Chemical and Biochemical Approaches for the Synthesis of

Article pubs.acs.org/joc

Cite This: J. Org. Chem. 2019, 84, 6982−6991

Chemical and Biochemical Approaches for the Synthesis of Substituted Dihydroxybutanones and Di- and TriHydroxypentanones Derar Al-Smadi,†,§ Thilak Reddy Enugala,† Vadim Kessler,‡ Anil Ranu Mhashal,† Shina Caroline Lynn Kamerlin,† Jan Kihlberg,† Thomas Norberg,† and Mikael Widersten*,† †

Department of ChemistryBMC, Uppsala University, Box 576, SE-751 23 Uppsala, Sweden Department of Molecular Sciences, Swedish University of Agricultural Sciences, Box 7015, SE-750 07 Uppsala, Sweden

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‡

S Supporting Information *

ABSTRACT: Polyhydroxylated compounds are building blocks for the synthesis of carbohydrates and other natural products. Their synthesis is mainly achieved by different synthetic versions of aldol-coupling reactions, catalyzed either by organocatalysts, enzymes, or metal−organic catalysts. We have investigated the formation of 1,4-substituted 2,3-dihydroxybutan-1-one derivatives from para- and meta-substituted phenylacetaldehydes by three distinctly different strategies. The first involved a direct aldol reaction with hydroxyacetone, dihydroxyacetone, or 2-hydroxyacetophenone, catalyzed by the cinchona derivative cinchonine. The second was reductive cross-coupling with methyl- or phenylglyoxal promoted by SmI2, resulting in either 5substituted 3,4-dihydroxypentan-2-ones or 1,4 bis-phenyl-substituted butanones, respectively. Finally, in the third case, aldolase catalysis was employed for synthesis of the corresponding 1,3,4-trihydroxylated pentan-2-one derivatives. The organocatalytic route with cinchonine generated distereomerically enriched syn-products (de = 60−99%), with moderate enantiomeric excesses (ee = 43−56%) but did not produce aldols with either hydroxyacetone or dihydroxyacetone as donor ketones. The SmI2promoted reductive cross-coupling generated product mixtures with diastereomeric and enantiomeric ratios close to unity. This route allowed for the production of both 1-methyl- and 1-phenyl-substituted 2,3-dihydroxybutanones at yields between 40− 60%. Finally, the biocatalytic approach resulted in enantiopure syn-(3R,4S) 1,3,4-trihydroxypentan-2-ones.

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catalyzed by an aldolase-mimicking catalytic antibody8 and with L-Pro.9 Here, we present a comparison of three different approaches for the synthesis of novel 1,4-substituted 2,3-dihydroxybutanones, 3,4-dihydroxypentan-2-ones, and 1,3,4-trihydroxypentanones from ring-substituted phenylacetaldehydes. We evaluated (a), the direct aldol reaction with α-hydroxyketones in the presence of the cinchona derivative cinchonine4h,10 as the catalyst or (b), by reductive cross-coupling of glyoxals promoted by samarium diiodide,11 or (c), by aldolase catalysis employing an in vitro-evolved enzyme variant12 (Scheme 1). We report on the relative reactivities observed in the two different synthetic approaches and the stereochemical out-

INTRODUCTION

Aldol reactions are fundamental to synthetic organic chemistry by providing a route for the facile formation of a carbon− carbon bond between two stereogenic centers.1,2 This versatile reaction is utilized in a multitude of synthetic strategies where compounds with hydroxylated skeletons are desired.3 Polyhydroxylated aldols are of special interest for the synthesis of compounds with biological activities and can be formed in aldol reactions of α-hydroxylated ketones and aldehydes4 or by cross aldol reactions.5 The use of enzymes for this transformation has proven extremely valuable, as exemplified by the efficient synthesis of a number of carbohydrate derivatives.6 Efficient and stereoselective aldol synthesis from α-unsubstituted aldehydes, such as, for example, phenylacetaldehyde, is a persisting challenge. This may, however, be achieved with aldolase biocatalysts7 and has also been demonstrated to be © 2019 American Chemical Society

Received: March 15, 2019 Published: May 8, 2019 6982

DOI: 10.1021/acs.joc.9b00742 J. Org. Chem. 2019, 84, 6982−6991

Article

The Journal of Organic Chemistry

Cinchonine-Catalyzed Aldol Reactions. Building on the successful use of cinchona derivatives for activating phenylsubstituted 2-hydroxyketones, as reported by Mlynarski and co-workers,4h we investigated the cinchonine-catalyzed aldol addition of unprotected 2-hydroxyketones 2a−c to aldehydes 1b−f (Table 1). A two-fold excess of the ketones was used because of their commercial availability and low cost, as opposed to aldehydes 1b−f that require preparation in two steps.13 The direct aldol reactions were successful with the phenylsubstituted ketone 2c as the donor but gave poor yields when using 2a or 2b. Thus, reaction of 2-hydroxyacetophenone (2c) with 1b−f, in the presence of 20−30 mol % of cinchonine in CHCl3 at room temperature, produced 1-phenyl-substituted aldols 5−9 in moderate yields (40−44%) and with moderate to excellent diastereomeric excess of the syn-isomers (de = 60−99%). The enantiomeric ratios of the syn-enantiomers ranged between 3.5 and 2.7:1, with the most stereoselective reaction being between para-methoxyphenylacetaldehyde (1b) and 2c. The assignment of diastereomer configurations is described in a separate section below. Samarium Diiodide-Promoted Reductive Cross-Couplings. Previous reports on the synthesis of diols 4 and 1011b by samarium diiodide-promoted coupling of glyoxals 3a and 3b to phenylacetaldehyde led us to compare this approach with the organocatalytic route with cinchonine. Two equivalents of either methyl or phenylglyoxal (3a and 3b) reacted with aldehydes 1a−f in the presence of 0.1 M SmI2 in THF at room temperature. The reactions of phenylglyoxal were faster and gave higher total yields than those of methylglyoxal (3a, Table 1). The substantial reductive power of SmI2 in THF and a reduction potential of −1.3 V15 renders this promoter highly reactive which can explain the relatively shorter reaction times, as compared to the cinchonine organocatalyst. The products (4−15) were mixtures of the anti- and syn-diastereomers, at ratios close to unity. Hence, the use of SmI2 widens the product scope to also provide the substituted 5-phenyl-3,4dihydroxypentan-2-ones 11−15. In terms of synthetic efficiency, the SmI2-promoted production of these aldols is also more efficient as compared to the cinchonine approach, simply due to the faster reaction kinetics. A rough estimate from isolated yields and incubation times suggests that for a given reaction period, the SmI2 method will produce 30−60fold more aldol. Even though no enrichment of product stereoisomers is observed, the diastereomers could be readily separated on reversed phase high-performance liquid chromatography (HPLC) systems. The respective racemic mixtures of enantiomers were also, in most cases, separable by chiral chromatography without prior derivatization (Figure S1). Aldolase-Catalyzed Aldol Reactions. The biocatalyzed reactions by the R134V/S166G (“VG”) variant of Escherichia coli fructose 6-phosphate aldolase (FSA) increased the product scope further, beyond that of the chemical approaches, to also provide routes to the corresponding 1,3,4-trihydroxylated pentanones 16−21. In all cases, only one stereoisomer was obtained, the syn-(3R,4S) enantiomer, as judged by the similarity with previously reported NMR and specific optical rotation data for 166c and order of elution in chiral chromatography (Figure S1). The yields ranged between (10−37%), albeit no attempts to optimize reaction or purification conditions were made here. Stereoconfigurations. Structure determination by X-ray crystallography following crystallization of the racemic mixture

Scheme 1. Synthesis of 1,4-Substituted 2,3Dihydroxybutanones Using Either an Aldol Reaction Catalyzed by Cinchonine (a) or Reductive Cross-Coupling (b) or (c) by Aldolase-Catalyzed Aldol Reaction

comes in the formation of the products. X-ray crystallography in combination with molecular dynamics simulations further allowed for linking experimental NMR JHH coupling constants to diastereomeric configurations.

