Carbon-nitrogen bond formation via catalytic alcohol activation
Yan, Tao
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Chapter 6
Ruthenium catalyzed N-alkylation of amino acid esters with
alcohols
-Amino acids are the most abundant chiral amine sources in nature. Selective functionalization of amino acids and their derivatives is a highly-desired transformation. In Chapter 5, the direct N-alkylation of unprotected amino acids is described. As common amino acid derivatives, the functionalization of amino acid esters holds vast interest, due to their better solubility in organic solvents compared to their acid analogues. This Chapter describes, for the first time, the direct N-alkylation of amino acid esters with alcohols, producing water as the only waste. The scope includes direct N-alkylation of phenylalanine, alanine, valine, proline esters and prolinamide with 1-pentanol and benzyl alcohols, with good to excellent yields and stereochemistry retention.
Part of this chapter will be submitted for publication: T. Yan, B. L. Feringa, K. Barta, to be submitted.
Introduction
N-alkyl amino acid esters are prominent chiral moieties in bio-active compounds
(Figure 1). For example, Cilazapril[1] and Enalapril[2] are angiotensin-converting enzyme inhibitors; Ximelagatran[3] is an anticoagulant that has been investigated as a replacement for warfarin.
Figure 1: N-alkyl amino acid ester contained pharmaceutical compounds.
An attractive way to synthesize N-alkyl amino acid esters is the direct alkylation of amino acid esters with alcohols through the borrowing hydrogen strategy. The advantage of using alcohols as alkylation reagents has been extensively discussed in previous chapters (Chapter 2, 3 and 5). In this Chapter we explore the possibility of the direct alkylation of N-alkyl amino acid esters with alcohols. With the development of the borrowing hydrogen strategy[4], the direct alkylation of amines with alcohols has been achieved under relatively mild reaction conditions[5]. However, this method still has not been applied to direct N-alkylation of amino acid esters bearing acidic α-proton[5g]. Probably this is due to the possibility of competing transesterification[6] and unsatisfactory ee retention[7], as common catalyst systems frequently require the addition of a strong base for activation of the catalyst or substrates[5].
Figure 2: A Alkylation of amines catalyzed by Cat 1 or Cat 3; B generation of active
Based on the work described in Chapter 2, 3 and 5, we envisioned the possibility of the direct N-alkylation of amino acid esters with alcohols (Figure 2, A). In our earlier studies we have shown that by using pre-catalysts based on Fe[8] or Ru (Figure 2, A), a catalytically active species Cat-O, can be generated[9] through several routes without the need of adding any strong base (Figure 2, B). This is a key aspect for performing such reactions without any racemization.
To establish our methodology, phenylalanine methyl ester (1a) and pentanol (2a) were first selected as the substrates, and Cat 3 was employed as the pre-catalyst (Scheme 1, A). Using toluene as the solvent, at 135 °C for 18 h, the transesterification products, pentyl phenylalanine pentyl ester (3c) and N-dipentyl phenylalanine pentyl ester (4a) were obtained as the major products. When phenylalanine ethyl ester (1b) was used, significant amount of transesterification was still observed, and 3c was obtained in 49% isolated yield. Unfortunately, a significant racemization occurred with only 19% ee measured in the obtained product 3c. On the other hand, when 4-methylbenzyl alcohol (2b) was reacted with phenylalanine esters, the imine side product 5a was observed as the major product (Scheme 1, B).
Scheme 1: Iron catalyzed N-alkylation of phenylalanine esters with (A) pentanol and (B) 4-methylbenzyl alcohol.
General reaction conditions: General procedure, 0.5 mmol 1, 3 mmol 2a or 2 mmol 2b, 0.02 mmol Cat 3, 0.04 mmol Me3NO, 1 ml toluene, 18 h, 135 °C, 95-105 mg molecular
sieves, unless otherwise specified, isolated yield in parenthesis. Conversion and selectivity were determined by GC-FID. aThe ee value of 3c is 19%; b1 mmol 2b was used.
Since unsatisfactory results were obtained with the Fe based Cat 3, next the Ru-based Shvo catalyst[10] (Cat 1), was investigated (Table 1). Phenylalanine pentyl ester (1c) and 4-methylbenzyl alcohol (2b) were selected as substrates and toluene as solvent. The use of only 0.5 mol% Cat 1, at 120 °C for 18 h, gave full conversion of 1c and 55% selectivity of N-(4-methyl)-benzyl phenylalanine pentyl ester (3f), although significant transesterification side-products were also observed (Table 1, entry 1). However, when phenylalanine benzyl ester (1f) was used as starting material, 69% conversion of 1f and 60% selectivity of N-(4-methyl)-benzyl phenylalanine benzyl ester (3g) were observed, showing lower reactivity but higher stability of the benzyl ester compared to the pentyl ester (Table 1, entry 2). Gratifying, when the reaction temperature was lowered to 100 °C, no significant trans-esterification was observed and 39% conversion of 1c and 38% selectivity for 3f were obtained (Table 1, entry 3). Next, in order to improve substrate conversion under milder reaction temperatures, we used 4 mol% of diphenyl phosphate (A1) based on previous studies by the group of Noyori in Brønsted acid assisted ruthenium catalyzed hydrogenation of ketones[11]. Indeed, conversion of 1c was improved to 55%, and 54% selectivity of 3f was achieved (Table 1, entry 4). While phenylalanine methyl ester (1a) gave 99% conversion and 69% yield of 3d, phenylalanine ethyl ester (1b) has shown 47% conversion and 45% selectivity of 3e (Table 1, entry 5-6). The positive results with phosphoric acid are likely due to the facilitation of the imine formation[12] step. Also, the formation of ruthenium-hydride-phosphonate complex (Figure 3, C) bearing a more acidic proton comparing to the original Cat 2-H (Figure 3, A and B), facilitates the imine reduction step.[11,13]
Figure 3: A Generation of active species Cat 2-H; B reduction of imine intermediate with Cat 2-H; C reduction of imine intermediate with Cat 2-H cooperated by diphenyl
Table 1: Ruthenium catalyzed N-alkylation of phenylalanine ester with 4-methylbenzyl alcohol.
