Elżbieta
Wojaczyńska
*a,
Jacek
Skarżewski
a,
Łukasz
Sidorowicz
a,
Robert
Wieczorek
b and
Jacek
Wojaczyński
b
aDepartament of Organic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland. E-mail: elzbieta.wojaczynska@pwr.edu.pl; Fax: +48 713202427; Tel: +48 713202410
bDepartment of Chemistry, University of Wrocław, 14 F. Joliot-Curie St., 50-383 Wrocław, Poland
First published on 30th September 2016
Chiral scaffolds of 2-azabicyclo[2.2.1]heptane and 2-azabicyclo[3.2.1]octane were used for the construction of new modular catalysts containing complexing moieties pyridine, 2,2′-bipyridine and 1,10-phenanthroline appended by an imine linkage. The coordination abilities of the new ligands towards Zn(II) were investigated using NMR and UV spectroscopy. The plausible structures of the [ZnL2]2+ and [ZnLXn](2−n)+ complexes formed were established by comparison of the experimental and DFT-calculated NMR spectra. The catalytic application of the [ZnLXn](2−n)+-type complexes in the asymmetric aldol reaction of ketones with aromatic aldehydes produced an excess of the respective syn-aldols in up to >98% ee.
In this contribution, we describe the use of two bicyclic chiral scaffolds, 2-azabicyclo[2.2.1]heptane (2-azanorbornane) and 2-azabicyclo[3.2.1]octane (bridged azepane), for the construction of bifunctional catalysts containing the metal-complexing moieties 1,10-phenanthroline and 2,2′-bipyridine (Fig. 1). We propose a simple method of module assembling by an imine linkage which introduces a favorably located additional donor atom. Changing the ring size of the chiral scaffold, the configuration of stereocenters and the heteroaromatic amine should allow for fine tuning of the catalytic properties and optimization of asymmetric induction.
2-Azanorbornane, bearing a stable bicyclic skeleton with an intrinsic chirality, has been recognized as a versatile scaffold for asymmetric synthesis.4 This system is readily available via the stereoselective aza-Diels–Alder reaction of chiral imines and cyclopentadiene. Its preparation in both enantiomeric forms in a gram or even kilogram scale has been described.5,6 The derivatives of 2-azabicyclo[2.2.1]heptane after various modifications of the basic structure lead to a number of (N,O), (N,N), (N,P), and (N,S)-donating ligands, which have already been applied in various enantioselective transformations.4,7 Thus, both alcohol epimers (1 and 2), differing in the configuration on the 3-C stereocenter can be prepared from the separated isomeric cycloadducts formed in one aza-Diels–Alder reaction. In the course of our earlier studies, we have observed that upon attempted nucleophilic substitution of a hydroxyl group in alcohol 2 a stereoselective ring expansion takes place, yielding 2-azabicyclo[3.2.1]octane.8 In this way, amines based on the bridged piperidine (3/4) or azepane (5/6, Fig. 2) can be prepared and applied to the construction of bifunctional catalysts bearing a stereodifferentiating bicyclic skeleton with a tertiary amine function.
Among the catalytic reactions leading to the formation of new C–C bonds, the aldol reaction plays an important role. In its asymmetric variant, two stereocenters can be generated with high stereoselectivity.9 Nature exploits this reaction catalyzed by aldolases for biosynthesis. While type I aldolases operate via an enamine mechanism, type II enzymes use enolate-type activation with a metal cofactor (typically Zn2+ ion). Accordingly, both organocatalysts and various metal complexes (in particular, Zn(II)-based catalysts) were effective in diastereo- and enantioselective processes.9,10 In this contribution, we describe our studies on the application of zinc complexes of phenanthroline- and bipyridine-derived chiral hybrid catalysts in the stereoselective aldol reaction.