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RESULTS AND DISCUSSION Synthesis Rationale. Our main goal was to evaluate routes to obtain the disubstituted diols 4−21 (Scheme 1 and Figure 1). The purpose was two-fold: (i) to identify facile access to all

Figure 1. Reactants and aldol products discussed in this work.

of the four possible stereoisomers of these aldols and (ii) to test the usefulness of a biocatalytic route to produce enantioand diastereomerically pure aldol derivatives. Although the possibility to synthesize enantiopure compounds can be regarded as highly advantageous, it may also be a limitation because the other three stereoisomers are not readily accessible. Thus, in this work, we have compared two synthetic approaches with a biocatalytic route for production of these substituted 2,3-dihydroxybutanones and 3,4-dihydroxypentanones. The acceptor aldehydes represent a structural series of paraand meta-substituted phenylacetaldehydes (1a−f, Figure 1)13 containing both electron-withdrawing as well as electrondonating substituents. In the direct aldol reaction, hydroxyacetone (2a), dihydroxyacetone (2b), and 2-hydroxyacetophenone (2c) were tested as donor reactants. In the SmI2afforded reductive coupling, methyl- (3a) and phenylglyoxals (3b) were allowed to react with aldehydes 1a−f. An R134V/ S166G variant of fructose 6-phosphate aldolase (FSA)12,14 was employed to catalyze aldol reactions of 1b−f and dihydroxyacetone (2b). 6983


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The Journal of Organic Chemistry Table 1. Synthesized Diols, Total and Isomeric Yields

synthesis approacha

compound

fraction antib (%)c

anti-enantiomer ratiod (%)

fraction synb (%)c

syn-enantiomer ratiod (%)

yielde (%/mg)

refs

R1 = H, R2 = Ph

4

SmI2

51

50:50

49

50:50

n.d.g

R1 = 4-OMe, R2 = Ph

5 6

R1 = 3-Cl, R2 = Ph

7

R1 = 4-F, R2 = Ph

8

R1 = 3-F, R2 = Ph

9

52 99 53 95 56 80 54 98

R1 = H, R2 = Me

10

SmI2 Cinchonine SmI2 Cinchonine SmI2 Cinchonine SmI2 Cinchonine SmI2 Cinchonine FSA (wt)f SmI2

40

50:50

60

50:50 78:22 50:50 75:25 48:52 75:25 50:50 75:25 48:52 73:27 (3R,4S) 50:50

60/124 46/131 54/158 47/137 56/163 55/160 43/119 41/113 49/203 40/108 48 n.d.

99 59 49 54 52 52

99

>98:99 (3R,4S) >96:99 (3R,4S)

37/18

this work

19

FSA (VG)

99

>99 (3R,4S)

24/12

this work

20 21

FSA (VG) FSA (VG)

99

>99 (3R,4S) >99 (3R,4S)

10/5 13/6

this work this work

R1 = 4-OMe, R2 = Me R1 R1 R1 R1 R1

= = = = =

4-Cl, R2 = Me 3-Cl, R2 = Me 4-F, R2 = Me 3-F, R2 = Me H, R2 = CH2OH

R1 = 4-OMe, R2 = CH2OH R1 = 4-Cl, R2 = CH2OH R1 = 3-Cl, R2 = CH2OH R1 = 4-F, R2 = CH2OH R1 = 3-F, R2 = CH2OH

11 12 13 14 15 16

50:50

11b, this work this work this work this work this work this work this work this work this work this work this work 6c 11b, this work 12 this work this work this work this work this work 6c this work 12

a SmI2 refers to synthesis using samarium diiodide and cinchonine to the use of the organocatalyst. bFor compounds 4−21, the different diastereomer pools were separated by reversed phase HPLC, where the first eluted pool corresponded to the anti-diastereomer and the second eluted pool to the syn-diastereomer, respectively. cDetermined from the area under peak after reversed phase HPLC on a C-8 column. d Determined from the area under peak after chiral HPLC on a CHIRALPAK AS-H column (Figure S1). ePurification procedures were not optimized. fAldolase catalysis using fructose 6-phosphate aldolase, FSA.6c gn.d., not determined. hAldolase catalysis using an R134V/S166G (“VG”) mutant of FSA.12

of the first eluted aldol 5 product pool, after reversed phase HPLC, produced by the samarium diiodide approach, resulted in a structure of the (2R,3R) enantiomer (anti-configuration, Figure 2a). Assuming “zig-zag”-staggered lowest energy conformations for CD3OD solutions of anti-5 and syn-5 implies H2−C2−C3−H3 dihedral angles such that the H2− H3 coupling constants are approximately 5−7 Hz for the antidiastereomer and 1−3 Hz for the syn-diastereomer. In line with this assumption, the 1H NMR spectrum of (2R,3R)-5 showed a H2−H3 coupling constant of 5.5 Hz. In comparison, the second eluted aldol 5 product pool, the assumed syndiastereomer, (from the first eluted aldol 5 pool) showed a H2−H3 coupling constant of 1.6 Hz. Furthermore, the antiand syn-fractions of all synthesized compounds (4−21) exhibited very similar coupling constants for these two protons, suggesting that the same arguments regarding diastereomeric configuration can be made also for compounds 4−21 (Table S2). The crystal structures of the 4′-chloro derivatives (2R,3R)-6 and (3S,4R)-12 were also determined (Figure 2b,c). The proton NMR data of the corresponding anti-6 and

syn-12 elution pools and the absolute configuration of the crystallized enantiomers support the previous argument with JHH coupling constants of 5.8 for anti-6 and 2.0 for syn-12, suggesting anti- and syn-diastereomeric configurations, respectively. Aldol (2R,3R)-5 crystallized in a non-centrosymmetric chiral space group (P21) which allowed for assignment of absolute configuration to the different elution pools of anti-5 after chiral chromatography of the redissolved crystal (Figure 3). Both (2R,3R)-6 and (3S,4R)-12 crystallized in centrosymmetric space groups precluding the assignment of absolute configurations of the HPLC-separated enantiomers by the same approach. The mechanistic reasons for the stereoselectivities of the organocatalyst and the enzyme are of special interest. The pinacol coupling of aldehydes in the presence of SmI2 is a twoelectron reduction of the aldehyde moieties of the reactants.11d Although diastereoselectivity in similar reactions have been reported where neighboring substituents together with electronic effects have been proposed to be the reasons for observed stereoselectivity,16 we did not observe any diastereo6984


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the glyoxals and the phenylacetaldehydes may react at either face of the carbonyl moiety. The cinchonine catalyst has been proposed to act via stabilization of the nucleophilic enediolate intermediate in the Z configuration through hydrogen bonding interactions with the protonated tertiary amine of cinchonine.4h The asymmetric environment and sterical constrains imposed by cinchonine then favor addition of the enediolate to the Si face of the aldehyde, which in combination with the enediolate being bound in the Z configuration, result in the observed selectivity for the syn-diastereomer product.4h The diastereomeric outcome of the products in the tested panel of aldehydes agrees very well with this mechanism. Phenylacetaldehydes 1b−1d and 1f, which have para-methoxy, para-chloro, metachloro, and meta-fluoro substituents all gave syn-/anti-ratios ≥95:5. A somewhat lower selectivity was obtained in the reaction of para-fluorophenylacetaldehyde (1e), which gave a syn-/anti-ratio of 80:20. The higher reactivity of the electrondeficient para-fluorophenylacetaldehyde (1e) may be the reason for the reduction in diastereomer selectivity, presumably by allowing a lower degree of complementarity for 1e in its interactions with the organocatalyst. The chemical mechanism of the enzyme catalyst, a class I aldolase, is distinct from this organocatalyst in that an enzymelinked enamine, originating from an active-site lysine residue, is the nucleophilic species. The active-site structure favor addition to the bound aldehyde to the Si face of the acceptor aldehyde which also agrees with the very high selectivity of formation of the syn-diastereomer product. Catalytic residues in the active site further contributes to stereoselectivity through hydrogen bonding and protonation of the alcoholate formed during formation of the C3−C4 bond, following attack of the enamine onto the Si face of bound aldehyde.18 The particular aldolase variant is applied here, and an R134V/ S166G mutant provides an engineered active site to better accommodate nonpolar and bulky acceptor aldehydes.12 As in the cinchonine case, in order to selectively form the syndiastereomers, a Z configuration of the enamine intermediate is required.19 Computational Modeling of the Aldol Structure and Dynamics. The H2−C2−C3−H3 dihedral angles of compound 5 were computed in order to build the relationship between the gauche-anti-conformations of the hydrogens bound to the chiral centers. The distributions of the dihedral angles are plotted in Figure 4a. The anti-diastereomer, the (2R,3R) and (2S,3S) enantiomers, showed a clear preference for the H2−H3 anti-conformation, whereas the syn-diastereomers, (the (2R,3S) and (2S,3R) enantiomers), exhibited approximately equal preference for the gauche and anticonformations of the same hydrogens. The modeled structures are presented in Figure S2. As a comment, the torsion angles between the planes of either the hydroxyls or the hydrogens bound to the asymmetric carbons are very similar when comparing the crystal structure of (2R,3R)-5 and the corresponding MD simulated structure (Figure S2). As mentioned, the coupling constants determined for aldol 5 display values of 5.5 and 1.6 Hz for anti-5 and syn-5, respectively. Upon translating the average dihedral angles computed from the simulation to the NMR proton coupling constants using the Karplus equation,20 we obtained coupling constants of 9.1 and 1.3 Hz for the anti- and syn-diastereomers of 5, respectively. While we overestimate the coupling constant for the anti-configuration of 5, overall, these numbers fit well

