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Enantioenriched ω-bromocyanohydrin derivatives. Improved selectivity by combination of two chiral catalysts
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.ORCID iD: 0000-0002-1743-7650
2012 (English)In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 68, no 37, 7680-7684 p.Article in journal (Refereed) Published
Abstract [en]

Highly enantioenriched (R)-4-bromo-1-cyanobutyl acetate and (R)-5-bromo-1-cyanopentyl acetate were prepared by acetylcyanation of 4-bromobutanal and 5-bromopentanal, respectively, catalyzed by (S,S)-[(4,6-bis(t-butyl)salen)Ti(Ό-O)] 2 and triethylamine followed by enzymatic hydrolysis of the minor enantiomer. A cyclic procedure employing the same two chiral catalysts provided inferior results due to a slowly reached steady state and, in reactions with the former substrate, to ring-closure of the free cyanohydrin formed as an intermediate in the reaction. Hydrolysis of the acylated cyanohydrins followed by AgClO 4-promoted cyclization provided (R)-2-cyanotetrahydrofuran and (R)-2-cyanotetrahydropyran in essentially enantiopure form.

Place, publisher, year, edition, pages
2012. Vol. 68, no 37, 7680-7684 p.
Keyword [en]
2-Cyanotetrahydrofuran, 2-Cyanotetrahydropyran, Acetylcyanation, Enzymatic hydrolysis, Kinetic resolution
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:kth:diva-101332DOI: 10.1016/j.tet.2012.05.090ISI: 000307802300024Scopus ID: 2-s2.0-84864465486OAI: oai:DiVA.org:kth-101332DiVA: diva2:547820
Funder
Swedish e‐Science Research Center
Note

QC 20120829

Available from: 2012-08-29 Created: 2012-08-27 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Enantioenriched Cyanohydrins and Acetoxyphosphonates – Synthesis and Applications
Open this publication in new window or tab >>Enantioenriched Cyanohydrins and Acetoxyphosphonates – Synthesis and Applications
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis, the synthesis of enantioenriched compounds using novel methodologies that employ metal- and biocatalysis is described.

In the first part, the synthesis of enantioenriched cyanohydrins, which are highly versatile synthetic intermediates, is described. A minor enantiomer recycling methodology, which uses a catalytic system consisting of a titanium salen dimer and a lipase, was highly successful in yielding the desired products, often in essentially enantiopure form. Alternatively, when the minor enantiomer recycling method gave unsatisfactory results, the same two catalysts were used in a sequential two-step process. The minor enantiomer recycling procedure was used to synthesize three different β-adrenergic antagonists with very high enantiomeric excesses via the corresponding O-acetylated cyanohydrins. With the same cyclic process, O-(α-bromoacyl) cyanohydrins were synthesized and subsequently transformed to aminofuranones via an intramolecular Blaise reaction. In addition, substitution of the bromide in the O-(α-bromoacyl) cyanohydrins with different nitrogen nucleophiles followed by reduction gave N-substituted β-amino alcohols. This reaction sequence was applied to the synthesis of the β3-adrenergic receptor agonist solabegron. Finally, the O-(α-bromoacyl) cyanohydrins were subjected to a palladium catalyzed cross-coupling with a range of boronic acids. This reaction proceeded with high yields, and was performed with enantiopure substrates with no or only minor racemization of the resulting products.

In the second part, the first asymmetric direct addition of acylphosphonates to aldehydes is described. This transformation is catalyzed by a tridentate Schiff base aluminum(III) Lewis acidic complex, a Lewis base, and a Brønstedt base. Several aromatic and aliphatic acetoxyphosphonates were isolated, in most cases in high yields. Unfortunately, the enantioselectivity in the reaction was only moderate. Therefore, an investigation to develop a minor enantiomer recycling system for the synthesis of acetoxyphosphonates was initiated, but a working cyclic process could not be found in this work.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2015. 76 p.
Series
TRITA-CHE-Report, ISSN 1654-1081 ; 2015:31
Keyword
asymmetric synthesis, cyanohydrins, acetoxyphosphonates, biocatalyst, titanium catalyst, minor enantiomer recycling, cross-coupling, amino alcohols
National Category
Organic Chemistry
Research subject
Chemistry
Identifiers
urn:nbn:se:kth:diva-172906 (URN)978-91-7595-627-5 (ISBN)
Public defence
2015-10-02, F3, Lindstedtsvägen 26, KTH, Stockholm, 13:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council, 621-2012-3391
Note

QC 20150908

Available from: 2015-09-08 Created: 2015-09-01 Last updated: 2016-03-21Bibliographically approved

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