25 Strychnosアルカロイド(-)-Strychnineの触媒的不斉全合成研究(口頭発表の部)
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Strychnine (1) is a representative member of the Strychnos family of indole alkaloids and has been a target of several synthetic investigations. In recent years, three research groups have culminated their research in the asymmetric total synthesis of (-)-1. To date, however, no catalytic asymmetric synthesis has been accomplished except for enzymatic method. We describe herein the development toward a novel stable, storable and reusable asymmetric catalyst (R,R)-La-linked-BINOL 10 and our synthetic studies of (-)-strychnine (1) employing catalytic asymmetric Michael reaction catalyzed by multifunctional asymmetric catalysts as the key step. We previously developed a highly practical catalytic asymmetric Michael reaction using AlLibis(binaphtoxide) (ALB 5). At high concentration (31M) the reaction was highly accelerated and the use of only 0.3mol% of (R)-ALB 5 promoted the Michael reaction of 6 with 7 to completion within 10h, giving Michael adduct 8 in 95% yield and 99% ee. Furthermore, we developed novel highly stable, storable and reusable asymmetric catalyst (R,R)-La-linked-BINOL 10, which also catalyzed this reaction efficiently to give Michael adduct 8 in 94% yield and >99% ee. The catalyst 10 was easily prepared from La(O-i-Pr)_3 and 1.0 equivalent of linked-BINOL 9, which were mixed in THF followed by removal of solvent under reduced pressure to afford 10 as a pale-yellow powder. This air-stable catalyst 10 is storable under air at ambient temperature. After 4 weeks storage, no change in catalytic activity, in terms of both chemical yield and ee, was observed using stock catalyst 10. In addition, the catalyst 10 can be reused several times. After the examination of the scope and limitations of different substrates, we found that the catalyst 10 promoted the Michael reaction of a variety of cyclic enones (n=0-4) with various malonates to afford Michael adducts with good to excellent ee's. The complex 10 was also effective for the Michael reaction of acyclic enones. To the best of our knowledge no efficient catalytic Michael reaction of 8- and 9-membered ring enones with malonates has been reported to date and this is the first example of a Michael reaction where the catalyst shows such broad generality. Having obtained nearly optically pure 8 in large quantities, we next planned to synthesize (-)-strychnine (1) using the Michael adduct 8 as a chiral building block. From the many disconnections, we chose the strategy based on the Stille coupling reaction, intramolecular 1,4-addition reaction of amine to enone, and intramolecular alkylation. This approach requires the precursor α-iodoenone 38, which could be prepared by regioselective enone forming reaction followed by iodination of the corresponding enone. Because the (E)-side chain of 40 would evolve to F and G rings of (-)-strychnine (1), stereoselective introduction of this unit would solve the stereochemical problem posed by the allylic ether double bond at C(20). The synthesis of the (E)-α,β-unsaturated ester 40 was achieved by using a modified Overmann's procedure. In this reaction, we found that the E/Z-selectivity and yield of this reaction are highly dependent on the reaction temperature. At ?55℃ the best result, 70% (2 steps) and E:Z=>15:1, was obtained. In the oxidation step of the corresponding allylic alcohol using MnO_2 the kinetic resolution was observed. (E)-allylic alcohol was oxidized much faster than (Z)-allylic alcohol to afford almost pure (E)-α,β-unsaturated aldehyde 45. After the introduction of C-ring moiety by reductive amination, we next examined the regioselective enone forming reaction. As we expected, more bulky base gave higher selectivity (48:47=up to 6:1). Using these inseparable mixtures, DMAP promoted the iodination of 48 to afford the α-iodoenone 38 with unreacted 47. Using the α-iodoenone 38, we next examined the Stille coupling reaction. At first we could get only trace amount of coupling product 50 even at higher temperature. However, we found that the addition of catalytic amount of CuI dramatically accelerated the coupling reaction even at room temperature to afford the coupling product 50 in quantitative yield. After the exchange of the protecting group of allylic alcohol from PMB to MEM followed by deprotection of Boc, we examined 1,4-addition reaction of amine. After many attempts, we finally found that only BnNMe_3OH is able to promote the reaction effectively to give cyclized compound 36 after deprotection of TBDPS. The primary alcohol of compound 36 was converted to phenyl sulfonate which was cyclized to give the key intermediate 35 subsequently.
- 天然有機化合物討論会の論文
- 2000-10-01
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