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    Home > Angelw: Anderson Group of Oxford University completed the total synthesis of four (- - rubriflordilactone B enantiomers

    Angelw: Anderson Group of Oxford University completed the total synthesis of four (- - rubriflordilactone B enantiomers

    • Last Update: 2019-11-01
    • Source: Internet
    • Author: User
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    Schisandra is rich in triterpenoids, most of which have antiviral and anticancer activities Rubriflordilactones A and B, which were isolated from Schisandra chinensis by academician sun Handong's team, have distinct anti HIV activities, and the construction of their multi substituted aromatic parent nuclei is challenging Li'ang group and Edward A Anderson Group of Oxford University completed the synthesis of rubriflordilactone a; however, the NMR data of rubriflordilactone B (1, scheme 1) synthesized by Li'ang and others are inconsistent with the data reported by academician sun Han Dong (C16 and C17 bits), indicating that there can be two kinds of rubriflordilactone B natural products, namely one corresponding to single crystal X-ray diffraction structure, another corresponding to the NMR spectral data Recently, in order to solve the above problems in stereochemistry, Edward A Anderson Group completed the synthesis of (- - rubriflordilactone B and (-) - pseudo rubriflordilactone B, which was published in angel Chem Int ed (DOI: 10.1002 / anie 201908917) (image source: angel Chem Int ed.) based on the previously established synthesis strategy of rubriflordilactonea, aromatic D-ring is the key to skeleton cutting The author thinks that the target natural product of triyne 3 can be obtained by [2 + 2 + 2] cyclotrimerization, and triyne 3 can be constructed by common ab cycloaldehyde 4 and diyne such as 5 (rubriflordilactone b) and 6 (pseudo rubriflordilactone b) In consideration of the sensitive conditions required for the binding of the above fragment with 4, the authors also consider the use of alternative iodoalkanes 7 and 8 to realize the connection through mild Nozaki-Hiyama-Kishi coupling Scheme 2: asymmetric [2 + 2] cycloaddition of aldehydes 9 and ketene to produce β - lactone 10, followed by ring opening of alcohol 11 to produce ester 12, followed by Ireland Claisen rearrangement and methylation to produce ester 13 Acetal 14 is produced by oxidative cracking and spontaneous cyclization of olefins Then, the two oxygen-containing side chains of 14 were converted into diyne-15, which was iodo terminated with alkyne, and added with 18 to form butenolide g-ring (mixture of enantiomers 7a and 7b) The structure and absolute configuration of 7b were confirmed by single crystal X-ray diffraction (picture source: angel Chem Int ed.) synthesis of 8-diyne fragment of pseudo-rubriflordilactone B (scheme 3): β - hydroxyester 19 is allylated to 20, and then further converted to lactone 21 according to the previous route Because the two substituents are located in the β - plane of its five membered lactone ring, lactone 22 obtained by methylation of 21 is a single stereoisomer After transforming the lactone into acetal 23, the author further converted it to diacetylene 26 according to the previous route However, the addition of butene lactone is lack of stereocontrol, and four non enantiomers, fgdiacetyl 8A - D (1:1:1:1:1), are obtained At last, the single stereoisomers of 8b and 8C were separated (the structure of 8C was confirmed by single crystal X-ray diffraction analysis), but 8a and 8D could not be separated (picture source: angel Chem Int ed.) rubriflordilactone B (1) synthesis (scheme4): firstly, the author carried out a simulation reaction on the cyclization and later synthesis of triyne: diyne 16 and 17 were added with 6-heptanaldehyde respectively, and then removed TMS for rhodium catalyzed triyne ring trimerization to obtain cdef ring 28, and the expected product was successfully obtained through subsequent reaction 30 Then, the addition of aldehydes 4 and diynes 17, the removal of TMS, and the ring trimerization catalyzed by rhodium, and the dehydration of benzyl alcohol reported by Grieco, resulted in the synthesis of hexacyclic intermediate 32 Then 32 reacts with furan 18 to obtain a mixture of 1 and its C23 EPI-1 (1:1, non separable) (picture source: angelw Chem Int ed.) the separation of C23 isomer prompted the author to consider introducing butene lactone ring in the early stage to obtain a more convergent synthesis route (scheme 5) By addition and TMS removal of iododene 7a and 7b with aldehyde 4 respectively, we have obtained triyne 34 and 35 Their cyclotrimerization can tolerate butene lactone ring, thus obtaining complete natural product skeleton Finally, rubiflordilactone B (1) and its C23 enantiomer EPI-1 were obtained by p-TsOH catalytic dehydration of 34 and 35 The former is consistent with the spectral data reported by Leon group, and its structure and absolute configuration were confirmed by single crystal X-ray diffraction The synthesis of pseudo rubriflordilactone B (2) (scheme 5): because iododene 8a and 8D are not separable, the author added its mixture with aldehydes 4 to get separable high alkynyl propanol, and then removed its TMS to get triyne 36; compared with rubriflordilactone B, the subsequent dehydration elimination of cyclotrimerization and acid catalysis requires higher catalyst loading and/ The predicted pseudo rubriflordilactone B (2) was obtained by prolonging the reaction time The C23 isomer epi-2 of pseudo-rubriflordilactone B was obtained by the same operation By comparing the NMR data of 2 (and epi-2) with the data reported by sun Handong's research group, the author found that the former, namely 2, was highly consistent with the natural products obtained by separation, thus providing strong evidence for the calculation and prediction of stereochemistry (picture source: angel Chem Int ed.) conclusion: Edward A Anderson Group completed the total synthesis of four non enantiomers of rubriflordilactoneb, one corresponding to the crystal structure of the separated natural product, the other corresponding to the NMR spectrum data of the separated natural product The key to its synthesis lies in the asymmetric synthesis of FG cyclodiyne and the highly convergent late coupling / cyclotrimerization / dehydration strategy In addition, the author also solved the stereochemistry dispute of this natural product and provided a strategy suitable for the diversified synthesis of natural products.
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