Amine 4 was prepared in an analogous manner from the respective endo aldehyde obtained from alcohol endo-2. Amines based on a bridged azepane skeleton 5 and 6 were obtained from alcohols 1 and 2, respectively, as described previously.8
A similar procedure was applied to the synthesis of derivatives 10 and 11 using 2,2′-bipyridyl-6-carboxaldehyde and 1,10-phenanthroline-2-carboxaldehyde, respectively. These aldehydes were prepared from their parent compounds (2,2′-bipyridyl and 1,10-phenanthroline) using the adopted literature procedure14 leading to primary alcohols which were oxidized under Swern conditions. 1,10-Phenanthroline-2-carboxaldehyde was also reacted with amines 4, 5, and 6 to yield ligands 12, 13, and 14, respectively. All imines were found to be unstable on silica and attempts of chromatographic purification were unsuccessful.
In modified variants of the procedure zinc acetate was replaced with zinc triflate; in certain cases 0.05 mmol acetic acid was added together with zinc(II) salt. The chosen reactions were conducted at 273 K.
Scheme 1 Synthesis of amines 3 and 5.8,13 |
In all cases, the possible interconversion between the uncoordinated ligand, [ZnL2]2+ and [ZnLXn](2−n)+ complexes was slow on the NMR scale; each form produced a separate set of sharp 1H NMR signals and their positions remained constant in the appropriate range of zinc salt concentrations.
The complex containing the acetate ligand(s) can be converted into the [ZnL2]2+ form by the addition of compound 11 to the methanolic solution of [ZnLXn](2−n)+. Complex [ZnL2]2+ was found to be insoluble in chloroform. When ligand 11 and zinc acetate were mixed in methanol in a 2:1 ratio and evaporated to dryness followed by dissolution of the residue in chloroform-d, the 1H NMR spectrum showed the presence of equimolar amounts of [ZnLXn](2−n)+ and the uncomplexed ligand. When we mixed compound 11 and zinc triflate in methanol in a 1:1 ratio, the residue obtained after solvent removal was insoluble in chloroform-d, and the 1H NMR spectrum measured in methanol-d4 revealed the presence of the [ZnL2]2+ complex, in agreement with previous observations that for the OTf− anion a monomeric complex was not formed.
Further information about the structures of the zinc(II) complexes comes from the analysis of the NMR chemical shifts. A complete assignment of the 1H and 13C NMR signals was based on correlations observed in the two-dimensional spectra (1H–1H COSY, 1H–13C HMQC, 1H–13C HMBC) and is given in Table S1 (ESI†). The most characteristic shift changes are indicated by the straight lines in Fig. 3 and are listed in Table 1. The differences in resonance positions of complex [ZnLXn](2−n)+ and ligand 11 (Table 1, entry 4) can be attributed to the coordination of the metal ion. The data shown in Table 1 clearly demonstrate that the most pronounced changes upon the formation of the Zn(II) complexes are observed for the phenanthroline fragment and for protons 1′′ and 3′′ which indicates the engagement of aromatic amine and imine nitrogen atoms in the binding of the metal ion. In contrast, the chemical shifts of the 2-azanorbornane fragment and its 2-substituent remain practically unaffected suggesting that the tertiary amine is not involved in coordination. Two five-membered chelate rings are thus formed, in analogy to the known complexes of phenanthroline ligands bearing the appropriately located imine, oxime or pyridine fragment.20 The coordination sphere of zinc(II) is presumably filled by acetate(s), although a separate 1H NMR methyl signal of the coordinated anion(s) could not be observed due to the exchange with the free CH3COO− even at 200 K. A similar 1H NMR pattern was observed for the analogous cadmium(II) complex, obtained by the addition of 1 equivalent of Cd(II) acetate to the ethanolic solution of ligand 11 (Fig. S9, ESI†). The differences in the chemical shifts can be attributed to the bigger size of the Cd2+ ion and the presence of ethanol.
