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Int. J. Mol. Sci. 2014, 15(2), 2087-2118; doi:10.3390/ijms15022087
Published: 29 January 2014
Abstract: Extending carbon frameworks via a series of C–C bond forming reactions is essential for the synthesis of natural products, pharmaceutically active compounds, active agrochemical ingredients, and a variety of functional materials. The application of stereoselective C–C bond forming reactions to the one-pot synthesis of biorelevant compounds is now emerging as a challenging and powerful strategy for improving the efficiency of a chemical reaction, in which some of the reactants are subjected to successive chemical reactions in just one reactor. However, organic reactions are generally conducted in organic solvents, as many organic molecules, reagents, and intermediates are not stable or soluble in water. In contrast, enzymatic reactions in living systems proceed in aqueous solvents, as most of enzymes generally function only within a narrow range of temperature and pH and are not so stable in less polar organic environments, which makes it difficult to conduct chemoenzymatic reactions in organic solvents. In this review, we describe the design and synthesis of chiral metal complexes with Zn2+ ions as a catalytic factor that mimic aldolases in stereoselective C–C bond forming reactions, especially for enantioselective aldol reactions. Their application to chemoenzymatic reactions in aqueous solution is also presented.
C–C bond formation is one of the fundamental transformations in organic synthesis. Extension of a carbon framework via a series of C–C bond forming reactions is essential to the synthesis of natural products, pharmaceutically active compounds, active agrochemical ingredients, and related functional materials . One of most important applications of C–C bond forming reactions is one-pot synthesis, whereby reactants are subjected to successive chemical reactions in just one reactor. This methodology is convenient not only in the laboratory, but also in industrial reactions, because lengthy separation and purification processes of the intermediates can be avoided, resulting in time and resource-saving and, eventually, in a more efficient chemical synthesis. Despite the remarkable progress achieved in one-pot multistep synthetic methodologies including enantioselective C–C bond formation in organic solvents, only a few attempts have been made to combine a chemical catalyst and a biocatalyst in a one-pot multistep process, especially in water-containing solvent systems .
It is clear that much can be learned from natural enzymes for the design of water-soluble asymmetric catalysts. Typical examples of enzymes that catalyze C–C bond forming reactions in living systems would be aldolases, a class of enzymes that accelerate aldol and retro-aldol reactions in a stereospecific and reversible manner in natural metabolic pathways . For example, fructose 1,6-bis(phosphate) aldolase (FBP-aldolase, EC 184.108.40.206) catalyzes the cleavage of d-fructose 1,6-bis(phosphate) (FBP) to give dihydroxyacetone phosphate (DHAP) and d-glyceraldehyde 3-phosphate (G3P), as well as the reverse formation of FBP from DHAP and G3P (Scheme 1). Natural aldolases can be classified into two groups on the basis of their reaction mechanisms. In the case of class I aldolases, an enamine intermediate is formed between the lysine residue of the enzyme and the carbonyl group of the substrate. In class II aldolases, a zinc(II) ion cofactor acts as a Lewis acid to generate enolates at the active site.
The use of aldolases in organic and bio-organic synthesis has been found to be an effective method for producing aldol products with high stereoselectivities in aqueous solution . Wong et al. reported on a short step synthesis of 1-deoxynojirimycin, a glycosidase inhibitor, in which aldol reaction between DHAP and 1, using FBP-aldolase is conducted to obtain the important intermediate, 2 (Scheme 2a) . In addition, Lerner and co-workers developed catalytic antibodies, which were obtained after screening of polyclonal antibodies for binding with the hapten [6,7]. The aldolase antibodies were found to catalyze aldol reactions by the enamine mechanism, analogous to class I aldolases. The aldol reaction between 3 and hydroxyacetone (HA, 4), catalyzed by aldolase antibody 38C2, has been applied in highly enantioselective total syntheses of (1R, 1′R, 5′R, 7′R)- and (1S, 1′R, 5′R, 7′R)-1-hydroxy-exo-brevicomin (Scheme 2b) .
Chiral organocatalysts have recently emerged as a reagent class representing a new methodology for stereoselective aldol reactions, in that they are capable of mimicking class I aldolases . In 2000, List, Lerner, and Barbas reported that l-proline serves as a catalyst for direct aldol reactions of acetone and benzaldehyde derivatives 6 to give aldol adducts such as 7 in good chemical yields and with moderate enantioselectivities (Scheme 3, CTN stands for catalytic turnover number) . It was suggested that l-proline forms an enamine intermediate that react with aldehydes to give aldol products .
As the direct aldol reaction catalyzed by l-proline was first reported, a variety of organocatalysts for aldol reactions have been reported . Representative examples are shown in Scheme 4. Maruoka and co-workers successfully extended the concept of amino acid catalysis to novel catalysts containing a binaphthyl or biphenyl axial chirality (e.g., 8) . The use of only 0.1 mol % of 8 in acetone afforded aldol products such as 7b with high yields and enantioselectivities (Scheme 4a). Barbas et al. reported on asymmetric aldol reactions between cyclohexanone 9 and benzaldehydes 6 in water catalyzed by a combination of a lipophilic diamine 10 and trifluoroacetic acid (TFA)  (Scheme 4b). Hayashi’s group developed a proline-based catalyst, diarylprolinol 12, for direct crossed-aldol reactions of acetaldehyde in DMF  (Scheme 4c). Barbas et al. performed syn-selective aldol reactions of unmodified dihydroxyacetone (DHA, 14) catalyzed by O-tBu-l Threonine 15 to yield acetylated triol products such as 16  (Scheme 4d).
A number of excellent studies on chiral metal catalysts for stereoselective aldol reactions have also been reported . Examples of Zn2+ catalysts for direct asymmetric aldol reactions include Et2Zn/linked BINOL 19 developed by Shibasaki , Trost’s Zn2+-semi crown ether 22 , and so forth, which can be considered as class II aldolase mimics functioning in organic solvents (Scheme 5). Both catalysts showed high catalytic activities on α-hydroxyketones (18 and 21) by dinuclear Zn2+ coordination sites for the enolate of α-hydroxyketones and aldehydes.
To date, natural and artificial catalysts that possess both functionalities, i.e., Schiff-base forming part and Zn2+ site, have scarcely been reported. Some Zn2+ complexes of proline derivatives have been demonstrated to have the ability to catalyze direct asymmetric aldol reactions in aqueous media, thus mimicking class I and class II aldolases (Scheme 6). Reymond, Darbre, et al. showed that the 1:2 complex of Zn2+ and l-proline 24 (Zn(l-Pro)2) catalyzes aldol reactions of acetone and dihydroxyacetone 14 in aqueous system [20,21]. The use of 5 mol % of 24 gave aldol products from acetone and 6b in quantitative yields, with 56% ee (R), at room temperature (Scheme 6a). They suggested that in the aldol reactions of these substrates, 24 forms enamine species with acetone, but that it forms Zn2+-enolate intermediates with 14. Mlynarski’s group reported on Zn2+ complexes of a C2-symmetric chiral ligands containing two amino acid units, such as 25 . These catalysts showed high reactivities and enantioselectivities in catalytic aldol reactions between acetone, cyclohexanone 9, and hydroxyacetone 4 and several aldehydes in aqueous systems (up to 99% ee) (Scheme 6b).
Meanwhile, it has been well established by Kimura and co-workers that a Zn2+ complex of cyclen 26 (ZnL1; cyclen = 1,4,7,10-tetraazacyclododecane or aneN4) is a good model for the naturally occurring Zn2+ enzymes (Scheme 7) [23,24]. A Zn2+ complex of 4-bromophenacyl-pendant cyclen 27 (ZnL2), for example, was reported to be a good model for the class II aldolases . The potentiometric pH titration of 27a (ZnL2(H2O)) and spectroscopic data indicated that the Zn2+-bound HO− in 27b (ZnL2(OH−)) facilitated the deprotonation of the carbonyl α-proton of the phenacyl side chain to give the Zn2+-enolate form 27c (Zn(H−1L2)) in aqueous solution. Note that Zn2+ ions in Zn2+-cyclen complexes exhibit strong Lewis acidity and that the pKa values of the Zn2+-bound water molecules in 26 and 27 are 7.8 and 8.4, respectively.