Entry R1 / 1
0.5 mmol mmol 2b / Sol. Addi. Temp [oC] 1 [%]Conv. a 3 [%]Sel. a Sel. 4 [%]a
1 n-pentyl/1c 0.75 Tol. / 120 >99 3f 55 <1 2 Bn/1f 0.75 Tol. / 120 69 3h 60 <1 3 n-pentyl/1c 1 Tol. / 100 39 3f 38 <1 4 n-pentyl/1c 1 Tol. A1 100 55 3f 54 <1 5 Me/1a 1 Tol. A1 100 98 3d 93 (69) <1 6 Et/1b 1 Tol. A1 100 47 3e 45 <1 7 n-pentyl/1c 1 CPME A1 100 26 3f 23 <1 8 n-pentyl/1c 1 THF A1 100 18 3f 10 <1 9 n-pentyl/1c 1 Hept. A1 100 34 3f 32 <1 10 n-pentyl/1c 2 Tol. A1 100 >99 3f 58 4b 32 11 n-pentyl/1c 2 Tol. A2 100 >99 3f 72 4b 20 12 n-pentyl/1c 2 Tol. A3 100 92 3f 85 4b 2 13 n-pentyl/1c 2 Tol. A1 95 >99 3f 93 (86) <1 General reaction conditions: General procedure, 0.5 mmol 1, 0.75-2 mmol 2b, 0.5 mol%
Cat 1, 2 ml toluene, 18 h, 95-120 °C, isolated yield in parentheses, unless otherwise
specified. Conversion and selectivity were determined by GC-FID.
Next, 1c was chosen for further optimization and solvent screening was performed whereby the use of cyclopentylmethyl ether (CPME), tetrahydrofuran (THF) and heptane as solvents gave 26%, 18% and 34% conversion of 1c, respectively (Table 1, entry 7-9). Toluene was chosen for further screening of Brønsted acid additives. When 4 mol% of A1 and 4 equiv of 2b were used, the desired product, 3f was obtained with 58% selectivity and 32% side product N,N-di-(4-methyl)-benzyl phenylalanine pentyl ester (4b) was observed (Table 1, entry 10). When the Brønsted acids p-toluenesulfonic acid (PTSA, A2) and benzoic acid (A3) were employed instead of A1, comparable results were obtained (Table 1, entry 11-12). When the temperature was lowered to 95 °C, under standard condition with addition of 4 mol% A1, 86% isolated yield of 3f with 96% ee retention were obtained, indicating the best result (Table 1, entry 13) under these optimized reaction conditions.
Table 2: Ruthenium catalyzed N-alkylation of amino acid ester with various alcohols. (Struction of the products are shown in Scheme 2)
Entry 1 2 t / h Conv. 1 [%] Sel. 3 [%] ee [%] 1ab /1c /2b 23 >99 3f 93 (86) 96 2 /1b /2b 18 >99 3e 95 (85) 94 3 /1c /2c 24 94 3i 87 (74) 95 4 /1c /2a 24 82 3c 81 (78) 91 5 /1c /2d 18 91 3j 89 (76) 89 6 /1e /2b 28 >99 3k 98 (64) 83 7 /1e /2c 30 >99 3l 81 (52) n.d. 8 /1e /2a 40 80 3m 76 (31) n.d. 9 /1f /2d 18 88 3n 85 (79) 96 10 /1f /2g 14 75 3o 74 (70) 97 11 /1f /2c 24 76 3p 73 (66) 92 12 /1g /2a 46 >99 3q 99 (86) 99 13 /1g /2b 16 >99 3r 86 (84) 99 14 /1g /2e 16 >99 3s 90 (87) 99 15 /1g /2c 28 >99 3t 84 (82) >99 16 /1h /2b 18 83 3u 48 (35) 99 General reaction conditions: General procedure, 0.5 mmol 1, 2 mmol 2, 1 mol% Cat 1, 2 ml toluene, 18 h, 100 °C, isolated yield in parentheses, unless otherwise specified. Conversion and selectivity were determined by GC-FID. a95 °C; b0.5 mol% Cat 1.
With the optimized reaction conditions in hand, the scope of the reaction was further explored (Table 2). Amino acid ester 3f was obtained in 86% yield and 96%
ee retention from phenylalanine pentyl ester (1c). N-(4-methyl)-benzyl
phenylalanine ethyl ester (3e) was obtained with 69% yield and 94% ee retention from phenylalanine ethyl ester (1b) (Table 2, entry 1-2). Other alcohols including 4-chlorobenzyl alcohol (2c), pentanol (2a) and 1-phenylethanol (2d) have also
been chosen to react with 1c, giving 74% yield and 95% ee of 3i, 78% yield and 91% ee of 3c, and 76% yield and 89% ee of 3j, respectively (Table 2, entry 3-5). Scheme 2: Ruthenium catalyzed N-alkylation of amino acid ester.
