Abstract
We have investigated the effect of nitrogen protecting groups in radical addition trapping experiments leading to β2-amino acids. Of the three N-protecting groups examined, the phthalimido group was optimal with respect to both yields and enantioselectivity. Additionally, radical additions to more complex acrylates were also investigated, which provided access to functionalized β2-amino acids in modest selectivity.
1. Introduction
β-Amino acids are key components of compounds with potential therapeutic value. Thus, the development of new methods for the asymmetric synthesis of β-amino acids is important.1 Many enantioselective catalytic methods have been developed recently for the synthesis of β-substituted β-amino acids (β3-amino acids).2 In contrast, there are very few reports on enantioselective methods for the synthesis of α-substituted β-amino acids (β2-amino acids).3 We have recently developed a novel enantioselective H-atom transfer4 methodology that provided access to a variety of β2-amino acids in good yields and selectivity (Scheme 1).
Scheme 1.
The main shortcoming of the above transformation, with a few exceptions, is that these reactions can not be carried out under catalytic conditions. The starting esters are very reactive and the rate of background reaction is very high. We surmised that variation of the nitrogen protecting group could allow for tuning of the reactivity and enable selective reactions using low catalytic loading. Herein we report the effect of the nitrogen protecting group on the enantioselective H-atom transfer reactions leading to β2-amino acids. Additionally, we also present a few examples of addition/H-atom transfer reactions with β-substituted amino acrylates.
2. Results and discussion
Our work began with the preparation of three differentially protected methylamino acrylates 7, 8, and 10 to evaluate the effect of the nitrogen protecting group on reactivity and selectivity in enantioselective H-atom transfer reactions. These compounds were prepared according to a literature procedure (Scheme 2).5 Substrates 7 and 8 were synthesized by treating the corresponding bromide with succinimide and potassium carbonate. The bis-protected Boc compound 9, was prepared from the corresponding bromide and then converted to 10 by cleavage with Sc(OTf)3.
Scheme 2.
In a previous work, we have shown that radical addition to 1 proceeds smoothly in the presence, or absence, of a Lewis acid to furnish 2 (Scheme 1). Of the different chiral Lewis acids examined, a combination of magnesium iodide and bisoxazoline derived from amino indanol provided optimal results. Furthermore, the nature of the H-atom donor had minimal impact on enantioselectivity while tributyltin hydride was the best of the three reagents examined. Based on this background information, our present work began with the addition of various radicals to substrates 7 and 8 in the presence of MgI2 as a Lewis acid (equation in Table 1) using tributyltin hydride as a H-atom donor and triethylborane/oxygen as the initiator.6 The results from these experiments are shown in Table 1. As can be discerned from the table, primary, secondary, and tertiary radicals (entries 1–3) gave good yields of the products, when methyl ester 7 was used as the substrate. Similarly, radical additions to the tert-butyl ester 8 were equally effective.
Table 1.
Radical addition to succinimides: racemic and chiral reactions
| MgI2 | 1 equiv MgI2 and ligand 13 |
|||||
|---|---|---|---|---|---|---|
| Entry | R1 | RX | Pdt. | Yielda(%) | Yielda(%) | eeb(%) |
| 1 | Me (7) | EtI | 11a | 70 | 69 | 21 |
| 2 | Me (7) | i-PrI | 11b | 95 | 66 | 33 |
| 3 | Me (7) | t-BuI | 11c | 72 | 55 | 15 |
| 4 | t-Bu (8) | EtI | 12a | 60 | 78 | 31 |
| 5 | t-Bu (8) | i-PrI | 12b | 76 | 50 | 39 |
| 6 | t-Bu (8) | c-PentI | 12c | 82 | 61 | 27 |
| 7 | t-Bu (8) | c-HexI | 12d | 78 | 50 | 15 |
Isolated yields after column chromatography.
Determined by chiral HPLC.
We also carried out H-atom transfer reactions using a stoichiometric amount of MgI2 and ligand 13, the optimal chiral Lewis acid from our previous study. Results from the experiments with 7 and 8 as substrates are shown in Table 1. As can be noted from the data in the table, the chemical yields for these experiments varied from modest to good (entries 1–7). Additionally, they were generally less efficient than the corresponding reaction with MgI2. The enantioselectivities in the H-atom transfer reactions were disappointing with 39% being the highest. In contrast to the reactions with phthalimido protected acrylates, where the tert-butyl ester was superior to the methyl ester, there was very little difference in selectivity in reactions with methyl 7 and tert-butyl substituted esters 8 with a succinimido protecting group.7 Reactions with substoichiometric amounts of the chiral Lewis acid (30 mol %) gave very low selectivity.