Figure 2. Molecular structures of (a) (2R,3R)-5, (b) (2R,3R)-6, and (c) (3S,4R)-12.

Figure 3. Assignment of the stereoconfiguration of the antidiastereomers of aldol 5 by combining crystal structure determination and chiral chromatography. The single crystal of (2R,3R)-5 was redissolved in isopropanol and analyzed on a CHIRALPAK AS-H column. The peak that elutes first from the sample of the redissolved crystal is enriched (71%, solid line) as compared to the racemic material that was used for crystallization (50%, dotted line), thus assigning this component as the crystallized enantiomer.

or enantioselective enrichment in the diol products between glyoxals 2a or 2c with aldehydes 1a−f. The proposed structure of SmI2 in THF describes a seven-coordinate pentagonal bipyramid with a planar equatorial ring of five tetrahydrofuranes coordinated to the central samarium ion with the iodines occupying the axial positions.17 The suggested symmetry of SmI2(THF)5 is in line with the absence of diastereomeric enrichment in the products synthesized in our work because the reacting aldehydes do not contain substituents that could otherwise steer the interactions with the SmI2 mediator; both 6985


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the product scope of the synthetic approaches. Because, as demonstrated here and by others,6b−g,i,12 the enzyme also accepts dihydroxyacetone as a ketone donor in the direct aldol reaction, it opens up avenues for the syntheses of the corresponding trihydroxylated butanones from the same class of aldehydes. To conclude, the applied combination of synthetic strategies described here allows for synthesis of a range of polyhydroxylated butanones of different stereoconfigurations. The samarium diiodide approach is the least stereoselective but, on the other hand, provides access to all stereoisomers, whereas the biocatalytic route produces enantiopure (3R,4S) syn-trihydroxylated products under reaction conditions that are “greener” than either of the other studied strategies.

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EXPERIMENTAL SECTION

General Methods. Concentrations were performed at reduced pressure (bath temperature < 40 °C). Phenylacetaldehydes 1a−1f were prepared as described.13 Other reagents and solvents were used as purchased without further purification unless otherwise stated. Thin-layer chromatography (TLC) was performed on silica gel F254 plates (Merck, Darmstadt, Germany) with detection by UV light. Preparative reversed phase HPLC was performed on a Kromasil C8 column (250 × 21.2 mm Ø, 5 μm) using a Gilson HPLC equipped with a Gilson 322 pump, UV/visible-156 detector, and 202 collector. Acetonitrile−water gradients were used as eluants with a flow rate of 15 mL/min and detection at 214 or 254 nm. Chiral HPLC was performed using a CHIRALPAK AS-H column (250 × 4.6 mm Ø) with isocratic mixtures of varying ratios of nhexane/isopropanol (Table S1) as the mobile phase. The system used an LC 20AD solvent delivery module, a Shimadzu SIL-10AF autosampler, and a Shimadzu SPDM20A photometric unit with a 0.6 mL/min flow rate and 50 min analysis time for each sample (Figure S1). X-ray Crystallography. Single-crystal X-ray diffraction data were recorded at room temperature with a Bruker D8 SMART APEX II CCD diffractometer (operating with graphite monochromated Mo Kα radiation, λ = 0.71073 Å). The structures were solved by direct methods. Coordinates of all nonhydrogen atoms were obtained from the initial solution and refined first in isotropic and then anisotropic approximation. Coordinates of hydrogen atoms connected to carbon atoms were calculated geometrically, while those attached to oxygen atoms were located in difference Fourier syntheses. All hydrogen atoms were included into the final refinement in isotropic approximation. Full details of solution and refinement can be obtained free-of-charge from the Cambridge Crystallographic Data Center at www.ccdc.cam.ac.uk citing the deposition number 1870819 for (2R,3R)-5, 1871813 for (2R,3R)-6, and 1900467 for (3S,4R)-12. 1 H and 13C NMR spectra were recorded for CD3OD solutions at 298 K with an Agilent NMR spectrometer utilizing a superconducting magnet and a radiofrequency of 400 MHz (1H NMR) or 100 MHz (13C NMR). Chemical shifts are given in ppm referenced to the middle CHD2OD peak = 3.31 ppm (1H NMR) or to the middle CD3OD peak = 49.00 (13C NMR). 1H−1H and 13C−F coupling constants (J) are given in Hz. Proton signal assignments were based on H−H COSY 2D-spectra. Carbon spectra were recorded with complete 1H decoupling. Spectra are shown in Figure S3. High-resolution mass spectra were obtained using Waters LCT Premier operating in ES+ or ES− mode. Conditions for ES+ mode: capillary voltage: 2 kV, sample cone voltage: 30 V, desolvation temperature: 350 °C, source temperature: 120 °C, cone gas flow (nitrogen): 10 L/h, desolvation gas flow (nitrogen): 400 L/h, MCP voltage: 2.1 kV. Conditions for ES− mode: capillary voltage: 2.5 kV, sample cone voltage: 150 V, desolvation temperature: 350 °C, source temperature: 120 °C, cone gas flow (nitrogen): 10 L/h, desolvation gas flow (nitrogen): 400 L/h, MCP voltage: 2.1 kV. For accurate mass: samples were referenced against leucine enkephalin or sulfadimethoxine.

Figure 4. Calculated distributions of the (a) H2−C2−C3−H3 dihedral angle, (b) the distance between the hydrogens on the hydroxylated carbon atoms, and (c) the corresponding distance between hydroxyl oxygens, during molecular dynamics simulations of different enantiomers of aldol 5. The (2R,3R)-5, (2R,3S)-5, (2S,3R)5, and (2S,3S)-5 enantiomers are shown in black, red, green, and blue, respectively.

with previous experimental findings.21 Furthermore, the hydrogen−hydrogen distance distribution (Figure 4b) correlates well with the dihedral angle data, that is, we note shorter distances for the (2R,3S) and (2S,3R) enantiomer conformations predicted to favor H-gauche-conformations and greater distances for enantiomers predicted to favor H-anti-conformations. We also examined the distance distribution between two hydroxyl oxygens to explore the possibility of intramolecular hydrogen bonding between these atoms (Figure 4c). These distance distribution plots indicate the possibility of hydrogen bond formation between the hydroxyl groups for the syndiastereomers. However, in the (2R,3R) and (2S,3S) enantiomers (anti-diastereomers), the distance distribution plots show the hydroxyl groups at greater distances apart (∼3.7 Å), suggesting that they are positioned too far away from each other, thus preventing formation of an intramolecular hydrogen bond, as would be expected from anti-conformations.