General reaction conditions: General procedure, 0.5 mmol 1, 1-2 mmol 2, 0.5-1 mol% Cat
1, 4 mol% A1, 2 ml toluene, 18 h, 95-100 °C, isolated yields and ee values are shown.
For details see Table 2.
The reactivity of different types of amino acid esters was next explored. When alanine isopropyl ester (1e) was reacted with alcohols 2b, 2c and 2a, products 3k, 3l and 3m were obtained with 64%, 52% and 31% isolated yields, respectively (Table 2, entry 6-8). The ee of 3k was measured as 83%, indicating that slight racemization occurred. Employing the corresponding pentyl ester 1f in the reaction with alcohols 2d, 2g and 2c, N-benzylated amino esters 3n, 3o and 3p were obtained as in good yields (79%, 70% and 66%) with excellent ee’s of 96%, 97% and 92%, respectively (Table 2, entry 9-11). When valine pentyl ester (1g) was reacted with alcohols 2a, 2b, 2e and 2c, the corresponding products 3q, 3r, 3s and 3t were obtained in good isolated yields (82-87%), with excellent retention of
ee 99 to >99% (Table 2, entry 12-15). Glutamic acid diethyl ester (1h) reacting
with 2b, gave 35% 2-pyrrolidinone derivative 3u with 99% ee, undergoing intramolecular amide formation during the reaction (Table 2, entry 16). The
isolated yields and optical purities of the obtained N-alkylated amino acid esters are described in Table 2 and are illustrated in Scheme 2.
Table 3: Ruthenium catalyzed N-alkylation of proline ester.
Entry t [h] Conv. 1 [%] Sel. 3v [%] ee [%]
1a 24 82 62 (42) 70
2b 15 73 62 71
3c 15 70 51 62
4d 15 53 47 78
General reaction conditions: General procedure, 0.5 mmol 1, 2 mmol 2b, 0.5-1 mol% Cat
1, 2 ml toluene, 18 h, 95-100 °C, isolated yield in parentheses, unless otherwise specified.
Conversion and selectivity were determined by GC-FID. a95 °C; b2 mol% A1; c2 mol% A2
instead of A1; dno A1.
Next, proline pentyl ester (1j), comprising a secondary amine moiety was chosen as substrate (Table 3). When 1j reacted with 2b, N-(4-methyl)-benzyl proline pentyl ester (3v) was obtained with 42% yield and 70% ee retention (Table 3, entry 1). The ee dropped significantly compared to the previously used substrates that have a primary amine moiety. When decreasing the amount of Brønsted acid additives A1 and A2 to 2 mol%, 71% and 62% ee for N-benzylated product 3v were obtained, respectively (Table 3, entry 2-3). Without using any Brønsted acid, 78% ee of 3v and lower conversion of proline pentyl ester 1j were observed (Table 3, entry 4).
Scheme 3: Catalytic N-alkylation of prolinamide with 4-methylbenzyl alcohol.
Further, we explored the possibility of using an amide, prolinamide (6), instead of the amino acid ester as the substrate, the corresponding product, N-(4-methyl)-benzyl prolinamide (7) was obtained in 83% yield and ee of 59% (Scheme 3). Interestingly, when Cat 3 was employed in the reaction between 6 and 2b, only the corresponding imidazolidin-4-one derivative 8 was obtained, indicating a
slower imine reduction step that allowed for an intramolecular addition of the formed imine with the amide (Scheme 3).
In the present case, with both the proline ester and prolinamide, the corresponding
N-alkylated products were obtained with ee values of 70% and 59%, respectively
(Table 3, entry 1; Scheme 3). However, the direct N-alkylation of the amino acid itself (L-proline), gave excellent retention of ee (Figure 2, A) as described in Chapter 5.
Conclusion
In summary, this chapter describes a general method for the direct N-alkylation of amino acid esters with alcohols through borrowing hydrogen strategy, with good to excellent yields and retention of ee. Only proline pentyl ester and prolinamide show significant racemization under the established reaction conditions for N-alkylation with alcohols. Future work should focus on the development of new catalytic systems that would allow for even milder reaction conditions, which could lead to higher ee retention and prevent transesterification. Future efforts should also focus on extending the scope of the reaction to achieve the selective N-functionalization of a broad variety of amino acid derivatives.
