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doi:10.1016/j.tet.2004.06.144 
Copyright © 2004 Elsevier Ltd All rights reserved.
Total synthesis of (−)-ephedradine A: an efficient construction of optically active dihydrobenzofuran-ring via C–H insertion reaction
Received 7 May 2004;
revised 4 June 2004;
accepted 5 June 2004.
Available online 24 August 2004.
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Abstract
The stereocontrolled total synthesis of (−)-ephedradine A (1) has been accomplished. Construction of optically active dihydrobenzofuran-ring was performed by a novel asymmetric C–H insertion reaction. After an intramolecular ester–amide exchange reaction and a Sharpless asymmetric aminohydroxylation reaction, construction of the complex macrocyclic ring was performed by Ns-strategy and an intramolecular aza-Wittig reaction.
Graphical Abstract
Keywords: Dihydrobenzofuran-ring; Asymmetric C–H insertion reaction; Ns-strategy; Macrocyclization; Aza-Wittig reaction
Article Outline
- 1. Introduction
- 2. Results and discussion
- 3. Conclusion
- 4. Experimental
- 4.1. General methods
- 4.1.1. 1-Allyloxy-4-bromo-benzene
- 4.1.2. 2-Allyl-4-bromo-phenol
- 4.1.3. 1-(4-Benzyloxy-benzyloxy)-2-allyl-4-bromo-benzene (8)
- 4.1.4. [2-(4-Benzyloxy-benzyloxy)-5-bromo-phenyl]-acetic acid (9)
- 4.1.5. [2-(4-Benzyloxy-benzyloxy)-5-bromo-phenyl]-acetic acid methyl ester
- 4.1.6. [2-(4-Benzyloxy-benzyloxy)-5-bromo-phenyl]-diazo-acetic acid methyl ester (10a)
- 4.1.7. 2-(4-Benzyloxy-phenyl)-5-bromo-2,3-dihydro-benzofuran-3-carboxylic acid methyl ester (11a, 12a)
- 4.1.8. 2- [2-(4-Benzyloxy-benzyloxy)-5-bromo-phenyl]-acetoxy -propionic acid methyl ester
- 4.1.9. 2- [2-(4-Benzyloxy-benzyloxy)-5-bromo-phenyl]-diazo-acetoxy -propionic acid methyl ester (10b)
- 4.1.10. 2-(4-Benzyloxy-phenyl)-5-bromo-2,3-dihydro-benzofuran-3-carboxylic acid 1-methoxycarbonyl-ethyl ester (12b)
- 4.1.11. (1′R)-[2-(4-Benzyloxy-benzyloxy)-5-bromo-phenyl]-acetic acid 1′-methyl-2′-oxo-2′-pyrrolidin-1′-yl-ethyl ester
- 4.1.12. (1′R,2R,3R)-2-(4-Benzyloxy-phenyl)-5-bromo-2,3-dihydro-benzofuran-3-carboxylic acid 1′-methyl-2′-oxo-2′-pyrrolidin-1′-yl-ethyl ester (17)
- 4.1.13. (2R,3R)-2-(4-Benzyloxy-phenyl)-5-bromo-2,3-dihydro-benzofuran-3-carboxylic acid (18)
- 4.1.14. (2R,3R)-2-(4′-Benzyloxy-phenyl)-5-bromo-2,3-dihydro-benzofuran-3-carboxylic acid 3-[[4′-(tert-butyl-diphenyl-silanyloxy)-butyl]-(2′-nitro-benzenesulfonyl)-amino]-propyl ester (20)
- 4.1.15. (2R,3R)-2-(4-Benzyloxy-phenyl)-5-bromo-2,3-dihydro-benzofuran-3-carboxylic acid 3-[4-(tert-butyl-diphenyl-silanyloxy)-butylamino]-propyl ester (21)
- 4.1.16. (2R,3R)-2-(4-Benzyloxy-phenyl)-5-bromo-2,3-dihydro-benzofuran-3-carboxylic acid [4′-(tert-butyl-diphenyl-silanyloxy)-butyl]-(3′-hydroxy-propyl)-amide (23)
- 4.1.17. (2′R,3′R)-Acetic acid 3- [2′-(4″-benzyloxy-phenyl)-5′-bromo-2′,3′-dihydro-benzofuran-3′-carbonyl]-[4′-(tert-butyl-diphenyl-silanyloxy)-butyl]-amino -propyl ester (24)
- 4.1.18. (2′R,3′R)-3-[3′- (3″-Acetoxy-propyl)-[4″-(tert-butyl-diphenyl-silanyloxy)-butyl]-carbamoyl -2′-(4″-benzyloxy-phenyl)-2′,3′-dihydro-benzofuran-5′-yl]-acrylic acid methyl ester (25)
- 4.1.19. (2S,3R,2′R,3′R)-3-[3′- (3″-Acetoxy-propyl)-[4″-(tert-butyl-diphenyl-silanyloxy)-butyl]-carbamoyl -2′-(4-benzyloxy-phenyl)-2′,3′-dihydro-benzofuran-5′-yl]-3-benzyloxycarbonylamino-2-hydroxy-propionic acid methyl ester (26)