With the backgrounds described above, we became interested in the reactivities and enantioselectivities of novel asymmetric catalysts, each dual-functionalized with an enamine-forming amino group and a Zn2+ complex of macrocyclic polyamines such as cyclen (aneN4) or aneN5. The development of enantioselective aldol reactions was envisaged, as they are one of the most important C–C bond forming reactions for producing β-hydroxy carbonyl compounds bearing two new stereogenic centers at the α- and β-positions of the carbonyl groups [17,26,27]. It should be noted that these reactions are performed mainly in aqueous solvents, which are considered to have enormous potential as a reaction mediums and are critical for chemoenzymatic reactions [28–30]. One of the advantages of these aldol reactions is that they would be applicable to the one-pot synthesis of biorelevantly important compounds by combination with enzymatic reactions. These results are reviewed below.
2. Results and Discussion
2.1. Chiral Catalysts that Are Dually Functionalized with Amino Acid and Zn2+ Complex Components for Direct Enantioselective Aldol Reactions Inspired by Natural Aldolases
2.1.1. Design and Synthesis of Chiral Zn2+ Complexes
The initially designed and synthesized Zn2+ complexes for stereoselective direct aldol reactions include 31 (l-ZnL3 prepared from l-prolyl-pendant aneN5 28 (l-L3)), 32 (l-ZnL4, prepared from l-prolyl-pendant cyclen 29 (l-L4)), and 33 (l-ZnL5 from l-valyl-pendant cyclen 30 (l-L5)), and the related complexes 34 (l-ZnL6), 35 (ZnL7), 36 (l-ZnL8), and 37 (d-ZnL8) (Figure 1). The ligands for Zn2+ complexes 31–37 (l-ZnL3–d-ZnL8) were synthesized from tetrakis(tert-butyloxycarbonyl)-aneN5 (4-Boc-aneN5) or tris(tert-butyloxycarbonyl)-aneN4 (3-Boc-aneN4) with N-protected amino-acid derivatives . The Zn2+ complexes were prepared in situ immediately prior to use by reacting the acid-free ligands with Zn2+ ions.
2.1.2. Complexation Properties of Chiral Zn2+ Complexes
Potentiometric pH titration is a general and reliable method to determine the deprotonation constants (Kai defined by Equation (1)) and the metal complexation constants (Zn2+ complexation constants, Ks(ZnL), as defined by Equation (2) in this work) of given ligands in aqueous solution. Analysis of typical potentiometric pH titration curves for 0.5 mM ligands (l-H5L3, l-H4L4, and l-H4L5) and for mixtures of 0.5 mM ligands 31–33 (l-H5L3, l-H4L4, and l-H4L5), plus 0.5 mM ZnSO4 gave complexation constants, log Ks(ZnL), and pKa(ZnL) values of Zn2+-bound water in Zn2+ complexes (defined by Equation (3)), as summarized in Scheme 8 .
The log Ks(ZnL) for 28 (L3) is 14.1 (Scheme 8), which is much greater than the corresponding values for aneN3 38 (L9, 8.4)  and 40 (L7, 8.0) , which have been established as tridentate ligands for Zn2+ (Scheme 9). The deprotonation constant for the Zn2+-bound water of l-ZnL3 (for 31a ⊂ 31b) (pKa(ZnL)) was calculated to be 9.2, which is greater than that for Zn2+-cyclen complex 26 (ZnL1) of 7.8 in Scheme 7. These data suggest that 28 (l-L3) serves as a tetradentate or pentadentate ligand to Zn2+. For example, 31 (l-ZnL3) (31a (l-ZnL3(H2O)) + 31b (l-ZnL3(OH−))) is formed almost quantitatively at pH 7.4 in a mixture of 25 mM l-L3 and 25 mM Zn2+.
In addition, as shown in Scheme 8, the pKa(ZnL) values for the Zn2+-bound water in 31–33 (l-ZnL3– l-ZnL5) were found to be 9.2, 8.2, and 8.6, respectively, which are larger than those for 26 (ZnL1) of 7.8 and 39 (ZnL9) of 7.3. These data indicate that the Lewis acidity of Zn2+ in 31–33 (l-ZnL3– l-ZnL5) is weaker than that in 26 (ZnL1) and 39 (ZnL9). The fact that the pKa(ZnL) values for 32 (8.2) and 33 (8.6) are somewhat larger than those of 35 (7.3) and 39 (7.3), which are Zn2+ complexes of tridentate ligands, suggested the possibility that the nitrogen components in the prolyl and valyl units of 32 and 33 coordinate only weakly to Zn2+ (the cyclen units of these ligands are tridentate binders for Zn2+).
2.1.3. Enantioselective Aldol Reactions in Aqueous Media Catalyzed by Chiral Zn2+ Complexes
On the basis of the data on the Zn2+ complexation behavior of the chiral ligands, described above, the aldol reaction between acetone and 2-chlorobenzaldehyde 6a in the presence of the chiral catalysts in DMSO/acetone or acetone/H2O systems was examined. The results are summarized in Table 1. Most of the reactions in Table 1 were carried out at 37 °C as an enzyme model study.
As described in the Introduction, l-proline (20 mol % relative to the aldehyde) gave 7a with a good chemical yield (85%) and enantioselectivity (67% ee (R)) in DMSO/acetone at 25 °C (entry 1). As listed in entries 2 and 3, 31 (l-ZnL3) and 32 (l-ZnL4) gave 7a with low yields and 1% ee (R) and 34% ee (R), respectively ([L] = [Zn2+] = 10 mM for quantitative formation of Zn2+ complexes, based on the results of potentiometric pH titrations).
In the acetone/H2O system, l-proline gave 7a in 22% yield and with 48% ee (R) at 37 °C (entry 4), both of which were lower than those in the DMSO/acetone system (entry 1). In contrast, 31 (l-ZnL3) gave better yield (43% yield with a nearly racemic adduct) at 37 °C (entry 5) than in DMSO/acetone (entry 2). Interestingly, 32 (l-ZnL4) gave 7a in good yield (73%) and enantioselectivity (80% ee (R)) in entry 6. Metal-free 29 (l-L4) gave only the racemic aldol product (entry 7), whereas the Cd2+ and Cu2+ complexes of l-L4 (41a and 41b) promoted aldol reactions only to a negligible extent (entries 8 and 9). It had previously been reported that the Lewis acidity of the Zn2+-cyclen complex is higher than that of Cd2+-cyclen . We therefore concluded that the Lewis acidity of Zn2+ is an important factor for this enantioselective aldol reaction.
Other Zn2+ complexes were also tested, as listed in entries 10–16. Zn2+ complex 33 (l-ZnL5), which contains a valine unit, gave results almost the same as those obtained with 32 (l-ZnL4) (entry 10). The Zn2+ complexes of N-methylprolyl-pendant cyclen 34 (l-ZnL6) and (S)-methylbenzylurenyl-pendant cyclen 35 (ZnL7) were used for comparison. Although it is unlikely that the tertiary amine on the side chain of 34 (l-ZnL6) would form a Schiff-base with acetone, 34 (l-ZnL6) gave 7a in moderate yield but with low ee (entry 11). On the other hand, 35 (ZnL7), having no amino group, scarcely yielded the aldol adduct (entry 12). 36 (l-ZnL8) and 37 (d-ZnL8), which contained l- and d-phenylalanyl side chains, respectively, gave 7a in somewhat higher chemical yields and enantioselectivities (91% ee (R) with 36 (l-ZnL8) and 91% ee (S) with 37 (d-ZnL8)) than those for 32 (l-ZnL4) and 33 (l-ZnL5) (entries 6 and 10 versus 13 and 14). Zn2+-cyclen 26 (ZnL1) alone, in which the Zn2+ is coordinated by four nitrogen atoms, and a combination of l-proline and 26 (ZnL1) showed negligible catalytic activity (entries 15 and 16).
