Asymmetric Total Syntheses of Strychnos Alkaloids via Selective Fischer Indolization.docx
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1、IOCte This以 Org. Chern. 2022f 7,5199-5212Read OnlineACCESS IM Metrics & MoreArticle RecommendationsO Supporting InformationThe Journal of Organic ChemistryArticlepubs.acs.org/jocXiaolei LiUj1 Mingliang Lou,1 Songlin Bai Guoxin Sun,* and Xiangbing Qi*ABSTRACT: The complex structures and important bio
2、logical functions of Strychnos alkaloids have attracted a great deal of attention from synthetic chemists. Herein; we describe the concise asymmetric total syntheses of the Strychnos alkaloids; ()-dehydrotubifbline; (-)-tubifoline; and (一)tubi- fblidine, as well as the formal total synthesis of ()-s
3、trychnine. Our strategy features the construction of the common tetracyclic pyrrolo2,3- d carbazole structure using regioselective Fischer indolization on unsym- metrical cyclic ketones and late-stage functionalization for divergent synthesis. We developed a stepwise Fischer indolization featuring s
4、elective formation of enol tHflate to solve the challenging regioselectivity problem, leading to the common tetracyclic ring skeleton in these Strychnos alkaloids. The regioselectivity of Fischer indolization on unsymmetrical cyclic ketones was studied on the basis of different types of ring systems
5、 and supported by density functional theory calculations. Overall, our success in the construction of this tetracyclic ring secured the syntheses of Strychnos alkaloids and may provide a general method for the total syntheses of various alkaloids containing this skeleton. INTRODUCTIONstructure, dist
6、ribution, and biological function? ContinuousAsymmetric Total Syntheses of Strychnos Alkaloids via Selective Fischer Indolizationefforts toward the synthesis of Strychnos alkaloids have led to divergent syntheses of these alkaloids.Fischer indole synthesis remains one of the most practical methods f
7、or the total synthesis of indole alkaloids.4 However, to the best of our knowledge, there have been no reports of the successful application of Fischer indole synthesis for the construction of this tetracyclic scaffold (1) to synthesize Strychnos alkaloids. In our synthetic design, the divergent syn
8、theses of Strychnos alkaloids could be achieved through latestage functionalization of the tetracyclic hexahydro-pyrrolol2,3- dcarbazole (1), which in turn could be prepared from ketone 6 by direct Fischer indolization (Figure 1). However, although it has been well established that regioselectivity
9、can s:/doi.org/10.1021/acs.joc.2c00015 J. Org. Chem. 2022, 87, 5199-5212Some of the most well-known monoterpene indole alkaloids, Strychnos alkaloids have attracted a great deal of attention from researchers due to their complicated structural features and important biological activities. For exampl
10、e, the representative member, (-)-strychnine 2 (Figure 1), is composed of seven congested ring systems with six contiguous stereogenic centersthe development of a variety of synthetic strategies.2 A notable structural feature of Strychnos alkaloids is the tetracyclic pyrrolo2,3-dcarbazole skeleton (
11、1), which is widely distributed in other indole alkaloids.3 We envision that the development of a unified yet versatile strategy for generating this common tetracyclic framework could help secure thefiltered, and concentrated to afford the crude product. The crude product was purified by flash chrom
12、atography on silica gel with a 1:1 EA/PE mixture and evaporated to give product 23 as a brown solid (402.0 mg, 92% yield for two steps): mp 148-150 ;H NMR (400 MHz, CDCh) 6 7.72 (d, J = 8.5 Hz, 2H), 7.36 (dd, J = 8.0, 0.5 Hz, 2H), 3.93-3.80 (m, 2H), 2.86-2.75 (m, 2H), 2.71 -2.57 (m, 2H), 2.45 (s, 3H
