Synthesis of novel simplified sarcodictyin/eleutherobin analogs with potent microtubule-stabilizing activity, using ring closing metathesis as the key-step

The synthesis of a number of novel simplified eleutheside analogs with potent tubulin-assembling and microtubule-stabilizing properties is described, using ring closing metathesis as the key-step for obtaining the 6-10 fused bicyclic ring system. The RCM precursors were synthesized starting from aldehyde 3 [prepared in 6 steps on a multigram scale from R-(−)-carvone in 30% overall yield] via multiple stereoselective Brown allylations. Second generation RCM catalyst 13 gave the desired ring closed 10-membered carbocycles as single Z stereoisomers in good yields. The RCM stereochemical course (100% Z) likely reflects thermodynamic control. The crucial role of the protecting groups of the homoallylic and allylic substituents for the efficiency of the RCM reactions is discussed. These simplified analogs of the natural product (lacking inter alia the C-4/C-7 ether bridge) retain potent microtubule-stabilizing activity. However, the cytotoxicity tests did not parallel the potent tubulin-assembling and microtubule-stabilizing properties: limited cytotoxicity was observed against three common tumor cell lines (human ovarian carcinoma and human colon carcinoma cell lines, IC₅₀ in the μM range given in Table 2), three orders of magnitude less than paclitaxel (IC₅₀ in the nM range).     

Pyrrole synthesis using a tandem Grubbs’ carbene-RuCl3 catalytic system

A straightforward pyrrole synthesis from diallylamines is developed by using a tandem catalyst system leading to ring-closing metathesis with the second generation Grubbs’ catalyst (10%) followed by dehydrogenation in the presence of RuCl₃ × H₂O (2%).     

The first stereoselective total synthesis of (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one

Iterative asymmetric allylations and ring-closing metathesis have been effectively performed for the first stereoselective total synthesis of (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one, a novel α,β-unsaturated-δ-lactone having antifungal activity, isolated from Ravensara crassifolia.     

Convergent synthesis of the FGHI ring system of yessotoxin: stereoselective construction of the G ring

A convergent synthetic route to the FGHI ring system of yessotoxin, a marine ladder polyether, has been developed. The synthesis features convergent coupling of the diol and the aldehyde to form α-cyano ethers via acetal formation followed by ring closing metathesis and reductive etherification to construct the oxocane ring G and tetrahydropyran ring H, respectively. The β-methyl group on the G ring was stereoselectively introduced by alkylation of the corresponding ketone.     

Double ring-closing metathesis reaction of nitrogen-containing tetraenes: efficient construction of bicyclic alkaloid skeletons and synthetic application to four stereoisomers of lupinine and their derivatives

The double ring-closing metathesis reaction of nitrogen-containing tetraenes was studied. The selectivity of the fused/dumbbell-type products can be controlled by the electronic/steric effects of the substituents attached to the C[double bond]C bonds and the s-cis/s-trans conformational ratios of the substrates. This methodology has also been successfully applied to the enantioselective synthesis of four stereoisomers of lupinine and their derivatives.     

Rapid access to epothilone analogs via semisynthetic degradation and reconstruction of epothilone D

A facile and efficient route to epothilone analogs has been developed from the natural product epothilone D (1). Degradation of 1 via an oxidative cleavage sequence provides acid intermediate 4 rapidly in six steps. From 4, a variety of epothilone analogs have been prepared utilizing ring-closing metathesis to reconstruct the trisubstituted-12,13-double bond. Using this approach, we report a number of epothilone analogs with varying C-15 aromatic side chains and C-14 allylic substitutions and their biological activities.     

Synthetic study on 13-oxyingenol: construction of the full carbon framework

13-Oxyingenol is a diterpenoid isolated from Euphorbia kansui, and its derivatives have strong anti-HIV activity. We achieved the construction of inside-outside framework of 13-oxyingenol by using ring-closing olefin metathesis.     

潜在的大环锌金属蛋白酶抑制剂的设计与合成

A series of succinate-derived macrocyclic amides 1 were synthezized using ring-closing metathesis in the keystep.The substrate scope includes tings of 11 to 14 members.The cyclic dicarboxylic acids 1 represent a family ofnew model compounds for potential zinc metalloprotease inhibitors.The metathesis precursors were provided byamide coupling of tert-butyl 3-earboxyhex-5-enoate 2 with numerous side chain alkenylated amino acid esters ofgeneral type 3 derived from L-tyrosine and L-cysteine.     

Synthesis of (2S,7S)-dibutyroxynonane, the sex pheromone of the orange wheat blossom midge, Sitodiplosis mosellana (Géhin) (Diptera: Cecidomyiidae), by diastereoselective silicon-tethered ring-closing metathesis

The sex pheromone of Sitodiplosis mosellana, (2S,7S)-dibutyroxynonane, has been synthesised using a mixed di-t-butylsilaketal prepared from (S)-5-hexen-2-ol and prochiral 1,4-pentadiene-3-ol. Ring-closing metathesis occurs diastereoselectively and after the removal of the silyl group and the reduction of the double bonds, generates (2S,7S)-nonanediol with a diastereoisomeric excess of 94% as measured by gas chromatographic analysis of the diacetylated product.