Angelw: Zhang Peicheng's research group of Concorde Institute realized the construction of iron catalyzed core of hexahydropentane [C] furan and the total synthesis of polyflavanostilbene B and C

Polyflavanostilbene A is a polyphenol compound (or Lett 2013, 15, 674-677) isolated from the rhizome of Polygonum cuspidatum by Zhang Peicheng research group, Institute of medicine, Peking Union Medical College, Chinese Academy of Medical Sciences in 2013 The compound has inhibitory activity on α - glucosidase (IC 50 value is 17.7 μ m) The hydrolysate polyflavanostilbene B (1) has stronger α - glucosidase inhibitory activity (IC 50 value is 1.54 μ m), and has significant protein tyrosine phosphatase 1B (PTP1B) inhibitory activity (IC 50 value is 5.05 μ m) There are eight phenolic hydroxyl groups and tetracyclic helix ketone in 1 molecule, which makes its synthesis challenging Recently, the research group reported on angelw.chem.int.ed the construction of iron catalyzed hexahydropentane [C] furan mother nucleus and the total synthesis of polyflavanostilbene B and C (DOI: 10.1002/anie.201804329) (picture source: angelw Chem Int ed.) the synthesis strategy of polyflavanostilbene B (1) is shown in scheme 1 Based on the possible biogenic pathway of polyflavanostilbene a, the author speculated on the process of epoxidation and intramolecular nucleophilic addition of stilbene Catechol and resveratrol are easy to be oxidized in a single electron process to produce stable free radicals, which are the key intermediates to transform simple phenols into complex polyphenols Hexahydrocyclopentane [C] furan skeleton is more likely to come from compound 3, which is an adduct of (- - epicatechingallate (ECG) and resveratrol Therefore, the author proposed a synthesis method of 1: adduct 3 was firstly oxidized to phenoxy radical 3a, and then the benzyl radical 3B was formed through the single electron transfer (set) process; then, the double bond of 3b and resveratrol was added intramolecularly and reacted with triplet oxygen to form peroxy radical, which obtained hydrogen atom from phenol to produce hydroperoxide2; finally, 2 2 A was obtained by reduction or hydrolysis, and 2 a formed 1 by intramolecular nucleophilic addition (photo source: angelw Chem Int ed.) firstly, the author synthesized the ECG derivatives It has been shown that polymer flavane-3-ol (PFS) can be converted into c-4-substituted flavane-3-ol derivatives by using appropriate nucleophiles such as mercapto nucleophiles and phloroglucinol, so as to rapidly synthesize flavane-3-ol derivatives with substituents at C-4 position Resveratrol may be nucleophilic similar to phloroglucinol The author first tried to use ECGP and resveratrol to synthesize β - C-4 tetrasubstituted ECG (scheme 2, a) However, because resveratrol is less nucleophilic than phloroglucinol, no target product 3 was obtained Because thiobenzyl is a good leaving group, and 4-thiobenzyl-substituted ECG is an alternative intermediate for the preparation of adduct 3 Therefore, the author tried to treat ECGP with benzyl mercaptan to prepare scheme 2, B (image source: angelw Chem Int ed.) after obtaining intermediate 6, the author continued to synthesize adduct 3 Firstly, the C (SP 3) - C (SP 2) bond between ECG and resveratrol C-4 was constructed Under the catalysis of - 10 ℃ and agbf 4, the product 3 was obtained in low yield Then, the author screened various reaction solvents and catalysts (Table 1) It was found that in the presence of anhydrous DMF and AgTFA, the yield of product 3 could be increased to 63% (image source: angelw Chem Int ed.) through 1H NMR and ECD data, we can see that the absolute configuration of adduct 3 is 2R, 3R, 4S, and 3 shows two sets of NMR data, indicating that there is a blocking isomer phenomenon in the C (SP 3) - C (SP 2) bond between ECG at C-4 and resveratrol It is a practical method to cyclize aromatic compounds by free radicals under the action of transition metals such as CuCl2 and FeCl3 Therefore, the author tried to carry out the reaction in anhydrous methanol and under the catalysis of FeCl 3 Only