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New Methods for Chiral Cyanohydrin Synthesis
KTH, School of Chemical Science and Engineering (CHE), Chemistry. (Christina Moberg)
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis deals with method development in asymmetric catalysis and specifically syntheses of enantioenriched O-functionalized cyanohydrins.

The first part describes the development of a method for the synthesis of O‑alkoxycarbonylated and O-acylated cyanohydrins. Ethyl cyanoformate and acyl cyanides were added to aldehydes in a reaction catalyzed by a chiral dimeric Ti-salen complex together with a tertiary amine. High yields and enantioselectivities were in most cases obtained. Mechanistic studies were performed and a reaction mechanism was proposed. ­

The second part describes a method in which the undesired minor enantiomer in a Lewis acid–Lewis base-catalyzed acylcyanation is continuously recycled into prochiral starting material. Close to enantiopure O‑acylated cyanohydrins were obtained in high yields.

The third part deals with asymmetric acylcyanations of ketones. Acetyl cyanide was found to add to α‑ketoesters in a reaction catalyzed by a chiral Lewis base. Yields up to 77% and 82% ee were obtained.

The final part describes an enzymatic method for high-throughput analysis of O‑acylated cyanohydrins. The enantiomeric excess and conversion were determined for products obtained from a number of aromatic and aliphatic aldehydes.

Place, publisher, year, edition, pages
Stockholm: KTH , 2009. , 54 p.
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2009:12
Keyword [en]
acyl cyanides, asymmetric synthesis, biocatalysis, cyanide, cyanohydrins, dual activation, enzymes, high-throughput screening, Lewis acid, Lewis base, metal catalysis, minor enantiomer recycling, salen, titanium
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:kth:diva-10205ISBN: 978-91-7415-263-0 (print)OAI: oai:DiVA.org:kth-10205DiVA: diva2:210859
Public defence
2009-05-08, F3, Lindstedtsvägen 26, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
QC 20100818Available from: 2009-05-07 Created: 2009-04-06 Last updated: 2010-09-22Bibliographically approved
List of papers
1. Dual Lewis Acid–Lewis Base Activation in Enantioselective Cyanation of Aldehydes Using Acetyl Cyanide and Cyanoformate as Cyanide Sources
Open this publication in new window or tab >>Dual Lewis Acid–Lewis Base Activation in Enantioselective Cyanation of Aldehydes Using Acetyl Cyanide and Cyanoformate as Cyanide Sources
2005 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 127, no 33, 11592-11593 p.Article in journal (Refereed) Published
Keyword
aldehyde; cyanide; formic acid; Lewis acid; Lewis base; trimethylsilyl derivative; article; chirality; cyanation; enantiomer; enantioselectivity; gas chromatography; mass spectrometry; reaction analysis; Aldehydes; Cyanides; Molecular Structure; Nitriles; Stereoisomerism
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-6915 (URN)10.1021/ja052804q (DOI)000231454100030 ()2-s2.0-23944488799 (Scopus ID)
Note
QC 20100809Available from: 2007-03-22 Created: 2007-03-22 Last updated: 2010-08-09Bibliographically approved
2. Lewis acid-Lewis base-catalysed enantioselective addition of alpha-ketonitriles to aldehydes
Open this publication in new window or tab >>Lewis acid-Lewis base-catalysed enantioselective addition of alpha-ketonitriles to aldehydes
2007 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 349, no 3, 364-372 p.Article in journal (Refereed) Published
Abstract [en]

Additions of structurally diverse alpha-ketonitriles to aromatic and aliphatic prochiral aldehydes yielding highly enantioenriched acylated cyanohydrins were achieved using a combination of a titanium salen dimer and an achiral or chiral Lewis base. In most cases high yields and high enantioselectivities were observed. The ee was moderate in the initial part of the reaction but increased over time. This could be avoided, and higher ees obtained, by keeping the titanium complex, in the presence or absence of aldehyde and ketonitrile, at -40 degrees C prior to the addition of the Lewis base. A mechanism initiated by nucleophilic attack of the tertiary amine at the carbonyl carbon atom of the ketonitile is supported by C-13 labelling experiments.

Keyword
Lewis acids; Lewis bases; O-acylcyanohydrins; Salen; Titanium
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-6916 (URN)10.1002/adsc.200600365 (DOI)000244268900015 ()2-s2.0-33947594481 (Scopus ID)
Note
QC 20100809Available from: 2007-03-22 Created: 2007-03-22 Last updated: 2010-08-09Bibliographically approved
3. O-Acylated Cyanohydrins: Versatile Intermediates and Products
Open this publication in new window or tab >>O-Acylated Cyanohydrins: Versatile Intermediates and Products
2007 (English)In: Chimica Oggi, ISSN 0392-839X, Vol. 25, no 5, 14-15 p.Article in journal (Refereed) Published
Abstract [en]

Addition of ketonitriles to prochiral aromatic or aliphatic aldehydes in the presence of a catalytic system consisting of a chiral Lewis acid and an achiral Lewis base gives access to chiral enantioenriched O-acylated cyanohydrins. The products are useful for diverse potential applications.

