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- Hertzberg, Robin, 1985-
(författare)
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Enantioenriched Cyanohydrins and Acetoxyphosphonates – Synthesis and Applications
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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- Hertzberg, Robin, et al.
(författare)
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Enantioenriched ω-bromocyanohydrin derivatives. Improved selectivity by combination of two chiral catalysts
- 2012
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Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020 .- 1464-5416. ; 68:37, s. 7680-7684
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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- Hertzberg, Robin, et al.
(författare)
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One-step preparation of O-(α-bromoacyl) cyanohydrins by minor enantiomer recycling : Synthesis of 4-amino-2(5H)-furanones
- 2013
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 78:18, s. 9174-9180
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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- Hertzberg, Robin, et al.
(författare)
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Palladium-Catalyzed C(sp3)–C(sp2) Cross-Couplings of O-(α-Bromoacyl) Cyanohydrins with Boronic Acids : An Entry to Enantioenriched N-Acylated β-Amino Alcohols
- 2016
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Ingår i: Synthesis (Stuttgart). - : Georg Thieme Verlag KG. - 0039-7881 .- 1437-210X. ; 48:19
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Tidskriftsartikel (refereegranskat)abstract
- Suzuki-type cross-coupling of enantiomerically enriched O-(α-bromoacyl) cyanohydrins with aromatic boronic acids substituted with electron-withdrawing or electron-donating groups gave the expected coupling products in high yields without racemization. These substrates exhibit higher reactivities than analogous substrates lacking the nitrile function, probably as a result of π-coordination of the nitrile to palladium. Reduction of the nitrile group of the products, with accompanying intramolecular acyl transfer, provides access to biologically interesting N-acylated β-amino alcohols.
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- Laurell Nash, Anna, et al.
(författare)
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Dual Lewis Acid/Lewis Base Catalyzed Acylcyanation of Aldehydes : A Mechanistic Study
- 2016
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Ingår i: Chemistry - A European Journal. - : Wiley-VCH Verlagsgesellschaft. - 0947-6539 .- 1521-3765. ; 22:11, s. 3821-3829
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Tidskriftsartikel (refereegranskat)abstract
- A mechanistic investigation, which included a Hammett correlation analysis, evaluation of the effect of variation of catalyst composition, and low-temperature NMR spectroscopy studies, of the Lewis acid-Lewis base catalyzed addition of acetyl cyanide to prochiral aldehydes provides support for a reaction route that involves Lewis base activation of the acyl cyanide with formation of a potent acylating agent and cyanide ion. The cyanide ion adds to the carbonyl group of the Lewis acid activated aldehyde. O-Acylation by the acylated Lewis base to form the final cyanohydrin ester occurs prior to decomplexation from titanium. For less reactive aldehydes, the addition of cyanide is the rate-determining step, whereas, for more reactive, electron-deficient aldehydes, cyanide addition is rapid and reversible and is followed by rate-limiting acylation. The resting state of the catalyst lies outside the catalytic cycle and is believed to be a monomeric titanium complex with two alcoholate ligands, which only slowly converts into the product.
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- Li, Ende, et al.
(författare)
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Regio- and stereoselective synthesis of conjugated trienes from silaborated 1,3-enynes
- 2016
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Ingår i: New Journal of Chemistry. - : Royal Society of Chemistry. - 1144-0546 .- 1369-9261. ; 40:7, s. 6340-6346
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Tidskriftsartikel (refereegranskat)abstract
- Products obtained from palladium-catalyzed regioselective cis-addition of (chlorodimethylsilyl)pinacolborane to the alkyne bond of 1,4-disubstituted 1,3-enynes were subjected to Suzuki-Miyaura coupling with alkenyl iodides. Hiyama coupling of the resulting silanol-functionalized trienes provided tetrasubstituted conjugated trienes with different substitution patterns, whereas protiodesilylation with fluoride gave trisubstituted trienes. The methodology presented gives access to conjugated trienes with control of regio- and stereochemistry.
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- Wen, Ye-Qian, et al.
(författare)
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Enantioselective Acylphosphonylation-Dual Lewis Acid-Lewis Base Activation of Aldehyde and Acylphosphonate
- 2014
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 79:13, s. 6172-6178
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Tidskriftsartikel (refereegranskat)abstract
- 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).
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- Wen, Ye-Qian, et al.
(författare)
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Minor Enantiomer Recycling : Application to Enantioselective Syntheses of Beta Blockers
- 2014
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Ingår i: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 20:13, s. 3806-3812
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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