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Asymmetric Hydrogenation of Di and Trisubstituted Enol Phosphinates with N,P-Ligated Iridium Complexes
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
2008 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, Vol. 130, no 16, 5595-5599 p.Article in journal (Refereed) Published
Abstract [en]

The iridium-catalyzed asymmetric hydrogenation of various di- and trisubstituted enol phosphinates has been studied. Excellent enantioselectivities (up to >99% ee) and full conversion were observed for a range of substrates with both aromatic and aliphatic side chains. Enol phosphinates are structural analogues of enol acetates, and the hydrogenated alkyl phosphinate products can easily be transformed into the corresponding alcohols with conservation of stereochemistry. We have also hydrogenated, in excellent ee, several purely alkyl-substituted enol phosphinates, producing chiral alcohols that are difficult to obtain highly enantioselectively from ketone hydrogenations.

Place, publisher, year, edition, pages
2008. Vol. 130, no 16, 5595-5599 p.
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97722DOI: 10.1021/ja711372cISI: 000255041400050OAI: oai:DiVA.org:uu-97722DiVA: diva2:172769
Available from: 2008-11-11 Created: 2008-11-11 Last updated: 2009-11-11Bibliographically approved
In thesis
1. Asymmetric Hydrogenations of Imines, Vinyl Fluorides, Enol Phosphinates and Other Alkenes Using N,P-Ligated Iridium Complexes
Open this publication in new window or tab >>Asymmetric Hydrogenations of Imines, Vinyl Fluorides, Enol Phosphinates and Other Alkenes Using N,P-Ligated Iridium Complexes
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The research described in this thesis is directed toward the efficient, enantioselective synthesis of chiral products that have useful functionality. This goal was pursued through catalytic asymmetric hydrogenation, a reaction class that selectively introduces one or two stereocenters into a molecule in an atom-efficient step. This reaction uses a small amount (often <1 mol%) of a chiral catalyst to impart stereoselectivity to the product formed. Though catalytic asymmetric hydrogenation is not a new reaction type, there remain many substrate classes for which it is ineffective. The present thesis describes efforts to extend the reaction to some of these substrates classes. Some of the products synthesized in these studies may eventually find use as building blocks for the production of chiral pharmaceuticals, agrochemicals, or flavouring or colouring agents. However, the primary and immediate aim of this thesis was to develop and demonstrate new catalysts that are rapid and effective in the asymmetric hydrogenation of a broad range of compounds.

Paper I describes the design and construction of two new, related chiral iridium compounds that are catalysts for asymmetric hydrogenation. They each contain an N,P-donating phosphinooxazoline ligand that is held together by a rigid bicyclic unit. One of these iridium compounds catalyzed the asymmetric hydrogenation of acyclic aryl imines, often with very good enantioselectivities. This is particularly notable because acyclic imines are difficult to reduce with useful enantioselectivity. The second catalyst was useful for the asymmetric hydrogenation of two aryl olefins. In Paper II, the class of catalysts introduced into Paper I is expanded to include many more related compounds, and these are also applied to the asymmetric hydrogenation of prochiral imines and olefins. By studying a range of related catalysts that differ in a single attribute, we were able to probe how different parts of the catalyst affect the yield and selectivity of the hydrogenation reactions.

Whereas iridium catalysts had been applied to the asymmetric hydrogenation of imines and largely unfunctionalized olefins prior to this work (with varied degrees of success), they had not been used to reduce fluoroolefins. Their hydrogenation, which is discussed in Paper III, was complicated by concomitant defluorination to yield non-halogenated alkanes. To combat this problem, several iridium-based hydrogenation catalysts were applied to the reaction. Two catalysts stood out for their ability to produce chiral fluoroalkanes in good enantioselectivity while minimizing the defluorination reaction, and one of these bore a phosphinooxazoline ligand of the type described in Papers I and II.

