抄録
(+)-PD 128907 is a potent and selective agonist for human dopamine subtype D3 receptor and its structure is a simple trans-tetrahydrobenzopyran-1,4-oxadine framework. Although its supply by chemical synthesis is required, there are only two reports on the synthesis PD 128907; one is the synthesis of the racemate and the other is asymmetric synthesis via resolution. 3-Amino-6-methoxy-3,4-dihydro-2H-l-benzopyran-4-ol derivatives (1a,b) are key intermediates for these syntheses. We expected that compounds la,b could be readily prepared by the intramolecular cyclization of N-protected 2-(2-hydroxy-5-methoxybenzoyl)aziridine 4, which could be obtained by aziridination of 2-hydroxy-5-methoxyphenyl vinyl ketone 3. We discovered that Ru(CO)-salen complex 5, which is an efficient catalyst for the asymmetric aziridination of simple olefins with N-SES* azide, also catalyzes the aziridination of various vinyl ketones (Table 1). The aziridination of vinyl ketone 3 was found to proceed with almost complete enantioselectivity (>99% ee), and the treatment of the resulting 4 with Hiinig's base gave 3-SES-6-methoxy- 1 -benzopyran-4-one 8 (96% ee), which was recrystallized form hexane/CH2C12 to organic purity. Then, compound 8 was converted into (4aR,10bR)-3,4,4a,10b- tetrahydro-9-methoxy-4-propy1-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazine (trans-2) via i) NaBH_4 reduction, ii) Aggarwal's 1,4-oxadine formation, iii) deprotection of SES group, and iv) N-propylation. Since demethylation of trans-2 has been reported by Wise et al., we could achieve formal total synthesis of (+)-PD 128907 using highly enantioselective aziridination of vinyl ketone as the key step, in eight steps. * SES= 2-trimethylsilyethanesulfony, a readily removable N-protecting group