These results suggest that primary or secondary amino groups on the side chains are important and that the amino acid portions of 31–33 (l-ZnL3– l-ZnL5), 36 (l-ZnL8) and 37 (d-ZnL8), function as bases for the deprotonation of acetone activated by Zn2+, rather than as Schiff-base forming units.
Aldol reactions between acetone and benzaldehyde derivatives 6b–e were carried out in acetone/H2O (4/1) in the presence of 50 mM ZnL catalysts (Table 2). When 4-nitrobenzaldehyde 6b was used as an acceptor in the presence of 32 (l-ZnL4) and 33 (l-ZnL5) (5 mol %), the product 7b was obtained in 63% ee (R) and 86% ee (R), respectively (entries 1 and 2). The use of 10 mol % of 36 (l-ZnL8) and 37 (d-ZnL8) gave the corresponding product 7b and 7c in almost quantitative yields with 90% ee (entries 4–6). Whereas the reactivities of 4-bromobenzaldehyde 6d and 2-naphthylaldehyde 6e were somewhat lower than 6b, 7d, and 7e were obtained in good enantioselectivities in the presence of 33 (l-ZnL5) (entries 8 and 10).
2.1.4. Fine Tuning of Structure of Chiral Zn2+ Complexes
In order to improve the aldol reaction between acetone and benzaldehyde derivatives, various Zn2+ complexes containing aliphatic, aromatic, anionic, cationic, and dipeptide side chains, 42–54 (l-ZnL10–ZnL22), were synthesized and their activity examined (Figure 2).
The aldol reaction between acetone and 2-chlorobenzaldehyde 6a was performed in acetone/H2O (4/1 or 9/1) in the presence of 50 mM Zn2+ complexes. The results are summarized in Table 3.
In entry 1, 42 (l-ZnL10), which contains alanine as the amino-acid unit, afforded 7a in high optical yield. In addition, 43 (l-ZnL11), 44 (l-ZnL12), and 45 (l-ZnL13), containing aliphatic side chains exhibited higher catalytic activities than 32 (l-ZnL4), 33 (l-ZnL5), and 36 (l-ZnL8) in Table 2 (entries 2–4). 46 (l-ZnL14) and 47 (l-ZnL15), which contained 4-trifluoromethylphenylalanine and 3,4-dimethoxyphenylalanine as amino-acids, respectively, afforded lower optical yields than 36 (l-ZnL8), which contained a phenylalanine group (entries 5 and 6). In addition, 48 (l-ZnL16) and 49 (l-ZnL17), which contained aromatic side chains, also afforded higher catalytic activities than 32 (l-ZnL4), 33 (l-ZnL5), and 36 (l-ZnL8) (entries 7 and 8). On the other hand, 50 (l-ZnL18), having a bulky diphenylmethyl group, gave 7a in moderate yield and 88% ee (R) (entry 9). These results suggest that Zn2+ complexes that contain sufficiently bulky side chains, such as decyl, naphthyl, and phenylethyl groups, are expected to have efficient catalytic activity. In entries 10 and 11, 51 (l-ZnL19), which contains an anionic propanoate side chain (from Glu), and 52 (l-ZnL20), which contains a cationic guanidium group (from Arg), afforded 7a in 78% ee (R) and 92% ee (R), respectively, thus, indicating negligible electrostatic effects on the enantioselectivity of the products. It was possible to improve the ee values by increasing the amount of acetone and performing the reaction at a lower temperature (entries 12–14 versus 2, 4 and 8, respectively).
Next, 53 and 54 (ZnL21 and ZnL22), which contained dipeptide side chains, were prepared based on the assumption that the presence of more hydrophobic and hydrogen bonding functionalities around the Zn2+ site would improve their catalytic activity. However, these Zn2+ complexes resulted in low chemical and optical yields (entries 15 and 16), thus, suggesting that one amino-acid side chain is suitable for aldol reactions catalyzed by the ZnL series.
Table 4 summarizes the aldol reactions between acetone and various benzaldehydes (6b–c and 6f–g), as catalyzed by 45 (l-ZnL13) and 49 (l-ZnL17) in acetone/H2O (9/1). When 4-chlorobenzaldehyde 6c was used, 7c was obtained in good yield and 94% ee (R) and 95% ee (R), respectively (entries 3 and 4) and, when 4-, 3-, and 2-nitrobenzaldehydes (6b, 6f, and 6g) were used as acceptors, high chemical and optical yields were similarly observed (entries 1, 2, and 5–8).
2.1.5. UV Titrations of Acetylacetone (Acac) with l-Proline, l-Valine, Zn(OTf)2, and Zn2+ Complexes (32 (l-ZnL4), 33 (l-ZnL5), 35 (ZnL7), and 26 (ZnL1)) in a Mechanistic Study
In order to examine the issue of whether amino groups of l-proline, 32 (l-ZnL4), and 33 (l-ZnL5) form Schiff-bases with substrates, we initially carried out a UV titration of acetone with l-proline and 32 (l-ZnL4). However, the UV spectral change was negligible.
As described in the Introduction, it was suggested that the mechanism of the aldolase antibodies involves enamine formation as the result of a reaction between the ɛ-amino group of Lys and the ketone substrate . In this scenario, it was reported that enaminone between the Lys residue of the antibody and β-diketone exhibit a strong UV absorption at 316 nm (ɛ316 ~ 15,000 M−1·cm−1).
Then, UV titrations of acetylacetone (acac) with l-proline and chiral Zn2+ complexes were conducted (Scheme 10). Figure 3a shows the results of the UV absorption titration of acac (0.2 mM) with l-proline in DMSO/H2O (1/2) at 25 °C, in which the absorption maxima of acac shifted from 276 to 316 nm at increasing concentrations of l-proline (0–500 equiv). These results suggest the formation of a Schiff-base between l-proline and acac. On the other hand, the absorption maxima of acac was shifted from 276 to 294 nm upon the addition of 32 (l-ZnL4) (0–50 equiv), as shown in Figure 3b. In order to assign the strong UV absorption at 294 nm shown in Figure 3b, the change in the UV spectra of acac as a function of pH in DMSO/H2O (1/2) was measured. The deprotonation constant of the carbonyl α-proton of acac was determined to be 8.9 by potentiometric pH titrations in H2O with I = 0.1 (NaNO3) at 25 °C. The UV absorption spectra of acac at pH 4.1 and 7.3 having a λmax (absorption maxima) at 276 nm shifted to 293 nm upon the addition of OH− (pH 9.8), possibly corresponds to the monoanionic form of acac ((acac)−).
These results suggest that l-proline forms the enaminone 55 with acac (λmax = 316 nm), while 32 (l-ZnL4) induces the formation of the 1:1 l-ZnL4-(acac)− complex 56 (λmax = 294 nm) (Scheme 10). Analysis of the titration curve in the inset of Figure 3a with the aid of the software program “BIND WORKS” gave an enaminone formation constant (Kapp) of ca. ~10 M−1 for acac with l-proline. In DMSO/H2O (95/5), the formation constant for l-proline-acac enaminone 55 was increased to 62 M−1, indicating that these equilibria are solvent-dependent. On the other hand, an analysis of the titration curve in the inset of Figure 3b gave a complexation constant for 56 of 2.1 × 102 M−1 in DMSO/H2O (1/2).
The apparent formation constants of enaminone from acac with l-valine (0–500 equiv) or ZnL-(acac)− complexes (Kapp) from Zn(OTf)2 (0–50 equiv), 33 (l-ZnL5) (0–50 equiv), 35 (ZnL7) (0–20 equiv), and 26 (ZnL1) (0–20 equiv), are summarized in Table 5. Upon addition of l-valine, the absorption maxima shifted from 276 to 316 nm, similarly to what was observed when l-proline was mixed with acac. On the other hand, Zn(OTf)2 showed an absorption maximum of 289 nm, similarly to what was observed for a mixture of 32 (l-ZnL4) and acac. The Zn2+ complexes 33 (l-ZnL5) and 35 (ZnL7) also showed absorption maxima at 292–295 nm. Interestingly, the change in the UV spectra of acac upon the addition of 26 (ZnL1), in which Zn2+ is 4-coordinated to four nitrogen atoms, was negligible. These results suggest that 33 (l-ZnL5) and 35 (ZnL7) have a higher activity for the recognition of (acac)− than Zn2+ complexes of tetradentate ligands.