Experimental section
General methods
Chromatography: Merck silica gel type 9385 230-400 mesh or Merck Al2O3 90 active neutral, TLC: Merck silica gel 60, 0.25 mm or Al2O3 60 F254 neutral. Components were visualized by UV, Ninhydrin or I2 staining. Progress of the reactions was determined by GC-MS (GC: HP 6890, MS: HP 5973) with an HP012 column (Agilent Technologies, Palo Alto, CA). Mass spectra were recorded on an AEI-MS-902 mass spectrometer (EI+) or a LTQ Orbitrap XL (ESI+). Conversions were determined by GC-FID (GC: HP 6890) with an HP-5 column (Agilent Technologies, Palo Alto, CA). GC-MS and GC-FID analysis method: 60 °C 5 min, 180 °C 5 min (10 °C /min), 260 °C 5 min (10 °C/min). 1H- and 13C NMR spectra were recorded on a Varian AMX400 (400 and 100 MHz, respectively) using CDCl3, CD3OD, or CD2Cl2 as solvent. Chemical shift values are reported in ppm with the solvent resonance as the internal standard (CDCl3: 7.26 for 1H, 77.00 for 13C; CD3OD: 3.31 for 1H, 49.00 for 13C; CD2Cl2: 5.32 for 1H, 53.84 for 13C). Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br. = broad, m = multiplet), coupling constants (Hz), and integration. All reactions were carried out under an Argon atmosphere using oven (110 °C) dried glassware and using standard Schlenk techniques. THF and toluene were collected from a MBRAUN solvent purification system (MB SPS-800). Dioxane (99.5%, extra dry), dichloroethane (DCE, 99.8%, extra dry), N,N-dimethylformamide (DMF, 99.8%, extra dry) and acetonitrile (CH3CN, 99.9%, extra dry) were purchased from Acros without further purification. Molecular sieves 4A were purchased from Acros, and heated in a Schlenck under 180 °C in vacuo overnight for activation before use. The synthesis of Cat 3 was carried out as described in Chapter 2. Cat 1 was purchased from Strem. All other reagents were
purchased from Sigma, TCI or Acros in reagent or higher grade and were used without further purification.
Representative procedure
General procedure: An oven-dried 20 ml Schlenk tube was equipped with a stirring bar. The solid starting materials were added into the Schlenk tube under air, the Schlenk tube was subsequently connected to a vacuum/argon Schlenk line and a vacuum-backfill cycle was performed three times. Liquid starting materials and solvent were charged under an argon stream. The Schlenk tube was sealed with a screw cap. The mixture was rapidly stirred at room temperature for 1 min, then it was placed into a pre-heated oil bath at the appropriate temperature and the mixture was stirred for a given time. The reaction mixture was cooled down to room temperature and the crude mixture was concentrated in vacuum and purified by flash column chromatography to provide the product. The enantiomeric excess (ee) was measured by chiral HPLC.
Procedure of N-alkylation of valine pentyl ester (1g) with 4-methyl benzyl alcohol (2b): An oven-dried 20 ml Schlenk tube, equipped with a stirring bar, was charged with 4-methylbenzyl alcohol (2 mmol, 0.244 g) and Cat 1 (1 mol%, 5.4 mg) under air. The Schlenk tube was subsequently connected to a vacuum/argon Schlenk line and a vacuum-backfill cycle was performed three times. Then valine pentyl ester (0.5 mmol, 0.094 g) and 2 ml toluene were charged under an argon stream. The Schlenk tube was sealed with a screw cap. The mixture was rapidly stirred at room temperature for 1 min, then was placed into a pre-heated oil bath at 100 °C for 18 h. The reaction mixture was cooled down to room temperature, concentrated in vacuum. The residue was purified by flash chromatography (SiO2, pentane/EtOAc 100:0 to 95:5) to provide the product N-(4-methylbenyl) valine penyl ester 3r (0.124 g, 84% yield) with ee value of 99% measured by chiral HPLC.
Spectral data and ee determination of isolated compounds
N-pentyl-phenylalanine pentyl ester (3c): Synthesized
according to General procedure. Phenylalanine penyl ester (0.118 g, 0.50 mmol) affords 3c (0.119 g, 78% yield). Light yellow oil compound obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.14 –
7.32 (m, 5H), 3.94 – 4.08 (m, 2H), 3.47 – 3.52 (m, 2H), 2.94 – 3.02 (m, 1H), 2.86 – 2.94 (m, 1H), 2.52 – 2.62 (m, 1H), 2.42 – 2.52 (m, 1H), 1.38 – 1.55 (m, 4H), 1.16 – 1.32 (m, 8H), 0.80 – 0.92 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 174.80, 137.34, 129.15, 128.34, 126.62, 64.70, 63.20, 48.15, 39.81, 29.71, 29.35, 28.20, 27.96, 22.49, 22.24, 13.99, 13.90. The physical data were identical in all respects to those previously reported HRMS (APCI+, m/z): calculated for C19H32NO2 [M+H]+: 306.24276; found: 306.24298.
The ee was determined by chiral HPLC analysis. Chiralcel OZ-H column, Phenomenex, Ltd; heptane/isopropanol (99.5:0.5); flow rate: 0.5 ml/min; detection: UV 221 nm; retention times 21.3 min (minor) and 24.1 min (major).
N-(4-methylbenzyl)-phenylalanine methyl ester (3d):
Synthesized according to General procedure. Phenylalanine methyl ester (0.090 g, 0.50 mmol) affords 3d (0.098 g, 69% yield). Light yellow oil compound obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.05 –
7.34 (m, 9H), 3.73 – 3.84 (m, 1H), 3.66 (s, 3H), 3.59 – 3.65 (m, 1H), 3.53 – 3.59 (m, 1H), 2.93 – 3.04 (m, 2H), 2.34 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 174.95, 137.25, 136.52, 136.41, 129.15, 128.95, 128.30, 128.03, 126.60, 61.94, 51.65, 51.55, 39.65, 21.02. The physical data were identical in all respects to those previously reported HRMS (APCI+, m/z): calculated for C18H22NO2 [M+H]+: 284.16451; found: 284.16520.
