S1
Supporting Information
Access to benzazepinones by Pd-catalyzed remote CH carbonylation of -arylpropylamine derivatives
Mario Martínez-Mingo, Nuria Rodríguez,* Ramón Gómez-Arrayás* and Juan C. Carretero*
Departamento de Química Orgánica. Facultad de Ciencias. Universidad Autónoma de Madrid.
Cantoblanco. 28049 Madrid. Spain
General Methods S2
1. Additional information
1.1. Optimization studies for the derivatization of (+)-1 (Table S1) 1.2. Unreactive tested substrates
S3
2. Synthesis of starting materials
2.1. Typical procedure for the synthesis of N-SO2Py protected amine derivatives
2.2. Typical procedure for the Pd-catalyzed γ-arylation of N-SO2Py protected amine and amino acid derivatives
2.2.1. Typical procedure for the synthesis of the monoarylated derivatives 2.2.2. Typical procedure for the synthesis of the diarylated derivatives
2.3. Synthesis of the N-(2-pyridyl)sulfonyl protected 2-benzylcyclohexanamines 2.4. Typical procedure for the synthesis of 2-aryltryptophane N-SO2Py derivatives 2.5. Synthesis of (S)-3-(4-methylbenzyl)-2-(pyridine-2-sulfonamido)-4-(p-tolyl)butanoic acid ((+)-28)
2.6. Typical procedure for the synthesis of peptides
S5
3. General protocol for the Pd-catalyzed -C(sp2)H carbonylative cyclization of amine and amino acid derivatives
S24
4. Typical procedure for the cleavage of the (2-pyridyl)sulfonyl group S42
5. Synthesis of PdII complex A S44
6. Mechanistic studies
6.1. Stoichiometric and catalytic studies with the isolated PdII Complex A 6.1.1. Using PdII Complex (±)-A as catalyst
6.2. H/D exchange experiments using deuterium donor species 6.2.1. Standard reaction using CD3CO2D as deuterium donor 6.2.2. Pre-formation of Complex (±)-A, and quenching with TFA-d 6.3. Reaction analysis by in situ HRMS
6.3.1. Reaction analysis by in situ HRMS of the -C(sp2)H carbonylative cyclization reaction using Complex (±)-A as starting material
6.3.2. Reaction analysis by in situ HRMS of the Complex (±)-A formation
S45
7. References S56
8. NMR Spectra S57
S2 Experimental procedures and data
General Methods. The corresponding starting materials were synthetized using oven- dried glassware under an argon atmosphere containing a teflon-coated stirrer bar and dry septum. All reactions were performed at ambient Ar pressure in oven-dried pressure tube, sealed with a Teflon-lined screw cap.
All general reagents were obtained from usual commercial sources and were used, except when noted, without further purification. Amino acid derivatives were purchased from Aldrich Chemical Co., TCI and Bachem and used without further purification.
Pd(OAc)2, silver acetate and molybdenum hexacarbonyl were purchased from Aldrich Chemical Co. Benzoquinone was sublimated previously its use yielding a yellow powder.
Solvents were purified by standard procedures prior to use. All other compounds are commercially available and were used without further purification.
Flash column chromatography was performed using 230-400 mesh ultra-pure silica gel.
NMR-spectra were obtained on 300 and 500 MHz spectrometers using acetone-d6 and chloroform-d, as solvents, with proton and carbon resonances at 300/500 MHz and 75/125 MHz, respectively.
Infrared experiments were carried out in an Agilent Cary 630 FTIR spectrometer. Mass spectral data were acquired on a VG AutoSpec mass spectrometer. Melting points were determined in a Büchi Melting Point apparatus. Optical rotations were measured at 20 °C or 25 °C on an Anton Paar Modular Compact Polarimeter (MCP 150) using a 10 cm cell with the solvent and concentration stated, at 589 nm (sodium lamp). HPLC experiments were conducted using Agilent 1260 Infinity analytical SFC apparatus with a Daicel Chiralpak-IA (conditions specified in each case).
The 2-pyridylsulfonyl chloride was synthesized from 2-mercaptopyridine following the procedure described in the literature.1
S3 1. Additional information
1.1. Optimization studies for the derivatization of (+)-1 (Table S1)
Entry Additives Solvent t (h) (+)-9a (%) a 9b (%) a
1 AgOAc HFIP 18 75
2b AgOAc HFIP 18
3 HFIP 18 43
4 NaOAc HFIP 18
5c AgOAc HFIP 18 7
6d AgOAc HFIP 18 26
7 AgOAc HFIP 6 58
8 Ag2CO3 HFIP 6 15
9 AgNO3 HFIP 6 20
10 Ag2O HFIP 6 12
11 Cu(OAc)2 HFIP 6 44
12 CuBr2 HFIP 6
13 CuTf2 HFIP 6
14 CuCO3 HFIP 6 24
15 CuO HFIP 6 17
16 AgOAc t-AmylOH 6
17 AgOAc p-Xylene 6 23
18 AgOAc NMP 6 19
19 AgOAc 1,4-Dioxane 6 69
20e AgOAc 1,4-Dioxane 6 80
21f AgOAc 1,4-Dioxane 6 42
Reaction conditions: Amino acid derivative (+)-1 (0.10 mmol, 1.00 equiv), Pd(OAc)2 (10 mol%, 0.01 mmol), Mo(CO)6 (33 mol%, 0.033 mmol), BQ (0.20 mmol, 2.00 equiv), Additive (0.15 mmol, 1.50 equiv), Solvent (anh.) (0.5 M), 110 oC, t (h), Argon. a Determined by 1H NMR of the crude mixture. b Without Pd(OAc)2. c Without BQ. d Employing Fe(CO)5 instead of Mo(CO)6. e 1,4-Dioxane (0.25 M). f 1,4-Dioxane (0.1 M). BQ = 1,4-benzoquinone. HFIP = 1,1,1,3,3,3-hexafluoro-2-propanol. NMP = N-Methyl-2- pyrrolidone.
Table S1. Optimization studies for the derivatization of (+)-1
We started our investigations by subjecting the -p-tolyl-substituted L-valine derivative (+)-1 to carbonylation with Mo(CO)6 (33 mol%) in the presence of a catalytic amount of Pd(OAc)2 (10 mol%) and a combination of AgOAc (1.50 equiv) and 1,4-benzoquinone (BQ, 2.00 equiv) as oxidants in HFIP (0.5 M) at 110 °C for 18 h.2 Under these reaction conditions (entry 1), an encouraging 75% conversion toward the desired benzazepinone (+)-9a was observed, without detecting the -lactam 9b.
Subsequent control experiments revealed the key role of each component of the reaction mixture. Thus, omitting the palladium source determined that the benzazepinone (+)-9a was not produced (entry 2). The absence of AgOAc resulted in an attenuation of the catalytic activity (43%, entry 3), inhibiting any reactivity when replacing the AgOAc with NaOAc (entry 4). Similar outcome was observed when preforming the reaction in the
S4 absence of BQ (entry 5). When other carbon monoxide source, as Fe(CO)5, was employed the yield was reduced to a 26% (entry 6). Now, reducing the reaction time from 18 to 6 h, we next screened silver salts different from AgOAc but we only observed worse reaction efficiency (entries 7-10). An evaluation of copper salts instead of AgOAc was neither beneficial (entries 11-15). However, a study of the influence of the solvent (entries 16-19) showed that the use of 1,4-dioxane, a non-polar cyclic ether, was the optimal choice for this transformation, obtaining the benzazepinone (+)-9a in 69% yield (entry 19). This yield increased when preforming the reaction in less concentrated conditions (0.25 M instead of 0.5 M, entry 20). However, the more the solution is diluted, the slower the reaction will occur (entry 21).