2.1.6. Stopped-Flow Experiments to Determine the Rates of ZnL-(acac)− Complexation
Herein, stopped-flow experiments were performed to more-precisely determine the rates of formation of ZnL-(acac)− complex. The increase in UV/Vis absorption of acac (0.2 mM) with 33 (l-ZnL5, 3 mM) at 294 nm was monitored and a rate constant of 6.18 (±0.03) × 10−2 s−1 was calculated from the resulting curve by fitting to a single exponential equation. Similar studies of the complexation between acac and 45 (l-ZnL13) and 49 (l-ZnL17) afforded rate constants of 9.03 (±0.07) × 10−2 s−1 and 7.47 (±0.05) × 10−2 s−1, respectively, which were almost the same as that of 33 (l-ZnL5). These formation rates of ZnL-(acac)− complex are about 1.4 × 105 higher than that for enaminone 55.
2.1.7. Comparison between Reactivity of Enamine and Zn2+-Enolate Intermediates
The reactivity of an enamine intermediate 57 (from acetone-d6 and l-proline) and a Zn2+-enolate intermediate 58 (from acetone-d6 and 50 mM 32 (l-ZnL4)), in D2O at 37 °C, were compared by 1H-NMR spectroscopy (Scheme 11). The aldol reaction of the enamine intermediate 57 with 2-chlorobenzaldehyde 6a had not gone to completion even after 50 h (dashed curve in Figure 4). On the other hand, in the presence of 32 (l-ZnL4), it was found that 6a was converted quantitatively in 24 h at 37 °C (plain curve in Figure 4). The initial reaction rate of the aldol reaction between acetone and 6a via 58 is approximately 10 times higher than that via 57, indicating that the Zn2+-enolate is more reactive than enamine species.
2.1.8. X-ray Crystal Structure of 48 (l-ZnL16)
Initially, it was assumed that the NH2 group of the amino acid moiety would coordinate weakly or not at all to Zn2+ center (Scheme 8). X-ray crystal structure analyses of 48 (l-ZnL16) disclosed that the Zn2+ was coordinated not only by three nitrogen atoms (N(5), N(8), and N(11)) of cyclen and a NO3 anion, but also by the nitrogen atom (N(14)) of β-naphthylalanyl moiety, as shown in Figure 5. The approximate Zn–N bond lengths are 2.12 Å for Zn–N(5), 2.14 Å for Zn–N(8), 2.15 Å for Zn–N(11), and 2.09 Å for Zn–N(14), thus, implying that these Zn–N coordinate-bond lengths are almost identical. In this structure, the NO3 anion coordinates to Zn2+ atom and the bond lengths for the two Zn–O (NO3−) coordinate-bonds are about 2.24 Å (Zn–O(30)) and about 2.51 Å (Zn–O(32)). It is very likely that this Zn2+-bound NO3 anion is replaced by H2O in aqueous solution, based on our previous findings [23,24]. The Zn2+ center in 50 (l-ZnL18) was also coordinated by the nitrogen atom of diphenylalanyl moiety and by one water molecule .
2.1.9. Proposed Mechanism for the Aldol Reaction of Acetone Catalyzed by Chiral Zn2+ Complexes
Proposed reaction mechanisms for the ZnL-catalyzed aldol reactions of acetone and benzaldehydes 6 based on the aforementioned results are shown in Scheme 12. Our initial hypothesis involved path A, in which the amine group of the side chain in Zn2+ complexes deprotonated the α-proton of acetone, which was activated by coordination to the Lewis acidic Zn2+ center, as shown in 60, to generate the Zn2+-enolate complex 61. However, given the data reported herein, this pathway appears to be less plausible, as the basicity of the amino side chain would be lowered by its coordination to the Zn2+ center, as observed in the X-ray crystal structure (Figure 5).
Herein, two other possibilities were considered, namely, paths B and C. It has been reported that Zn2+-bound HO− and alkoxide species can act as bases and nucleophiles [23,24]. As shown in Scheme 7, the Zn2+-bound HO− in the class II aldolase model complex 27b (ZnL2(OH−)) is considered to deprotonate the α-proton to the carbonyl group of the phenacyl side chain to give the Zn2+-enolate form 27c (Zn(H−1L2)) in aqueous solution . Accordingly, it is hypothesized in path B that the OH− of 59b deprotonates the α-proton of acetone with the aid of the Lewis acidic Zn2+ in 63 and generates the Zn2+-enolate intermediate 64.
Path C shows another possibility, in which the Zn2+-bound OH− deprotonates the NH2 group to give rise to a NH− species 62, which deprotonates acetone, thus resulting in the formation of Zn2+-enolate intermediate 64. However, this is unlikely because the pKa value of the amine group would be over 30, which is much higher than those of Zn2+-bound H2O and alcohol moieties in typical Zn2+-cyclen complexes (pKa value: 7~9) [23,24].
A consideration of these points allows us to conclude that path B is the most plausible among the three possibilities, although we do not completely rule out the path A scenario. Then, Zn2+-enolate intermediate 64 reacts with an acceptor aldehyde through six-membered transition state 65 to afford 66, from which the aldol product is released and 59 is regenerated. The enantioselectivity could be explained in terms of the Zimmerman-Traxler-type transition state 65 . We assume that the Zn2+ in 65 is 5- (or 6-) coordinated by four nitrogen atoms of ligand, the enolate of the acetone, and the carbonyl group of the aldehyde, by analogy with the 5- (or 6-)coordinated Zn2+ in 32-(acac)− complex 56 in Scheme 10, and that enolate predominantly attacks at the Re-face of the aldehydes.
2.2. Asymmetric Aldol Reactions of Hydroxylated Acetones and Cyclic Ketones
2.2.1. Asymmetric Aldol Reactions of Hydroxylated Acetones (Hydroxyacetone 4 and Dihydroxyacetone 14)
Aldol reactions of unprotected α-hydroxyketones such as hydroxyacetone (HA) 4 and dihydroxyacetone (DHA) 14, were examined (Tables 6 and 7). This approach would provide effective methods for the synthesis of 1,2-diol derivatives and, hopefully carbohydrate derivatives. The reaction between 4 and 4-nitrobenzaldehyde 6b (in THF/4/H2O, DMSO/4/H2O, and 4/CH3CN) in the presence of 32 (l-ZnL4) gave 67 in good yield, but with poor enantioselectivities (entries 1–3). In these reactions, the anti-stereoisomer was obtained as the major product. On the other hand, in the presence of 33 (l-ZnL5) containing a primary amine unit, the enantioselectivity in favor of 67 was improved (entries 4–6). When a 4/CH3CN solvent system was employed, 33 (l-ZnL5) gave the aldol product syn-selectively (anti/syn = 37/63) in 91% yield and with 45% ee (3S, 4R) (entry 7).
Table 7 shows the results for the aldol reaction between 14 and 6b to give the triol aldol adduct, which was immediately acetylated to afford 16 in order to determine its stereoselectivity. As listed in entries 1 and 4, 32 (l-ZnL4) and 33 (l-ZnL5) poorly facilitated the aldol reaction in THF/H2O (H2O is required for the solvation of both substrates). In the DMSO/H2O solvent system, which gave a homogeneous reaction mixture, 32 (l-ZnL4) and 33 (l-ZnL5) afforded 16 in 22% and 27% yields, respectively, but with poor enantioselectivities (entries 2 and 5). When the NMP/H2O solvent system was used, syn-selectivity was observed (anti/syn = 26/74 and 34/66) (entries 3 and 6) with moderate enantioselectivities (44% ee (3R, 4S)) in favor of syn-16 (entry 6).
Whereas 32 (l-ZnL4) afforded the aldol products anti-67, from 4 and 6b, and syn-16, from 14 and 6b, with poor enantioselectivities, 33 (l-ZnL5) gave the syn forms of 67 and 16 with moderate enantioselectivities (Tables 6 and 7). These results suggest that a primary amine unit on the side chain is required for enantiodiscrimination in aldol reactions between α-hydroxyketones, such as 4 and 14 and aldehydes . It was assumed that the enantioselectivity in aldol reactions of 14 is influenced by two hydroxyl groups.