N-(4-methylbenzyl)-phenylalanine ethyl ester (3e):
Synthesized according to General procedure. Phenylalanine ethyl ester (0.097 g, 0.50 mmol) affords 3e (0.126 g, 85% yield). Light yellow oil compound obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl 3) δ 7.05 – 7.34 (m, 9H), 4.06 – 4.17 (m, 2H), 3.75 – 3.83 (m, 1H), 3.58 – 3.67 (m ,1H), 3.50 – 3.57 (m, 1H), 2.90 – 3.03 (m, 2H), 2.33 (s, 3H). 13C NMR (100 MHz, CDCl 3) δ 174.54, 137.34, 136.53, 136.51, 129.23, 128.96, 128.26, 128.06, 126.56, 62.01, 60.52, 51.65, 39.73, 21.04, 14.15. The physical data were identical in all respects to those previously reported HRMS (APCI+, m/z): calculated for C19H24NO2 [M+H]+: 298.18053; found: 298.18016.
The ee was determined by chiral HPLC analysis. Chiralcel OD-H column, Phenomenex, Ltd; heptane/isopropanol (99.2:0.8); flow rate: 0.5 ml/min; detection: UV 190 nm; retention times 24.5 min (minor) and 27.1 min (major).
N-(4-methylbenzyl)-phenylalanine pentyl ester (3f): Synthesized according
to General procedure. Phenylalanine pentyl ester (0.118 g, 0.50 mmol) affords 3f (0.146 g, 86% yield). Light yellow oil compound obtained after column
chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.05 – 7.34 (m, 9H), 3.97 – 4.10 (m, 2H), 3.73 – 3.84 (m, 1H), 3.58 – 3.66 (m, 1H), 3.50 – 3.57 (m, 1H), 2.90 – 3.03 (m, 2H), 2.33 (s, 3H), 1.48 – 1.60 (m, 2H), 1.17 – 1.37 (m, 4H), 0.82 – 0.96 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 174.69, 137.36, 136.53, 129.22, 128.97, 128.28, 128.07, 126.57, 77.32, 77.00, 76.68, 64.74, 62.07, 51.67, 39.79, 28.22, 27.97, 22.24, 21.05, 13.91. The physical data were identical in all respects to those previously reported HRMS (APCI+, m/z): calculated for C22H30NO2 [M+H]+: 340.22711; found: 340.22764. The ee was determined by chiral HPLC analysis. Chiralcel OD-H column, Phenomenex, Ltd; heptane/isopropanol (99.7:0.3); flow rate: 0.5 ml/min; detection: UV 230 nm; retention times 61.5 min (major) and 69.4 min (minor).
N-(4-chlorobenzyl)-phenylalanine pentyl ester (3i):
Synthesized according to General procedure. Phenylalanine pentyl ester (0.118 g, 0.50 mmol) affords 3i (0.133 g, 74% yield). Light yellow oil compound obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl 3) δ 7.10 – 7.34 (m, 9H), 3.99 – 4.12 (m, 2H), 3.75 – 3.84 (m, 1H), 3.55 – 3.65 (m, 1H), 3.44 – 3.53 (m, 1H), 2.89 – 3.03 (m, 2H), 1.46 – 1.63 (m, 2H), 1.16 – 1.39 (m, 4H), 0.83 – 0.96 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 174.55, 138.08, 137.22, 132.55, 129.34, 129.17, 128.32, 128.26, 126.59, 64.80, 61.90, 51.11, 39.76, 28.16, 27.92, 22.20, 13.89. HRMS (APCI+, m/z): calculated for C21H27ClNO2 [M+H]+: 360.17248; found: 360.17287.
The ee was determined by chiral HPLC analysis. Chiralcel OD-H column, Phenomenex, Ltd; heptane/isopropanol (99.7:0.3); flow rate: 0.5 ml/min; detection: UV 223 nm; retention times 49.7 min (minor) and 54.8 min (major).
N-(1-phenylethyl)-phenylalanine pentyl ester (3j):
Synthesi-zed according to General procedure. Phenylalanine pentyl ester (0.118 g, 0.50 mmol) affords 3j (0.129 g, 76% yield). Light yellow oil compound obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl 3) δ 7.17 – 7.33 (m, 6H), 7.05 – 7.16 (m, 4H), 3.97 – 4.12 (m, 2H), 3.65 – 3.75 (m, 1H), 3.22 – 3.32 (m, 1H), 2.80 – 2.95 (m, 2H), 1.48 – 1.60 (m, 2H), 1.18 – 1.37 (m, 7H), 0.83 – 0.95 (m, 3H). 13C NMR (100 MHz, CDCl 3) δ 175.25, 144.78, 137.38, 129.28, 128.25, 128.14, 126.84, 126.71, 126.46, 77.00, 64.64, 60.30, 56.52, 40.14, 28.22, 27.96, 25.34, 22.23, 13.93. HRMS (APCI+, m/z): calculated for C22H30NO2 [M+H]+: 340.22711; found: 340.22739.
GC spectrum of crude mixture, contains 2 pair of enantiomeric isomers:
GC spectrum of isolated one pair of enantiomeric isomers:
The ee was determined by chiral HPLC analysis. Chiralcel OD-H column, Phenomenex, Ltd; heptane/isopropanol (99.7:0.3); flow rate: 0.5 ml/min; detection: UV 217 nm; retention times 35.7 min (minor) and 52.4 min (major).
