The activation of olefins for asymmetric chemical synthesis traditionally relies on transition metal catalysts. In contrast, biological enzymes with Brønsted acidic sites of appropriate strength can protonate olefins and thereby generate carbocations that ultimately react to form natural products. Although chemists have recently designed chiral Brønsted acid catalysts to activate imines and carbonyl compounds, mimicking these enzymes to protonate simple olefins that then engage in asymmetric catalytic reactions has remained a substantial synthetic challenge. Here, we show that a class of confined and strong chiral Brønsted acids enables the catalytic asymmetric intramolecular hydroalkoxylation of unbiased olefins. The methodology gives rapid access to biologically active 1,1-disubstituted tetrahydrofurans, including (-)-Boivinianin A.
a-Isocyanoacetates are well-known glycine templates for the synthesis of racemic a,a-disubstituted a-amino acids. [1] However, catalytic enantioselective alkylation of a-isocyanoacetates remains underexploited. Ito, Hayashi, and co-workers pioneered the field by discovering the first palladiumcatalyzed enantioselective allylation of methyl a-phenyl-aisocyanoacetate [Eq. (1), Scheme 1; DBU = 1,8-diazabicyclo-[5.4.0]undec-7-ene]. [2] The enantioselectivity of this reaction was, however, moderate (< 39 % ee). In contrast, a number of Lewis-acid-and small-organomolecule-catalyzed enantioselective [2+3] cycloadditions of a-isocyanoacetates with aldehydes, [3] imines, [4] azodicarboxylates, [5] and polarized carboncarbon double bonds, such as nitroalkenes, [6] a,b-unsaturated ketones, [7] and maleimides, [8] have been developed to access enantioenriched five-membered heterocycles. In contrast, catalytic enantioselective Michael addition of a-isocyanoacetates was met with only limited success. Indeed, it has been established that any Lewis acid catalyzed nucleophilic addition of a-isocyanoacetates to polarized double bonds inevitably provided the [2+3] cycloadducts. The same trend holds true for organocatalytic processes. [8] However, a recent paper from Xu, Wang, and co-workers [9] on a tertiary amine thiourea catalyzed enantioselective Michael addition of aphenyl-a-isocyanoacetate to N-aryl maleimides demonstrated that the aforementioned reaction can be stopped at the Michael adduct stage under appropriate reaction conditions [Eq.(2), Scheme 1].In connection with our ongoing total synthesis project, we needed rapid access to enantiomerically enriched a-aryl-a-(2'-FG-alkyl)-a-amino acids (FG = functional group). [10] We were aware of the seminal contributions of Deng and coworkers on the enantioselective Michael addition of aphenyl-a-cyanoacetate to vinyl phenylsulfone and the subsequent conversion of the enantiomerically enriched adduct into a,a-disubstituted amino acids [Eq. (3), Scheme 1]. [11] However, six steps were needed to convert both the cyano and sulfone groups into other organic residues. Stimulated by this observation, we became interested in examining the chiral Brønsted base catalyzed nucleophilic addition of aaryl-a-isocyanoacetates (1) to vinyl phenyl selenone (2) [12][13][14] for the synthesis of the enantiomerically enriched a-aryl-a-(2'-FG-alkyl)-a-amino acids 3 [Eq. (4), Scheme 1]. [15] The advantage of this approach is that the resulting adduct can be readily converted into an array of functionalized amino acids. Indeed, phenylselenonyl is an excellent leaving group, [16] while the isocyano group is easily hydrolyzed under mild acidic conditions into the free amino function. We report herein the successful development of an organocatalytic enantioselective Michael addition of 1 to 2 for the synthesis of the enantiomerically enriched a,a-disubstituted a-isocyanoacetates 3 and their subsequent transformations into the linear and the cyclic quaternary a-amino acids. Enantioselective total synthe...
A novel heteroannulation reaction between α-amino imides and in situ generated arynes has been developed for the synthesis of 2,2-disubstituted indolin-3-ones. An enantioselective total synthesis of the marine alkaloid (+)-hinckdentine A was subsequently accomplished using this reaction as a key step. A catalytic enantioselective Michael addition of an α-aryl-α-isocyanoacetate to phenyl vinyl selenone was employed for the construction of the enantioenriched α-quaternary α-amino ester.
