- A trans-vinylogous ester anion equivalent and its application to the synthesis of (+)-brefeldin A
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A new trans-vinylogous ester anion equivalent which reacts with a variety of carbonyl systems has been developed. In addition, the concise total synthesis of (+)-brefeldin A utilizing facile acylation of this new variant of vinylogous acyl anion equivalent has been accomplished.
- Suh, Young-Ger,Seo, Seung-Yong,Jung, Jae-Kyung,Park, Ok-Hui,Jeon, Ra-Ok
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- An olefin disconnection strategy for the practical synthesis of (+)-brefeldin A: olefin cross metathesis and intramolecular Horner-Wadsworth-Emmons olefination
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The practical and convergent total synthesis of (+)-brefeldin A has been achieved by an olefin disconnection strategy. Key features of the total synthesis include the efficient formation of C2 and C10 olefins, employing an olefin cross metathesis (CM) reaction and an intramolecular HWE olefination, respectively.
- Seo, Seung-Yong,Jung, Jae-Kyung,Paek, Seung-Mann,Lee, Yong-Sil,Kim, Seok-Ho,Suh, Young-Ger
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- Application of Ru(II)-Catalyzed Enyne Cyclization in the Synthesis of Brefeldin A
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The approach to brefeldin A described herein hinges on Ru(II)-catalyzed cycloisomerization of an enyne obtained by the reaction of an alkynylzinc reagent with an α-chloro sulfide. Other key steps include Mislow-Evans rearrangement, cross-metathesis, and macrocyclization using a Roush-Masamune protocol.
- Raghavan, Sadagopan,Yelleni, Mahesh Kumar Rao
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- Total synthesis of the antitumor macrolides, (+)-brefeldin A and 4-epi-brefeldin A from d-glucose: Use of the Padwa anionic allenylsulfone [3 + 2]-cycloadditive elimination to construct trans-configured chiral cyclopentane systems
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A new synthesis of (+)-brefeldin A is reported via Padwa allenylsulfone [3 + 2]-cycloadditive elimination. Cycloadduct 13 was initially elaborated into iodide 27, which, following treatment with Zn, gave aldehyde 28 whose C(9) stereocenter was epimerized. Further elaboration into enoate 38 and Julia-Kocienski olefination with 5 subsequently afforded 39, which was deprotected at C(1) and O(15). Yamaguchi macrolactonization of the seco-acid thereafter afforded a macrocycle that underwent O-desilylation and inversion at C(4) to give (+)-brefeldin A following deprotection.
- Xiong, Ziyue,Hale, Karl J.
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- Synthesis and cytotoxic evaluation of acylated brefeldin a derivatives as potential anticancer agents
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Brefeldin A has attracted considerable attention because of its potential function in cancer prevention. However, its therapeutic use is limited by its poor bioavailability. The modifications on brefeldin A were difficult because of its low stability and selectivity toward two hydroxyl groups within the same molecule. In this study, we report the selective acylation of brefeldin A under mild conditions and the preparation of a series of monoacylated and diacylated brefeldin A derivatives. Their cytotoxicity, antitumor activity against TE-1 cell, and molecular properties of adsorption, distribution, metabolism, and elimination were evaluated. Brefeldin A 7-O-benzoate, brefeldin A 4,7-O-dibenzoate, and brefeldin A 7-O-biotin carboxylate showed the most potent cytotoxic activity, with GI50 values of 0.39, 0.46, and 0.50 μm, respectively. Molecular docking of these analogs revealed that the derivatives were well tolerated at the interface between ARF1 and its guanine nucleotide exchange factor ARNO. Our results may serve as a basis for the development of novel potential anticancer agents from brefeldin A derivatives.
- He, Bingyong,Wang, Yajun,Zheng, Yuguo,Chen, Wei,Zhu, Qing
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- Elucidation of strict structural requirements of Brefeldin A as an inducer of differentiation and apoptosis
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Brefeldin A (BFA) can induce a wide variety of human cancer cells to differentiation and apoptosis and is in development as an anticancer agent. To elucidate structural requirements for cytotoxicity and induction of differentiation and apoptosis, BFA was structurally modified into various derivatives including 4-epi-BFA in this study. Their inducing activities of apoptosis were evaluated with their cytotoxicities, DNA fragmentation and morphological changes in human colon cancer cell HCT 116. The cytotoxicity of 4-epi-BFA (TX-1923) (IC50 = 60 μM) was 300 times lower than that of BFA (IC50= 0.2 μM). Furthermore, 4-epi-BFA induced DNA fragmentation and apoptotic morphological changes at much higher concentrations (70 and 50 μM, respectively) than BFA (0.11 and 0.36 μM, respectively). These results indicated that the configuration of 4-hydroxyl group of brefeldin A plays a key role in the cytotoxicity and induction of apoptosis. On the other hand, 7-O-acetyl-BFA, 4-O-acetyl-BFA, and 4,7-di-O-acetyl-BFA exhibited potential activities in cytotoxicity and inducibility of apoptosis. We suggested that the structural determinants for BFA include the moiety of the Michael acceptor, the conformational rigidity of the 13-membered ring, and the configuration of 4-hydroxyl group. (C) 2000 Elsevier Science Ltd.
