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. 2019 Dec 26;5(1):859–863. doi: 10.1021/acsomega.9b03760

Chemoselective Ring Closure of 4-(3-Methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanal Leading to Pandalizine A

Mahesh B Yadav †,‡, Kailas R Pandhade †,‡, Narshinha P Argade †,‡,*
PMCID: PMC6964528  PMID: 31956837

Abstract

graphic file with name ao9b03760_0005.jpg

Starting from methylmaleic anhydride, a facile total synthesis of pandalizine A alkaloid is described via the regioselective reduction of methylmaleimide and acid-catalyzed enolization of 4-(3-methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanal followed by chemoselective intramolecular dehydrative cyclization as the key steps. It is noteworthy that the analogous model system with an additional β-methyl group followed an alternative chemoselective intermolecular aldol condensation pathway.

Introduction

Alkaloids are important compounds that possess a broad range of effective biological activities, and some novel azabicyclic alkaloids are shown in Figure 1.1−5 Tropical Pandanus amaryllifolius shrub from Southeast Asia is used in folk medicine for the treatment of gout, hyperglycemia, hypertension, and rheumatism.6,7 Recently, the azabicyclic alkaloids pandalizines A (5.2 mg), B (4.5 mg), C (1.2 mg), D (1.3 mg), and E (1.2 mg) have been isolated from 6.0 kg of aerial parts of P. amaryllifolius species, and their structural and stereochemical assignments have been done on the basis of NMR, 2D NMR, and circular dichroism studies (Figure 2).6,7 The authors have also proposed that glutamic acid and leucine are biogenetic precursors of all of these alkaloids. A large number of well-established synthetic protocols to design azabicyclic frameworks are known in the contemporary literature.8 In this context, very recently, elegant total syntheses of pandalizine A, (±)-pandalizines B, and (±)-pandalizines C have been accomplished via photo-oxidation of specifically synthesized furylalkylamine by Vassilikogiannakis and co-workers from Greece (Scheme 1).9,10 However, synthesis of pandalizines D and E bearing an additional hydroxyl group at two different positions in ring-B is still awaited. To date, we have accomplished the total synthesis of a large number of bioactive natural products using cyclic anhydrides and their derivatives as the potential precursors.11−15 Now we report the total synthesis of pandalizine A via the regioselective reduction of citraconimide followed by a substrate-specific chemoselective ring closure as crucial reactions (Schemes 2 and 3).

Figure 1.

Figure 1

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Representative bioactive azabicyclic natural products.2−5

Figure 2.

Figure 2

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Azabicyclic pandalizines A–E alkaloids from P. amaryllifolius.6,7

Scheme 1. Photooxygenation-Based Known Approach to Pandalizines A–C9,10.

Scheme 1

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Scheme 2. Concise Retrosynthetic Analysis of Pandalizine A.

Scheme 2

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Scheme 3. Structure-Based Chemoselective Intramolecular Condensation versus Intermolecular Aldol Reaction: Simple and Efficient Synthesis of Pandalizines A.

