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Hydroxylated piperidine or pyrrolidine systems are indeed a useful building block for the nucleus present in several major classes of pyrrolizidine, indolizidine, and quinolizidine alkaloids. One most reliable methodology to access those systems is a regioand stereoselective ring closure of epoxides by internal nitrogen nucleophile. According to Baldwin rules, ring closure of epoxides generally proceeds via the favored 5-exo mode rather than the 6-endo mode as shown in Scheme 1. In order to reverse this tendency, the introduction of vinyl group adjacent to epoxide is one of the widely employed methods. In contrast to the numerous reports for the ring closure of vinyl epoxides with the internal oxygen nucleophile, there have been only handful examples in the intramolecular ring closure of vinyl epoxides by nitrogen nucleophiles. Moreover, to our best knowledge, there has been no report for acid-induced ring closure of vinyl epoxides with deactivated nitrogen nucleophiles, e.g. protected by Cbz group. Herein we wish to report our results of the ring closure of a number of vinyl epoxides under acidic conditions and its application to the synthesis of alkaloids. In order to explore the scope of the ring closure of the vinyl epoxides, we synthesized various substrates from the corresponding NCbz protected aminoalcohols as shown in Scheme 2. Swern oxidation of the alcohols 1a-c and subsequent HornerWadsworth-Emmons olefination of aldehydes using LiOH, triethyl 4-phosphonocrotonate, and 4 A-MS furnished the (E,E)-dienoates 2a-c in 73-80% yields. Regioselective epoxidation of 2a-c using mCPBA and Na2HPO4 afforded the desired amino epoxy alkenes 3a-c in 80-93% yields. To obtain the epoxy dibromoalkene 6, Swern oxidation of 1b, followed by Wittig olefination (PPh3=CHCO2Et) afforded the unsaturated ester 4 in 68% overall yield. DIBAL reduction and subsequent epoxidation using mCPBA gave the epoxy alcohol 5 in 68% overall yield, which was oxidized with SO3·pyr complex and subsequent dibromoolefination (CBr4, PPh3) to afford the epoxy dibromoolefin 6 in 55% overall yield. Partial reduction of 7 in the presence of Lindlar catalyst and quinoline furnished the (Z)-olefin 8 in 85% yield, which was then subjected to dephthaloylation using excess NH2NH2 and subsequent Cbz protection reaction to afford 9 in 54% yield. Epoxidation of 9 afforded the epoxy alcohol 10 (81%), which was transformed to the vinyl cis-epoxide 11 by oxidation (SO3·pyr complex) and Wittig olefination (PPh3= CHCO2Et) in 61% yield. Our initial task was to find an active acid system in the intramolecular ring closure (Table 1). Thus, the trans-epoxide 3b was treated with various acids (0.1 eq.), such as ZnCl2, Cu(OTf)2, MgBr2, CuBr2, LiClO4, BF3·OEt2, and camphorsulfonic acid (CSA), in methylene chloride at 0 °C. Cu(OTf)2 gives very little cyclized products (< 5%) and MgBr2 (1 eq.) resulted in undesired side reaction to give trans-γ-bromo-δ-hydroxy-α,β-unsatutrated ester (structure not shown) in 89% yield, which was generated by attack of Scheme 1 Scheme 2. (a) (COCl)2, DMSO, Et3N, -78 °C; (b) (E)-(EtO)2P(O)CH2CH=CHCO2Et, LiOH, 4 A-MS, THF, reflux; (c) mCPBA, Na2HPO4, CH2Cl2, r.t; (d) PPh3=CHCO2Et, benzene, reflux; (e) DIBAL, CH2Cl2, -78 °C; (f) SO3·pyridine, CH2Cl2 : DMSO (4 : 1); (g) PPh3, CBr4, CH2Cl2, 0 °C.

Studies for Intramolecular Ring Closure of Amino Vinyl Epoxides. Stereoselective Synthesis of Piperidine and Pyrrolidine Systems