- Zhu, Ji-Wen,Nagasawa, Hideko,Nagura, Fumi,Mohamad, Saharuddin B.,Uto, Yoshihiro,Ohkura, Kazuto,Hori, Hitoshi
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- Synthesis of (+)-Brefeldin-A
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Two routes to (+)-brefeldin A have been investigated.In one the bicyclic ketone 2 was transformed into the hydroxy lactone 7.Subsequent reduction, opening of the heterocyclic ring and epimerization furnished the aldehyde 13.Further steps towards the natural product from this late stage intermediate 13 were not investigated.In the second route, the readily available hydroxy lactone 17 was converted into the enone 22.Conjugate addition of the requisite cuprate reagent to this afforded the 3,4-disubstituted cyclopentanone 24 which was converted into brefeldin-A 29 in five steps.
- Carnell, Anrdew J.,Casy, Guy,Gorins, Gilles,Kompany-Saeid, Arefeh,McCague, Ray,et al.
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- Trans-hydrogenation: Application to a concise and scalable synthesis of brefeldin a
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The important biochemical probe molecule brefeldin A (1) has served as an inspirational target in the past, but none of the many routes has actually delivered more than just a few milligrams of product, where documented. The approach described herein is clearly more efficient; it hinges upon the first implementation of ruthenium-catalyzed trans-hydrogenation in natural products total synthesis. Because this unorthodox reaction is selective for the triple bond and does not touch the transannular alkene or the lactone site of the cycloalkyne, it outperforms the classical Birch-type reduction that could not be applied at such a late stage. Other key steps en route to 1 comprise an iron-catalyzed reductive formation of a non-terminal alkyne, an asymmetric propiolate carbonyl addition mediated by a bulky amino alcohol, and a macrocyclization by ring-closing alkyne metathesis catalyzed by a molybdenum alkylidyne.
- Fuchs, Michael,Fürstner, Alois
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p. 3978 - 3982
(2015/03/30)
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- Asymmetric total synthesis of (+)-brefeldin A: Intramolecular epoxide-opening/RCM strategy
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A highly efficient asymmetric total synthesis of (+)-brefeldin A was accomplished by using intramolecular epoxide opening of an epoxy allylsilane and RCM reaction for the constructions of the cyclopentane and macrocyclic lactone rings of (+)-brefeldin A,
- Kim, Myung-Yeol,Kim, Hyemi,Tae, Jinsung
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experimental part
p. 1303 - 1306
(2009/11/30)
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- Total synthesis of (+)-brefeldin a
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(+)-Brefeldin A was synthesized through an efficient route, which features (1) construction of the five-membered ring from a Crimmins aldol via tandem Li-I exchange and carbanion-mediated cyclization with concurrent removal of the chiral auxiliary, (2) introduction of the lower side chain (C10 to C16) via a Rh-catalyzed Michael addition of a vinyl boronic acid, (3) stereoselective reduction of the C7 ketone with Sml2, and (4) a 2-methyl-6- nitrobenzoic anhydride-mediated (Shiina) lactonization.
- Wu, Yikang,Gao, Jian
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supporting information; experimental part
p. 1533 - 1536
(2009/04/12)
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- A "Chiral Aldehyde" Equivalent as a Building Block Towards Biologically Active Targets
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Chiral γ-aryloxybutenolides, readily accessible through dynamic kinetic asymmetric transformation (DYKAT) of racemic acyloxybutenolides, were utilized as "chiral aldehyde" building blocks for intermolecular cycloadditions and Michael reactions. Unprecedented selectivity in trimethylenemethane cycloadditions with this building block allowed an efficient synthesis of a novel metabotropic glutamate receptor 1 antagonist in development by the Bayer corporation. These studies further inspired work that culminated in the total synthesis of (+)-brefeldin A, a natural product with a range of significant biological properties. All of the stereochemistry in this target molecule was derived from two palladium-catalyzed asymmetric allylic alkylation reactions. The trans-alkenes were synthesized by a Julia olefination and a ruthenium-catalyzed trans-hydrosilylation-protodesilylation protocol. The route to (+)-brefeldin A lends itself to analogue syntheses and was completed in 18 steps in 6% overall yield.