1.2. Unreactive tested substrates
N-alkylation is not tolerated: Secondary sulfonamides are necessary.
Study of the influence of the directing/protecting group.
ε-C(sp3)-H bonds are not suitable for this transformation.
S5 2. Synthesis of starting materials
2.1. Typical procedure for the synthesis of N-SO2Py protected amine derivatives Synthesis of (S)-methyl 3-methyl-2-(pyridine-2-sulfonamido)butanoate ((+)-I).3 In a
100 mL round bottom flask, L-valine methyl ester hydrochloride (551 mg, 3.30 mmol, 1.00 equiv) was introduced and flushed with Ar. Next, anhydrous CH3CN (25.0 mL) and pyridine (1.46 mL, 18.0 mmol, 6.00 equiv) were added. The mixture was then placed in a 0 °C bath (ice-water) and 2-pyridylsulfonyl chloride (533 mg, 3.00 mmol, 1.00 equiv) was added dropwise. The mixture was stirred for 18 h at room temperature.
The solvent was removed under reduced pressure and the resulted crude product was dissolved in CH2Cl2 and washed with 1 M HCl. The organic phase was then washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The resulted residue was purified by flash column chromatography (cyclohexane:AcOEt 3:1) to obtain (+)-I as a white solid, yield: 881 mg (98%); mp = 108-109 °C. 1H NMR (300 MHz, CDCl3, δ): 8.59 (ddd, J = 4.7, 1.5, 0.9 Hz, 1H), 7.93 (dt, J = 7.8, 1.1 Hz, 1H), 7.86 (td, J = 7.7, 1.7 Hz, 1H), 7.44 (ddd, J = 7.4, 4.7, 1.3 Hz, 1H), 5.56 (d, J = 9.6 Hz, 1H), 4.11 (dd, J = 9.7, 5.0 Hz, 1H), 3.53 (s, 3H), 2.15 – 1.99 (m, 1H), 0.96 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3, δ): 171.9, 157.9, 149.7, 138.1, 126.7, 121.8, 62.1, 52.2, 31.7, 19.0, 17.4. HRMS-ESI (m/z): calcd. for C11H17N2O4S (M+H)+: 273.0909;
Found: 273.0911. [α]D25: +17 (c = 1.0; CH2Cl2).
(2S*,3R*)-Methyl 3-methyl-2-(pyridine-2-sulfonamido)pentanoate ((±)-II).
Step 1. Protection of the acid group. To a suspended mixture of DL-allo-isoleucine (2.00 g, 15.2 mmol, 1.00 equiv) in MeOH (30.5 mL) at 0 °C, thionyl chloride (1.22 mL, 16.7 mmol, 1.10 equiv) was added dropwise under Ar atmosphere. Once the thionyl chloride was added, the solution was refluxed for 3 h. After this time the volatiles were removed in vacuo affording the pure aminoester hydrochloride, which was used without further purification.
Step 2. Protection of the amino group. The previously synthetized methyl ester hydrochloride (600 mg, 3.30 mmol, 1.10 equiv) was submitted to the conditions of the general protocol for the synthesis of N-SO2Py protected amino acid derivatives, to give (±)-II as a white solid; yield: 3.92 g (90%); mp = 111-112 °C.
1H NMR (300 MHz, CDCl3, δ): 8.59 (d, J = 4.6 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.85 (td, J = 7.7, 1.6 Hz, 1H), 7.44 (ddd, J = 7.4, 4.7, 1.2 Hz, 1H), 5.47 (d, J = 9.9 Hz, 1H), 4.29 (dd, J = 9.9, 4.1 Hz, 1H), 3.52 (s, 3H), 1.88 – 1.75 (m, 1H), 1.56 – 1.42 (m, 1H), 1.30 – 1.15 (m, 1H), 0.90 (t, J = 7.4 Hz, 3H), 0.80 (d, J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3, δ): 172.2, 157.9, 149.7, 138.1, 126.7, 121.8, 60.2, 52.3, 38.2, 26.0, 14.3, 11.5.
HRMS-ESI (m/z): calcd. for C12H19N2O4S (M+H)+: 287.1066; Found: 287.1060.
(2S,3S)-Methyl 3-methyl-2-(pyridine-2-sulfonamido)pentanoate ((+)-III). Compound (+)-III was prepared following the typical procedure from L-isoleucine methyl ester hydrochloride (600 mg, 3.30 mmol, 1.10 equiv) to give (+)-III as a white solid; yield: 664 mg (77%);
mp = 98-100 °C. 1H NMR (300 MHz, CDCl3, δ): 8.61 (ddd, J = 4.7, 1.5, 0.9 Hz, 1H), 7.94 (dt, J = 7.9, 1.1 Hz, 1H), 7.87 (td,
S6 J = 7.7, 1.7 Hz, 1H), 7.45 (ddd, J = 7.5, 4.7, 1.3 Hz, 1H), 5.47 (d, J = 9.6 Hz, 1H), 4.17 (dd, J = 9.6, 5.3 Hz, 1H), 3.54 (s, 3H), 1.89 – 1.76 (m, 1H), 1.50 – 1.36 (m, 1H), 1.24 – 1.09 (m, 1H), 0.93 (d, J = 6.8 Hz, 3H), 0.87 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3, δ): 171.9, 157.9, 149.8, 138.1, 126.8, 121.9, 61.4, 52.2, 38.7, 24.7, 15.5, 11.4.
HRMS-ESI (m/z): calcd. for C12H19N2O4S (M+H)+: 287.1066; Found: 287.1052.
[α]D25: +25 (c = 7.5; CH2Cl2).
(R)-N-(3-Methylbutan-2-yl)pyridine-2-sulfonamide ((+)-IV). Compound (+)-IV was prepared following the typical procedure from (R)-3-methylbutan-2- amine (0.35 mL, 3.00 mmol, 1.00 equiv), to give (+)-IV as a white solid; yield: 572 mg (83%); mp = 72-74 °C. 1H NMR (300 MHz, CDCl3, δ): 8.70 (ddd, J = 4.7, 1.6, 0.8 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.89 (td, J = 7.7, 1.7 Hz, 1H), 7.47 (ddd, J = 7.6, 4.7, 1.2 Hz, 1H), 4.87 (d, J = 8.3 Hz, 1H), 3.35 – 3.24 (m, 1H), 1.74 – 1.59 (m, 1H), 0.94 (d, J = 6.7 Hz, 3H), 0.83 (d, J = 6.8 Hz, 6H).13C NMR (75 MHz, CDCl3, δ): 158.5, 150.1, 138.0, 126.6, 122.0, 55.6, 33.6, 18.2, 18.1, 18.0. HRMS-ESI (m/z): calcd. for C10H17N2O2S (M+H)+: 229.1011; Found:
229.1006. [α]D25: +10 (c = 1.0; CH2Cl2).
