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Enantiopure 2-Aryl-2-Methyl Cyclopentanones by an Asymmetric Chelation-Controlled Heck Reaction Using Aryl Bromides: Increased Preparative Scope and Effect of Ring Size on Reactivity and Selectivity
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. ORGFARM.
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2008 (Engelska)Ingår i: Tetrahedron: asymmetry, ISSN 0957-4166, E-ISSN 1362-511X, Vol. 19, nr 9, s. 1120-1126Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Quaternary 2-aryl-2-methyl cyclopentanones were obtained in 85–94% ee via Pd(0)-catalyzed chelation-controlled asymmetric arylation of a cyclopentenyl ether with aryl bromides and subsequent hydrolysis. Two new cyclohexenyl ethers were synthesized and evaluated as Heck substrates with both aryl iodides and bromides under different reaction conditions. Arylations of the six-membered vinyl ether 1-methyl-2-(S)-(cyclohex-1-enyloxymethyl)-pyrrolidine with aryl bromides were achieved with t-Bu3P-promoted palladium catalysis using either classical or microwave heating. Isolated Heck products were also obtained in high diastereoselectivities (94–98% de).

Ort, förlag, år, upplaga, sidor
2008. Vol. 19, nr 9, s. 1120-1126
Nationell ämneskategori
Farmaceutiska vetenskaper
Identifikatorer
URN: urn:nbn:se:uu:diva-97435DOI: 10.1016/j.tetasy.2008.04.004ISI: 000256935800012OAI: oai:DiVA.org:uu-97435DiVA, id: diva2:172385
Tillgänglig från: 2008-08-27 Skapad: 2008-08-27 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
Ingår i avhandling
1. Heck Reactions with Aryl Chlorides: Studies of Regio- and Stereoselectivity
Öppna denna publikation i ny flik eller fönster >>Heck Reactions with Aryl Chlorides: Studies of Regio- and Stereoselectivity
2008 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Homogeneous palladium-catalyzed Heck vinylation of aryl chlorides was investigated under air using Herrmann’s palladacycle and the P(t-Bu)3-liberating salt [(t-Bu)3PH]BF4. Based on the results, controlled microwave heating was utilized to accelerate model Heck reactions with aryl chlorides down to 30 min employing an electron-poor olefin and a mixture of an ionic liquid and 1,4-dioxane as solvent.

For the first time, a highly regioselective general protocol has been developed for palladium-catalyzed terminal (β-) arylation of acyclic vinyl ethers using inexpensive aryl chlorides as starting materials and the preligand [(t-Bu)3PH]BF4 as the key additive. This swift and straightforward protocol exploits non-inert conditions and controlled microwave heating to reduce handling and processing times, and aqueous DMF or environmentally friendly PEG-200 as the reaction medium. Somewhat higher selectivity for the linear β-product was observed in PEG-200. DFT calculations were performed at the B3LYP level of theory for the regioselectivity-determining insertion step in the Heck reaction following the neutral pathway. A series of para-substituted phenylpalladium(II) complexes was investigated in the computational study. The calculations support a ligand-driven selectivity rationale, where the electronic and steric influence of the bulky P(t-Bu)3 ligand provides improved β-selectivity. The preparative methodology was used to synthesize the β-adrenergic blocking agent Betaxolol.

Highly stereoselective Pd(0)-catalyzed β-arylation and β-vinylation of a tetra-substituted cyclopentenyl ether have been accomplished using a chiral, pyrrolidine-based and substrate-bound palladium(II)-directing group under neutral reaction conditions. To the best of the author’s knowledge, this P(t-Bu)3-mediated method represents the first examples of the successful utilization of aryl and vinyl chlorides in asymmetric Heck reactions. The Heck arylation products formed were hydrolyzed and isolated as the corresponding quaternary 2-aryl-2-methyl cyclopentanones in good to moderate two-step yields with excellent stereoselectivity (90-96% ee). Inclusion of vinyl triflates under neutral reaction conditions and one aryl triflate equipped with a strongly electron-withdrawing para-cyano substituent under cationic conditions increased the preparative usefulness of the methodology.

Furthermore, diastereoselective Heck arylation of both five- and six-membered cyclic vinyl ethers with aryl bromides, using the identical chiral auxiliary and suitable Pd sources, was performed. Arylated products from the tetra-substituted cyclopentenyl ether were also in this case hydrolyzed to the corresponding 2-aryl-2-methyl cyclopentanones with high to excellent enantioselectivity (85-94% ee). Despite low reaction rates and relatively modest yields, arylation reactions with the tri-substituted cyclohexenyl ether were found to be highly diastereoselective (94-98% de).

Thus, an attractive supplement to direct Pd(0)-catalyzed α-arylation protocols, particularly when the use of organic chlorides, aryl bromides, and milder reaction conditions are of great importance, have been developed.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2008. s. 77
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 76
Nyckelord
Heck reaction, aryl chloride, vinyl ether, regioselective, stereoselective, palladium, chelation control, microwave
Nationell ämneskategori
Läkemedelskemi
Identifikatorer
urn:nbn:se:uu:diva-9202 (URN)978-91-554-7256-6 (ISBN)
Disputation
2008-09-24, B42, BMC, Husarg. 3, Uppsala, 13:15
Opponent
Handledare
Tillgänglig från: 2008-08-27 Skapad: 2008-08-27 Senast uppdaterad: 2018-01-13Bibliografiskt granskad

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Nordeman, PatrikNilsson, PeterLarhed, Mats

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