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    Home > Synthesis and structural modification of c31-c67 fragment in marine natural product amphidinol 3

    Synthesis and structural modification of c31-c67 fragment in marine natural product amphidinol 3

    • Last Update: 2018-04-19
    • Source: Internet
    • Author: User
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    The author of the paper: amphidinol 3 (AM3) is a marine natural product produced by marine dinoflagellate Amphidinium klebsii, which has strong antifungal and hemolytic activities, but its mode of action is not clear The plane structure of AM3 (J am Chem SOC 1991, 113, 9859) was reported by Naoki research group in 1991 Due to the extremely limited amount of separation and the existence of many stereoisomeric centers on the acyclic carbon chain, the determination of its absolute configuration has become a difficult task Finally, in 1999, the Tachibana team determined its absolute configuration through NMR analysis (including configuration analysis based on coupling constant) (Figure 1a, J am Chem SOC 1999, 121, 870) So far, a large number of amphidinol and its related compounds have been found and confirmed Among these homologues, karlotoxin-2 (KmTx2) was found and reported in 2010, and its structure was modified in 2015 It is reported that its THP ring is opposite to that of AM3 (Figure 1c) (source: angel Chem Int ed.) because the absolute configuration of B-ring in KmTx2 is opposite to that in AM3, the researchers confirmed the absolute configuration of B-ring in AM3 through natural product degradation reaction and chemical correlation, and modified the absolute configuration of C2 and C51 to R and s respectively (Figure 1b, org Lett 2008, 10, 5203; org Lett 2013, 15, 2846) The reason for C51 configuration error is that the coupling constant J value (jh50-h51 = 3.4hz) is in the middle range by using jbca method; the same situation occurs in the determination of C38 absolute configuration, that is, although the absolute configuration of C39 is determined by Mosher method, the relative configuration of c38-c39 is determined by jbca method, and the observed coupling constant J value (jh38, h39 = 5.1hz) is also in the middle range If the absolute configuration of C38 bit determined by jbca is wrong, the absolute configuration of C32, C33, C34, C35 and C36 should also be incorrect Therefore, it is very important to confirm the absolute configuration of C38 Recently, the team of Tohru Oishi, Kyushu University, Japan, published the synthesis of c31-c67 fragment in amphidinol 3 (DOI: 10.1002 / anie 201712167) on angelw Chem Int ed., and modified the absolute configuration of some chiral centers by the methods of natural product degradation and intermediate synthesis compared with natural product NMR The authors plan to determine the absolute configuration of C38 in AM3 by comparing the NMR data between natural products and synthetic model compounds 1A or 1B (Figure 2) C31-c67 fragment 1a is the AM3 structure fragment modified in 2013, while 1b has the opposite stereochemical configuration at c32-c38 1A and 1b constructed C39 chiral centers through the allylidene aldehyde coupling reaction between B-ring and A-ring or its enantiomers, and then were respectively olefinized by Julia ‑ kocienski (source: angel Chem Int ed.) the synthesis of c31-c67 fragment (1a) is shown in figure (scheme 1) Using compound 2 as the starting material, primary alcohol 3 was obtained by protecting and deprotecting the protecting group, then α, β - unsaturated ketone was obtained by DESs Martin oxidation, Horner Wadsworth Emmons olefinization, and saturated methyl ketone 5 was obtained by hydrogenation Then ketone 5 was esterified with enol trifluoromethylsulfonic acid of Comins reagent 6, coupled with me 3 snsnsnme 3 and converted into alkenyl iodine 7 by tin iodine exchange reaction Allylidene lithium 8 was obtained by treating iodide 7 with t-BuLi, and then it was coupled with aldehyde 9 to obtain secondary alcohol 10 and C43 epimer 11 (2.2:1) After the separation and protecting group operation, the primary alcohol 13 was oxidized to aldehyde and sulfone 14 for Julia kocienski olefinization and deprotection, and c31-c67 part 1a was obtained, which was a single e-isomer (source: angel Chem Int ed.) the synthesis of diastereomer 1b is shown in figure (scheme2) Firstly, secondary alcohol 15 was converted to methanesulfonate and BN was removed Epoxide 16 was obtained by intramolecular SN2 reaction, and stereochemistry was reversed at C39 Alcohol 18 was obtained by the nucleophilic ring opening of lithium reagent 17, converted to 19 after TBS protection, and then the terminal alkyne was converted to iodo alkene by Ni catalyzed regioselective hydrogenation / iodization After PMB group was removed, iodo alkene 20 was obtained by TES protection According to the similar route in scheme 1, secondary alcohol 22 and C43 epimer 23 were obtained by coupling iodide 20 and aldehyde 9, and then the mixture of c31-c67 fragment 1b was further transformed (E: z = 3:1) (source: angelw Chem Int ed.) after obtaining 1a and 1b, the author compares their NMR data with natural products, and the difference of chemical shifts of c31-c51 parts of AM3 and 1A or 1b is shown in Figure 3 The chemical shifts of c52-c67 and AM3 are the same, but the chemical shifts of c31-c33 and AM3 are different In 1H and 13C NMR, the chemical shifts of 1A were quite different, which indicated that AM3 structure confirmed before was not correct For 1b, the deviation is basically within the error range; however, the deviation observed by C38 and h40a cannot be ignored Due to the NOE effect between CH3 (c69) and CH2 (C70), it is suggested that the conformational distortion of c30-c31 olefin in AM3 may be close to that of c38-c41 The difference of conformation between model compounds and natural products may lead to different chemical shifts, but NMR analysis shows that the conformation of compound 1b may be similar to that of AM3 Therefore, the deviation of chemical displacement at c38-c41 may be due to the magnetic anisotropy effect caused by the lack of c30-c31 olefin in 1b structure Because 1a (4.6 Hz) and 1B (5.4 Hz) J h38 and h39 are close to each other, jbca method can not be used for configuration determination (source: angel Chem Int ed.) then, the sample was transformed into MTPA ester 26a-c (scheme 3), which contains no c30-c31 double bond but retains c38-c39 fragment 38 r diastereomer 26a was prepared from precursor 10 of 1a, 38 s diastereomer 26b from precursor 22 of 1b, and 26c from natural product AM3 (source: angelw Chem Int ed.) compared the hydrogen spectrum data of (s) - MTPA ester 26a (38 R, 39 R) and 26b (38 s, 39 R) with the data of natural product (s) - MTPA ester 26c The difference of chemical shift of c36-c47 is shown in Figure 4 Obviously, the deviation between 26c and 26a is very large (red stripe), but the chemical shifts of 26c and 26b are the same Therefore, the correct absolute configuration of C32-C36 and C38 bits is contrary to the original proposed configuration, which should be modified to 32 s, 33 R, 34 s, 35 s, 36 s and 38 s (source: angel Chem Int ed.) conclusion: we synthesized c31-c67 fragment (1a) and C32-C36 and C38 non enantiomers (1b) of AM3, and confirmed the absolute configuration of the natural product The absolute configuration of AM3 was modified to 32 s, 33 R, 34 s, 35 s, 36 s and 38 s by comparing the NMR data of AM3 related fragments and degradation products of compounds 1a and 1b Corresponding author: Tohru Oishi
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