Chiral Synthons Research Articles

Novel comprehensive multidimensional liquid chromatography approach for elucidation of the microbosphere of shikimate-producing Escherichia coli SP1.1/pKD15.071 strain.

Shikimic acid is a intermediate of aromatic amino acid biosynthesis and the preferred starting material for production of the most commonly prescribed anti-influenza drug, Tamiflu. Its six-membered carbocyclic ring is adorned with several chiral centers and various functionalities, making shikimic acid a valuable chiral synthon. When microbially-produced, in addition to shikimic acid, numerous other metabolites are exported out of the cytoplasm and accumulate in the culture medium. This extracellular matrix of metabolites is referred to as the microbosphere. Due to the high sample complexity, in this study, the microbosphere of shikimate-producing Escherichia coli SP1.1/pKD15.071 was analyzed by liquid chromatography and comprehensive two-dimensional liquid chromatography coupled to photodiode array and mass spectrometry detection. GC analysis of the trimethylsilyl derivatives was also carried out in order to support the elucidation of the selected metabolites in the microbosphere. The elucidation of the metabolic fraction of this bacterial strain might be of valid aid for improving, through genetic changes, the concentration and yield of shikimic acid synthesized from glucose. Graphical abstract.

Regioselective Epoxidations by Cytochrome P450 3A4 Using a Theobromine Chemical Auxiliary to Predictably Produce N‐Protected β‐ or γ‐Amino Epoxides

AbstractN‐Protected β‐ and γ‐amino epoxides are useful chiral synthons. We report here that the enzyme cytochrome P450 3A4 can catalyze the formation of such compounds in a regio‐ and stereoselective manner, even in the presence of multiple double bonds or aromatic substituents. To this end, the theobromine chemical auxiliary is used not only to control the selectivity of the enzyme, but also as a masked amine, and to facilitate product recovery. Theobromine predictably directed epoxidation at the double bond of the fourth carbon from the theobromine group. Unlike with most catalysts, the selectivity did not depend on electronic or steric factors but rather on the position of the olefin relative to the theobromine group.magnified image

Catalytic asymmetric synthesis of Leukotriene B4

Leukotriene B41 was prepared from two chiral synthons 8 and 14. The chiral secondary alcohols of 8 and 14 were constructed by BINOL/Ti(OiPr)4 catalyzed enantioselective alkynylzinc addition to aldehydes.

Studies on asymmetric synthesis of bicyclomycin precursors. A chemoenzymatic route to chiral 2,5-diketopiperazines and 2-oxa-bicyclo[4.2.2]decane-8,10-diones

A novel asymmetric route to bicyclomycin analogues, 2-oxa-bicyclo[4.2.2]decane-8,10-diones, is described. The key chiral synthons 3-(ω-hydroxyalkyl)-2,5-diketopiperazines 3a-c were obtained via enzymatic kinetic resolution of their respective acetates 2a-c using hydrolases (up to >98% ee, E>200). The chiral 2,5-diketopiperazines were then transformed into their bicyclic derivatives in a stereospecific manner. Circular dichroism and NMR studies were performed to determine the absolute and relative configuration of the obtained products. The biocatalytic approach gave high stereoselectivities in comparison to the chiral pool synthesis from glutamic acid (58% ee) and thus demonstrated the ability of hydrolases to discriminate a remote stereocenter.

Rational design of Kluyveromyces marxianus ZJB14056 aldo-keto reductase KmAKR to enhance diastereoselectivity and activity.

t-Butyl 6-cyano-(3R,5R)-dihydroxyhexanoate ((3R,5R)-1b) is a valuable chiral synthon of atorvastatin calcium. A novel NADPH-specific aldo-keto reductase (AKR) was identified from a thermotolerant yeast Kluyveromyces marxianus ZJB14056 by genome database mining, displaying t-butyl 6-cyano-(5R)-hydroxy-3-oxohexanoate ((5R)-1a) reducing activity and moderate diastereoselectivity (dep∼80.5%). Molecular homology modeling and docking studies demonstrated that the side chain of Trp297 blocks binding of (5R)-1a to KmAKR. The mutation of Trp297 to His led to dramatic conformational changes and significant improvement in both diastereoselectivity and activity. In comparison with KmAKR, KmAKR-W297H displayed strict diastereoselectivity, and 2.8-fold, 3.9-fold improvement in kcat and kcat/Km toward (5R)-1a, which were 10.36s-1 and 6.56s-1·mM-1 respectively. Coupling KmAKR-W297H with Exiguobacterium sibiricum glucose dehydrogenase (EsGDH) for coenzyme regeneration, 100mM (5R)-1a was completely reduced to (3R,5R)-1b within 12h, in a dep >99.5%.

Synthesis of (+)‐Patulolide C Using R‐(+)‐γ‐Valerolactone as a Chiral Synthon.