Entry | Species | 1 | 3 | 4 | 5 | 1′′ | 3′′ | P3 | P4 | P8 | P9 |
---|---|---|---|---|---|---|---|---|---|---|---|
1 | Ligand 11 | 3.72 | 2.49 | 2.31 | 1.38, 1.71 | 2.71, 3.11 | 8.27 | 8.23 | 8.42 | 7.79 | 9.10 |
2 | [ZnL2]2+ | 3.36 | 1.06 | 0.86 | −1.46, 0.25 | 2.50, 3.04 | 8.84 | 8.88 | 9.45 | 7.63 | 7.63 |
3 | [ZnLXn](2−n)+ | 3.73 | 2.57 | 2.45 | 1.41, 1.69 | 2.89, 3.45 | 7.78 | 8.12 | 8.91 | 7.99 | 9.08 |
4 | Difference 3-1 | 0.01 | 0.08 | 0.14 | 0.03, −0.02 | 0.18, 0.34 | −0.49 | −0.11 | 0.49 | 0.20 | −0.02 |
5 | Difference 2-3 | −0.37 | −1.51 | −1.59 | −2.87, −1.44 | −0.39, −0.41 | 1.06 | 0.76 | 0.54 | −0.36 | −1.45 |
In contrast, significant 1H NMR shift changes were observed upon the formation of the [ZnL2]2+ complex. They can also be in part attributed to the coordination of the metal ion, but the most pronounced changes are connected with the mutual influence of the two ligand molecules. To estimate this effect, differences in the chemical shifts of [ZnL2]2+ and [ZnLXn](2−n)+ can be calculated (Table 1, entry 5). The aromatic ring current of the phenanthroline fragment causes upfield shifts of all protons of the 2-azanorbornane fragment of the second coordinated ligand. In particular, signals of 5-H protons found at 0.25 and −1.46 ppm can be regarded as a diagnostic feature of the formation of the [ZnL2]2+ complex. Significant upfield shifts were also observed for the fragments directly attached to the bicyclic skeleton (1′-H, 1′-Me, 1′′-H) and for the part of phenanthroline protons, while the location of the remaining protons of the aromatic amine and 3′′-H in the deshielding region resulted in their downfield chemical shifts.
Chemical shift changes caused by the coordination of the Zn2+ ion (for the [ZnLXn](2−n)+ and [ZnL2]2+ complexes) and aromatic ring current (for [ZnL2]2+) were also observed in the 13C NMR spectra (ESI,† Table S2). They confirm the participation of the phenanthroline and imine nitrogen atoms in the formation of the metal complexes.
Zinc acetate titration of compound 14 containing the phenanthroline fragment attached to a ring-expanded skeleton resulted in 1H NMR spectral changes similar to those observed for the isomeric ligand 11. A stepwise formation of the [ZnL2]2+ and [ZnLXn](2−n)+ forms was found, and the general tendencies of the chemical shift changes resembled those described above for the 2-azanorbornane derivative. Also, the replacement of phenanthroline in compound 11 with 2,2′-bipyridyl did not cause qualitative differences in the ligand coordination modes, as it can be seen in Fig. 5 showing zinc acetate titration of derivative 10. Chemical shifts of the formed complexes are given in Tables S3 and S4 (ESI†) along with the differences showing coordination-induced changes and changes caused by the ring current effect of the neighboring aromatic moieties. These values indicate zinc chelation by the three nitrogen atoms of bipyridyl and the appropriately located imine and the placement of the bicyclic fragment in the vicinity of the aromatic fragment of the second ligand in the [ZnL2]2+ complex.
In contrast, the removal of one of the pyridine subunits of 10 leads to a completely different picture. Addition of zinc acetate to the methanol-d4 solution of the 2-azanorbornane-based ligand containing 2-pyridyl substituent 9 resulted in the 1H NMR line broadening and, when a 2-fold excess of zinc salt was added to shift the equilibrium toward the formation of the product, a set of new signals attributed to the [ZnLXn](2−n)+ complex was observed (Fig. 6, trace B). Significant shift changes (in the range of 0.2–0.4 ppm) were observed for pyridine, 1′′ and 3′′ resonances suggesting that the pyridine and imine nitrogen atoms are engaged in coordination (ESI,† Table S5). These two donors were found to be insufficient for the formation of the intermediate [ZnL2]2+-type complex observed previously for analogs 10 and 11.
