Recent Progress on the Total Synthesis of Brefeldins.

Kobayashi, Yuichi; Watatani, Kengo

doi:10.5059/yukigoseikyokaishi.55.110

Cited by 8 publications

(8 citation statements)

References 1 publication

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“…BFA has received remarkable attention in the synthetic community. Since the first total synthesis of (racemic) BFA by Corey and Wollenberg, around 30 total/formal syntheses , have been reported in the literature. Interest 15d,, in probing the mode of action as well as establishing the structure−activity relationship has also obviously grown in recent years.…”

Section: Introductionmentioning

confidence: 99%

Enantioselective Total Synthesis of (+)-Brefeldin A and 7-epi-Brefeldin A

Shen

Yang

et al. 2004

J. Org. Chem.

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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 TiCl(4) 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 LiBH(4) 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 alpha,beta-double bond of the key intermediate cyclopentenone 49 with DBU was highly solvent dependent (very sluggish in CH(2)Cl(2) 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 alpha-isomer was (S)-2-methyl-CBS-borolidine/BH(3) and that for the beta-isomer was L-Selectride. The alpha- and beta-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.

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Section: Introductionmentioning

confidence: 99%

Enantioselective Total Synthesis of (+)-Brefeldin A and 7-epi-Brefeldin A

Shen

Yang

et al. 2004

J. Org. Chem.

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“…Recently, one of BFA's effects at the molecular level was found to involve the inhibition of activation of the GTPase, adenosine diphosphate-ribosylation factor 1 (Arf1) by inducing a nonproductive complex with its membrane-associated GTP exchange factor (GEF) . These unique and potent bioactivities have stimulated extensive synthetic efforts from several laboratories over the past 25 years . BFA continues to be an excellent proving ground for new synthetic methodologies, in particular, stereoselective cyclopentane construction.…”

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confidence: 99%

“…The application of olefin metathesis in natural product synthesis has primarily focused on RCM, and this has been particularly effective for medium-sized ring and macrocycle synthesis, including BFA 5b. In contrast, far fewer studies of CM reactions applied to natural product synthesis have appeared .…”

mentioning

confidence: 99%

Concise Total Synthesis of (+)-Brefeldin A: A Combined β-Lactone/Cross-Metathesis-Based Strategy

Wang

Romo

2002

Org. Lett.

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[reaction: see text] A highly convergent total synthesis of (+)-brefeldin A that relies on a diastereoselective, beta-lactone-based cyclopentane synthesis combined with complex cross-metathesis reactions is described. The utility of beta-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 beta-lactone.

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“…Brefeldin C was prepared for the first time by total synthesis in 1988 by Schreiber and Meyers followed by Takano, Guingant (along with aspects of the biological properties of BFA) and Tsunoda . Following the pioneer work of Corey and Wollenberg, the majority of the syntheses of brefeldin A and C accessed the 13‐membered ring lactone in high yields by macrolactonization . On the other hand, the preparation of the polysubstituted 5‐membered ring has been achieved using very diverse strategies.…”

Section: Figurementioning

confidence: 99%

A Short Synthesis of (+)‐Brefeldin C through Enantioselective Radical Hydroalkynylation

Gnägi

Martz

Meyer

et al. 2019

Chemistry A European J

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Av ery conciset otal synthesis of (+ +)-brefeldin C starting from 2-furanylcyclopentene is described. This approach is based on an unprecedented enantioselective radical hydroalkynylation process to introduce the two cyclopentanes tereocenters in as ingle step. The use of a furan substituent allows ah igh trans diastereoselectivity to be achieved duringt he radicalp rocess and it contains the four carbona toms C1-C4 of the natural product in an oxidation state closely relatedt ot he one of the target molecule. The eight-step synthesis requires six product purifications and it provides (+ +)-brefeldin Ci n1 8% overall yield.[**] Ap revious versiono ft his manuscript has been deposited on ap reprint server (https://doi.org/10.26434/chemrxiv.8397731.v1)Supporting information and the ORCID identification number(s) for the author(s) of this articlecan be found under: https://doi.

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Recent Progress on the Total Synthesis of Brefeldins.

Cited by 8 publications

References 1 publication

Enantioselective Total Synthesis of (+)-Brefeldin A and 7-epi-Brefeldin A

Enantioselective Total Synthesis of (+)-Brefeldin A and 7-epi-Brefeldin A

Concise Total Synthesis of (+)-Brefeldin A: A Combined β-Lactone/Cross-Metathesis-Based Strategy

A Short Synthesis of (+)‐Brefeldin C through Enantioselective Radical Hydroalkynylation

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