Perumalsamy Parasuramana,
Zubeda Beguma,
Madhu Chennapurama,
Chigusa Sekia,
Yuko Okuyamab,
Eunsang Kwonc,
Koji Uwaia,
Michio Tokiwad,
Suguru Tokiwad,
Mitsuhiro Takeshitad and
Hiroto Nakano*a
aDivision of Sustainable and Environmental Engineering, Graduate School of Engineering, Muroran Institute of Technology, 27-1 Mizumoto-cho, Muroran 050-8585, Japan. E-mail: catanaka@mmm.muroran-it.ac.jp
bTohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-Ku, Sendai 981-8558, Japan
cResearch and Analytical Center for Giant Molecules, Graduate School of Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-Ku, Sendai 980-8578, Japan
dTokiwakai Group, 62 Numajiri Tsuduri-Chou Uchigo, Iwaki 973-8053, Japan
First published on 5th May 2020
A simple two catalyst component system consisting of primary β-amino alcohols as a catalyst and amino acids as a co-catalyst put together works as an efficient organocatalyst system in the hetero Diels–Alder reaction of isatins with enones to afford the chiral spirooxindole–tetrahydropyranones in good chemical yields and stereoselectivities (up to 86%, up to 85:15 dr., up to 95% ee).
Based on these backgrounds, we have designed a simple two catalysts component system for this reaction (Scheme 1). About the catalysts system, we focused on a concept of the combination of simple β-amino alcohol D as an organocatalyst for the generation of a diene species and common simple amino acid E as a co-catalyst for the activation of isatin substrate acting as a dienophile comparatively to the complex catalyst system of Tanaka and co-workers having one catalyst and two co-catalysts. Recently, we have reported that simple β-amino alcohols D and their derivatives work as an efficient organocatalyst in various asymmetric reactions.10 As an advantage of catalyst D, it can be easily prepared from commercially available amino acids in a single step and also contains the primary amino group as covalent site, hydroxyl group as a non-covalent site and steric influence site in the single molecule (Scheme 2). Furthermore, simple amino acids as co-catalyst are commercially available. Therefore, combined these properties of amino alcohols as a catalyst and amino acids as a co-catalyst may enable the formation of a simple catalytic component system. This organocatalysed asymmetric HDA reaction might proceed via transition state II (comparing to Tanaka's proposed reaction course I)9 in which the diene species D′ is formed by the reaction of primary amino group on catalyst D with enones Y, and then isatin dienophile X is activated by amino acids co-catalyst E by the two points of hydrogen bonding interactions (Scheme 2). In this transition state II, diene species D′ might attack stereoselectively from less sterically hindered site of the incoming generated dienes to afford the chiral spirooxindoles Z.
Herein, we describe a simple two catalysts component system, primary β-amino alcohols D having only one chiral carbon center on the molecule as a catalyst and simple non-chiral N-protected amino acids E as a co-catalyst, together acts as an efficient component organocatalysts system in the HDA reaction of X with Y to afford the chiral Z in good chemical yields (up to 86%) and with excellent stereoselectivities (up to 85:15 dr., 95% ee).
Entry | Enone 7a, (eq.) | Cat. 2a–e, 4a–e (mol%) | Co-cat. 5a–k (mol%) | Temp. (°C) | Yielda (%) | drb | Eec (%) |
---|---|---|---|---|---|---|---|
a Isolated yield.b Diastereoselectivity (dr) was determined by 1HNMR of the crude reaction mixture (major diastereomer: 8a).c The ee value were determined by HPLC (Daicel chiralpak IB column). | |||||||
1 | 4 | 2a (20) | — | rt | 15 | 8515 | 92 |
2 | 4 | 4a (20) | — | rt | trace | — | — |
3 | 4 | 1a (20) | — | rt | — | — | — |
4 | 4 | 2a (20) | a (40) | rt | 14 | 7525 | 95 |
5 | 4 | 2a (20) | b (40) | rt | 80 | 7921 | 91 |
6 | 4 | 2a (20) | c (40) | rt | 86 | 8020 | 92 |
7 | 4 | 2a (20) | d (40) | rt | 61 | 8218 | 88 |
8 | 4 | 2a (20) | e (40) | rt | 87 | 8119 | 87 |
9 | 4 | 2a (20) | f (40) | rt | 90 | 8218 | 88 |
10 | 4 | 2a (20) | g (40) | rt | 97 | 7525 | 84 |
11 | 4 | 2a (20) | h (40) | rt | 68 | 7525 | 86 |
12 | 4 | 2a (20) | i (40) | rt | 68 | 8416 | 87 |
13 | 4 | 2a (20) | j (40) | rt | tra | — | — |
14 | 4 | 2a (20) | k (40) | rt | 19 | 7327 | 75 |
15 | 4 | 2b (20) | c (40) | rt | 16 | 7525 | 86 |
16 | 4 | 2c (20) | c (40) | rt | 66 | 5545 | 72 |
17 | 4 | 2d (20) | c (40) | rt | 78 | 6436 | 81 |