Scheme 3

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Results and Discussion

A systematic plan was prepared to synthesize pandalizine A from methylmaleic anhydride and the accordingly proposed concise retrosynthetic analysis is depicted in Scheme 2. The regioselective reduction of citraconimide and chemoselective intramolecular cyclization of a well-structured substrate over possible intermolecular aldol condensation were the foreseen challenges in our synthetic strategy. The reaction of methylmaleic anhydride (1a) with 4-aminobutanol in a refluxing mixture of acetic acid plus toluene directly furnished the corresponding imide 2a in 92% yield via the dehydrative cyclization of the formed intermediate regioisomeric maleamic acids and the thermal acylation of free primary alcohol (Scheme 3). The reaction of imide 2a with a bulky reducing agent such as DIBAL-H at −78 °C directly provided a column chromatographically inseparable regioisomeric mixture of desired deacylated major lactamol 3a and the corresponding undesired minor isomer in a ∼9:1 ratio (by 1H NMR) with 88% yield. The structural assignment of lactamol 3a was initially done on the basis of more deshielded 1H NMR signal for β-vinylic proton at δ = 6.55, which was finally confirmed on completion of the total synthesis of pandalizine A. Further reduction of the above-mentioned mixture of lactamols using BF3OEt2–Et3SiH via a plausible formation of the corresponding iminium ion intermediates and purification of the crude product by silica gel column chromatography yielded pure lactam 4a in 82% yield. The PCC oxidation of the primary alcohol unit in lactam 4a delivered the essential lactam aldehyde 5a in 76% yield for further systematic intramolecular condensation studies. In our hands, the reactions of compound 5a with bases such as DBU, NaH, LiHMDS, and NaHMDS resulted in a complex reaction mixture.16 The lactam aldehyde 5a on treatment with p-TSA in toluene at room temperature remained completely unreacted. However, the same reaction at 60 °C chemoselectively resulted in our target compound pandalizine A (7a) in 63% yield via the formation of the corresponding enol intermediate 6a and the intramolecular dehydrative condensation. In the present reaction, the formation of the significant enol intermediate 6a initiated prior to the possible enolization of aldehyde moiety and feasible intermolecular aldol condensation. All our attempts to further improve the efficiency of the above-specified reaction by changing the reaction time and temperature were unsuccessful. The obtained NMR data for an analytically pure sample of pandalizine A (7a) was completely matching with reported data.6,9,10 The total synthesis of pandalizine A (7a) was completed in five steps with 29% overall yield. The obtained natural product was highly prone to oxidative degradation under normal atmospheric conditions and got transformed into a complex mixture in 48 h.

To demonstrate yet another example of such type of chemoselective cyclization, maleimide 2b was synthesized in 93% yield by dehydrative condensation of dimethylmaleic anhydride (1b) with 4-aminobutanol in refluxing toluene17 (Scheme 3). Symmetrical imide 2b on NaBH4 reduction formed lactamol 3b, and its treatment with BF3OEt2–Et3SiH provided lactam 4b in 68% overall yield over two steps. The PCC oxidation of alcohol 4b yielded the desired substrate 5b in 71% yield. Surprisingly, the reaction of lactam aldehyde 5b with p-TSA in toluene at room temperature followed another pathway and underwent the chemoselective intermolecular dehydrative aldol condensation furnishing the undesired product 7b in 64% yield via the preferential formation of an alternate enol intermediate 6b. The repetition of the above-specified reaction at 60 °C also exclusively resulted in the same product 7b, but with 55% yield. Overall, the lactam aldehydes 5a and 5b follow two different reaction pathways under a similar set of reaction conditions due to the difference in acidity of methylene proton in lactam moieties and relatively less steric hindrance noted by a conjugate base in the formation of the intermediate 6a.

Conclusions

In summary, from readily available starting materials, we have completed protection-free practical total synthesis of pandalizine A via a remarkable regioselective reduction and chemoselective intramolecular cyclization pathway. Present studies represent a unique example wherein actual natural product precursor indeed followed expected chemoselective intramolecular cyclization route and furnished the target compound, while the analogous substrate with an additional β-methyl group delivered the undesired aldol product. We feel that the favored formation of an appropriately reactive cyclic enol intermediate for intramolecular cyclization is the genesis of delicately balanced chemoselectivity. Overall, the absence/presence of β-methyl group governs the course of competitive carbon–carbon bond-forming reactions and functions as a chemoselectivity switch.

Experimental Section

General Description

Melting points are uncorrected. The 1H NMR spectra were recorded on 200, 400, and 500 MHz NMR spectrometers using tetramethylsilane (TMS) as an internal standard. The 13C NMR spectra were recorded on 200 NMR (50 MHz), 400 NMR (100 MHz), and 500 NMR (125 MHz) spectrometers. High-resolution mass spectra [electrospray ionization (ESI)] were taken on Orbitrap (quadrupole plus ion trap) and TOF mass analyzer. The IR spectra were recorded on a Fourier transform infrared spectrometer. Column chromatographic separations were carried out on silica gel (60–120 and 230–400 mesh). Commercially available starting materials and reagents were used.