AbstractThe total synthesis of (+)‐Patulolide‐C is accomplished by using enantiopure R‐(+)‐γ‐valerolactone & R‐(+)‐epichlorohydrin as chiral synthons. The strategy adopted for the synthesis is a convergent approach wherein two advanced intermediates were synthesized independently using the chiral synthons and coupled to achieve the skeleton of Patulolide‐C. The important synthetic steps of the synthesis are two carbon homologation of the cyclic lactol, Julia olefination of enone with sulfone in DME, DIBAl‐H mediated regioselective opening of benzylidine acetal, selective oxidation of primary alcohol to aldehyde using BAIB/TEMPO and lactonization of seco‐acid adopting Yamaguchi protocol to afford the macrolide skeleton.

Catalytic allylic oxidation of internal alkenes to a multifunctional chiral building block.

The stereoselective oxidation of hydrocarbons represents one of the most significant advances in synthetic chemistry over the last fifty years1–3. Inspired by nature, chemists have developed enantioselective dihydroxylations, epoxidations, and other oxidations of unsaturated hydrocarbons. More recently, the catalytic enantioselective allylic C–H oxidation of alkenes has emerged as a powerful chemical strategy, streamlining the production of pharmaceuticals, natural products, fine chemicals and other functional materials4–7. Allylic functionalization provides a direct path to chiral synthons with a newly formed stereocenter from petrochemical feedstocks while preserving the olefin functionality as a handle for further elaboration. Various metal-based catalysts have been discovered for the enantioselective allylic C–H oxidation of simple alkenes with cyclic or terminal double bonds8–16. However, a general and selective allylic oxidation remains elusive with the more common internal alkenes. Here, we report the enantioselective, regioselective, and E/Z selective allylic oxidation of unactivated internal alkenes via a catalytic asymmetric hetero-ene reaction with a chalcogen-based oxidant. This method represents the first example of selectively converting unsymmetrical internal alkenes into allylic functionalized products with high stereoselectivity and regioselectivity. Stereospecific transformations of the multifunctional allylic oxidation products highlight the potential for rapidly converting internal alkenes into a broad range of enantioenriched structures that can be utilized in the synthesis of complex target molecules.

Asymmetric Bioreduction of β‐Acylaminonitroalkenes: Easy Access to Chiral Building Blocks with Two Vicinal Nitrogen‐Containing Functional Groups

AbstractThe reduction of (Z)‐β‐acylaminonitroalkenes catalyzed by ene‐reductases is described for the first time. The reaction occurs with a high conversion and excellent enantioselectivity and shows a wide substrate scope. The reduced products are valuable chiral synthons characterized by two vicinal nitrogen‐containing functional groups that can be further modified by functional group inter‐conversion thanks to the synthetic versatility of the nitro moiety. The chemo‐enzymatic synthesis of (R)‐N,N′‐(1‐phenylethane‐1,2‐diyl)diacetamide from easily accessible (Z)‐N‐(2‐nitro‐1‐phenylvinyl)acetamide is herein reported as a representative application of this synthetic procedure.

Asymmetric whole-cell bioreduction of sterically bulky 2-benzoylpyridine derivatives in aqueous hydrophilic ionic liquid media

The asymmetric reduction of 2-benzoylpyridine derivatives for enantiopure alcohols with excellent enantioselectivity and atom economy is still a challenging synthetic problem due to the coordination effects of 2-pyridine and substituents. In this study, we investigated an alternative cost-effective and green route for the enantioselective bioreduction of prochiral 2-benzoylpyridine derivatives employing a novel biocatalyst Cryptococcus sp. whole-cell to corresponding (S)-alcohols. This biocatalyst was more enantioselective toward the reduction of 2-benzoylpyridine derivatives with a para-substituent on the phenyl group, rather than those with an ortho- or meta-substituent. This property was quite contrary to the cases of known chemical catalysts. Moreover, Cryptococcus sp. whole-cell-catalyzed reduction of (4-chlorophenyl)-(pyridin-2-yl) methanone (CPMK) could proceed with perfect enantioselectivity in aqueous hydrophilic ionic liquid (IL) media, affording the product (S)-(4-chlorophenyl)-(pyridin-2-yl)methanol [(S)-CPMA] with excellent enantioselectivity (99% ee) and good conversion (89%), which is a crucial chiral synthon of new antiallergic drug, Betahistine. To overcome the known toxicity of hydrophilic ILs to cells, a high IL-tolerant mutant of Cryptococcus sp. (M9-3) was adopted in the reaction. The excellent tolerance of the biocatalyst to various hydrophilic ILs enabled the exploration of the positive effects of ILs on the biocatalytic efficiency and enantio-selectivity. In addition, the enzymatic hydrolyzate of bagasse was firstly used as the co-substrate during the asymmetric bioreduction of CPMK, with a higher conversion achieved (92%) than using pure glucose. This is a novel and economical route for the green synthesis of chiral diarylmethanols.