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CONCLUSIONS We have assessed three distinctly different routes for aldol reactions that provide 1,4-disubstituted 2,3-dihydroxybutanones. In this process, we generated 15 new vicinal diols that were formed to varying degrees in both diastereomeric forms. The use of cinchonine catalysis allowed for the synthesis of diasteromerically relatively pure syn-products that are also enantiomerically enriched, although to moderate degrees (ee = 40−60%). However, among the three hydroxyketones used as donors, only 2-hydroxyacetophenone gave aldol products in moderate yields. The SmI2-promoted reaction of aldehydes and methyl- or phenylglyoxal-generated product mixtures for both glyoxals but without any stereochemical enrichment. Thus, this approach provides facile access to both the syn- and anti-diasteromers of these 2,3-dihydroxybutanones. We have recently demonstrated the successful synthesis of a limited series of aldols sharing the same skeleton structure as 4, using the engineered variant of fructose 6-phosphate aldolase also employed here together with an R134M/S166A variant.12 Employing aldolase catalysis can complement and expand on 6986


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Properties of Synthesized Compounds (for Yields, See Table 1). 2,3-Dihydroxy-4-phenyl-1-phenylbutan-1-one (AntiIsomer, 4).11b,29 H NMR: δ 2.704 (dd, J = 9.1, 14.0, 1H, H-4a), 2.897 (dd, J = 3.2, 14.0, 1H, H-4b), 4.103 (ddd, J = 3.2, 5.6, 9.1, 1H, H-3), 5.055 (d, J = 5.6, 1H, H-2), 7.136 (m, 2H, ArH), 7.196 (m, 2H, ArH), 7.473 (m, 2H, ArH), 7.608 (m, 2H, ArH), 7.958 (m, 2H, ArH); 13C{1H} NMR: δ 39.6, 75.5, 77.6, 127.1, 129.1, 129.6, 129.7, 130.6, 134.6, 137.4, 140.1, 202.5. It is obtained as a colorless amorphous solid. 2,3-Dihydroxy-4-phenyl-1-phenylbutan-1-one (Syn-Isomer, 4).11b,29 1H NMR: δ 2.917 (dd, J = 6.9, 13.2, 1H, H-4a), 3.053 (dd, J = 7.7, 13.2, 1H, H-4b), 4.112 (m, 1H, H-3), 4.944 (d, J = 1.6, 1H, H-2), 7.310 (m, 2H, ArH), 7.434 (m, 2H, ArH), 7.584 (m, 2H, ArH), 7.689 (m, 2H, ArH), 8.025 (m, 2H, ArH); 13C{1H} NMR: δ 41.4, 75.7, 76.4, 127.5, 129.4, 129.6, 129.8, 130.6, 134.6, 135.9, 139.8, 201.8. It is obtained as a colorless amorphous solid. 2,3-Dihydroxy-4-(4′-methoxyphenyl)-1-phenylbutan-1-one (Anti-Isomer, 5). 1H NMR: δ 2.643 (dd, J = 8.7, 14.1, 1H, H-4a), 2.835 (dd, J = 3.6, 14.1, 1H, H-4b), 3.736 (s, 3H, OCH3), 4.060 (ddd, J = 3.6, 5.5, 8.7, 1H, H-3), 5.025 (d, J = 5.5, 1H, H-2), 6.756 (m, 2H, ArH), 7.027 (m, 2H, ArH), 7.485 (m, 2H, ArH), 7.608 (m, 1H, ArH), 7.931 (m, 2H, ArH); 13C{1H} NMR: δ 38.6, 55.6, 75.7, 77.5, 114.6, 129.67, 129.70, 131.5, 131.8, 134.5, 137.4, 159.6, 202.5. HRMS m/z: calcd for [M + HCO2−] C18H19O6, 331.1182; found, 331.1174. It is obtained as colorless crystals (from methanol), mp 104−106 °C. 2,3-Dihydroxy-4-(4′-methoxyphenyl)-1-phenylbutan-1-one (Syn-Isomer, 5). 1H NMR: δ 2.845 (dd, J = 6.7, 13.4, 1H, H-4a), 2.985 (dd, J = 7.8, 13.4, 1H, H-4b), 3.790 (s, 3H, OCH3), 4.069 (ddd, 1.6, 6.7, 7.8, 1H, H-3), 4.936 (d, J = 1.6, 1H, H-2), 6.900 (m, 2H, ArH), 7.219 (m, 2H, ArH), 7.441 (m, 2H, ArH), 7.590 (m, 1H, ArH), 7.699 (m, 2H, ArH); 13C{1H} NMR: δ 40.5, 55.7, 75.5, 75.6, 115.0, 129.4, 129.8, 131.560, 131.561, 134.6, 136.0, 159.9, 201.9. HRMS m/z: calcd for [M + HCO2−] C18H19O6, 331.1182; found, 331.1174. It is obtained as a colorless amorphous solid. 2,3-Dihydroxy-4-(4′-chlorophenyl)-1-phenylbutan-1-one (AntiIsomer, 6). 1H NMR: δ 2.698 (dd, J = 9.0, 14.1, 1H, H-4a), 2.894 (dd, J = 3.3, 14.1, 1H, H-4b), 4.063 (ddd, J = 3.3, 5.8, 9.0, 1H, H-3), 5.017 (d, J = 5.8, 1H, H-2), 7.123 (m, 2H, ArH), 7.203 (m, 2H, ArH), 7.498 (m, 2H, ArH), 7.618 (m, 1H, ArH), 7.959 (m, 2H, ArH); 13 C{1H} NMR: δ 38.9, 75.2, 77.4, 129.1, 129.70, 129.75, 132.2, 133.0, 134.6, 137.4, 138.9, 202.4. HRMS m/z: calcd for [M + HCO2−] C17H16O5Cl, 335.0686; found, 335.0680. It is obtained as colorless crystals (from methanol), mp 123−126 °C. 2,3-Dihydroxy-4-(4′-chlorophenyl)-1-phenylbutan-1-one (SynIsomer, 6). 1H NMR: δ 2.895 (dd, J = 7.6, 13.4, 1H, H-4a), 3.036 (dd, J = 6.7, 13.4, 1H, H-4b), 4.099 (ddd, 1.7, 6.7, 7.6, 1H, H-3), 4.965 (d, J = 1.7, 1H, H-2), 7.277 (m, 4H, ArH), 7.472 (m, 2H, ArH), 7.608 (m, 1H, ArH), 7.785 (m, 2H, ArH); 13C{1H} NMR: δ 40.6, 75.0, 76.2, 129.51, 129.53, 129.8, 132.2, 133.3, 134.6, 136.1, 138.8, 201.7. HRMS m/z: calcd for [M + HCO2−] C17H16O5Cl, 335.0686; found, 335.0689. It is obtained as colorless crystals. 2,3-Dihydroxy-4-(3′-chlorophenyl)-1-phenylbutan-1-one (AntiIsomer, 7). 1H NMR: δ 2.704 (dd, J = 9.1, 14.0, 1H, H-4a), 2.909 (dd, J = 3.2, 14.0, 1H, H-4b), 4.072 (ddd, J = 3.2, 5.8, 9.1, 1H, H-3), 5.019 (d, J = 5.8, 1H, H-2), 7.069 (m, 1H, ArH), 7.180 (m, 3H, ArH), 7.505 (m, 2H, ArH), 7.607 (m, 1H, ArH), 7.967 (m, 2H, ArH): 13 C{1H} NMR: δ 39.3, 75.1, 77.4, 127.2, 129.0, 129.7, 129.8, 130.60, 130.65, 134.6, 134.9, 137.4, 142.6, 202.4. HRMS m/z: calcd for [M + HCO2−] C17H16O5Cl, 335.0686; found, 335.0684. It is obtained as a colorless amorphous solid. 2,3-Dihydroxy-4-(3′-chlorophenyl)-1-phenylbutan-1-one (SynIsomer, 7). 1H NMR: δ 2.910 (dd, J = 7.7, 13.4, 1H, H-4a), 3.038 (dd, J = 6.5, 13.4, 1H, H-4b), 4.115 (ddd, 1.8, 6.5, 7.7, 1H, H-3), 4.969 (d, J = 1.8, 1H, H-2), 7.241 (m, 2H, ArH), 7.295 (m, 1H, ArH), 7.333 (m, 1H, ArH), 7.478 (m, 2H, ArH), 7.612 (m, 1H, ArH), 7.798 (m, 2H, ArH); 13C{1H} NMR: δ 40.9, 75.0, 76.2, 127.6, 129.0, 129.5, 129.8, 130.6, 131.0, 134.6, 135.2, 136.0, 142.4, 201.7. HRMS m/z: calcd for [M + HCO2−] C17H16O5Cl, 335.0686; found, 335.0688. It is obtained as a colorless amorphous solid. 2,3-Dihydroxy-4-(4′-fluorophenyl)-1-phenylbutan-1-one (AntiIsomer, 8). 1H NMR: δ 2.696 (dd, J = 9.0, 14.1, 1H, H-4a), 2.889

