Eric M. carreira, editor in chief of org. Lett, completed the total synthesis of (- - merochlorin a

(-) - merochlorina (1, scheme 1) is a new isoprene compound isolated from marine sediment actinomycetes (cnh-189) off the coast of California in 2012 by fenical and Moore et al It has significant in vitro antibacterial activity against Clostridium difficile and various multi resistant Staphylococcus aureus Its structure is characterized by the highly crowded parent nucleus of bicyclic [3.2.1] octane, which contains four adjacent chiral centers, bridgehead chlorine and resorcinol fragments The complex structure and attractive biological activity have aroused the interest of organic synthetic chemists Recently, Erick M carreira group of Swiss Federal Institute of Technology reported the first asymmetric total synthesis of (-) - merochlorin a (1) on angelw.chem.int.ed., and determined its previously unknown absolute configuration (DOI: 10.1002/anie.201813090) (photo source: angelw Chem Int ed.) (-) - merochlorin a (1) reverse synthesis analysis: firstly, the author determined that cyclopentene 3 is the key intermediate (scheme 2, a) for the synthesis of merochlorin a, and wondered whether it can be transformed into 3 (scheme 2, b) through two consecutive cyclization reactions The conversion of 2 to 3 mainly involves 1,3-acyloxy transfer, Nazarov cyclization and aldol reaction Fensterbank and malacria reported the chiral transfer reaction of 7, which was converted to 9 (scheme 2, c) by cyclopropane of Au (I) - vinyl carbene 8 Therefore, the author would like to know whether 2 can be converted into 6 by a similar method, and whether Au (I) catalyst has enough Lewis acid to promote intramolecular hydroxyaldehyde reaction, so as to obtain 3 in one step Two ring structures of merochlorin A and two chiral centers of the parent nucleus of bicyclic [3.2.1] octane can be constructed by the conversion from 2 to 3 The second chiral quaternary carbon center and α - CL were introduced by conjugated addition and chlorination The side chain of the second chiral quaternary carbon center and α - CL was constructed by cross cycloaldol reaction and Diels alder cycloaddition / aromatization sequence reaction (picture source: angew Chem Int ed.) synthesis of cyclized precursor 2 (scheme 3): the author took triphenylphosphoryl bromide 10 and aldehyde 11 as starting materials, and obtained 12 through improved Wittig Schlosser reaction and iodization; 12 was converted to cyclized precursor 2 through Sonogashira coupling, borohydride, protective group operation and Swern oxidation (picture source: angelw Chem Int ed.) introduction of isopropyl segment (scheme 4): after obtaining 2, the author carried out cyclization cascade reaction under the action of echavarren catalyst (14), constructed alkene 3 containing bicyclic [3.3.0] octane parent nucleus, and introduced C9 chiral center at the same time Its absolute configuration is similar to fensterbank and malacria The established model is confirmed Then, 3-dealcoholized and regioselectively oxidized to ketone 16 by Tsuji Wacker At present, there are few reports on the synthesis of tetrasubstituted alkenes by direct carbonylation In addition, Wittig, Peterson, metal carbene and other olefinization conditions have been tried, and no target product has been obtained Finally, ketene 17 was synthesized by La (III) - mediated Grignard reaction and reduction Next, the author added the isoprene segment 18 to the ketene 17, introduced the second quaternary carbon chiral center, and then obtained the isoprene segment 19 through chlorination and deprotection (picture source: angelw Chem Int ed.) (-) - merochlorin a (1) synthesis (scheme 5): after getting 19, the author oxidizes it to carboxylic acid, and then esterifies it to enol lactone 20, which is rearranged to tricyclic ketone 23 So far, the author has completed the assembly of the parent nucleus of bicyclic [3.2.1] octane with four consecutive chiral centers, and its stereochemistry has been confirmed by noe experiment Because the diketone produced by the oxidation of 23 is unstable on silica gel and prone to reverse Claisen reaction, the author oxidizes 23 with PCC and filters it with diatomite to obtain diketone Then, the author achieved ketone desaturation to get ketene 25 according to the method developed by Mukaiyama Finally, Diels alder reaction and Saegusa ITO oxidation were carried out between 25 and diene 26 to obtain 27; demethylation to obtain (- - merochlorin a (1) The spectral data of synthesized 1 are identical with the reported natural products, and its absolute configuration is determined by ECD (picture source: angelw Chem Int ed.) conclusion: Eric M carreira group reported the first asymmetric total synthesis of (-) - merochlorin a (1) The highlight of the synthesis is: stereoselective tandem 1 catalyzed by Au (I), The core structure of bicyclic [3.3.0] octane was constructed by 3-acyloxy-transfer / Nazarov / hydroxyaldehyde cascade reaction, and resorcinol fragments were constructed by improved Wittig Schlosser reaction and Diels alder cycloaddition / aromatization sequence reaction.