ichikawa, T.; Kitajima, M.; Nonato, M. G.; Aimi, N. Chem. Pharm. Bull. 2002, 50, 1303–1304. 23. Sjaifullah, A.; Garson, M. J. ACGC Chem. Res. Commun. 1996, 5, 24–27. 24. Takayama, H.; Ichikawa, T.; Kuwajima, T.; Kitajima, M.; Seki, H.; Aimi, N.; Nonato, M. G. J. Am. Chem. Soc. 2000, 122, 8635–8639. 25. Tan, M. A.; Kitajima, M.; Kogure, N.; Nonato, M. G.; Takayama, H. Tetrahedron 2010, 66, 3353–3359. 26. Takayama, H.; Ichikawa, T.; Kitajima, M.; Aimi, N.; Lopez, D.; Nonato, M. G. Tetrahedron Lett. 2001, 42, 2995–2996. 27. Tan, M. A.; Kogure, N.; Kitajima, M.; Takayama, H. Philip. Sci. Lett. 2011, 4, 98–102. 28. Cheng, Y.-B.; Tsai, Y.-H.; Lo, I.-W.; Haung, C.-C.; Tsai, Y.-C.; Beerheus, L.; ElShazly, M.; Hou, M.-F.; Yuan, S.-S.; Wu, C.-C.; Chang, F.-R.; Wu, Y.-C. Bioorg. Med. Chem. Lett. 2015, 25, 4333–4336. 29. Seah, K. Y.; Macnaughton, S. J.; Dallimore, J. W. P.; Robertson, J. Org. Lett. 2014, 16, 884–887. 30. Byrne, L. T.; Guevara, B. Q.; Patalinghug, W. C.; Recio, B. V.; Ualat, C. R.; White, A. H. Aust. J. Chem. 1992, 45, 1903–1908. 31. Kalaitzakis, D.; Noutsias, D.; Vassilikogiannakis, G. Org. Lett. 2015, 17, 3596–3599. 32. Kawasumi, M.; Iwabuchi, Y. Org. Lett. 2013, 15, 1788–1790. 33. Jiang, Y.-J.; Zhang, G.-P.; Huang, J.-Q.; Chen, D.; Ding, C.-H.; Hou, X.-L. Org. Lett. 2017, 19, 5932–5935.
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34. Moriyama, K.; Sugiue, T.; Nishinohara, C.; Togo, H. J. Org. Chem. 2015, 80, 9132–9140. 35. Tan, D.; Xu, M.; Xu, Z.; Wu, Y.; You, J. Chin. J. Chem. 2016, 34, 669–677. 36. Hiroya, K.; Takuma, K.; Inamoto, K.; Sakamoto, T. Heterocycles 2009, 77, 493–505. 37. Gogoi, S.; Argade, N. P. Synthesis 2008, 1455–1459. 38. Ye, J.-L.; Zhang, Y.-F.; Liu, Y.; Zhang, J.-Y.; Ruan, Y.-P.; Huang, P.-Q. Org. Chem. Front. 2015, 2, 697–704. 39. Kalaitzakis, D.; Triantafyllakis, M.; Sofiadis, M.; Noutsias, D.; Vassilikogiannakis, G. Angew. Chem. Int. Ed. 2016, 55, 4605–4609.
Recent Progress in the Chemistry of Pandanus Alkaloids Mario A. Tana, Hiromitsu Takayamab,* a
Department of Chemistry, College of Science, Research Center for the Natural and Applied Sciences, University of Santo Tomas, Manila, Philippines Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan *Corresponding author: e-mail address: [email protected] b
Contents 1. Introduction 2. New Alkaloids from Pandanus Species 3. Synthetic Studies on the Pandanus Alkaloids 3.1 Synthesis of Pandamarilactone-1 3.2 Synthesis of Pandamarine 3.3 Synthesis of epi-Pandamarilactonine-H 3.4 Synthesis of Dubiusamine-A and its Enantiomer 3.5 Synthesis of Dubiusamine-B 3.6 Synthesis of Dubiusamine-C 3.7 Synthesis of Pandanamine, Norpandamarilactonines, and Pandamarilactonines 3.8 Synthesis of Pandalizine-A and -B 4. Pharmacology of the Pandanus Species 5. Summary References
2 2 12 12 13 14 15 18 19 21 24 25 26 26
Abstract The genus Pandanus (Pandanaceae) is widely distributed in the tropical and subtropical regions. With about 700 species worldwide, three Pandanus species (P. amaryllifolius, P. utilis, and P. dubius) have been investigated and found to contain new alkaloids possessing a pyrrolidinyl-α,β-unsaturated γ-lactone, a γ-butylidene-α-methyl-α,βunsaturated γ-lactam, and/or indolizidine residues. Several total syntheses of Pandanus alkaloids have been accomplished. Several pharmacological studies on Pandanus species, including scientific validations of their antibacterial, antiinflammatory, antidiarrheal, and cytotoxic activities, have been conducted in relation to their traditional folk medicine uses.
The Alkaloids ISSN 1099-4831 https://doi.org/10.1016/bs.alkal.2018.12.001
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2019 Elsevier Inc. All rights reserved.