Ethyl 4-phenyl-2-(pyridine-2-sulfonamido)butanoate ((±)-48). Compound (±)-48 was prepared following the typical procedure from ethyl 2-amino- 4-phenylbutanoate (622 mg, 3.00 mmol, 1.00 equiv), to give (±)-48 as a white solid; yield: 1.01 g (97%).
1H NMR (300 MHz, CDCl3, δ): 8.64 (ddd, J = 4.7, 1.5, 0.9 Hz, 1H), 7.97 (dt, J = 7.9, 1.0 Hz, 1H), 7.89 (td, J = 7.7, 1.7 Hz, 1H), 7.47 (ddd, J = 7.5, 4.7, 1.2 Hz, 1H), 7.30 – 7.27 (m, 1H), 7.25 – 7.23 (m, 1H), 7.21 – 7.15 (m, 3H), 5.55 (d, J = 8.7 Hz, 1H), 4.39 – 4.32 (m, 1H), 4.03 (q, J = 7.0 Hz, 2H), 2.74 (t, J = 8.1 Hz, 2H), 2.21 – 2.09 (m, 1H), 2.04 – 1.91 (m, 1H), 1.18 (t, J = 7.1 Hz, 3H).
13C NMR (75 MHz, CDCl3, δ): 171.7, 158.0, 149.9, 140.7, 138.2, 128.6, 126.8, 126.3, 121.9, 61.8, 56.7, 35.6, 31.4, 14.2. HRMS-FAB (m/z): calcd. for C17H21N2O4S (M+H)+: 349.1222; Found: 349.1215.
N-(3-Phenylpropyl)pyridine-2-sulfonamide (50). Compound 50 was prepared following the general protocol for the synthesis of N-SO2Py protected amino acid derivatives from 3- phenylpropanamine (0.43 mL, 3.00 mmol, 1.00 equiv), to give 50 as a white solid; yield: 359 mg (88%);
mp = 77-79 °C. 1H NMR (300 MHz, CDCl3, δ): 8.71 – 8.69 (m, 1H), 8.00 (d, J = 7.8, 0.9 Hz, 1H), 7.90 (td, J = 7.7, 1.7 Hz, 1H), 7.49 (ddd, J = 7.6, 4.7, 1.2 Hz, 1H), 7.28 – 7.23 (m, 2H), 7.19 – 7.09 (m, 3H), 5.28 (bs, 1H), 3.10 – 3.04 (m, 2H), 2.66 – 2.60 (t, J = 8.0 Hz, 2H), 1.82 (p, J = 8.0 Hz, 2H).13C NMR (75 MHz, CDCl3, δ): 157.5, 150.1, 141.0, 138.2, 128.6, 128.5, 126.8, 126.2, 122.4, 43.2, 32.8, 31.5.
HRMS-ESI (m/z): calcd. for C14H17N2O2S (M+H)+: 227.1011; Found: 227.1016.
S7 2.2. Typical procedure for the Pd-catalyzed γ-arylation of N-SO2Py protected amine and amino acid derivatives3
2.2.1. Typical procedure for the synthesis of the monoarylated derivatives
Synthesis of (2S,3S)-methyl 3-methyl-2-(pyridine-2-sulfonamido)-4-(p-tolyl) butanoate ((+)-1). An oven-dried pressure tube was charged with Pd(OAc)2 (5.61 mg, 0.025 mmol, 10 mol %), AgOAc (41.7 mg, 0.25 mmol), 4-iodotoluene (54.5 mg, 0.25 mmol, 1.00 equiv), L-valine derivative (+)-I (68.1 mg, 0.25 mmol, 1.00 equiv) and HFIP (0.25 mL). The reaction mixture was then placed in an oil bath at 140 °C for 4 h. After the reaction time was completed, the reaction mixture was diluted with AcOEt, filtered through a short pad of Celite®, and concentrated in vacuo. The residue was purified by flash column chromatography (30:1 CH2Cl2:Et2O) to obtain derivative (2S,3S)-methyl 3-methyl-2-(pyridine-2-sulfonamido)-4-(p- tolyl)butanoate (+)-1 as a white oil in 62% yield (56.3 mg). 1H NMR (300 MHz, CDCl3, δ): 8.63 – 8.61 (m, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.86 (td, J = 7.7, 0.9 Hz, 1H), 7.47 – 7.43 (m, 1H), 7.06 (d, J = 7.9 Hz, 2H), 7.00 (d, J = 7.9 Hz, 2H), 5.63 (d, J = 9.3 Hz, 1H), 4.24 (dd, J = 9.1, 4.3 Hz, 1H), 3.54 (s, 3H), 2.75 (dd, J = 12.7, 4.0 Hz, 1H), 2.37 – 2.21 (m, 5H), 0.92 (d, J = 6.1 Hz, 3H). 13C NMR (75 MHz, CDCl3, δ): 171.6, 157.8, 149.8, 138.1, 136.3, 135.7, 129.1, 129.1, 126.8, 122.0, 61.2, 52.3, 39.0, 37.9, 21.1, 15.9. HRMS-ESI (m/z): calcd. for C18H23N2O4S (M+H)+: 363.1379; Found:
363.1373. IR (νmax/cm): 1735, 1347, 1180. [α]D25: +63 (c = 1.0; CH2Cl2).
(2S,3S)-Methyl 4-(4-methoxyphenyl)-3-methyl-2-(pyridine-2-sulfonamido)- butanoate ((+)-2). Compound (+)-2 was prepared following the general protocol from L-valine derivative (+)-I (68.1 mg, 0.25 mmol, 1.00 equiv) and 4-iodoanisole (58.5 mg, 0.25 mmol, 1.00 equiv) to give (+)-2 as a white oil; yield: 60.6 mg (64%).
1H NMR (300 MHz, CDCl3, δ): 8.62 (d, J = 4.7 Hz, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.86 (t, J = 7.6 Hz, 1H), 7.47 – 7.42 (m, 1H), 7.02 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.3 Hz, 2H), 5.68 (d, J = 9.3 Hz, 1H), 4.22 (dd, J = 9.3, 4.5 Hz, 1H), 3.76 (s, 3H), 3.53 (s, 3H), 2.72 (dd, J = 13.1, 4.6 Hz, 1H), 2.35 – 2.20 (m, 2H), 0.90 (d, J = 6.4 Hz, 3H). 13C NMR (75 MHz, CDCl3, δ): 171.6, 158.1, 157.8, 149.9, 138.1, 131.4, 130.2, 126.8, 122.0, 113.8, 61.1, 55.3, 52.3, 39.1, 37.5, 15.9. HRMS-ESI (m/z):
calcd. for C18H23N2O5S (M+H)+: 379.1328; Found: 379.1322. IR (νmax/cm): 1738, 1343, 1175. [α]D25: +55 (c = 1.0; CH2Cl2).
(2S,3S)-Methyl 3-methyl-4-phenyl-2-(pyridine-2-sulfonamido)butanoate ((+)-3).
