| 1. |
- Almqvist, Fredrik, et al.
(författare)
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An Improved Procedure for the Synthesis of Bicyclo[2.2.2]octane- 2,6-dione
- 1993
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Ingår i: Synthetic Communications. - : Informa UK Limited. - 0039-7911 .- 1532-2432. ; 23:11, s. 1499-1505
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Tidskriftsartikel (refereegranskat)abstract
- Conjugate addition of Meldrum's acid to 2-cyclohexenone followed by direct cyclization in PPA/acetic acid constitutes a shorter, more reproducible and higher yielding route to bicyclo[2.2.2]octane-2,6-dione than previous methods. The crude dione could be used as substrate for the baker's yeast reduction to (IR, 4S, 6S)-bicyclo[2.2.2]octane-6-ol-2-one.
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| 2. |
- Almqvist, Fredrik, et al.
(författare)
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Neighboring Group Participation in a Regio- and Stereoselective Chlorination of a Bicyclo[2.2.2]octanone
- 1996
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 1520-6904 .- 0022-3263. ; 61:20, s. 6947-6951
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Tidskriftsartikel (refereegranskat)abstract
- The zinc chloride-mediated acetylation of the optically active silyl enol ether 2a gave the beta-diketone 3a (48%) together with the regio- and stereoselectively chlorinated compound 4 (27%). The yield of 4 increased to 70% by starting from the O-acetyl derivative 2c. The chlorination most likely occurs via neighboring group participation by the endo acetoxy group.
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| 3. |
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| 4. |
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| 5. |
- Almqvist, Fredrik, et al.
(författare)
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Spirobicyclo[2.2.2]octane derivatives: mimetics of baccatin III and paclitaxel (Taxol)
- 2004
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Ingår i: Organic and Biomolecular Chemistry. - 1477-0539. ; 2:21, s. 3085-3090
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Tidskriftsartikel (refereegranskat)abstract
- The formylated spirobyclic alcohol 8a was computer modeled to be a mimetic of paclitaxel. In this model, the formyl group was used as a truncated paclitaxel side chain in order to reduce the computational work. Compound 8c, carrying the paclitaxel side chain, was synthesized in six steps from optically active 1,3-diketone 12. Microtubule stabilization was not observed for 8c, indicating that the model needs to be adjusted.
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| 6. |
- Almqvist, Fredrik, et al.
(författare)
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Spirobicyclo[2.2.2]octane derivatives: mimetics of baccatin III and paclitaxel (Taxol)
- 2004
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Ingår i: ORGANIC & BIOMOLECULAR CHEMISTRY. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 2:21, s. 3085-90
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Tidskriftsartikel (refereegranskat)abstract
- The formylated spirobyclic alcohol 8a was computer modeled to be a mimetic of paclitaxel. In this model, the formyl group was used as a truncated paclitaxel side chain in order to reduce the computational work. Compound 8c, carrying the paclitaxel side chain, was synthesized in six steps from optically active 1,3-diketone 12. Microtubule stabilization was not observed for 8c, indicating that the model needs to be adjusted.
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| 7. |
- Almqvist, Fredrik, et al.
(författare)
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Synthesis of Optically Active endo, endo Bicyclo[2.2.2]octane-2,5- diol, Bicyclo[2.2.2]octan-2,5-dione and Related Compounds
- 1996
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 1520-6904 .- 0022-3263. ; 61:11, s. 3794-3798
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Tidskriftsartikel (refereegranskat)abstract
- Optically active C-2-symmetric (1S,2S,4S,5S)-bicyclo[2.2.2]octane-2,5-diol ((+)-12; 98% ee) and several selectivity protected optically active intermediates useful for synthetic transformations were synthesized via a 1,2-carbonyl transposition route starting from the easily available optically active (1R,4S,6S)-6-hydroxybicyclo[2.2.2]octan-2-one ((-)-2). The synthetic route also allowed the preparation of optically active (1S,4S)-bicyclo[2.2.2]octane-2,5-dione ((+)-14; 98% ee).
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| 8. |
- Bertozzi, Fabio, et al.