The formation of the zinc complexes of phenanthroline derivative 11 was also followed using UV-vis spectroscopy. Addition of zinc acetate to the methanolic solution of ligand 11 resulted in a decrease of one of the two major bands at 277 nm and build-up of a band at ca. 295 nm accompanied by a less intense maxima at ca. 340 and 357 nm (Fig. 7A). Only very subtle differences were observed between the 2:1 and 1:1 complexes: the positions and intensities of all bands are almost identical (for the [ZnL2]2+ complex λmax (logε) = 230 (4.55), 296 (4.31), 327 sh, 341 (3.65), 357 (3.52), for the [ZnL(OAc)n](2−n)+ form λmax (logε) = 231 (4.54), 294 (4.32), 325 (3.71), 340 (3.68), 356 (3.62); for a better comparison, the values of logε for the 2:1 complex were given per mole of the coordinated ligand). Not surprisingly, Job's plot (Fig. 6B) showing the changes in absorbance at 356 nm as a function of the mole fraction of zinc acetate exhibited a maximum for a 2:1 ligand to Zn2+ ratio (x(Zn(OAc)2 = 0.33)). It is justified by the fact that for this composition the ligand is fully saturated with zinc and the concentration of the coordinated phenanthroline ligand (responsible for absorption) attains a maximum value.
Calculations were performed for compounds 10 and 11 and their zinc complexes in methanolic solution. Using different starting points, we found two conformations of ligands 10 and 11 differing mainly in the relative positions of the two substituents of the bicyclic scaffold. The energy of the more compact one (Fig. 8A) appeared to be 3.74 kcal mol−1 (ligand 10) or 4.71 kcal mol−1 (ligand 11) higher than that for the open conformation (Fig. 8B). The calculated 1H NMR chemical shifts for the latter one were in a better agreement with the experimental values, particularly for the bicyclic fragment (ESI,† Tables S7–S17, Fig. S10–S23). However, for the remaining parts of the molecule the conformational freedom does not allow us to expect a perfect fit.
Fig. 8 DFT calculated structures of hybrid ligand 11. Two conformations of the molecule are shown with their relative energies. Hydrogen atoms are omitted for clarity. |
For zinc complexes of a 1:1 stoichiometry, the calculations were performed for two modes of coordination. Structures in which ligand 10 or 11 coordinated to the metal ion using only two nitrogen atoms of the aromatic fragment were found to be significantly less stable (by 15–20 kcal mol−1, ESI,† Table S6) than the complexes utilizing an imine donor as well. In addition, for this (3N) coordination the N-2 atom of 2-azanorbornane was also located at a binding distance of 2.12 Å from the zinc(II) cation. One should notice, however, that the competition of other possible ligands, in particular acetate anions, alcohol or water molecules, was not considered in these calculations. Our experiments indicated (3N) coordination and the presence of additional ligand(s) in the [ZnLXn](2−n)+ complexes. Therefore, calculations were also undertaken assuming additional coordination of one or two acetate anions. The agreement of the obtained NMR data with the experimental chemical shifts was not satisfactory which points toward another possible structure of the 1:1 complex. One cannot exclude, for example, the formation of polynuclear species with bridging acetate anions. We performed several ESI MS experiments which showed the presence of either the [ZnL(OAc)]+ ion (m/z = 543.18) or the [ZnL–H]+ ion (m/z = 483.15) which can be formed under the experimental conditions from any mono- and polynuclear species. So far, we were not able to further characterize the isolated complex in the solid state (in particular, by using X-ray diffraction).
