Molecular Diversity

, Volume 14, Issue 3, pp 479–491 | Cite as

One-pot multicomponent synthesis of two novel thiolactone scaffolds

  • B. Beck
  • S. Srivastava
  • K. Khoury
  • E. Herdtweck
  • Alexander DömlingEmail author
Full-length paper


We designed two novel thiolactone scaffolds. Both scaffolds can be accessed by a convergent Ugi multicomponent reaction (MCR) and are, thus, amenable to library synthesis. Design, stereoselectivity, structures, full experimental details, and virtual libraries will be reported.


Multicomponent reaction (MCR) Isocyanide Thiolactone Virtual library 



Multicomponent reaction


Homocysteine thiolactone-induced protein modification


Homocysteine thiolactone


Ugi–deprotection–cyclization sequences


Isocyanide based MCR


Food and drug administration


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Supplementary material

11030_2010_9249_MOESM1_ESM.pdf (6.5 mb)
ESM 1 (PDF 6,666 kb)


  1. 1.
    Sasaki H, Oishi H, Hayashi T, Matsuura I, Ando K, Sawada M (1982) Thiolactomycin, a new antibiotic. II. Structure elucidation. J Antibiot (Tokyo) 35: 396–400Google Scholar
  2. 2.
    Dal Negro RW, Visconti M, Micheletto C, Tognella S (2008) Changes in blood ROS, e-NO, and some pro-inflammatory mediators in bronchial secretions following erdosteine or placebo: a controlled study in current smokers with mild COPD. Pulm Pharmacol Ther 21:304–308. doi: S1094-5539(07)00069-7. [pii] doi: 10.1016/j.pupt.2007.07.004 Google Scholar
  3. 3.
    Farid NA, Smith RL, Gillespie TA, Rash TJ, Blair PE, Kurihara A, Goldberg MJ (2007) The disposition of prasugrel, a novel thienopyridine, in humans. Drug Metab Dispos 35: 1096–1104. doi: 10.1124/dmd.106.014522 CrossRefPubMedGoogle Scholar
  4. 4.
    Chen L, Lai WW, Nettekoven M, Roshe O, Zheng D (2008) 4,5,6,7-Tetrahydro-theino[3,2-C] pyradine derivatives as H3 modulators. PCT Int Appl, WO 2008068173Google Scholar
  5. 5.
    Townsend C, Kuhajda F, Subburaj K, Sturdivant JM (2008) Novel compounds, pharmaceutical compositions containing same and methods of use for same. WO2008057585Google Scholar
  6. 6.
    Toohey JI (2007) Mercaptopropionaldehyde from homocysteine: implications for Alzheimer’s disease. J Alzheimers Dis 12: 241–243PubMedGoogle Scholar
  7. 7.
    Miller WH, Pearson ND, Pendrak I, Seefeld MA (2003) Preparation of aminopiperidine derivatives for treatment of bacterial infections. PCT Int Appl, WO 2003064421Google Scholar
  8. 8.
    Abbas S, Ferris L, Norton AK, Powell L, Robinson GE, Siedlecki P, Southworth RJ, Stark A, Williams EG (2008) Application of an enantiomerically pure bicyclic thiolactone in the synthesis of a farnesyl transferase inhibitor. Org Process Res Dev 12: 202–212. doi: 10.1021/op700218j CrossRefGoogle Scholar
  9. 9.
    Cawthorne L, Dodd K, Tindal A (2007) Personal care article comprising hair modification actives, such as sulfur compounds. CODEN: PIXXD2, WO 2007128983Google Scholar
  10. 10.
    Stryer L (1988) Biochemistry. W.H. Freeman and Company, New YorkGoogle Scholar
  11. 11.
    Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D’Agostino RB, Wilson PW, Wolf PA (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 346:476–483. doi: 10.1056/NEJMoa011613346/7/476 [pii]Google Scholar
  12. 12.
    Paryzek Z, Skiera I (2007) Synthesis and cleavage of lactones and thiolactones applications in organic synthesis. Org Prep Proced Int 39: 203–296CrossRefGoogle Scholar
  13. 13.
    Chhabra SR, Harty C, Hooi DS, Daykin M, Williams P, Telford G, Pritchard DI, Bycroft BW (2003) Synthetic analogues of the bacterial signal (quorum sensing) molecule N-(3-oxododecanoyl)-L-homoserine lactone as immune modulators. J Med Chem 46: 97–104. doi: 10.1021/jm020909n CrossRefPubMedGoogle Scholar
  14. 14.
    Grigg R, Sarker MAB (2006) UK XY-ZH compounds as potential 1,3-dipoles. Part 63: Silver catalysed azomethine ylide cycloaddition—the synthesis of spiro homoserine lactone analogues. Tetrahedron 62: 10332–10343. doi: 10.1016/j.tet.2006.08.077 CrossRefGoogle Scholar
  15. 15.
    Hanessian S, Moitessier N, Gauchet C, Viau M (2001) N-Aryl sulfonyl homocysteine hydroxamate inhibitors of matrix metalloproteinases: further probing of the S(1), S(1)′, and S(2)′ pockets. J Med Chem 44: 3066–3073. doi: 10.1021/jm010097f CrossRefPubMedGoogle Scholar
  16. 16.
    Seki M, Shimizu T, Inubushi K (2002) A novel synthesis of a key intermediate for (+)-biotin from l-aspartic acid. Synthesis 2002: 361–364. doi: 10.1055/s-2002-20035 CrossRefGoogle Scholar
  17. 17.
    Grigg R, Montgomery J, Somasunderam A (1992) X=Y-ZH systems as potential 13-dipoles. Part 39 Metallo-azomethine ylides from aliphatic aldimines Facile regio- and stereo-specific cycloaddition reactions. Tetrahedron 48: 10431–10442. doi: 10.1016/S0040-4020(01)88346-0 CrossRefGoogle Scholar
  18. 18.
    Lai C-H, Ko S, Dharma Rao P, Liao C-C (2001) Thiophenes act as dienophiles in novel cycloadditions with masked o-benzoquinones. Tetrahedron Lett 42: 7851–7854. doi: 10.1016/S0040-4039(01)01648-3 CrossRefGoogle Scholar
  19. 19.
    Schoberl A, Tauber G (1956) Über die Synthese der optisch aktiven Diastereomeren Cystathionin und Allocystathionin und über Methoden zu deren Trennung. Justus Liebigs Ann Chem 599: 23–37CrossRefGoogle Scholar
  20. 20.
    Saito T, Nihei H, Otani T, Suyama T, Furukawa N, Saito M (2008) Thiocarbonyl induced heterocumulenic Pauson–Khand type reaction: expedient synthetic method for thieno[2,3-b]indol-2-ones. Chem Commun (Camb):172–174. doi: 10.1039/b712739a
  21. 21.
    Zhu J, Bienayme H (2005) Multicomponent reactions. Wiley-VCH, WeinheimCrossRefGoogle Scholar
  22. 22.
    Domling A (2006) Recent developments in isocyanide based multicomponent reactions in applied chemistry. Chem Rev 106: 17–89. doi: 10.1021/cr0505728 CrossRefPubMedGoogle Scholar
  23. 23.
    Beck B, Srivastava S, Domling A (2007) New end-on thiolactone scaffold by an isocyanide-based multicomponent reaction. Heterocycles 73: 177–182. doi: 10.3987/COM-07-S(U)17 CrossRefGoogle Scholar
  24. 24.