2.2.2. Asymmetric Aldol Reactions of Cyclic Ketones (Cyclohexanone 9 and Cyclopentanone 68)
Next, the aldol reaction of cyclohexanone 9 and 6b was carried out using 45 (l-ZnL13) (5 mol %, 25 mM) in different solvent systems, as listed in entries 1–10 of Table 8. Although only trace amounts of aldol product 11 were obtained under neat conditions (entry 1), the reaction was accelerated in the case of 9/H2O (95/5) to give 11 in 79% yield with 89% ee (2R, 1′R), while the anti/syn ratio was almost 1:1 (entry 2). When 5 mol % TFA was added, the diastereo- and enantioselectivity of syn-11 were improved (entry 3) [37,38] (as was confirmed by 1H-NMR that 45 (l-ZnL13) did not decompose under these conditions). Among the alcohol solvents tested (MeOH, EtOH, and 2-propanol), MeOH gave anti-11 in 72% ee (2S, 1′R) with an anti/syn ratio of 82/18 (entries 4–6). The use of aprotic polar solvents, such as NMP and DMF, gave anti-11 as the major isomer (anti/syn = 90/10) with good enantioselectivities, although the chemical yields were rather low (entries 7 and 8). When a 9/NMP/H2O mixture was used, the reaction proceeded smoothly to afford 11 in 85% yield with 83% ee (2R, 1′R) and an anti/syn ratio of ca. 1/1 (entry 9). On the other hand, anti-11 was obtained as the major isomer with good diastereo- and enantioselectivity (anti/syn = 88/12, 84% ee (2S, 1′R)) when 9/NMP/MeOH was used as the solvent (entry 10). A similar dependency of the stereochemistry of the aldol products on the solvent system used was observed when 49 (l-ZnL17) was used (entries 11 and 12). In entries 13 and 14, syn-69 was obtained as a major isomer in a 68/H2O system in high yield and with good enantioselectivities (entry 13), while the yield and stereoselectivities of 69 were low in 68/NMP/MeOH (entry 14).
2.3. One-Pot Chemoenzymatic Synthesis of Chiral 1,3-Diols Using an Enantioselective Aldol Reaction and Enzymatic Reduction
2.3.1. Introduction for One-Pot Chemoenzymatic Synthesis
Chemoenzymatic synthesis by the combined use of chemical catalysis and biocatalysis is a powerful methodology for the multistep synthesis of biologically important compounds, drugs, and so on. Organic reactions by artificial catalysts are generally conducted in organic solvents, as many organic molecules, such as reagents, catalysts, and intermediates, are usually not stable or soluble in water. In contrast, enzymatic reactions in living systems are conducted in aqueous solvents, because most of enzymes are functional only within a narrow range of temperature and pH levels and not so stable in less polar organic environments. This discrepancy makes it difficult to conduct one-pot chemoenzymatic reactions in an organic environment. Recently, the development of bioorthogonal reactions are growing as chemical reactions that neither interact with nor interfere with a biological system under physiological conditions  and it could be applied to chemoenzymatic synthesis.
To date, a number of examples of one-pot processes have been developed, based on chemocatalytic tandem reactions, multienzymatic reactions, and biotechnological reactions [41–43]. It is assumed that one-pot processes involving chemical catalysts and biocatalysts take full advantage of the productivity of chemical catalysts and the chemo-, region-, and stereoselectivity of biocatalysts . For example, Gröger et al. reported on an enantioselective synthesis of ethyl (S)-3-aminobutanoic acid 74 by means of combinations of aza-Michel reaction between 70 and 71, and the kinetic resolution via aminolysis catalyzed by Candida antarctica lipase to give 72, followed by hydrolysis and hydrogenation (Scheme 13a) . Chiral 1,3-diols derivatives of aromatic compounds such as 76 were synthesized by enantioselective aldol reactions of acetone with 6c using organocatalysts 75 and successive enantioselective reduction of ADH and NADH system (Scheme 13b) . Chiral biaryl-containing alcohols, 78 and 80, were synthesized in very high optically yields using a combination of cross-coupling reactions of 77 with 79 promoted by palladium catalysts and enantioselective enzymatic reduction (Scheme 13c) .
To date, numerous publications for the stereoselective synthesis of 1,3-diols that contain two stereogenic centers and important interemediate for various purposes have been reported [1,47], involving asymmetric homogeneous and heterogeneous hydrogenation and diastereoselective reduction , radical chain elongation , enzymatic and non-enzymatic asymmetrization [50,51], dynamic kinetic resolution , and stereoselective aldol-Tishchenko reactions . However, there is still substantial demand for stereoselective synthetic methods to produce all possible stereoisomers of chiral 1,3-diols.
It was expected that the one-pot chemoenzymatic synthesis by the combined use of chiral Zn2+ catalysts and enzymes in an aqueous solvent would be useful for the selective synthesis of all of the possible stereoisomers of 1,3-diols 76 in a one-pot manipulation involving enantioselective aldol reactions of acetone with benzaldehydes to give 7 using chiral Zn2+ complexes, and the successive enantioselective reduction of 7 to give 76 using oxidoreductases with the regeneration of the NADH (reduced form of nicotinamine adenine dinucleotide) cofactor (Scheme 14) .
2.3.2. Enantioselective Reductions of β-Hydroxyketones 7a–c Using Oxidoreductase
For the reduction of β-hydroxyketones 7a–c, we first chose Baker’s yeast alcohol dehydrogenase (ADH) and oxidoreductases from Saccharomyces cerevisiae (S. cerevisiae) and Lactobacillus kefir (L. kefir) as these enzymes have been reported to catalyze the enantioselective reduction of 4-phenyl-4-hydroxy-2-butanone . However, Baker’s yeast ADH and S. cerevisiae ADH were not very effective for the reduction of 7a (entries 1 and 2 in Table 9). In entry 3, it was found that the ADH from L. kefir is effective for the stereoselective reduction of 7a, albeit this enzyme produces only the (R)-form of 76a.
We, thus, decided to test the “Chiralscreen® OH” kit, which is available from Daicel Co., Ltd, Niigata, Japan, and contains a library of recombinant NADH-dependent oxidoreductases . Generally, oxidoreductases require an equivalent amount of NAD(P)H (reduced form) for activity. The reductases in “Chiralscreen® OH” themselves can reduce NAD+ (oxidized form) to NADH using 2-propanol as a hydride source, so that the concentration of NADH can be reduced to a catalytic amount. It has been also reported that “Chiralscreen® OH” can be used to catalyze the reduction of a variety of ketone even if the solubility of the substrate is low in aqueous solution .
The results of the stereoselective reduction of racemic 7a–c using “Chiralscreen® OH” enzymes in 100 mM phosphate buffer (pH 7.2) at 30 °C were listed in entries 4–12. Among the nine enzymes of “Chiralscreen® OH” tested (E001, 021, 031, 039, 041, 051, 057, 092, and 119), four enzymes such as E001, E031, E039, and E092, were found to be effective for the reduction of 7a (entries 4–7) . In general, E001 and E039 gave better chemical yields than E031 and E092 (entries 4 and 6 versus entries 5 and 7). Interestingly, it was found that E001 and E039 give (S)- and (R)-forms of 76a (99% ee), respectively, with respect to the stereogenic center (position 3) in 76a. It should also be noted that the anti/syn ratios of 76a were almost 1:1, thus indicating that kinetic resolution negligibly occurred (except for E092 in entry 7). It was also found that 7b and 7c are converted into 76b and 76c by E001 and E039, respectively (entries 8–11), and the reduction of (S)-7a (90% ee) with E001 exclusively gave anti-76a (1S, 3S) as the main product (entry 12).
