Recent advances on the synthesis of natural pyrrolizidine alkaloids: alexine, and its stereoisomers

doi:10.1007/s13659-022-00324-5

Abstract

Abstract: Natural products have attracted the interest of the scientific community due to their importance and application. Alexine is a naturally polyhydroxylated pyrrolizidine alkaloid that is broadly found in plant sources and isolated from Alexa leiopetala. The biological properties such as glycosidase inhibitors, anti-virus, and anti-HIV activities, makes it interesting target for synthetical studies. This review reports different approaches and methodologies to the synthesis of alexine, and its stereoisomers as the target compounds in numerous studies.

Key words: Polyhydroxylated pyrrolizidine alkaloids, Alexine, Natural products, Alexa leiopetala

摘要： Natural products have attracted the interest of the scientific community due to their importance and application. Alexine is a naturally polyhydroxylated pyrrolizidine alkaloid that is broadly found in plant sources and isolated from Alexa leiopetala. The biological properties such as glycosidase inhibitors, anti-virus, and anti-HIV activities, makes it interesting target for synthetical studies. This review reports different approaches and methodologies to the synthesis of alexine, and its stereoisomers as the target compounds in numerous studies.

关键词: Polyhydroxylated pyrrolizidine alkaloids, Alexine, Natural products, Alexa leiopetala

Ghodsi Mohammadi Ziarani, Negar Jamasbi, Fatemeh Mohajer. Recent advances on the synthesis of natural pyrrolizidine alkaloids: alexine, and its stereoisomers[J]. Natural Products and Bioprospecting, 2022, 12(1): 1-15.

Ghodsi Mohammadi Ziarani, Negar Jamasbi, Fatemeh Mohajer. Recent advances on the synthesis of natural pyrrolizidine alkaloids: alexine, and its stereoisomers[J]. 应用天然产物, 2022, 12(1): 1-15.

