JACS: Scheidt group of Northwestern University completed the simple asymmetric synthesis of yohimbine alkaloids

The natural products of yohimbines are pentacyclic indole alkaloids (scheme 1) derived from tryptophan and iridoid monoterpenes Since yohimbine (1) was isolated from Spiegel in 1900 and its structure was determined by Witkop in 1943, chemists have identified a variety of yohimbine isomers Due to the different stereochemical arrangement around the D-ring, it can be divided into four different subfamilies: normal, allo, pseudo or epillo The representative members are yohimbine (1), rauwolscine (2), pseudo yohimbine (3) and reserpine (4) (scheme 1) These alkaloids show central nervous system activity, which has aroused great interest of researchers Recently, Karl a Scheidt group of Northwestern University of the United States completed the simple asymmetric synthesis of yohimbine alkaloids, which was published in J am Chem SOC (DOI: 10.1021 / JACS 9b12319) Inverse synthesis analysis (scheme 1): the author conceives that (-) - rauwolscine (2) can be synthesized by asymmetric reduction of known β - keto ester 5 β - keto ester 5 can be obtained by reduction and homologation of diester 6 and then closed-loop reaction The key intermediate comes from amidation of enol-lactone 7 / cation cyclization of isoindole-quinoline 7 can be produced by aldehyde 8 on the market The dimerization reaction catalyzed by NHC was obtained In addition, tetracycline 6 was used as a potential precursor to construct enantiomeric normal, pseudoand epimeric henbin nuclei by selective stereochemical inversion at the junction of C / D and D / E rings (photo source: J am Chem SOC.) firstly, the enantiomeric enrichment of enol lactone 7 (83%, 99:1 Er, ＞ 95:5 DR) was constructed by using scheme 2, a commercial aldehyde 8 as the starting material, and then the key amidation / isoindole quinoline cation cyclization process with tryptamine was explored Through further optimization of the reaction conditions, the author treated 7 with 2eq 10 in CH2Cl2 / Na2CO3 aqueous solution two-phase solvent system, and then carried out acidification and TFA promoted cyclization reaction, and obtained a separable 6-enantiomer mixture (80:20), whose lactam was selectively reduced to tertiary amine 11 by BH 3 · DMS (photo source: J am Chem SOC.) after assembling ABCD ring, the author turned his attention to the construction of E ring However, the target product was not obtained by Arndt eisert or kowalksi Later, the author turned his attention to Wittig Horner condition Through the screening of temperature and reducing agent, it is found that the yield of 13% can be obtained by treating 11 with ldbba at 0 ℃ in the presence of excess 12 Although p-TsOH (10 Eq.), MeOH, 80 ℃) can convert 13 to bis (methyl ester), the subsequent cyclization produces a 14a / 14b non separable mixture Finally, the author used the mild condition [P -TsOH (2 Eq.), DCM/MeOH, 0-45 ℃] to treat 13 to obtain the separated α - oxonene two thioacetal 15 and a small amount of regional isomer by-product (60:40), and then used HgCl 2 /BF 3 · OEt 2 to remove the α - oxonene two thioacetal in methanol to obtain the methyl ester 5 β - keto ester 5 was reduced by NaBH 4 to 17 epirauwolscine 16, but no 2 was formed Under the catalysis of SMI 2, when H 2O was used as proton additive, (- - rauwolscine 2 was obtained in 65% yield, which was a single non enantiomer After decarboxylation of β - keto ester 5 by LiOH, the improved WOL ff Kishner reduced to the unsubstituted E-ring product (-) - alloyohimbane 17 In addition, the step economy of 2,16 and 17 synthesized by the authors is better than that of asymmetric synthesis previously reported After the construction of the isoyohimbine, the author tried to synthesize other yohimbine isomers, and investigated the conditions of non enantioselective cyclization of isoindole quinoline cations (Table 1) After hydrolysis of imine, the intermediate hydroxylactam 18 (∼ 85:15 D.R.) was separated by extraction At higher temperature or with acetate activator, the reaction efficiency and selectivity decreased; at - 78 ℃, the reaction showed high selectivity and efficiency (78%, 95:5 D.R.) However, the reaction at 40 ℃ resulted in a reversal of enantioselectivity of 19 (69%, 73:27d R.) (photo source: J am Chem SOC.) in order to further study the enantioselectivity, the author treated pure 6 with entry 7 and reacted at 40 ℃ for 4 days to obtain the same ratio of enantiomers (6:19 = 27:73); neither prolonging the reaction time nor using chiral additives (thiourea or phosphoric acid) changed the ratio In addition, the same product proportion was not produced in the treatment of 18 with anhydrous HCl instead of tmscl at 40 ℃, indicating that acid catalysis did not affect the reaction equilibrium Therefore, the high enantioselectivity observed at low temperature is the result of closed-loop kinetic control, while at higher temperature, the equilibrium mechanism plays a role and a more stable four ring 19 is obtained as the main product Through the above conditions, we can obtain the alloyohimbine precursor 6 (scheme 3) with high enantioselectivity In THF EtOH (1:1) treated with naoet at - 20 ℃, the C15 site can be selectively isomerized into pseudo yohimbine precursor 20 In oxygen atmosphere, 20 was oxidized to enamide by cupric acetate (II), and then reduced by NaBH4 to obtain yohimbine precursor 21, which is a single non enantiomer Finally, the enantioselectivity (73:27d R.) was optimized to obtain 19 (69%) of the precursor (photo source: J am Chem SOC.) conclusion: Karl a Scheidt research group completed the simple and asymmetric synthesis of (- - rauwolscine 2 and (- - alloyohimbane 17 with ethyl 4-oxobutyrate 8 as raw material The key cyclization product 7 catalyzed by NHC can be converted into complex tetracyclic lactam 6, which can be used as a general intermediate to synthesize other yohimbine isomers In addition, all eight stereoisomers of the alkaloid can be constructed by using the chiral NHC catalyst (+ or -), which provides a chemical basis for the discovery of new bioactive molecules.