Synthesis and Biological Evaluation of Cremastrine and an Unnatural Analogue

Overview

Journal Tetrahedron Lett

Publisher Elsevier

Specialty Chemistry

Date 2012 Jul 24

PMID 22822275

Citations 3

Authors

Kristopher N Hahn

Olugbeminiyi O Fadeyi

Hyekyung P Cho

Craig W Lindsley

Affiliations

Soon will be listed here.

Abstract

In this Letter, we describe the first total synthesis of cremastrine, a pyrrolizidine alkaloid from Cremastra appendiculata, with anticholinergic activity as well as an unnatural analogue. The streamlined synthesis proceeds in 9 steps, 7 steps longest linear sequence, in 25.2% overall yield, and features novel methodology to construct the pyrrolizidine core. Biological evaluation of cremastrine and the unnatural analogue indicated that both are pan-mAChR functional antagonists.

Citing Articles

Towards the Total Synthesis of Marineosin A: Construction of the Macrocyclic Pyrrole and an Advanced, Functionalized Spiroaminal Model.

Aldrich L, Berry C, Bates B, Konkol L, So M, Lindsley C European J Org Chem. 2014; 2013(20).

PMID: 24415906 PMC: 3885260. DOI: 10.1002/ejoc.201300643.

Total synthesis of stemaphylline N-oxide and related C9a-epimeric analogues.

Schulte M, Turlington M, Phatak S, Harp J, Stauffer S, Lindsley C Chemistry. 2013; 19(36):11847-52.

PMID: 23956045 PMC: 3925759. DOI: 10.1002/chem.201302669.

A General, Enantioselective Synthesis of 1-Azabicyclo[.0]alkane Ring Systems.

Senter T, Schulte M, Konkol L, Wadzinski T, Lindsley C Tetrahedron Lett. 2013; 54(13):1645-1648.

PMID: 23459400 PMC: 3580858. DOI: 10.1016/j.tetlet.2013.01.041.

References

Schulte M, Lindsley C . Highly diastereoselective and general synthesis of primary β-fluoroamines. Org Lett. 2011; 13(20):5684-7. PMC: 3196525. DOI: 10.1021/ol202415j. View

Sugiura M, Mori C, Kobayashi S . Enantioselective transfer aminoallylation: synthesis of optically active homoallylic primary amines. J Am Chem Soc. 2006; 128(34):11038-9. DOI: 10.1021/ja064106r. View

Ikeda Y, Nonaka H, Furumai T, Igarashi Y . Cremastrine, a pyrrolizidine alkaloid from Cremastra appendiculata. J Nat Prod. 2005; 68(4):572-3. DOI: 10.1021/np049650x. View

Conn P, Jones C, Lindsley C . Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders. Trends Pharmacol Sci. 2009; 30(3):148-55. PMC: 2907736. DOI: 10.1016/j.tips.2008.12.002. View

Sun X, Liu M, Xu M, Lin G . Remarkable salt effect on In-mediated allylation of N-tert-butanesulfinyl imines in aqueous media: highly practical asymmetric synthesis of chiral homoallylic amines and isoindolinones. Org Lett. 2008; 10(6):1259-62. DOI: 10.1021/ol8001514. View

Vanecko J, West F . Ring expansion of azetidinium ylides: rapid access to the pyrrolizidine alkaloids turneforcidine and platynecine. Org Lett. 2005; 7(14):2949-52. DOI: 10.1021/ol050915o. View

Robak M, Herbage M, Ellman J . Synthesis and applications of tert-butanesulfinamide. Chem Rev. 2010; 110(6):3600-740. DOI: 10.1021/cr900382t. View

Shin I, Lee M, Lee J, Jung M, Lee W, Yoon J . Synthesis of optically active phthaloyl D-aminooxy acids from L-amino acids or L-hydroxy acids as building blocks for the preparation of aminooxy peptides. J Org Chem. 2000; 65(22):7667-75. DOI: 10.1021/jo0006573. View

Brinner K, Ellman J . A rapid and general method for the asymmetric synthesis of 2-substituted pyrrolidines using tert-butanesulfinamide. Org Biomol Chem. 2005; 3(11):2109-13. DOI: 10.1039/b502080h. View

10.

Lebois E, Bridges T, Lewis L, Dawson E, Kane A, Xiang Z . Discovery and characterization of novel subtype-selective allosteric agonists for the investigation of M(1) receptor function in the central nervous system. ACS Chem Neurosci. 2011; 1(2):104-121. PMC: 3180826. DOI: 10.1021/cn900003h. View

11.

Peretto I, Petrillo P, Imbimbo B . Medicinal chemistry and therapeutic potential of muscarinic M3 antagonists. Med Res Rev. 2009; 29(6):867-902. DOI: 10.1002/med.20158. View

12.

El-Naggar M, Piggott A, Capon R . Bistellettazines A-C and bistellettazole A: new terpenyl-pyrrolizidine and terpenyl-imidazole alkaloids from a southern Australian marine sponge, Stelletta sp. Org Lett. 2008; 10(19):4247-50. DOI: 10.1021/ol8016512. View

13.

Furstner A, Korte A . Total synthesis of epohelmin B and its analogues. Chem Asian J. 2007; 3(2):310-8. DOI: 10.1002/asia.200700288. View

14.

Fadeyi O, Senter T, Hahn K, Lindsley C . A versatile enantioselective synthesis of azabicyclic ring systems: a concise total synthesis of (+)-grandisine D and unnatural analogues. Chemistry. 2012; 18(19):5826-31. PMC: 3540812. DOI: 10.1002/chem.201200629. View