Angelw. Chem. Int. ed.: the first asymmetric synthesis of highly active substances secreted by higher termites

The defensive secretion of high termite soldiers is a fascinating chemical treasure house and a rich source of tetracycline diterpenoids So far, most of them are unknown biological activities A small number of reports have reported the structure identification, activity test and racemic synthesis of some of these compounds, and found some valuable natural products However, there is no report on Asymmetric Total Synthesis of secretion from higher termites The reported synthesis route (source: angelw Chem Int ed.) led by Professor Peter Metz from Dresden University of technology, Germany, has recently developed the first asymmetric selective reaction route of related natural products by catalytic asymmetric quinone Diels alder reaction The complex decomposition reaction is the key to the conversion They reported the synthesis of 3-hydroxy-7-kemp-8 (9) - en-6-one (1), which is a kempan extracted from the defense secretion of Nasutitermes octopolis Its relative configuration was determined by X-ray diffraction of p-bromobenzoate derivatives The biological effect of kempane 1 has not been reported This tetracyclic compound has a delicate ketone structure and C7 hydrogen points to the cavity of bowl-shaped molecules, which is a challenging synthesis target So it's no surprise that all previous efforts to synthesize this unique natural product ended in failure In the past, two main methods of racemic system have been published Paquette uses the bicyclic substrate 4 to join the five membered ring by trimethylene methane PD cycloaddition, and then conducts intramolecular aldol condensation to close the seven membered ring However, only substitutes of natural product 1 can be synthesized, some isomers 5, 6, 7 Similar Deslongchamps failed to achieve the goal through the cross ring Diels alder cycloaddition / aldehydes cyclization of macrotriene 8, but ended up with three conjugated ketene 7, 9 and 10 The 14-26 reaction route (source: angelw Chem Int ed.) Peter Metz and his team are convinced that the domino decomposition strategy may provide a solution for the total synthesis of hydroxyketone 1 The rearrangement of vinyl epoxide 11 catalyzed by Lewis acid should produce 1 B, g-unsaturated enone Kempadienol 12 can be asymmetric synthesized into 11 The key domino decomposition reaction transformed 12 from dienyne 13 Because the right six membered ring of hydroxykempenone 1 is not the opposite of kempenone-2 (2), they decided to use Wieland Miescher keystone 14 instead of quinone Diels alder to synthesize dienyne 13 directly The reaction route from 26 to 36 (source: angelw Chem Int ed.) firstly, according to the previously reported method, the chiral pure product of Wieland Miescher ketone 14 was obtained after single recrystallization in high yield After 8 steps of reaction, dienone 26 was obtained The six membered ring of dienone 26 on the left side was further modified The important intermediate ketone 13 and by-product 33 were obtained by four steps By Claisen rearrangement, 33 was transformed into ketone 13 Kempane 35 was obtained by treating ketone 13 with Grubbs catalyst 34 However, the chiral isomer 36 of kempadienol 12 was obtained by reduction The reaction route from 13 to 42 (source: angelw.chem Int ed.) therefore, the research team changed its strategy, starting from dienyne 13, first reducing ketone to obtain 37 of the appropriate chiral alcohol, and then protecting the chiral alcohol by adding a protective group After four steps of reaction, sulfur-containing thiocarbonate 42 was obtained Thiocarbonate 42 removes the sulfur-containing five membered ring and obtains the important precursor B, g-unsaturated ketone 45 The success of total synthesis is in sight, and the goal is in sight For example, enone 7 can be obtained by oxidizing it, removing the h in the upper left corner, and removing the tbso protecting group The target product hydroxykemperone 1 can be obtained by turning the upper left hydrogen to meet the target chirality and removing the protecting group After that, its structure was identified, NMR, X-ray and optical rotation were tested In a word, the first total synthesis of 3-hydroxy-7-kemp-8 (9) - en-6-one (1) was realized by 31 steps reaction with Wieland Miescher ketone 14 as raw material The addition of sulfa Michael results in the production of fine B, g-unsaturated ketone, while the tetracycline skeleton can be easily constructed by the domino decomposition Paper link: http://onlinelibrary.wiley.com/doi/10.1002/anie.201708561/abstract brief introduction of corresponding author: https://tu-dresden.de/mn/chemie/oc/oc1/die-professional/prof-dr-peter-metz Professor Peter Metz