Compound (+)-3 was prepared following the general protocol from L-valine derivative (+)-I (68.1 mg, 0.25 mmol, 1.00 equiv) and iodobenzene (28.0 μL, 0.25 mmol, 1.00 equiv) to give (+)-3 as a yellow oil; yield: 51.6 mg (59%). 1H NMR (300 MHz, CDCl3, δ): 8.61 (d, J = 4.2 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.84 (td, J = 7.7, 1.7 Hz, 1H), 7.43 (ddd, J = 7.4, 4.7, 1.3 Hz, 1H), 7.24 – 7.21 (m, 2H), 7.18 – 7.16 (m, 1H), 7.12 – 7.09 (m, 2H), 5.78 (d, J = 9.3 Hz, 1H), 4.23 (dd, J = 9.3, 4.7 Hz, 1H), 3.52 (s, 3H), 2.79 (dd,
S8 J = 12.9, 4.5 Hz, 1H), 2.40 – 2.23 (m, 2H), 0.91 (d, J = 6.5 Hz, 3H). 13C NMR (75 MHz, CDCl3, δ): 171.5, 157.8, 149.8, 139.4, 138.1, 129.2, 128.4, 126.8, 126.2, 121.9, 61.2, 52.3, 38.9, 38.4, 15.9. HRMS-ESI (m/z): calcd. for C17H21N2O4S (M+H)+: 349.1222;
Found: 349.1216. IR (νmax/cm): 1741, 1342, 1175. [α]D25: +52 (c = 1.0; CH2Cl2).
(2S,3S)-Methyl 4-(4-chlorophenyl)-3-methyl-2-(pyridine-2-sulfonamido)butanoate ((+)-4). Compound (+)-4 was prepared following the general protocol L-valine derivative (+)-I (68.1 mg, 0.25 mmol, 1.00 equiv) and 4-chloroiodobenzene (59.6 mg, 0.25 mmol, 1.00 equiv) to give (+)-4, as a 89:11 diasteromeric mixture, yield:
50.1 mg (52%). 1H NMR (300 MHz, CDCl3, δ): 8.63 – 8.60 (m, 1H), 7.94 – 7.84 (m, 2H), 7.48 – 7.44 (m, 1H), 7.22 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.3 Hz, 2H), 5.75 (d, J = 9.2 Hz, 1H), 4.19 (dd, J = 9.2, 5.0 Hz, 1H), 3.55 (s, 3H), 2.78 (dd, J = 13.4, 5.1 Hz, 1H), 2.37 (dd, J = 13.4, 9.4 Hz, 1H), 2.30 – 2.18 (m, 1H), 0.90 (d, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3, δ): 171.4, 157.7, 149.9, 138.1, 138.0, 132.1, 130.6, 128.5, 126.8, 122.0, 61.0, 52.4, 39.0, 37.8, 15.8. HRMS-ESI (m/z): calcd. for C17H20ClN2O4S (M+H)+: 383.0832; Found: 383.0827.
IR (νmax/cm): 1738, 1345, 1177. [α]D25: +57 (c = 1.0; CH2Cl2).
(2S,3S)-Methyl 4-(4-bromophenyl)-3-methyl-2-(pyridine-2-sulfonamido)butanoate ((+)-5). Compound (+)-5 was prepared following the general protocol from L-valine derivative (+)-I (68.1 mg, 0.25 mmol, 1.00 equiv) and 4-bromoiodobenzene (70.7 mg, 0.25 mmol, 1.00 equiv) to give (+)-5 as a yellow oil; yield: 53.4 mg (50%).
1H NMR (300 MHz, CDCl3, δ): 8.60 – 8.58 (m, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.83 (td, J = 7.7, 1.5 Hz, 1H), 7.45 – 7.41 (m, 1H), 7.32 (d, J = 8.3 Hz, 2H), 6.97 (d, J = 8.2 Hz, 2H), 6.11 (d, J = 9.3 Hz, 1H), 4.16 (dd, J = 9.3, 5.1 Hz, 1H), 3.50 (s, 3H), 2.75 (dd, J = 13.2, 4.7 Hz, 1H), 2.33 (dd, J = 13.2, 9.5 Hz, 1H), 2.25 – 2.18 (m, 1H), 0.86 (d, J = 6.5 Hz, 3H). 13C NMR (75 MHz, CDCl3, δ): 171.3, 157.5, 149.7, 138.4, 138.0, 131.3, 130.9, 126.8, 121.9, 119.9, 60.9, 52.2, 38.7, 37.7, 15.7.
HRMS-ESI (m/z): calcd. for C17H20BrN2O4S (M+H)+: 427.0321; Found: 427.0310.
IR (νmax/cm): 1742, 1339, 1181. [α]D25: +50 (c = 1.0; CH2Cl2).
Methyl 4-((2S,3S)-4-methoxy-2-methyl-4-oxo-3-(pyridine-2-sulfonamido)butyl)- benzoate ((+)-6). Compound (+)-6 was prepared following the general protocol from L-valine derivative (+)-I (68.1 mg, 0.25 mmol, 1.00 equiv) and methyl 4-iodobenzoate (65.5 mg, 0.25 mmol, 1.00 equiv) to give (+)-6, as a 86:14 diasteromeric mixture, yield: 51.8 mg (51%). 1H NMR (300 MHz, CDCl3, δ):
8.61 (ddd, J = 4.7, 1.6, 0.9 Hz, 1H), 7.97 – 7.91 (m, 3H), 7.89 (td, J = 7.6, 1.6 Hz, 1H), 7.46 (ddd, J = 7.3, 4.7, 1.5 Hz, 1H), 7.19 (d, J = 8.2 Hz, 2H), 5.66 (d, J = 9.2 Hz, 1H), 4.23 (dd, J = 9.2, 5.0 Hz, 1H), 3.89 (s, 3H), 3.56 (s, 3H), 2.87 (dd, J = 13.4, 5.0 Hz, 1H), 2.44 (dd, J = 13.4, 9.6 Hz, 1H), 2.36 – 2.25 (m, 1H), 0.91 (d, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3, δ): 171.4, 167.1, 157.8, 149.8, 145.1, 138.1, 129.7, 129.3, 128.3, 126.8, 122.0, 61.1, 52.4, 52.1, 38.8, 38.5, 15.9.
S9 HRMS-ESI (m/z): calcd. for C19H23N2O6S (M+H+): 407.1269; Found: 407.1271.
IR (νmax/cm): 1742, 1714, 1336, 1175. [α]D20: +60 (c = 1.0; CH2Cl2).
(2S,3S)-Methyl 3-methyl-2-(pyridine-2-sulfonamido)-4-(4-(trifluoromethyl)phenyl)- butanoate ((+)-V). Compound (+)-V was prepared following the general protocol from L-valine derivative (+)-I (68.1 mg, 0.25 mmol, 1.00 equiv) and 4-iodobenzotrifluoride (36.7 μL, 0.25 mmol, 1.00 equiv) to give (+)-V, as a 87:13 diasteromeric mixture, as a yellow oil; yield: 46.9 mg (45%). 1H NMR (300 MHz, CDCl3, δ): 8.52 (dt, J = 4.7, 0.8 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.77 (td, J = 7.7, 1.6 Hz, 1H), 7.42 – 7.35 (m, 3H), 7.16 (d, J = 8.0 Hz, 2H), 6.04 (d, J = 9.3 Hz, 1H), 4.12 (dd, J = 9.3, 5.2 Hz, 1H), 3.45 (s, 3H), 2.81 (dd, J = 13.5, 5.0 Hz, 1H), 2.38 (dd, J = 13.4, 9.5 Hz, 1H), 2.28 – 2.17 (m, 1H), 0.82 (d, J = 6.7 Hz, 3H).
