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Efficient Synthesis and Analysis of Chiral Cyanohydrins
KTH, School of Chemical Science and Engineering (CHE), Chemistry.
2007 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

This thesis deals with the development of new methods for efficient synthesis and analysis in asymmetric catalysis. It focuses on the preparation of chiral cyanohydrins by enantioselective addition of cyanide to prochiral aldehydes.

The initial part of the thesis describes the development of a dual Lewis acid– Lewis base activation system for efficient synthesis of chiral O-acylated and Ocarbonylated cyanohydrins. This system was used for the preparation of a variety of cyanohydrins in high isolated yields and with up to 96% ee. Activation of the cyanide by nucleophilic attack of the Lewis base at the carbonyl carbon atom was supported experimentally.

Secondly, convenient procedures for the synthesis of polymer-bound chiral YbCl3-pybox and Ti-salen complexes are described. The polymeric complexes were employed in cyanation of benzaldehyde.

A T-shaped microreactor was used for screening of reaction conditions for the enantioselective cyanation of benzaldehyde using trimethylsilyl cyanide and acetyl cyanide as cyanide sources. A microreactor charged with the polymeric Tisalen complex was used for enantioselective cyanation of benzaldehyde.

Finally, an enzymatic method for high throughput analysis of ee and conversion of products from chiral Lewis acid–Lewis base-catalysed additions of α- ketonitriles to prochiral aldehydes was developed. The method could be used for the analysis of a variety of O-acylated cyanohydrins. Microreactor technology was successfully combined with high throughput analysis for efficient catalyst optimisation.

Place, publisher, year, edition, pages
Stockholm: KTH , 2007. , 54 p.
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2007:11
Keyword [en]
asymmetric catalysis, cyanohydrins, microreactor, polymersupported catalyst, ketonitriles, titanium, lanthanide, Lewis acid, Lewis base
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-4315ISBN: 978-91-7178-599-2 (print)OAI: oai:DiVA.org:kth-4315DiVA: diva2:11769
Public defence
2007-04-13, Sal F3, KTH, Lindstedtsvägen 26, Stockholm, 10:15 (English)
Opponent
Supervisors
Note
QC 20100809Available from: 2007-03-22 Created: 2007-03-22 Last updated: 2010-08-09Bibliographically 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: 2017-12-14Bibliographically 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: 2017-12-14Bibliographically approved
3. Polymer-Supported Pyridine-Bis(oxazoline). Application to Ytterbium Catalyzed Silylcyanation of Benzaldehyde
Open this publication in new window or tab >>Polymer-Supported Pyridine-Bis(oxazoline). Application to Ytterbium Catalyzed Silylcyanation of Benzaldehyde
2003 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 5, no 20, 3663-3665 p.Article in journal (Refereed) Published
Abstract [en]

Terminal acetylenes containing hydroxy and carboxylic acid groups were subjected to Sonogashira coupling with 4-bromo-2,6-bis[(R)-4-phenyloxazolin-2-yl]pyridine and the resulting pybox derivatives were immobilized on Tentagel resins. Ytterbium(ill) chloride complexes of the polymeric ligands catalyzed the addition of trimethylsilyl cyanide to benzaldehyde with 80-81% ee. The ligands were reused more than 30 times without any loss in selectivity or activity, and the metal complexes could be recovered and reused at least four times, although with slightly decreasing activity.

Keyword
benzaldehyde; oxazoline derivative; polymer; pyridine derivative; ytterbium; addition reaction; article; asymmetric catalysis; chemical reaction; reaction analysis; silylation
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-6917 (URN)10.1021/ol0353363 (DOI)000185565500031 ()
Note
QC 20100809Available from: 2007-03-22 Created: 2007-03-22 Last updated: 2017-12-14Bibliographically approved
4. Enantioselective Cyanation of Benzaldehyde: an Asymmetric Polymeric Catalyst in a Microreactor
Open this publication in new window or tab >>Enantioselective Cyanation of Benzaldehyde: an Asymmetric Polymeric Catalyst in a Microreactor
2008 (English)In: ARKIVOC, ISSN 1424-6376, Vol. 6, 73-80 p.Article in journal (Refereed) Published
Abstract [en]

A chiral salen ligand containing a carboxylic acid group was attached to macroporous monosized polystyrene-divinylbenzene beads grafted with (4-hydroxybutyl) vinyl ether groups. A Ti(IV) complex of the beads was used for enantioselective cyanations of benzaldehyde using trimethylsilyl cyanide and acetyl cyanide as cyanide sources using both conventional batch techniques and a microreactor.

