It's not a hoax! It can't synthesize all the natural products. It can also send angelw

In November 1995, many Dutch people ate mussels cultured in killary port, Ireland, which caused nausea, vomiting, diarrhea, gastrointestinal spasm and other toxic reactions After a long period of research, it was found that the poisoning was caused by the proto polyalgate shellfish toxins (azas) Azas is a lipophilic toxin produced by some species of procarydomonas (Fig 1) Aza is produced and enriched by Filter Feeding Shellfish and enters the human food chain Although people have a preliminary understanding of this kind of toxin, poisoning incidents happen occasionally The reason is that there are 59 kinds of azas, but not all of them have been confirmed The fuzziness of the structure makes it difficult to carry out the detection and supervision work, and also causes obstacles to the related toxicology research Figure 1 The report structure source of azas1-3: early in 1998, Yasumoto, Satake and others summarized the structure of aza1 (J am Chem SOC 1998, 120, 9967-9968) Nicolaou and Satake, on the other hand, correlated the oxidative degradation fragments of aza1 with the synthetic products to reduce the possibility of structure (angel Chem Int ed 2004, 43, 4312-4318) This promoted the total synthesis of aza1-3, and it is possible to complete the structure identification Aza3 is a C22 demethylation variant of aza1 Only supported by spectral and synthetic data can aza1-3 have the same stereochemistry In mussels, the oxidation of C22 methyl in aza1 may produce aza17 of C22 carboxylic acid, while the decarboxylation of C22 can produce aza3 Recently, a team of researchers from the United States, China, Canada, Ireland, Norway, New Zealand and other countries, led by Professor Craig Forsyth of Ohio State University, published a paper on angel Chem Int ed., reported the total synthesis with aza3 as the goal, and directly compared the synthetic products with the naturally produced aza3 The reverse synthesis analysis of aza3 is shown in Figure 2 The author envisages that aza3 can be obtained by the oxidation of ketone 4 through desilication ether protecting group and C1, and 4 can be converted from allyl alcohol 5 Previous synthesis methods of aza1-3 and ent-aza rely on the late functionalization of c20-21 bond, that is, to construct C20 solid geometric center through the reduction of ketones or the coupling reaction with poor enantioselectivity In contrast, the key coupling reaction between C21 and C22, i.e aldehydes 6 and alkynes 7 are coupled to form 5, which can minimize the coupling steps and enhance the atomic utilization Figure 2 Reverse synthesis analysis source of compound 3: angelw Chem Int ed total synthesis takes L - (+) - tartaric acid as the starting material, as shown in Figure 3 After a series of reactions such as acylation, oxidation, hydroxyl protection, aldol condensation and cyclization, the author obtained aldehyde compound 10, which is the c13-c21 part of the target compound Then, 10 reacts with C1-C12 alkyne iodide 9 in Nozaki Hiyama Kishi (NHK), then undergoes oxidation, conjugate reduction, spiro ketalization, deprotection and other steps to obtain intermediate aldehyde 6 On the other hand, the synthesis process of c22-c40 coupling component 7 is shown in Fig 4 Compound 31 can be modified by iodization and allyl ether to obtain alkyne 7 Figure 3 Synthesis route source of coupling component 6: angelw Chem Int ed Figure 4 Synthesis route source of coupling component 7: angelw Chem Int ed with key intermediates 6 and 7, the remaining task is to complete the NHK reaction of these two compounds (Figure 5) The author has optimized the reaction and found that the addition of 4-tert-butylpyridine can promote the successful completion of the reaction The reason may be that 4-tert-butylpyridine plays the role of dissolving and activating metal salts and buffering acidity, and also accelerates the reaction rate If 4-tert-butylpyridine is not added, 7 will decompose in NHK reaction Allyl alcohol 5 was synthesized by the reaction of 6 and 7 It was oxidized to alkyne ketone 34 and then reduced to ketone 4 by chemical selective lipshutz Stryker In the newly prepared TBAF solution, all the protective groups can be removed to obtain primary alcohol 35 Finally, the target product 3 can be obtained by two steps of oxidation Fig 5.6 and 7 synthesis 3 source: after synthesis of compound 3 by angelw Chem Int ed., the author compared it with natural aza3 In LC-MS spectrum, there is almost no difference in ms between 3 and aza3, but the retention time is quite different There are also significant differences between 1H and 13C NMR, which are manifested in the presence of multiple peaks of c19-h and the chemical shifts of multiple peaks of c20-h and c22-h Subsequently, the author determined that the compound is (6 R, 10 R, 13 R, 14 R, 16 R, 17 R, 19 S, 20 R, 21 R, 24 S, 25 s, 28 s, 30 s, 32 R, 33 R, 34 R, 36 s, 37 s, 39 R) - 3, which is the isomer of natural aza3 Although the Forsyth team did not synthesize a compound that was completely consistent with the natural aza3, the work was not meaningless Their work has opened up a way for conquering the mountain peak of protodomoic acid shellfish toxin, and laid a foundation for the future development The road of scientific research is tortuous and long Sometimes, the discovery and invention of a major achievement are often accumulated by numerous previous researches The chemical brick workers who are working hard to move bricks should not be discouraged if the experiment fails Who says that the incomplete successful experiment can't be published? Paper link: http://onlinelibrary.willey.com/doi/10.1002/anie.201711006/full Craig Forsyth introduction: https://chemistry.osu.edu/people/forsyth.14 craigforsyth Professor