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1. Introduction Pandanus represents the largest genus among the four genera in the family Pandanaceae.1 Consisting of about 700 species, they are distributed in tropical and subtropical regions, including the Pacific Islands, Malaysian islands, and Australia. Several Pandanus species are medicinal plants that have been used in traditional medicine because they possess pharmacological activities such as antihyperlipidemic,2 antihyperglycemia,3 anticancer,4 antiviral,5 antiinflammatory,6 antimicrobial,7 and antidiarrheal8 activities. The genus Pandanus is also an excellent source of secondary metabolites, including steroids,9 terpenoids,9a,10 flavonoids,11 lignans,12 benzenoids,13 and alkaloids.14 Among these secondary metabolites, the isolation of alkaloids has been emphasized in phytochemical studies on the genus Pandanus, specifically Pandanus amaryllifolius, Pandanus dubius, and Pandanus utilis. A review on Pandanus alkaloids was published in 2008 in Volume 66 of the series The Alkaloids.14 This review offers an update, covering literatures on the identification of new alkaloids and synthetic studies published up to September 2018.
2. New Alkaloids from Pandanus Species As most alkaloids have been identified from the leaves of P. amaryllifolius, the roots were prioritized and given importance in the isolation and identification of alkaloids. A sample of P. amaryllifolius roots collected from the Philippines yielded five new alkaloids named pandamarilactonine-E (1), -F (2), -F N-oxide (3), -G (4), and -H (5) (Fig. 1).15,16 Pandamarilactonine-E (1) is an optically active alkaloid with a molecular formula C18H29NO4 as determined by HR-ESIMS. It contains a 3,5disubstituted γ-butyrolactone unit comprising the upper part where a trans configuration is observed between the H-3 and H-5 methine protons as evidenced by NOE correlation of the characteristic 1H peaks at H-5 (δH 4.50 ppm) and H-21 methyl (δH 1.27 ppm). The presence of a γ-pyrrolidinyl-α-methyl-γ-butyrolactone unit in the lower part was identified by 1D and 2D NMR experiments. The relative stereochemistry at the C-14 and C-15 stereocenters was elucidated on the basis of the observed NOE correlation between H-15 methine (δH 4.43 ppm) with H-14 (δH 2.86 ppm) and H-17 (δH 2.78 ppm) methines, and the NOE correlation between H-17 and H3-20 (δH 1.28 ppm) methyl, indicating a syn
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Fig. 1 Alkaloids from the roots of Pandanus amaryllifolius.
orientation of H-15 and H-17 methine protons. The relative threo configuration was further supported by the observed NOE at H-14 and H3-20 protons. If an erythro configuration is proposed, this NOE correlation will not be observed on the basis of the Dreiding model analysis. The absolute configuration of pandamarilactone-E (1) was finally established to be (3R, 5R, 14R, 15R, 17R) by a stereoselective hydrogenation of synthetically pure dubiusamine-B (6) (Scheme 1) with a threo configuration at the C-14 and C-15 positions.
Scheme 1 Conversion of dubiusamine-B (6) to pandamarilactonine-E (1).
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Pandamarilactonine-F (2) has the same molecular formula as 1. Spectroscopic analysis indicated that 2 had almost the same structure as 1. The relative erythro configuration at C-14 and C-15 in the pyrrolidinyl-γbutyrolactone moiety was deduced by comparison of the chemical shifts and coupling constants with those of previously isolated alkaloids, pandamarilactonines-A to -D. In accordance with that, the relative stereochemistry of (3R*, 5R*, 14R*, 15S*, 17R*) for 2 was proposed. The molecular formula of pandamarilactonine-F N-oxide (3) denotes an additional oxygen atom compared to alkaloids 1 and 2. Its polar nature in chromatography and the downfield-shifted signals of H-9 (δ 3.57, δ 3.33), H-11 (δ 3.65, δ 3.16), H-14 (δ 3.42) and H-15 (δ 5.47) further indicate that it is an N-oxide of alkaloid 1 or 2. The structure of pandamarilactonine-F N-oxide (3) was established by the m-CPBA oxidation of natural 2. The spectroscopic data of the semisynthetic product were in complete agreement with the natural compound. Pandamarilactonine-G (4) was established to contain pyrrolidinone moiety in its lower part on the basis of 2D NMR analysis. Its structure and (3R, 5R) absolute configuration were unambiguously elucidated via the condensation of 2-pyrrolidinone (7) and iodo-γ-butyrolactone 8, which was prepared from butyrolactone alcohol 9 (Scheme 2).
Scheme 2 Synthesis of pandamarilactonine-G (4).
Pandamarilactonine-H (5) has a Z-configured γ-butylidene-α-methylα,β-unsaturated butyrolactone unit in the upper part as shown by the characteristic NMR signals at δH 6.98 (1H, dd, J ¼ 1.6, 0.9 Hz, H-4), 5.15 (1H, t, J ¼ 8.0 Hz, H-6), 1.99 ppm (3H, d, J ¼ 0.9 Hz, H3-17); δC 171.1 (C-2), 129.1 (C-3), 137.7 (C-4), 148.5 (C-5), 114.1 (C-6), 10.5 ppm (C-17), in addition to the strong UV absorption at 275 nm.16
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A methyl 2-(pyrrolidin-2-yl)acetate functionality in the lower part was established by 1D and 2D NMR experiments. Alkaloid 5 was isolated as diastereomeric mixture with 5a (Fig. 1) having an E-configured γ-butylideneα-methyl-α,β-unsaturated butyrolactone unit. The enantiomers of compounds 5 and 5a were synthesized (vide infra) in diastereomerically and enantiomerically pure forms and the absolute configuration of 14S was established. The presence of a methyl 2-(pyrrolidin-2-yl)acetate indicates a new type of structure in Pandanus alkaloids. The biogenesis (Scheme 3) of pandamarilactonine-H (5) was postulated to involve a condensation reaction of N-(3-carboxypropyl)-GABA (10) and 4-hydroxy-4-methylglutamic acid (11) to form an amine 12. A series of reactions including decarboxylation, transamination, dehydration, and cyclization would furnish an iminium ion 13. A Mannich type reaction involving the addition of methyl acetate (or acetyl-CoA) to the iminium ion 13 would finally yield pandamarilactonine-H (5).17
Scheme 3 Plausible biogenesis of pandamarilactonine-H (5).