- Trost, Barry M.,Crawley, Matthew L.
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p. 2237 - 2252
(2007/10/03)
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- Enantioselective total synthesis of (+)-brefeldin A and 7-epi-brefeldin A
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A convergent enantioselective route to brefeldin A (BFA) and 7-epi-BFA was developed. The key C-4/C-5 chiral centers were established by using chiral auxiliary induced intermolecular asymmetric aldolization in the presence of TiCl4 and TMEDA. The results with the thiazolidinethione/TiCl 4 mediated intermolecular asymmetric aldolization added some new information about the scope and limitations to the existing knowledge of that type of reactions (which so far was essentially limited to the reactions with N-propionyl thiazolidinethiones). During the course a method for protecting the liable aldol hydroxyl groups by using inexpensive TBSCl in DMF with 2, 6-lutidine as the base was developed to replace the otherwise unavoidable TBSOTf procedure. Due to the excessive steric hindrance, removal of the auxiliary was much more difficult than most literature cases. Cleavage of the oxazolidinone by reduction was almost impossible. The thiazolidinethione auxiliary was relatively easier to remove. However, several reactions reported for facile removal of thiazolidinethione auxiliaries in the literature still failed. Reductive removal of the thiazolidinethione auxiliary was most effectively realized with LiBH4 in diethyl ether in the presence of 1 equiv of MeOH (a modification of a literature procedure for removal of oxazolidinone auxiliaries in less hindered substrates). Apart from the auxiliary removal, oxidation of the alcohol into aldehyde and the deprotection of the dithiolane protecting group were also rather difficult in the present context. A range of methods were screened before final solutions were found. The five-membered ring was constructed by employing an intramolecular Mukaiyama reaction after many attempts with the intramolecular aldolization under a variety of conditions failed. The rate of elimination of the alkoxyl to form the α,β-double bond of the key intermediate cyclopentenone 49 with DBU was highly solvent dependent (very sluggish in CH2Cl2 but rather fast in MeOH). Introduction of the lower chain (which was synthesized by using a Jacobsen KHR to establish the C-15 chirality) was achieved through a Michael addition similar to the precedents in the literature. It has not been noticed before that the yield of this Michael reaction could be dramatically raised by using 3 equiv of the copper-lithium reagent 55. Reduction of the C-7 carbonyl was apparently more difficult than similar cases in the literature. After examination of many reagents under various conditions, it was found that the best reagent for yielding the α-isomer was (S)-2-methyl-CBS-borolidine/BH3 and that for the β-isomer was L-Selectride. The α- and β-isomers were then further elaborated into (+)-brefeldin A and 7-epi-BFA, respectively. An unexpected yet very interesting solubility difference between BFA and 7-epi-BFA was also observed.
- Wu, Yikang,Shen, Xin,Yang, Yong-Qing,Hu, Qi,Huang, Jia-Hui
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p. 3857 - 3865
(2007/10/03)
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- An aldol approach to the total synthesis of (+)-brefeldin a
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A convergent selective route to (+)-brefeldin A (BFA) and 7-epi-BFA was developed, with the crucial C-4/C-5 stereogenic centers were established using Crimmins asymmetric aldolization.
- Wu, Yikang,Shen, Xin,Yang, Yong-Qing,Hu, Qi,Huang, Jia-Hui
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p. 199 - 202
(2007/10/03)
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- 4-Aryloxybutenolides as "chiral aldehyde" equivalents: An efficient enantioselective synthesis of (+)-brefeldin A
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4-(2′-Naphthoxy)-2-butenolide, readily available with high enantiopurity by a dynamic kinetic asymmetric transformation (DYKAT) of racemic 4-acyloxybutenolides (available in two steps from furfural), serves as an excellent chiral building block where the naphthoxy group strongly directs the stereochemistry of cycloadditions to the double bond. Notably, the cycloadditions of trimethylenemethanepalladium intermediates which do not exhibit good diastereoselectivity in additions to acceptors that possess many common and important chiral auxiliaries undergo cycloadditions with excellent regio- and stereocontrol. The utility of this process set the stage for an efficient new synthesis of (+)-brefeldin A, a compound of growing pharmacological significance. This synthesis also highlights the Pd-catalyzed DYKAT of crotyl carbonate to create the remote stereocenter. A new two-step method to convert aldehydes to δ-hydroxy-E-α,β-enoates is also outlined. Copyright
- Trost, Barry M.,Crawley, Matthew L.