13C NMR (75 MHz, CDCl3, δ): 171.3, 157.6, 149.8, 143.7, 138.1, 129.6, 128.5 (q, J = 32.3 Hz), 126.8, 125.2 (q, J = 3.8 Hz), 124.3 (q, J = 271.8 Hz), 60.9, 52.3, 38.7, 38.2, 15.7. HRMS-ESI (m/z): calcd. for C18H20F3N2O4S (M+H)+: 417.1096; Found: 417.1090.
IR (νmax/cm): 1742, 1325, 1120. [α]D25: +53 (c = 1.0; CH2Cl2).
(2S,3S)-Methyl 3-methyl-2-(pyridine-2-sulfonamido)-4-(m-tolyl)butanoate ((+)-7).
Compound (+)-7 was prepared following the general protocol from L-valine derivative (+)-I (68.1 mg, 0.25 mmol, 1.00 equiv) and 3-iodotoluene (32.1 μL, 0.25 mmol, 1.00 equiv) to give (+)-7 as a yellow oil; yield: 44.5 mg (49%). 1H NMR (300 MHz, CDCl3, δ): 8.63 (d, J = 4.3 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.87 (td, J = 7.7, 1.7 Hz, 1H), 7.45 (ddd, J = 7.4, 4.7, 1.3 Hz, 1H), 7.14 (t, J = 7.4 Hz, 1H), 6.99 (d, J = 7.3 Hz, 1H), 6.93 – 6.90 (m, 2H), 5.67 (d, J = 9.3 Hz, 1H), 4.25 (dd, J = 9.3, 4.6 Hz, 1H), 3.55 (s, 3H), 2.77 (dd, J = 12.0, 3.3 Hz, 1H), 2.37 – 2.26 (m, 5H), 0.92 (d, J = 6.4 Hz, 3H).
13C NMR (75 MHz, CDCl3, δ): 171.6, 157.8, 149.8, 139.4, 138.1, 137.9, 130.0, 128.3, 127.0, 126.8, 126.3, 122.0, 61.3, 52.3, 38.9, 38.3, 21.4, 16.0. HRMS-ESI (m/z): calcd.
for C18H23N2O4S (M+H)+: 363.1379; Found: 363.1373. IR (νmax/cm): 1738, 1343, 1175.
[α]D25: +55 (c = 1.0; CH2Cl2).
(2S,3S)-Methyl 3-methyl-2-(pyridine-2-sulfonamido)-4-(o-tolyl)butanoate ((+)-8).
Compound (+)-8 was prepared following the general protocol from L-valine derivative (+)-I (68.1 mg, 0.25 mmol, 1.00 equiv) and 2-iodotoluene (31.8 μL, 0.25 mmol, 1.00 equiv) to give (+)-8, as a 73:27 diasteromeric mixture, as a brown oil; yield:
18.2 mg (20%). 1H NMR (300 MHz, CDCl3, δ): 8.63 (d, J = 4.6 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.87 (td, J = 7.7, 1.6 Hz, 1H), 7.46 (ddd, J = 7.4, 4.7, 1.2 Hz, 1H), 7.12 – 7.06 (m, 4H), 5.65 (d, J = 9.3 Hz, 1H), 4.30 (dd, J = 9.3, 4.3 Hz, 1H), 3.58 (s, 3H), 2.79 (dd, J = 12.9, 3.7 Hz, 1H), 2.39 – 2.31 (m, 1H), 2.27 – 2.24 (m, 4H), 0.95 (d, J = 6.5 Hz, 3H).
13C NMR (75 MHz, CDCl3, δ):171.6, 157.7, 149.8, 138.1, 137.6, 136.3, 130.4, 130.1, 126.7, 126.4, 125.7, 121.9, 61.4, 52.3, 37.3, 35.4, 19.3, 15.9. HRMS-ESI (m/z): calcd.
for C18H22N2O4SNa (M+Na)+: 385.1198; Found: 385.1192. IR (νmax/cm): 1753, 1342, 1185. [α]D25: +58 (c = 1.0; CH2Cl2).
S10 (2S*,3S*)-Methyl 3-(4-methylbenzyl)-2-(pyridine-2-sulfonamido)pentanoate ((±)-
43). Compound (±)-43 was prepared following the general protocol from DL-allo-isoleucine derivative (±)-II (71.6 mg, 0.25 mmol, 1.00 equiv) and 4-iodotoluene (54.5 mg, 0.25 mmol, 1.00 equiv) to give (±)-43 as a white solid; yield:
67.9 mg (72%); mp = 96-97 °C. 1H NMR (300 MHz, CDCl3, δ):
8.63 – 8.61 (m, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.85 (td, J = 7.6, 1.7 Hz, 1H), 7.44 (ddd, J = 7.4, 4.7, 1.4 Hz, 1H), 7.05 (d, J = 7.9 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 5.53 (d, J = 9.5 Hz, 1H), 4.43 (dd, J = 9.5, 3.5 Hz, 1H), 3.47 (s, 3H), 2.57 – 2.41 (m, 2H), 2.29 (s, 3H), 2.14 – 2.03 (m, 1H), 1.59 – 1.45 (m, 1H), 1.40 – 1.26 (m, 1H), 0.94 (t, J = 7.3 Hz, 3H).
13C NMR (75 MHz, CDCl3, δ): 172.1, 157.8, 149.8, 138.0, 136.3, 135.7, 129.1, 129.1, 126.7, 121.9, 58.2, 52.4, 45.5, 35.4, 22.9, 21.1, 11.6. HRMS-ESI (m/z): calcd. for C19H25N2O4S (M+H+): 377.1535; Found: 377.1530. IR (νmax/cm): 1735, 1174, 1339.
(2S*,3S*)-Methyl 3-benzyl-2-(pyridine-2-sulfonamido)pentanoate ((±)-44).
Compound (±)-44 was prepared following the general protocol from DL-allo-isoleucine derivative (±)-II (71.6 mg, 0.25 mmol, 1.00 equiv) and iodobenzene (28.0 μL, 0.25 mmol, 1.00 equiv) to give (±)-44 as a yellow oil; yield: 63.6 mg (70%).
1H NMR (300 MHz, CDCl3, δ): 8.60 (d, J = 4.6 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.83 (td, J = 7.6, 1.6 Hz, 1H), 7.43 (ddd, J = 7.3, 4.7, 1.3 Hz, 1H), 7.25 – 7.21 (m, 2H), 7.18 – 7.14 (m, 1H), 7.13 – 7.07 (m, 2H), 5.60 (d, J = 9.5 Hz, 1H), 4.42 (dd, J = 9.5, 3.5 Hz, 1H), 3.46 (s, 3H), 2.61 – 2.46 (m, 2H), 2.16 – 2.06 (m, 1H), 1.61 – 1.46 (m, 1H), 1.39 – 1.25 (m, 1H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3, δ): 172.0, 157.8, 149.8, 139.5, 138.0, 129.2, 128.4, 126.7, 126.2, 121.9, 58.2, 52.4, 45.4, 35.9, 23.0, 11.5.