Melting points were determined with a Stuart Scientific 2MP3 capillary-type melting point apparatus and are corrected. Molecular Simulations. Molecular dynamics simulations were employed to study the dynamical nature of the syn- or anticonformational presence of aldol 5 as a function of simulation time. The crystal structure of the (2R,3R) enantiomer of 1-methyl-2,3dihydroxybutanone (compound 5) was used to construct the other enantiomers of this compound, that is, (2R,3S), (2S,3R), and (2S,3S). The force-field parameters for these ligands were obtained from the CGenFF server,22 as the force field parameters obtained from this server have been found to be capable of reproducing physicochemical properties for a wide range of molecules.23 As our starting point, all four enantiomers of 5 were solvated in a cubic box of TIP3P24 water molecules with dimensions of ca. 38 × 38 × 38 Å. All the systems were energy-minimized for 1000 steps using the conjugate gradient algorithm and then simulated for 5 μs at 300 K. The MD simulations were performed using an isobaric−isothermal (NPT) ensemble, in which the number of particles, the pressure, and the temperature were kept constant. The Langevin dynamics was used to maintain the simulation temperature at 300 K, and the Langevin piston25 was employed to keep the pressure close to 1 atm. Periodic boundary conditions were employed for all systems, and the longrange electrostatic interactions were accounted for using the particlemesh Ewald (PME) approach.26 A pair-list distance cutoff of 1.4 nm was used in all simulations. The electrostatic and short-range van der Waal cutoffs were set to 1.2 nm, and a smooth 1.0 nm cutoff of van der Waals forces was employed. The equations of motion were integrated using a 2.0 fs time step, and the SHAKE algorithm27 was used to constrain the length of covalent bonds to the hydrogen atoms. All simulations were performed using NAMD 2.13.28 General Procedure for Preparing 1,4-Substituted 2,3Dihydroxybutanones (Samarium Diiodide Method). A dry, two-necked 250 mL round-bottom flask was charged with a solution of phenyl- or methylglyoxal (5.32 mmol, 2.0 equiv) in dry THF (10 mL). The flask was stirred magnetically and blanketed with nitrogen while the aldehyde (2.66 mmol, 1.0 equiv) was added, followed by SmI2 in THF (0.1 M, 100 mL, 10 mmol). After stirring for 2 h at room temperature under nitrogen, aqueous HCl (0.1 M, 50 mL) was added to the mixture, and it was then extracted (3 × 100 mL) with diethyl ether. The combined ethereal layers were washed with aq. Na 2 S 2 O 3 (4%, w/v) and then brine, dried (MgSO 4 ), and concentrated. The residue was purified by preparative reversed phase HPLC using acetonitrile/water 20:80% as the mobile phase. For HPLC details, see the General Methods subsection. General Procedure for Preparing 1,4-Substituted 2,3Dihydroxybutanones (Cinchonine Method). A round-bottom flask was charged with a solution of cinchonine (0.2−0.3 mmol) and hydroxyacetophenone or hydroxyacetone (2 mmol, 2 equiv) in CHCl3 (2.5 mL). Aldehyde (1.0 mmol, 1.0 equiv) was added while stirring at room temperature. Stirring was continued until TLC (ethyl acetate/pentane 1:3) showed complete disappearance of the starting material (60−120 h). The mixture was taken up in ethyl acetate (25 mL) and washed with water, saturated aq. NaHSO3 (2 × 10 mL), water, and brine, and then it was dried (MgSO4) and concentrated. The residue was purified by preparative reversed phase HPLC as described in the previous paragraph. General Procedure for Preparing 1,5-Substituted 1,3,4Trihydroxypentanones (Aldolase Catalysis). The R134V/S166G mutant of FSA A14 was produced as previously described.12 Ketone (2b, 0.8 mmol) and aldehyde (1a, 1c−f, 0.2 mmol) were mixed in 50 mM triethanolamine, pH 8.0. To this mixture, enzyme (5 μmol limiting reactant/catalyst ratio = 40:1) was added to a total reaction volume of 20 mL. Reactions were incubated in the dark at 30 °C and 75 rpm for 24 h. Thereafter, the reaction mixtures were filtered through a 0.45 μM pore size polyvinylidene difluoride membrane. The pH was adjusted to 5.0, and products were extracted with ethyl acetate (3 × 10 mL). The combined organic pools were dried over Na2SO4 and filtered. The solvent was subsequently removed under vacuum. The crude products were purified by preparative reversed phase HPLC as described in the General Methods section. 6987