N-(4-methylbenzyl)-alanine isopropyl ester (3k): Synthesized
according to General procedure. Alanine isopropyl ester (0.066 g, 0.50 mmol) affords 3k (0.075 g, 64% yield). Light yellow oil compound obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.12 – 7.32 (m, 4H), 5.03 – 5.19 (m, 1H), 3.74 – 3.86 (m, 1H), 3.60 – 3.73 (m, 1H), 3.30 – 3.42 (m, 1H),
2.37 (s, 3H), 1.23 – 1.38 (m, 9H). 13C NMR (100 MHz, CDCl3) δ 175.19, 136.66, 136.52, 129.00, 128.16, 77.00, 67.95, 55.96, 51.56, 21.84, 21.71, 21.00, 18.98. HRMS (APCI+, m/z): calculated for C14H22NO2 [M+H]+: 236.16451; found: 236.16467.
The ee was determined by chiral HPLC analysis. Chiralcel OZ-H column, Phenomenex, Ltd; heptane/isopropanol (99.5:0.5); flow rate: 0.5 ml/min; detection: UV 217 nm; retention times 28.0 min (minor) and 32.3 min (major).
N-(4-chlorobenzyl)-alanine isopropyl ester (3l): Synthesized
according to General procedure. Alanine isopropyl ester (0.066 g, 0.50 mmol) affords 3l (0.075 g, 52% yield). Light yellow oil compound obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl
3) δ 7.24 – 7.35 (m, 4H), 4.98 – 5.12 (m, 1H), 3.70 – 3.82 (m, 1H), 3.54 – 3.68 (m, 1H), 3.24 – 3.33 (m,
1H), 1.05 – 1.45 (m, 9H). 13C NMR (100 MHz, CDCl3) δ 175.11, 138.21, 132.73, 129.55, 128.47, 68.17, 64.28, 55.99, 51.13, 21.87, 21.73, 19.02. HRMS (APCI+, m/z): calculated for C13H19ClNO2 [M+H]+: 256.10988; found: 256.11062.
N-pentyl-alanine isopropyl ester (3m): Synthesized according to
General procedure. Alanine isopropyl ester (0.066 g, 0.50 mmol) affords 3m (0.31 g, 31% yield). Light yellow oil compound obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 4.96 – 5.10 (m, 1H), 3.21 – 3.32 (m, 1H), 2.50 – 2.59
(m, 1H), 2.41 – 2.50 (m, 1H), 1.38 – 1.55 (m, 2H), 1.17 – 1.37 (m, 13H), 0.80 – 0.95 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 175.39, 67.93, 56.86, 47.98, 29.87, 29.44, 22.51, 21.86, 21.73, 19.05, 13.97.
N-(4-methylbenzyl)-alanine pentyl ester (3n): Synthesized
according to General procedure. Alanine pentyl ester (0.080 g, 0.50 mmol) affords 3n (0.104 g, 79% yield). Light yellow oil compound obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl 3) δ 7.17 – 7.25 (m, 2H), 7.07 – 7.16 (m, 2H), 4.07 – 4.17 (m, 2H), 3.72 – 3.82 (m, 1H), 3.57 – 3.67 (m, 1H), 3.32 – 3.42 (m, 1H), 2.33 (s, 3H), 1.58 – 1.73 (m, 2H), 1.26 – 1.42 (m, 7H), 0.84 – 0.98 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 175.82, 136.62, 136.61, 129.05, 128.20, 64.80, 55.89, 51.64, 28.33, 28.03, 22.28, 21.07, 19.14, 13.95. HRMS (APCI+, m/z): calculated for C16H26NO2 [M+H]+: 264.19581; found: 264.19614. The ee was determined by chiral HPLC analysis. Chiralcel OD-H column, Phenomenex, Ltd; heptane/isopropanol (99.5:0.5); flow rate: 0.5 ml/min; detection: UV 223 nm; retention times 20.6 min (major) and 25.5 min (minor).
N-benzyl-alanine pentyl ester (3o): Synthesized according to
General procedure. Alanine pentyl ester (0.080 g, 0.50 mmol) affords 3o (0.087 g, 70% yield). Light yellow oil compound obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.05 – 7.55 (m, 5H), 4.03 – 4.18 (m, 2H), 3.75 –
3.85 (m, 1H), 3.61 – 3.71 (m, 1H), 3.31 – 3.42 (m, 1H), 1.57 – 1.72 (m, 2H), 1.22 – 1.42 (m, 7H), 0.82 – 0.97 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 175.79, 139.69, 128.38, 128.23, 127.04, 77.00, 64.82, 55.98, 51.93, 28.33, 28.03, 22.27, 19.15, 13.94. HRMS (APCI+, m/z): calculated for C15H24NO2 [M+H]+: 250.18016; found: 250.18030.
The ee was determined by chiral HPLC analysis. Chiralcel OD-H column, Phenomenex, Ltd; heptane/isopropanol (99.5:0.5); flow rate: 0.5 ml/min; detection: UV 211 nm; retention times 22.2 min (major) and 28.0 min (minor).
N-(4-chlorobenzyl)-alanine pentyl ester (3p): Synthesized
according to General procedure. Alanine pentyl ester (0.080 g, 0.50 mmol) affords 3p (0.093 g, 66% yield). Light yellow oil compound obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl 3) δ 7.15 – 7.30 (m, 4H), 4.02 – 4.16 (m, 2H), 3.70 – 3.79 (m, 1H), 3.53 – 3.64 (m, 1H), 3.25 – 3.36 (m, 1H), 1.54 – 1.67 (m, 2H), 1.22 – 1.38 (m, 7H), 0.80 – 0.95 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 13C NMR (101 MHz, cdcl3) δ 175.68, 138.21, 132.69, 129.51, 128.44, 64.85, 55.88, 51.15, 28.29, 27.99, 22.24, 19.16, 13.93. HRMS (APCI+, m/z): calculated for C15H23ClNO2 [M+H]+: 284.14118; found: 284.14156.