References

1. Smith LW, Culvenor CC. Plant sources of hepatotoxic pyrrolizidine alkaloids. J Nat Prod. 1981;44:129-52.
2. Hartmann T, Witte L. Chemistry, biology and chemoecology of the pyrrolizidine alkaloids. In:Pelletier SW, editor. Alkaloids:chemical and biological perspectives, vol. 9. Oxford:Pergamon; 1995. p. 155-233.
3. Nash RJ, Fellows LE, Plant AC, Fleet GWJ, Derome AE, Baird PD, Hegarty MP, Scofield AM. Isolation from castanospermum australe and x-ray crystal structure of 3,8-diepialexine, (1r, 2r, 3s, 7s, 8r)-3-hydroxymethyl-1,2,7-trihydroxypyrrolizidine[(2s, 3r, 4r, 5s, 6r)-2-hydroxymethyl-1-azabicyclo[3.3.0]octan-3,4,6-triol]. Tetrahedron. 1988;44:5959-64.
4. Nash RJ, Fellows LE, Dring JV, Fleet GWJ, Girdhar A, Ramsden NG, Peach JM, Hegarty MP, Scofield AM. Two alexines[3-hydroxymethyl-1,2,7-trihydroxypyrrolizidines] from Castanospermum australe. Phytochemistry. 1990;29:111-4.
5. Nash RJ, Fellows LE, Dring JV, Fleet GWJ, Derome AE, Hamor TA, Scofield AM, Watkin DJ. Isolation from alexa leiopetala and x-ray crystal structure of alexine, (1r, 2r, 3r, 7s, 8s)-3-hydroxymethyl-1,2,7-trihydroxypyrrolizidine[(2r, 3r, 4r, 5r, 6s)-2-hydroxymethyl-1 azabicyclo[3.3.0]octan-3,4,6-triol], a unique pyrrolizidine alkaloid. Tetrahedron Lett. 1988;29:2487-90.
6. Jones L, Hollinshead J, Fleet GW, Thompson AL, Watkin DJ, Gal ZA, Jenkinson SF, Kato A, Nash RJ. Isolation of the pyrrolizidine alkaloid 1-epialexine from Castanospermum australe. Phytochem Lett. 2010;3:133-5.
7. Tropea JE, Molyneux RJ, Kaushal G, Pan Y, Mitchell M, Elbein AD. Australine, a pyrrolizidine alkaloid that inhibits amyloglucosidase and glycoprotein processing. Biochemistry. 1989;28:2027-34.
8. Kato A, Kano E, Adachi I, Molyneux RJ, Watson AA, Nash RJ, Fleet GWJ, Wormald MR, Kizu H, Ikeda K, Asano N. Australine and related alkaloids:easy structural confirmation by ¹³CNMR spectral data and biological activities. Tetrahedron Asymmetry. 2003;14:325-31.
9. Taylor D, Nash R, Fellows L, Kang M, Tyms A. Naturally occurring pyrrolizidines:inhibition of α-glucosidase 1 and anti-HIV activity of one stereoisomer. Antivir Chem Chemother. 1992;3:273-7.
10. Asano N, Ikeda K, Kasahara M, Arai Y, Kizu H. Glycosidase-inhibiting pyrrolidines and pyrrolizidines with a long side chain in Scilla peruviana. J Nat Prod. 2004;67:846-50.
11. Pyne SG, Tang M. The structure, biological activities and synthesis of 3-hydroxylpyrrolizidine alkaloids and related compounds. Curr Org Chem. 2005;9:1393-418.
12. Robertson J, Stevens K. Pyrrolizidine alkaloids:occurrence, biology, and chemical synthesis. Nat Prod Rep. 2017;34:62-89.
13. Mohammadi Ziarani G, Mohajer F, Moradi R, Mofatehnia P. The molecular diversity scope of urazole in the synthesis of organic compounds. Curr Org Synth. 2019;16:953-67.
14. Mohammadi Ziarani G, Mohajer F, Kheilkordi Z. Recent progress towards synthesis of the Indolizidine alkaloid 195B. Curr Org Synth. 2020;17:82-90.
15. Mohajer F, Mohammadi Ziarani G, Moradi R. The study of several synthesis methods of Indolizidine (±)-209I and (±)-209B as natural alkaloids. Curr Org Chem. 2020;24:516-35.
16. Mohammadi Ziarani G, Mohajer F, Jamali SM, Ebrahim NA. Quantitative and qualitative bibliometric scope toward the synthesis of rose oxide as a natural product in perfumery. Curr Org Synth. 2020;17:610-24.
