echemi logo
Product
  • Product
  • Supplier
  • Inquiry
    Home > Nat. Commun.: enantioselective synthesis of CIS hydrobenzofuran containing quaternary carbon chiral center and its application in (-) - morphine synthesis

    Nat. Commun.: enantioselective synthesis of CIS hydrobenzofuran containing quaternary carbon chiral center and its application in (-) - morphine synthesis

    • Last Update: 2019-06-23
    • Source: Internet
    • Author: User
    Search more information of high quality chemicals, good prices and reliable suppliers, visit www.echemi.com
    Morphine (1a) was isolated from opium poppy by SERT ü rner et al in 1806 It has obvious pharmacological effects, such as analgesic and sedative effects Therefore, it is widely used in clinical treatment and research As the most important drug for the treatment of human pain, morphine has been listed as the basic drug by the World Health Organization (who) In terms of structure (Fig 1), morphine (1a) contains a tension five ring skeleton, on which there are dense functionalized CIS hydrodibenzofuran core and five consecutive chiral centers, including a key quaternary carbon chiral center The complex molecular structure of morphine and its clinical pharmacological effects have attracted extensive attention of researchers However, there are still limited reports on the asymmetric synthesis of (-) - morphine In recent years, the team of academician Tu Yongqiang has been devoted to the construction of quaternary carbon centers by using 1,2-carbon atom transfer reaction, and applied to the efficient synthesis of some important bioactive natural products Recently, the team has achieved efficient enantioselective total synthesis of (-) - morphine through the longest linear step of 16 steps Relevant research results were published in NAT Commun (DOI: 10.1038/s41467-019-10398-4) The corresponding authors are tu Yongqiang, academician of Lanzhou University / Shanghai Jiaotong University and Zhang Fumin, Professor of Lanzhou University (source: Nat Commun.) reverse synthesis analysis (Fig 2): target molecule 1A can be cyclized from known precursor I, which can be obtained by the introduction of tetracycline II through the stereocenter and the transformation of some functional groups Ketene II was constructed by B ring of tricyclic compound III Based on the team's recent research results on the asymmetric construction of quaternary carbon chiral centers catalyzed by SPD, the author speculates that the key tricyclic compound III can be synthesized by organic catalyzed asymmetric Robinson cyclization of intermediate IV under suitable reaction conditions Substrate IV can be produced by coupling acetylene amide V with bromide 2, which can be prepared from commercially available compounds 3 and 4, respectively (source: Nat Commun.) preparation of enone precursor: the synthesis route starts from the gram scale preparation of compound 7 (Fig 3) The commercial 3-butyne-1-ol-3 was treated with n-methoxy-n-methylcarbamoyl chloride to obtain Weinreb amide 5 Compound 5 was boronized and then Suzuki coupled with aryl bromide 2 to obtain trisubstituted aromatic compound 6 After the addition of MGBR, the acetal group was deprotected to obtain the required precursor 7 (source: Nat Commun.) optimization of reaction conditions: after obtaining a large number of precursors 7, the author is committed to the intramolecular Robinson cyclization designed by the Institute Firstly, benzoic acid (A1) was used as additive to screen different secondary amine catalysts (Table 1) at room temperature Although there is no target tricyclic product 10, the intramolecular Michael addition product 8 is obtained At present, there is no asymmetric synthesis method of cis-h-benzofuran skeleton with a large block benzyl type quaternary carbon center, and the skeleton can be used to synthesize a variety of bioactive natural products and clinical drug molecules, such as diterpene (‒) - isoabietenin A and drug (‒ - galanthamine Therefore, the Michael addition reaction was studied in depth It is worth noting that in order to accurately determine the EE value of Michael addition product, the aldehyde 8 obtained was converted into vinyl ester derivative 9 in situ by Wittig reaction (source: Nat Commin.) the author found that compared with other common catalysts cat 1-4, SPD catalyst (cat 5-6) can provide the target product 9 with good enantioselectivity, and the reaction rate is faster (Table 1, entries 1-6) Among them, cat 6, the SPD catalyst with larger potential resistance, has the best effect After a lot of conditions such as temperature and additives were selected, the author found that with 2,4,6-diisopropylbenzoic acid (A3) as the additive, the intermediate 7 could react at - 30 ℃ for 48 hours, and the product 9 could be obtained with 87% yield and 96% ee value After developing the SPD catalyzed intramolecular Michael addition reaction, the author turned to study the designed intramolecular Robinson cyclization (Fig 4) It is gratifying that when the crude compound 8 is treated with p-toluenesulfonic acid at 90 ℃, the required product 10 can be separated with 66% yield and excellent enantioselectivity (94% ee) (source: Nat Commun.) (‒) - codeine and (‒) - Asymmetric Total Synthesis of morphine: after efficient construction of AEC ring system of morphine, the author continued to complete the construction of B ring (Fig 5) Under the action of LiHMDS, allylation of ketene 10 and 3,3-dimethylallylidene iodine resulted in the formation of two inseparable isomers 11 Then, the electron rich double bonds were decomposed by selective ozonation, and then reduced by ph3p to aldehydes The aldehydes were cyclized by Friedel crafts under the catalysis of polyphosphate (PPA), and the single enantiomeric ferofuran 12 was obtained α, β - Epoxy ketones with high regioselectivity and enantioselectivity were obtained by selective epoxidation of 12 with hydrogen peroxide After treatment with n 2H 4 · HCl, allyl alcohol 13 was obtained with a two-step yield of 54% Then the excess DDQ was used for oxidative debenzylation of chlorobenzene and water, and the required alcohol 14 was obtained in 85% yield The enantiomeric sulfonamide 15 was obtained from alcohol 14 by highly regioselective intermolecular Mitsunobu reaction, in which primary alcohol was converted to sulfonamide prior to allyl alcohol, which may be due to the small steric hindrance of primary alcohol The structure of allyl alcohol 15 was reversed by continuous oxidation-reduction process, and the intermediate I was obtained efficiently Then, under the action of t-BuOH and 4,4 '- di-tert-butyl biphenyl, I provided (-) - codeine (1b) in 68% yield through the key hydroamination reaction Finally, (-) - codeine can be easily converted into (-) - morphine (1a) by demethylation of boron tribromide The spectral data of (-) - morphine and (-) - codeine are consistent with those reported in literature Conclusion: starting from the 3-butyne-1-ol sold on the market, the team of academician Tu Yongqiang realized the asymmetric synthesis of (-) - morphine through the longest linear step of 16 steps The efficient enantioselective SPD catalyzed Michael addition / PTSA catalytic cyclization not only constructed the stereocenters of AEC tricyclic framework and target molecular neighborhood, but also showed the excellent catalytic performance of SPD catalyst in the initial Michael addition reaction (yield up to 87%, 96% ee) In addition, the key method of constructing quaternary carbon chiral center based on direct and catalytic asymmetry enriches the synthesis strategy of (-) - morphine.
    This article is an English version of an article which is originally in the Chinese language on echemi.com and is provided for information purposes only. This website makes no representation or warranty of any kind, either expressed or implied, as to the accuracy, completeness ownership or reliability of the article or any translations thereof. If you have any concerns or complaints relating to the article, please send an email, providing a detailed description of the concern or complaint, to service@echemi.com. A staff member will contact you within 5 working days. Once verified, infringing content will be removed immediately.

    Contact Us

    The source of this page with content of products and services is from Internet, which doesn't represent ECHEMI's opinion. If you have any queries, please write to service@echemi.com. It will be replied within 5 days.

    Moreover, if you find any instances of plagiarism from the page, please send email to service@echemi.com with relevant evidence.