    Szardenings AK, Burkoth TS, Lu HH, Tien DW, Campbell DA (1997) A simple procedure for the solid phase synthesis of diketopiperazine and diketomorpholine derivatives. Tetrahedron 53: 6573–6593. doi: 10.1016/S0040-4020(97)00218-4 CrossRefGoogle Scholar
  25. 25.
    Hulme C, Cherrier M-P (1999) Novel applications of ethyl glyoxalate with the Ugi MCR. Tetrahedron Lett 40: 5295–5299. doi: 10.1016/S0040-4039(99)00960-0 CrossRefGoogle Scholar
  26. 26.
    Marcaccini S, Pepino R, Polo C, Pozo MC (2001) Studies on isocyanides and related compounds; a facile synthesis of 4-phenyl-1-(2h)phthalazinone-2-alkanoic acid amides. Synthesis 2001: 85–89. doi: 10.1055/s-2001-9745 CrossRefGoogle Scholar
  27. 27.
    Beck B, Larbig G, Mejat B, Magnin-Lachaux M, Picard A, Herdtweck E, Domling A (2003) Short and diverse route toward complex natural product-like macrocycles. Org Lett 5: 1047–1050. doi: 10.1021/ol034077e CrossRefPubMedGoogle Scholar
  28. 28.
    Janvier P, Sun X, Bienayme H, Zhu J (2002) Ammonium chloride-promoted four-component synthesis of pyrrolo[3,4-b]pyridin-5-one. J Am Chem Soc 124: 2560–2567. doi: 10.1021/ja017563a CrossRefPubMedGoogle Scholar
  29. 29.
    Rivera DG, Wessjohann LA (2006) Supramolecular compounds from multiple Ugi multicomponent macrocyclizations: peptoid-based cryptands, cages, and cryptophanes. J Am Chem Soc 128: 7122–7123. doi: 10.1021/ja060720r CrossRefPubMedGoogle Scholar
  30. 30.
    El Kaim L, Gageat M, Gaultier L, Grimaud L (2007) New Ugi/Pictet-Spengler multicomponent formation of polycyclic diketopiperazines from isocyanides and α-keto acids. Synlett 2007: 500–502. doi: 10.1055/s-2007-968026 CrossRefGoogle Scholar
  31. 31.
    Umkehrer M, Kolb J, Burdack C, Ross G, Hiller W (2004) Synthesis of tetrazolopiperazine building blocks by a novel multi-component reaction. Tetrahedron Lett 45: 6421–6424. doi: 10.1016/j.tetlet.2004.06.133 CrossRefGoogle Scholar
  32. 32.
    Sun X, Janvier P, Zhao G, Bienayme H, Zhu J (2001) A novel multicomponent synthesis of polysubstituted 5-aminooxazole and its new scaffold-generating reaction to pyrrolo[3,4-b]pyridine. Org Lett 3: 877–880. doi: 10.1021/ol007055q CrossRefPubMedGoogle Scholar
  33. 33.
    Kim YB, Park SJ, Keum G, Jang MS, Kang SB, Lee DH, Kim Y (2002) An efficient synthesis of α-amino-δ-valerolactones by the Ugi five-center three-component reaction. Korean Chem Soc 23: 1277–1284CrossRefGoogle Scholar
  34. 34.
    Ugi I (1982) From isocyanides via four-component condensations to antibiotic syntheses. Angew Chem Int Ed Engl 21: 810–819. doi: 10.1002/anie.198208101 CrossRefGoogle Scholar
  35. 35.
    Mironov MA, Ivantsova MN, Mokrushin VS (2003) Ugi reaction in aqueous solutions: a simple protocol for libraries production. Mol Divers 6: 193–197. doi: 10.1023/B:MODI.0000006758.61294.57 CrossRefPubMedGoogle Scholar
  36. 36.
    Ugi I, Demharter A, Horl W, Schmid T (1996) Ugi reactions with trifunctional α-amino acids, aldehydes, isocyanides and alcohols. Tetrahedron 52: 11657–11664. doi: 10.1016/0040-4020(96)00647-3 CrossRefGoogle Scholar
  37. 37.