In the case of the complexes of a 2:1 ligand to metal stoichiometry, [ZnL2]2+, DFT calculations were performed taking into account the possible coordination by only the phenanthroline or bipyridyl fragment, leading to tetrahedral geometry (4N-type complexes) and the possible engagement of the imine nitrogen atoms in the formation of the zinc complexes (6N-type octahedral structures). Again, the participation of the additional nitrogen donor in coordination resulted in more stable structures; the energy difference equalled 28.32 kcal mol−1 (for ligand 10) and 23.54 kcal mol−1 (ligand 11). In these structures shown in Fig. 9, bicyclic fragments are located in the vicinity of the aromatic fragments which should result in significant changes in the chemical shifts caused by the ring current effect.
Fig. 9 DFT calculated structures of 6N-coordinated [ZnL2]2+ zinc(II) complexes with ligand 10 (A) and 11 (B). Hydrogen atoms are omitted for clarity. |
DFT calculations of the 1H NMR chemical shifts reproduced well the experimental patterns observed for the [ZnL2]2+ complexes, including upfield shifts of 5-H in the complex of 11. The greatest deviations were observed for the N-2 substituent; possibly the averaged orientation of the phenyl moiety which has a pronounced effect on the chemical shifts of 1′-H and 1′-methyl protons differs for the calculated conformation. A representative illustration of the similarities in the calculated and measured values is presented in Fig. 10. All plots and tables showing the calculated chemical shifts are given in the ESI.† While in the case of ligand 10 the differences between the calculated and experimental values are similar regardless of the coordination number, for ligand 11 much better correlation was found for 6N-type coordination compared to 4N-type coordination which is in agreement with our analysis of the NMR spectra.
Fig. 10 Comparison of experimental and DFT calculated averaged chemical 1H NMR shift values (in ppm) of the 6N-coordinated [ZnL2]2+ complex of compound 11. |
The main conclusions drawn from the DFT calculations are in agreement with those obtained from the NMR studies: participation of three nitrogen donors in metal ion binding which can leave vacant coordination sites in monomeric complexes, but not for the dimeric [ZnL2]2+ form. This implies the rational application of these complexes in asymmetric catalysis.
We decided to test the newly synthesized enantiopure hybrid catalysts in the zinc-catalyzed aldol reaction between ketones and aromatic aldehydes. The results of the structural studies strongly suggested the use of [ZnLXn](2−n)+ complexes, where the metal coordination sphere offers enough space for additional coordination of the reacting species. Moreover, the reaction was performed in chloroform – a solvent in which the [ZnL2]2+ complex (with the ligands occupying 6 coordination sites) was found to be insoluble. Therefore, the reaction of cyclohexanone and 4-nitrobenzaldehyde with 10 mol% of catalyst (zinc acetate and 10–14 in a 1:1 molar ratio) was first tested (Table 2, entries 1–6).
