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    Home > JACS: Professor Luo tuoping's research group of Peking University has realized the enantioselective total synthesis of (- - oridonin (2) for the first time

    JACS: Professor Luo tuoping's research group of Peking University has realized the enantioselective total synthesis of (- - oridonin (2) for the first time

    • Last Update: 2019-12-27
    • Source: Internet
    • Author: User
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    Among the numerous ent kaurene diterpenoids, (-) - oridonin (2) is one of the most widely used molecules in clinical and preclinical studies In fact, it is the main active component of Rabdosia rubescens, a common over-the-counter anti-inflammatory medicine Diterpenoid 2 shows potential activity in vitro and in vivo for a variety of cancer cells, which makes researchers conduct a lot of Pharmaceutical Chemistry Research on it, and fine tune a series of oridonin derivatives for drug development Although chemists have completed the semisynthesis of oridonin and made great progress in the synthesis of highly oxidized ent kaurene diterpenoids, the total synthesis of (- - oridonin (2) is still full of challenges, so it is necessary to develop new and effective synthesis strategies Recently, the team of Professor Luo tuoping of Peking University realized the enantioselective synthesis of (- - oridonin (2) by using a key interrupted Nazarov reaction Relevant research results were published in J am Chem SOC (DOI: 10.1021 / JACS 9b12034) The reverse synthesis analysis is shown in Figure 1 In the later stage, intermediate 3 can be prepared by epoxide 4 through 1,2-migration and deprotection Another 1,2-migration (pairing rearrangement) can trace 4 back to 5 This ring reduction strategy shows the key synthesis intermediate 6 An interrupted Nazarov cyclization reaction is envisaged, in which the hydroxyallylic cation 7a is captured by the side chain allylic silane to synthesize 6 effectively The key reaction substrate ketone 8A can be prepared by two single ring synthons 9 and 10 (source: J am Chem SOC.) the author first prepared ketone 8 (Table 1) with 1:1 diastereomer mixture to evaluate the effect of stereochemistry (C1 and C16) on the series reaction of Nazarov / hosomi Sakurai Through the screening of Lewis acid, the author found that only etalcl2 was beneficial to the transformation of the reaction The obtained product (11-14) shows two important characteristics of the reaction: (1) the optical rotation selectivity of the product can be adjusted by C1 and C20 benzyl protecting groups; (2) the reaction is the product of the interrupted Nazarov reaction formed by stereoselectivity The yields of 11 and 14 were more than 30% and more than 20% (entries6 and 7), respectively (source: J am Chem SOC.) based on the research results of Nazarov / hosomi Sakurai series reaction, the author adjusted the synthesis route to prepare (+ - 9 (scheme 1) Ketone 15 was reacted by Vilsmeier to produce β - bromoaldehyde 16, which was then oxidized and methylated by pinnick to ester 17 Through the selection of allyl oxidation conditions, the author found that CrO 3 can produce ketene 18 in 45% yield at the scale of 20 G Compound 18 was directly reduced to chiral diol (+) - 19 by excellent enantioselective reduction under the action of excess BMS (borane dimethyl sulfide complex) and CBS (2-methyl-cbs-oxazoliborane), which was protected by benzyl group to obtain (+) - 9 Next, the author synthesized the right fragment 10 from (+ - 20) Ketone 20 was converted to vinyl iodide 21 by iodine monochloride treatment, and then it was cross coupled with trimethylsilylmethylzinc reagent by PD catalysis Allylsilane 22 was obtained in two steps of 55% yield A trifluoromethylsulfonate enol ester was synthesized by regioselective deprotonation of α - methylene with a small steric hindrance of carbonyl group on 22 The ester 23 was obtained by palladium catalyzed carbonylation in a two-step yield of 63% 23 was transformed into Weinreb amide 24, and then reduced by dibal-h to obtain enantiomeric enriched aldehyde (+) - 10 (source: J am Chem SOC.) after obtaining the above two fragments, the author continued to carry out the total synthesis of (- - oridonin (2) (scheme 2) A pair of enantiomeric secondary alcohols were obtained by the addition of Li reagent prepared by Li br exchange of (+) - 9 and t Buli with (+) - 10, and then formed (+) - 8b by PDC oxidation Under the optimized conditions of Nazarov / hosomi Sakurai series reaction, (+) - 8b is converted to (-) - 11 The crude product was directly reacted with singlet oxyene, and then treated with acetic anhydride The yield of aldehyde (+ - 25 (J.Org Chem 1983, 48, 4135 − 4137.) was 43% in two steps Subsequently, aldehyde 25 was dehydroacetylated with rhodium catalyst, and ketone 26 was obtained in 67% yield at gram scale After selecting various nucleophilic reagents, the author realized 1,2-addition reaction by using vinyl lithium The c13-c14 olefin on the alcohol was selectively epoxidated by m-chlorophenobenzoic acid, and a single enantiomer 27 was obtained Firstly, electrophilic bromine was introduced into the carbon carbon double bond, and then B-ring was constructed through the rearrangement reaction of pinacol like, and then 28 was obtained Its structure was determined by X-ray diffraction In order to avoid the ring opening of epoxides and the side reactions related to unstable bromides caused by C20 OBN group under Lewis acid condition, a series of oxidation transformations were carried out for 28 Two benzyl protecting groups were converted to benzoyl group, and then alkanone 29 was obtained by DBU treatment The yield of alkanone 29 was 30% in two steps of 70% by dihydroxylation After screening Lewis acid, the author found that etalcl2 can effectively promote the key ring rearrangement reaction, thus constructing the C / D ring system Hexanol 32 was obtained by reducing C6 carbonyl of ketone 31 and removing two benzoyl protecting groups at the same time The crude product of 1,2-diol, which has a small steric hindrance, was selectively cracked to give hemiacetal 33 in 69% yield in two steps (source: J am Chem SOC.) intermediate 33 was protected by acetone analogue and then oxidized by DESs Martin Ketone 34 was formed in 66% yield by one pot method By carefully optimizing the reduction / deprotection sequence and reaction conditions, the author first used dibal-h to reduce C1 ketone in DCM / ether (3:1) at - 100 ° C, and then reduced C6 carbonyl with red Al, so that the enantiomers (-) - 35 and (-) - 3 were obtained in 21% and 56% yields respectively after in-situ deprotection In the end, the author found that (BOC) 2O can effectively convert the allylic hydroperoxides derived from (-) - 3 to alkene and protect C14 hydroxy group Therefore, with the addition of HCl, the natural product 2 can be obtained in 47% yield In a word, the author has realized the synthesis of (- - oridonin (2) for the first time This work further proves that the interrupted Nazarov cyclization reaction has great application value in total synthesis Another highlight of this strategy is the key skeleton rearrangement through two 1,2-migration transformations In addition, two synthons (+) - 9 and (+) - 10, which were prepared on a gram scale, can also be used to synthesize other terpenoids.
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