Phytochemical investigation of P. amaryllifolius leaves collected in Taiwan afforded the new alkaloids N-acetylnorpandamarilactonine-A (14),17 and -B (15)17; norpandamarilactonine-C (16)18 and -D (17)18; pandalizine-A (18),17 -B (19),17 -C (20),18 -D (21),18 and -E (22)18; pandanusine-A (23)18 and -B (24)18; pandamarilactone-2 (25)17 and -3 (26)17; (5E)-pandamarilactonine-32 (27)17; pandanmenyamine (28)17; and pandalactonine (29)17 (Fig. 2). N-acetylnorpandamarilactonines-A (14) and -B (15) contain an acetyl pyrrolidinyl-α,β-unsaturated γ-lactone moiety. The pyrrolidinylα,β-unsaturated γ-lactone group was resolved on the basis of 1D and 2D
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Fig. 2 New alkaloids from the leaves of Pandanus amaryllifolius.
NMR experiments and by comparison with known norpandamarilactonineB.19 The acetyl group attached to the N atom was established from IR (1643 cm1) and 13C NMR data and by comparison with N-acetylpyrrolidine. The absolute stereochemistry of 14 and 15 was determined on the basis of
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calculated electronic circular dichroism (ECD) at the B3LYP/6-311++G (2d,2p)//BY3Yp/6-31++G(dd) level using the Gaussian 9.0 program. Comparison of the experimental ECD data with the calculated ECD, 14 showed a positive Cotton effect (CE) at λmax 228 nm and negative CEs at 208 and 255 nm. Similarly, comparison of the experimental ECD with the calculated ECD, 15 showed positive CEs at 236 and 276 nm and a negative CE at 209 nm. These data suggested that 14 and 15 are epimers and were assigned an absolute configuration of (5R, 8R) for N-acetylnorpandamarilactonine-A (14) and (5R, 8S) for N-acetylnorpandamarilactonine-B (15). Norpandamarilactonines-C (16) and -D (17) were isolated as a mixture in 9:10 ratio.18 The spectral data were similar to those of 14 and 15 indicating a formamide group instead of an acetamide. Norpandamarilactonine-C (16) was elucidated to contain an N-formylpyrrolidinyl-α,β-unsaturated γ-lactone moiety with (5R, 6R) absolute configuration. Norpandamarilactonine-D (17) contains an N-formylpyrrolidinyl-α,β-unsaturated γ-lactone moiety with (5R, 6S) absolute configuration. Structure characterization of pandalizine-A (18) suggested the presence of an α-methyl-α,β-unsaturated γ-lactam fused to a tetrahydropyridine ring.18 Pandalizine-A (18) was established to be 2-methyl-6,7dihydroindolizin-3(5H)-one. Pandalizine-B (19) was elucidated to be 8a-methoxy-2-methyl-6,7,8,8a-tetrahydroindolizin-3(5H)-one. The absolute stereochemistry of R at C-8a was determined on the basis of the observed positive CEs at λmax 246 and 350 nm and a negative CE at 300 nm, which were similar to those of the calculated ECD spectrum of 8aR enantiomer. Structure elucidation of pandalizine-C (20) established the presence of fused piperidine and α-methyl-α,β-unsaturated γ-lactam moieties with a hydroxyl group at C-8a position. The C-8aR absolute stereochemistry was determined by comparing the experimental ECD with the calculated ECD for both 8aR and 8aS enantiomers. A positive CE at 211 nm and negative CEs at 187, 223, and 288 nm data were consistent with the 8aR enantiomer. Pandalizine-D (21) and pandalizine-E (22) were elucidated to have similar structures to pandalizine-C (20) with an additional hydroxyl group at C-8 for 21 and at C-7 for 22. The 8aS configuration of 21 was assigned based on a similar skeleton pattern with pandalizine-B (19) and -C (20). The experimental ECD for pandalizine-D (21) also demonstrated a positive CE at λmax 204 nm and negative CEs at 186, 247, and 283 nm, similar to the calculated ECD for an 8R, 8aS enantiomer, indicating an absolute stereochemistry of (8R, 8aS). On the other hand, the absolute stereochemistry of (7R, 8aR) was elucidated for pandalizine-E (22) based on ECD and vibrational circular dichroism (VCD) experiments.