4-(3-Methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butyl Acetate (2a)

To a solution of 4-aminobutanol (0.99 g, 11.13 mmol) in AcOH/PhMe (20 mL, 3:1) was added citraconic anhydride (1a, 1.25 g, 11.13 mmol), and the stirring reaction mixture was refluxed for 12 h. The reaction mixture was concentrated in vacuo, after attaining room temperature. The obtained residue was dissolved in EtOAc. The organic layer was washed with 10% aqueous NaHCO3, brine, and dried over Na2SO4. The organic layer was concentrated in vacuo, and the obtained product was purified by using column chromatography (silica gel, 60–120 mesh, EtOAc–PE, 3:7) to furnish pure citraconimide 2a as a colorless liquid (2.31 g, 92% yield). 1H NMR (CDCl3, 200 MHz) δ 6.30 (q, J = 1.9 Hz, 1H), 4.05 (t, J = 6.1 Hz, 2H), 3.50 (t, J = 6.8 Hz, 2H), 2.06 (d, J = 1.8 Hz, 3H), 2.02 (s, 3H), 1.62 (quintet, J = 3.0 Hz, 4H); 13C NMR (CDCl3, 50 MHz) δ 171.8, 171.0, 170.8, 145.5, 127.2, 63.7, 37.4, 25.9, 25.2, 20.9, 10.9; HRMS (ESI) [M + Na]+ calcd for C11H15NO4Na 248.0893, found 248.0894; IR (CHCl3) νmax 1721, 1709, 1644 cm–1.

5-Hydroxy-1-(4-hydroxybutyl)-3-methyl-1,5-dihydro-2H-pyrrol-2-one [3a (Major Isomer) and the Corresponding Minor Regioisomer]

To a solution of imide (2a, 1.0 g, 4.44 mmol) in dry THF (15 mL) was slowly added a solution of DIBAL-H in cyclohexane (1 M, 13.32 mL, 13.32 mmol) at −78 °C under a nitrogen atmosphere. The reaction mixture was stirred for 1 h at the same temperature. The reaction was quenched with a saturated aqueous solution of potassium sodium tartrate tetrahydrate, and the reaction mixture was concentrated in vacuo. The formed product was dissolved in EtOAc, and the organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated in vacuo. The column chromatographic purification of the obtained crude product (silica gel, 60–120 mesh, EtOAc–PE, 8:2) gave pure compound 3a as a yellowish liquid (726 mg, 9:1 mixture, 88% yield). 1H NMR (CDCl3, 200 MHz) δ 6.55 (t, J = 1.5 Hz, 0.9H), 5.75 (br s, 0.1H), 5.29 (s, 0.9H), 5.14 (s, 0.1H), 4.60–4.00 (br s, 1H), 3.75–3.55 (m, 2H), 3.55–3.27 (m, 2H), 3.10–2.50 (br s, 1H), 2.05 (s, 0.30H), 1.87 (s, 2.70H), 1.80–1.45 (m, 4H); 13C NMR (CDCl3, 50 MHz) δ 170.7, 138.5, 136.7, 82.0, 62.1, 39.6, 29.5, 25.2, 10.9; HRMS (ESI) [M + Na]+ calcd for C9H15NO3Na 208.0944, found: 208.0945; IR (CHCl3) νmax 3340, 1683 cm–1.