13、), 2.35-2.25 (m, 2 H), 2.09 -1.95 (m, 2H); ,3C ,H) NMR (100 MHz, CDCh) 6 195.6,159.5,144.8, 135.0, 130.2, 127.1, 119.9,50.1,36.4,24.2,24.1,22.5 , 21.6; HRMS (ESI) calcd for C 15H18NO3S M + H+ m/z 292.1007 , found 292.1007.l-Tosyl-2,3,5,6,7,7ahexahydro-lHindol-4-ylTrifluoromethanesulfonate (25). A fl
14、ame-dried 50 mL flask with a Teflon stir bar was charged with 1 -tosyl-1,2,3,5,6,7-hexahydro-4H- indol-4-one (23, 1.08 mmol, 315.0 mg, 1.00 equiv) and anhydrous DCM (5.5 mL), and then TfiO (2.16 mmol, 611.0 mg, 2.00 equiv) and EtsSiH (2.16 mmol, 251.0 mg, 2.00 equiv) were added successively at rt. T
15、he mixture was stirred at rt for 21 h. Then the reaction was quenched with a saturated NaHCO? aqueous solution, and the mixture was extracted with DCM (3 x 20 mL). The organic phase was collected, dried over Na 2SO4, filtered, and concentrated to afford the crude product. The crude product was purif
16、ied by flash chromatography on silica gel with a 1:10 EA/PE mixture and evaporated to give 25 as a white solid (426.0 mg, 93% yield): mp 81-83 ; 1H NMR (400 MHz, CDCh) 6 7.71 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 7.9 Hz, 2 H),3.70-3.60 (m, 1H), 3.46 (dt, J = 10.6, 7.6 Hz, 1H), 3.32 (ddd, J 二 10.6, 9.4,
17、4.4 Hz, 1H), 2.74-2.61 (m, 1H), 2.60-2.52 (m, 1H), 2.45 (s, 3H), 2.40-2.28 (m, 2H), 2.24-2.12 (m, 1H), 2.10-1.98 (m, 1 H), 1.75-1.58 (m, 1H), 1.50-1.34 (m, 1H); ,3CH NMR (100 MHz, CDCh) 6 144.2, 142.5, 133.2, 130.9, 130.0, 127.8, 118.3 (q, Jc-f = 317.5 Hz), 59.8, 47.7, 28.9, 26.5, 25.6, 21.6, 20.5;
18、,9F NMR (376 MHz, CDCh) 6 -74.68; HRMS (ESI) calcd for Ci6H18F3NO5s2Na M + NaJ+ m/z 448.0476, found 448.0482.3-Tosyl-2,3,3a,4,5,6-hexahydro-lH-pyrrolo2z3-dcarbazole (20). A 25 mL round-bottom flask with a Teflon stir bar was charged with 1 -tosyl-2,3,5,6,7,7a-hexahydro-1 H-indol-4-yl trifluoromethan
19、esulfonate (25, 0.25 mmol, 105.0 mg, 1.00 equiv), PhNBocNHBoc (0.35 mmol, 108.0 mg, 1.40 equiv), tBusPHBF4 (0.025 mmol, 8.0 mg, 0.10 equiv), Pd(OAc)2(0.013 mmol, 3.0 mg, 0.05 equiv), LiCl (1.75 mmol, 75.0 mg, 7.00 equiv), CS2CO3 (0.50 mmol, 163.0 mg, 2.00 equiv), and anhydrous toluene (8 mL). The su
20、spension was degassed with Ar for 10 min. Then the reaction mixture was stirred at 110 for 48 h under an Ar atmosphere. After the reaction had reached completion, the mixture was cooled to room temperature (25 ), the solid filtered, and the filtrate used for the next step directly without further pu
21、rification. A 10 mL microwave tube with a Teflon stir bar was charged with the filtrate and ZnCb (1.50 mmol, 204.0 mg, 6.00 equiv), and then the mixture was stirred three times at 90 for 2 h under microwave irradiation using a microwave reactor ( CEM Explorer). After cooling to room temperature, the
22、 solid was filtered, and the filtrate was concentrated in vacuum. The residue was subjected to flash column chromatography on silica gel (EA/PE, from 1:5 to 1:1) to afford the product as a light-yellow solid (75.0 mg, 83 % yield fbr two steps). The spectroscopic data obtained for this product were i
23、dentical to those of the sample of 20 prepared from substrate 19 using direct Fischer indolization. (Z)-3-(2-lodobut-2-en-l-yl)-2,3,3a,4,5,6- hexahydro-lH-pyrrolo2,3-dcarbazole (29). A 10 mL microwave tube with a Teflon stir bar was charged with 3-losyl-2,3,3a,4,5,6- hexahydro-lH-pyrrolo2,3-dcarbazo
24、le (20, 1.00 mmol, 366.0 mg, 1.00 equiv), AcOH (4 mL), and HCIO4 (2 mL). The reaction mixture was stirred at 120 for 2-4 h under microwave irradiation using a microwave reactor (CEM Explorer). The solid was filtered, and AcOH and a portion of water were removed under reduced pressure.The residue was
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