17. Mohajer F, Mohammadi Ziarani G, Taghipour F. The multi steps synthetic methods of (±)-Indolizidine 209D as an amphibian natural product in the family of alkaloids. Nat Prod J. 2020;11:448-62.
18. Mohammadi Ziarani G, Chênevert R, Badiei A. Chemoenzymatic enantioselective formal synthesis of (-)-gephyrotoxin-223. Iran J Chem Chem Eng. 2006;25:31-8.
19. Chênevert R, Mohammadi Ziarani G, Morin MP, Dasser M. Enzymatic desymmetrization of meso cis-2, 6-and cis, cis-2, 4, 6-substituted piperidines. Chemoenzymatic synthesis of (5S, 9S)-(+)-indolizidine 209D. Tetrahedron Asymmetry. 1999;10:3117-22.
20. Chênevert R, Mohammadi Ziarani G, Dasser M. Chemoenzymatic enantoselective synthesis of (-)-Indolizidine 167 B. Heterocycles. 1999;51:593-8.
21. Chênevert R, Mohammadi Ziarani G, Caron D, Dasser M. Chemoenzymatic enantioselective synthesis of (-)-enterolactone. Can J Chem. 1999;77:223-6.
22. Fleet GW, Haraldsson M, Nash RJ, Fellows LE. Synthesis from d-glucose of alexine[(1R, 2R, 3R, 7S, 8S)-3-hydroxymethyl-1,2,7-trihydroxypyrrolizidine], 3-epialexine and 7-epialexine. Tetrahedron Lett. 1988;29:5441-4.
23. Fleet GW, Smith PW. Methyl 2-azido-3-O-benzyl-2-deoxy-α-dmamnofuranoside as a divergent intermediate for the synthesis of polyhydroxylated piperidines and pyrrolidines:synthesis of 2,5-dideoxy-2,5-imino-d-mannitol[2R,5R-dihydroxymethyl-3R,4R-dihydroxypyrrolidine]. Tetrahedron. 1987;43:971-8.
24. Mancuso AJ, Huang SL, Swern D. Oxidation of long-chain and related alcohols to carbonyls by dimethyl sulfoxide "activated" by oxalyl chloride. J Org Chem. 1978;12:2480-2.
25. Choi S, Bruce I, Fairbanks A, Fleet G, Jones A, Nash R, Fellows L. Alexines from heptonolactones. Tetrahedron Lett. 1991;32:5517-20.
26. Beacham AR, Bruce I, Choi S, Doherty O, Fairbanks AJ, Fleet GW, Skead BM, Peach JM, Saunders J, Walking DJ. Acetonides of heptonolactones:powerful chirons. Tetrahedron Asymmetry. 1991;2:883-900.
27. Ikota N, Hanaki A. Synthesis of (2S, 3S, 4S)-4-amino-2, 3-dihydroxyhexanedioic acid derivatives from (R)-pyroglutamic acid. Chem Pharm Bull. 1989;37:1087-9.
28. Ikota N, Hanaki A. Synthesis of (-)-Swainsonine and optically active 3,4-dihydroxy-2-hydroxymethylpyrrolidines. Chem Pharm Bull. 1987;35:2140-3.
29. Ikota N. Synthesis of (2R, 3R, 4R, 5R)-3,4-dihydroxy-2,5-dihydroxymethylpyrrolidine and (-)-anisomycin derivative from (S)-pyroglutamic acid derivative. Heterocycles. 1995;5:983-94.
30. Ikota N. Stereocontrolled synthesis of 1,7a-diepialexine. Tetrahedron Lett. 1992;33:2553-6.
31. Ikota N, Nakagawa H, Ohno S, Noguchi K, Okuyama K. Stereoselective synthesis of alexine stereoisomers from (S)-pyroglutamic acid. Tetrahedron. 1998;54:8985-98.
32. Yoda H, Katoh H, Takabe K. Asymmetric total synthesis of natural pyrrolizidine alkaloid,(+)-alexine. Tetrahedron Lett. 2000;41:7661-5.
33. Takahashi M, Maehara T, Sengoku T, Fujita N, Takabe K, Yoda H. New asymmetric strategy for the total synthesis of naturally occurring (+)-alexine and (-)-7-epi-alexine. Tetrahedron. 2008;64:5254-61.
34. Kawana M, Kuzuhara H, Emoto S. The use of Grignard reagents in the synthesis of carbohydrates. III. The one-way anomerization of methyl glycofuranosides and the opening of their furanose rings. Bull Chem Soc Jpn. 1981;54:1492-504.
35. Cram DJ, Elhafez FAA. Studies in stereochemistry. X. The rule of "Steric control of asymmetric induction" in the syntheses of acyclic systems. J Am Chem Soc. 1952;74:5828-35.