1-(4-Hydroxybutyl)-3-methyl-1,5-dihydro-2H-pyrrol-2-one (4a)

To a solution of compound (3a plus minor isomer, 600 mg, 3.24 mmol) in dry DCM (15 mL) were added BF3·OEt2 (1.39 mL, 4.86 mmol) and Et3SiH (0.57 mL, 4.86 mmol) dropwise at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred for 4 h and allowed to reach room temperature. The reaction mixture was concentrated in vacuo, and the formed product was dissolved in EtOAc. The organic layer was washed with 10% aqueous NaHCO3 and brine and dried over Na2SO4. The concentration of the organic layer in vacuo and column chromatographic purification of the obtained product (silica gel, 230–400 mesh, MeOH/DCM, 2:8) furnished pure lactam 4a as a colorless liquid (458 mg, 82% yield). 1H NMR (CDCl3, 200 MHz) δ 6.66 (q, J = 1.7 Hz, 1H), 3.84 (t, J = 1.9 Hz, 2H), 3.68 (t, J = 6.2 Hz, 2H), 3.51 (t, J = 6.7 Hz, 2H), 3.30–2.90 (br s, 1H), 1.89 (d, J = 1.8 Hz, 3H), 1.80–1.45 (m, 4H); 13C NMR (CDCl3, 50 MHz) δ 172.2, 135.8, 135.0, 62.1, 50.6, 42.1, 29.4, 25.2, 11.3; HRMS (ESI) [M + Na]+ calcd for C9H15NO2Na 192.0995, found 192.0997; IR (CHCl3) νmax 3423, 1659 cm–1.

4-(3-Methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanal (5a)

To a solution of alcohol (4a, 400 mg, 2.36 mmol) in dry DCM (10 mL) was added PCC on Celite (0.66 g, 3.07 mmol) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred for 2 h allowing to reach room temperature. The reaction mixture was diluted with DCM and filtered through Celite using sintered funnel. The residue was washed with DCM, and the filtrate was concentrated in vacuo. The obtained product was purified by using column chromatography (silica gel, 230–400 mesh, MeOH/DCM, 1:9) to furnish pure aldehyde 5a as a colorless liquid (302 mg, 76% yield). 1H NMR (CDCl3, 200 MHz) δ 9.78 (s, 1H), 6.68 (q, J = 1.6 Hz, 1H), 3.84 (t, J = 1.9 Hz, 2H), 3.50 (t, J = 6.9 Hz, 2H), 2.53 (t, J = 7.2 Hz, 2H), 2.00–1.80 (m, 5H); 13C NMR (CDCl3, 50 MHz) δ 201.5, 172.3, 135.7, 135.1, 50.6, 41.7, 41.1, 21.1, 11.3; HRMS (ESI) [M + H]+ calcd for C9H14NO2 168.1019, found 168.1019; IR (CHCl3) νmax 2856, 1714, 1665 cm–1.

2-Methyl-6,7-dihydroindolizin-3(5H)-one (Pandalizine A, 7a)

To a stirred solution of aldehyde (5a, 200 mg, 1.20 mmol) in dry toluene (8 mL) was added p-TSA (617 mg, 3.59 mmol) under a nitrogen atmosphere, and the reaction mixture was heated at 60 °C for 1 h. The reaction mixture was concentrated in vacuo upon reaching room temperature. The obtained residue was dissolved in EtOAc. The organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated in vacuo, and the product was purified by column chromatography (silica gel, 230–400 mesh, MeOH/DCM, 1:9) to get pure product 7a as a yellow liquid (112 mg, 63% yield). 1H NMR (CDCl3, 200 MHz) δ 6.56 (q, J = 1.6 Hz, 1H), 5.43 (t, J = 4.7 Hz, 1H), 3.63 (dd, J = 6.4 and 5.9 Hz, 2H), 2.32 (q, J = 5.6 Hz, 2H), 1.96 (d, J = 0.9 Hz, 3H), 1.90 (quintet, J = 5.9 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 169.4, 137.9, 133.9, 127.8, 110.1, 37.9, 22.7, 21.6, 10.9; HRMS (ESI) [M + H]+ calcd for C9H12NO 150.0913, found 150.0913. IR (CHCl3) νmax 1656 cm–1.