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Structure elucidation of pandanusine-A (23) disclosed the presence of a piperidine ring and an α-methyl-γ-lactam moiety linked together in a diazaspirocyclic ring at C-5 position.18 A new dihydrofurocoumarin was also isolated from P. tectorius called pandanusin A, its name is almost similar with that of alkaloid 23.20 The absolute stereochemistry at C-5 was elucidated by J-based configuration analysis and ECD prediction. The conformation was analyzed by the observed3 JH-6/C-4 (3.0 and 6.1 Hz) in the HMBC spectrum. Then, by comparison of experimental ECD data with those of calculated ECD at the B3LYP/6-31 + G* level using the Gaussian 9.0 software which yielded a positive CE at 224 nm and negative CEs at 256 and 279 nm for S configuration, on the contrary, a negative CE at 224 nm and positive CEs at 256 and 279 nm for R configuration, the absolute configuration at C-5 in 23 was determined to be S. The same functional moieties were elucidated in pandanusine-B (24) on the basis of spectral analysis and comparison of NMR data of 23 and 24. One major difference in the structure was the presence of an ethylbenzene attached to the nitrogen of the piperidine ring. The absolute stereochemistry of S at C-5 of 24 was disclosed on the basis of similarity of experimental CD data to those of pandanusine-A (23). Pandamarilactone-2 (25) has a piperidine ring linked to a γ-butylideneα,β-unsaturated γ-lactone moiety and an α-methyl-α,β-unsaturated γ-lactone moiety. Its structure was determined by comparison of NMR data with those of previously isolated pandamarilactone-121 and pandamarilactonine-C.22 The E configuration at Δ5,6 position was established on the basis of NOE correlation between H-4 and H-7 protons. Pandamarilactone-3 (26) has a Z-configured γ-butylidene-α,β-unsaturated γ-lactone in the upper part. The lower part is composed of a spirostructure that includes a piperidine ring and an α-methyl-α,β-unsaturated γ-lactam moiety. The structure and NMR data of (5E)-pandamarilactonine-32 (27) are similar to those of previously isolated pandamarilactone-3221 containing a γ-butylidene-α,β-unsaturated γ-lactone and a 5-methylene-2-cyclopentenone annulated to a piperidine ring. An E Δ5,6 configuration was confirmed on the absence of an NOE correlation at H-4 and H-6, in contrast to the Z-configuration of pandamarilactone-32. Pandanmenyamine (28) has a γ-butylidene-α-methyl-α,β-unsaturated γ-butyrolactone with a Z configuration at Δ5,6 position as determined by NOESY and comparison with the previously isolated pandamarilactam-3y.17,23 Moreover, an N-acetyl fragment was deduced to be linked
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to the butylidene unit as evidenced by HMBC correlation of the H2-9 proton of the butylidene and the C-11 carbonyl of the amide group. Pandalactonine (29) possesses similar NMR data to the previously isolated pandamarilactonine-A24 having a γ-butylidene-α,β-unsaturated butyrolactone at the upper part. In contrast to pandamarilactonine-A, the lower part in pandalactonine (29) is composed of a fused tricyclic ring structure with spirolactone and pyrrolo[1,2-c]oxazole units as indicated by an additional oxygen atom and the HMBC correlation between H-9 and C-15. NOESY and NOE experiments enabled the disclosure of the relative configuration of 29 as (9R*, 14R*, 15S*). The fused tricyclic ring system in pandalactonine (29) represents a new type of Pandanus alkaloid. A plausible biogenetic pathway for the alkaloids isolated from the leaves of P. amaryllifolius from Taiwan is presented in Scheme 4.17 Condensation of 4hydroxy-4-methylglutamic acid (11) and γ-aminobutyric acid (GABA) yields an amine 30, which undergoes decarboxylation, transamination, dehydration, reduction, and cyclization forming the bicyclic amine 31, and will eventually led to form pandalizines-A to -E (18–22). The formation of pandanmenyamine (28) involved an amine 33 from the condensation of 11 and
Scheme 4 Proposed biosynthesis of new alkaloids from the leaves of Pandanus amaryllifolius.
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N-acetyl-GABA (32), which then undergoes cyclization, deamination, reduction, transamination, and reduction reactions. N-acetylnorpandamarilactonines (14 and 15) are formed from the cyclization of 28. Condensation of 11 and N-carboxypropyl-GABA (34) forms an amine 35. Condensation of 35 and another molecule of 11 yields amine 36, which undergoes a reaction sequence including dehydration, decarboxylation, cyclization, and oxidation at C-9 to form pandalactonine (29). Apart from P. amaryllifolius, two other species were found to contain alkaloids. Purification of the crude base of P. dubius collected in the Philippines led to the identification of dubiusamine-A (37) and -B (6) (Fig. 3).25 Dubiusamine-A (37) was identified as a saturated symmetrical amine whose structure is similar to that of pandanamine.26 An α-methyl-γ-butyl-γbutyrolactone unit with an anti relationship between C-3 and C-5 methine protons was evidenced by NOE analysis. A minor diastereomer, dubiusamine-C (38),25,27 was also identified, which had a syn relationship between C-3 and C-5 methine protons. Several total syntheses (vide infra) resulted in the characterization of dubiusamine-A (37) and the determination of its absolute configuration as (3R, 5R). Dubiusamine-B (6) has a 3,5disubstituted γ-butyrolactone with an anti relationship between C-3 and C-5 methine protons in the upper part. The lower part is composed of a pyrrolidinyl-substituted α-methyl-α,β-unsaturated γ-butyrolactone with a threo configuration at C-14 and C-15 positions. The (3R, 5R, 14R, 15R) absolute configuration of dubiusamine-B (6) was unambiguously confirmed by its asymmetric total synthesis (vide infra). An Egyptian shrub, P. utilis, was investigated to yield two novel indolizidine alkaloids, pandalisine-A (39) and -B (40) (Fig. 4).28 Pandalisine-A (39) has an α-methylbutenolide that is connected to the indolizidine moiety at C-50 and C-8 positions, as evidenced by HMBC 0 experiments. An E configuration for Δ5 ,8 was also elucidated on the basis
Fig. 3 New alkaloids isolated from Pandanus dubius.