HRMS-ESI (m/z): calcd. for C18H23N2O4S (M+H+): 363.1379; Found: 363.1380.
IR (νmax/cm): 1733, 1338, 1174.
(2S*,3S*)-Methyl 2-(pyridine-2-sulfonamido)-3-(4-(trifluoromethyl)benzyl)- pentanoate ((±)-45). Compound (±)-45 was prepared following the general protocol from DL-allo-isoleucine derivative (±)-II (71.6 mg, 0.25 mmol, 1.00 equiv) and 4-iodobenzotrifluoride (36.7 μL, 0.25 mmol, 1.00 equiv) to give (±)-45 as a yellow solid;
yield: 77.4 mg (72%); mp = 128-131 °C. 1H NMR (300 MHz, CDCl3, δ): 8.61 – 8.58 (m, 1H), 7.89 (dt, J = 7.8, 1.3 Hz, 1H), 7.84 (td, J = 7.3, 1.7 Hz, 1H), 7.48 (d, J = 8.1 Hz, 2H), 7.45 – 7.41 (m, 1H), 7.22 (d, J = 8.0 Hz, 2H), 5.80 (d, J = 9.2 Hz, 1H), 4.36 (dd, J = 9.2, 3.7 Hz, 1H), 3.48 (s, 3H), 2.69 – 2.55 (m, 2H), 2.18 – 2.07 (m, 1H), 1.62 – 1.47 (m, 1H), 1.34 – 1.20 (m, 1H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3, δ): 171.8, 157.7, 149.8, 143.9 (q, J = 1.2 Hz), 138.1, 129.6, 128.6 (q, J = 32.3 Hz), 126.8, 125.3 (q, J = 3.7 Hz), 124.3 (q, J = 271.8 Hz), 122.0, 58.1, 52.4, 45.3, 35.7, 22.9, 11.4. 19F NMR (282 MHz, CDCl3, δ): -62.6. HRMS-ESI (m/z): calcd. for C19H22F3N2O4S (M+H+): 431.1247;
Found: 431.1247. IR (νmax/cm): 1741, 1323, 1118.
S11 (2S*,3S*)-Methyl 3-(3-methylbenzyl)-2-(pyridine-2-sulfonamido)pentanoate ((±)-46). Compound (±)-46 was prepared following the general protocol from DL-allo-isoleucine derivative (±)-II (71.6 mg, 0.25 mmol, 1.00 equiv) and 3-iodotoluene (32.1 μL, 0.25 mmol, 1.00 equiv) to give (±)-46 as a yellow oil; yield: 64.4 mg (68%).
1H NMR (300 MHz, CDCl3, δ): 8.61 (d, J = 4.6 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.84 (td, J = 7.7, 1.7 Hz, 1H), 7.44 (ddd, J = 7.4, 4.7, 1.3 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.90 – 6.87 (m, 2H), 5.62 (d, J = 9.5 Hz, 1H), 4.43 (dd, J = 9.5, 3.5 Hz, 1H), 3.47 (s, 3H), 2.58 – 2.41 (m, 2H), 2.29 (s, 3H), 2.16 – 2.05 (m, 1H), 1.60 – 1.45 (m, 1H), 1.40 – 1.26 (m, 1H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3, δ): 172.0, 157.8, 149.8, 139.4, 138.0, 137.9, 130.0, 128.2, 127.0, 126.7, 126.2, 121.9, 58.2, 52.3, 45.3, 35.8, 22.9, 21.4, 11.5. HRMS-ESI (m/z): calcd. for C19H25N2O4S (M+H+): 377.1535;
Found: 377.1539. IR (νmax/cm): 1737, 1340, 1176.
(2S*,3S*)-Methyl 3-(naphthalen-1-ylmethyl)-2-(pyridine-2-sulfonamido)pentanoate ((±)-47). Compound (±)-47 was prepared following the general protocol from DL-allo-isoleucine derivative (±)-II (71.6 mg, 0.25 mmol, 1.00 equiv) and 2-iodonaphthalene (32.1 μL, 0.25 mmol, 1.00 equiv) to give (±)-47 as a yellow oil; yield:
53.7 mg (52%). 1H NMR (300 MHz, CDCl3, δ): 8.58 (ddd, J = 4.7, 1.6, 0.9 Hz, 1H), 7.88 – 7.76 (m, 4H), 7.71 (d, J = 8.1 Hz, 1H), 7.50 – 7.43 (m, 2H), 7.42 – 7.38 (m, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 6.4 Hz, 1H), 5.64 (d, J = 9.4 Hz, 1H), 4.53 (dd, J = 9.5, 3.1 Hz, 1H), 3.45 (s, 3H), 3.07 (dd, J = 13.9, 5.9 Hz, 1H), 2.92 (dd, J = 14.7, 8.1 Hz, 1H), 2.36 – 2.26 (m, 1H), 1.70 – 1.55 (m, 1H), 1.47 – 1.33 (m, 1H), 0.95 (t, J = 7.3 Hz, 3H).
13C NMR (75 MHz, CDCl3, δ): 172.1, 157.8, 149.8, 138.0, 135.3, 134.0, 132.1, 129.0, 128.0, 127.3, 126.7, 126.0, 125.6, 125.4, 123.6, 121.9, 58.1, 52.3, 44.2, 33.3, 23.3, 11.6.
HRMS-ESI (m/z): calcd. for C22H25N2O4S (M+H+): 413.1535; Found: 413.1532.
IR (νmax/cm): 1735, 1340, 1176.
(2S,3R)-Methyl 3-(4-methylbenzyl)-2-(pyridine-2-sulfonamido)pentanoate ((+)-VI).
Compound (+)-VI was prepared following the general protocol from L-isoleucine derivative (+)-III (71.6 mg, 0.25 mmol, 1.00 equiv) and 4-iodotoluene (54.5 mg, 0.25 mmol, 1.00 equiv) to give (+)-VI as a yellow oil; yield: 33.1 mg (35%).
1H NMR (300 MHz, CDCl3, δ): 8.63 (ddd, J = 4.7, 1.6, 0.9 Hz, 1H), 7.96 (dt, J = 7.8, 1.1 Hz, 1H), 7.87 (td, J = 7.7, 1.7 Hz, 1H), 7.46 (ddd, J = 7.4, 4.7, 1.3 Hz, 1H), 7.10 (bs, 4H), 5.37 (d, J = 9.8 Hz, 1H), 4.34 (dd, J = 9.8, 3.6 Hz, 1H), 3.51 (s, 3H), 2.71 (dd, J = 14.0, 7.7 Hz, 1H), 2.56 (dd, J = 14.0, 6.5 Hz, 1H), 2.32 (s, 3H), 2.11 – 2.01 (m, 1H), 1.38 – 1.28 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3, δ): 172.2, 158.0, 149.9, 138.1, 136.8, 135.7, 129.3, 129.2, 126.8, 121.9, 58.6, 52.4, 46.0, 36.0, 22.1, 21.2, 11.7. HRMS-ESI (m/z): calcd. for C19H25N2O4S (M+H+): 377.1535; Found:
377.1536. IR (νmax/cm): 1735, 1338, 1174. [α]D20: +49 (c = 1.0; CH2Cl2).
S12 N-((2R,3S)-3-Methyl-4-(p-tolyl)butan-2-yl)pyridine-2-sulfonamide ((+)-VII).