1-(4-Hydroxybutyl)-3,4-dimethyl-1H-pyrrole-2,5-dione (2b)

To a solution of 4-aminobutanol (0.71 g, 7.93 mmol) in toluene (20 mL) was added dimethylmaleic anhydride (1b, 1.0 g, 7.93 mmol), and the stirring reaction mixture was refluxed for 4 h. After reaching room temperature, the reaction mixture was concentrated in vacuo. The obtained product was dissolved in EtOAc. The organic layer was washed with 10% aqueous NaHCO3 and brine and dried over Na2SO4. The organic layer was concentrated in vacuo, and column chromatographic purification of the formed residue (silica gel, 60–120 mesh, EtOAc–PE, 4:6) gave pure product 2b as a colorless liquid (1.45 g, 93% yield). 1H NMR (CDCl3, 500 MHz) δ 3.60 (t, J = 7.6 Hz, 2H), 3.47 (t, J = 8.6 Hz, 2H), 2.34 (br s, 1H), 1.91 (s, 6H), 1.65–1.57 (m, 2H), 1.54–1.46 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 172.3, 137.0, 62.0, 37.5, 29.5, 25.0, 8.5; HRMS (ESI) [M + H]+ calcd for C10H16NO3 198.1125, found 198.1121; IR (CHCl3) νmax 3451, 1768, 1703 cm–1.

5-Hydroxy-1-(4-hydroxybutyl)-3,4-dimethyl-1,5-dihydro-2H-pyrrol-2-one (3b)

To a solution of imide (2b, 1.0 g, 6.08 mmol) in MeOH (20 mL) was added CeCl3·7H2O (2.26 g, 6.08 mmol) at 0 °C, and the reaction mixture was stirred for 5 min. To the above reaction mixture was added NaBH4 (231 mg, 6.08 mmol), and it was further stirred for 1 h. The formed reaction mixture was concentrated in vacuo, and the product was diluted with EtOAc. The organic layer was washed with saturated aqueous NH4Cl and brine and dried over Na2SO4. The concentration of the organic layer in vacuo provided the crude product, and its column chromatographic purification (silica gel, 60–120 mesh, EtOAc–PE, 9:1) furnished pure compound 3b as a colorless liquid (876 mg, 87% yield). 1H NMR (CDCl3, 500 MHz) δ 5.70–5.25 (br s, 1H), 5.03 (s, 1H), 4.25–3.85 (br s, 1H), 3.62–3.50 (m, 2H), 3.47–3.35 (m, 1H), 3.35–3.22 (m, 1H), 1.90 (s, 3H), 1.70 (s, 3H), 1.65–1.45 (m, 4H); 13C NMR (CDCl3, 125 MHz) δ 171.5, 149.0, 128.5, 84.0, 61.7, 39.3, 29.5, 25.1, 11.1, 8.3; HRMS (ESI) [M + H]+ calcd for C10H18NO3 200.1281, found 200.1277; IR (CHCl3) νmax 3419, 1664 cm–1.

1-(4-Hydroxybutyl)-3,4-dimethyl-1,5-dihydro-2H-pyrrol-2-one (4b)

To a solution of compound 3b (500 mg, 2.51 mmol) in dry DCM (15 mL) were added BF3·OEt2 (1.44 mL, 5.02 mmol) and Et3SiH (0.59 mL, 5.02 mmol) dropwise at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred for 4 h, and after reaching room temperature, it was concentrated in vacuo. The obtained residue was dissolved in EtOAc. The obtained organic layer was washed with 10% aqueous NaHCO3 and brine and dried over Na2SO4. The concentration of the organic layer in vacuo and column chromatographic purification of the residue (silica gel, 230–400 mesh, MeOH/DCM, 2:8) furnished pure product 4b as a colorless liquid (357 mg, 78% yield). 1H NMR (CDCl3, 500 MHz) δ 3.70 (s, 2H), 3.63–3.58 (m, 2H), 3.45–3.39 (m, 2H), 3.39–3.10 (br s, 1H), 1.91 (s, 3H), 1.73 (s, 3H), 1.66–1.56 (m, 2H), 1.55–1.46 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 172.9, 145.5, 128.6, 61.9, 54.1, 41.7, 29.4, 25.1, 12.8, 8.5; HRMS (ESI) [M + H]+ calcd for C10H18NO2 184.1332, found 184.1329; IR (CHCl3) νmax 3413, 1662 cm–1.

