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Activated vinylaziridines (N-benzoyl, N-p-toluenesulfonyl, N-t-butoxycarbonyl and N-benzyloxycarbonyl) have been prepared from N-substituted 1,4-aminoalcohols using Mitsunobu conditions. Activated vinylaziridines containing an electron withdrawing group are versatile synthetic building blocks, because the N-substituent facilitates regiospecific aziridine opening by a nucleophile. 1,2 2-Vinylaziridines are particularly useful intermediates for organic synthesis and thus have been used in the synthesis of various natural products. 3 Hudlicky has reviewed the chemistry of vinyl aziridines, 4 and used a vinyl N-ptoluenesulfonyl (Ts) aziridine in the first asymmetric synthesis of the antitumor alkaloid pancratistatin. 5 Unfortunately, the lowest yielding step in the synthesis was the aziridination of enantiomerically pure 3-bromo-1,2-isopropylidenedioxycyclohexa-3,5-diene. 2 A widely employed activating group is the p-toluenesulfonyl group because of the accessible methods for the preparation of N-Ts aziridines. 6 However, removal of this protecting group frequently requires harsh conditions. 7 Synthetic efforts have been directed toward the development of direct methods of preparing aziridines containing other activating groups. 8There is a plethora of methods for the preparation of aziridines, and they have been recently reviewed by Sweeney 9a and Tanner. 9b An obvious method utilizes 1,2-aminoalcohols as precursors. 10 The reaction is readily achieved when the alcohol is converted to a nucleofuge. However, this method is limited to N-phosphonylated 11 and N-Ts aziridines; 6 when applied to the synthesis of N-acyl or N-carbamoyl aziridines, the nucleophilic attack by the carbonyl oxygen leads to the formation of oxazolines. 12 Conceptually, vinylaziridines should also be easily accessed from 1,4-aminoalcohols as shown in Scheme 1. Scheme 1We present in this communication a new method for the preparation of 2-vinylaziridines from 1,4-aminoalcohols. This method allows the preparation of functionalized aziridines while avoiding protectiondeprotection steps and permits the direct preparation of aziridines containing N-Ts, N-acyl and N-carbamoyl activating groups. Enantiomerically pure aziridines are prepared by enantiospecific synthesis from enantiomerically pure dienes.1,4-Aminoalcohols are prepared easily in a high yielding two-step sequence starting from a conjugated diene. Nitroso dienophiles are then generated in situ as transient intermediates by oxidation of the corresponding hydroxamic acid with periodate (NaIO 4 , MeOH-H 2 O). 13 Nitroso dienophiles generated in the presence of a conjugated double bond furnish 3,6-dihydro-1,2-oxazines. 14 This hetero Diels-Alder cycloaddition reaction occurs regio-and stereospecifically with chiral dienes. 15 The cis-1,4-aminoalcohols are obtained by reductive cleavage of the nitrogen-oxygen bond of the corresponding 1,2-oxazines using either Keck's aluminium amalgam procedure 16 or refluxing the oxazine in acetonitrile in the presence of molybdenum hexacarbonyl. 17 Cycli...

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Epibatidine (1) is a natural product that was isolated from the skin of the Ecuadorian poison frog Epipedobates tricolor in trace amounts (less than 1 mg from 700 frogs). 1 This alkaloid has attracted a lot of attention because it showed remarkable analgesic activity (200-500 times more potent than morphine) and displayed a very distinct mode of action. 2 Interestingly, both optical isomers displayed similar activity. 3 Since its structural elucidation by Daly in 1992, a surprisingly large number of syntheses have appeared in the literature. 4 However, no total synthesis using a biocatalytic approach has yet been described. 5Microbial oxidation of unfunctionalized carbons can be a powerful tool for providing hydroxylated molecules that otherwise might not be easily accessible. We envisioned that an appropriately N-substituted 7-azanorbornane derivative would be a good substrate for oxidation of an unfunctionalized carbon and that the metabolite would make a valuable intermediate for a total synthesis of epibatidine. Oxidation of N-substituted 7-azanorbornanes with the fungus Beauveria bassiana has been studied independently by Johnson's group and ourselves. 5 We recently reported that easily prepared 7-azanorbornanes carrying an appropriate N-substituent are microbially oxidized stereoselectively on an unfunctionalized methylene carbon. 5,6 In this note, we communicate our total synthesis of epibatidine using a selected metabolite generated from this biotransformation. Results and DiscussionWe selected the N-benzoyl group as the anchoring/ directing group in the microbial oxidation of 7-azanorbornane because of the reproducibility of the biotransformation experiments, good yield, and minimal production of side products. 5b The desired N-benzoyl-7-azanorbornane (2a) was easily prepared in three steps from commercially available trans-4-aminocyclohexanol hydrochloride (Scheme 1). Microbial hydroxylation of substrate 2a utilizing B. bassiana furnished stereoselectively 2-endo-hydroxy-7-azanorbornane (3a) in 56% yield and 22% ee. 5b Optical rotation experiments showed that the slightly favored enantiomer generated in the microbial transformation was (-)-(1R). NMR spectra of substrate 2a and metabolite 3a showed the presence of a mixture of rotamers. Thus, we reduced the benzamides 2a and 3a to their corresponding benzylic amines with lithium aluminum hydride to facilitate their structural assignment. 1 H-and 13 C NMR spectra of the benzylic amine 3b were identical to those reported by Fletcher. 7 We have also studied the effect of several phosphorus-containing N-substituents on the microbial hydroxylation of 7-azanorbornanes. 6 We and Johnson's group have found that B. bassiana is able to accept a variety of functionalities on the heteroatom of the substrate. 5,6 We found that good reproducible yields are obtained when the N-substituent is a benzoyl group and therefore selected the corresponding metabolite as the intermediate to complete a synthesis of epibatidine. We might attribute the low enantioselectivity of th...