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Fig. 4 Novel indolizidine alkaloids from Pandanus utilis. 0
0
of the observed NOESY cross peaks of H2-1/H-4 and H-4 /H-9. The absolute configuration of R at C-9 was determined on the basis of experimental CD and calculated ECD data. The experimental CD showed a positive CE at 290 nm and a negative CE at 240 nm, consistent with the calculated ECD data for 9R configuration. Pandalisine-B (40) has similar functional moieties to pandalisine-A (39) except for the Z-configuration 0 of the C-5 /C-8 double bond. The configuration of R at C-9 was also observed on the basis of similar experimental CD and calculated ECD patterns to a 9R configuration. A plausible biogenetic pathway (Scheme 5)28 for
Scheme 5 Plausible biogenesis of novel indolizidine alkaloids.
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39 and 40 has been described as follows. Condensation followed by reduction of N-carboxypropyl-GABA (34) and 4-hydroxy-4-methylglutamic acid (11) yields amine 35, which undergoes a series of reactions including cyclization, decarboxylation, transamination, and dehydration to afford pandalisine-A (39) and -B (40). Most of the Pandanus alkaloids found in early studies feature a γ-butylidene-α-methyl-α,β-unsaturated γ-lactam, a γ-butylidene-αmethyl-α,β-unsaturated γ-lactone, and/or a pyrrolidinyl-substituted α,βunsaturated γ-lactone residue. It is noteworthy that new alkaloids such as pandalizine-A to -E (18–22) and pandalisine-A (39) and -B (40), possess an indolizidine core in their molecules.
3. Synthetic Studies on the Pandanus Alkaloids 3.1 Synthesis of Pandamarilactone-1 Pandamarilactone-1 (41) was isolated from the leaves of P. amaryllifolius in optically active form in 1993.21 It consists of a spirostructure with a piperidine ring linked to a γ-butylidene-α,β-unsaturated γ-lactone moiety and an α-methyl-α,β-unsaturated γ-lactone moiety. Its first total synthesis was accomplished in 2014, which features the oxidation of symmetrical furan derivative 46 with singlet oxygen.29 Substrate 46 for the key reaction was prepared as follows. The acetylide generated from 5-chloro-1pentyne was coupled with TMS-acetol (hydroxyacetone) and then treated with AgNO3–SiO2 to give furan derivative 42, which was then transformed into cyanopropyl-substituted furan 43 by a substitution reaction. Cyanopropyl-substituted furan 43 thus obtained was converted into furan carbaldehyde 44 and aminobutyl-substituted furan 45 under different reductive conditions. Condensation of 44 and 45 by reductive amination and protection of the resultant secondary amine with Boc afforded symmetrical difuran 46. Finally, 46 was subjected to 1O2mediated furan oxidation in the presence of rose Bengal followed by deprotection of Boc with TMSBr to give bis(methoxybutenolide) 47, which was then treated with H2SO4/CH2Cl2 under vigorous stirring to yield ()-pandamarilactone-1 (41) in 12% yield via spiro-N,O acetal formation and elimination of methanol. In this reaction a mixture of pandamarilactonines-A to -D were also obtained when 47 was treated with H2SO4 (Scheme 6).29
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Scheme 6 Synthesis of pandamarilactone-1 (41).
3.2 Synthesis of Pandamarine ()-Pandamarine (48) is the first alkaloid isolated from Pandanus plants.30 Its structure, which is composed of diazaspiro[4.5] and 5-butylidenepyrrol-2 (5H)-one units, was determined by X-ray diffraction. The first total synthesis of this alkaloid was accomplished in 2015 (Scheme 7),31 although the strategy is similar to that of the synthesis of pandamarilactone-1 (41) (vide supra). Commercially available 5-hexynenitrile was condensed with hydroxyacetone to give alkynyldiol 49, which was converted into cyanopropyl-substituted furan 43 by treatment with AgNO3. Compound
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Scheme 7 Synthesis of pandamarine (48).
43 was then converted into furan carbaldehyde 44 and aminobutylsubstituted furan 46, which were used in the reductive amination to furnish symmetrical difuran 50. Difuran 50 having a protecting group-free amine was then subjected to a series of operations, that is, oxidation with singlet oxygen generated by methylene blue (MB) and visible light, addition of MB and Me2S, and addition of aqueous ammonia, to form intermediate 51. Finally, removal of the volatile contaminants from the reaction mixture ˚) followed by addition of TFA in CHCl3 containing molecular sieves (4 A afforded ()-pandamarine (48) in 30% overall yield from the difuran 50.
3.3 Synthesis of epi-Pandamarilactonine-H epi-Pandamarilactonine-H (52) was synthesized in the course of the structure elucidation of pandamarilactonine-H (5) (vide supra).16 4-Iodobutylenesubstituted butyrolactone 56 which corresponds to the upper fragment of alkaloid 5, was prepared according to the protocol developed for the synthesis of pandamarilactonine-C and -D.22 Another fragment, i.e., methyl
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pyrrolidinylacetate 55, was synthesized from D-proline. The Arndt–Eistert reaction of the mixed anhydride prepared from Cbz-protected D-proline 53 yielded α-diazoketone 54. A Wolff rearrangement homologation reaction of 54 followed by hydrogenolysis afforded the methyl pyrrolidinylacetate 55. Condensation of a 3:2 (Z/E) mixture of 56 and 55 using Ag2CO3 in CH3CN gave the alkaloid 52 and its E-diastereomer 57, both having the 14R configuration. Comparison of the optical rotation of synthetic 52 {[α]21 D +62 (c. 0.07, CHCl3)} with that of natural pandamarilactonine-H (5) {[α]24 D 43 (c. 0.04, CHCl3)} established the 14S absolute configuration of natural alkaloid 5 (Scheme 8).