Keyword
lewis-base activation; asymmetric-synthesis; aldehydes; esters; optimization; insecticides; degradation; complexes; sediment; cyanide
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-10364 (URN)000256192700003 ()2-s2.0-36048999872 (Scopus ID)
Note

QC 20100818

Available from: 2009-05-07 Created: 2009-05-07 Last updated: 2016-12-19Bibliographically approved
4. Minor enantiomer recycling: Metal catalyst, organocatalyst and biocatalyst working in concert
Open this publication in new window or tab >>Minor enantiomer recycling: Metal catalyst, organocatalyst and biocatalyst working in concert
Show others...
2009 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 15, no 44, 12107-12113 p.Article in journal (Refereed) Published
Abstract [en]

 A minor enantiomer recycling one-pot procedure employing two reinforcing chiral catalysts has been developed. Continuous regeneration of the achiral starting material is effected via selective enzyme-catalyzed hydrolysis of the minor product enantiomer from Lewis acid-Lewis base catalyzed addition of acyl cyanides to prochiral aldehydes in a two-phase solvent system. The process provides O-acylated cyanohydrins in close to perfect enantioselectivities, higher than those obtained in the direct process, and in high yields. A combination of a (SS)salen Ti Lewis acid and Candida antarctica lipase B provides the products with R absolute configuration, whereas the opposite enantiomer is obtained from the (R,R)-salen Ti complex and Candida rugosa lipase.

Keyword
asymmetric catalysis, enantioselectivity, enzyme catalysis, Lewis acids, organocatalysis
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-10365 (URN)10.1002/chem.200901338 (DOI)000272109100036 ()2-s2.0-72949121762 (Scopus ID)
Note
QC 20100922. Uppdaterad från Manuskript till Artikel (20100922). Tidigare titel "Minor Enantiomer Recycling: Metal Catalyst and Biocatalyst Working in Concert".Available from: 2009-05-07 Created: 2009-05-07 Last updated: 2014-12-02Bibliographically approved
5. Chiral Lewis base catalyzed enantioselective acetylcyanation of α-oxo esters
Open this publication in new window or tab >>Chiral Lewis base catalyzed enantioselective acetylcyanation of α-oxo esters
2009 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, Vol. 23, 3917-3922 p.Article in journal (Refereed) Published
Abstract [en]

Acetyl cyanide adds to alkyl benzoylformates and to 2-oxoalkanoates to yield enantioenriched acylated cyanohydrins in one step in the presence of a catalytic amount of a chiral base. The reaction is accelerated by Lewis acids and by the addition of a catalytic amount of methanol. Under optimized conditions, 94% of a 94:6 mixture of the O-acetylated and non-protected cyanohydrins was formed from, methyl benzoylformate in the presence of cinchonidine; from, this mixture the acylated compound with 66% ee was isolated in 77% yield. Ethyl pyruvate and ierf-butyl 2-oxobutanoate were more reactive, and essentially full conversion to the products with 69 and 82% ee, respectively, was achieved. The reaction proceeds by a non-selective addition of cyanide ion to give the non-protected cyanohydrin followed by a dynamic kinetic resolution to provide the enantioenriched acetylated product.

Keyword
Acylation; Addition reactions; Asymmetric catalysis; Cyanides; Kinetic resolution; Lewis bases
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-10366 (URN)10.1002/ejoc.200900055 (DOI)000269103600014 ()2-s2.0-68049139704 (Scopus ID)
Note

Tidigare titel: Chiral Lewis Base-Catalyzed Enantioselective Acetylcyanation of α-Ketoesters QC 20100818

Available from: 2009-05-07 Created: 2009-05-07 Last updated: 2016-12-19Bibliographically approved
6. High Throughput Synthesis and Analysis of Acylated Cyanohydrins
Open this publication in new window or tab >>High Throughput Synthesis and Analysis of Acylated Cyanohydrins
Show others...
2007 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 13, no 15, 4334-4341 p.Article in journal (Refereed) Published
Abstract [en]

The yields and optical purities of products obtained from chiral Lewis acid/Lewis base-catalysed additions of alpha-ketonitriles to prochiral aldehydes could be accurately determined by an enzymatic method. The amount of remaining aldehyde was determined after its reduction to an alcohol, whilst the two product enantiomers were analysed after subsequent hydrolysis first by the (S)-selective Candida antarctica lipase B and then by the unselective pig liver esterase. The method could be used for analysis of products obtained from a number of aromatic aldehydes and aliphatic ketonitriles. Microreactor technology was successfully combined with high-throughput analysis for efficient catalyst optimization.

Keyword
asymmetric synthesis; cyanohydrins; enantioselectivity; enzymes; high-throughput screening; microreactors
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-7108 (URN)10.1002/chem.200601638 (DOI)000246879100022 ()2-s2.0-34250318478 (Scopus ID)
Note
QC 20100809Available from: 2007-05-15 Created: 2007-05-15 Last updated: 2010-08-09Bibliographically approved

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