trace 1 was produced, but no 1 was obtained in acetone and tetrahydrofuran When FeCl 3 · 6h 2O was used as the catalyst, the yield increased to 14% Considering that the trace water increased the yield of 1, the author added different proportion of water in the follow-up reaction, and the yield increased However, when other catalysts such as CuCl2, K3 [Fe (CN) 6], MnO2, FeCl2 and agoac were selected, the yield of the reaction did not increase The optimum reaction conditions were as follows: CH3OH / H2O (4:1, V / V) was used as the mixed solvent and FeCl3 · 6H2O (50 mol%) as the catalyst at room temperature Under the optimum reaction conditions, polyflavanostilbene B (1) was prepared by three steps The absolute configuration of (image source: angel Chem Int ed.) 1 was confirmed by 1H NMR and ROESY spectra The ROESY correlation between H-2 and H-8 'indicates that they are on the same side of the molecule (Figure 2) The coupling constants of H-7 'and H-8' are 8.0 Hz, indicating that H-7 'and H-8' are on the same side The chemical shift of H-14 'is 4.75 (1H, BRS), indicating that H-14' is located in the shielding area of E-ring, which also supports the CIS relationship between D-ring and E-ring in THF ring ECD data of 1 is also consistent with polyflavanostilbene a (image source: angel Chem Int ed.) polyflavanostilbene C (a similar compound of polyflavanostilbene b) was also synthesized by egcgp through a similar route However, the author did not separate the presumed intermediate 2 / 2a from the reaction of adduct 3 The reduction of reaction temperature, reaction time or the amount of catalyst has not reached 2 / 2A It is suggested that hydroperoxides 2 can be hydrolyzed to form 2a, and then 1 can be produced rapidly by nucleophilic addition In order to study its mechanism, racemic substrate 9 (rac-9) with low rigidity was synthesized from 2,4-dihydroxyacetophenone 13 At - 30 ℃, rac-9 was catalyzed by FeCl 3 · 6h 2O (10 mol%) in a mixed solvent (CH 3OH / H 2O, 4:1, V / V) to produce hydroperoxides 10, which were converted into compound 11 (scheme 3) in DMSO at room temperature In addition, two control experiments were used to elucidate the mechanism of the reaction First of all, tempo, a free radical inhibitor, was added to the transformation from RAC - 9 to 10, and the reaction could not take place smoothly In addition, using PMB to protect the phenolic hydroxyl groups at C-2 and C-4 positions in the compound rac-9, the resulting rac-12 (scheme 4) failed to react under the catalysis of FeCl 3 · 6h 2O This shows that the formation of 10 is through the process of free radical cyclization The possible reaction mechanism proposed by the author is shown in Figure 3 Firstly, the phenolic compound RAC - 9 was reversibly combined with iron salt to obtain the complex 9A Then, with the participation of oxygen, 9A forms free radical complex 9b through deprotonation and set process Then, the double bonds of 9b and resveratrol were added to form stable benzyl radicals, which reacted with triplet oxygen to form hydroperoxy radical complex 9C Finally, 9C combines with the hydrogen atom of another phenol to form the key intermediate 10, which is then hydrolyzed or reduced to compound 11 (picture source: angel Chem Int ed.) conclusion: Zhang Peicheng's research group has completed the first full synthesis of polyflavanostilbene B and C, and the synthesis scale has reached gram level The synthesis highlights include regioselective and stereoselective substitution of resveratrol for 4-derivatives of ECG and iron catalyzed cyclization The synthesis strategy can also be used for the synthesis of other hexahydrocyclopentane [C] furan analogues The possible mechanism of free radical cyclization in the formation of the parent nucleus of hexahydrocyclopentane [C] furan has also been elucidated Research fields of Zhang Peicheng: 1 Discovery and methodology of active natural products with various structures; 2 Structural modification and synthesis of active natural products; 3 Quality control of traditional Chinese medicine and research of new traditional Chinese medicine.