2.3.3. One-Pot Chemoenzymatic Synthesis of Optically Active 1,3-Diols 76a–c from Acetone and Benzaldehydes 6a–c
To examine the one-pot synthesis of 1,3-diols 76a–c from acetone and benzaldehydes 6a–c, simultaneous one-pot aldol-reduction reactions was attempted in a mixture containing acetone, 6a–c, Zn2+ complexes (36 (l-ZnL8) and 37 (d-ZnL8)), NADH, and “Chiralscreen® OH”-E001 or E039 (Scheme 15). It was assumed that acetone, which would be generated as a byproduct of the regeneration of NADH from 2-propanol and NAD+, could be used as the substrate of aldol reaction, so that the amount of acetone could be reduced and the aldol-reduction cycle could proceed in just one reactor. However, this system did not work, because an excess amount of acetone was required to promote the aldol reaction, during which the Chiralscreen® enzymes were inactivated. As a result, only aldol product 7 was obtained with the negligible formation of 76.
Then, step-wise chemoenzymatic reaction was performed, as summarized in Scheme 16. The enantioselective aldol reaction between acetone and 6 with 36 (l-ZnL8) or 37 (d-ZnL8) (10 mol %) was conducted in acetone/H2O to give 7. The reaction mixture was then diluted with phosphate buffer (100 mM, pH 7.2), and the enzyme, NAD+, and 2-propanol were added for the reduction of the aldol product 7.
The results are also listed in Table 10. The aldol reaction of 6a with acetone in the presence of 36 (l-ZnL8) and the successive reduction by E001 gave 76a in 88% yield with a syn/anti ratio of approximately 4/96 ((1R, 3S)-76a is a major isomer; as listed in entry 1). Employing E039 instead of E001 switched the product to (1R, 3R)-76a (entry 2). The use of 37 (d-ZnL8) with E001 and E039 gave (1S, 3S)-76a and (1S, 3R)-76a, respectively, with >95% ee (entries 3 and 4). These results suggest that all four stereoisomers of 1,3-diols can be prepared by selecting the appropriate chiral Zn2+ complexes and oxidoreductases. Similarly, entries 5–8 and 9–12 indicate that 4-nitrobenzaldehyde 6b and 4-chlorobenzaldehyde 6c can be converted into all possible stereoisomers of the corresponding 1,3-diols, 76b and 76c.
We reviewed the design and synthesis of chiral Zn2+ complexes comprising chiral amino acids and Zn2+-cyclen complexes, inspired by two classes of natural aldolases. The combined findings indicate that these Zn2+ complexes are efficient catalysts for asymmetric aldol reactions of acetone with benzaldehydes in water-containing solvent systems and that Zn2+ complexes that contain appropriate hydrophobic and bulky side chains give high chemical and optical yields (up to 97% yield and 96% ee). Mechanistic studies including UV/Vis titrations of ZnL with acac and X-ray crystal structure analysis of the Zn2+ complexes indicate that these catalysts accelerate the aldol reactions via a Zn2+-enolate intermediate, which is generated by the cooperative functions of Zn2+ ion of Zn2+ complexes that activate ketone substrates as Lewis acids and the Zn2+-bound OH− that deprotonates the α-proton of ketones.
One of the advantages of these aldol reactions is that they are applicable to the one-pot synthesis of biorelevantly important compounds such as the optically active 1,3-diol 76 by using a combination of the enantioselective aldol reactions catalyzed by chiral Zn2+ complexes and successive reduction by the recombinant oxidoreductase system “Chiralscreen® OH”. Typical examples include the one-pot chemoenzymatic synthesis from acetone and 6a with 36 (l-ZnL8) and E001 to afford (1R, 3S)-76a in 88% yield with 96% ee. Using these methodologies, all of the possible stereoisomers of 76a–c can be obtained when the appropriate ZnL aldol catalyst and oxidoreductases are used.
We conclude that these results afford useful information concerning the design, synthesis, and mechanistic study of new artificial catalysts for catalytic enantioselective aldol reactions. Further catalyst design promises to lead, not only to the development of efficient stereoselective reactions, but also to the development of more practical and useful chemoenzymatic and biocompatible synthesis methods.
This work was supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan (No. 18390009, 19659026, 22390005, 22659005, and 24659058) and High-Tech Research Center Project for Private Universities (matching fund subsidy from MEXT). We appreciate Akihito Yamano (Rigaku Corporation, Akishima, Japan), and Kenji Yoza (Bruker AXS K. K., Yokohama, Japan) for the X-ray crystal structure analysis. We also appreciate the opportunity to conduct helpful discussions with Yasuyuki Yamada (Nagoya University, Nagoya, Japan), Yoshiyuki Kageyama (Hokkaido University, Sapporo, Japan), Yosuke Hisamatsu (Tokyo Universtiy of Science, Noda, Japan), Shinya Ariyasu (Tokyo Universtiy of Science, Noda, Japan), and Tomohiro Tanaka (Tokyo University of Science, Noda, Japan), Motoko Hayashi (Daicel Co., Ltd, Niigata, Japan), Masahiro Nishikawa (Daicel Co., Ltd, Niigata, Japan), and Reiko Kuroda (Research Institute for Science and Technology, Tokyo University of Science, Noda, Japan).
Conflicts of Interest
The authors declare no conflict of interest.
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|Table 1. Results for an asymmetric aldol reaction between acetone and 6a catalyzed by l-proline and Zn2+ complexes.|
|Entry||Catalyst [a] (mM)||Mol %||Solvent [b]||Conditions||Yield [c] (%)||CTN [d]||ee (%) [e]|
|1||l-proline (20)||20||DMSO/acetone||4 h, 25 °C||85||4||67 (R)|
|2||31 (l-ZnL3) [f] (10)||10||DMSO/acetone||26 h, 25–50 °C||3||–||1 (R)|
|3||32 (l-ZnL4) [f] (10)||10||DMSO/acetone||4 h, 25 °C||12||1||34 (R)|
|4||l-proline (50)||5||acetone/H2O||20 h, 37 °C||22||4||48 (R)|
|5||31 (l-ZnL3) [f] (50)||5||acetone/H2O||20 h, 37 °C||43||9||1 (R)|
|6||32 (l-ZnL4) [g] (50)||5||acetone/H2O||20 h, 37 °C||73||15||80 (R)|
|7||29 (l-L4) [h] (50)||5||acetone/H2O||20 h, 37 °C||72||14||racemic|
|8||41a (l-CdL4) [f] (50)||5||acetone/H2O||20 h, 37 °C||5||1||50 (R)|
|9||41b (l-CuL4) [f] (50)||5||acetone/H2O||20 h, 37 °C||trace||–||–|
|10||33 (l-ZnL5) [f] (50)||5||acetone/H2O||20 h, 37 °C||87||17||80 (R)|
|11||34 (l-ZnL6) [f] (50)||5||acetone/H2O||20 h, 37 °C||54||11||9 (R)|
|12||35 (ZnL7) [g] (50)||5||acetone/H2O||20 h, 37 °C||5||1||2 (S)|
|13||36 (l-ZnL8) [f] (50)||5||acetone/H2O||24 h, 25 °C||85||17||91 (R)|
|14||37 (d-ZnL8) [f] (50)||5||acetone/H2O||24 h, 25 °C||85||17||91 (S)|
|15||26 (ZnL1) [g] (50)||5||acetone/H2O||20 h, 37 °C||trace||–||–|
|16||l-proline + 26 (ZnL1) [g] (50)||5||acetone/H2O||20 h, 37 °C||trace||–||–|
aNumbers in parentheses are the concentrations of catalysts in solvent;bSolvent ratio: DMSO/acetone = 4/1 (entries 1–3), acetone/H2O = 4/1 (entries 4–16);cIsolated yield;dCatalytic Turnover Number (=yield/equivalents of catalyst);eDetermined by HPLC analysis using a chiral column (references [31,34]);fZn2+ complexes, l-CdL4, and l-CuL4 were formed in situ;gIsolated Zn2+ complexes were used;hl-L4 was extracted with CHCl3 from aq. NaOH (pH > 12) prior to use.