Compound (+)-VII was prepared following the general protocol from (R)-N-(3-methylbutan-2-yl)pyridine-2-sulfonamide (+)-IV (57.1 mg, 0.25 mmol, 1.00 equiv) and 4-iodotoluene (54.5 mg, 0.25 mmol, 1.00 equiv) to give (+)-VII as a brown oil; yield: 20.2 mg (25%).
1H NMR (300 MHz, CDCl3, δ): 8.69 (d, J = 4.6 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.86 (td, J = 7.7, 1.6 Hz, 1H), 7.46 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 7.04 (d, J = 7.8 Hz, 2H), 6.93 (d, J = 7.9 Hz, 2H), 5.04 (d, J = 8.1 Hz, 1H), 3.44 – 3.33 (m, 1H), 2.65 (dd, J = 13.5, 5.7 Hz, 1H), 2.30 (s, 3H), 2.22 (dd, J = 13.5, 9.3 Hz, 1H), 1.93 – 1.79 (m, 1H), 1.02 (d, J = 6.8 Hz, 3H), 0.79 (d, J = 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3, δ): 158.2, 150.1, 138.0, 137.2, 135.4, 129.1, 128.9, 126.6, 122.2, 53.9, 40.5, 39.1, 21.1, 17.0, 14.2.
HRMS-ESI (m/z): calcd. for C17H23N2O2S (M+H+): 319.1480; Found: 319.1488.
IR (νmax/cm): 1332, 1173. [α]D20: +45 (c = 1.0; CH2Cl2).
S13 2.2.2. Typical procedure for the synthesis of the diarylated derivatives
Synthesis of (S)-methyl 3-(4-methylbenzyl)-2-(pyridine-2-sulfonamido)-4-(p-tolyl)- butanoate ((+)-17). An oven-dried pressure tube was charged with Pd(OAc)2 (5.61 mg, 0.025 mmol, 10 mol %), AgOAc (125 mg, 0.75 mmol), 4-iodotoluene (272 mg, 1.25 mmol, 5.00 equiv), L-valine derivative (+)-I (68.1 mg, 0.25 mmol, 1.00 equiv) and HFIP (0.25 mL). The reaction mixture was then placed in a preheated oil bath at 150 °C for 4 h. After the reaction time was completed, the reaction mixture was diluted with AcOEt, filtered through a short pad of Celite®, and concentrated in vacuo. The residue was purified by flash column chromatography (30:1 CH2Cl2:Et2O) to obtain derivative (S)-methyl 3-(4-methylbenzyl)-2-(pyridine-2- sulfonamido)-4-(p-tolyl)butanoate (+)-17 as a white solid in 92% yield (104 mg);
mp = 142-145 °C. 1H NMR (300 MHz, CDCl3, δ): 8.60 (d, J = 4.6 Hz, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.82 (td, J = 7.6, 1.5 Hz, 1H), 7.44 – 7.40 (m, 1H), 7.09 (bs 4H), 7.06 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 5.70 (d, J = 9.4 Hz, 1H), 4.36 (d, J = 9.4 Hz, 1H), 3.38 (s, 3H), 2.89 – 2.81 (m, 1H), 2.60 – 2.57 (m, 4H), 2.31 (s, 3H), 2.30 (s, 3H).
13C NMR (75 MHz, CDCl3, δ): 171.6, 157.7, 149.8, 137.9, 136.5, 136.0, 135.8, 135.7, 129.3, 129.1, 129.1, 129.1, 126.7, 122.0, 58.2, 52.3, 46.0, 36.2, 35.1, 21.1, 21.0.
HRMS-ESI (m/z): calcd. for C25H29N2O4S (M+H+): 453.1825; Found: 453.1842.
IR (νmax/cm): 1741, 1364, 1182. [α]D20: +79 (c = 1.0; CH2Cl2).
(S)-Methyl 3-(4-methoxybenzyl)-4-(4-methoxyphenyl)-2-(pyridine-2-sulfonamido)- butanoate ((+)-18). Compound (+)-18 was prepared following the general protocol from L-valine derivative (+)-I (68.1 mg, 0.25 mmol, 1.00 equiv) and 4-iodoanisole (340 mg, 1.25 mmol, 5.00 equiv) to give (+)-18 as a yellow oil; yield: 98.7 mg (81%).
1H NMR (300 MHz, CDCl3, δ): 8.60 (d, J = 4.5 Hz, 1H), 7.88 – 7.81 (m, 2H), 7.46 – 7.41 (m, 1H), 7.11 (d, J = 8.6 Hz, 2H), 6.99 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 6.78 (d, J = 8.6 Hz, 2H), 5.40 (d, J = 9.4 Hz, 1H), 4.32 (d, J = 9.3 Hz, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 3.39 (s, 3H), 2.80 (dd, J = 13.6, 7.1 Hz, 1H), 2.58 – 2.48 (m, 4H). 13C NMR (75 MHz, CDCl3, δ): 171.7, 158.2, 158.2, 157.7, 149.9, 138.0, 131.7, 131.2, 130.4, 130.2, 126.8, 122.0, 114.0, 113.9, 58.2, 55.3, 55.3, 52.4, 46.5, 35.8, 34.7.
HRMS-ESI (m/z): calcd. for C25H29N2O6S (M+H+): 485.1735; Found: 485.1740.
IR (νmax/cm): 1731, 1244, 1174. [α]D20: +79 (c = 1.0; CH2Cl2).
(S)-Methyl 3-benzyl-4-phenyl-2-(pyridine-2-sulfonamido)butanoate ((+)-19).
Compound (+)-19 was prepared following the general protocol from L-valine derivative (+)-I (68.1 mg, 0.25 mmol, 1.00 equiv) and iodobenzene (140 μL, 1.25 mmol, 5.00 equiv) to give (+)-19 as a brown oil; yield: 83.8 mg (79%). 1H NMR (300 MHz, CDCl3, δ): 8.59 (dd, J = 4.7, 0.7 Hz, 1H), 7.87 (d, J = 7.3 Hz, 1H), 7.81 (td, J = 7.6, 1.4 Hz, 1H), 7.44 – 7.39 (m, 1H), 7.31 – 7.08 (m, 10H), 5.81 (d, J = 9.3 Hz, 1H), 4.38 (d, J = 9.3 Hz, 1H), 3.37 (s, 3H), 2.97 – 2.89 (m, 1H), 2.69 – 2.56 (m, 4H).13C NMR (75 MHz, CDCl3, δ): 171.5, 157.6, 149.8, 139.6, 139.1, 138.0, 129.4, 129.2, 128.5, 128.4, 126.7, 126.4, 126.3, 122.0,
S14 58.3, 52.3, 46.0, 36.7, 35.5. HRMS-ESI (m/z): calcd. for C23H24N2O4SNa (M+Na+): 447.1354; Found: 447.1349. IR (νmax/cm): 1735, 1338, 1174. [α]D20: +77 (c = 1.0; CH2Cl2).