(författare)
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Temporary in situ aluminum and zinc tethering in Diels-Alder reactions
- 2000
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Ingår i: Organic Letters. - : American Chemical Society (ACS). - 1523-7060 .- 1523-7052. ; 2:9, s. 1283-1286
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Tidskriftsartikel (refereegranskat)abstract
- (formula presented) Temporary tethering using aluminum or zinc in Diels-Alder reactions made possible the use of otherwise "noncompatible" combinations of dienes and dienophiles, resulting in the one-step formation of substituted cyclohexene 1,2-bis-methanols. Excellent regioselectivity and also significant stereoselectivity were obtained.
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| 9. |
- Blomberg, David, 1971-
(författare)
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Synthesis of β-turn and pyridine based peptidomimetics
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Despite the unfavorable pharmacokinetic properties associated with peptides, they are still of great interest in drug development due to a multitude of interesting biological functions. The development of peptidomimetics strives to maintain or improve the biological activity of a peptide concurrently with removing the unwanted properties. This thesis describes two synthetic approaches to peptidomimetics with particular emphasis on secondary structure mimetics. First the design, synthesis and evaluation of two beta-turn mimetics incorporated in the endorphin Leu-enkephalin is presented. The beta-turn mimetics were stabilized by replacement of the intramolecular hydrogen bond with an ethylene bridge, and the amide bond between Tyr and Gly was replaced with an ether linkage. Linear analogues of the two mimetics were also synthesized. The peptidomimetics and their linear analogues were evaluated in a competitive binding assay at two opiate receptors, my and delta. One of the cyclized beta-turn mimetics was found to be a delta receptor antagonist with an IC50 value of 160 nM. Second a synthetic strategy to a beta-strand mimetic using 2-fluoro-4-iodopyridine as scaffold is described. The synthesis involved a Grignard exchange reaction on the pyridine scaffold using an amino acid derivative as electrophile followed by an SNAr reaction using an amine as nucleophile. The synthesis of a tripeptidomimetic of Leu-Gly-Gly and attempts to introduce chiral building blocks at the C-terminal, as well as studies towards elongated mimetics are presented. Two additional studies deal with the synthesis of two classes of potential thrombin inhibitors based on the pyridine scaffold. The first class contain pyridine as central fragment (P2 residue) substituted with a para-amidinobenzylamine group as P1 residue and various benzoyl groups as P3 residues. Three potential thrombin inhibitors were synthesized and found to be microM inhibitors in an enzymatic assay. In the second class, the pyridine ring serves as P3 residue. This class also lacks a strongly basic group in the P1 position. A small library of eight compounds were synthesized and evaluated in the enzymatic assay. Unfortunately, these compounds lacked inhibitory activity.
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| 10. |
- Botes, AL, et al.
(författare)
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Screening of yeast species for the stereo-selective reduction of bicyclo[2.2.2]octane-2,6-dione
- 2002
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Ingår i: Journal of the Chemical Society - Perkin Transactions 1. - : Royal Society of Chemistry (RSC). - 1472-7781 .- 1364-5463. ; :8, s. 1111-1114
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Tidskriftsartikel (refereegranskat)abstract
- Yeast strains from more than 31 different genera were screened for the enantioselective reduction of bicyclo[2.2.2]-octane-2,6-dione (1). Reducing activity was found in 80% of the screened yeasts. Bicyclo[2.2.2]octane-2,6-dione was enantioselectively reduced (> 98% ee) to (1R, 4S, 6S)-6-hydroxybicyclo[2.2.2]octane-2-one (-)-2 by 69% of the strains. Enantioselective reduction of the diketone to (1S, 4R, 6S)-6-hydroxybicyclo[2.2.2]octane-2-one ((+)-3, >98% ee) as a major product is reported for the first time. Candida tropicalis UOFS Y-0534 and Candida wickerhamii UOFS Y-0652 displayed this unusual diastereoselectivity.
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| 11. |
- Carlquist, Magnus, et al.
