Professor Dai Weimin of Hong Kong University of science and technology completed the total synthesis and absolute configuration determination of laingolide B isomer

The author: danyan marine cyanobacteria can produce a variety of novel and bioactive secondary metabolites, which can be used in chemical and biological research, and also as an important source of lead compounds for drug discovery In addition to the modified peptide, keto ester, keto peptide, polyketone compound and peptide polyketone hybrid, a small part of the metabolites of cyanobacteria are macrolides with trans-n-methyleneamide structure These unique macrolides include the following compounds (Figure 1): palmyrolidea (1), laingolide (2), laingolide a (3), laingolide B (4) and madangolide (5) The structural difference is that palmyrolidea and laingolides both contain 15 membered macrolides, while madangolide has 17 membered macrolides The absolute configuration of palmyrolidea has been modified by total synthesis The planar structures of laingolides and madangolide have been reported, but the absolute configuration has not been determined In addition, the lack of optical rotation data in laingolide (2), laingolide a (3) and madangolide (5) makes it difficult to determine the absolute configuration Based on the previous study on the total synthesis of palmyrolide A and laingolides, recently, Professor Dai Weimin's research group of Hong Kong University of science and technology reported the total synthesis of laingolide B stereoisomer on organic letters and determined its absolute configuration as (2S, 9R) (DOI: 10.1021 / ACS Orglett 8b01269) (photo source: Organic letters) laingolide B (4) has three unique structural units, including tert butyl methanol, trans-n-methyleneamide subunits and chloroform methylene At present, there are three types of molecular cyclization methods that have been used to construct trans-n-methyleneamide subunits: (1) Cui catalyzes the large-scale intramolecular amidation of primary amides and trans alkenyliodine, and then N-methylation, or n-methylamide replaces primary amides; (2) n-allyl-n-formamide and olefin closed-loop metathesis (RCM), and then olefin isomerization; (3) TFA mediated Dehydration and cyclization of n-methylamide and aldehyde Based on this, the author proposes the following reverse synthesis analysis (scheme 1): the author proposes to construct the parent nucleus of laingolideb by RCM olefin isomerization, which has been reported in the total synthesis of palmyrolidea and (2S) - sancolide a The isomerization of conjugated double bonds in 15 membered lactones to trans olefinamide is the key step of the total synthesis, which has been proved to be feasible in the total synthesis of laingolide a stereoisomer The isomerization of RCM olefins is more advantageous than the large intramolecular acylation catalyzed by Cui and the dehydration cyclization with lower efficiency In addition, the macrocyclic products containing CIS olefinamide can be realized by the large intramolecular amidation catalyzed by Cui In the presence of protonic acid, the yield of the product is generally low because of the easy ring opening and hydration of the enamide According to the sequence of amidation, acryl chloride esterification, RCM and olefin isomerization with n-allylmethylamine, the author synthesized two kinds of laingolideb stereoisomers (2R, 9S) - 6a and (2S, 9S) - 6B from corresponding hydroxyacids 7a and 7b, respectively Both 7a and 7b can be prepared by a two-step reaction of the common trisubstituted alkenyl iodine (s) - 10 Then, the author prepared alkenylstantane rac-13 and rac-14 from racemic compounds rac-12 and high propargylic alcohol by PD catalyzed methylsilylstannization, which can be converted into rac-10 and rac-15 (scheme 2) after exchanging stantane with iodine The chiral 4-acyloxazolidone 16 is methylated to 17, and then borohydride to alkylborane 11 under the action of dimer 9-BBN In PD catalyzed cross coupling reaction of alkenyl bromide 18 with alkylborane 11, the product 19 was obtained However, when 11 was cross coupled with rac-10 and rac-15 under the same conditions, the expected product was not obtained, and only products 20 and 21 were separated, which indicated that TMS group was in rac-10 and rac-15 It is difficult to transfer metallization of alkylborane due to the spatial orientation in the (photo source: Organic letters) next, the author used 4-ethoxy-4-oxobutylbromide zinc (9), (s) - (-) - 3-methoxy-2-methyl-3-oxopropyl-zinc bromide (22a) and 6-ethoxy-6-oxhexyl-zinc bromide (22b) to carry out Negishi coupling reaction with (z) - silalkylated alkenyliodine (scheme 3), respectively The results showed that the reaction of 22a with vinyl iodine 15 was very good in the presence of 10 mol% PD (PPh3) 4 at room temperature After coupling with rac-10 and rac-15 in THF, 24b and 24C were obtained in 77% and 79% yields, respectively The chiral (z) - alkenyliodine (s) - 10 was prepared from (s) - 12 in 74% yield, and then TBS ether (s) - 23a (97% yield) was obtained by silylation; the latter was coupled with 9 in 77% yield for 24 days In addition, 22b was coupled with 15 and 23B to obtain 24E and 24F in 67% and 83% yields, respectively Finally, the coupling reaction between rac-23c and 22b prepared by rac-10 was carried out to obtain 24g of the product in 74% yield In a similar way, acrylate (s) - 23C was coupled with 9 to obtain the product in 82% yield for 24 h (photo source: Organic letters) synthesis of laingolide B stereoisomer (2R, 9S) - 6A (scheme 4): after being treated with NCS for 24 days, its alkenyltms group is converted to alkenyl chloride, then it is reduced by ester and primary alcohol is converted to alkyliodide 25 Myers alkylation of (1s, 2S) - 8 with 25 gave 26 Then n-allylmethylamine amination and acryloyl chloride acylation were carried out successively 27% of the total yield was obtained in three steps of 66% 27 Macrolide 28 and a small amount of undetermined minor components were obtained in 90% yield in the olefin metathesis reaction catalyzed by Grubbs II, and no dechlorination by-product 29 was detected The isomerization products (2R, 9S) - 6a and by-products (7:1) were obtained by treating 28 with 10 mol% RUH (PPh3) 3 (CO) CL According to the coupling constant of hydrogen atom on the double bond of compound 28, it can be judged that the internal double bond configuration of compound 28 is E-type At the same time, we prepared (2S, 9S) - 6B by using (1R, 2R) - 8 and the same alkyl iodide 25 (photo source: Organic letters) by comparing 13C NMR data, we can see that (2R, 9S) - 6a is the enantiomer of the natural product laingolide B (Figure 2) In addition, the optical rotation of the synthesized sample 6a, which contains 30 by-products of non separable dechlorination, is almost the same as that of the natural laingolide B Conclusion: the author has completed the synthesis of two stereoisomers (-) - (2R, 9S) - 6a and (+) - (2S, 9S) - 6B of laingolide B the highlight of the synthesis lies in the construction of macrocyclic trans-n-methyleneamide by closed-loop metathesis (RCM) and olefin isomerization In addition, the author compared the natural laingolide B with the synthesized two isomers by 13C NMR data, and determined the absolute configuration of natural laingolide B as (2S, 9R) by comparing the optical rotation data.