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    Home > NHC catalyzed asymmetric acetalization of carboxylic acids to prepare chiral phthalate prodrugs

    NHC catalyzed asymmetric acetalization of carboxylic acids to prepare chiral phthalate prodrugs

    • Last Update: 2019-04-28
    • Source: Internet
    • Author: User
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    Carboxylic acid is the most common group in drugs In order to improve the efficacy or reduce the side effects, researchers usually convert it into corresponding esters Among them, phthalate, as a precursor, is particularly effective (Fig 1a) The prodrugs containing phthalates include acetyl phthalide, fluonicotinate, paecilomycin and tamoxin All phthalates contain acetal skeleton with chiral carbon, which is difficult to construct enantioselectively (Fig 1b) Up to now, phthalates are usually prepared by the reaction of carboxylic acid and 3- bromophthalein Two kinds of phthalates have been studied This method is simple and effective, but it can not control the stereoselectivity of the chiral center Therefore, only racemic mixtures of phthalates can be obtained Recently, Professor Yonggui Robin Chi of Nanyang University of technology in Singapore and Professor Pan Lutai of Guizhou University of traditional Chinese medicine solved the above problems They developed an organic catalytic strategy for enantioselective functionalization of carboxylic acids and effectively prepared optically pure phthalates Relevant research results were published in nature communications (DOI: 10.1038/s41467-019-09445-x) The method includes N-heterocyclic carbene (NHC) catalyzing the activation of phenyldialdehyde, which then reacts with carboxylic acid to form phthalate The main route of the reaction is the kinetic resolution process (Fig 1c) One of the aldehyde derived Breslow intermediates was oxidized to produce the intermediate I of azoonium ester The enantiomeric intermediates II and III are obtained by the addition of another aldehyde group of intermediate I, which combines carboxylic acid with chiral NHC Intermediate III preferentially undergoes intermolecular cyclization to obtain chiral phthalates with high enantiomeric ratio The enantioselectivity of the reaction is controlled by NHC catalyst (source: Nat Commun.) the author explored the reaction conditions with aspirin (1) and o-phthalaldehyde (2) as model substrate, triazole salt as NHC pre catalyst, quinone as oxidant and K 2CO 3 as base (Table 1) When n-homotrimethylphenyl substituted triazolium salt a is used as NHC pre catalyst and LiCl is used as additive, the reaction is carried out in CH2Cl2 at room temperature The required phthalate product 3 can be obtained in 66% yield with ER value of 60:40 (entry 1) After that, the author investigated the precatalyst and found that when the precatalyst was replaced by C, the ER value of the reaction was further improved (85:15, entry 3) Then, the author used C as the pre catalyst to optimize other conditions When CHCl3 was used as solvent, er value of product 3 increased to 90:10 (entry 4) When the reaction temperature is reduced to - 20 ℃, the reaction effect is the best, the yield of product 3 is 89%, Er is 95:5 (entry 5) The control test shows that NHC pre catalyst is very important for the reaction (source: Nat Commun.) after obtaining the optimal reaction conditions, the author first studied the universality of carboxylic acid derivatives (Fig 2) Even benzoic acid (4 - 16) with many substituents (such as halogen, methyl, cyano, etc.) has good tolerance Heteroaryl carboxylic acids also react efficiently (19) Based on the X-ray diffraction structure of ferrocene carboxylic acid (20) and p-iodobenzoic acid (21), the absolute configuration of the product was determined (source: Nat Commun.) next, the author examined the scope of application of fatty acids (Fig 3) It is worth noting that fatty acids are widely found in small molecule drugs, peptides and proteins, and have significant therapeutic potential It is found that the corresponding phthalate can be obtained in 82% yield and 97:3 Er value with acetic acid (22) as substrate The alkyl chain length of carboxylic acid had little effect on the yield and ER value (22 - 26) Primary, secondary and tertiary alkyl carboxylic acids (22-44) and unsaturated carboxylic acids (45-48) are all suitable substrates, and can obtain the corresponding cyclized products with good yield and excellent enantioselectivity The catalytic reaction can also be carried out in gram scale The substituted phthalaldehyde tested in this paper can react effectively, and the corresponding ester products (49 - 52) are obtained The yield is good and ER value is excellent (source: Nat Commun.) in order to further prove the universality and practicability of the strategy (Fig.5), the author modified several natural products with carboxylic acid groups and a variety of commercial drug molecules under standard catalytic conditions, and the reactions can be successfully converted into corresponding ester products (53-63), and the yield is good Nitrogen mustard phenylbutyrate (63) is an anticancer drug for chronic lymphoblastic leukemia (CLL), Hodgkin's lymphoma (HL) and non Hodgkin's lymphoma (NHL) Then, the author studied the bioactivity of two kinds of phthalate enantiomers (fig.5c) The results showed that at the concentration of 100 μ g / ml, (R) - enantiomer (r-63, > 99:1 Er, IC 50:53.6mg / ml) phthalate was more effective than the corresponding (s) enantiomer (S-63, 3:97 Er, IC 50:83.6mg / ml), racemate (rac-63, IC 50:91.7mg / ml) and unmodified mustard benzoate (IC 50:157.0mg / ml) HeLa cells The different effects of these compounds may be attributed to better permeability of cell membrane or different interaction with target DNA caused by chiral modification (source: Nat Commun.) conclusion: This study has realized enantioselective acetalization of carboxylic acids, and prepared the phthalate derivatives enriched with enantiomers The organic catalysis strategy has the advantages of mild conditions, wide application range of substrates and good tolerance of functional groups This method will provide an important way for the discovery and development of better chiral prodrugs.
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