(författare)
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Flavonoids as inhibitors of human carbonyl reductase 1
- 2008
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Ingår i: Chemico-Biological Interactions. - : Elsevier BV. - 1872-7786 .- 0009-2797. ; 174:2, s. 98-108
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Tidskriftsartikel (refereegranskat)abstract
- Human carbonyl reductase 1 (CBR1), that is one of the enzymes responsible for the reduced efficiency of treatments by the antineoplastic agents anthracyclines, was functionally expressed in Saccharomyces cerevisiae. CBR1 was purified and kinetically characterised using daunorubicin as substrate. CBR1-catalysed reduction of daunorubicin followed an apparent Michaelis-Menten kinetics with K-M = 85.2 +/- 26.7 mu M and V-max =3490 +/- 220 mu mol/(min g protein). The type of inhibition for the flavonoid compound rutin was determined by studying initial reaction rates in the presence of rutin. The inhibition kinetics was found to follow an apparent mixed inhibition with K-ic = 1.8 +/- 1.2 mu M and K-iu = 2.8 +/- 1.6 mu M. IC50-values were also determined for a set of flavonoids in order to identify essential structure for inhibition activity. Computational docking experiments of the four best inhibitors to the catalytic site of CBR1 showed that the flavonoid skeleton structure was the binding part of the molecule. The presence of a sugar moiety in I and 2, or a sugar mimicking part in 9. directed the orientation of the flavonoid so that the sugars were pointing outwards, giving rise to a stabilising effect to the binding. Finally, additional binding epitopes that interacted with various parts of the flavonoid ligand were identified and could potentially be targeted for further improvement of inhibition activity. These included; hydrogen-binding sites surrounding Ser139 and Cys226, Met234 and Tyr193 or Trp229; aromatic-aromatic interaction with Tyr193, Trp229 or NADPH; van der Waals interactions with IIe140. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
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| 12. |
- Carlquist, Magnus, et al.
(författare)
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Kinetic resolution of racemic 5,6-epoxy-bicyclo[2.2.1]heptane-2-one using genetically engineered Saccharomyces cerevisiae
- 2009
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Ingår i: Journal of Molecular Catalysis B: Enzymatic. - : Elsevier BV. - 1873-3158 .- 1381-1177. ; 58:2, s. 98-102
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Tidskriftsartikel (refereegranskat)abstract
- (+)-5,6-Epoxy-bicyclo[2.2.1]heptane-2-one, (+)-1, and endo-(−)-5,6-epoxy-bicyclo[2.2.1]heptane-2-ol, endo-(−)-2, were obtained by kinetic resolution of rac-1 by asymmetric bioreduction catalyzed by whole cells of a genetically engineered Saccharomyces cerevisiae yeast strain. The strain, TMB4100, had 1% phosphoglucose isomerase (PGI) activity and overexpressed a specific short-chain dehydrogenase, encoded by the gene YMR226c. The whole cell biocatalystwas demonstrated to be significantly inactivated within 24 h, thus restricting the reaction to lowconcentration. Despite this, the resolution method could be used to produce optically pure (+)-1 and endo-(−)-2 from the racemic mixture at 5 g/L substrate. At optimal conditions, 1 g of rac-1 was kinetically resolved to give (+)-1 in 95% ee and 28% yield and endo-(−)-2 in 74% ee, 80% de and 45% yield.
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| 13. |
- Ek, Fredrik, et al.
(författare)
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Aromatic allylation via diazotization: Metal-free C-C bond formation
- 2002
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 1520-6904 .- 0022-3263. ; 67:18, s. 6376-6381
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Tidskriftsartikel (refereegranskat)abstract
- A new method for the synthesis of allyl aromatic compounds not involving any metal-containing reagent or catalyst has been developed. Arylamines substituted with a large number of different substituents were converted via diazotizative deamination with tert-butyl nitrite in allyl bromide and acetonitrile to the corresponding allyl aromatic compounds. The allylation reaction was found to be suitable for larger scale synthesis due to short reaction times, a nonextractive workup, and robustness toward moisture, air, and type of solvent.
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| 14. |
- Ek, Fredrik, et al.