- 4.1.20. (2R,3R,2′R,3′R)-3-[3′- (3″-Acetoxy-propyl)-[4″-(tert-butyl-diphenyl-silanyloxy)-butyl]-carbamoyl -2′-(4″-benzyloxy-phenyl)-2′,3′-dihydro-benzofuran-5′-yl]-3-benzyloxycarbonylamino-2-chloro-propionic acid methyl ester (27)
- 4.1.21. (3R,2′R,3′R)-3-[3′- (3″-Acetoxy-propyl)-[4″-(tert-butyl-diphenyl-silanyloxy)-butyl]-carbamoyl -2′-(4″-benzyloxy-phenyl)-2′,3′-dihydro-benzofuran-5′-yl]-3-amino-propionic acid methyl ester (28)
- 4.1.22. (3R,2′R,3′R)-3-[3′- (3″-Acetoxy-propyl)-[4″-(tert-butyl-diphenyl-silanyloxy)-butyl]-carbamoyl -2′-(4″-benzyloxy-phenyl)-2′,3′-dihydro-benzofuran-5-yl]-3-(2-nitro-benzenesulfonylamino)-propionic acid methyl ester (29)
- 4.1.23. (3R,2′R,3′R)-3-[3′- (3″-Acetoxy-propyl)-[4″-(tert-butyl-diphenyl-silanyloxy)-butyl]-carbamoyl -2′-(4″-benzyloxy-phenyl)-2′,3′-dihydro-benzofuran-5′-yl]-3- (2″-nitro-benzenesulfonyl-[3′-(tert-butyl-dimethyl-silanyloxy)-propyl]-amino)-propionic acid methyl ester (31)
- 4.1.24. (3R,2′R,3′R)-3-[3′- (3″-Acetoxy-propyl)-[4″-(tert-butyl-diphenyl-silanyloxy)-butyl]-carbamoyl -2′-(4″-benzyloxy-phenyl)-2′,3′-dihydro-benzofuran-5′-yl]-3-[3′-(tert-butyl-dimethyl-silanyloxy)-propylamino]-propionic acid methyl ester
- 4.1.25. (3R,2′R,3′R)-3-[3′- (3″-Acetoxy-propyl)-[4″-(tert-butyl-diphenyl-silanyloxy)-butyl]-carbamoyl -2′-(4″-benzyloxy-phenyl)-2′,3′-dihydro-benzofuran-5′-yl]-3- benzyloxycarbonyl-[3′-(tert-butyl-dimethyl-silanyloxy)-propyl]-amino -propionic acid methyl ester (32)
- 4.1.26. (3R,2′R,3′R)-3-[3′- (3″-Acetoxy-propyl)-[4″-(tert-butyl-diphenyl-silanyloxy)-butyl]-carbamoyl -2′-(4″-benzyloxy-phenyl)-2′,3′-dihydro-benzofuran-5′-yl]-3-[benzyloxycarbonyl-(3′-hydroxy-propyl)-amino]-propionic acid methyl ester
- 4.1.27. (3R,2′R,3′R)-3-[3′- (3″-Acetoxy-propyl)-[4″-(tert-butyl-diphenyl-silanyloxy)-butyl]-carbamoyl -2′-(4″-benzyloxy-phenyl)-2′,3′-dihydro-benzofuran-5-yl]-3- benzyloxycarbonyl-[3′-(2″-nitro-benzenesulfonylamino)-propyl]-amino -propionic acid methyl ester (33)
- 4.1.28. (3R,2′R,3′R)-3-[3′-[(3″-Acetoxy-propyl)-(4″-hydroxy-butyl)-carbamoyl]-2′-(4″-benzyloxy-phenyl)-2′,3′-dihydro-benzofuran-5-yl]-3- benzyloxycarbonyl-[3′-(2″-nitro-benzenesulfonylamino)-propyl]-amino -propionic acid methyl ester (34)
- 4.1.29. (13R,19R,20R)-3-(3′-Acetoxy-propyl)-19-(4′-benzyloxy-phenyl)-13-methoxycarbonylmethyl-8-(2′-nitro-benzenesulfonyl)-2-oxo-18-oxa-3,8,12-triaza-tricyclo[12.5.2.00,0]heneicosa-14(21),15,17(20)-triene-12-carboxylic acid benzyl ester (35)
- 4.1.30. 19-(4-Benzyloxy-phenyl)-3-(3-hydroxy-propyl)-13-methoxycarbonylmethyl-8-(2-nitro-benzenesulfonyl)-2-oxo-18-oxa-3,8,12-triaza-tricyclo[12.5.2.00,0]heneicosa-14(21),15,17(20)-triene-12-carboxylic acid benzyl ester (36)
- 4.1.31. 3-(3-Azido-propyl)-19-(4-benzyloxy-phenyl)-13-methoxycarbonylmethyl-8-(2-nitro-benzenesulfonyl)-2-oxo-18-oxa-3,8,12-triaza-tricyclo[12.5.2.00,0]heneicosa-14(21),15,17(20)-triene-12-carboxylic acid benzyl ester (37)
- 4.1.32. 3-(3-Azido-propyl)-19-(4-benzyloxy-phenyl)-13-carboxymethyl-8-(2-nitro-benzenesulfonyl)-2-oxo-18-oxa-3,8,12-triaza-tricyclo[12.5.2.00,0]heneicosa-14(21),15,17(20)-triene-12-carboxylic acid benzyl ester
- 4.1.33. 3-(3-Azido-propyl)-19-(4-benzyloxy-phenyl)-13-pentfluororphenoxycarbonylmethyl-8-(2-nitro-benzenesulfonyl)-2-oxo-18-oxa-3,8,12-triaza-tricyclo[12.5.2.00,0]heneicosa-14(21),15,17(20)-triene-12-carboxylic acid benzyl ester (38)
- 4.1.34. O-Benzyloxy-N1-benzyloxycarbonyl-N2-nitrobenzensulfonyl-ephedradine-A (41)
- 4.1.35. O-Benzyloxy-N1-benzyloxycarbonyl-ephedradine-A
- 4.1.36. Ephedradine-A (1)
- Acknowledgements
- References
