Active site diversification of P450cam with indole generates catalysts for benzylic oxidation reactions

• Paul P. Kelly,
• Anja Eichler,
• Susanne Herter,
• David C. Kranz,
• Nicholas J. Turner and
• Sabine L. Flitsch

Beilstein J. Org. Chem. 2015, 11, 1713–1720, doi:10.3762/bjoc.11.186

• hydroxylations. Keywords: active site mutagenesis; biotransformation; C–H activation; cytochrome P450cam monooxygenase; hydroxylation; Introduction Selective C–H activation and oxyfunctionalisation of hydrocarbons offers a route to chiral alcohols and other industrially important synthetic building blocks from

• hydroxylation by P450cam [10][11] and various other P450s, including the bacterial P450 BM3 [12][13] and human CYPs 2A6, 2C19 and 2E1 [14][15] has been previously identified to translate well to mutants activities toward structurally distinct and more demanding substrates such as diphenylmethane [10

• Escherichia coli (E. coli), variants of the fusion enzyme catalysed the efficient, highly selective hydroxylation of ionones without the need to supply expensive nicotinamide cofactors [20]. Given the previously demonstrated affinity of P450cam for hydrophobic substrates, we were interested to see if P450cam

Novel stereocontrolled syntheses of tashiromine and epitashiromine

• Loránd Kiss,
• Enikő Forró and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2015, 11, 596–603, doi:10.3762/bjoc.11.66

• intramolecular cyclization of a chiral alkenylated pyrrolidinone, followed by hydroxylation [32], or by the intramolecular ring closure of chiral pyrrolidine diesters followed by ester and oxo group reduction [33], while the syntheses of (+)-epitashiromine starts from a chiral morpholine derivative, with nitrone

Electrochemical oxidation of cholesterol

• Jacek W. Morzycki and
• Andrzej Sobkowiak

Beilstein J. Org. Chem. 2015, 11, 392–402, doi:10.3762/bjoc.11.45

• considered as analogical to the Gif-system. In this approach, hydrogen peroxide was exchanged for a process of dioxygen activation with electrochemically generated [FeII(PA)3OH2]− ions. With the system, stereoselective allylic hydroxylation of cholesteryl acetate was carried out [35]. The H-shaped one

A simple and efficient method for the preparation of 5-hydroxy-3-acyltetramic acids

• Johanna Trenner and
• Evgeny V. Prusov

Beilstein J. Org. Chem. 2015, 11, 323–327, doi:10.3762/bjoc.11.37

• oxygen is reported. The deprotection of the resulting compounds was also achieved. Keywords: heterocyclic chemistry; hydroxylation; natural products; tetramic acids; Findings 5-Hydroxy-3-acyltetramic acid is an unusual structural element which is found in the molecules of such biologically active

• . Synthesis of model tetramic acids. Synthesis of hemiaminal ethers and deprotection of the tetramic acids. Initial study of oxidation of tetramic acid 7. Condition optimization for hydroxylation of tetramic acid 7. Oxidation of tetramic acids 8 and 11. Supporting Information Supporting Information File 81

Enantioselective synthesis of polyhydroxyindolizidinone and quinolizidinone derivatives from a common precursor

• Nemai Saha and
• Shital K. Chattopadhyay

Beilstein J. Org. Chem. 2014, 10, 3104–3110, doi:10.3762/bjoc.10.327

• for the stated purpose as demonstrated retro-synthetically in Figure 2. Thus, the cis-hydroxy groups in the tetrahydroxyindolizidine/quinolizidine derivative represented by the general structure I were thought to be obtainable by a substrate-controlled hydroxylation of the corresponding cycloalkene II

Effect of cyclodextrin complexation on phenylpropanoids’ solubility and antioxidant activity

• Miriana Kfoury,
• David Landy,
• Lizette Auezova,
• Hélène Greige-Gerges and
• Sophie Fourmentin

Beilstein J. Org. Chem. 2014, 10, 2322–2331, doi:10.3762/bjoc.10.241

• hydroxylation. This could explain why 1 and 2, which carry no hydroxy group, reacted little with DPPH•. The activity of 3, 4, 5, 6 and 7 was kept unchanged upon complexation with CDs. This indicated that CDs did not interfere with the active groups of these PPs during inclusion complex formation which was still

