13 Rearrangement from Indolines to Tetrahydroquinolines via Aziridine Intermediate Inspired by a Hypothetical Biogenesis : Total Syntheses of (+)-Benzastatin E and (-)-Virantmycin
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Benzastatins and (-)-virantmycin (2a) are a family of indoline and tetrahydroquinoline alkaloids isolated from Streptomyces nitrosporeus. Benzastatins show neuronal cell protecting activity that can be used to prevent brain ischemia injury, and (+)-benzastatin E (1) is the most potent inhibitor of glutamate toxicity using neuronal hybridoma N18-RE-105 among the benzastatin family. (-)-Virantmycin (2a) has been found to exhibit antifungal activity as well as inhibitory activities against various RNA and DNA viruses. From the structures of these alkaloids, a biosynthesis involving an aziridine intermediate has been suggested. Based on this hypothesis, we designed the PPh_3-CCl_4 mediated rearrangement from α,α-disubstituted indoline-2-methanol 3 to 2,2,3-trisubstituted tetrahydroquinoline 4 via the aziridine intermediate followed by the ring opening attack of the chloride anion. Chiral α,α-disubstituted indoline-2-methanol 3 were readily synthesized by the diastereoselective addition of Grignard reagents to 2-acylindoline 9. Reaction of 2-acylindoline 9 possessing various alkyl groups with metal reagents in THF at -78℃ gave tert-alcohols 10 as separable diastereoisomers. These additions were highly diastereoselective as demonstrated in Table 1. The stereochemical outcome of this reaction can be explained by the Felkin-Anh model as depicted in Figure 1. The total synthesis of (+)-benzastatin E (1) was accomplished utilizing this method, in three steps from the acetonide 11. The chiral α,α-disubstituted indoline-2-methanol 3, obtained by deprotecting the Boc group of 10, was treated with PPh_3-CCl_4 in CH_2Cl_2 to afford the desired tetrahydroquinoline 4 as a sole stereoisomer. The dechlorinated derivative of 4b was identical with the dechlorinated compound of 4a except for the optical rotation, suggesting that the rearrangement is stereospecific. All the reactions provide single stereoisomers in moderate to good yield as shown in Table 2. The utility of this reaction was clearly demonstrated by the efficient total synthesis of (-)-virantmycin (2a), which was carried out in only nine steps from commercially available starting material. In summary, we have developed a novel synthetic route of chiral trisubstituted tetrahydroquinolines by the combination of the diastereoselective Grignard addition and the stereospecific rearrangement. Using this methodology, we have achieved the efficient total syntheses of (+)-benzastatin E (1) and (-)-virantmycin (2a). We believe that our rearrangement reaction provides some support for the proposed biogenesis of virantmycin and benzastatins involving the aziridine intermediate.
