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In this case the reaction can proceed via the exo-E-anti transition structure 37 or the endo-E-syn transition structure 39 because of the structure of the educt molecule. In a noncatalyzed, high temperature cyclization sterically demanding precursors such as 12 are known to react via the exo-E-anti transition state 41 to furnish the corresponding trans-fused product 42.13 In the transition structure the diene is placed under the dienophile because of the «-methyl group at C-5 which leads to formation of compound 42. Subsequent treatment of the reaction mixture with an excess of DBU effects complete isomerization of 42 to the thermodynamically more stable c/'v-lactone 43. TEMPO is again used as radical scavenger during this reaction. The prolonged reaction time results in the formation of substantial amounts of TV-deprotected amine, which is converted to 13 by treatment of the crude reaction mixture with Â ÎÑ anhydride in the presence of 20 % aqueous sodium hydroxide.
• This step is a catalytic reduction.
1. Raney Ni, H2, MeOH, r. t., 2.5 h, 72 %
Reduction using a large excess of Raney nickel in methanol is extremely regioselective; only the internal double bond is affected. This is possibly because of the highly hindered nature of the external disubstituted double bond, which is flanked by the tricyclic ring system and the N-BOC substituent. The transformation occurred stereoselectively from the less hindered «-lace of the molecule producing the required R configuration.
• The amine is deprotected.
• Which methods for /V-alkylation do you know?
1. TFA, CH2C12, r. t., 1 h
2. HCHO (37 % in H20), NaBH3CN, r. t„ 1 h 78 % (over two steps)
Direct conversion of 14 to (+)-himbacine is achieved in a one-pot procedure by removing the Â ÎÑ group with trifluoroacetic acid and reaction of the resulting free amine with aqueous formaldehyde and sodium cyanoborohydride. This reductive elimination furnishes the imine which is in situ reduced to the tertiary amine. Another common method for Ë'-methylation is the reaction with a base like sodium hydride and methyl iodide. But this method is not suitable for molecules with C-H acidic protons.
The intramolecular Diels-Alder reaction of an appropriately substituted tetraene that bears the entire latent carbon framework and functional group substitution of himbacine has to be mentioned as the key step of this synthesis. It allows an efficient construction of the tricyclic ring system. In conclusion, this total synthesis provides a highly convergent synthesis of (+)-himbacine in about 10 % overall yield and also establishes a practical route to analogs.
1 J. T. Pinhey, E. Ritchie, W. C. Taylor, Aust. J. Chem. 1961, 14, 106-134.
2 M. J. Malaska, A. H. Fauq, A. P. Kozikowski, P. J. Aagaard, M. McKinney, Bioorg. Med. Chem. Lett. 1995, 5, 61-66.
3 J. H. Miller, P. J. Aagaard, V. A. Gibson, M. McKinney, J. Pharmacol. Exp. Ther. 1992, 263, 663-667.
4 S. Chackalamannil, R. J. Davies, Y. Wang, T. Asberom, D. Doller, J. Wong, D. Leone, A. T. McPhail, J. Org. Chem. 1999, 64, 1932-1940.
5 D. Doller, R. Davies, S. Chackalamannil, Tetrahedron: Asymmetry 1997, 8, 1275-1278.
6 P. Beak, W. K. Lee, J. Org. Chem. 1993, 58, 1109-1117.
7 R. Hoffmann, Chem. Rev. 1989, 89, 1841 -1860.
8 K. Takai, K. Nitta, K. Utimoto, J. Am. Chem. Soc. 1986, 108, 7408-7410.
9 H. C. Brown, P. V. Ramachandran, S. A. Weissman, S. Swaminathan, J. Org. Chem. 1990, 55, 6328-6333.
10 A. Hassner, V. Alexanian, Tetrahedron Lett. 1978, 46, 4475-4478.
11 J. Brieger, J. N. Bennett, Chem. Rev. 1980, 80, 63-97.
100 6 (+)-Himbacine
12 a) L. F. Tietze, G. Kettschau, Top. Curr. Chem. 1997, 189, 1-120; b) L. F. Tietze, J. Bachmann, J. Wichmann, Y. Zhou, T. Raschke, Liebigs Ann./Recueil 1997, 881-886.
13 D. Craig, Chem. Soc. Rev. 1987,16, 187-238.
Organic Synthesis Workbook II
C. Bittner, A. S. Busemann, U. Griesbach, F. Haunert, W.-R. Krahnert, A. Modi, J. Olschimke, P. L. Steck
Copyright © 2001 Wiley-VCH Verlag GmbH ISBNs: 3-527-30415-0 (Softcover); 3-527-60013-2 (Electronic)
Hirsutine (Tietze 1999)
The alkaloids hirsutine (1) and its Çà-epimer dihydrocorynantheine (2a) belong to the corynanthe group of indole alkaloids. They have been isolated from the plant Uncaria rhynchophylla MIQ, which was used for the preparation of the old Chinese folk medicine ’’kampo”. Nowadays, 1 and related compounds attract great attention in medicine because of their growth inhibition of the influenza A subtype H3N2 virus. With an EC50 value of 0.40-0.57 ug/mL 1 has shown itself to be 10-20 times more active than the clinically used drug ribavirine (3).1'2 Furthermore, 1 is known for its antihypertensive and antiarrhythmic activity.3
The absolute configuration of 1 was established in 1967.4 Since then,