The ee was determined by chiral HPLC analysis. Chiralcel OD-H column, Phenomenex, Ltd; heptane/isopropanol (99.5:0.5); flow rate: 0.5 ml/min; detection: UV 190 nm; retention times 17.3 min (minor) and 18.1 min (major).
N-pentyl-valine pentyl ester (3q): Synthesized according to
General procedure. Valine pentyl ester (0.094 g, 0.50 mmol) affords 3q (0.111 g, 86% yield). Light yellow oil compound obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.09 – 7.28 (m, 4H), 4.03 – 4.15 (m, 2H), 2.88 – 2.97 (m, 1H), 2.47 – 2.58 (m, 1H), 2.32 – 2.43 (m, 1H), 1.78 – 1.94 (m, 1H), 1.55 – 1.68 (m, 1H), 1.36 – 1.53 (m, 3H), 1.17 – 1.36 (m, 8H), 0.77 – 0.98 (m, 12H). 13C NMR (100 MHz, CDCl 3) δ 175.45, 67.56, 64.37, 48.74, 31.64, 29.88, 29.41, 28.37, 28.07, 22.53, 22.23, 19.09, 18.82, 13.99, 13.89. HRMS (APCI+, m/z): calculated for C15H32NO2 [M+H]+: 258.24276; found: 258.24287. The ee was determined by chiral HPLC analysis. Chiralcel OZ-H column, Phenomenex, Ltd; heptane/isopropanol (99.8:0.2); flow rate: 0.5 ml/min; detection: UV 223 nm; retention times 13.6 min (major) and 15.6 min (minor).
N-(4-methylbenzyl)-valine pentyl ester (3r): Synthesized
according to General procedure. Valine pentyl ester (0.094 g, 0.50 mmol) affords 3r (0.124 g, 84% yield). Light yellow oil compound obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 4.03 – 4.15 (m, 2H), 2.88 – 2.97
(m, 1H), 2.47 – 2.58 (m, 1H), 2.32 – 2.43 (m, 1H), 1.78 – 1.94 (m, 1H), 1.55 – 1.68 (m, 1H), 1.36 – 1.53 (m, 3H), 1.17 – 1.36 (m, 8H), 0.77 – 0.98 (m, 12H). 13C NMR (100 MHz, CDCl
3) δ 175.45, 67.56, 64.37, 48.74, 31.64, 29.88, 29.41, 28.37, 28.07, 22.53, 22.23, 19.09, 18.82, 13.99, 13.89. HRMS (APCI+, m/z): calculated for C18H30NO2 [M+H]+: 292.22711; found: 292.22741.
The ee was determined by chiral HPLC analysis. Chiralcel OD-H column, Phenomenex, Ltd; heptane/isopropanol (99.5:0.5); flow rate: 0.5 ml/min; detection: UV 221 nm; retention times 14.1 min (major) and 20.9 min (minor).
N-benzyl-valine pentyl ester (3s): Synthesized according to
General procedure. Valine pentyl ester (0.094 g, 0.50 mmol) affords 3s (0.120 g, 87% yield). Light yellow oil compound obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.20 – 7.45 (m, 5H), 4.07 – 4.20 (m, 2H), 3.78 – 3.89 (m, 1H), 3.54 – 3.68 (m, 1H), 2.95 – 3.05 (m, 1H), 1.85 – 1.99 (m, 1H), 1.58 – 1.73 (m, 2H), 1.27 – 1.43 (m, 4H), 0.83 – 1.02 (m, 9H). 13C NMR (100 MHz, CDCl3) δ 175.32, 140.13, 128.24, 128.22, 126.91, 66.61, 64.51, 52.52, 31.69, 28.39, 28.10, 22.26, 19.31, 18.61, 13.94. HRMS (APCI+, m/z): calculated for C17H28NO2 [M+H]+: 278.21146; found: 278.21182.
The ee was determined by chiral HPLC analysis. Chiralcel OD-H column, Phenomenex, Ltd; heptane/isopropanol (99.5:0.5); flow rate: 0.5 ml/min; detection: UV 221 nm; retention times 13.7 min (major) and 19.3 min (minor).
N-(4-chlorobenzyl)-valine pentyl ester (3t): Synthesized
according to General procedure. Valine pentyl ester (0.094 g, 0.50 mmol) affords 3t (0.128 g, 87% yield). Light yellow oil compound obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.18 – 7.36 (m, 4H), 4.05 – 4.17 (m, 2H), 3.75 – 3.83 (m, 1H), 3.47 – 3.58 (m, 1H), 2.90 – 2.98 (m,
1H), 1.84 – 1.97 (m, 1H), 1.57 – 1.70 (m, 2H), 1.25 – 1.42 (m, 4H), 0.75 – 1.03 (m, 9H). 13C NMR (100 MHz, CDCl3) δ 175.21, 138.62, 132.56, 129.52, 128.32, 77.32, 77.00, 76.68, 66.44, 64.56, 51.73, 31.65, 28.36, 28.07, 22.24, 19.33, 18.50, 13.92. HRMS (APCI+, m/z): calculated for C17H27ClNO2 [M+H]+: 312.17248; found: 312.17291.
