A practical enantioselective synthesis of epibatidine

Synthesis of Alkaloid Natural Products Using Solid-Supported Reagents and Scavengers

“…This reproducibly furnished the desired amino mesylate (36) rapidly and under mild conditions, and was found to be superior to the use of sodium borohydride with NiCl2 under the usual reduction conditions [34]. The commercially available PS-BEMP allowed the key transannular cyclisation to proceed in higher yield and more rapidly than under the attempted thermal conditions (toluene, D, overnight, 46%) previously reported [35]. As no trace of the potential by-product arising from intermolecular amino-mesylate displacement was observed in these reactions (LC-MS, 1 H NMR), the most significant impurity remaining was the epimeric cis amino mesylate of (36) (approximately 10%).…”

“…Reduction of the ketone (33) with polymer-supported borohydride gave a 7:1 diastereomeric ratio in favour of the all equatorial substituted cyclohexanol (34). Conversion of the alcohol (34) to the corresponding mesylate (35) was achieved by adding a solution of the alcohol in dichloromethane to a preformed mixture of PS-DMAP and mesyl chloride and then stirring the reaction mixture at room temperature until the reaction was complete. Reduction of the aliphatic nitro functionality of mesylate (35) with retention of configuration initially proved problematic.…”

Selective Access to Both Diastereoisomers in an Enantioselective Intramolecular Michael Reaction by Using a Single Chiral Organocatalyst and Application in the Formal Total Synthesis of (−)‐Epibatidine

“…Treating the pure trans ‐isomer with two equivalents of NaBH 4 in CH 3 OH at 0 °C afforded the corresponding alcohol 5 in 87 % yield and 10:1 d.r. From alcohol 5 , only four additional synthetic steps (mesylation, reduction/cyclization, and epimerization) are needed to reach the target 6 22. Starting from chloropyridine aldehyde 7 , this is, to the best of our knowledge, the shortest (seven steps) and most selective, organocatalytic, formal total synthesis of (−)‐epibatidine 23…”

“…From alcohol 5, only four additional synthetic steps (mesylation, reduction/cyclization, and epimerization) are needed to reach the target 6. [22] Starting from chloropyridine aldehyde 7, this is, to the best of our knowledge, the shortest (seven steps) and most selec-tive, organocatalytic, formal total synthesis of (À)-epibatidine. [23] In summary, we have demonstrated that both diastereoisomers of 4-nitro-3-substituted cyclohexanones can be accessed selectively by an intramolecular Michael reaction using a single chiral aminocatalyst.…”

Synthetic Route to Ergot Alkaloids

“…A similar CÀN bond cleavage in urethanes has already been observed and described in our earlier publication [12]. Since we successfully used KF/Al 2 O 3 as base in a cyclization step in the course of our practical synthesis of epibatidine [30], a solution of 33 in benzene was allowed to react with this reagent, resulting in the first successful intramolecular aldol Scheme 6 Helvetica Chimica Acta ± Vol. 88 (2005) Scheme 7 cyclization of 33 to give the tetracyclic ketone 35 in 63% yield; however, rearrangement of the ring system was evidenced by NMR measurements.…”