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One-step preparation of O-(α-bromoacyl) cyanohydrins by minor enantiomer recycling: Synthesis of 4-amino-2(5H)-furanones
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
2013 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 78, no 18, 9174-9180 p.Article in journal (Refereed) Published
Abstract [en]

O-(α-Bromoacyl) cyanohydrins were prepared in a single step from a range of different aldehydes in combination with α-bromoacyl cyanides. By the use of a cyclic procedure where the two minor diastereoisomers from a chiral Lewis acid-catalyzed reaction undergo Candida antarctica lipase B (CALB)-catalyzed hydrolysis followed by dehydrocyanation to regenerate the starting material, the products were obtained in good to high yields and in most cases with excellent diastereoselectivites. The synthetic importance of these compounds was demonstrated by the synthesis of 4-amino-2(5H)-furanones, a class of compounds that have shown both biological activity and utility as synthetic intermediates. This transformation was achieved by an intramolecular Blaise reaction, which gave the products in high to excellent yields and enantiomeric ratios.

Place, publisher, year, edition, pages
2013. Vol. 78, no 18, 9174-9180 p.
Keyword [en]
Candida antarctica lipase B, Diastereoisomers, Enantiomeric ratio, Furanones, High yield, Lewis acid-catalyzed reactions, Single-step, Synthetic intermediates
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-133262DOI: 10.1021/jo401401cISI: 000330159500026Scopus ID: 2-s2.0-84884559931OAI: oai:DiVA.org:kth-133262DiVA: diva2:660631
Funder
Swedish Research Council, 621-2012-3391
Note

QC 20140224

Available from: 2013-10-30 Created: 2013-10-29 Last updated: 2017-12-06Bibliographically 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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