P(O)R₂-directed Pd-catalyzed C–H functionalization of biaryl derivatives to synthesize chiral phosphorous ligands

• Rong-Bin Hu,
• Hong-Li Wang,
• Hong-Yu Zhang,
• Heng Zhang,
• Yan-Na Ma and
• Shang-dong Yang

Beilstein J. Org. Chem. 2014, 10, 2071–2076, doi:10.3762/bjoc.10.215

• were produced using the non-chiral S-phos ligand. By using 2-chlorophenylboronic acid as coupling component, we demonstrated that we could obtain the phosphate compound, but it failed to yield the P(O)Ph2 group in the arylation step. In addition, in the processes of hydroxylation, arylation

• group: The reactions of alkenylation, acetoxylation, hydroxylation and acylation occurred smoothly. Even if the products were obtained in low to moderate yields, they were optically pure (Figure 1, 2c–f). For the substrate of 4-methoxy substituted binaphthyl, we could achieve the alkenylation product 2g

• alkenylation, acetoxylation and hydroxylation. The OMe group is a relatively small group, so the ee was not very high. If the substituent was OEt, the products of alkenylation and acetoxylation (Figure 1, 2m and 2n) were obtained in moderate yield and the results showed good enantioselectivities. Although the

C–H-Functionalization logic guides the synthesis of a carbacyclopamine analog

• Sebastian Rabe,
• Johann Moschner,
• Marina Bantzi,
• Philipp Heretsch and
• Athanassios Giannis

Beilstein J. Org. Chem. 2014, 10, 1564–1569, doi:10.3762/bjoc.10.161

• inexpensive dehydroepiandrosterone (5) by the means of a copper-mediated C–H hydroxylation in the 12-position and a palladium-catalyzed coupling of methyl acrylate to an activated enol ether in the 17-position. In synthetic direction (Scheme 2), dehydroepiandrosterone (5) was protected as its

An economical and safe procedure to synthesize 2-hydroxy-4-pentynoic acid: A precursor towards ‘clickable’ biodegradable polylactide

• Quanxuan Zhang,
• Hong Ren and
• Gregory L. Baker

Beilstein J. Org. Chem. 2014, 10, 1365–1371, doi:10.3762/bjoc.10.139

• hydroxylation of propargylic malonate 5 without work-up of any intermediate. Keywords: alkylation; ‘click’ chemistry; ‘clickable’ polylactide; decomposition; diethyl 2-acetamidomalonate; 2-hydroxy-4-pentynoic acid; one-pot; optimization; propargyl bromide; propargyl tosylate; safe and economical; Introduction

• hydroxylation of propargylic malonate 5 without work-up of any intermediates. Results and Discussion The synthesis of the desired precursor 1 was straightforward and outlined in Scheme 4. Propargyl alcohol, a cheap source of an acetylene moiety, was tosylated with tosyl chloride following a modified procedure

• of intermediate 6 to 1 via diazotization and hydroxylation without additional work-up or isolation of 6 [35][36][37][38][39][40]. In addition, proper choice of H2SO4 instead of HCl [41][42] for one-pot conversion of 5 to 6 could avoid the formation of the possible side product 2-chloro-4-pentynoic

Selective allylic hydroxylation of acyclic terpenoids by CYP154E1 from Thermobifida fusca YX

• Anna M. Bogazkaya,
• Clemens J. von Bühler,
• Sebastian Kriening,
• Alexandrine Busch,
• Alexander Seifert,
• Jürgen Pleiss,
• Sabine Laschat and
• Vlada B. Urlacher

Beilstein J. Org. Chem. 2014, 10, 1347–1353, doi:10.3762/bjoc.10.137

• . Regioselective oxidation of parental alkenes is a challenging task for chemical catalysts and requires several steps including protection and deprotection. Many cytochrome P450 enzymes are known to catalyse selective allylic hydroxylation under mild conditions. Here, we describe CYP154E1 from Thermobifida fusca

• -box for allylic hydroxylation in synthetic chemistry. Keywords: allylic hydroxylation; cytochrome P450; natural products; protein engineering; regiochemistry; terpenoids; Introduction Direct allylic hydroxylation yielding highly valuable allylic alcohols has been recognised for a while as one of the