|Table 2. Results for asymmetric aldol reactions between acetone and benzaldehydes (6b–e) catalyzed by 32 (l-ZnL4), 33 (l-ZnL5), 36 (l-ZnL8), and 37 (d-ZnL8).|
|Entry||Substrate||Catalyst [a]||mol %||Conditions||Product||Yield (%) [b]||CTN [c]||ee (%) [d]|
|1||6b||32 (l-ZnL4)||5||20 h, 37 °C||7b||78||16||63 (R)|
|2||6b||33 (l-ZnL5)||5||20 h, 37 °C||7b||86||17||86 (R)|
|3||6b||36 (l-ZnL8)||10||24 h, 30 °C||7b||quant||10||90 (R)|
|4||6b||37 (d-ZnL8)||10||24 h, 30 °C||7b||quant||10||90 (S)|
|5||6c||36 (l-ZnL8)||10||72 h, 30 °C||7c||quant||10||90 (R)|
|6||6c||37 (d-ZnL8)||10||72 h, 30 °C||7c||quant||10||90 (S)|
|7||6d||32 (l-ZnL4)||10||20 h, 37 °C||7d||70||7||52 (R)|
|8||6d||33 (l-ZnL5)||10||20 h, 37 °C||7d||49||5||75 (R)|
|9||6e||32 (l-ZnL4)||10||120 h, 37 °C||7e||59||6||57 (R)|
|10||6e||33 (l-ZnL5)||10||120 h, 37 °C||7e||55||6||83 (R)|
aConcentrations of catalysts in the solvent were 50 mM. Zn2+ complexes were formed in situ;bIsolated yield;cCatalytic turnover number (=chemical yield/equivalents of catalyst);dDetermined by HPLC analysis using a chiral column (references [31,34]).
|Table 3. Results for an asymmetric aldol reaction between acetone and 6a catalyzed by 42–54 (l-ZnL10–ZnL22) in acetone/H2O.|
|Entry [a]||Catalyst [b]||Yield (%) [c]||CTN [d]||ee (%) [e]|
|1||42 (l-ZnL10)||30||6||91 (R)|
|2||43 (l-ZnL11)||89||18||94 (R)|
|3||44 (l-ZnL12)||84||17||86 (R)|
|4||45 (l-ZnL13)||91||18||94 (R)|
|5||46 (l-ZnL14)||67||13||87 (R)|
|6||47 (l-ZnL15)||86||17||78 (R)|
|7||48 (l-ZnL16)||93||19||93 (R)|
|8||49 (l-ZnL17)||95||19||94 (R)|
|9||50 (l-ZnL18)||54||11||88 (R)|
|10||51 (l-ZnL19)||44||9||78 (R)|
|11||52 (l-ZnL20)||79||16||92 (R)|
|12||43 (l-ZnL11)||90||18||96 (R)|
|13||45 (l-ZnL13)||85||17||95 (R)|
|14||49 (l-ZnL17)||96||19||96 (R)|
|15||53 (ZnL21)||24||5||9 (R)|
|16||54 (ZnL22)||19||4||33 (S)|
aReaction conditions: acetone/H2O = 4/1, 24 h, 30 °C (Entries 1–11), acetone/H2O = 9/1, 24 h, 25 °C (Entries 12–14), and acetone/H2O = 4/1, 24 h, 25 °C (Entries 15–16);bConcentrations of catalysts in the solvent were 50 mM. Zn2+ complexes were formed in situ;cIsolated yield;dCatalytic Turnover Number (=yield/equivalents of catalyst);eDetermined by HPLC analysis using a chiral column (reference ).
|Table 4. Results for asymmetric aldol reactions between acetone and benzaldehydes (6b–c, and 6f–g) catalyzed by 45 (l-ZnL13) and 49 (l-ZnL17) in acetone/H2O.|
|Entry [a]||Substrate||Catalyst [b]||Product||Yield (%) [c]||CTN [d]||ee (%) [e]|
|1||6b||45 (l-ZnL13)||7b||92||18||96 (R)|
|2||6b||49 (l-ZnL17)||7b||92||18||95 (R)|
|3||6c||45 (l-ZnL13)||7c||74||15||94 (R)|
|4||6c||49 (l-ZnL17)||7c||83||17||95 (R)|
|5||6f||45 (l-ZnL13)||7f||92||18||95 (R)|
|6||6f||49 (l-ZnL17)||7f||97||19||95 (R)|
|7||6g||45 (l-ZnL13)||7g||96||19||90 (R)|
|8||6g||49 (l-ZnL17)||7g||89||18||92 (R)|
aReaction conditions: 24 h, 25 °C (Entries 1, 2, and 5–8), 72 h, 25 °C (Entries 3 and 4);bConcentrations of catalysts in the solvent were 50 mM. Zn2+ complexes were formed in situ;cIsolated yield;dCatalytic Turnover Number (=yield/equivalents of catalyst);eDetermined by HPLC analysis using a chiral column (reference ).
|Table 5. The apparent enaminone or Zn2+-enolate formation constants (Kapp) for l-proline, l-valine, Zn(OTf)2, 32 (l-ZnL4), 33 (l-ZnL5), 35 (ZnL7), and 26 (ZnL1) with acetylacetone (acac) in DMSO/H2O (1/2) at 25 °C (λmax and Kapp are absorption maxima and apparent formation constants of the catalyst-(acac) complexes, respectively).|
|l-proline||l-valine||Zn(OTf)2||32 (l-ZnL4)||33 (l-ZnL5)||35 (ZnL7)||26 (ZnL1)|
|λmax||316 nm (enaminone)||316 nm (enaminone)||289 nm (Zn2+-enolate)||294 nm (Zn2+-enolate)||292 nm (Zn2+-enolate)||295 nm (Zn2+-enolate)||–|
|Kapp||~10 (62 [a])||~10||157||212||139||589 (49 [b])||n. i. [c]|
aThe Kapp value in DMSO/H2O (95/5);bThe Kapp value obtained by potentiometric pH titration in H2O with I = 0.1 (NaNO3) at 25 °C (pKa of acac = 8.9);cNegligible interaction with acac.
|Table 6. Results for an asymmetric aldol reaction between 4 and 6b catalyzed by 32 (l-ZnL4) and 33 (l-ZnL5).|
|Entry||Catalyst [a] (mM)||Solvent||Conditions||Yield [b] (%)||CTN [c]||d.r. [d] (anti/syn)||ee [%] [e] (anti/syn)|
|1||32 (l-ZnL4) (25)||THF/4/H2O (5/4/1)||24 h, 37 °C||83||17||75/25||racemic/racemic|
|2||32 (l-ZnL4) (50)||DMSO/4/H2O (21/1.1/1)||20 h, 37 °C||80||16||52/48||racemic/4 (3S, 4R)|
|3||32 (l-ZnL4) (25)||4/CH3CN (1/1)||24 h, 25 °C||90||18||75/25||1 (3R, 4R)/8 (3S, 4R)|
|4||33 (l-ZnL5) (25)||THF/4/H2O (2/1/1)||20 h, 37 °C||89||18||64/36||7 (3S, 4S)/5 (3S, 4R)|
|5||33 (l-ZnL5) (25)||4/H2O (3/1)||20 h, 37 °C||68||14||58/42||9 (3S, 4S)/14 (3S, 4R)|
|6||33 (l-ZnL5) (25)||4/NMP [f] (1/1)||24 h, 25 °C||96||19||63/37||18 (3S, 4S)/2 (3R, 4S)|
|7||33 (l-ZnL5) (25)||4/CH3CN (1/1)||24 h, 25 °C||91||18||37/63||8 (3R, 4R)/45 (3S, 4R)|
aNumbers in parentheses are the concentrations of catalysts in solvent. Zn2+ complexes were formed in situ;bIsolated yield;cCatalytic Turnover Number (=yield/equivalents of catalyst);dDetermined by 1H-NMR spectroscopy and HPLC analysis;eDetermined by HPLC analysis using a chiral column (reference );fNMP = N-methylpyrrolidone.