Scheme 8 Synthesis of epi-pandamarilactonine-H (52).
3.4 Synthesis of Dubiusamine-A and its Enantiomer Three asymmetric syntheses have been reported for dubiusamine-A (37). The first asymmetric total synthesis utilized a proline-catalyzed asymmetric α-aminoxylation as the key step.25 Thus, a three-step reaction that included the α-aminoxylation of aldehyde 58 with nitrosobenzene in the presence of L-proline, followed by Horner–Emmons reaction, and the O–N bond cleavage utilizing CuSO4 in MeOH, afforded highly enantioselectively ester 59 with 99% ee. The R configuration on the stereocenter of 59 was deduced on the basis of a well-established mechanism for the proline-catalyzed α-aminoxylation. Ester 59 underwent subsequent hydrogenation, cyclization, diastereoselective α-methylation, and deprotection to form the butyrolactone alcohol 9. The Mitsunobu
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reaction of 9 using 2-nitrobenzenesulfonamide gave amine 60. The second Mitsunobu reaction of 9 with 60 and the subsequent deprotection produced enantiomerically and diastereomerically pure dubiusamine-A (37) (Scheme 9). Comparison of the spectroscopic data and optical rotation of the synthetic and natural products led to the establishment of the (3R, 5R) absolute configuration.
Scheme 9 Synthesis of dubiusamine-A (37) using proline-catalyzed α-aminoxylation.
The second approach for the synthesis of dubiusamine-A (37) involved a one-pot conversion of cis,cis-1,3-cyclooctadiene (61) into oxabicyclononenol 62 with >99% ee by a sequential photooxygenation and deMeQAc-catalyzed Toste–Kornblum–DeLaMare rearrangement.32 PhI(OH)OTs (HTIB)-mediated oxidative fragmentation of 62 in the presence of Na2H2PO42H2O afforded unsaturated butyrolactone 63 without loss of enantiomeric integrity. Unsaturated butyrolactone 63 was subjected to hydrogenation and TBS-protection to yield butyrolactone 64. Further reactions of 64, including diastereoselective α-methylation, the Mitsunobu reaction, and deprotection, afforded dubiusamine-A (37) (Scheme 10). The spectroscopic data, including the optical rotation, are in complete agreement with those of the natural product.
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Scheme 10 Synthesis of dubiusamine-A (37) using HTIB-promoted oxidative fragmentation.
The synthesis of ent-dubiusamine-A (65) was carried out via a palladiumcatalyzed asymmetric allylic alkylation reaction.33 A nucleophile generated from N,N-diphenylpropionamide and LiHMDS was reacted with allylphosphate 66 in the presence of palladium catalyst (5 mol% Pd(OAc)2) and phosphine ligand 67 to afford alkylated product 68 with high enantioselectivity (er 96:4). Iodolactonization of 68 followed by deiodination using n-Bu3SnH/Et3B and debenzylation gave butyrolactone 69 exhibiting negative optical rotation. Thus, the formal total synthesis of the enantiomer of natural dubiusamine-A was completed (Scheme 11).
Scheme 11 Synthesis of ent-dubiusamine-A (65) using Pd-catalyzed allylic alkylation.
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3.5 Synthesis of Dubiusamine-B The unambiguous determination of the structure including the absolute configuration of dubiusamine-B (6) was achieved by total synthesis (Scheme 12).25 Iodo-γ-butyrolactone 8 having the (3R, 5R) absolute configuration was prepared from butyrolactone alcohol 9 (Scheme 9). The lower part, composed of a pyrrolidinyl-substituted α-methyl-α,βunsaturated γ-butyrolactone with a threo configuration, was prepared from D-prolinol (70). Thus, N-protected D-prolinol was subjected to oxidation and vinylation reactions to give diastereomeric adducts 71 and 72. To elucidate the stereochemistry at the newly generated stereogenic centers, both adducts were converted into their oxazolidone derivatives 73 and 74, respectively. Measurement of the3 JH-1,H-7a coupling constant and the NOE correlation between H-7a and H-1 in 73 and 74 confirmed the presence of an erythro configuration for adduct 71 and a threo configuration for adduct 72. After removal of the protecting group in 72, the resulting amine
Scheme 12 Synthesis of dubiusamine-B (6).
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was condensed with iodo-γ-butyrolactone 8 utilizing Ag2CO3 to form adduct 75. Esterification using methacrylic anhydride and ring-closing metathesis using Grubb’s II catalyst afforded dubiusamine-B (6), whose spectroscopic data and optical rotation, are in complete agreement with the natural product.