• hydroxylation reactions leading to synthetically relevant intermediates [5][6][7][8][9][10][11]. In addition to chemical catalysts a range of enzymes has been studied for selective allylic hydroxylation of alkenes [12][13]. Among biosynthetic routes selective allylic hydroxylation of monoterpene olefines to

Intermediates in monensin biosynthesis: A late step in biosynthesis of the polyether ionophore monensin is crucial for the integrity of cation binding

• Wolfgang Hüttel,
• Jonathan B. Spencer and
• Peter F. Leadlay

Beilstein J. Org. Chem. 2014, 10, 361–368, doi:10.3762/bjoc.10.34

• lipophilic backbone can form strong ionophoric complexes with certain metal cations. In this work, we demonstrate for monensin biosynthesis that, as well as ether formation, a late-stage hydroxylation step is crucial for the correct formation of the sodium monensin complex. We have investigated the last two

• steps in monensin biosynthesis, namely hydroxylation catalysed by the P450 monooxygenase MonD and O-methylation catalysed by the methyl-transferase MonE. The corresponding genes were deleted in-frame in a monensin-overproducing strain of Streptomyces cinnamonensis. The mutants produced the expected

• for the key role of late-stage hydroxylation at C-26 of the monensin molecule. Like other polyether ionophores, monensin is assembled by the polyketide biosynthetic pathway on a modular polyketide synthase (PKS) multienzyme [14]. A model has been proposed [14] for monensin biosynthesis in which an

Stereoselectively fluorinated N-heterocycles: a brief survey

• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2013, 9, 2696–2708, doi:10.3762/bjoc.9.306

• atom, this time onto the indole moiety (40); this further improvement in bioavailability was attributed to blockage of the metabolic degradation of 38 and 39 which commenced with hydroxylation of the indole moiety. In the next example, we return to the world of iminosugars. Isofagomine (31, Figure 11

The chemistry of isoindole natural products

• Klaus Speck and
• Thomas Magauer

Beilstein J. Org. Chem. 2013, 9, 2048–2078, doi:10.3762/bjoc.9.243

• . Hydroxylation and sequential methylation of 143 leads to 144. Oxidative phenol coupling then forms the cularine alkaloid skeleton. The generated cularine enneaphylline (145) and the regioisomeric iso-cularine sarcocapnidine (141) could serve as branching points for the synthesis of further cularine derivatives

A practical synthesis of long-chain iso-fatty acids (iso-C₁₂–C₁₉) and related natural products

• Mark B. Richardson and
• Spencer J. Williams

Beilstein J. Org. Chem. 2013, 9, 1807–1812, doi:10.3762/bjoc.9.210

• sources [1] including the myxobacterium Stigmatella aurantiaca [21][65], and the oral bacterium Veillonella parvula [66], although the absolute configuration has not been reported. Diastereoselective hydroxylation [67] of the chelated Z-enolate derived from 28 using the Davis oxaziridine [68] afforded the

Efficient regio- and stereoselective access to novel fluorinated β-aminocyclohexanecarboxylates

• Loránd Kiss,
• Melinda Nonn,
• Reijo Sillanpää,
• Santos Fustero and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2013, 9, 1164–1169, doi:10.3762/bjoc.9.130

• derivatives with the fluorine attached to position 4 of the ring. The synthesis starts from either cis- or trans-β-aminocyclohex-4-enecarboxylic acids and involves regio- and stereoselective transformation of the ring C–C double bond through iodooxazine formation and hydroxylation, followed by hydroxy

• –fluorine or oxo–fluorine exchange. Keywords: amino acids; epoxidation; fluorination; hydroxylation; stereoselective reaction; Introduction Fluorine chemistry is an expanding area of research that has generated increasing interest in pharmaceutical and medicinal chemistry in recent years because of its

• skeleton of a β-aminocyclohexanecarboxylic acid. The synthesis starts from the Boc-protected 2-aminocyclohex-4-enecarboxylic acid or 2-aminocyclohex-3-enecarboxylic acid and involves ring C–C bond transformation by regio- and stereoselective hydroxylation via iodolactonization, followed by hydroxy–fluorine

Complete σ* intramolecular aromatic hydroxylation mechanism through O₂ activation by a Schiff base macrocyclic dicopper(I) complex