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3.950 (d, J = 5.7, 1H, H-3), 7.251 (m, 4H, ArH); 13C{1H} NMR: δ 27.4, 39.5, 75.1, 81.2, 129.2, 132.3, 133.0, 138.9, 212.7. HRMS m/z: calcd for [M + HCO2−] C12H14O5Cl, 273.0530; found, 273.0524. It is obtained as colorless crystals. 3,4-Dihydroxy-5-(4′-chlorophenyl)-pentan-2-one (Syn-Isomer, 12). 1H NMR: δ 2.196 (s, 3H, H-1a−c), 2.840 (dd, J = 7.8, 13.5, 1H, H-5a), 2.925 (dd, J = 6.5, 13.5, 1H, H-5b), 3.941 (d, J = 2.0, 1H, H-3), 4.136 (ddd, J = 2.0, 6.5, 7.8, 1H, H-4), 7.281 (m, 4H, ArH); 13 C{1H} NMR: δ 26.5, 40.3, 74.5, 79.9, 129.4, 132.1, 133.2, 138.8, 212.3. HRMS m/z: calcd for [M + HCO2−] C12H14O5Cl, 273.0530; found, 273.0533. It is obtained as colorless crystals. 3,4-Dihydroxy-5-(3′-chlorophenyl)-pentan-2-one (Anti-Isomer, 13). 1H NMR: δ 2.211 (s, 3H, H-1a−c), 2.684 (dd, J = 8.4, 13.7, 1H, H-5a), 2.889 (dd, J = 3.3, 13.7, 1H, H-5b), 3.934 (m, 2H, H-3, H-4), 7.233 (m, 4H, ArH); 13C{1H} NMR: δ 27.4, 39.8, 75.0, 81.1, 127.3, 129.2, 130.7, 130.8, 135.0, 142.5, 212.7. HRMS m/z: calcd for [M + HCO2−] C12H14O5Cl, 273.0530; found, 273.0529. It is obtained as a colorless amorphous solid. 3,4-Dihydroxy-5-(3′-chlorophenyl)-pentan-2-one (Syn-Isomer, 13). 1H NMR: δ 2.204 (s, 3H, H-1a−c), 2.849 (dd, J = 7.9, 13.5, 1H, H-5a), 2.931 (dd, J = 6.3, 13.5, 1H, H-5b), 3.957 (d, J = 1.9, 1H, H-3), 4.152 (ddd, J = 1.9, 6.3, 7.9, 1H, H-4), 7.259 (m, 4H, ArH); 13 C{1H} NMR: δ 26.5, 40.6, 74.4, 80.0, 127.4, 129.0, 130.6, 130.9, 135.1, 132.5, 212.2. HRMS m/z: calcd for [M + HCO2−] C12H14O5Cl, 273.0530; found, 273.0535. It is obtained as a colorless amorphous solid. 3,4-Dihydroxy-5-(4′-fluorophenyl)-pentan-2-one (Anti-Isomer, 14). 1H NMR: δ 2.198 (s, 3H, H-1a−c), 2.691 (dd, J = 8.5, 14.0, 1H, H-5a), 2.881 (dd, J = 3.8, 14.0, 1H, H-5b), 3.915 (m, 1H, H-4), 3.950 (d, J = 5.6, 1H, H-3), 6.980 (m, 2H, ArH), 7.257 (m, 2H, ArH); 13C{1H} NMR: δ 27.4, 39.3, 75.2, 81.1, 115.7 (d, JCF = 21.3 Hz), 132.3 (d, JCF = 7.7 Hz), 135.9 (d, JCF = 3.0 Hz), 163.0 (d, JCF = 242.4 Hz), 212.8. HRMS m/z: calcd for [M + HCO2−] C12H14O5F, 257.0825; found, 257.0824. It is obtained as a colorless amorphous solid. 3,4-Dihydroxy-5-(4′-fluorophenyl)-pentan-2-one (Syn-Isomer, 14). 1H NMR: δ 2.194 (s, 3H, H-1a−c), 2.837 (dd, J = 7.7, 13.5, 1H, H-5a), 2.929 (dd, J = 6.7, 13.4, 1H, H-5b), 3.938 (d, J = 1.9, 1H, H-3), 4.129 (ddd, J = 1.9, 6.7, 7.7, 1H, H-4), 7.011 (m, 2H, ArH), 7.295 (m, 2H, ArH); 13C{1H} NMR: δ 26.5, 40.1, 74.7, 79.8, 115.9 (d, JCF = 21.3 Hz), 132.2 (d, JCF = 7.7 Hz), 135.9 (d, JCF = 3.3 Hz), 163.0 (d, JCF = 242.4 Hz), 212.4. HRMS m/z: calcd for [M + HCO2−] C12H14O5F, 257.0825; found, 257.0827. It is obtained as a colorless amorphous solid. 3,4-Dihydroxy-5-(3′-fluorophenyl)-pentan-2-one (Anti-Isomer, 15). 1H NMR: δ 2.210 (s, 3H, H-1a−c), 2.716 (dd, J = 8.2, 14.0, 1H, H-5a), 2.905 (dd, J = 3.5, 14.0, 1H, H-5b), 3.940 (m, 2H, H-3, H-4), 6.915 (m, 1H, ArH), 7.011 (m, 1H, ArH), 7.067 (m, 1H, ArH), 7.272 (m, 1H, ArH); 13C{1H} NMR: δ 27.4, 39.90, 39.92, 75.0, 81.2, 113.8 (d, JCF = 20.9 Hz), 117.3 (d, JCF = 21.3 Hz), 126.5 (d, JCF = 2.9 Hz), 130.8 (d, JCF = 8.4 Hz), 142.9 (d, JCF = 7.6 Hz), 164.2 (d, JCF = 244.0 Hz), 212.7. HRMS m/z: calcd for [M + HCO2−] C12H14O5F, 257.0825; found, 257.0830. It is obtained as a colorless amorphous solid. 3,4-Dihydroxy-5-(3′-fluorophenyl)-pentan-2-one (Syn-Isomer, 15). 1H NMR: δ 2.202 (s, 3H, H-1a−c), 2.868 (dd, J = 7.8, 13.4, 1H, H-5a), 2.910 (dd, J = 6.5, 13.4, 1H, H-5b), 3.951 (d, J = 1.9, 1H, H-3), 4.163 (ddd, J = 1.9, 6.5, 7.8, 1H, H-4), 6.934 (m, 1H, ArH), 7.047 (m, 1H, ArH), 7.105 (m, 1H, ArH), 7.297 (m, 1H, ArH; 13 C{1H} NMR: δ 26.5, 40.66, 40.67, 74.4, 79.9, 114.0 (d, JCF = 21.2 Hz), 117.2 (d, JCF = 21.3 Hz), 126.4 (d, JCF = 2.8 Hz), 131.1 (d, JCF = 8.3 Hz), 142.9 (d, JCF = 7.5 Hz), 164.3 (d, JCF = 243.5 Hz), 212.2. HRMS m/z: calcd for [M + HCO2−] C12H14O5F, 257.0825; found, 257.0827. It is obtained as a colorless amorphous solid. (3R,4S)-1,3,4-Trihydroxy-5-phenylpentan-2-one (Syn-Isomer, 16).6c 1H NMR: δ 2.840 (dd, J = 7.4, 13.3, 1H, H-5a), 2.941 (dd, J = 7.1, 13.3, 1H, H-5b), 4.035 (d, J = 1.9, 1H, H-3), 4.135 (ddd, J = 1.9, 7.1, 7.4, 1H, H-4), 4.434 (d, J = 19.2, H-1a), 4.512 (d, J = 19.2, H-1b), 7.270 (m, 5H, ArH); 13C{1H} NMR: δ 40.7, 67.9, 75.0, 78.3, 127.4, 129.4, 130.5, 139.8, 214.1. HRMS m/z: calcd for [M − H+]