(författare)
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Aromatic Allylation via Diazotization, Variation of the Allylic Moiety and a Short Route to a Benzazepine Derivative.
- 2003
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 1520-6904 .- 0022-3263. ; 68:5, s. 1911-1918
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Tidskriftsartikel (refereegranskat)abstract
- A continued study of the recently discovered diazotizative allylation (DiazAll) reaction of aniline derivatives is reported. Several allyl reagents, commonly used in radical allylation reactions, were evaluated, and some of these reagents resulted in allylation when used in the DiazAll reaction. The best result was obtained with allyl bromide. Substituted allylic bromides gave the corresponding allyl aromatic compounds in poor to excellent yields. In comparison with an established method for aromatic allylation, the DiazAll reaction performed well and was superior when a more complex allylic bromide was used. Finally, a new allylation-bromocyclization reaction was demonstrated and used in the synthesis of a known inhibitor of phenylethanolamine N-methyltransferase (PNMT), an enzyme involved in the biosynthesis of adrenaline.
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| 15. |
- Ek, Fredrik, et al.
(författare)
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Synthesis of Fused Tertazole- and Imidazole Derivatives via Iodocyclization.
- 2003
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Ingår i: Tetrahedron. - 0040-4020. ; 59:35, s. 6759-6769
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Tidskriftsartikel (refereegranskat)abstract
- The possibility to prepare fused tetrazole- and imidazole derivatives by iodocyclization in moderate to excellent yields is demonstrated. In some examples the cyclizations were not following Baldwin's rules entirely, i.e. exo-selectivity. Nucleophilic substitution of the formed iodides gave different results depending on the hardness of the nucleophile. Thus, elimination of the iodide could be a problem but a substitution reaction with ethyl potassium xanthate and a radical reaction using acrylonitrile were tolerated. In addition, we showed that it is possible to selectively use three iodo substituents individually in one of the fused imidazole derivatives.
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| 16. |
- Ek, Fredrik, et al.
(författare)
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Synthesis of fused tetrazole derivatives via a tandem cycloaddition and N-allylation reaction and parallel synthesis of fused tetrazole amines
- 2004
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 1520-6904 .- 0022-3263. ; 69:4, s. 1346-1352
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Tidskriftsartikel (refereegranskat)abstract
- A method for the synthesis of novel fused tricyclic tetrazoles from allylic bromides generated by the recently discovered DiazAll reaction has been developed. This new tandem reaction comprises a cycloaddition between a nitrile and (TMS)N-3 followed by an intramolecular N-allylation. The variation of functionalities in the benzene moiety was well-tolerated, and only a moderate difference in yield and degree of purity was noticed. An exo-methylene group in these new compounds permitted further derivatization. Structural resemblance with substances which possess important pharmacological properties motivated the synthesis of a series of ketones and a small library of amines.
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| 17. |
- Friberg, Annika, et al.
(författare)
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Bicyclo[2.2.2]octane-derived chiral ligands-synthesis and application of BODOLs in the asymmetric reduction of acetophenone with catecholborane
- 2008
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Ingår i: Tetrahedron: Asymmetry. - : Elsevier BV. - 0957-4166. ; 19:15, s. 1765-1777
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Tidskriftsartikel (refereegranskat)abstract
- An improved synthetic route to the bicyclo[2.2.2]octane-2,6-diol ligands (2,6-BODOLS) allowed an increased structural variation of the ligand side-arm. The addition of aromatic or vinylic Grignard reagents to hydroxyketone 1 was highly selective and ligands 3f-3I were isolated in 84-97% yield. The addition of alkyl Grignard reagents containing beta-hydrogens resulted in lower yields (13-71%) due to competing ketone reduction. A number of 2,5-BODOLs were synthesized using a similar methodology. The ligands, together with Ti(OiPr)(4), were tested in the asymmetric reduction of acetophenone with catecholborane (up to 98% ee). 1-Naphthyl-BODOL 3i was employed as an allylboration reagent to benzaldehyde together with Sc(OTf)(3), resulting in (1S)-1-phenyl-3-buten-1-ol in 80% ee. (C) 2008 Elsevier Ltd. All rights reserved.