Enhancing the biocatalytic manufacture of the key intermediate of atorvastatin by focused directed evolution of halohydrin dehalogenase

Halohydrin dehalogenases (HHDHs) are biocatalytically interesting enzymes due to their ability to form C-C, C-N, C-O, and C-S bonds. One of most important application of HHDH was the protein engineering of HheC (halohydrin dehalogenase from Agrobacterium radiobacter AD1) for the industrial manufacturing of ethyl (R)-4-cyano-3-hydroxybutanoate (HN), a key chiral synthon of a cholesterol-lowering drug of atorvastatin. During our development of an alternative, more efficient and economic route for chemo-enzymatic preparation of the intermediate of atorvastatin, we found that the HheC2360 previously reported for HN manufacture, had insufficient activity for the cyanolysis production of tert-butyl (3 R,5 S)-6-cyano-3,5-dihydroxyhexanoate (A7). Herein, we present the focused directed evolution of HheC2360 with higher activity and enhanced biocatalytic performance using active site mutagenesis. Through docking of the product, A7, into the crystal structure of HheC2360, 6 residues was selected for combined active sites testing (CASTing). After library screening, the variant V84G/W86F was identified to have a 15- fold increase in activity. Time course analysis of the cyanolysis reaction catalyzed by this variant, showed 2- fold increase in space time productivity compared with HheC2360. These results demonstrate the applicability of the variant V84G/W86F as a biocatalyst for the efficient and practical production of atorvastatin intermediate.

Efficient Synthesis of an Indinavir Precursor from Biomass-Derived (–)-Levoglucosenone

Lignocellulosic biomass pyrolysis with acid catalysis selectively produces the useful chiral synthon 6,8-dioxabicyclo[3.2.1]oct-2-ene-4-one ((–)-levoglucosenone, LGO). In this report, LGO was used to prepare (3R,5S)-3-benzyl-5-(hydroxymethyl)-4,5-dihydrofuran-2(3H)-one, which is an intermediate used in the construction of antivirals including the protease inhibitor indinavir. To achieve the synthesis, the hydrogenated derivative of LGO was functionalised using aldol chemistry and various aromatic aldehydes were used to show the scope of the reaction. Choice of base affected reaction times and the best yields were obtained using 1,1,3,3-tetramethylguanidine. Hydrogenation of the α-benzylidene-substituted bicyclic system afforded a 4 : 3 equatorial/axial mixture of isomers, which was equilibrated to a 97 : 3 mixture under basic conditions. Subsequent Baeyer–Villiger reaction afforded the target lactone in 57 % overall yield for four steps, a route that avoids the protection and strong base required in the traditional approach. The aldol route is contrasted with the α-alkylation and a Baylis–Hillman approach that also both start with LGO.

Synthesis of Methyl trans-Oxazolidine-5-carboxylate, a Chiral Synthon for threo-β-Amino-α-hydroxy Acid

Synthesis of Methyl trans-Oxazolidine-5-carboxylate, a Chiral Synthon for threo-β-Amino-α-hydroxy Acid

Enantiocomplementary Synthesis of γ-Nitroketones Using Designed and Evolved Carboligases.

Artificial enzymes created by computational design and directed evolution are versatile biocatalysts whose promiscuous activities represent potentially attractive starting points for divergent evolution in the laboratory. The artificial aldolase RA95.5-8, for example, exploits amine catalysis to promote mechanistically diverse carboligations. Here we report that RA95.5-8 variants catalyze the asymmetric synthesis of γ-nitroketones via two alternative enantiocomplementary Michael-type reactions: enamine-mediated addition of acetone to nitrostyrenes, and nitroalkane addition to conjugated ketones activated as iminium ions. In addition, a cascade of three aldolase-catalyzed reactions enables one-pot assembly of γ-nitroketones from three simpler building blocks. Together, our results highlight the chemical versatility of artificial aldolases for the practical synthesis of important chiral synthons.

Efficient biosynthesis of ethyl (R)-4-chloro-3-hydroxybutyrate using a stereoselective carbonyl reductase from Burkholderia gladioli.

