Aza-Achmatowicz re-arranged the pro-nuclear plus with radon to achieve (-) - Alstofolinine A for the first time.

Recently, the Qi Xiangbing Task Force of the Beijing Institute of Life Sciences achieved the first full synthesis of (-) alstofnine A with the aza-Achmatowicz rearrangement of furan derivatives and the pro-nuclear plus of the molybdenum, published in Angew.Chem.Int.Ed.
bionic synthesis, diversity divergence synthesis, and synergetic strategies of chemical synthesis and synthetic biology are paid more and more attention in the full synthesis of natural products.
especially the natural rich renewable resources or easy-to-obtain simple compounds as raw materials to green environmental protection of atomic economics synthesis concept and high-efficiency high-dimensional selective series reaction of the novel design applied to natural products ideal synthesis has more practical value.
furan saline and its derivatives, a widely used and cheap renewable raw material in nature, have been successfully used in polymer polymeric materials and various organic reactions, one of which is known as the Achmatowicz rearrangement reaction.
Achmatowicz rearrangement was developed in 1971 by the Polish chemist Osman Achmatowicz Jr., which can easily convert furanalcohol into dihydro-pyridox ring under mild oxidation conditions, and thus more subsequent derivatives such as glycogenization, ring-plus, Michael plus-gen, etc. into more valuable complex structures.
has been widely used in chemical synthesis for many years because of its high efficiency and simplicity.
the Stephen F. Martin of The University of Texas, the Lee Cheng-cheng team of The Southern University of Science and Technology, and the Tongrong Standard Task Force of hkUST, all have done a lot of good work in using achmatowicz rearrangement for the full synthesis of natural products.
Aza-Achmatowicz reaction is a derivative of the Achmatowicz reaction, the reaction substrate is furanamine-type compounds, after oxidation and re-emission to produce pyridine derivatives, this type of nitrogen-containing structure in many natural products, especially bioactive alkaloids and pharmaceutical molecules occupy the core skeleton position.
in this article, the author for the Aza-Achmatowicz reaction product, using the pro-nuclear addition of radon high-efficiency selective characteristics, to achieve the construction of the ring containing the co-ring of radon, and its condition optimization and substrate expansion, and then applied to the full synthesis, to achieve (-) - Alstofolinine A's first full synthesis.
Qi Xiangbing's team has a strong interest in developing highly efficient synthesis methods based on the rich renewable resources or cheap raw materials of nature and applying them to the ideal synthesis of complex natural products, especially the alkaloids of pyridine.
based on furans and their derivatives are raw materials for a very wide range of biomass sources, are cheap and easy to obtain and combine with the huge derivative potential of Aza-Achmatowicz reactions, they envisage whether they can be applied to the full synthesis of the natural products of the pyridines, and thus a series of ideas for high-efficiency series reactions.
as shown in Figure 2, if the radon and furan are constructed on both sides of the nitrogen atom, such as compound 1, then the reaction of Aza-Achmatowicz may form the intermediate Ts-1, because the intermediate has an attackable subamine structure, then the pro-nuclear pyridine 2-bit may attack this site, resulting in a tetracyclic compound 2.
compound 2 is an important structural skeleton of a series of natural products of the ferns, such as Pleiocarpamine, and if the radon and amine are replaced by carbon chains on the same side of the furan 2-and 3-bits, such as compound 3, then the Reaction of Aza-Achmatowicz may form the intermediate Ts-2, at which point 2-bit of radon may be attacked with compound 4.
further conversion of compound 4 would synthesize the skeleton of the natural product Aspidophylline;
after a reaction of Aza-Achmatowicz may form the intermediate Ts-3, the same, if the 2-bit of radon to the amine attack to form a new six-ring, will form a four-ring system containing radon 3.3.1 system 6.
Compound 6 is a common intermediate for a range of natural products such as Macroline/Sarpagine/Ajmaline alkaloids, so once this conversion is completed, a large class of natural products can be synthesized in a variety of ways.
it's worth noting that the design in Scheme 1 is only a partial example of a series reaction based on a simple cyatic amine substrate (alkyl substitution in the 3rd bit of pyridine), and other types of arrangement combinations will produce more similar pyridine polycyclic systems.