(dd, J = 3.2, 14.1, 1H, H-4b), 4.060 (ddd, J = 3.2, 5.7, 9.0, 1H, H-3), 5.026 (d, J = 5.7, 1H, H-2), 6.925 (m, 2H, ArH), 7.138 (m, 2H, ArH), 7.500 (m, 2H, ArH), 7.620 (m, 1H, ArH), 7.957 (m, 2H, ArH): 13 C{1H} NMR: δ 38.7, 75.4, 77.4, 115.7 (d, JCF = 21.3 Hz), 129.71, 129.74, 132.2 (d, JCF = 7.7 Hz), 134.6, 135.9 (d, JCF = 3.4 Hz), 135.98, 162.9 (d, JCF = 242.4 Hz), 202.5. HRMS m/z: calcd for [M + HCO2−] C17H16O5F, 319.0982; found, 319.0986. It is obtained as a colorless amorphous solid. 2,3-Dihydroxy-4-(4′-fluorophenyl)-1-phenylbutan-1-one (SynIsomer, 8). 1H NMR: δ 2.893 (dd, J = 7.4, 13.4, 1H, H-4a), 3.036 (dd, J = 7.0, 13.4, 1H, H-4b), 4.090 (ddd, 1.6, 7.0, 7.4, 1H, H-3), 4.961 (d, J = 1.6, 1H, H-2), 7.046 (m, 2H, ArH), 7.308 (m, 2H, ArH), 7.464 (m, 2H, ArH), 7.603 (m, 1H, ArH), 7.764 (m, 2H, ArH); 13 C{1H} NMR: δ 40.4, 75.3, 76.0, 116.1 (d, JCF = 21.4 Hz), 129.5, 129.8, 132.2 (d, JCF = 7.7 Hz), 134.6, 135.8 (d, JCF = 3.2 Hz), 136.1, 163.1 (d, JCF = 243.1 Hz), 201.8. HRMS m/z: calcd for [M + HCO2−] C17H16O5F, 319.0982; found, 319.0988. It is obtained as a colorless amorphous solid. 2,3-Dihydroxy-4-(3′-fluorophenyl)-1-phenylbutan-1-one (AntiIsomer, 9). 1H NMR: δ 2.719 (dd, J = 9.1, 14.0, 1H, H-4a), 2.923 (dd, J = 3.0, 14.0, 1H, H-4b), 4.079 (ddd, J = 3.0, 5.8, 9.1, 1H, H-3), 5.022 (d, J = 5.8, 1H, H-2), 6.881 (m, 2H, ArH), 6.948 (d, 1H, ArH), 7.213 (dd, 1H, ArH), 7.506 (t, 2H, ArH), 7.624 (t, 1H, ArH), 7.975 (d, 2H, ArH); 13C{1H} NMR: δ 39.4, 75.2, 77.4, 113.8 (d, JCF = 21.4 Hz), 117.3 (d, JCF = 21.3 Hz), 126.4 (d, JCF = 2.9 Hz), 129.7, 129.8, 130.7 (d, JCF = 8.4 Hz), 134.6, 137.4, 143.1 (d, JCF = 7.5 Hz), 164.2 (d, JCF = 244.1 Hz), 202.5. HRMS m/z: calcd for [M + HCO2−] C17H16O5F: 319.0982; found, 319.0980. It is obtained as a colorless amorphous solid. 2,3-Dihydroxy-4-(3′-fluorophenyl)-1-phenylbutan-1-one (SynIsomer, 9). 1H NMR: δ 2.923 (dd, J = 7.6, 13.4, 1H, H-4a), 3.058 (dd, J = 6.7, 13.4, 1H, H-4b), 4.125 (ddd, 1.7, 6.7, 7.6, 1H, H-3), 4.971 (d, J = 1.7, 1H, H-2), 6.963 (m, 1H, ArH), 7.052 (m, 1H, ArH), 7.115 (m, 1H, ArH), 7.325 (m, 1H, ArH), 7.468 (m, 2H, ArH), 7.605 (m, 1H, ArH), 7.778 (m, 2H, ArH); 13C{1H} NMR: δ 41.0, 75.0, 76.2, 114.1 (d, JCF = 20.0 Hz), 117.2 (d, JCF = 21.3 Hz), 126.4 (d, JCF = 2.9 Hz), 129.5, 129.8, 131.1 (d, JCF = 8.4 Hz), 134.6, 136.1, 142.7 (d, JCF = 7.5 Hz), 164.3 (d, JCF = 244.2 Hz), 201.7. HRMS m/z: calcd for [M + HCO2−] C17H16O5F, 319.0982; found, 319.0981. It is obtained as a colorless amorphous solid. 3,4-Dihydroxy-5-phenylpentan-2-one (Anti-Isomer, 10).11b 1H NMR: δ 2.189 (s, 3H, H-1a−c), 2.705 (dd, J = 7.9, 13.8, 1H, H-5a), 2.906 (dd, J = 3.8, 13.8, 1H, H-5b), 3.956 (m, 2H, H-3, H-4), 7.259 (m, 5H, ArH); 13C{1H} NMR: δ 27.4, 40.2, 75.4, 81.2, 127.2, 129.2, 130.7, 140.0, 212.8. It is obtained as a colorless amorphous solid. 3,4-Dihydroxy-5-phenylpentan-2-one (Syn-Isomer, 10).6c,11b 1H NMR: δ 2.185 (s, 3H, H-1a−c), 2.855 (dd, J = 7.3, 13.3, 1H, H-5a), 2.818 (dd, J = 7.0, 13.3, 1H, H-5b), 3.933 (d, J = 1.8, 1H, H-3), 4.161 (ddd, J = 1.8, 7.0, 7.3, 1H, H-4), 7.285 (m, 5H, ArH); 13C{1H} NMR: δ 26.5, 41.0, 74.8, 79.7, 127.4, 129.4, 130.5, 139.9, 212.4. It is obtained as a colorless amorphous solid. 3,4-Dihydroxy-5-(4′-methoxyphenyl)-pentan-2-one (Anti-Isomer, 11). 1H NMR: δ 2.172 (s, 3H, H-1a−c), 2.648 (dd, J = 8.2, 14.0, 1H, H-5a), 2.840 (dd, J = 4.1, 14.0, 1H, H-5b), 3.756 (s, 3H, OCH3), 3.916 (m, 1H, H-4), 3.960 (d, J = 5.4, 1H, H-3), 6.826 (m, 2H, ArH), 7.159 (m, 2H, ArH); 13C{1H} NMR: δ 27.4, 39.3, 55.6, 75.6, 81.2, 114.7, 131.7, 131.8, 159.7, 212.8. HRMS m/z: calcd for [M + HCO2−] C13H17O6, 269.1025; found, 269.1027. It is obtained as a colorless amorphous solid. 3,4-Dihydroxy-5-(4′-methoxyphenyl)-pentan-2-one (Syn-Isomer, 11). 1H NMR: δ 2.179 (s, 3H, H-1a−c), 2.789 (dd, J = 7.2, 13.4, 1H, H-5a), 2.891 (dd, J = 7.3, 13.4, 1H, H-5b), 3.762 (s, 3H, OCH3), 3.923 (d, J = 1.6, 1H, H-3), 4.136 (ddd, J = 1.6, 7.2, 7.3, 1H, H-4), 6.850 (m, 2H, ArH), 7.194 (m, 2H, ArH); 13C{1H} NMR: δ 26.5, 40.1, 55.6, 74.9, 79.6, 114.9, 131.4, 131.7, 159.8, 212.5. HRMS m/z: calcd for [M + HCO2−] C13H17O6, 269.1025; found, 269.1028. It is obtained as a colorless amorphous solid. 3,4-Dihydroxy-5-(4′-chlorophenyl)-pentan-2-one (Anti-Isomer, 12). 1H NMR: δ 2.204 (s, 3H, H-1a−c), 2.694 (dd, J = 8.4, 14.0, 1H, H-5a), 2.879 (dd, J = 3.7, 14.0, 1H, H-5b), 3.912 (m, 1H, H-4), 6988


Article

The Journal of Organic Chemistry C11H13O4, 209.0814; found, 209.0810. [α]21 D = +21 ± 2° (c = 0.085, CHCl3). It is obtained as a colorless amorphous solid. 1,3,4-Trihydroxy-5-(4′-methoxyphenyl)-pentan-2-one (Syn-Isomer, 17).12 1H NMR: δ 2.775 (dd, J = 13.5, 7.2, 1H, H-5a), 2.879 (dd, J = 13.5, 7.3, 1H, H-5b), 3.759 (s, 3H, OCH3), 4.025 (d, J = 2.0 Hz, 1H, H-3), 4.085 (dt, J = 2.0, 7.2, 7.3, 1H, H-4), 4.428 (d, J = 19.2, 1H, H-1a), 4.507 (d, J = 19.2, 1H, H-1b), 6.845 (m, 2H, ArH), 7.176 (m, 2H, ArH); 13C{1H} NMR: δ 39.8, 55.6, 67.7, 75.2, 78.1, 114.9, 131.4, 131.7, 159.8, 214.1. It is obtained as a colorless amorphous solid. (3R,4S)-1,3,4-Trihydroxy-5-(4′-chlorophenyl)-pentan-2-one (SynIsomer, 18). 1H NMR: δ 2.827 (dd, J = 7.8, 13.5, 1H, H-5a), 2.912 (dd, J = 6.5, 13.5, 1H, H-5b), 4.050 (d, J = 2.1, 1H, H-3), 4.115 (ddd, J = 2.1, 6.5, 7.8, 1H, H-4), 4.434 (d, J = 19.2, H-1a), 4.515 (d, J = 19.2, H-1b), 7.272 (m, 4H, ArH); 13C{1H} NMR: δ 40.0, 67.9, 74.7, 78.4, 129.4, 132.1, 133.2, 138.7, 213.8. HRMS m/z: calcd for [M − H+] C11H12O4Cl, 243.0424; found, 243.0426. [α]21 D = +24 ± 2° (c = 0.22, CHCl3). It is obtained as a colorless amorphous solid. (3R,4S)-1,3,4-Trihydroxy-5-(3′-chlorophenyl)-pentan-2-one (SynIsomer, 19). 1H NMR: δ 2.836 (dd, J = 7.9, 13.5, 1H, H-5a), 2.919 (dd, J = 6.4, 13.5, 1H, H-5b), 4.062 (d, J = 2.1, 1H, H-3), 4.128 (ddd, J = 2.1, 6.4, 7.9, 1H, H-4), 4.440 (d, J = 19.2, H-1a), 4.519 (d, J = 19.2, H-1b), 7.185−7.320 (m, 4H, ArH); 13C{1H} NMR: δ 40.3, 67.9, 74.6, 78.4, 127.4, 128.9, 130.5, 130.9, 135.1, 142.4, 213.8. HRMS m/z: calcd for [M − H+] C11H12O4Cl, 243.0424; found, 243.0430. [α]21 D = +20 ± 2° (c = 0.22, CHCl3). It is obtained as a colorless amorphous solid. (3R,4S)-1,3,4-Trihydroxy-5-(4′-fluorophenyl)-pentan-2-one (SynIsomer, 20). 1H NMR: δ 2.835 (dd, J = 7.7, 13.6, 1H, H-5a), 2.916 (dd, J = 6.7, 13.6, 1H, H-5b), 4.045 (d, J = 2.0, 1H, H-3), 4.105 (ddd, J = 2.0, 6.7, 7.7, 1H, H-4), 4.435 (d, J = 19.2, H-1a), 4.514 (d, J = 19.2, H-1b), 7.005 (m, 2H, ArH), 7.273 (m, 2H, ArH); 13C{1H} NMR: δ 39.8, 67.9, 74.9, 78.3, 115.9 (d, JCF = 21.3 Hz), 132.1 (d, JCF = 7.7 Hz), 135.8 (d, JCF = 3.1 Hz), 163.1 (d, JCF = 242.6 Hz), 213.9. HRMS m/z: calcd for [M − H+] C11H12O4F, 227.0720; found, 227.0716. [α]21 D = +20 ± 2° (c = 0.15, CHCl3). It is obtained as a colorless amorphous solid. (3R,4S)-1,3,4-Trihydroxy-5-(3′-fluorophenyl)-pentan-2-one (SynIsomer, 21). 1H NMR: δ 2.855 (dd, J = 7.8, 13.5, 1H, H-5a), 2.939 (dd, J = 6.5, 13.5, 1H, H-5b), 4.060 (d, J = 2.1, 1H, H-3), 4.139 (ddd, J = 2.1, 6.5, 7.8, 1H, H-4), 4.441 (d, J = 19.2, H-1a), 4.520 (d, J = 19.2, H-1b), 6.927 (m, 1H, ArH), 7.027 (m, 1H, ArH), 7.292 (m, 1H, ArH), 7.014 (m, 1H, ArH); 13C{1H} NMR: δ 40.4, 67.9, 74.6, 78.4, 114.0 (d, JCF = 21.3 Hz), 117.1 (d, JCF = 21.3 Hz), 126.3 (d, JCF = 2.7 Hz), 131.0 (d, JCF = 8.3 Hz), 142.8 (d, JCF = 7.1 Hz), 164.3 (d, JCF = 243.6 Hz), 213.8. HRMS m/z: calcd for [M − H+] C11H12O4F, 227.0720; found, 227.0714. [α]21 D = +25 ± 2° (c = 0.18, CHCl3). It is obtained as a colorless amorphous solid.