Idiopathic pulmonary fibrosis (IPF) is a rare and devastating chronic lung disease of unknown etiology. Despite the approved treatment options nintedanib and pirfenidone, the medical need for a safe and well-tolerated antifibrotic treatment of IPF remains high. The human prostaglandin F receptor (hFP-R) is widely expressed in the lung tissue and constitutes an attractive target for the treatment of fibrotic lung diseases. Herein, we present our research toward novel quinoline-based hFP-R antagonists, including synthesis and detailed structure–activity relationship (SAR). Starting from a high-throughput screening (HTS) hit of our corporate compound library, multiple parameter improvementsincluding increase of the relative oral bioavailability F rel from 3 to ≥100%led to a highly potent and selective hFP-R antagonist with complete oral absorption from suspension. BAY-6672 (46) representsto the best of our knowledgethe first reported FP-R antagonist to demonstrate in vivo efficacy in a preclinical animal model of lung fibrosis, thus paving the way for a new treatment option in IPF.
Reaction of α-substituted α-isocyanoacetates with phenyl vinyl selenones in the presence of a catalytic amount of base (DBU or Et3N, 0.05-0.1 equiv) followed by addition of p-toluenesulfonic acid (PTSA, 0.1-0.2 equiv) afforded 4,4,5-trisubstituted 1,3-oxazinan-2-ones in good to excellent yields. Enantiomerically enriched heterocycles can also be prepared using a Cinchona alkaloid-derived bifunctional organocatalyst for the Michael addition step. The phenylselenonyl group served as an activator for the Michael addition, a leaving group and a latent oxidant in this integrated reaction sequence.
Trigonoliimine B, a hexacyclic alkaloid, is synthesized in seven steps from simple starting materials. The synthesis features the use of an α-isocyanoacetate as a glycine template for the preparation of an α,α-disubstituted α-amino ester that is appropriately functionalized for the construction of C, D, and E rings. Sulfolane was found to be the solvent of choice for the unprecedented Bischler-Napieralski reaction implemented for the construction of a seven-membered ring with concurrent formation of an exo-imine function.
a-Isocyanoacetates are well-known glycine templates for the synthesis of racemic a,a-disubstituted a-amino acids. [1] However, catalytic enantioselective alkylation of a-isocyanoacetates remains underexploited. Ito, Hayashi, and co-workers pioneered the field by discovering the first palladiumcatalyzed enantioselective allylation of methyl a-phenyl-aisocyanoacetate [Eq. (1), Scheme 1; DBU = 1,8-diazabicyclo-[5.4.0]undec-7-ene]. [2] The enantioselectivity of this reaction was, however, moderate (< 39 % ee). In contrast, a number of Lewis-acid-and small-organomolecule-catalyzed enantioselective [2+3] cycloadditions of a-isocyanoacetates with aldehydes, [3] imines, [4] azodicarboxylates, [5] and polarized carboncarbon double bonds, such as nitroalkenes, [6] a,b-unsaturated ketones, [7] and maleimides, [8] have been developed to access enantioenriched five-membered heterocycles. In contrast, catalytic enantioselective Michael addition of a-isocyanoacetates was met with only limited success. Indeed, it has been established that any Lewis acid catalyzed nucleophilic addition of a-isocyanoacetates to polarized double bonds inevitably provided the [2+3] cycloadducts. The same trend holds true for organocatalytic processes. [8] However, a recent paper from Xu, Wang, and co-workers [9] on a tertiary amine thiourea catalyzed enantioselective Michael addition of aphenyl-a-isocyanoacetate to N-aryl maleimides demonstrated that the aforementioned reaction can be stopped at the Michael adduct stage under appropriate reaction conditions [Eq.(2), Scheme 1].In connection with our ongoing total synthesis project, we needed rapid access to enantiomerically enriched a-aryl-a-(2'-FG-alkyl)-a-amino acids (FG = functional group). [10] We were aware of the seminal contributions of Deng and coworkers on the enantioselective Michael addition of aphenyl-a-cyanoacetate to vinyl phenylsulfone and the subsequent conversion of the enantiomerically enriched adduct into a,a-disubstituted amino acids [Eq. (3), Scheme 1]. [11] However, six steps were needed to convert both the cyano and sulfone groups into other organic residues. Stimulated by
Reaction of alkyl isocyanides, phenyl vinyl selenone, and water in the presence of a catalytic amount of Cs2 CO3 afforded oxazolidin-2-ones in good yields. This unprecedented heteroannulation process created four chemical bonds in a single operation with the isocyano group acting formally as a polarized double bond and phenyl vinyl selenone as a latent 1,3-dipole. The phenylselenonyl group played a triple role as an electron-withdrawing group to activate the 1,4-addition, a leaving group, and a latent oxidant in this transformation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.