    Demharter A, Hörl W, Herdtweck E, Ugi I (1996) Synthesis of chiral 1,1prime-iminodicarboxylic acid derivatives from alpha-amino acids, aldehydes, isocyanides, and alcohols by the diastereoselective five-center-four-component reaction. Angew Chem Int Ed Engl 35. doi: 10.1002/anie.199601731
  38. 38.
    Sung K, Chen FL, Chung MJ (2003) Application of MCR: facile one-pot diastereoselective syntheses of novel chiral alpha,alpha’-iminodiacetic acid analogues. Mol Divers 6: 213–221. doi: 10.1023/B:MODI.0000006783.21086.0d CrossRefPubMedGoogle Scholar
  39. 39.
    Park SJ, Keum G, Kang SB, Koh HY, Kim Y, Lee DH (1998) A facile synthesis of N-carbamoylmethyl-α-aminobutyrolactones by the Ugi multicomponent condensation reaction. Tetrahedron Lett 39: 7109–7112. doi: 10.1016/S0040-4039(98)01509-3 CrossRefGoogle Scholar
  40. 40.
    Kadzimirsz D, Hildebrandt D, Merz K, Dyker G (2006) Isoindoles and dihydroisoquinolines by gold-catalyzed intramolecular hydroamination of alkynes. Chem Commun (Camb):661–662. doi: 10.1039/b516017k
  41. 41.
    Kim YB, Choi EH, Keum G, Kang SB, Lee DH, Koh HY, Kim Y (2001) An efficient synthesis of morpholin-2-one derivatives using glycolaldehyde dimer by the Ugi multicomponent reaction. Org Lett 3: 4149–4152. doi: 10.1021/ol016716w CrossRefPubMedGoogle Scholar
  42. 42.
    Ku IW, Cho S, Doddareddy MR, Jang MS, Keum G, Lee JH, Chung BY, Kim Y, Rhim H, Kang SB (2006) Morpholin-2-one derivatives as novel selective T-type Ca2+ channel blockers. Bioorg Med Chem Lett 16: 5244–5248. doi: 10.1016/j.bmcl.2006.05.031 CrossRefPubMedGoogle Scholar
  43. 43.
    Crysalis data collection software and data processing software for Oxford Xcalibur diffractometer. Oxford Diffraction Ltd., Oxfordshire (2005)Google Scholar
  44. 44.
    Altomare A, Cascarano G, Giacovazzo C, Guagliardi A, Burla MC, Polidori GMC (1994) SIR92—a program for automatic solution of crystal structures by direct methods. J Appl Cryst 27. doi: 10.1107/S002188989400021X
  45. 45.
    Prince E (1992) International tables for crystallography. Kluwer, DordrechtGoogle Scholar
  46. 46.
    Sheldrick G (1998) M. SHELXL-97. University of Göttingen, GöttingenGoogle Scholar
  47. 47.
    Spek AL (2008) PLATON, a multipurpose crystallographic tool. Utrecht University, UtrechtGoogle Scholar
  48. 48.
    Farrugia LJ (1999) WinGX (version 1.70.01 January 2005). J Appl Cryst 32: 837–838CrossRefGoogle Scholar
  49. 49.
    Cie S (2004) Data collection software and data processing software for stoe IPDS 2T diffractometer, X-ARERA. DarmstadtGoogle Scholar
  50. 50.
    Cie S (2004) Data processing software for stoe IPDS 2T diffractometer, XRED, XSHAPE. DarmstadtGoogle Scholar
  51. 51.
    Koch KE, Roberts JC, Lubec G (1997) Radiation protection by alpha-methyl-homocysteine thiolactone in vitro. Life Sci 60: 341–350. doi: 10.1016/S0024-3205(96)00515-2 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • B. Beck
    • 1
  • S. Srivastava
    • 1
  • K. Khoury
    • 1
  • E. Herdtweck
    • 2
  • Alexander Dömling
    • 1
    Email author
  1. 1.Department of PharmacyUniversity of PittsburghPittsburghUSA
  2. 2.Technical University MunichMunichGermany

Personalised recommendations