3.6 Synthesis of Dubiusamine-C Dubiusamine-C (38) is a minor alkaloid isolated as a diastereomeric mixture with dubiusamine-A (37) from P. dubius.25 NOE experiments showed a syn relationship between the H-3 and H-5 methine protons of 38, in contrast to the anti configuration of the methine protons of 37. To elucidate the stereostructure of 38, a racemic total synthesis was carried out.27 1,5Pentanediol was subjected to a series of reactions that included partial oxidation and vinylation to form compound 76. Subsequent esterification, ring-closing metathesis, and stereoselective hydrogenation of 76 afforded butyrolactone 77. NOE analysis of 77 revealed the desired syn configuration for the H-3 and H-5 methine protons. The Mitsunobu reaction of 77 with 2-nitrobenzenesulfonamide afforded aminopropylbutyrolactone 78. The second Mitsunobu reaction of 77 and 78 gave the symmetrical amine 79. Removal of the Ns group completed the synthesis of dubiusamine-C (39) (Scheme 13).
Scheme 13 Racemic total synthesis of dubiusamine-C (38).
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An asymmetric total synthesis of dubiusamine-C (38) was reported, which utilized a diastereoselective bromolactonization with potassium bromide and Oxone as the key step.34 Initially, according to the Evans protocol, compound 80 was methylated using NaHMDS and MeI and then subjected to the removal of the chiral auxiliary to yield chiral pentenoic acid 81. A cis-selective bromolactonization using KBr/ Oxone in AcOEt provided bromolactone 82 with 77/23 dr. After separation by column chromatography, the major cis-diastereomer 82 was subjected to alkyl–allyl coupling using allyltributyltin, and this was followed by hydroboration-oxidation to afford butyrolactone alcohol 83. According to a known procedure that involved coupling of 83 and its Ns-derivative using the Mitsunobu reaction and N-deprotection, the total synthesis of (+)-dubiusamine-C (38) was accomplished in 36% overall yield (Scheme 14).
Scheme 14 Asymmetric total synthesis of dubiusamine-C (38).
A formal synthesis of dubiusamine-C (38) was also reported using 35 D-mannose as the starting material. Lactone 84, a D-mannose-derived chiral molecule, was treated with 60% AcOH and then refluxed with I2/PPh3/imidazole to afford ethenylbutyrolactone 85. Cross metathesis of butyrolactone 85 and 3-butenol afforded the butyrolactonediol 86. A series of Mitsunobu reactions gave symmetrical alkenylbutyrolactone 87. Reduction followed by deprotection of the amine group successfully generated dubiusamine-C (38) (Scheme 15).
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Scheme 15 Formal synthesis of dubiusamine-C (38).
3.7 Synthesis of Pandanamine, Norpandamarilactonines, and Pandamarilactonines The synthesis of the known alkaloids pandanamine, pandamarilactonines, and norpandamarilactonines have been reported in three separate papers. Pandanamine (88) was postulated to be a precursor of pandamarilactonines24 and later isolated as a natural product from P. amaryllifolius,26 thereby, supporting the proposed biogenetic pathway for various Pandanus alkaloids. It is a symmetrical amine containing γ-butylidene-α-methyl-α,βunsaturated γ-lactone moieties. Pandamarilactonine-A to -D contain the γ-butylidene-α-methyl-α,β-unsaturated γ-lactone in the upper part and the pyrrolidinyl-substituted α,β-unsaturated γ-lactone in the lower part. The C-14 and C-15 positions of the pyrrolidinyl α,β-unsaturated γ-lactone may have a threo configuration as described in pandamarilactonine-A (89) and -C (90) (see Scheme 17), or an erythro configuration, as exhibited by pandamarilactonine-B (91) and -D (92).22 The C-5 and C-6 positions of the γ-butylidene-α,β-unsaturated γ-lactone maybe in the Z configuration (89 and 91) or the E configuration (90 and 92).22 Norpandamarilactonine-A (93) and -B (94) were isolated in 2001 containing the pyrrolidinyl-substituted α,β-unsaturated γ-butyrolactone structure with the threo configuration for 93 and the erythro configuration for 94.
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The synthesis of pandanamine (88) was accomplished via a basepromoted 5-exo-dig selective cyclization of bis(oct-2-en-4-ynoic) derivative 95.36 Compound 95 was prepared as follows. Propargyl alcohol 96 was converted into ether 97 in a three-step process. The Sonogashira coupling of 97 and pent-4-yn-1-ol (98) gave alkyne 99. This was followed by a Mitsunobu reaction with Boc-protected nosylamine and the removal of the protecting group to afford amide 100. Amide 100 was allowed to react with iodide 101 to afford dialkylated alkyne 102. Then, compound 102 was converted to the desired bis(oct-2-en-4-ynoic) derivative 95, which underwent selective cyclization using Et3N and removal of the amino protecting group to provide the desired pandanamine (88) (Scheme 16).
Scheme 16 Synthesis of pandanamine (88).
Adopting the reductive intramolecular aza-Michael-type addition as the key step, the synthesis of pandamarilactonine-A to -D, norpandamarilactonine-A and -B, and pandanamine was accomplished using 3-methylfuran-2 (5H)-one (104).37 Initially, butane-1,4-diol was converted to aldehyde 103, which was then reacted with 104 to obtain alcohol 105. Via a two-step process, compound 105 was converted into butylidenebutyrolactone 106 in 57:43 E/Z ratio, and this was converted into azidobutenolide
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derivative 107 using sodium azide. The conversion of 107 into norpandamarilactonine-A (93) and norpandamarilactonine-B (94) was introduced via a triphenylphosphine-induced reductive regioselective intramolecular aza-Michael-type addition to the exocyclic activated double bond (Scheme 17). Coupling of the norpandamarilactonine mixture with iodobutenolide 108 in the presence of silver carbonate gave the pandamarilactonine-A to -D in a 4:4:1:1 ratio, respectively. Treatment of the pandamarilactonine mixture with silica gel gave pandanamine (88).
