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    Home > Bruno figadere group, University of Paris Thackeray completed the synthesis of amphidinolide f

    Bruno figadere group, University of Paris Thackeray completed the synthesis of amphidinolide f

    • Last Update: 2018-05-29
    • Source: Internet
    • Author: User
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    The author of the paper: danyan amphidinolides is a kind of marine macrolide, which contains more than 30 family members, all of which are isolated from Amphidinium Amphidinolides f (1), C (2), C2 (3) and C3 (4) have unique structures: there are two trans tetrahydrofuran structures at c9-c11 and c25-c28, and the molecules contain 11 to 12 stereocenters and two diene skeletons These compounds have also been shown to have significant cytotoxic activity on some cancer cell lines Therefore, these molecules have attracted the attention of organic synthetic chemists The stereochemical structure of amphidinolide f (1) was originally derived from its analogues, amphidinolide C (2), and there were only differences between them on the side chain In addition, 2 has a stereoisomeric center at C29, while the natural derivatives amphidinolide C2 (3) and C3 (4) are only different here, that is, the hydroxyl groups on C29 are acylated and oxidized respectively (Figure 1) Recently, the Bruno figadere research group of Paris Thackeray University in France reported the total synthesis of amphidinolide f (1) (DOI: 10.1021 / ACS Orglett 8b01020) on the organic letters (photo source: Organic letters) based on the understanding of the molecular structure of this kind of marine macrolides, the author proposed the following reverse synthesis analysis (scheme 1): the author initially planned to construct THF ring with C-glycosylation to form C19-C20 bond, and found that the diene skeleton and the generated intermediate were incompatible in the reaction Therefore, the author turned to use the sulfone condensation / desulfonylation reaction to construct the macrolide parent nucleus to realize the connection between fragments 5 (c18-c29) and 6 (c10-c17); then through Stille cross coupling to connect fragments 7 (c1-c9); finally, through macrolide to achieve the closed-loop Fragments 5, 6 and 7 can be synthesized by non enantioselective or asymmetric reactions using simple and easily available chiral synthetic blocks (photo source: Organic letters) the specific synthesis route is as follows: the synthesis of segment 5 (c18-c29) (scheme 2): using chiral lactone 8 as starting material, the author obtained ketal 10 by tbdps protecting hydroxyl and dibal-h reduction / acetylation Under the action of TiCl 4, the only enantiomer 12 (86%, Dr ≥ 95:5) of ketal 10 and oxazolidinethione 11 was obtained by the reaction of titanium enol and methanol Then 12 undergoes hydroxyl deprotection and oxidizes to carboxylic acid 13 under the action of ruthenium tetroxide Then carboxylic acid 13 is activated to acyl chloride, which reacts with thiocresol and converts to thioester 14 In the presence of copper thiophene carboxylate and PD 2dba 3 / P (OME) 3, the cross coupling of 14 with boric acid derivative 15A was initially attempted Due to the instability of boric acid 15a, the reaction results of diene ketone 16 can not be reproduced However, when the more stable stannic 15b is used for cross coupling with 14 under the conditions of cudpp (copper diphenylphosphonate) and PD 2dba 3 / P (o-fur) 3, dienone 16 is obtained in 70% yield Subsequently, 16 was reduced by luche to yield CIS product 17 (DR ≥ 90:10) with felkin Anh type selectivity Finally, TMS was used to protect the hydroxyl group and dibal-h was used to selectively reduce ester 17 to aldehyde 5 Scheme 3: using commercial alkyne 18 as the starting material, the author first selectively reduced it to corresponding (z) - alkene with Pd / BaSO4 − quinoline, and then obtained epoxy alcohol 19 (ER = 93:7) by Sharpless asymmetric epoxidation When the hydroxyl group is protected / activated by TS, under the action of BF 3 · OET 2 and trimethyl aluminum complex, the ring opening of epoxide is completed when TMS acetylene attacks the side with smaller steric resistance of epoxy Then p-toluenesulfonate was substituted internally by sodium alcohol to obtain terminal epoxide 21 In the presence of Cui, the second ring opening of epoxide was carried out with (z) - allyl Grignard reagent to obtain (z) - high allyl alcohol 22 Compound 23 was obtained by protecting hydroxyl group with TBS and decomposing TMS protecting group with methanol Under the synergistic action of ethyl lithium sulfone and BF 3 · OET 2, epoxide 23 was opened and converted to compound 24 under the protection of TEs ether The product 25 was obtained by PD mediated regioselective and stereoselective stannization of alkyne 24, and then was substituted by iodo and dimethylcopper lithium to obtain compound 26 Finally, 26 TMS was iodized with NIS to obtain fragment 6 (photo source: Organic letters) connection of segments 5 and 6 (scheme 4, box): the author found that alkali, concentration and temperature are the key parameters for the success of sulfone condensation Sulfone 6 is deprotonated with LDA at 0 ℃, then aldehydes 5 are added at - 78 ℃, and then slowly heated to 0 ℃, four kinds of non enantiomers are obtained Compound 27 was obtained by DES Martin oxidation of C18 Oh in 2,6-dimethylpyridine buffer solution and SMI 2-mediated desulfonylation at - 78 ℃ Scheme 4: according to the method reported in the literature (org Lett 2010, 12, 4976), the intermediate methyl ester 28 was synthesized in 9 steps, and then 28 reacted with tmsok to obtain free acid 7 Due to the demetallization problem between free acid and vinyl copper species, the author decided to treat free acid 7 with NAH in DMF, and then add vinyl iodine 27 and other required reagents for Stille coupling Although this condition led to the deprotection of some TMS, cross coupling is very efficient Next, TMS was selectively removed from the crude mixture under the action of dilute HCl and the compound 29 was obtained after purification (yield 72%), then macrolide was generated under the action of Yamaguchi reagent to produce compound 30 (ratio of isomers detected by NMR is 3:1) In THF / pyridine, HF · pyridine was used to selectively remove the C15 tes group in compound 30, and the mixture of hydroxyl ketone and ketal was obtained The existence of conformational isomers makes the characterization of this intermediate very difficult Because there is no ketone absorption band at 1715 cm-1 in the infrared spectrum of the compound, the author thinks that the ketal form is dominant Finally, the oxidation of C15 hydroxyl group was realized by Tpap according to the reaction conditions reported by F ü rstner, and compound 31 was obtained in good yield In THF / pyridine, HF · pyridine was used to remove all three TBS protecting groups from compound 31 and the target product 1 was obtained Conclusion: the author has completed the total synthesis of amphidinolide f (1) with a maximum of 23 linear steps and 47 total reaction steps, and the characterization data is consistent with the data of the total synthetic products and natural products previously reported The highlights of this synthesis include the stereoselective construction of two trans THF rings by carbonylation of oxazolidinethione under the action of enol titanium; the introduction of diene side chains by cross coupling; the completion of fragment connection by sulfone condensation / desulfonylation series reaction, still cross coupling and macrolides.
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