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p. 9328 - 9329
(2007/10/03)
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- Asymmetric total synthesis of (+)-brefeldin A from (S)-lactate by triple chirality transfer process and nitrile oxide cycloaddition
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A novel synthesis of (+)-brefeldin A (1) has been accomplished on the basis of triple chirality transfer methodology, intramolecular ester enolate alkylation, and both intra- and intermolecular nitrile oxide cycloaddition strategies.
- Kim, Deukjoon,Lee, Jongkook,Phil, Jong Shim,Joong, Inn Lim,Jo, Hyunil,Kim, Sanghee
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p. 764 - 771
(2007/10/03)
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- Concise total synthesis of (+)-brefeldin a: A combined β-lactone/ cross-metathesis-based strategy
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equation presented A highly convergent total synthesis of (+)-brefeldin A that relies on a diastereoselective, β-lactone-based cyclopentane synthesis combined with complex cross-metathesis reactions is described. The utility of β-lactones for natural product synthesis and the versatility of cross-metathesis in this context were demonstrated, including the tolerance of an epimerizable aldehyde and a β-lactone.
- Wang, Yingcai,Romo, Daniel
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p. 3231 - 3234
(2007/10/03)
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- Facile Synthesis of (+)-Brefeldin A Utilizing Two Optically Active Synthons Prepared by Different Enzyme-catalysed Reactions
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The lactone 4a and the alcohol 6 (both available in optically active form from biocatalytic processes) have been used as synthons in the preparation of (+)-brefeldin A.
- Casy, Guy,Gorins, Gilles,McCague, Ray,Olivo, Horacio F.,Roberts, Stanley M.
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p. 1085 - 1086
(2007/10/02)
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- Enantioselective Synthesis of (+)-Brefeldin A
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A new enantioselective synthesis of (+)-brefeldin A is described.The five chiral centers are created by the following methodology: asymmetric Diels-Alder reaction to prepare the cyclopentanone 13, stereocontrolled reduction of the carbonyl in the ketone 14, stereocontrolled creation of the chiral centers C-4 and C-15 by a chiral sulfoxide group.
- Solladie, Guy,Lohse, Olivier
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p. 4555 - 4563
(2007/10/02)
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- Cyclopentane construction with control of side chain configuration synthesis of (+)-brefeldin A
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Intramolecular opening of an enantiomerically pure epoxide by an amide enolate (1 → 2) is shown to be an effective method for cyclopentane construction with control of both ring and side chain absolute configuration. This opening serves as the key step in a synthesis of the Golgi apparatus-blocking macrolide (+)-brefeldin A (3). Other features of the synthesis include improved procedures for the enantioselective hydrogenation of a β-keto ester to the corresponding β-hydroxy ester, and for the Julia-Lythgoe reduction of a β-acetoxy sulfone to the trans alkene.
- Taber, Douglas F.,Silferberg, Lee J.,Robinson, Edward D.
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p. 6639 - 6645
(2007/10/02)
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- A simplified synthesis of (+)-brefeldin A
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An effective and enantioselective process for the total synthesis of (+)-brefeldin A (1) is described which starts from the dextrorotatory ketone 2.
- Corey,Carpino, Philip
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p. 7555 - 7558
(2007/10/02)
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- Cyclopentenone Derivatives, VIII. - Reactions with Acetoxycyclopentenones, Brefeldin-A Cyclizations
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Investigation of the lactonization process leading to brefeldin-A proves this reaction in the presense of a C4-thioacetal function not to be depending on the configuration at C15.Wittig-Horner cyclizations however, are shown to be stereospecific.
- Koeksal, Yetkin,Raddatz, Peter,Winterfeldt, Ekkehard
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p. 462 - 473
(2007/10/02)
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- Efficient Stereocontrolled Total Syntheses of Racemic and Natural Brefeldin-A
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Brefeldin-A, an antiobiotic fungal metabolite, has been obtained in both racemic and natural forms through a direct approach that employs norbornenone and 6-heptyn-2-ol as the basic starting materials.
- Drian, Claude Le,Greene, Andrew E.
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p. 5473 - 5483
(2007/10/02)
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