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    Home > Stereoselective construction of trisubstituted double bonds with improved Julia kocienski reagent and its application in the total synthesis of limazepine E and barmumycin

    Stereoselective construction of trisubstituted double bonds with improved Julia kocienski reagent and its application in the total synthesis of limazepine E and barmumycin

    • Last Update: 2018-04-24
    • Source: Internet
    • Author: User
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    The author: limazepine (6), a natural product of pyrrole [1,4] benzodiazepines (PBD), was isolated from Micrococcus icbb 81771 by Mahmud research group in 2009 Most PBD natural products can covalently bind to the small groove of DNA and show anticancer activity, and many PBD and its antibody conjugates (ADC) have been evaluated as anticancer drugs, and clinical trials are ongoing (photo source: J org Chem.) most of pyrrole [1,4] benzodiazepines (PBD) natural products have a right-handed tricyclic system and contain C2 alkylene, as shown in Figure 1 Biological studies show that C2 double bond can significantly increase the anticancer activity, but the stereoselective introduction of C2 alkylene is still a considerable challenge The classical methods of building double bonds (such as Wittig and Julia kocienski) are lack of selectivity or mainly get Z-isomers In addition, the introduction of three substituted double bonds based on stereoselective Ireland Claisen rearrangement is also a common method, but the required 3-ethyleneproline synthesis block needs at least 9 linear steps, lacking economy and simplicity Recently, GITS Smits research group of Latvia published on J org Chem That using the improved Julia kocienski reagent for stereoselective construction of three substituted double bonds, and used it in the total synthesis of limazepine e (DOI: 10.1021 / ACS JOC 8b00643) Inverse synthesis analysis is shown in figure (scheme 1) The key point of this route is the introduction of three substituted double bonds in the later stage, and then selective reduction of C11 carbonyl to obtain limazepine E The intermediate bislactam 9 can be constructed from isoniacin and trans-4-hydroxy-l-proline, which are cheap and easy to obtain, and then oxidized to ketone 8 (photo source: J org Chem.) the specific synthesis route is as follows: first, the synthesis of ketone 13 (scheme 2), starting with isoniacin, according to the literature (Tetrahedron lett 2017, 58, 2426-2428) was synthesized by multi-step reaction to form Nitrobenzoic Acid 10, which was condensed with trans-4-hydroxy-l-proline to form intermediate 11 The amide 11 was reduced and hydrogenated, and then the alcohol 12 was treated with benzaldehyde dimethylacetal at high temperature, and then the ketone 13 was oxidized by DES Martin (photo source: J org Chem.) after obtaining ketone 13, the author tried to introduce three substituted double bonds (Table 1) into C2 site stereoselectively Based on the previous studies, the author determined to introduce trisubstituted double bond into Julia kocienski Olefination reaction In order to find the best Julia reagent, classical benzothiazolylsulfone 14a, 2-pyridylsulfone 14b and tetrazolsulfone 14C and 14d were synthesized, and Julia kocienski Olefination reaction with ketone 13 was carried out in the presence of three different bases (Li, Na and khmds) (Table 1) The results showed that sulfone 14a and 14b were lack of stereoselectivity and the yield was low, but tetrazolium sulfone 14C and 14d used khmds as alkali reaction to obtain the expected product 15 with 53% - 75% yield and good stereoselectivity (photo source: J org Chem.) in order to optimize the reaction conditions, the author further screened the reaction solvent (Table 2) In five different solvents, only DCM and THF were found to have the same stereoselectivity, but the reactivity was reduced (photo source: J Org Chem.) next, the author speculates that the stereochemical effect of Julia-Kocienski reagent 14 may have a decisive impact on the stereochemical results of the reaction In order to test this hypothesis, several larger Julia kocienski reagents were synthesized and olefinized (Table 3) The experimental results show that all sulfones except 14h have good stereoselectivity However, the low reactivity of 14h may be due to the steric hindrance Using (2,4,6-tricyclohexylphenyl) - tetrazolium sulfone 14J and ketone 13, the effect of Julia kocienski olefinization is the best The expected isomer ratio e / Z of olefin 15 is 97:3 (photo source: J org Chem.) after obtaining bislactam 15, according to the previously reported route (org Lett 2013, 15, 4406 – 4409), the full synthesis of limazepine e (6) can be completed in one step Compared with the previous 12 step synthesis route, the new method can complete the full synthesis of limazepine e (6) in only 9 steps, and can also modify the C2 bit later The stereoselective construction of trisubstituted double bonds by using the improved Julia kocienski reagent can be further applied to the total synthesis of barmumycin 19 (scheme 3) (photo source: J org Chem.) for the total synthesis of barmumycin (19), the author took the proline derivative 16 reported in the literature as the raw material and oxidized it to ketone 17 by DESs Martin Next, the newly developed sulfone 14J and the classical sulfone 14C were used for Julia kocienski olefinization to prepare 18 The results showed that 14J (E / Z 3:1) had better stereoselectivity than 14C (E / Z 2:1) Finally, according to the literature method (J org Chem 2010, 75, 8508 – 8515), the intermediate 18 was further converted into barmumycin by multi-step reaction Conclusion: the author developed a modified Julia kocienski olefinization method, using a new type of aryltetrazolium sulfone with large steric hindrance as Julia kocienski reagent to realize stereoselective introduction of trisubstituted double bonds, and successfully applied the method to the total synthesis of limazepine E and barmumycin.
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