4-(3,4-Dimethyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanal (5b)

To a solution of alcohol 4b (200 mg, 1.09 mmol) in dry DCM (10 mL) was added PCC on Celite (706 mg, 3.28 mmol) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred for 2 h and allowed to reach room temperature. The reaction mixture after diluting with DCM was filtered through Celite using a sintered funnel. The residue was washed with DCM, and the filtrate was concentrated in vacuo. Column chromatographic purification of the obtained residue (silica gel, 230–400 mesh, MeOH/DCM, 1:9) furnished pure aldehyde 5b as a colorless liquid (141 mg, 71% yield). 1H NMR (CDCl3, 400 MHz) δ 9.76 (s, 1H), 3.72 (s, 2H), 3.46 (t, J = 6.9 Hz, 2H), 2.51 (t, J = 7.6 Hz, 2H), 1.96 (s, 3H), 1.89 (quintet, J = 7.6 Hz, 2H), 1.78 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 201.6, 173.0, 145.7, 128.7, 54.1, 41.3, 41.1, 21.1, 12.9, 8.6; HRMS (ESI) [M + H]+ calcd for C10H16NO2 182.1176, found 182.1174; IR (CHCl3) νmax 3433, 1707, 1665 cm–1.

(E)-6-(3,4-Dimethyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)-2-[2-(3,4-dimethyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl]hex-2-enal (7b)

To a solution of aldehyde 5b (100 mg, 0.55 mmol) in dry toluene (10 mL) was added p-TSA (283 mg, 1.65 mmol) under a nitrogen atmosphere, and the reaction mixture was stirred for 2 h. The reaction mixture was concentrated in vacuo, and the obtained product was dissolved in EtOAc. The organic layer was washed with brine and dried over Na2SO4. The dried organic layer was concentrated in vacuo, and the obtained product was purified by column chromatography (silica gel, 230–400 mesh, MeOH/DCM, 1:9) to furnish pure aldol product 7b as a colorless liquid (61 mg, 64% yield). 1H NMR (CDCl3, 500 MHz) δ 9.36 (s, 1H), 6.61 (t, J = 9.6 Hz, 1H), 3.77 (d, J = 4.8 Hz, 4H), 3.50 (t, J = 8.6 Hz, 2H), 3.42 (t, J = 8.6 Hz, 2H), 2.52 (t, J = 9.6 Hz, 2H), 2.44 (q, J = 9.6 Hz, 2H), 1.97 (s, 3H), 1.95 (s, 3H), 1.85–1.70 (m, 2H), 1.81 (s, 3H), 1.76 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 194.8, 172.9, 172.8, 156.1, 146.0, 145.7, 140.7, 128.8, 128.5, 54.6, 54.3, 41.5, 40.9, 27.7, 26.3, 23.3, 13.0 (2C), 8.7, 8.6; HRMS (ESI) [M + H]+ calcd for C20H29N2O3 345.2173, found 345.2167; IR (CHCl3) νmax 1701, 1659 cm–1.

Acknowledgments

M.B.Y. thanks UGC, New Delhi, for the award of research fellowship (19/06/2016(i)-EU-V). K.R.P. thanks CSIR, New Delhi, for the award of research fellowship (31/011/(0945)/2016-EMR-I). N.P.A. thanks Science and Engineering Research Board (SERB), New Delhi, for financial support (SB/S1/OC-01/2013).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.9b03760.

  • 1H NMR and 13C NMR spectra of all of the synthesized compounds (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao9b03760_si_001.pdf (1.7MB, pdf)

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