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Diels-Alder Reaction-Aromatization Approach toward Functionalized Ring C Allocolchicinoids. Enantioselective Total Synthesis of (-)-7S-Allocolchicine.

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Bibliographic Details
Title: Diels-Alder Reaction-Aromatization Approach toward Functionalized Ring C Allocolchicinoids. Enantioselective Total Synthesis of (-)-7S-Allocolchicine.
Authors: Vorogushin, Andrei V., Predeus, Alexander V., Wulff, William D., Hansen, Hans-Jürgen
Source: Journal of Organic Chemistry. 7/25/2003, Vol. 68 Issue 15, p5826. 6p. 10 Diagrams, 1 Chart.
Subjects: Colchicine, Antimitotic agents, Biosynthesis
Abstract: Allocolchicinoids are analogues of the important antimitotic compound (-)-colchicine 1. A strategy is reported for the synthesis of ring C functionalized allocolchicinoids, which is based on a DielsAlder reaction-aromatization sequence. This route is complementary to the previously disclosed benzannulation approach involving Fischer carbene complexes and alkynes. Dienes 12 and 14 incorporate the natural substitution pattern on ring A and undergo Diels-Alder reactions with various dienophiles. Subsequent aromatization affords the set of differently functionalized ring C allocolchicinoids 15-19, 23, and 25, with high regioselectively and in moderate to good yields. An intramolecular Diels-Alder reaction-aromatization sequence allows for access to allocolchicinoids with reversed regiochemical introduction of ring C substituents. The equilibria of the atropisomers of 15 and 19 are studied in three NMR solvents. Reactions of the dienes 12 and 14 with DMAD lead to the corresponding cycloadducts, but the subsequent aromatization is complicated. A regioselective Diels-Alder reaction-aromatization sequence is utilized as the key step in the first stereoselective total synthesis of (-)-allocolchicine 2. Asymmetric introduction of hydroxy group at C7 is achieved by the enantioselective reduction of ketone 29. The correct stereochemistry is then established by Mitsunobu inversion reaction using Zn(N[sub 3])[sub 2]-2Py. [ABSTRACT FROM AUTHOR]
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Database: Engineering Source
Description
Abstract:Allocolchicinoids are analogues of the important antimitotic compound (-)-colchicine 1. A strategy is reported for the synthesis of ring C functionalized allocolchicinoids, which is based on a DielsAlder reaction-aromatization sequence. This route is complementary to the previously disclosed benzannulation approach involving Fischer carbene complexes and alkynes. Dienes 12 and 14 incorporate the natural substitution pattern on ring A and undergo Diels-Alder reactions with various dienophiles. Subsequent aromatization affords the set of differently functionalized ring C allocolchicinoids 15-19, 23, and 25, with high regioselectively and in moderate to good yields. An intramolecular Diels-Alder reaction-aromatization sequence allows for access to allocolchicinoids with reversed regiochemical introduction of ring C substituents. The equilibria of the atropisomers of 15 and 19 are studied in three NMR solvents. Reactions of the dienes 12 and 14 with DMAD lead to the corresponding cycloadducts, but the subsequent aromatization is complicated. A regioselective Diels-Alder reaction-aromatization sequence is utilized as the key step in the first stereoselective total synthesis of (-)-allocolchicine 2. Asymmetric introduction of hydroxy group at C7 is achieved by the enantioselective reduction of ketone 29. The correct stereochemistry is then established by Mitsunobu inversion reaction using Zn(N[sub 3])[sub 2]-2Py. [ABSTRACT FROM AUTHOR]
ISSN:00223263
DOI:10.1021/jo034420t