BackgroundEthyl (R)-4-chloro-3-hydroxybutyrate ((R)-CHBE) is a versatile chiral precursor for many pharmaceuticals. Although several biosynthesis strategies have been documented to convert ethyl 4-chloro-3-oxobutanoate (COBE) to (R)-CHBE, the catalytic efficiency and stereoselectivity are still too low to be scaled up for industrial applications. Due to the increasing demand of (R)-CHBE, it is essential to explore more robust biocatalyst capable of preparing (R)-CHBE efficiently.ResultsA stereoselective carbonyl reductase toolbox was constructed and employed into the asymmetric reduction of COBE to (R)-CHBE. A robust enzyme designed as BgADH3 from Burkholderia gladioli CCTCC M 2012379 exhibited excellent activity and enantioselectivity, and was further characterized and investigated in the asymmetric synthesis of (R)-CHBE. An economical and satisfactory enzyme-coupled cofactor recycling system was created using recombinant Escherichia coli cells co-expressing BgADH3 and glucose dehydrogenase genes to regenerate NADPH in situ. In an aqueous/octanol biphasic system, as much as 1200 mmol COBE was completely converted by using substrate fed-batch strategy to afford (R)-CHBE with 99.9 % ee at a space-time yield per gram of biomass of 4.47 mmol∙L−1∙h−1∙g DCW−1.ConclusionsThese data demonstrate the promising of BgADH3 in practical synthesis of (R)-CHBE as a valuable chiral synthon. This study allows for the further application of BgADH3 in the biosynthesis of chiral alcohols, and establishes a preparative scale process for producing (R)-CHBE with excellent enantiopurity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12896-016-0301-x) contains supplementary material, which is available to authorized users.

ChemInform Abstract: Total Synthesis of Δ12‐Prostaglandin J3: Evolution of Synthetic Strategies to a Streamlined Process.

The total synthesis of Δ(12) -prostaglandin J3 (Δ(12) -PGJ3 , 1), a reported leukemia stem cell ablator, through a number of strategies and tactics is described. The signature cross-conjugated dienone structural motif of 1 was forged by an aldol reaction/dehydration sequence from key building blocks enone 13 and aldehyde 14, whose lone stereocenters were generated by an asymmetric Tsuji-Trost reaction and an asymmetric Mukaiyama aldol reaction, respectively. During this program, a substituent-governed regioselectivity pattern for the Rh-catalyzed C-H functionalization of cyclopentenes and related olefins was discovered. The evolution of the synthesis of 1 from the original strategy to the final streamlined process proceeded through improvements in the construction of both fragments 13 and 14, exploration of the chemistry of the hitherto underutilized chiral lactone synthon 57, and a diastereoselective alkylation of a cyclopentenone intermediate. The described chemistry sets the stage for large-scale production of Δ(12) -PGJ3 and designed analogues for further biological and pharmacological studies.

Asymmetric Total Synthesis of (–)‐Azaspirene by Utilizing Ti‐Claisen Condensation and Ti‐Direct Aldol Reaction

A successful asymmetric total synthesis of (–)‐azaspirene has been accomplished by utilizing (3R)‐6‐cinnamyl‐3‐methyl‐3‐phenyl‐1,4‐dioxane‐2,5‐dione, a readily accessible chiral template. The present method involves two distinctive TiCl4/amine‐mediated reactions: (i) an asymmetric Ti‐crossed‐Claisen condensation of the chiral template with propanoyl chloride followed by methanolysis to afford methyl (2R)‐(4E)‐2‐hydroxy‐5‐phenyl‐2‐propanoylpent‐4‐enoate, the key chiral synthon and (ii) a robust Ti‐direct aldol addition reaction, instead of the reported lithium diisopropylamide/hexamethylphosphorictriamide (LDA/HMPA) or potassium hexamethyldisilazide (KHMDS)‐mediated reaction, by using the trimethylsilyl (TMS) ether of α‐acyl‐γ‐lactam to successfully furnish the new aldol adduct. Final oxidation, cyclization, and tert‐butyldimethylsilyl (TBS) removal produced (–)‐azaspirene from the key template in 23 steps (total yield 1.7 %).

ChemInform Abstract: A Decade of Advance in the Asymmetric Vinylogous Mannich Reaction

AbstractReview: [70 refs.

ChemInform Abstract: Diastereoselective Radical Hydroacylation of Alkylidenemalonates with Aliphatic Aldehydes Initiated by Photolysis of Hypervalent Iodine(III) Reagents.

AbstractThe mild, metal‐free reaction delivers chiral ketones in a highly diastereoselective manner.

Diastereoselective B(C6F5)3-Catalyzed Reductive Carbocyclization of Unsaturated Carbohydrates.

A B(C6F5)3-catalyzed method for the selective conversion of unsaturated carbohydrates to cyclopentanes and cyclopropanes is disclosed. Catalyst activation of tertiary silanes generates the ion pair [(C6F5)3B-H][ROSi2] whose components synergistically activate C-O bonds for diastereoselective C-C bond formation. Sila-THF cations are invoked as key intermediates facilitating carbocyclizations. Complex chiral synthons are thereby obtained in a single pot.

ChemInform Abstract: Synthetic Applications of Carbohydrate‐Derived Donor—Acceptor Cyclopropanes

AbstractReview: [24 refs.