Entry | Ligand L* | Ar | T (K) | Additive | Yield of product (%) |
dr
erb |
---|---|---|---|---|---|---|
a Reaction conditions:15 1 mL of chloroform, 1 mL of cyclohexanone, 0.5 mmol of aldehyde, 0.05 mmol of ligand, 0.05 mmol mol of zinc salt, and 0.05 mmol of acetic acid (entries 9, 16 and 17). b Configuration assignment based on the literature data.22 c 1% mol of both ligand and zinc acetate were used. | ||||||
1 | 10 | 4-NO2-C6H4 | 298 | Zn(OAc)2 | 85 |
syn/anti80:20
(2R,1′R):(2S,1′S) 72:28, (2R,1′S):(2S,1′R) 46:54 |
2 | 11 | 4-NO2-C6H4 | 298 | Zn(OAc)2 | 92 |
syn/anti 60:40
(2R,1′R):(2S,1′S) 51:49, (2R,1′S):(2S,1′R) 53:47 |
3 | 11 | 4-NO2-C6H4 | 298 | Zn(OAc)2 | 16 |
syn/anti 71:29
(2R,1′R):(2S,1′S) 55:45, (2R,1′S):(2S,1′R) 53:47 |
4 | 12 | 4-NO2-C6H4 | 298 | Zn(OAc)2 | 95 |
syn/anti 70:30
(2R,1′R):(2S,1′S) 50:50, (2R,1′S):(2S,1′R) 48:52 |
5 | 13 | 4-NO2-C6H4 | 298 | Zn(OAc)2 | 61 |
syn/anti 69:31
(2R,1′R):(2S,1′S) 51:49, (2R,1′S):(2S,1′R) 47:53 |
6 | 14 | 4-NO2-C6H4 | 298 | Zn(OAc)2 | 84 |
syn/anti 57:43
(2R,1′R):(2S,1′S) 50:50, (2R,1′S):(2S,1′R) 50:50 |
7 | 10 | 4-NO2-C6H4 | 273 | Zn(OAc)2 | 50 |
syn/anti83:17
(2R,1′R):(2S,1′S) 45:55, (2R,1′S):(2S,1′R) 52:48 |
8 | 11 | 4-NO2-C6H4 | 273 | Zn(OAc)2 | 45 |
syn/anti74:26
(2R,1′R):(2S,1′S) 62:38, (2R,1′S):(2S,1′R) 55:45 |
9 | 11 | 4-NO2-C6H4 | 298 | Zn(OAc)2 + HOAc | 74 |
syn/anti 67:33
(2R,1′R):(2S,1′S) 59:41, (2R,1′S):(2S,1′R) 46:54 |
10 | 11 | 4-NO2-C6H4 | 298 | ZnCl2 | 80 |
syn/anti 71:29
(2R,1′R):(2S,1′S) 70:30, (2R,1′S):(2S,1′R) 50:50 |
11 | 11 | 4-NO2-C6H4 | 298 | Zn(OTf)2 | 70 |
syn/anti 40:60
(2R,1′R):(2S,1′S) 51:49, (2R,1′S):(2S,1′R) 70:30 |
12 | 11 | 4-NO2-C6H4 | 273 | Zn(OTf)2 | 31 |
syn/anti 55:45
(2R,1′R):(2S,1′S) 36:64, (2R,1′S):(2S,1′R) 44:56 |
13 | 10 | 4-NO2-C6H4 | 273 | Zn(OTf)2 | >95 |
syn/anti 50:50
(2R,1′R):(2S,1′S) 55:45, (2R,1′S):(2S,1′R) 35:65 |
14 | 11 | 4-Cl-C6H4 | 273 | Zn(OAc)2 | 10 |
syn/anti 59:41
(2R,1′R):(2S,1′S) 93:7, (2R,1′S):(2S,1′R) 74:26 |
15 | 11 | 4-Cl-C6H4 | 298 | Zn(OAc)2 | 12 |
syn/anti74:26
(2R,1′R):(2S,1′S) 91:9, (2R,1′S):(2S,1′R) 53:47 |
16 | 11 | 4-Cl-C6H4 | 298 | Zn(OAc)2 + HOAc | 17 |
syn/anti >98:2
(2R,1′R):(2S,1′S) >99:1 |
17 | 14 | 4-Cl-C6H4 | 273 | Zn(OTf)2 + HOAc | 15 |
syn/anti82:18
(2R,1′R):(2S,1′S) 94:6, (2R,1′S):(2S,1′R) 41:59 |
18 | 11 | 2-NO2-C6H4 | 298 | Zn(OAc)2 | >95 |
syn/anti75:25
(2R,1′R):(2S,1′S) 84:16, (2R,1′S):(2S,1′R) 53:47 |
The highest diastereomeric ratio (80:20) with 42% enantiomeric excess of the main syn isomer accompanied by a 85% overall yield was obtained for bipyridyl ligand 10. Pyridine derivative 9 led to low diastereoselectivity (syn/anti 55:45, 65% yield) and racemic products, similarly to bridged azepane-based phenanthroline ligand 14. However, the use of the isomer of 14, 2-azanorbornyl derivative 11, resulted in a high yield but still low stereoselectivity. The decrease of the amount of catalyst from 10% to 1% drastically lowered the reaction yield, but slightly improved the dr and ee (entry 3). The yield dropped significantly, while the diastereomeric ratio increased with the decrease in reaction temperature (Table 2, entries 7–8).
