Skip to main content
SpringerLink
Log in

Parallel synthesis of natural product-like polyhydroxylated pyrrolidine and piperidine alkaloids

  • Full-length paper
  • Published:
Molecular Diversity Aims and scope Submit manuscript

Abstract

The preparation of natural product-like polyhydroxylated pyrrolidine and piperidine alkaloids using a combination of solid– and solution-phase organic synthesis is described. The key intermediates, enantiopure five- or six-membered tri-O-benzyl cyclic nitrones, were efficiently prepared on solid support from accessible chiral furanosides and pyranosides, respectively. The substituent diversity was achieved by a diastereoselective addition of a variety of Grignard reagents to the cyclic nitrones in solution-phase synthesis. All reaction steps and work-up procedures were modified to allow the use of automated equipment. A 36-membered demonstration library with three diversity elements (core, configuration, and substituent) was prepared in good yield and purity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Dolle RE, Le Bourdonnec B, Goodman AJ, Morales GA, Thomas CJ, Zhang W (2009) Comprehensive survey of chemical libraries for drug discovery and chemical biology: 2008. J Comb Chem 11: 739–790. doi:10.1021/cc9000828

    Article  PubMed  CAS  Google Scholar 

  2. Nandy JP, Prakesch M, Khadem S, Reddy PT, Sharma U, Arya P (2009) Advances in solution- and solid-phase synthesis toward the generation of natural product-like libraries. Chem Rev 109: 1999–2060. doi:10.1021/cr800188v

    Article  PubMed  CAS  Google Scholar 

  3. Zhang W (2003) Fluorous technologies for solution-phase high-throughput organic synthesis. Tetrahedron 59: 4475–4489. doi:10.1016/S0040-4020(03)00592-1

    Article  CAS  Google Scholar 

  4. Bookser BC, Zhu SR (2001) Solid phase extraction purification of carboxylic acid products from 96–well format solution phase synthesis with DOWEX 1x8–400 formate anion exchange resin. J Comb Chem 3: 205–215. doi:10.1021/cc000086s

    Article  PubMed  CAS  Google Scholar 

  5. Carpintero M, Cifuentes M, Ferritto R, Haro R, Toledo MA (2007) Automated liquid–liquid extraction workstation for library synthesis and its use in the parallel and chromatography–free synthesis of 2-alkyl-3-alkyl-4-(3H)-quinazolinones. J Comb Chem 9: 818–822. doi:10.1021/cc070051t

    Article  PubMed  CAS  Google Scholar 

  6. Dondoni A, Massi A (2006) Design and synthesis of new classes of heterocyclic C-glycoconjugates and carbon-linked sugar and heterocyclic amino acids by asymmetric multicomponent reactions (AMCRs). Acc Chem Res 39: 451–463. doi:10.1021/ar068023r

    Article  PubMed  CAS  Google Scholar 

  7. Reader JC (2004) Automation in medicinal chemistry. Curr Top Med Chem 4: 671–686. doi:10.2174/1568026043451069

    Article  PubMed  CAS  Google Scholar 

  8. Brunsveld L, Watzke A, Durek T, Alexandrov K, Goody RS, Waldmann H (2005) Synthesis of functionalized Rab GTPases by a combination of solution- or solid-phase lipopeptide synthe- sis with expressed protein ligation. Chem Eur J 11: 2756–2772. doi:10.1002/chem.200401041

    Article  CAS  Google Scholar 

  9. Bleicher KH, Wuthrich Y, Adam G, Hoffmann T, Sleight AJ (2002) Parallel solution- and solid-phase synthesis of spiropyrrolo–pyrroles as novel neurokinin receptor ligands. Bioorg Med Chem Lett 12: 3073–3076. doi:10.1016/S0960-894X(02)00659-5

    Article  PubMed  CAS  Google Scholar 

  10. Watson AA, Fleet GWJ, Asano N, Molyneux RJ, Nash RJ (2001) Polyhydroxylated alkaloids—natural occurrence and therapeutic applications. Phytochemistry 56: 265–295. doi:10.1016/S0031-9422(00)00451-9

    Article  PubMed  CAS  Google Scholar 

  11. O’Hagan D (2000) Pyrrole, pyrrolidine, pyridine, piperidine and tropane alkaloids. Nat Prod Rep 17: 435–446. doi:10.1039/a707613d

