Spirobicyclo[2.2.2]octane derivatives: mimetics of baccatin III and paclitaxel (Taxol)

Abstract

The formylated spirobyclic alcohol was computer modeled to be a mimetic of paclitaxel. In this model, the formyl group was used as a truncated paclitaxel side chain in order to reduce the computational work. Compound , carrying the paclitaxel side chain, was synthesized in six steps from optically active 1,3-diketone . Microtubule stabilization was not observed for , indicating that the model needs to be adjusted.

Palladium-Catalyzed Synthesis and Anticancer Activity of Paclitaxel–Dehydroepiandrosterone Hybrids

“…Compound 4a, yield 88%: 1 H NMR (400 MHz, CDCl 3 ): δ 6.99 (s, 2H), 6.88 Compound 4g, yield 89%: 1 H NMR (400 MHz, CDCl 3 ): δ 7.22 (t, J = 8.0 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.93−6.90 (m, 1H), 6.78 (dd, J = 8.0, 2.4 Hz, 1H), 5.93 (dd, J = 3.1, 1.7 Hz, 1H), 5.93 (dd, J = 3.2, 2.0 Hz, 1H), 5.41−5.37 (m, 1H), 3.81 (s, 3H), 3.46−3.59 (m, 1H), 2.37−2.18 (m, 3H), 2.13− 1.97 (m, 3H), 1.88−1.46 (m, 11H), 1.07 (s, 3H), 1.05 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 159. 33 Compound 4p, yield 91%: 1 H NMR (400 MHz, CDCl 3 ): δ 5.64 (d, J = 1.2 Hz, 1H), 5.38 13 C NMR (100 MHz, CDCl 3 ): δ 165.…”

“…13 C NMR (100 MHz, CDCl 3 ): δ 159. 33 Compound 4p, yield 91%: 1 H NMR (400 MHz, CDCl 3 ): δ 5.64 (d, J = 1.2 Hz, 1H), 5.38 13 C NMR (100 MHz, CDCl 3 ): δ 165. 7, 159.8, 144.3, 141.3, 132.5, 121.4, 112.5, 71.8, 56.9, 50.7, 49.5, 42.4, 37.3, 36.9, 35.4, 32.3, 31.7, 31.7, 30.9, 21.0, 19.5, 16.4 General Procedure for Compounds 6a−6r.…”

“…Compound 6a, yield 82%: 1 H NMR (400 MHz, CDCl 3 ): δ 7.60−7.12 (m, 13H), 7.02 (s, 2H), 6.91 1.11 (s, 3H), 1.07 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 169. 1.11 (s, 3H), 1.05 (s, 3H).…”

Asymmetric baker’s yeast reductions of bridgehead-substituted bicyclo[2.2.2]octane-2,6-dione derivatives followed by conversion into catalytically active BODOLs for the diethylzinc addition to benzaldehyde

“…29,30 Several examples exist where optically active hydroxy bicyclo [2.2.2]octanones serve as important chiral building blocks in the synthesis of bioactive natural products. 9,[31][32][33] The development of bicyclo [2.2.2]octane derivatives, to be used as ligands 17,18,20,23,24,[34][35][36][37][38] and scaffolds in natural product mimetics, 39,40 is an ongoing project in our laboratories. Recently, we published two synthetic routes towards novel bridgehead hydroxy bicyclo [2.2.2]octane-2,6-dione 9 (Scheme 1).…”

Design, synthesis and bioactivity of simplified taxol analogues on the basis of bicyclo[3.3.1]nonane derivatives

“…During the last ten years, such attempts have been reported. [3][4][5][6][7][8] In 2002, based on the hypothesis that the main function of the taxane skeleton is to provide proper orientation of the substituents important for tubulin binding, 9 we suggested a general theoretical model of a 'simplified' taxol analogue with bicyclo[3.3.1]nonane core (1, Figure 1). 10 This moiety has a definite structural similarity to the AB rings of the parent molecule.…”