|Table 7. Results for an asymmetric aldol reaction between 14 [a] and 6b catalyzed by 32 (l-ZnL4) and 33 (l-ZnL5).|
|Entry||Catalyst [b] (mM)||mol %||Solvent||Conditions (for aldol)||Yield [%] [c] (for 2 steps)||d.r. [d] (anti/syn)||ee [%] [e] (anti/syn)|
|1||32 (l-ZnL4) (12)||5||THF/H2O (1/1)||96 h, 37 °C||Trace||–||–|
|2||32 (l-ZnL4) (6)||5||DMSO/H2O (3/1)||72 h, 37 °C||22||37/63||racemic/6 (3R, 4S)|
|3||32 (l-ZnL4) (100)||10||NMP/H2O (33/1)||24 h, 25 °C||4||26/74||3 (3R, 4R)/2 (3S, 4R)|
|4||33 (l-ZnL5) (17)||5||THF/H2O (3/5)||72 h, 37 °C||4||42/58||3 (3S, 4S)/9 (3R, 4S)|
|5||33 (l-ZnL5) (6)||5||DMSO/H2O (2/1)||72 h, 37 °C||27||37/63||racemic/6 (3R, 4S)|
|6||33 (l-ZnL5) (100)||10||NMP/H2O (33/1)||42 h, 25 °C||26||34/66||8 (3R, 4R)/44 (3R, 4S)|
aWe used the DHA monomer (entries 1, 2, 4, and 5) or DHA dimer (entries 3 and 6). The equivalents of DHA (as monomer) relative to 6b used were 3.4 (entry 1), 3 (entries 2 and 5), 5 (entry 4), and 2 equiv (entries 3 and 6);bNumbers in parentheses are concentrations of catalysts in the solvent. Zn2+ complexes were formed in situ;cIsolated yield;dDetermined by 1H-NMR spectroscopy and HPLC analysis;eDetermined by HPLC analysis using a chiral column (reference ).
|Table 8. Results for asymmetric aldol reactions between cyclic ketones (9 and 68) and 6b catalyzed by 45 (l-ZnL13) and 49 (l-ZnL17).|
|Entry||Catalyst [a]||Solvent [b]||Product||Yield [c] (%)||CTN [d]||d.r. [e] (anti/syn)||ee [%] [f] (anti/syn)|
|1||45 (l-ZnL13)||9||11||4||1||99/1||28 (2S, 1′R)/19 (2R, 1′R)|
|2||45 (l-ZnL13)||9/H2O (95/5)||11||79||16||49/51||11 (2S, 1′R)/89 (2R, 1′R)|
|3||45 (l-ZnL13) [g]||9/H2O (95/5)||11||67||13||30/70||2 (2R, 1′S)/92 (2R, 1′R)|
|4||45 (l-ZnL13)||9/MeOH (50/50)||11||81||16||82/18||72 (2S, 1′R)/61 (2R, 1′R)|
|5||45 (l-ZnL13)||9/EtOH (50/50)||11||61||12||67/33||68 (2S, 1′R)/86 (2R, 1′R)|
|6||45 (l-ZnL13)||9/2-propanol (50/50)||11||13||3||80/20||68 (2S, 1′R)/54 (2R, 1′R)|
|7||45 (l-ZnL13)||9/DMF (50/50)||11||4||1||91/9||84 (2S, 1′R)/52 (2R, 1′R)|
|8||45 (l-ZnL13)||9/NMP (50/50)||11||19||4||90/10||88 (2S, 1′R)/17 (2R, 1′R)|
|9||45 (l-ZnL13)||9/NMP/H2O (40/50/10)||11||85||17||49/51||7 (2R, 1′S)/83 (2R, 1′R)|
|10||45 (l-ZnL13)||9/NMP/MeOH (40/50/10)||11||96||19||88/12||84 (2S, 1′R)/46 (2R, 1′R)|
|11||49 (l-ZnL17)||9/H2O (95/5)||11||62||12||51/49||6 (2S, 1′R)/90 (2R, 1′R)|
|12||49 (l-ZnL17)||9/NMP/MeOH (40/50/10)||11||89||18||87/13||83 (2S, 1′R)/51 (2R, 1′R)|
|13||49 (l-ZnL17)||68/H2O (95/5)||69||90||18||31/69||23 (2R, 1′S)/87 (2R, 1′R)|
|14||49 (l-ZnL17)||68/NMP/MeOH (40/50/10)||69||6||1||55/45||37 (2R, 1′S)/7 (2R, 1′R)|
aConcentrations of catalysts in the solvent were 25 mM. Zn2+ complexes were formed in situ;bReaction solution is homogeneous in entries 1, 4–10, 12, and 14. Reaction solution is heterogeneous in entries 2–3, 11, and 13;cIsolated yield;dCatalytic Turnover Number (=yield/equivalents of catalyst);eDetermined by 1H-NMR spectroscopy and HPLC analysis;fDetermined by HPLC analysis using a chiral column (reference );gTFA (5 mol %) was used as a additive.
|Table 9. Results for the asymmetric reduction of β-hydroxyketones 7a–c catalyzed by oxidoreductase with NADH regeneration in 100 mM phosphate buffer (pH 7.2) at 30 °C for one day.|
|Entry||Substrate||Oxidoreductase [a] (syn/anti)||Product [c]||Yield [%] [b] (syn/anti)||ee [%] [c] (syn/anti)||3R/3S [c]|
|1||rac-7a [d]||Baker’s yeast||–||trace||–||–|
|2||rac-7a [d]||ADH from S. cerevisiae||–||trace||–||–|
|3||rac-7a [d]||ADH from L. Kefir||76a (52/48)||quant||>99 (1R, 3R)/>99(1S, 3R)||>99/<1|
|4||rac-7a [d]||E001 [e]||76a (54/46)||quant||>99 (1S, 3S)/>99 (1R, 3S)||<1/>99|
|5||rac-7a [d]||E031 [e]||76a (47/53)||50||95 (1S, 3S)/93 (1R, 3S)||3/97|
|6||rac-7a [d]||E039 [e]||76a (48/52)||quant||>99 (1R, 3R)/>99 (1S, 3R)||>99/<1|
|7||rac-7a [d]||E092 [e]||76a (78/22)||64||>99 (1S, 3S)/94 (1R, 3S)||1/99|
|8||rac-7b [d]||E001 [e]||76b (50/50)||quant||>99 (1S, 3S)/>99 (1R, 3S)||<1/>99|
|9||rac-7b [d]||E039 [e]||76b (48/52)||quant||>99 (1R, 3R)/>99 (1S, 3R)||>99/<1|
|10||rac-7c [d]||E001 [e]||76c (50/50)||quant||>99 (1S, 3S)/>99 (1R, 3S)||<1/>99|
|11||rac-7c [d]||E039 [e]||76c (49/51)||quant||>99 (1R, 3R)/>99 (1S, 3R)||>99/<1|
|12||7a (90% ee (S))||E001 [e]||76a (95/5)||quant||>99 (1S, 3S)/>99 (1R, 3S)||<1/>99|
aConditions for the enzymatic reductions: [ketone] = 10 mM in 100 mM phosphate buffer, 24 h, 30 °C in the presence of 2-propanol (100 mM) and NAD+ (2 mM);bIsolated yield;cDetermined by 1H-NMR and HPLC analysis using a chiral column (reference );dRacemate of 7 was used as the substrate;eEnzyme of Chiralscreen purchased from Daicel Co., Ltd.
|Table 10. Results for the one-pot chemoenzymatic synthesis of chiral 1,3-diols 76a–c in aqueous solvent by the combined use of enantioselective aldol reactions catalyzed by chiral Zn2+ complexes and enantioselective reduction using “Chiralscreen® OH”.|
|Entry||Substrate||ZnL [a]||Oxidoreductase [b] (“Chiralscreen® OH”)||Product||Yield (%) [c]||Product ratio [d]|
aConcentrations of catalysts for the aldol reaction were 50 mM. Zn2+ complexes were formed in situ;bConditions for reductions by enzymes: [ketone] = 10 mM in 100 mM phosphate buffer (pH 7.2), 24 h, 30 °C in the presence of 2-propanol (100 mM) and NAD+ (2 mM);cIsolated yield;dDetermined by HPLC analysis of a mixture of all stereoisomers by column chromatography using a chiral column (reference ).
© 2014 by the authors; licensee MDPI, Basel, Switzerland This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).