Keyword
Cyanation; Microreactors; Polymer-supported; Salen; Titanium
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-6918 (URN)000260410000007 ()2-s2.0-42249086107 (Scopus ID)
Note
QC 20100809. Uppdaterad från Manuskript till Artikel i tidskrift 20100809.Available from: 2007-03-22 Created: 2007-03-22 Last updated: 2017-12-14Bibliographically approved
5. Asymmetric Catalysis in a Micro Reactor: Ce, Yb and Lu Catalysed Enantioselective Addition of Trimethylsilyl Cyanide to Benzaldehyde
Open this publication in new window or tab >>Asymmetric Catalysis in a Micro Reactor: Ce, Yb and Lu Catalysed Enantioselective Addition of Trimethylsilyl Cyanide to Benzaldehyde
2004 (English)In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 60, no 46, 10515-10520 p.Article in journal (Refereed) Published
Abstract [en]

A T-shaped micro reactor was used for the optimisation of reaction conditions for the enantioselective silyleyanation of benzaldehyde catalysed by lanthanide-pybox complexes. Compared to a conventional batch procedure, higher conversion was observed within shorter reaction time. The micro reactor process involving Lu(III) afforded essentially the same enantioselectivity as the batch process (73 vs 76% ee), whereas the enantioselectivity was lower in the micro reactor for catalysts containing Yb(III) (53 compared to 72%). Ce(III) provided very low selectivity in both types of processes (1 and 11 % ee, respectively). A study of the effect of additives showed that the enantioselectivity in the Yb catalysed reaction performed in the micro reactor could be increased to 66%, whereas only a minor improvement, to 78% ee, was observed in the reaction with Lu.

Keyword
Asymmetric metal catalysis; Lanthanide; Micro reactor; Pybox; Silylcyanations; benzaldehyde; cerium; cyanide; lanthanide; lutetium; trimethylsilyl derivative; ytterbium; addition reaction; article; asymmetric catalysis; catalyst; chemical analysis; chemical structure; cyanation; enantioselectivity; priority journal; reaction analysis; reactor; structure analysis
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-6919 (URN)10.1016/j.tet.2004.08.080 (DOI)000224632300015 ()2-s2.0-4944237872 (Scopus ID)
Note
QC 20100809 QC 20110916Available from: 2007-03-22 Created: 2007-03-22 Last updated: 2017-12-14Bibliographically approved
6. High-Throughput Enzymatic Method for Enantiomeric Excess Determination of O-Acetylated Cyanohydrins
Open this publication in new window or tab >>High-Throughput Enzymatic Method for Enantiomeric Excess Determination of O-Acetylated Cyanohydrins
Show others...
2006 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 128, no 7, 2234-2235 p.Article in journal (Refereed) Published
Keyword
acetic acid derivative; cyanohydrin; enzyme; acetylation; article; catalyst; chemical modification; enantiomer; enzyme activity; high throughput screening; Acetylation; Animals; Benzaldehydes; Esterases; Hydrolysis; Lipase; Liver; NAD; Nitriles; Stereoisomerism; Swine
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-6920 (URN)10.1021/ja058474r (DOI)000235562900040 ()2-s2.0-33644501771 (Scopus ID)
Note
QC20100809Available from: 2007-03-22 Created: 2007-03-22 Last updated: 2017-12-14Bibliographically approved
7. 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: 2017-12-14Bibliographically approved

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