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    Home > Angelw: selective allyl substitution of chiral secondary alkylcopper reagent and its application in the total synthesis of (+ - lasiol and other pheromones

    Angelw: selective allyl substitution of chiral secondary alkylcopper reagent and its application in the total synthesis of (+ - lasiol and other pheromones

    • Last Update: 2018-11-16
    • Source: Internet
    • Author: User
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    Chiral organolithium reagents have been widely used in asymmetric synthesis The alkyllithium 1 can be prepared by I / Li exchange of the corresponding alkyliodide 2, and the configuration is maintained (scheme 1) In addition, 1 and CuBr · P (OET) 3 can be stereoselectively transferred to produce paraalkyl copper reagent 3 The reaction of chiral alkylcopper reagents with activated alkynes, epoxides and 1-bromoalkynes can also be maintained in configuration, and allyl substitution can be carried out in organic copper reagents Recently, Paul knockel group of the University of Munich, Germany, used chiral secondary alkyl copper reagents to replace allyl electrophilic reagents (4A or 4b) with regioselective and stereoselective SN2 or SN2 ', and applied the method to the enantioselective synthesis of three kinds of ant pheromones (+ - lasiol, (+) - 13-norfaranal and (+ - faranal The related papers were published on angel.chem.int.ed (DOI: 10.1002/anie.201811330) (picture source: angel Chem Int ed.) as shown in Table 1, the author carried out I / Li exchange and metal transfer of alkyl iodine syn-2a to obtain corresponding alkyl copper syn-3a, which was treated with allyl phosphate 4a to obtain syn-5a, a product of SN2, with medium regional selectivity (SN2 / SN2 '= 80:20, Dr = 10:90) After a large number of experiments, the author found that removing the original solvent and replacing it with THF can produce a structurally stable second-order alkylcopper reagent The reaction with 4A will improve the regional and stereoselectivity (SN2: SN2 '= 95:5, Dr = 5:95) Under the same conditions, anti-3a can be obtained (SN2: SN2 '= 96:4, Dr = 95:5) The regioselectivity of the reaction (SN2: SN2 '> 99:1) can be further improved by using isopentenyl bromide 4B instead of phosphate 4a In addition, anti-3b and 2s, 3s-3c can also carry out highly selective SN2 substitution under the action of 4B, and anti-5b (SN2: SN2 '> 99:1, Dr = 98:2) and 2R, 3r-5c (SN2: SN2' > 99:1, Dr = 98:2, 99% ee) can be obtained respectively Among them, the ant pheromone (+ - lasiol (7) can be obtained by the removal of TBS by 2R, 3R - 5C under the action of TBAF The total yield is 21% (image source: angelw Chem Int ed.) under the action of these organometallic compounds, the use of chiral allyl phosphate can carry out highly selective SN2 'substitution (Table 2) Therefore, the author treated copper syn-3a with ZnCl2, and then added allyl phosphate 4a to obtain syn-6a (SN2: SN2 '= 5:95, Dr = 5:95); and anti-6a (SN2: SN2' = 8:92, Dr = 95:5) was obtained from anti-3a Similarly, syn-3d, a syn OTBs substituted alkyl copper derivative, reacts with 4a to obtain the expected syn-6b (SN2: SN2 '= 9:91, Dr = 9:91) In addition, 3 s, 4 s-6c (S N 2: S N 2 '< 1:99, Dr = 95:5, 99% ee) was obtained by substituting (z) - (s) - allyl phosphate 4C with (s) s-2s-3e The alkenes 3R, 4s-6d (SN2: SN2 '< 1:99, Dr = 10:90) and 3S, 4s-6d (SN2: SN2' < 1:99, Dr = 90:10) can be obtained from the enantiomeric pure alkylcopper 2r-3f and 2s-3f, respectively The chiral cyclic allyl iodide 3R, 4r-6e and 3R, 4r-6f can be obtained by anti-s2 'substitution of 4D and 4E with 2r-3f, respectively (image source: angel Chem Int ed.) next, the author applied this allyl substitution to the preparation of ant pheromone (+ - 13 norfaranal (8) (scheme 2) Firstly, ester 2R, 3r-11 (DR = 1:99, 99% ee) was produced by selective methylation and o-benzylation of (R) - hydroxybutyrate (r-10, 99% ee), which was reduced by LiAlH 4, oxidized by Swern and Wittig enolized with pH 3P = CH2 to obtain terminal olefin 2R, 3s-14 (DR = 1:99, 99% ee) 2 R, 3 s - 14 is borohydride and oxidized to produce primary alcohol, which is protected by TBS to obtain 3 s, 4 R - 16 (DR = 1:99, 99% ee) Syn alcohol 2R, 3s-17 (DR = 1:99, 99% ee) was obtained by reduction and debenzylation of 3S, 4r-16 Then, 2R, 3s-17 was transformed into Anti iodide 3S, 4s-1d (DR = 98:2, 99% ee) Secondary alkylcopper 2S, 3s-3i was obtained by I / Li exchange and metal transfer Then, coupling product 3S, 4r-18 (DR = 97:3, 99% ee) was obtained by quenching the newly prepared geranyl bromide Finally, 3 s, 4 R - 18 was removed by Bi (OTF) 3-catalyzed oxidative deprotection to obtain pheromone (+ - 13 norfaranal (8) (DR = 97:3, 99% ee) The total yield is 2.6% (photo source: angelw Chem Int ed.) before synthesizing the ant pheromone (+ - faranal (9), the author first synthesized 4G of the bromine derivative of vanillin (scheme 3) Iodide 22 was obtained by titanium mediated metallization of alcohol 19, toluene sulfonylation and Finkelstein reaction, and alkyne 23 was obtained by reaction of alcohol 19 with lithium acetylene 23 The intermediate 24 is produced by zirconium catalyzed Aluminization of carbons, and the iododiene 25 is obtained after iodization Then I / Li exchange was carried out under the action of n-BuLi, and then allyl alcohol 26 was obtained by reacting with gaseous formaldehyde Finally, 4 g was obtained by bromination (picture source: angelw Chem Int ed.) the synthetic route of ant pheromone (+ - faranal (9) is shown in scheme 4 It was found that the TBS protecting precursor 3S, 4r-27 of (+ - faranal (9) was not obtained in the reaction of chiral secondary alkylcopper 2S, 3s-3i with allyl electrophilic reagent 4G Therefore, the author modified the synthesis route and obtained the related precursor 2R, 3r-28 (DR = 97:3, 99% ee) by the reaction of chiral alkylcopper 2S, 3s-3c with 4G Then, the TBS protecting group was removed by TBAF to obtain alcohol 2R, 3r-29 2R, 3R - 29 was sulfonated with toluene to obtain 2R, 3R - 30, which reacted with sodium cyanide to obtain corresponding nitrile 3S, 4R - 31 Finally, the author used dibal-h to reduce 3S, 4r-31 to get 9 (DR = 97:3, 99% ee) The total yield is 6.9% (picture source: angelw Chem Int ed.) conclusion: Paul knockel group has developed a method of regioselective reaction of chiral secondary alkylcopper reagent with allylelectrophilic reagent by S N 2 or S N 2 'substitution reaction In addition, the method was applied to the synthesis of the pheromones (+ - lasiol, (+) - 13-norfaranal and (+ - faranal  
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