The ee was determined by chiral HPLC analysis. Chiralcel OD-H column, Phenomenex, Ltd; heptane/isopropanol (99.5:0.5); flow rate: 0.5 ml/min; detection: UV 221 nm; retention times 12.3 min (major) and 13.3 min (minor). ethyl N-(4-methylbenzyl)-5-oxopyrrolidine-2-carboxylate (3u):
Synthesized according to General procedure. Glutamic acid diethyl ester (0.102 g, 0.50 mmol) affords 3u (0.038 g, 35% yield). Light yellow oil compound obtained after column chromatography (SiO2, Pentane/EtOAc 70:30 to 50:50). 1H NMR (400 MHz, CDCl3) δ 7.03 –
7.15 (m, 4H), 4.94 – 5.04 (m, 1H), 4.05 – 4.20 (m, 2H), 3.88 – 3.97 (m, 2H), 2.48 – 2.62 (m, 1H), 2.34 – 2.45 (m, 1H), 2.31 (s, 3H), 2.13 – 2.28 (m, 1H), 1.98 – 2.09 (m, 1H), 1.18 – 1.28 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 174.93, 171.74, 137.42, 132.67, 129.31, 128.46, 77.00, 61.36, 58.70, 45.23, 29.57, 22.75, 21.05,
14.08. HRMS (APCI+, m/z): calculated for C15H20NO3 [M+H]+: 262.14377; found: 262.14421.
The ee was determined by chiral HPLC analysis. Chiralcel OD-H column, Phenomenex, Ltd; heptane/isopropanol (96:4); flow rate: 0.5 ml/min; detection: UV 223 nm; retention times 31.3 min (minor) and 40.0 min (major).
N-(4-methylbenzyl)-proline pentyl ester (3v): Synthesized
according to General procedure. Proline pentyl ester (0.093 g, 0.50 mmol) affords 3u (0.061 g, 42% yield). Light yellow oil compound obtained after column chromatography (Al2O3, Pentane/EtOAc 95:5 to 90:10). 1H NMR (400 MHz, CDCl3) δ 7.03 – 7.28 (m, 4H), 3.98 – 4.18 (m, 2H), 3.83 – 3.94 (m, 1H), 3.45 – 3.58 (m, 1H), 3.17 – 3.31 (m, 1H), 2.96 – 3.08 (m, 1H), 2.30 – 2.44 (m, 1H), 2.32 (s, 3H), 2.04 – 2.18 (m, 1H), 1.83 – 2.01 (m, 2H), 1.70 – 1.81 (m, 1H), 1.55 – 1.69 (m, 2H), 1.21 – 1.43 (m, 4H), 0.78 – 1.02 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 174.17, 136.53, 135.19, 129.12, 128.78, 65.13, 64.61, 58.13, 52.99, 29.27, 28.29, 28.01, 22.85, 22.27, 21.07, 13.93. HRMS (APCI+, m/z): calculated for C18H28NO2 [M+H]+: 290.21146; found: 290.21177.
The ee was determined by chiral HPLC analysis. Chiralcel OZ-H column, Phenomenex, Ltd; heptane/isopropanol (99.5:0.5); flow rate: 0.5 ml/min; detection: UV 225 nm; retention times 23.1 min (minor) and 26.8 min (major).
N-(4-methylbenzyl)-prolinamide (7): Synthesized according to
General procedure. Prolinamide (0.057 g, 0.50 mmol) affords 3v (0.090 g, 83% yield). Light yellow oil compound obtained after column chromatography (SiO2, Pentane/EtOAc 20:80 to 0:100). 1H NMR (400 MHz, CDCl3) δ 7.20 – 7.35 (br.s, 1H), 7.07 – 7.20 (m, 4H), 6.20 – 6.40
(br.s, 1H), 3.84 – 3.97 (m, 1H), 3.35 – 3.50 (m, 1H), 3.09 – 3.23 (m, 1H), 2.94 – 3.04 (m, 1H), 2.26 – 2.40 (m, 1H), 2.33 (s, 3H), 2.14 – 2.25 (m, 1H), 1.85 – 1.97 (m, 1H), 1.64 – 1.82 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 178.30, 136.78, 135.38, 129.02, 128.54, 67.15, 59.31, 53.62, 30.50, 23.93, 21.02. HRMS (APCI+, m/z): calculated for C13H19NO2 [M+H]+: 219.14919; found: 219.14921.
The ee was determined by chiral HPLC analysis. Chiralcel OD-H column, Phenomenex, Ltd; heptane/isopropanol (94:6); flow rate: 0.5 ml/min; detection: UV 190 nm; retention times 34.8 min (minor) and 51.0 min (major).
Representative NMR and HPLC spectrums
1H NMR (400 MHz, CDCl
3) and 13C NMR (100 MHz, CDCl3) spectrums of N-(4-methylbenzyl) valine pentyl ester (3r)
HPLC spectrums of racemic and one enantiomer of N-(4-methylbenzyl) valine pentyl ester (3r)
HPLC Conditions: Chiralcel OD-H column, Phenomenex, Ltd; heptane/isopropanol (99.5:0.5); flow rate: 0.5 ml/min; detection: UV 221 nm; retention times 14.1 min (major) and 20.9 min (minor).
Racemic 3r
References
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