We then evaluated the reactions with methylamino acrylate 10 containing a carbamate protecting group. The results from these experiments are tabulated in Table 2. As can be seen from the table, the yields for radical addition to 10 were high under racemic conditions. Chiral reactions were also examined with substrate 10 (Table 2). The yields obtained in these reactions were also very high; however, the enantioselectivity was low. A maximum selectivity of 60% was observed for the addition of an ethyl radical (Table 2, entry 1). From the limited amount of data at hand, a small radical provided better enantioselectivity in the addition/H-atom transfer experiments (compare entry 1 with 2). Overall, the protecting group changes did not lead to modulation of the reactivity of the starting material. Of the three different nitrogen protecting groups evaluated, the phthalimido group gave the best results with regard to selectivity.
Table 2.
Radical addition to N-Boc derivative
| MgI2 | MgI2 and ligand 13 |
||||
|---|---|---|---|---|---|
| Entry | RX | Pdt. | Yielda (%) | Yielda (%) | eeb (%) |
| 1 | EtI | 14a | 99 | 90 | 60 |
| 2 | i-PrI | 14b | 91 | 95 | 35 |
| 3 | c-PentI | 14c | 98 | 88 | 12 |
| 4 | c-HexI | 14d | 96 | 85 | 10 |
Isolated yields after column chromatography.
Determined by chiral HPLC for the corresponding benzoate.
We were also interested in synthesizing highly functional β2-amino acids by radical addition to β-substituted acrylates. The starting material to probe this goal was readily prepared from Baylis–Hillman adduct 15. The synthesis of compound 17 is shown in Scheme 3.8
Scheme 3.
Three key issues need to be addressed in these conjugate radical addition experiments: (1) the reactivity of the β-functionalized substrates, (2) the enantioselectivity for the radical addition step, and (3) the diastereoselectivity during the hydrogen atom transfer step. Initially, we investigated racemic reactions with 17 by adding isopropyl radical (Table 3). In the absence of a Lewis acid, the radical addition to 17 was not efficient (Table 3, entry 1). However, radical addition was more efficient in the presence of a Lewis acid, but dependent on its nature. Although Yb(OTf)3 proved to be an inefficient Lewis acid (entry 3), MgI2 provided the product in good yield and high diastereoselectivity (entry 2). The addition of a bulky tert-butyl radical was also efficient providing the product in 80% yield (entry 4). In this case, the starting material was also obtained as a minor product. The diastereoselectivity obtained in this reaction was lower than that obtained for the isopropyl radical addition.
Table 3.
Radical addition to β-substituted acrylates
| Entry | LA | RX | Pdt. | Yielda (%) | drb |
|---|---|---|---|---|---|
| 1 | — | i-PrI | 18a | 7 (85) | 4:1 |
| 2 | MgI2 | i-PrI | 18a | 92 | 15:1 |
| 3 | Yb(OTf)3 | i-PrI | 18a | 22 (60) | 5:1 |
| 4 | MgI2 | t-BuI | 18b | 80 (16) | 7:1 |
Numbers in parentheses represent recovered starting material.
Isolated yields after column chromatography.
Determined by NMR.
MgI2 was selected as the optimal Lewis acid, and chiral reactions were performed using ligands 13 or 19 (Table 4). The combination of MgI2 and ligand 13 at −78 °C resulted in recovered starting material (Table 4, entry 1). When the temperature was increased to 0 °C, a moderate yield of the product was obtained with high diastereoselectivity and a modest level of enantioselectivity (entry 2). Ligand 19 provided lower diastereoselectivity as well as poor ee (entry 3) in the addition/H-atom transfer experiment.
Table 4.
Radical addition to β-amino acrylate 17
Isolated yields after column chromatography.
Determined by NMR.
Determined by chiral HPLC.
Recovered starting material.
Reaction was performed at 0 °C.
3. Conclusion
Herein, we have investigated two alternative nitrogen protecting groups in radical addition trapping experiments leading to β2-amino acids. These changes did not allow us to lower the catalytic loadings. Of the three N-protecting groups examined, the phthalimido group was optimal with respect to both yields and enantioselectivity. Additionally, radical additions to more complex acrylates were also investigated, which provided access to functionalized β2-amino acids in modest selectivity.
Acknowledgments
This work was supported by the National Institutes of Health (NIH-GM-54656).
References
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