18 | 4 | 2e (20) | c (40) | rt | 61 | 5050 | 88 |
19 | 4 | 4b (20) | c (40) | rt | 14 | 7525 | 24 |
20 | 4 | 4c (20) | c (40) | rt | 18 | 7426 | 41 |
21 | 4 | 4d (20) | c (40) | rt | 28 | 8317 | 14 |
22 | 4 | 4e (20) | c (40) | rt | 24 | 7822 | 6 |
23 | 2 | 2a (20) | c (40) | rt | 47 | 7723 | 90 |
24 | 1 | 2a (20) | c (40) | rt | 17 | 7327 | 89 |
25 | 4 | 2a (20) | c (40) | 0 | 56 | 8119 | 93 |
26 | 4 | 2a (20) | c (20) | rt | 54 | 7822 | 89 |
27 | 4 | 2a (20) | c (10) | rt | 52 | 7921 | 87 |
28 | 4 | 2a (10) | c (10) | rt | 54 | 77822 | 89 |
29 | 4 | 2a (10) | c (20) | rt | 60 | 88119 | 89 |
30 | 4 | 2a (10) | c (5) | rt | 52 | 7921 | 87 |
Just in case, the catalytic activity of amino acid 1a (L-tert-leucine) with the primary amino group for generating diene species was also examined under the same reaction condition (entry 3). However, its catalytic activity was not confirmed at all, for a reason that neutral amino acids exist in betaine form which might not work for the generation of the diene species. The most curious thing is that enantioselectivity was controlled almost completely (92% ee) to afford the HDA adduct 8a using simple small β-amino alcohol molecules independently. Thus, amino alcohol alone worked as a catalyst for almost completely shielding one side of the enantiotopic face when diene attack to dienophile. These results indicated the necessity of our two catalysts component system comprising of amino alcohol catalyst for generating diene species and for controlling stereoselective reaction course and amino acid co-catalyst for activating isatin dienophile. Based on the results in entries 1 and 3, we next examined this reaction using the combinations of catalyst 2a (20 mol%) with amino acids 5a–g or common organic acids 5h–j as co-catalysts (40 mol%) at room temperature for 48 h (entries 4–13). First, the reaction using the simplest amino acid 5a having free amino group as a co-catalyst was carried out in the presence of catalyst 2a (entry 4). Contrary to expectation, neutral acid 5a, which hardly worked as co-catalyst for activating of isatin dienophile 7a, showed excellent enantioselectivity (95% ee) with good diastereoselectivity, although chemical yield was quite low (14% ee). Interestingly, the use of 2a and 5a combined together increased the enantioselectivity (95% ee) then the result (92% ee) of the independently use of amino alcohol 2a (entry 1). Amino acid 5a might act as steric factor for controlling the attacking direction of diene to afford 8a with superior enantioselectivity. Next, we tried the combinations of superior catalyst 2a with other N-protected amino acids 5b–g or common organic acids 5h–j as co-catalysts in this reaction condition (entries 5–13). All of co-catalysts 5b–g assisted the progress of the reaction for affording chiral 8a with moderate to good results. Especially, highly satisfactory results for chemical yields and stereoselectivities were obtained when the reactions were carried out in the presence of simple non-chiral amino acids, N-Cbz-protected 5b and N-Boc-protected 5c with good chemical yields and stereoselectivities (5b: 80%, 79:21 dr., 91% ee, 5c: 86%, 80:20, 92% ee) (entries 5 and 6). On the other hand, the uses of common organic acids 5h, i brought about the decrease of chemical yield, even though good stereoselectivities were obtained (entries 11 and 12). Furthermore, strongest trifluoro acetic acid (TFA) 5j did not work as a co-catalyst in this reaction condition (entry 13). Moreover, thioureas 5k that was used as co-catalyst in Tanaka's three catalysts component system9 was also applied with amino alcohol organocatalyst 2a in this reaction. However, this component system of 2a and 5k did not work effectively in this reaction (19%, 73:27 dr., 75% ee) (entry 14). In addition, three catalysts component system of catalyst 2a and co-catalysts of both amino acid 5c and thiourea 5k also did not show better catalytic activity (85%, 75:25 dr., 82% ee) than two catalysts component system of 2a and 5c (86%, 80:20 dr., 92% ee). We next examined the reaction of 6a with 7a in the presence of β-amino alcohols 2b–e (20 mol%) as catalysts along with superior simple non-chiral N-Boc-amino acid 5c, as a co-catalyst (40 mol%) in this reaction condition (entries 15–18). Although, all catalysts combination systems, of catalysts 2b–e and co-catalyst 5c showed good catalytic activities to afford the HDA adduct 8a with moderate to good