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Asymmetric Hydrogenations of Imines, Vinyl Fluorides, Enol Phosphinates and Other Alkenes Using N,P-Ligated Iridium Complexes
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry, Organic Chemistry.
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. , p. 64
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 447
Keywords [en]
Organic chemistry, Catalysis, Asymmetric, Hydrogenations, Reductions, Alkenes, Imines, Vinyl fluorides, Enolphosphinates, Transition metal, Complexes, Iridium
Keywords [sv]
Organisk kemi
National Category
Other Basic Medicine
Identifiers
URN: urn:nbn:se:uu:diva-8971ISBN: 978-91-554-7236-8 (print)OAI: oai:DiVA.org:uu-8971DiVA, id: diva2:172255
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: 2018-01-13Bibliographically approved
List of papers
1. Application of Phosphine-Oxazoline Ligands in Ir-Catalyzed Asymmetric Hydrogenation of Acyclic Aromatic N-Arylimines
Open this publication in new window or tab >>Application of Phosphine-Oxazoline Ligands in Ir-Catalyzed Asymmetric Hydrogenation of Acyclic Aromatic N-Arylimines
2004 In: Organic Letters, Vol. 6, no 21, p. 3825-3827Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-97350 (URN)
Available from: 2008-05-13 Created: 2008-05-13Bibliographically approved
2. Hydrogenation of Imines and Olefins Using Phosphine-Oxazoline Iridium Complexes as Catalysts
Open this publication in new window or tab >>Hydrogenation of Imines and Olefins Using Phosphine-Oxazoline Iridium Complexes as Catalysts
2006 In: Chemistry-A European Journal, Vol. 12, no 8, p. 2318-2328Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-97351 (URN)
Available from: 2008-05-13 Created: 2008-05-13Bibliographically approved
3. Iridium-Catalyzed Asymmetric Hydrogenation of Fluorinated Olefins Using N,P-Ligands: A struggle with hydrogenolysis and selectivity
Open this publication in new window or tab >>Iridium-Catalyzed Asymmetric Hydrogenation of Fluorinated Olefins Using N,P-Ligands: A struggle with hydrogenolysis and selectivity
2007 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 129, no 15, p. 4536-4537Article in journal (Refereed) Published
Abstract [en]

To broaden the substrate scope of asymmetric iridium-catalyzed hydrogenation, fluorine-functionalized olefins were synthesized and hydrogenated with iridium complexes. Preliminary results showed high levels of fluorine elimination together with low selectivity. The loss of vinylic fluorine at first seemed difficult to handle, but further studies revealed that a catalyst with an azanorbornyl scaffold in the ligand gave more promising results. With this in mind, a new ligand was developed. This gave among the best results published to date for fluorine asymmetric hydrogenation, yielding high conversion and very high ee's with very little fluorine elimination. Further increasing the selectivity, the trials also revealed that tetrasubstituted fluorine-containing olefins can be hydrogenated with high ee's, despite that this class of compounds has usually shown low reactivity in this reaction type.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-97352 (URN)10.1021/ja0686763 (DOI)000245739700016 ()17375924 (PubMedID)
Available from: 2008-05-13 Created: 2008-05-13 Last updated: 2017-12-14Bibliographically approved
4. Asymmetric Hydrogenation of Di and Trisubstituted Enol Phosphinates with N,P-Ligated Iridium Complexes
Open this publication in new window or tab >>Asymmetric Hydrogenation of Di and Trisubstituted Enol Phosphinates with N,P-Ligated Iridium Complexes
2008 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 130, no 16, p. 5595-5599Article 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.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-97722 (URN)10.1021/ja711372c (DOI)000255041400050 ()
Available from: 2008-11-11 Created: 2008-11-11 Last updated: 2017-12-14Bibliographically approved

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