(see supporting information) Qi Xiangbing task force first explored the third route starting with compound 5 as the starting material, and synthesized the ring skeleton structure of the radon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Cook et al. have developed ways to build the ring in the last century: starting with tryptophan, experiencing reactions such as Pictet-Spengler ringing, Dieckman shrinkage, de-removal, and so on.
Cook team has so far beautifully completed dozens of bioalkali synthesis based on this kind of skeleton, the author developed a method using furans, pyridine derivatives, raw materials cheap and easy to obtain, and the reaction is more efficient and concise, three-dimensional selectivity, these advantages make this series reaction application will be more widely extended to the full synthesis of biobases such as Macroline/Sarpagine/Ajmaline.
the author of the reaction has carefully studied the effect of the protective base on the reaction, under m-CPBA oxidation conditions, if not the protection of ammonia, pyridine nitrogen (protection base R1, R2), the target product can not be obtained, the other product 7-1 (Figure 3), if only for the use of pyridine nitrogen Boc Protection, also can not get the target compound 6, get another product 7-2, only m-CPBA oxidation of two nitrogen respectively using Boc, CF3CO simultaneous protection, and then in the conditions of silicone toluene reflux to remove the protective base of pyridine, can get the final target compound 6, and yield only 5%.
the authors then optimized the reaction conditions (Figure 4): the first attempt at different protective bases of amino (R2), Acetyl (Yield, 29%) was significantly less effective than Ts (Yield, 47%).
increased acidity in the system did not increase the yield (entry 3), the different oxidants were examined and found that Oxone, H2O2, and TBHP were not suitable for the reaction system (Entries 4-6), but NBS had better results (entry7).
then changed the proportion of the solvent and finally sifted to the optimal conditionNBS 1.2 eq., MeCN/H2O, 4:1, (80%, entry13).
under this condition, the author then carried out the expansion of the substrate (Figure 5): change the replacement base and position (R1), the replacement base type (R2) on the amine and the replacement base on the furan ring (R3), and found that the reaction has good hydrographic tolerance, and more importantly, it can also be used to construct the large ring of the reaction of the s.4.3.1, the large ring of 5.3.1, and still have a good yield (6p, 6q).
then, the authors used this reaction to make the first full synthesis attempt of plant-derived natural products (-) -Alstofolinine A (Figure 6).
its full synthesis can be divided into the construction of the basic skeleton (8-6g) and the subsequent modification (6g-final product) two parts.
the authors first used Ellman's sulfinamide as a hand control reagent, synthesized the hand compound 9, then m-CPBA oxidation to obtain the compound 5g, and then used optimized conditions to obtain its basic skeleton compound 6g.
the basic skeleton is completed after the completion of the functional group modification process, first of all, the methylation of pyridine N, the synthesis of compound 10, and then the use of bicarbonate and phNTf2 to convert 10 into compound 11, and then the use of Stille cross-coupled to obtain compound 12, Pd/C hydrogenation, and finally de-de-desalonal-based R.
the authors first used TfOH or TFA to degrade compound 13, and eventually the authors found that the used quantity of AlCl3 was able to successfully remove the R-group, and eventually successfully synthesized (-) Alstofolinine A, whose nuclear magnetic data and rotation data were consistent with the reported data.
on the basis of completing the full synthesis, the authors conducted a detailed toxicity test on all the key complex intermediates and end products of the method for four different cancer cells (see SI), and found that seven of these compounds exhibited highly selective specific cytotoxicity to four different cancer cell lines, which provided novel skeleton structure and useful core structural information for the discovery of drug-led molecules and subsequent optimization of the structural relationship.
, Qi Xiangbing task force of Beijing Institute of Life Sciences, used cheap and easy-to-access raw materials such as furans and pyridine derivatives as substrates, and realized the efficient construction of one of the radon rings by Aza-Achmatowicz reaction and pyridine- the first synthesis of the first natural product.
this method can be applied not only to the synthesis of other Alstofolinine analogues, but also to the full synthesis of more complex pyridine alkaloids.
Source: Chemical Plus.