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    Home > Wang Zhongwen research group of Nankai University completed the synthesis of englelins A / B, Oriental OLS E / F and oxyphyllol

    Wang Zhongwen research group of Nankai University completed the synthesis of englelins A / B, Oriental OLS E / F and oxyphyllol

    • Last Update: 2018-04-26
    • Source: Internet
    • Author: User
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    The authors: Beipiao (-) - englerin a (1) and B (2) were isolated from the stem / root bark of Euphorbiaceae Phylanthus engleri in 2008 by Beutler and his colleagues (org Lett 2009, 11, 57 − 60) Biological studies show that 1 has a very good inhibitory activity on renal cancer cells (Figure 1) Orientalyse / F (phytochemistry 2003, 63, 877 − 881) and oxyhydrol (Tetrahedron 2003, 59, 9991 − 9995) are three structure related natural products Due to their extremely low natural content, their biological activities have not been fully studied All the five natural products belong to the gemarane sesquiterpene family, which is characterized by a bicyclic [5.3.0] decane skeleton and an embedded oxa - [3.2.1] octane skeleton These sesquiterpenes have attracted wide attention in the field of organic chemistry due to their novel structures and remarkable anticancer activities Since their first separation, several total synthetic routes have been reported in a few years (photo source: Organic letters) so far, since christmann et al First completed the full synthesis of (+ - englerin a in 2009 (angew Chem., int ed 2009, 48, 9105 − 9108), more than 20 reports have been reported on the full synthesis of these compounds (including their enantiomers and racemates) Key synthesis strategies include ring closing [1-8] by cross metathesis, gold catalyzed [2 + 2 + 2] cycloaddition [9-11], 1,3-dipolar [3 + 2] cycloaddition [12-14], [4 + 3] cycloaddition [15-19], intermolecular cross coupling reaction [20], Michael addition / free radical cyclization [21], cyclocondensation [22] and Nazarov cyclization [23] Recently, Wang Zhongwen's research group of Nankai University reported that the total synthesis of (- - englerinsa / B, (+) - Orientals E / F and (-) - oxyphyllol was completed through the intramolecular cross cycloaddition (IMCC) strategy of cyclopropane (DOI: 10.1021/acs Org lett 8b00552) The author takes (- - englerin a as an example to carry out inverse synthesis analysis, as shown in figure (scheme 1) First, two ester groups in (- - englerin a molecule are broken down into diol 6, which can be prepared from compound 7 or 11 Compounds 7 or 11 can be constructed by intramolecular cross [3 + 2] cycloaddition of 8 or 12, respectively Compounds 8 or 12 can be prepared from the same intermediate 9 by cyclopropylation of carbon carbon double bond a or cyclopropylation of carbon carbon double bond B, respectively Triaenol 9 can be prepared from a known compound 10, which can be obtained in two steps by the commercially available (R) -(+) - limonene (photo source: Organic letters) the author initially tried to use carbon carbon double bond a to carry out intramolecular cyclopropylation, but no cyclopropylation product was observed; then, through intermolecular and intramolecular approaches, the cyclopropylation of carbon carbon double bond B (scheme2) was successfully carried out In this paper, aldehyde-10 was converted into alcohol-9 (DR = 10:1) by Shapiro reaction Compound 15A or 15b was obtained by hydroxyl protection and intermolecular cyclopropylation Steric hindrance may play a key role in chemically selective cyclopropylation The single crystal X-ray analysis of 15A shows that the absolute stereochemical configuration of the quaternary carbon atom in cyclopropane is r configuration, which means that RH carbene attacks from the re surface of double bond B The double bond a is decomposed by ozone to obtain 8b, and then the cycloaddition product 7b is obtained by [3 + 2] - IMCC under the catalysis of Yb (OTF) 3 / Cui, while the product of 8A reaction is relatively complex 16b / 16b '(16b: 16b' = 10:1) was obtained from decarboxylation of 7b by krapcho The stereochemistry of C7 and C10 in the secondary diastereomer 16b 'was confirmed to be contrary to that of the natural product by single crystal X-ray analysis The results showed that the reaction mechanism of [3 + 2] - IMCC was similar to that of SN2 (photo source: Organic letters) due to the stereoselectivity of intermolecular cyclopropylation, which tends to attack the re surface, the author believes that in the strategy of intramolecular cyclopropylation, the result of stereochemistry matching with the target will be obtained (scheme 3) Among them, the hydroxyl group is the guiding group of stereochemistry If RH carbene is partially connected to the hydroxyl group, the expected stereochemistry can be obtained After Mukaiyama esterification, regitz diazotization and chemical selective intramolecular cyclopropylation of double bond B, compound 9 was transformed into lactone 14, and then the ester exchange product 15 was obtained by sodium methoxide / methanol treatment Using chloroacetyl chloride to protect the hydroxyl group in compound 15, the double bond a was decomposed by ozone to obtain [3 + 2] - IMCC precursor 8C Finally, the cycloaddition product 7C was obtained by [3 + 2] - IMCC in 79% yield under the catalysis of Lewis acid SC (OTF) 3 Its absolute configuration was confirmed by single crystal X-ray diffraction analysis, which was consistent with that of natural products (photo source: Organic letters) after getting 7C, the author began to try to complete (- - englerin A / b synthesis (scheme4) 7C was first decarboxylated by krapcho to produce 16C monoester (DR = 3:1), and dibal-h was used to reduce the ester group to obtain 17 monoenantiomer diol Without purification, α was obtained by DES Martin oxidation and enema Saegusa oxidation, β - unsaturated aldehydes 19 were decarbonylated by Tsuji Wilkinson to get 20, then hydrogenated and oxidized to get diol 21 (DR > 20:1, its absolute configuration was confirmed by single crystal X-ray) After Pd / c-hydrogenated to get 6, and Dr = 3.3:1 After double esterification and deprotection, the synthesis of (- - englerin a (1) was finished At the same time, (- - englerin B (2) was synthesized under mild saponification conditions (photo source: Organic letters) finally, the author has also completed the total synthesis of (+ - Oriental f (3), (- oxyphyllol (4) and (+ - Oriental E (5) by using intermediate 18 After the decarbonylation of intermediate 18 by Tsuji Wilkinson and the reduction by luche, we obtained (+ - Orient ol f (3) After Pd / C hydrogenation, (- - oxyphylol (4) (DR = 4:1) was obtained According to the previously reported scheme (chem - EUR J 2013, 19, 2539), the total synthesis of (+ - Oriental E (5) was completed And the data of all synthetic products are consistent with the data reported in the literature (photo source: Organic letters) conclusion: the author first completed the synthesis of (+ - orientalol e from commercial source (R) -(+) - limonene, and carried out the synthesis of (- - englerin a, (-) - englerin B, (+) - orientalol F and (- - oxyphyllol The key steps include the hydroxy oriented stereoselective and regioselective intramolecular cyclopropylation and the stereoselective [3 + 2] - IMCC of cyclopropane 1,1-diester with carbonyl group, which are used to construct the core core core hetero - [3.2.1] octane bicycles At the same time, we obtained the 7,10-enantiomeric precursor of englerins Because IMCC can realize the diversity of molecular structure, it is believed that this synthesis strategy will have application prospects in drug discovery in the future ; 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