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Enantioenriched Cyanohydrins and Acetoxyphosphonates – Synthesis and Applications
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry. (Christina Moberg)
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 [en]
asymmetric synthesis, cyanohydrins, acetoxyphosphonates, biocatalyst, titanium catalyst, minor enantiomer recycling, cross-coupling, amino alcohols
National Category
Organic Chemistry
Research subject
Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-172906ISBN: 978-91-7595-627-5 (print)OAI: oai:DiVA.org:kth-172906DiVA: diva2:850291
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
List of papers
1. Enantioenriched ω-bromocyanohydrin derivatives. Improved selectivity by combination of two chiral catalysts
Open this publication in new window or tab >>Enantioenriched ω-bromocyanohydrin derivatives. Improved selectivity by combination of two chiral catalysts
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.

Keyword
2-Cyanotetrahydrofuran, 2-Cyanotetrahydropyran, Acetylcyanation, Enzymatic hydrolysis, Kinetic resolution
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-101332 (URN)10.1016/j.tet.2012.05.090 (DOI)000307802300024 ()2-s2.0-84864465486 (Scopus ID)
Funder
Swedish e‐Science Research Center
Note

QC 20120829

Available from: 2012-08-29 Created: 2012-08-27 Last updated: 2017-12-07Bibliographically approved
2. One-step preparation of O-(α-bromoacyl) cyanohydrins by minor enantiomer recycling: Synthesis of 4-amino-2(5H)-furanones
Open this publication in new window or tab >>One-step preparation of O-(α-bromoacyl) cyanohydrins by minor enantiomer recycling: Synthesis of 4-amino-2(5H)-furanones
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.

Keyword
Candida antarctica lipase B, Diastereoisomers, Enantiomeric ratio, Furanones, High yield, Lewis acid-catalyzed reactions, Single-step, Synthetic intermediates
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-133262 (URN)10.1021/jo401401c (DOI)000330159500026 ()2-s2.0-84884559931 (Scopus ID)
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
3. Minor Enantiomer Recycling: Application to Enantioselective Syntheses of Beta Blockers
Open this publication in new window or tab >>Minor Enantiomer Recycling: Application to Enantioselective Syntheses of Beta Blockers
2014 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 20, no 13, 3806-3812 p.Article in journal (Refereed) Published
Abstract [en]

Continuous recycling of the minor product enantiomer obtained from the acetylcyanation of prochiral aldehydes provided access to highly enantiomerically enriched products. Cyanohydrin derivatives, which under normal conditions are obtained with modest or poor enantiomeric ratios, were formed with high enantiomeric purity by using a reinforcing combination of a chiral Lewis acid catalyst and a biocatalyst. The primarily obtained products were transformed into -adrenergic antagonists (S)-propanolol, (R)-dichloroisoproterenol, and (R)-pronethalol by means of a two-step procedure.

Keyword
aldehydes, beta blockers, biocatalysis, enantioselectivity, Lewis acids
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-144946 (URN)10.1002/chem.201303890 (DOI)000332757100031 ()2-s2.0-84925284985 (Scopus ID)
Funder
Swedish Research Council, 621-2012-3391
Note

QC 20140505

Available from: 2014-05-05 Created: 2014-05-05 Last updated: 2017-05-30Bibliographically approved
4. Enantioselective Acylphosphonylation-Dual Lewis Acid-Lewis Base Activation of Aldehyde and Acylphosphonate
Open this publication in new window or tab >>Enantioselective Acylphosphonylation-Dual Lewis Acid-Lewis Base Activation of Aldehyde and Acylphosphonate
2014 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 79, no 13, 6172-6178 p.Article in journal (Refereed) Published
Abstract [en]

Acetoxyphosphonates were obtained by a one-step procedure consisting of reaction of diethyl acetylphosphonate with prochiral aldehydes in the presence of a catalytic system comprising a chiral Lewis acid, an achiral Lewis base, and a Bronstedt base. Best results were obtained using a tridentate Schiff base aluminum(III) Lewis acidic complex, 1H-1,2,3-benzotriazole, and a tertiary amine such as DBU. The target compounds were in most cases obtained in high yields, but with moderate enantiomeric ratios (up to 78:22).

Keyword
Aldehydes, Complexation, Functional groups, Acylphosphonate, Catalytic system, Chiral Lewis acid, Enantiomeric ratio, Enantioselective, Prochiral aldehydes, Target compound, Tridentate Schiff-base
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-148610 (URN)10.1021/jo500895u (DOI)000338693300026 ()2-s2.0-84903717843 (Scopus ID)
Funder
Wenner-Gren FoundationsSwedish Research Council, 621-2012-3391
Note

QC 20140811

Available from: 2014-08-11 Created: 2014-08-11 Last updated: 2017-12-05Bibliographically approved
5. Synthesis of the beta(3)-Adrenergic Receptor Agonist Solabegron and Analogous N-(2-Ethylamino)-beta-amino Alcohols from O-Acylated Cyanohydrins - Expanding the Scope of Minor Enantiomer Recycling
Open this publication in new window or tab >>Synthesis of the beta(3)-Adrenergic Receptor Agonist Solabegron and Analogous N-(2-Ethylamino)-beta-amino Alcohols from O-Acylated Cyanohydrins - Expanding the Scope of Minor Enantiomer Recycling
2015 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 80, no 5, 2937-2941 p.Article in journal (Refereed) Published
Abstract [en]

A novel methodology to produce highly enantioenriched N-(2-ethylamino)-beta-amino alcohols was developed. These compounds were obtained from O-(alpha-bromoacyl) cyanohydrins, which were synthesized by the minor enantiomer methodology employing a Lewis acid and a biocatalyst, followed by nucleophilic substitution with amines and reduction. The importance of the developed methodology was demonstrated by completing a highly enantioselective total synthesis of the beta(3)-adrenergic receptor agonist Solabegron.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-163973 (URN)10.1021/acs.joc.5b00322 (DOI)000350841600054 ()25689345 (PubMedID)2-s2.0-84924326489 (Scopus ID)
Funder
Swedish Research Council, 621-2012-3391
Note

QC 201504507

Available from: 2015-05-07 Created: 2015-04-13 Last updated: 2017-12-04Bibliographically approved
6. Palladium-Catalyzed C(sp3)-C(sp2) Cross-Couplings BetweenO-(α-Bromoacyl) Cyanohydrins and Boronic Acids
Open this publication in new window or tab >>Palladium-Catalyzed C(sp3)-C(sp2) Cross-Couplings BetweenO-(α-Bromoacyl) Cyanohydrins and Boronic Acids
(English)Manuscript (preprint) (Other academic)
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-172960 (URN)
Note

QS 2015

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

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