36. Luche JL. Lanthanides in organic chemistry. 1. Selective 1,2 reductions of conjugated ketones. J Am Chem Soc. 1978;100:2226-7.
37. Pearson WH, Hines JV. A synthesis of (+)-7-epiaustraline and (-)-7-epialexine. Tetrahedron lett. 1991;32:5513-6.
38. Pearson WH, Hines JV. Total syntheses of (+)-australine and (-)-7-epialexine. J Org Chem. 2000;65:5785-93.
39. MacCoss M, Chen A, Tolman RL. Syntheses of all four possible diastereomers of the acyclonucleoside 9-(1,3,4-trihydroxy-2-butoxymethyl) guanine from carbohydrate precursors. Tetrahedron Lett. 1985;26:4287-90.
40. Romero A, Wong C-H. Chemo-enzymatic total synthesis of 3-epiaustraline, australine, and 7-epialexine. J Org Chem. 2000;65:8264-8.
41. Donohoe TJ, Cheeseman MD, O'Riordan TJC, Kershaw JA. Synthesis of (+)-DGDP and (-)-7-epialexine. Org Biomol Chem. 2008;6:3896-8.
42. Donohoe TJ, Thomas RE, Cheeseman MD, Rigby CL, Bhalay G, Linney ID. Flexible strategy for the synthesis of pyrrolizidine alkaloids. Org Lett. 2008;10:3615-8.
43. Chikkanna D, Singh OV, Kong SB, Han H. A general asymmetric route for the synthesis of the alexine and australine family of pyrrolizidine alkaloids. The first asymmetric synthesis of 1,2-diepi-alexine and 1,2,7-triepi-australine. Tetrahedron Lett. 2005;46:8865-8.
44. Chatterjee AK, Choi T-L, Sanders DP, Grubbs RH. A general model for selectivity in olefin cross metathesis. J Am Chem Soc. 2003;125:11360-70.
45. Dressel M, Restorp P, Somfai P. Total synthesis of (+)-alexine by utilizing a highly stereoselective[3 + 2] annulation reaction of an N-tosyl-α-amino aldehyde and a 1,3-bis(silyl)propene. Chem A Eur J. 2008;14:3072-7.
46. Jurczak J, Gryko D, Kobrzycka E, Gruza H, Prokopowicz P. Effective and mild method for preparation of optically active α-amino aldehydes via TEMPO oxidation. Tetrahedron. 1998;54:6051-64.
47. Guijarro A, Yus M. 1,3-dichloropropene as a source of the 1,3-dianion derived from propene:synthesis of unsaturated 1,5-diols and dihydropyrans. Tetrahedron. 1994;50:13269-76.
48. Yu W, Mei Y, Kang Y, Hua Z, Jin Z. Improved procedure for the oxidative cleavage of olefins by OsO₄-NaIO₄. Org lett. 2004;6:3217-9.
49. Yu L, Somfai P. Enantioselective synthesis of anti-3-alkenyl-2-amido-3-hydroxy esters:application to the total synthesis of (+)-alexine. RSC Adv. 2019;9:2799-802.
50. Seashore-Ludlow B, Saint-Dizier F, Somfai P. Asymmetric transfer hydrogenation coupled with dynamic kinetic resolution in water:synthesis of anti-β-hydroxy-α-amino acid derivatives. Org Lett. 2012;14:6334-7.
51. Brock EA, Davies SG, Lee JA, Roberts PM, Thomson JE. Polyhydroxylated pyrrolizidine alkaloids from transannular iodoaminations:application to the asymmetric syntheses of (-)-hyacinthacine A1, (-)-7a-epi-hyacinthacine A1, (-)-hyacinthacine A2, and (-)-1-epi-alexine. Org Biomol Chem. 2013;11:3187-202.
52. Brock EA, Davies SG, Lee JA, Roberts PM, Thomson JE. Asymmetric synthesis of polyhydroxylated pyrrolizidines via transannular iodoamination with concomitant N-debenzylation. Org Lett. 2011;13:1594-7.
53. Myeong I-S, Jung C, Ham W-H. Total syntheses of (-)-7-epi-alexine and (+)-alexine using stereoselective allylation. Synthesis. 2019;51:3471-6.
54. Myeong I-S, Jung C, Kim J-Y, Park S-H, Ham W-H. Asymmetric total syntheses of (+)-2,5-dideoxy-2,5-imino-d-glucitol[(+)-DGDP] and (-)-1-deoxymannojirimycin[(-)-DMJ] via an extended chiral 1,3-oxazine. Tetrahedron Lett. 2018;59:2422-5.

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