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| 18. |
- Friberg, Annika, et al.
(författare)
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Cleft molecules as organocatalysts in an asymmetric hetero-Diels-Alder reaction
- 2007
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Ingår i: Tetrahedron: Asymmetry. - : Elsevier BV. - 0957-4166. ; 18:7, s. 885-891
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Tidskriftsartikel (refereegranskat)abstract
- The synthesis and application of chiral carbocyclic cleft molecules derived from 2,3:6,7-dibenzobicyclo[3.3.1]nona-2,6-diene-4,8-diene in the hetero-Diels-Alder reaction of benzaldehydes and aminodiene 14 is presented. Catalysis by single hydrogen-bond activation gave up to 52% ee.
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| 19. |
- Friberg, Annika, et al.
(författare)
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Efficient bioreduction of bicyclo[2.2.2]octane-2,5-dione and bicyclo[2.2.2]oct-7-ene-2,5-dione by genetically engineered Saccharomyces cerevisiae
- 2006
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Ingår i: Organic and biomolecular chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 4:11, s. 2304-2312
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Tidskriftsartikel (refereegranskat)abstract
- A screening of non-conventional yeast species and several Saccharomyces cerevisiae ( baker's yeast) strains overexpressing known carbonyl reductases revealed the S. cerevisiae reductase encoded by YMR226c as highly efficient for the reduction of the diketones 1 and 2 to their corresponding hydroxyketones 3 - 6 ( Scheme 1) in excellent enantiomeric excesses. Bioreduction of 1 using the genetically engineered yeast TMB4100, overexpressing YMR226c, resulted in > 99% ee for hydroxyketone (+)- 4 and 84 - 98% ee for (-)- 3, depending on the degree of conversion. Baker's yeast reduction of diketone 2 resulted in > 98% ee for the hydroxyketones (+)- 5 and (+)- 6. However, TMB4100 led to significantly higher conversion rates ( over 40 fold faster) and also a minor improvement of the enantiomeric excesses (> 99%).
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| 20. |
- Gustafsson, Magnus, et al.
(författare)
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Regioselectivity in the rhodium catalysed 1,4-hydrosilylation of isoprene. Aspects on reaction conditions and ligands
- 2004
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Ingår i: Journal of Organometallic Chemistry. - : Elsevier BV. - 0022-328X. ; 689:2, s. 438-443
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Tidskriftsartikel (refereegranskat)abstract
- The regioselectivity in the Rh catalysed 1,4-hydrosilylation of isoprene was investigated. Variation of solvents and temperature did not significantly affect the isomer distribution between tail-product (I) and head-product (II). The choice of ligands had the greater influence, where Rh-I-based catalysts with the strong electron withdrawing ligand CO favoured production of isomer II, while Rh-I catalysts with strong electron donating ligands (for example triarylphosphines) gave isomer I as the main product. In contrast to the square planar carbonyl complex RhCl(CO)(PPh3)(2), the square planar thiocarbonyl complex RhCl(CS)(PPh3)(2), gave I as the major isomer. (C) 2003 Elsevier B.V. All rights reserved.
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| 21. |
- Gustafsson, Magnus, et al.
(författare)
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The effect of oxygen on the regioselectivity in the rhodium catalysed hydrosilylation of 1,3-dienes
- 2002
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Ingår i: Journal of the Chemical Society - Perkin Transactions 1. - : Royal Society of Chemistry (RSC). - 1472-7781 .- 1364-5463. ; :1, s. 102-107
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Tidskriftsartikel (refereegranskat)abstract
- The regioselectivity of the hydrosilylation of substituted 1,3-dienes catalysed by several rhodium complexes in the presence and absence of oxygen was studied. In addition to the already known accelerating effect, the presence of oxygen strongly affected the product distribution. For 2-substituted 1,3-dienes in the presence of oxygen the regioselectivity was in the range of 1 : 6 to 1 : 10 in favour of the head-product, while the absence of oxygen changed the ratios to 1 : 1 to 3 : 1 in fa our of the tail-product. When HSiPh3 was used in the presence of oxygen a single isomer was isolated in 87% yield, while in the absence of oxygen a mixture of products was produced. Control experiments indicated that a heterogeneous/colloidal catalytic system may be responsible for the preferred head-product formation.