chemical yields, diastereoselectivities and enantioselectivities, but showed inferior results compared to catalyst 2a and co-catalyst 5c (entry 6). Moreover, the utility of combination of the catalysts bulkier amino alcohol catalysts 4a–e and superior simplest non-chiral N-Boc-amino acid co-catalyst 5c were also examined in this reaction condition (entries 19–22). However, better catalytic activities were not confirmed at all than that of the combination of simple catalysts 2a–e with aprimary hydroxyl group and 5c (entry 6). From these results, it was revealed that the best catalyst combination was β-amino alcohols 2a with primary hydroxyl group as a catalyst and non-chiral N-Boc-amino acid as a co-catalyst 5c. Next, the ratio of substrate amounts 6a and 7a (6a:7a = 1:2 and 6a:7a = 1:1) were examined in the presence of optimised 2a and co-catalyst 5c under same reaction condition (entries 23 and 24). However, these results displayed considerable decrease in chemical yields and the reaction temperature performed at 0 °C also showed a large decrease in chemical yield up to 56% (entry 25). Next, we examined the molar ratio of catalyst 2a and co-catalyst 5c in this reaction of 6a with 7a (4 equiv.) at room temperature (entries 26–30). Satisfactory enantioselectivities and diastereoselectivities were confirmed under all of the molar ratios of 2a and 5c. However, chemical yields comparatively decreased when the reaction was carried out under the molar ratio of 20 mol% of catalyst 2a and 40 mol% of co-catalyst 5c (entry 6).
We also examined the effects of various solvents and the reaction times to this reaction with an optimized catalyst combination of 2a (20 mol%) and 5c (40 mol%) at room temperature (Table 2). As a result, aromatic solvents performed better giving satisfactory chemical yields and stereoselectivities (entries 1–3). Particularly, toluene was found to be effective in this reaction (entry 1). Furthermore, no significant improvement in chemical yields and stereoselectivities was observed when the reaction times were shortened for 24 h and prolonged for 72 h and 96 h, respectively (entries 14–16). From these results, it was revealed that the catalyst combination of simple catalyst 2a (20 mol%) and simple non-chiral N-Boc-glycine 5c (40 mol%), toluene as solvent, room temperature and 48 h reaction time was best reaction condition for this reaction. This reaction using three catalysts component system by Tanaka and co-workers mainly afforded HDA adduct 8a which was obtained by concerted HDA cycloaddition, while this reaction also slightly afforded aldol product 9 which is obtained by aldol reaction as a by-product. Similarly, our catalysts component system also slightly afforded similar aldol product 9 in low chemical yield (12%) and stereoselectivities (72:28 dr, 16% ee) like Tanaka and co-workers.9
Entry | Solvent | Time (h) | Yielda (%) | drb | Eec (%) |
---|---|---|---|---|---|
a Isolated yield.b Diastereoselectivity (dr) was determined by 1HNMR of the crude reaction mixture (major diastereomer: 8a).c The ee value were determined by HPLC (Daicel chiralpak IB column). | |||||
1 | Toluene | 48 | 86 | 8020 | 92 |
2 | Benzene | 48 | 60 | 7822 | 90 |
3 | Xylene | 48 | 73 | 7723 | 88 |
4 | Cyclohexane | 48 | 66 | 7426 | 89 |
5 | Hexane | 48 | trace | — | — |
6 | Et2O | 48 | 55 | 7822 | 90 |
7 | iPr2O | 48 | 68 | 7723 | 89 |
8 | THF | 48 | 40 | 7921 | 82 |
9 | CH2Cl2 | 48 | 74 | 7921 | 90 |
10 | CHCl3 | 48 | 34 | 8416 | 92 |
11 | C2H4Cl2 | 48 | 75 | 7723 | 88 |
12 | CH3CN | 48 | 70 | 7525 | 88 |
13 | MeOH | 48 | 38 | 6832 | 83 |
14 | Toluene | 24 | 73 | 7921 | 90 |
15 | Toluene | 72 | 86 | 7822 | 86 |
16 | Toluene | 96 | 78 | 7822 | 86 |
17 | Neat | 24 | 87 | 7129 | 86 |
18 | Neat | 48 | 75 | 6832 | 82 |
We also examined this reaction using a large amount of substrate (6a: 1 g, 7a: 3.05 g) to demonstrate the practically utility of the two component system in best reaction condition. As a result, the HDA adduct 8a was successfully obtained with 87% chemical yield with good stereoselectivites (dr = 80:20, 85% ee), although a slight decrease of ee was observed. From this result, it is expected that this HDA reaction using our two catalyst components system may be useful for practical aspect.
Footnote |
† Electronic supplementary information (ESI) available: Experimental details and HPLC data. See DOI: 10.1039/d0ra03006f |
This journal is © The Royal Society of Chemistry 2020 |