    Article  PubMed  Google Scholar 

  12. Kato A, Kato N, Kano E, Adachi I, Ikeda K, Yu L, Okamoto T, Banba Y, Ouchi H, Takahata H, Asano N (2005) Biological properties of d- and l-1-deoxyazasugars. J Med Chem 48: 2036–2044. doi:10.1021/jm0495881

    Article  PubMed  CAS  Google Scholar 

  13. Shibano M, Tsukamoto D, Masuda A, Tanaka Y, Kusano G (2001) Two new pyrrolidine alkaloids, radicamines A and B, as inhibitors of alpha-glucosidase from Lobelia chinensis Lour. Chem Pharm Bull 49: 1362–1365. doi:10.1248/cpb.49.1362

    Article  PubMed  CAS  Google Scholar 

  14. Shibano M, Tsukamoto D, Kusano G (2002) Polyhydroxylated alkaloids with lipophilic moieties as glycosidase inhibitors from higher plants. Heterocycles 57: 1539–1553. doi:10.3987/REV-02-551

    Article  CAS  Google Scholar 

  15. Stütz AE (1999) Iminosugars as glycosidase inhibitors. Wiley-VCH, Weinheim, pp 8–11. doi:10.1002/3527601740

    Google Scholar 

  16. Compain P, Martin OR (2003) Design, synthesis and biological evaluation of iminosugar-based glycosyltransferase inhibitors. Curr Top Med Chem 3: 541–560. doi:10.2174/1568026033452474

    Article  PubMed  CAS  Google Scholar 

  17. Meutermans W, Le GT, Becker B (2006) Carbohydrates as scaffolds in drug discovery. Chem Med Chem 1: 1164–1194. doi:10.1002/cmdc.200600150

    PubMed  CAS  Google Scholar 

  18. Shih HW, Cheng WC (2008) Solution-phase parallel synthesis of highly diverse spiroisoxazolinohydantoins. Tetrahedron Lett 49: 1008–1011. doi:10.1016/j.tetlet.2007.12.008

    Article  CAS  Google Scholar 

  19. Huang CM, Liu RS, Wu TS, Cheng WC (2008) Structural establishment of polygalatenosides A and B by total synthesis. Tetrahedron Lett 49: 2895–2898. doi:10.1016/j.tetlet.2008.03.032

    Article  CAS  Google Scholar 

  20. Cheng TJR, Sung MT, Liao HY, Chang YF, Chen CW, Huang CY, Chou LY, Wu YD, Chen Y, Cheng YSE, Wong CH, Ma C, Cheng WC (2008) Domain requirement of moenomycin binding to bifunctional transglycosylases and development of high-throughput discovery of antibiotics. Proc Natl Acad Sci USA 105: 431–436. doi:10.1073/pnas.0710868105

    Article  PubMed  CAS  Google Scholar 

  21. Chang YF, Jiang YR, Cheng WC (2008) Traceless sulfone linker cleavage triggered by ozonolysis: solid-phase synthesis of diverse alpha-beta-unsaturated carbonyl compounds. Tetrahedron Lett 49: 543–547. doi:10.1016/j.tetlet.2007.11.064

    Article  CAS  Google Scholar 

  22. Chang YF, Liu CY, Guo CW, Wang YC, Fang JM, Cheng WC (2008) Solid-phase organic synthesis of polyisoprenoid alcohols with traceless sulfone linker. J Org Chem 73: 7197–7203. doi:10.1021/jo8010182

    Article  PubMed  CAS  Google Scholar 

  23. Tsou EL, Chen SY, Yang MH, Wang SC, Cheng TRR, Cheng WC (2008) Synthesis and biological evaluation of a 2-aryl polyhydroxylated pyrrolidine alkaloid-based library. Bioorg Med Chem 16: 10198–10204. doi:10.1016/j.bmc.2008.10.063

    Article  PubMed  CAS  Google Scholar 

  24. Tsou EL, Yeh YT, Liang PH, Cheng WC (2009) A convenient approach toward the synthesis of enantiopure isomers of DMDP and ADMDP. Tetrahedron 65: 93–100. doi:10.1016/j.tet.2008.10.096

    Article  CAS  Google Scholar 

  25. Holzapfel CW, Crous R (1998) Synthesis and reactions of chiral cyclic nitrones derived from d-ribose. Heterocycles 48: 1337–1342. doi:10.3987/COM-98-8166