• Albert Poater and
• Miquel Solà

Beilstein J. Org. Chem. 2013, 9, 585–593, doi:10.3762/bjoc.9.63

• Grahit 101, E-17003 Girona, Spain 10.3762/bjoc.9.63 Abstract In this work we analyze the whole molecular mechanism for intramolecular aromatic hydroxylation through O2 activation by a Schiff hexaazamacrocyclic dicopper(I) complex, [CuI2(bsH2m)]2+. Assisted by DFT calculations, we unravel the reaction

• pathway for the overall intramolecular aromatic hydroxylation, i.e., from the initial O2 reaction with the dicopper(I) species to first form a CuICuII-superoxo species, the subsequent reaction with the second CuI center to form a μ-η2:η2-peroxo-CuII2 intermediate, the concerted peroxide O–O bond cleavage

• and C–O bond formation, followed finally by a proton transfer to an alpha aromatic carbon that immediately yields the product [CuII2(bsH2m-O)(μ-OH)]2+. Keywords: aromatic hydroxylation; C–H bond activation; C–H functionalization; copper; DFT calculations; mechanism; Schiff base; Introduction Bearing

A new approach toward the total synthesis of (+)-batzellaside B

• Jolanta Wierzejska,
• Shin-ichi Motogoe,
• Yuto Makino,
• Tetsuya Sengoku,
• Masaki Takahashi and
• Hidemi Yoda

Beilstein J. Org. Chem. 2012, 8, 1831–1838, doi:10.3762/bjoc.8.210

• hydroxylation conditions [39][40][41]. Using AD-mix-α and -β, we obtained mixtures of 12a-A and 12a-B in 45:55 and 13:87 ratios with overall isolated yields of 32 and 77%, respectively (Table 1, entries 1 and 2). Analogously, the asymmetric dihydroxylations of 6b and 6c produced predominantly the undesired less

Synthesis of a library of tricyclic azepinoisoindolinones

• Bettina Miller,
• Shuli Mao,
• Kara M. George Rosenker,
• Joshua G. Pierce and
• Peter Wipf

Beilstein J. Org. Chem. 2012, 8, 1091–1097, doi:10.3762/bjoc.8.120

• . When the RCM reaction of 7 was conducted on larger scale in the absence of Ti(OiPr)4, and the crude intermediate was subjected to m-CPBA oxidation, epoxy alcohol 6 was isolated in 11% overall yield. LC–MS as well as NMR analyses suggested a 5:1 ratio of epimers at the hemiacetal carbon. Hydroxylation

Recent advances towards azobenzene-based light-driven real-time information-transmitting materials

• Jaume García-Amorós and
• Dolores Velasco

Beilstein J. Org. Chem. 2012, 8, 1003–1017, doi:10.3762/bjoc.8.113

• azophenol 10 (type-II). Solvent effect on the thermal relaxation time at 298 K, τ, for the type-II ortho-substituted azophenols 14–16. Cooperative effect of the para- and ortho-hydroxyl groups in azophenol 17. Effect of the poly-hydroxylation of the azobenzene core on the thermal relaxation time at 298 K, τ

Synthesis and antifungal properties of papulacandin derivatives

• Marjolein van der Kaaden,
• Eefjan Breukink and
• Roland J. Pieters

Beilstein J. Org. Chem. 2012, 8, 732–737, doi:10.3762/bjoc.8.82

• synthesis assay) but cannot reach the target site of C. albicans [12]. The same is true for the hydrogenated form of papulacandin D [12]. Clearly some form of unsaturation is needed to maintain biological activity, but it is not known to what extent unsaturation (and alkylation and/or hydroxylation) needs

Phytoalexins of the Pyrinae: Biphenyls and dibenzofurans

• Cornelia Chizzali and
• Ludger Beerhues

Beilstein J. Org. Chem. 2012, 8, 613–620, doi:10.3762/bjoc.8.68

• of the BIS reaction, 3,5-dihydroxybiphenyl, undergoes O-methylation to give 3-hydroxy-5-methoxybiphenyl (1), as recently detected in elicitor-treated S. aucuparia cell cultures (Khalil and Beerhues, unpublished). Subsequent 4-hydroxylation and additional O-methylation yield noraucuparin (2) and

Regio- and stereoselective oxidation of unactivated C–H bonds with Rhodococcus rhodochrous

• Elaine O’Reilly,
• Suzanne J. Aitken,
• Gideon Grogan,
• Paul P. Kelly,
• Nicholas J. Turner and
• Sabine L. Flitsch