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Jan Kihlberg: 0000-0002-4205-6040 Mikael Widersten: 0000-0002-3203-3793 Present Address §

Department of Chemistry, Faculty of Science, An-Najah National University, Nablus, Palestine. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The work was supported by Stiftelsen Olle Engkvist Byggmästare and the Carl Trygger Foundation (M.W.).

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.9b00742. Data on X-ray crystallography and chiral separations, MD simulated structures of aldol 5, NMR spectra of new and reference compounds, and ORTEP plots of crystal structures (PDF) (CIF) (CIF) (CIF)

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REFERENCES

(1) The submitted version of this manuscript was uploaded to the ChemRxiv preprint repository, doi: 10.26434/chemrxiv.7851455.v1. (2) Yamashita, Y.; Yasukawa, T.; Yoo, W.-J.; Kitanosono, T.; Kobayashi, S. Catalytic Enantioselective Aldol Reactions. Chem. Soc. Rev. 2018, 47, 4388−4480. (3) (a) Peng, H.; Chen, F.-E. Recent Advances in Asymmetric Total Synthesis of Prostaglandins. Org. Biomol. Chem. 2017, 15, 6281−6301. (b) Bihani, M.; Zhao, J. C.-G. Advances in Asymmetric Diastereodivergent Catalysis. Adv. Synth. Catal. 2017, 359, 534−575. (4) (a) Gasparski, C. M.; Miller, M. J. Synthesis of β-Hydroxy-αamino Acids by Aldol Condensation Using a Chiral Phase Transfer Catalyst. Tetrahedron 1991, 47, 5367−5378. (b) Yoshikawa, N.; Kumagai, N.; Matsunaga, S.; Moll, G.; Ohshima, T.; Suzuki, T.; Shibasaki, M. Direct Catalytic Asymmetric Aldol Reaction: Synthesis of Either syn- or anti-α,β-Dihydroxy Ketones. J. Am. Chem. Soc. 2001, 123, 2466−2467. (c) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III Amino Acid Catalyzed Direct Asymmetric Aldol Reactions: A Bioorganic Approach to Catalytic Asymmetric Carbon−Carbon Bond-Forming Reactions. J. Am. Chem. Soc. 2001, 123, 5260−5267. (d) Yoshikawa, N.; Suzuki, T.; Shibasaki, M. Diastereo- and Enantioselective Direct Catalytic Aldol Reaction of 2-Hydroxyacetophenones with Aldehydes Promoted by a Heteropolymetallic Complex: Catalytic Asymmetric Synthesis of anti-1,2-Diols. J. Org. Chem. 2002, 67, 2556−2565. (e) Li, J.; Luo, S.; Cheng, J.-P. Chiral Primary−Tertiary Diamine Catalysts Derived from Natural Amino Acids for syn-Aldol Reactions of Hydroxy Ketones. J. Org. Chem. 2009, 74, 1747−1750. (f) Paradowska, J.; Rogozińska, M.; Mlynarski, J. Direct Asymmetric Aldol Reaction of Hydroxyacetone Promoted by Chiral Tertiary Amines. Tetrahedron Lett. 2009, 50, 1639−1641. (g) Wu, C.; Fu, X.; Li, S. Simple and Inexpensive Threonine-Based Organocatalysts for the Highly Diastereo- and Enantioselective Direct Large-Scale syn-Aldol and anti-Mannich Reactions of α-Hydroxyacetone. Tetrahedron: Asymmetry 2011, 22, 1063−1073. (h) Bas, S.; Woźniak, Ł.; Cygan, J.; Mlynarski, J. Asymmetric syn-Aldol Reaction of α-Hydroxy Ketones with Tertiary Amine Catalysts. Eur. J. Org. Chem. 2013, 6917−6923. (i) Trost, B. M.; Bartlett, M. J. ProPhenolCatalyzed Asymmetric Additions by Spontaneously Assembled Dinuclear Main Group Metal Complexes. Acc. Chem. Res. 2015, 48, 688−701. (5) Trost, B. M.; Brindle, C. S. The Direct Catalytic Asymmetric Aldol Reaction. Chem. Soc. Rev. 2010, 39, 1600−1632. (6) (a) Fessner, W.-D.; Helaine, V. Biocatalytic Synthesis of Hydroxylated Natural Products Using Aldolases and Related Enzymes. Curr. Opin. Biotechnol. 2001, 12, 574−586. (b) Garrabou, X.; Castillo, J. A.; Guérard-Hélaine, C.; Parella, T.; Joglar, J.; Lemaire, M.; Clapés, P. Asymmetric Self- and Cross-Aldol Reactions of Glycolaldehyde Catalyzed by D-Fructose-6-phosphate Aldolase. Angew. Chem., Int. Ed. 2009, 48, 5521−5525. (c) Concia, A. L.; Lozano, C.; Castillo, J. A.; Parella, T.; Joglar, J.; Clapés, P. D-Fructose6-phosphate Aldolase in Organic Synthesis: Cascade ChemicalEnzymatic Preparation of Sugar-Related Polyhydroxylated Compounds. Chem.Eur. J. 2009, 15, 3808−3816. (d) Castillo, J. A.; Guérard-Hélaine, C.; Gutiérrez, M.; Garrabou, X.; Sancelme, M.; Schürmann, M.; Inoue, T.; Hélaine, V.; Charmantray, F.; Gefflaut, T.;

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*E-mail: [email protected]. ORCID

Thilak Reddy Enugala: 0000-0001-5915-1514 Shina Caroline Lynn Kamerlin: 0000-0002-3190-1173 6989


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