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    Home > Angelw: the tambar group of the University of Texas completed the synthesis of (±) - lundurine a by intercalation of Pictet Spengler

    Angelw: the tambar group of the University of Texas completed the synthesis of (±) - lundurine a by intercalation of Pictet Spengler

    • Last Update: 2018-06-27
    • Source: Internet
    • Author: User
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    Pictet Spengler cyclization based on tryptamine substrate is one of the most powerful strategies for the construction of the condensed polycyclic structure of indole (scheme 1a) In the presence of Lewis acid or Br? Nsted Acid, tetrahydro - β - carboline can be obtained by cyclization of the intermediate of active iminium ion This method is commonly used in the total synthesis of indole alkaloids and other bioactive compounds So far, there are few reports on the construction of tetrahydroazocininoindole mother nucleus by Pictet Spengler cyclization, especially the alkaloids with completely substituted carbon centers at the adjacent nitrogen atoms Recently, a Pictet Spengler cyclization reaction mediated by me 3 SiCl was reported by the team of uttam K tambar, Southwest Medical Center, University of Texas, at angew Chem Int ed to construct tetrahydroazocininoindole mother nucleus, and it was used in the total synthesis of indole alkaloids (±) - lundurine a (DOI: 10.1002 / anie 201803702) (picture source: angel Chem Int ed.) the reverse synthesis analysis of lundurine a (1) is as follows (scheme 1c): tetrahydroazocinindole mother nucleus containing all substituted carbon centers in molecule 2 can be produced by intercalation Pictet Spengler cyclization of n-acylimonium ion 3, and the active intermediate can be synthesized by hydroxy lactam 4 Firstly, we studied the cyclization of Pictet Spengler, and screened a series of Lewis acids (Table 1) for activating substrate 5 The results showed that when 1.25 equivalent TiCl 4, SnCl 4, BCl 3 or AlCl 3 were present, hydroxy lactam 5 could be converted into the expected tetrahydroazocinindole (6); when me 3 SiCl was used as Lewis acid, the expected yield of the substrate could be 82%; when me 3 SiCl was used as catalyst, the yield of the reaction decreased Then, the possible reaction mechanism is described (Table 1) After being treated with Lewis acid, γ - hydroxy lactam 5 is converted into active n-acylimonium ion 7 Its vinyl nucleophilic attack on n-acylimonium ion produces tetracycline 8, and then deprotonation produces tetrahydroazocinindole (6) (path a) Alternatively, the nucleophilic attack of indole-7 on C3 site resulted in spiro-9, which was transferred by 1,4-to form tetrahydroazocininoole product (path B) (picture source: angelw Chem Int ed.) after determining that me3sicl is the best Lewis acid, the author studied the application scope of the reaction (Table 2) By introducing alkyl chain, benzene ring, functionalized aromatic ring, heteroaromatic ring, ether and acetal into the side chain of hydroxy lactam 10, the corresponding substrate was resistant to the reaction, and the yield of tetrahydroazocinindole was not affected In addition to the completely substituted carbon, the author also produced the expected product with methyleneamine (image source: angelw Chem Int ed.) at the same time, the author also explored the substituent range of hydroxylactam 10 indole ring (table 2b) After the introduction of methyl and ether, the reaction can proceed smoothly The unsaturated functional group at C2 site of indole reacts with trisubstituted olefins to form intercalated Pictet Spengler cyclization products The cyclization can be carried out smoothly by introducing electron protecting groups on indole nitrogen, such as p-methoxybenzyl, methyl and allyl; after introducing electron absorbing BOC protecting group, the cyclization needs heating to get the expected products Finally, the author used this transformation to synthesize the indole alkaloid (±) - lundurinea (scheme 2) Tryptophan derivative 13 is coupled with Grignard reagent 14 to form a substrate 15 for the intercalated Pictet Spengler cyclization reaction In the presence of me 3sicl, hydroxy lactam 15 was converted into tetrahydroazocinindole (16) in 70% yield Meanwhile, the 8-membered ring structure and fully substituted carbon center in lundurina were constructed (image source: angelw Chem Int ed.) after obtaining the mother nuclear structure of lundurine a, the author has carried out a total synthesis study (scheme 2) The tetracyclic intermediate 16 was completely hydrogenated in two steps, and the primary alcohol was deprotected by TBS to obtain silica ether 17 The indole nitrogen of Si ether 17 was carboxymethylated with imidazolium carbamate 18, and the alcohol 19 was obtained by removing TBS After being oxidized by Swern, enol ether 20 was obtained by treating the substrate with ET 3 SiCl under the condition of weak enol Next, alkanol ether 20 forms silyloxy epoxide 21 under the action of tungsten catalyst and H 2O 2, and then oxidises to generate aldehyde 22 After aldehydes 22 are converted to hydrazone, Lewis acid mediated cyclopropanization is carried out to obtain polycyclic intermediate 23 Finally, amide 23 was converted into α - phenylsulfonylketone, and the target product was obtained by introducing α, β - unsaturated structure through CIS elimination The spectral data of (±) - lundurine a (1) synthesized by the authors are consistent with those reported in the literature Conclusion: a novel intercalated Pictet Spengler cyclization reaction has been developed The reaction can be used to construct the middle sized ring in the system of indole condensation, and has been successfully applied to the synthesis of (±) - lundurina Research direction of Dr uttam K tambar: 1) development of new catalytic reactions (enantioselective molecular rearrangement); 2) synthesis of bioactive natural products (especially polycyclic alkaloids); 3) integration of work in these two fields into pharmaceutical chemistry cooperation to find new therapeutic drugs  
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