Scheme 17 Synthesis of pandamarilactonines (72–75), pandanamine (88), and norpandamarilactonines (93–94).
In an attempt to perform the asymmetric synthesis of pandamarilactonineB, an unexpected syn-diastereoselective vinylogous Mannich reaction (VMR) between (Rs)-N-tert-butanesulfinimine 109 and 3-methyl-2-(tertbutyldimethylsilyloxy)furan (111) was observed. Thus, the asymmetric total synthesis of ()-pandamarilactonine-A (89) was accomplished in a
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three-pot reaction (Scheme 18).38 Initially, compound 110 was prepared by the CuSO4-mediated coupling of 4-chlorobutanal and (Rs)tert-butanesulfinamide 109. VMR of 110 and 3-methyl-2-(tert-butyldimethylsilyloxy)furan (111) resulted in the formation of two separable isomers, syn-112 and anti-113, in 95:5 syn:anti ratio. The syn-112 isomer was treated with HCl and K2CO3/NaI and iodobutenolide 108 (Z/E 9:1) to yield pandamarilactonine-A (89), -C (90), and -B (91) in 77:13:11 ratio, respectively. Attempts to separate 89 and 90 proved to be difficult. An 87:13 by 1H NMR and an 89:11 ratio by HPLC (compound 89:90) were determined. The optical rotation of 89 with 12% amount of 90 was [α]D 87.2 (c. 0.12, CHCl3). The enantiomeric excess of the synthetic 89 was determined to be 95.5% by chiral HPLC.
Scheme 18 Synthesis of ()-pandamarilactonine-A (89).
3.8 Synthesis of Pandalizine-A and -B The new alkaloids pandalizines-A (18) and -B (19) contain an indolizidine core and are designated as a new class of alkaloids from the genus Pandanus. The synthesis of these new alkaloids utilized an unprotected primary furylalkylamine that underwent photooxygenation.39 Specifically, a 4-(4methylfuran-2-yl)butan-1-amine (114) was subjected to photooxygenation using methylene blue (MB) as photosensitizer to afford intermediate
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compound 20 as a biogenetic precursor, as proposed by Tsai et al.17 This compound was later isolated from P. amaryllifolius as a natural product named pandalizine-C (20) in 2017.18 Further treatment of 20 with TFA in CHCl3 will eventually lead to pandalizine-A (18), whereas treatment with TFA in MeOH gave pandalizine-B (19) (Scheme 19).
Scheme 19 Synthesis of pandalizine-A (18) and pandalizine-B (19).
4. Pharmacology of the Pandanus Species Investigation of antibacterial activity using the microwell assay for known alkaloids pandamarilactone-1, pandamarilactone-32, pandamarilactonine-A and pandamarilactonine-B revealed that pandamarilactonine-A exhibited a minimum inhibitory concentration of 15.6 μg/mL and minimum bactericidal concentration of 31.25 μg/mL against Pseudomonas aeruginosa ATCC 27853.7 All alkaloids showed weak to no activity against Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 25923. Although there is a limited data on the biological activities of the Pandanus alkaloids, several pharmacological studies were conducted on the extracts of various Pandanus species. The methanolic extract of P. odoratissimus showed significant antiinflammatory activity at a dose of 100mg/kg in carrageenan-induced acute (68%) and formalin-induced chronic (64.2%) paw edema in rats.6 In vitro investigation of the ethanolic extract of P. amaryllifolius using cell cycle progression analysis, the Annexin V assay, and TUNEL assay showed that it mediated mitochondrial activated apoptosis pathways in MDA-MB-231 breast cancer cells. The proposed mechanism in the induction of apoptosis involved the up regulation of the tumor
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suppressor protein p53 and the downregulation of the inhibitor of apoptosis protein XIAP.4 P. foetidus leaf extracts, including the methanol, petroleum ether, chloroform, and aqueous fractions, were investigated for their antidiarrheal activity and cytotoxicity.8 The extract showed antidiarrheal activity, reducing the number of defecations and maintaining stool consistency. The methanol and chloroform fractions reduced the castor oil induced enteropooling and fluid accumulation, whereas the aqueous fraction reduced gastrointestinal motility. The brine shrimp assay for cytotoxicity showed that the chloroform extract gave an LC50 of 106.97 μg/mL.
5. Summary This review covers the literature on Pandanus alkaloids published between April 2008 and September 2018. Three Pandanus species (P. amaryllifolius, P. utilis, and P. dubius) were found to contain new alkaloids. A total of 26 new alkaloids were identified, which contained γ-butylidene-αmethyl-α,β-unsaturated γ-lactam, γ-butylidene-α-methyl-α,β-unsaturated γ-lactone, pyrrolidinyl-substituted α,β-unsaturated γ-lactone, and/or indolizidine core residues. The interesting structures of the Pandanus alkaloids have prompted synthetic studies by various research groups. These include known Pandanus alkaloids (pandamarine, pandamarilactone-1, pandanamine, pandamarilactonine-A to -D) as well as the newly isolated alkaloids dubiusamine-A and -B and pandalizine-A and -B. The use of Pandanus species in traditional folk medicine have also encouraged several pharmacological studies that include the scientific validation of their antibacterial, antiinflammatory, antidiarrheal, and cytotoxic activities. Given the large number of Pandanus species distributed worldwide, it is expected that new alkaloids will be studied in the future and that these Pandanus species would be excellent sources of biologically active secondary metabolites.
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