    Article  CAS  Google Scholar 

  26. Marradi M, Cicchi S, Delso JI, Rosi L, Tejero T, Merino P, Goti A (2005) Straightforward synthesis of enantiopure 2-aminomethyl and 2-hydroxymethyl pyrrolidines with complete stereocontrol. Tetrahedron Lett 46: 1287–1290. doi:10.1016/j.tetlet.2004.12.119

    Article  CAS  Google Scholar 

  27. Desvergnes S, Py S, Vallee Y (2005) Total synthesis of (+)–hyacinthacine A(2) based on SmI2-induced nitrone umpolung. J Org Chem 70: 1459–1462. doi:10.1021/jo048237r

    Article  PubMed  CAS  Google Scholar 

  28. Peer A, Vasella A (1999) Synthesis of an l-fucose-derived cyclic nitrone and its conversion to alpha-l-fucosidase inhibitors. Helv Chim Acta 82: 1044–1065. doi:10.1002/(SICI)1522-2675(19990707)82:7<1044::AID-HLCA1044>3.0.CO;2-3

    Article  CAS  Google Scholar 

  29. Racine E, Bello C, Gerber-Lemaire S, Vogel P, Py S (2009) A short and convenient synthesis of 1-deoxymannojirimycin and N-oxy analogues from d-fructose. J Org Chem 74: 1766–1769. doi:10.1021/jo802255t

    Article  PubMed  CAS  Google Scholar 

  30. Shih HW, Guo CW, Lo KH, Huang MY, Cheng WC (2009) Solution-phase parallel synthesis of novel spirooxazolinoisoxazolines. J Comb Chem 11: 281–287. doi:10.1021/cc800158t

    Article  PubMed  CAS  Google Scholar 

  31. Tallarico JA, Depew KM, Pelish HE, Westwood NJ, Lindsley CW, Shair MD, Schreiber SL, Foley MA (2001) An alkylsilyl-tethered, high-capacity solid support amenable to diversity-oriented synthesis for one-bead, one-stock solution chemical genetics. J Comb Chem 3: 312–318. doi:10.1021/cc000107i

    Article  PubMed  CAS  Google Scholar 

  32. Custar DW, Zabawa TP, Hines J, Crews CM, Scheidt KA (2009) Total synthesis and structure-activity investigation of the marine natural product neopeltolide. J Am Chem Soc 131: 12406–12414. doi:10.1021/ja904604x

    Article  PubMed  CAS  Google Scholar 

  33. Yu CY, Huang MH (2006) Radicamines A and B: synthesis and revision of the absolute configuration. Org Lett 8: 3021–3024. doi:10.1021/ol0609210

    Article  PubMed  CAS  Google Scholar 

  34. Merino P, Delso I, Tejero T, Cardona F, Marradi M, Faggi E, Parmeggiani C, Goti A (2008) Nucleophilic additions to cyclic nitrones en route to iminocyclitols-Total syntheses of DMDP, 6-deoxy-DMDP, DAB-1, CYB-3, nectrisine, and radicamine B. Eur J Org Chem:2929–2947. doi:10.1002/ejoc.200800098

  35. Gurjar MK, Borhade RG, Puranik VG, Ramana CV (2006) Total synthesis of (–)–radicamine B. Tetrahedron Lett 47: 6979–6981. doi:10.1016/j.tetlet.2006.07.120

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Genomics Research Center, Academia Sinica, No. 128, Academia Road Sec. 2, Nankang District, Taipei, 11529, Taiwan, ROC

    Yi-Fan Chang, Chih-Wei Guo, Ting-Hao Chan, Yi-Wen Pan, En-Lun Tsou & Wei-Chieh Cheng

Authors
  1. Yi-Fan Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chih-Wei Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ting-Hao Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yi-Wen Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. En-Lun Tsou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wei-Chieh Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wei-Chieh Cheng.

Electronic Supplementary Material

Below is the Electronic Supplementary Material.

ESM 1 (DOC 2.81 mb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chang, YF., Guo, CW., Chan, TH. et al. Parallel synthesis of natural product-like polyhydroxylated pyrrolidine and piperidine alkaloids. Mol Divers 15, 203–214 (2011). https://doi.org/10.1007/s11030-010-9255-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11030-010-9255-4

Keywords

Search

Navigation