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| 22. |
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| 23. |
- Ionescu, Ruxandra, et al.
(författare)
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Eu(III) complexation of phenyltrisalanine and phenylbisalanine in aqueous solution studied by photoluminescence and UV spectroscopy
- 2004
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Ingår i: Journal of Luminescence. - : Elsevier BV. - 0022-2313. ; 106:2, s. 133-139
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Tidskriftsartikel (refereegranskat)abstract
- The Eu(III)-coordination of phenyltrisalanine (Pta) 1, in aqueous solution was investigated. The photoluminescence data suggested that the chelating effect of Pta places the metal ion on the face of the aromatic ring as proposed in 4. Furthermore, Eu(III) is usually used as a substitute for Ca(II) in spectroscopic studies and the formation of a 1:1 complex between Pta and Eu(III) indicated the possibility that Pta may be used as a Ca(II) binder. For comparison, phenylbisalanine (Pba) 2, was subjected to similar studies and was found to behave more like phenylalanine. (C) 2003 Elsevier B.V. All rights reserved.
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| 24. |
- Johanson, Ted, et al.
(författare)
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Reaction and strain engineering for improved stereo-selective whole-cell reduction of a bicyclic diketone
- 2008
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Ingår i: Applied Microbiology and Biotechnology. - : Springer Science and Business Media LLC. - 1432-0614 .- 0175-7598. ; 77:5, s. 1111-1118
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Tidskriftsartikel (refereegranskat)abstract
- Reduction of bicyclo[2.2.2]octane-2,6-dione to (1R, 4S, 6S)-6-hydroxy-bicyclo[2.2.2]octane-2-one by whole cells of Saccharomyces cerevisiae was improved using an engineered recombinant strain and process design. The substrate inhibition followed a Han-Levenspiel model showing an effective concentration window between 12 and 22 g/l, in which the activity was kept above 95%. Yeast growth stage, substrate concentration and a stable pH were shown to be important parameters for effective conversion. The over-expression of the reductase gene YDR368w significantly improved diastereoselectivity compared to previously reported results. Using strain TMB4110 expressing YDR368w in batch reduction with pH control, complete conversion of 40 g/l (290 mM) substrate was achieved with 97% diastereomeric excess (de) and >99 enantiomeric excess (ee), allowing isolation of the optically pure ketoalcohol in 84% yield.
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| 25. |
- Katz, Michael, et al.
(författare)
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An improved stereoselective reduction of a bicyclic diketone by Saccharomyces cerevisiae combining process optimization and strain engineering
- 2002
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Ingår i: Applied Microbiology and Biotechnology. - : Springer Science and Business Media LLC. - 1432-0614 .- 0175-7598. ; 59:6, s. 641-648
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Tidskriftsartikel (refereegranskat)abstract
- The stereoselective reduction of the bicyclic diketone bicyclo[2.2.2]octane-2,6-dione, to the ketoalcohol (1R,4S,6S)-6-hydroxybicyclo[2.2.2]octane-2-one, was used as a model reduction to optimize parameters involved in NADPH-dependent reductions in Saccharomyces cerevisiae with glucose as co-substrate. The co-substrate yield (ketoalcohol formed/glucose consumed) was affected by the initial concentration of bicyclic diketone, the ratio of yeast to glucose, the medium composition, and the pH. The reduction of 5 g l(-1) bicyclic diketone was completed in less than 20 h in complex medium (pH 5.5) under oxygen limitation with an initial concentration of 200 g l(-1) glucose and 5 g l(-1) yeast. The co-substrate yield was further enhanced by genetically engineered strains with reduced phosphoglucose isomerase activity and with the gene encoding alcohol dehydrogenase deleted. Co-substrate yields were increased 2.3-fold and 2.4-fold, respectively, in these strains.
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