Stereoselective reaction Strychnine, synthesis

Another challenge associated with the synthesis of strychnine, as well as other Strychnos alkaloids, is the stereoselective construction of the F-hydroxyethylidene side chain (Scheme 4.5). Strategies that rely on a late-stage olefination reaction of a C20 ketone often suffered from low diasterocontrol for the newly formed alkene, with the best exception provided by Kuehne (15 > 16) [10a, b, d, f]. Overman,... 

Among the wide variety of unsaturated functionalities which participate in the cobalt-mediated [2+2+2] cycloaddition that has proved to be a powerful tool for the assembly of complex polycyclic molecules are a number of aromatic heterocyclic double bonds, such as those in pyrrole and indole <20000L2479, 2001JA9324 and references therein>. Indoles, including those substituted at C-3, can be cyclized, both intra- and intermolecularly, with a wide variety of alkynes to yield functionalized products in moderate to good yields. A stereoselective cobalt-mediated [2+2+2] cycloaddition reaction between the W(pent-2-en-4-ynoyl)indole moiety of tryptamine derivative 1093 (R = (CH2)2NHAc) and acetylene has been employed for the formal total synthesis of strychnine 1097, the most famous Strychnos alkaloid and a commonly used rodenticide and animal stimulant (Scheme 213). 

AB ABCE ABCDE - ABCDEF W-G aldehyde (-)-Strychnine] (27) After his racemic synthesis of strychnine (26), Kuehne also achieved an enantioselective synthesis of (—)-strychnine (Scheme 9). To avoid the low yield conversion of isostrychnine to strychnine, the second approach was directed to the W-G aldehyde. Starting from L-tryptophan methyl ester (86), the cyclization precursor 87 was prepared in seven steps in a similar way as in the previous racemic synthesis. The domino condensation-electrocyclization reaction of 87 with dienal 88 proceeded with quite high diastereoselectivity (>95% de) [AB ABCE, C7 quaternary center] (85). After conversion of the tetracyclic compound 89 to tosylate 92, removal of the benzyl group resulted in the clean formation of the D ring [ABCE ABCDE ]. Unlike in the first synthesis, introduction of the hydroxyethylidene side chain by a Horner-Wadsworth-Emmons reaction of ketone 93 proceeded with high stereoselectivity (E Z = 17 1). Einally, the E isomer 94E was converted to (-)-strychnine via the W-G aldehyde (50). 

Very recently, Padwa reported a total synthesis of strychnine based on an intramolecular Diels-Alder reaction/rearrangement cascade, which was previously developed in his group to assemble the tetracyclic core ring system of indole alkaloids (Scheme 16) (174-178). Intramolecular cycloaddition reactions often benefit from higher reactivity and greater control of stereoselectivity relative to their intermolecular counterparts. Unlike Bodwell s lEDDA reaction (Scheme 13), the reaction of an electron-rich furan moiety with an N-acyl indole moiety required only a single tether. His synthesis also involved... 

The Strychnos alkaloids possess diverse chemical structures that have attracted considerable attention in organic synthesis during the last decades. Recent studies on the synthesis of akuammicine, strychnine and leuconicine A and by Andrade et al. proved that the intramolecular Heck reaction is extremely valuable for the construction of complex polycyclic molecules. Based on Rawal s method for the construction of the D ring of Strychnos alkaloids, vinyl iodides 37, 39, and 42 undergo a regioselective and stereoselective palladium-catalyzed cychzation in the presence of Pd(OAc)2, PPha in Et3N to furnish ( )-akuammi-cine 38, and the advanced intermediates 40 and 43 in excellent chemical yields (Scheme 13.11). 

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