Beilstein J. Org. Chem. 2012, 8, 496–500, doi:10.3762/bjoc.8.56

• Chemistry, University of York, Heslington, York, YO10 5DD, UK, Tel: +44 (0)1904 328256 10.3762/bjoc.8.56 Abstract The ability of Rhodococcus rhodochrous (NCIMB 9703) to catalyse the regio- and stereoselective hydroxylation of a range of benzyloxy-substituted heterocycles has been investigated. Incubation

• isomers in yields of up to 26%. Most interestingly, 2-(4-nitrobenzyloxy)tetrahydrofuran and 2-(4-nitrobenzyloxy)tetrahydropyran were transformed in high yields to the 4-hydroxylated and 5-hydroxylated products, respectively. Keywords: biocatalysis; cytochrome P450; hydroxylation; Rhodococcus rhodochrous

• hydrocarbons, including n-alkanes and isoalkanes, and has been reported to catalyse the terminal hydroxylation of chloroalkanes and long-chain alkenes [13]. It has been suggested that this strain contains an alkane-inducible NADH-dependent hydroxylase that catalyses the oxidation of n-octane to 1-octanol [13

Biocatalytic hydroxylation of n-butane with in situ cofactor regeneration at low temperature and under normal pressure

• Svenja Staudt,
• Christina A. Müller,
• Jan Marienhagen,
• Christian Böing,
• Stefan Buchholz,
• Ulrich Schwaneberg and
• Harald Gröger

Beilstein J. Org. Chem. 2012, 8, 186–191, doi:10.3762/bjoc.8.20

• Aachen, Germany Evonik Oxeno GmbH, Paul-Baumann-Straße 1, 45772 Marl, Germany Evonik Degussa GmbH, Industrial Chemicals, Paul-Baumann-Straße 1, 45772 Marl, Germany Faculty of Chemistry, Bielefeld University, Universitätsstraße 25, 33615 Bielefeld, Germany 10.3762/bjoc.8.20 Abstract The hydroxylation of

• n-alkanes, which proceeds in the presence of a P450-monooxygenase advantageously at temperatures significantly below room temperature, is described. In addition, an enzymatic hydroxylation of the “liquid gas” n-butane with in situ cofactor regeneration, which does not require high-pressure

• conditions, was developed. The resulting 2-butanol was obtained as the only regioisomer, at a product concentration of 0.16 g/L. Keywords: biotransformations; cofactor regeneration; green chemistry; hydroxylation; P450-monooxygenase; Introduction The (regioselective) oxidative functionalization of

Tertiary alcohol preferred: Hydroxylation of trans-3-methyl-L-proline with proline hydroxylases

• Christian Klein and
• Wolfgang Hüttel

Beilstein J. Org. Chem. 2011, 7, 1643–1647, doi:10.3762/bjoc.7.193

• oxidation of tertiary alkyl centers is a most-straightforward but challenging approach, since these positions are sterically hindered. In contrast to P450-monooxygenases, there is little known about the potential of non-heme iron(II) oxygenases to catalyze such reactions. We have studied the hydroxylation

• approach whose potential has not yet been fully exploited is the stereospecific hydroxylation of tertiary alkyl moieties with oxygenases. Most oxidations to tertiary alcohols described so far were observed during degradation of steroids and other terpenoid bioactive compounds by microbial whole cells [10

• stereospecific hydroxylation of trans-3-methyl-L-proline to (3R)-3-hydroxy-3-methyl-L-proline with two different proline hydroxylases. In contrast to the mechanistically related and more common prolyl hydroxylases, which accept peptide bound proline as a substrate and play a key role in collagen biosynthesis

Natural product biosyntheses in cyanobacteria: A treasure trove of unique enzymes

• Jan-Christoph Kehr,
• Douglas Gatte Picchi and
• Elke Dittmann

Beilstein J. Org. Chem. 2011, 7, 1622–1635, doi:10.3762/bjoc.7.191

• responsible for uracil ring formation, although biochemical evidence is currently missing. The final hydroxylation step towards cylindrospermopsin has been shown to be catalyzed by CyrI, a 2-oxoglutarate-dependent iron oxygenase [31]. Interestingly, two epimers were described for the corresponding hydroxyl