Entries 9–13 show the impact of additives and metal sources on the outcome of the catalytic reaction. The addition of a Brønsted acid – acetic acid – slightly increased the stereoselectivity of the process (entries 9, 16, and 17). It can be accounted for in the protonation of the tertiary amine, thus additionally stabilizing the respective transition state via the hydrogen bond. The use of zinc triflate in place of zinc acetate with ligand 11 reversed the ratio of diastereomers and the major anti diastereomer was obtained with 40% ee. Furthermore, temperature lowering changed the stereochemical preference, suggesting that a specific mechanism operates for this catalyst composition.
When the reaction was performed with ligand 11 and zinc acetate was replaced with cadmium acetate, racemic products were obtained with low dr (syn/anti 52:48) in a 58% yield. Copper(II) acetate was only slightly more effective (82% yield, syn/anti 46:54, racemic products), while for copper(II) chloride the reaction exhibited some diastereo- and enantioselectivity (syn/anti 52:48; (2R,1′R):(2S,1′S) 42:58, (2R,1′S):(2S,1′R) 56:44), albeit accompanied by a lower yield (56%).
It is well established that the outcome of the aldol reaction can strongly depend on the solvent used.9d,22a In our hands, the results of the catalytic tests with ligand 11 and zinc acetate in methanol were found comparable with those in chloroform (88% yield, syn/anti 55:45, (2R,1′R):(2S,1′S) 53:47, (2R,1′S):(2S,1′R) 48:52). The reaction performed without solvent, with the addition of 5% mol of water, resulted in a reasonable yield (81%), but low diastereoselectivity (syn/anti 56:44) and a complete loss of enantioselectivity.
When 4-chlorobenzaldehyde was used as a substrate, low reaction yields (up to 17%) were observed. However, they were accompanied with high diastereoselectivities (up to over 98:2 dr) and enantioselectivities (82 to >98% ee for the major syn diastereomer; Table 2, entries 14–17). Promising results were also obtained when 4-nitrobenzaldehyde was reacted with cyclopentanone in the presence of 10 mol% of zinc acetate and 11 (syn:anti 55:45, (2R,1′R):(2S,1′S) 70:30, (2R,1′S):(2S,1′R) 35:65, >95% yield) and in the reaction of the same aldehyde with acetone (R:S 9:91, 58% yield).
As for ligands 11 and 14, we tested their utility as organocatalysts in the aldol reaction of cyclohexanone and 4-nitrobenzaldehyde. In both cases, similar yields (80/81%) and diastereomeric ratios (67:33) were noted, but only for the bridged azepane-based compound 14 were nonracemic products obtained ((2R,1′R):(2S,1′S) 55:45, (2R,1′S):(2S,1′R) 32:68).
The observed preference for the formation of an syn diastereomer can be explained by the favored formation of the Z-enolate in the transition state and placement of the aromatic substituent of the aldehyde in the less hindered region (Fig. 11).23
Fig. 11 The plausible transition states for the aldol reaction catalyzed by a zinc complex of ligand 11. Adapted from the literature.23 |
The reversed diastereoselectivity for the catalysis with 11 and zinc triflate and its change with temperature may result from a simultaneous operation of diverse mechanisms: the reaction can be catalyzed by the ligand itself, which may also cooperate with the zinc salt present in the solution. Though we have not observed the formation of a monomeric zinc(II) complex of ligand 11 when Zn(OTf)2 was used as a metal source, the active species may be formed under the catalytic reaction conditions (chloroform/cyclohexanone solution).
Footnote |
† Electronic supplementary information (ESI) available: Copies of NMR spectra, tables showing assignments of NMR signals of zinc complexes, DFT calculated energies, comparison of DFT calculated and experimental 1H NMR chemical shifts. See DOI: 10.1039/c6nj02251k |
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