29 四級炭素の触媒的不斉合成と医薬品、天然有機化合物合成への応用(口頭発表の部)
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Benzylic quaternary carbon centers are found in various bioactive molecules such as eptazocine (1), morphine (2) and halenaquinol (3), and the construction of such centers in a catalytic, enantioselective manner continues to provide an interesting challenge for organic chemists. We thought that catalytic asymmetric syntheses of such benzylic quaternary carbon centers would be feasible by utilizing an asymmetric Heck reaction (ref. 1). Our strategy for the construction of benzylic quarternary carbon centers in an optically active form is illustrated in Scheme I. It was expected that the prsence of a chiral ligand in the Heck-type arylation of 4 would result in the discrimination of the re and si-faces of the trisubstituted olefin, but the effect of olefin geometry on the asymmetric induction remained ambiguous. The asymmetric Heck reaction of (E)-olefins 10 and 11 was then investigated. Treatment of 10 with Pd_2(dba)_3・CHCl_3 (5 mol%), (R)-BINAP (10 mol %), and K_2CO_3 (3 mol equiv) in THF at 70℃ was found to give the best results, affording (S)-trans-13 of 39% ee as the major product (70% yield) and (S)-cis-13 of 32% ee as the minor product (19% yield). A kinetic resolution in the syn-β-hydrogen elimination step could easily explain the differences observed in the enantiomeric excess of trans- and cis-13. On the oter hand, subjection of 11 to the conditions described above resulted in the formation of (S)-14 of 51% ee as a chromatographically inseparable mixture of olefin isomers in 95% yield (trans: cis= 84:11). Furthermore, treatment of 12 with Pd(OAc)_2 (10 mol%), (R)-BINAP (20 mol%), and K_2CO_3 (3 mol equiv) in THF at 50℃ gave the (R)-isomer 14 of 91% ee in 79% yield (trans: cis=98:2). Apparently, the absolute configuration of the product obtained with the (R)-BINAP system is reversed in going from the (E)- to (Z)-trisubstituted olefin, and the degree of enantioselectivity is influenced significantly by the olefin geometry. With our system, the use of (Z)-trisubstituted olefins appeares essential for the synthesis of benzylic quaternary centers of high ee. Next, we sought to apply this methodology to the synthesis of (-)-eptazocine (1). For therapeutic use, (-)-eptazocine (1), the more biologically active enantiomer, is currently prepared through resolution. The trisubstituted benzene derivative 21 was prepared in three steps (78% yield) from 3-methoxyphenol and then converted to 22 in 69% overall yield by the use of Suzuki cross-coupling reaction as a key step. Exposure of 22 to Pd(OAc)_2 (7 mol%), (R)-BINAP (17 mol%), and K_2CO_3 (3 mol equiv) in THF at 60℃ gave 23 (trans: cis=21:3) of 90% ee in 90% yield. This methoxy-substituted tetralin derivative 23 was converted to (-)-eptazocine in short steps. An approach to a catalytic asymmetric synthesis of 3 is currently under investigation.
- 天然有機化合物討論会の論文
- 1994-09-20
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