126(P-86) (+)-リゼルギン酸の不斉合成研究(ポスター発表の部)

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(+)-Lysergic acid (1) is the core structure of ergot alkaloids family and has been known possessing a variety of biological activities such as prolactin-inhibiting, antihypertensive, and antiparkinson activities. Because of its medicinal importance, lysergic acid has attracted synthetic organic chemists and racemic syntheses of 1 have been already reported by several research groups. However, the total synthesis of (+)-lysergic acid (1) has not been achieved yet. Herein, we report synthetic studies of 1 as an optically active form using amino acid as a chiral building block, and construct the its four ring systems by metal-catalyzed C-C bond formation reactions. Our synthetic strategy is shown in Figure 2. Lysergic acid could be separated into two segments. Namely, one is northern part 8, which will be synthesized from L-serine as an optically active form and the other is southern part 9 derived from commercially available 3-aminophenol (10). The both segments will be combined by Suzuki-Miyaura cross coupling and finally B and C rings can be constructed at the same time by copper(II) catalyzed sequential cyclization reaction, which was developed by our research group (Type II cyclization, Figure 1). First, we investigated northern part synthesis (Schemes 2 and 3). L-Serine was converted to the aldehyde 17 by reported procedure and was alkynylated to afford the desired alcohol 19a as a major product (7:1 diastereomer ratio) under Felkin-Anh control. Next, N-Boc piperidinone 23 was synthesized from 19a in 7 steps and it was then converted to cyclic enamine 25 in two steps. The reaction of 25 with NBS gave the unexpected bicyclo[3,2,1]octane 27 via acetal exchange reaction followed by intramolecular cyclization. We expected that the stereochemistry for later functionalization might be controlled by the rigid structure of 27. The final stage of northern part synthesis is now under investigation. The southern part synthesis has been achieved as shown in Scheme 4. The successful treatment of 30 to BuLi, followed by DMF gave desired 1,2,3-trisubstituted aromatic compound 31. After being subjected 31 to deprotection-functionalization sequences, synthesis of southern part 9 has been concluded. Next, Suzuki-Miyaura coupling reaction for C10-C11 bond formation was investigated. After several efforts for coupling reaction between vinylboronate 37 and triflates 9 or 38 as the model studies, we could find the good coupling condition (Table: Entry 6). Further improvements of this coupling reaction conditions and model experiments of tandem cyclization reaction are currently in progress in our laboratory.
天然有機化合物討論会の論文
2004-10-01

126(P-86) (+)-リゼルギン酸の不斉合成研究(ポスター発表の部)

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