Enol phosphinates are another class of olefins that had not previously been subjected to iridium-catalyzed asymmetric hydrogenation. They do, however, constitute an attractive substrate class, because the product chiral alkyl phosphinates can be transformed into chiral alcohols or chiral phosphines with no erosion of enantiopurity. Iridium complexes of the phosphinooxazoline ligands described in Papers I and II were extremely effective catalysts for the asymmetric hydrogenation of enol phosphinates. They produced alkyl phosphinates from di- and trisubstituted enol phosphinate, β-ketoester-derived enol phosphinates, and even purely alkyl-substituted enol phopshinates, in very high yields and enantioselectivities.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 64 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 447
Keyword
Organic chemistry, Catalysis, Asymmetric, Hydrogenations, Reductions, Alkenes, Imines, Vinyl fluorides, Enolphosphinates, Transition metal, Complexes, Iridium, Organisk kemi
National Category
Other Basic Medicine
Identifiers
urn:nbn:se:uu:diva-8971 (URN)978-91-554-7236-8 (ISBN)
Public defence
2008-06-03, B21, BMC, Husargatan 3, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2008-05-13 Created: 2008-05-13 Last updated: 2009-06-26Bibliographically approved
2. Asymmetric Hydrogenations: Syntheses of Ligands and Expansion of Substrate Scope
Open this publication in new window or tab >>Asymmetric Hydrogenations: Syntheses of Ligands and Expansion of Substrate Scope
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Asymmetric hydrogenation has emerged as a versatile methodology to obtain a wide range of chiral precursors. This thesis focused on the synthesis of new chiral ligands and the expansion of the substrate scope of asymmetric hydrogenations. Paper I described the synthesis and evaluation of N,P-ligands for the Ir-catalyzed hydrogenations of unfunctionalized olefins. The substrate scope of Ir-catalyzed asymmetric hydrogenations is limited to a narrow range of “test” olefins. The foremost focus of this thesis was to expand the substrate scope of Ir-catalyzed asymmetric hydrogenations. Papers II and III disclosed the potential of the N,P-ligated Ir complexes in hydrogenation of the enol phosphinates. This substrate class is attractive because the hydrogenated products are chiral alkylphosphinates that can be transformed into chiral alcohols and chiral phosphines without sacrificing enantiopurity. A wide range of enol phosphinates were hydrogenated to excellent conversions and enatioselectivities. The hydrogenation of purely alkyl-substituted enol phosphinates in very high conversions and ee values was emphasized in these studies. Paper IV described the investigation of unfunctionalized enamines as substrates in Ir-catalyzed hydrogenation studies. The hydrogenation results and structural limitations of the substrates are presented. Paper V described the asymmetric hydrogenation of diphenylvinylphosphine oxides, di- and trisubstituted vinyl phosphonates. The hydrogenation of diphenylvinylphosphine oxides gives direct access to protected chiral phosphines. The hydrogenated products of vinylphosphonates are highly synthetically useful in pharmaceutical and material chemistry. Hydrogenation of E/Z mixtures of carboxyethyl vinylphosphonates with perfect enantioselectivities was striking in these studies. In paper VI, we have reported the development of a new, highly enantioselective synthetic route to building blocks with CF3 at the chiral center. Several functionalized and unfunctionalized CF3-substituted olefins were hydrogenated with varied degree of success. This methedilogy is useful in the formation of chiral fluorine-containing molecules for a wide range of applications. Paper VII described the hydrogenation of imines using the phosphine-free Cp*Ru/diamine complexes. Chiral version of this reaction was also examined. Despite the modest results, this is the first study to use phosphine-free Cp*Ru/diamine complexes as catalysts for the reduction of C=N double bonds.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 67 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 569
Keyword
Catalysis, Asymmetric, Hydrogenations, Reductions, Olefins, Imines, Enol phosphinates, Transition metal, Complexes, Iridium, Enamines, Ruthenium, Ligands, Trifluoromethyl, Diphenylvinylphosphine oxides, Vinyl phosphonates
National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-9353 (URN)978-91-554-7329-7 (ISBN)
Public defence
2008-12-02, B7:101a, BMC, Husargatan 3, Uppsala, 13:15
Opponent
Supervisors
Available from: 2008-11-11 Created: 2008-11-11 Last updated: 2014-01-21Bibliographically approved

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