(S)-Methyl 3-(4-fluorobenzyl)-4-(4-fluorophenyl)-2-(pyridine-2-sulfonamido)- butanoate ((+)-20). Compound (+)-20 was prepared following the general protocol from L-valine derivative (+)-I (68.1 mg, 0.25 mmol, 1.00 equiv) and 4-fluoroiodobenzene (144 μL, 1.25 mmol, 5.00 equiv) to give (+)-20 as a yellow oil; yield:
86.3 mg (75%). 1H NMR (300 MHz, CDCl3, δ): 8.58 (d, J = 4.6 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.82 (td, J = 7.6, 1.7 Hz, 1H), 7.43 (ddd, J = 7.3, 4.7, 1.4 Hz, 1H), 7.16 (dd, J = 8.6, 5.5 Hz, 2H), 7.03 (dd, J = 8.6, 5.5 Hz, 2H), 6.98 – 6.88 (m, 4H), 5.96 (d, J = 9.4 Hz, 1H), 4.34 (dd, J = 9.4, 2.1 Hz, 1H), 3.40 (s, 3H), 2.89 (dd, J = 13.9, 6.8 Hz, 1H), 2.61 – 2.49 (m, 4H). 13C NMR (75 MHz, CDCl3, δ): 171.4, 161.6 (d, J = 244.1 Hz), 161.5 (d, J = 244.5 Hz), 157.6, 149.8, 138.1, 135.2 (d, J = 3.2 Hz), 134.8 (d, J = 3.2 Hz), 130.8 (d, J = 7.9 Hz), 130.6 (d, J = 7.8 Hz), 126.8, 122.0, 115.3 (d, J = 21.1 Hz), 115.2 (d, J = 21.2 Hz), 58.1, 52.4, 46.4, 35.7, 34.6. 19F NMR (282 MHz, CDCl3, δ): -116.7, -117.0. HRMS-ESI (m/z): calcd. for C23H23F2N2O4S (M+H+): 461.1347; Found: 461.1341. IR (νmax/cm): 1738, 1332, 1175. [α]D20: +80 (c = 1.0; CH2Cl2).
(S)-Methyl 3-(4-chlorobenzyl)-4-(4-chlorophenyl)-2-(pyridine-2-sulfonamido)- butanoate ((+)-21). Compound (+)-21 was prepared following the general protocol from L-valine derivative (+)-I (68.1 mg, 0.25 mmol, 1.00 equiv) and 4-chloroiodobenzene (298 mg, 1.25 mmol, 5.00 equiv) to give (+)-21 as a brown oil; yield:
82.8 mg (67%). 1H NMR (300 MHz, CDCl3, δ): 8.54 – 8.52 (m, 1H), 7.84 – 7.76 (m, 2H), 7.39 (ddd, J = 6.8, 4.7, 2.2 Hz, 1H), 7.20 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 5.81 (d, J = 9.2 Hz, 1H), 4.26 (dd, J = 9.2, 1.9 Hz, 1H), 3.37 (s, 3H), 2.88 – 2.81 (m, 1H), 2.56 – 2.47 (m, 4H).13C NMR (75 MHz, CDCl3, δ): 171.3, 157.5, 149.9, 138.1, 137.9, 137.5, 132.3, 132.2, 130.8, 130.6, 128.7, 128.6, 126.9, 122.0, 58.1, 52.5, 46.1, 35.8, 34.9. HRMS-ESI (m/z): calcd. for C23H23Cl2N2O4S (M+H+): 494.0743; Found:
494.0750. IR (νmax/cm): 1740, 1335, 1172. [α]D20: +91 (c = 1.0; CH2Cl2).
(S)-Methyl 3-(4-bromobenzyl)-4-(4-bromophenyl)-2-(pyridine-2- sulfonamido)butanoate ((+)-22). Compound (+)-22 was prepared following the general protocol from L-valine derivative (+)-I (68.1 mg, 0.25 mmol, 1.00 equiv) and 4-bromoiodobenzene (354 mg, 1.25 mmol, 5.00 equiv) to give (+)-22 as a brown oil; yield: 96.4 mg (66%). 1H NMR (300 MHz, CDCl3, δ): 8.56 (d, J = 4.6 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.83 (td, J = 7.3, 1.6 Hz, 1H), 7.43 – 7.39 (m, 1H), 7.36 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.3 Hz, 2H), 6.24 (d, J = 9.4 Hz, 1H), 4.30 (d, J = 9.3 Hz, 1H), 3.39 (s, 3H), 2.91 – 2.83 (m, 1H), 2.60 – 2.50 (m, 4H).13C NMR (75 MHz, CDCl3, δ): 171.2, 157.3,
S15 149.7, 138.4, 138.0, 131.4, 131.4, 131.1, 130.9, 126.7, 121.9, 120.1, 120.1, 57.9, 52.4, 45.7, 35.7, 34.8. HRMS-ESI (m/z): calcd. for C23H23Br2N2O4S (M+H+): 580.9745; Found:
580.9740. IR (νmax/cm): 1735, 1338, 1174. [α]D20: +92 (c = 1.0; CH2Cl2).
(S)-Dimethyl 4,4'-(2-(2-methoxy-2-oxo-1-(pyridine-2-sulfonamido)ethyl)propane- 1,3-diyl)dibenzoate ((+)-23). Compound (+)-23 was prepared following the general protocol from L-valine derivative (+)-I (68.1 mg, 0.25 mmol, 1.00 equiv) and methyl 4-iodobenzoate (327 mg, 1.25 mmol, 5.00 equiv) to give (+)-23 as a white solid; yield: 81.4 mg (60%);
mp = 125-127 °C. 1H NMR (300 MHz, CDCl3, δ): 8.57 (d, J = 4.6 Hz, 1H), 7.95 (d, J = 8.3 Hz, 2H), 7.91 (d, J = 8.3 Hz, 2H), 7.87 – 7.81 (m, 2H), 7.46 – 7.41 (m, 1H), 7.26 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 5.65 (d, J = 9.0 Hz, 1H), 4.32 (d, J = 9.0 Hz, 1H), 3.89 (s, 3H), 3.89 (s, 3H), 3.41 (s, 3H), 3.00 (dd, J = 16.0, 8.9 Hz, 1H), 2.71 – 2.60 (m, 4H). 13C NMR (75 MHz, CDCl3, δ): 171.2, 167.1, 166.9, 157.6, 149.8, 144.9, 144.5, 138.1, 129.9, 129.8, 129.4, 129.3, 128.5, 128.4, 126.8, 122.0, 58.2, 52.5, 52.1, 52.0 45.7, 36.6, 35.6. HRMS-ESI (m/z): calcd. for C27H29N2O6S (M+H+): 541.1632; Found:
541.1639. IR (νmax/cm): 1750, 1340, 1189. [α]D20: +92 (c = 1.0; CH2Cl2).
(S)-Methyl 2-(pyridine-2-sulfonamido)-3-(4-(trifluoromethyl)benzyl)-4-(4-(trifluoro methyl)phenyl)butanoate ((+)-24). Compound (+)-24 was prepared following the general protocol from L-valine derivative (+)-I (68.1 mg, 0.25 mmol, 1.00 equiv) and 4-iodobenzotrifluoride (183 μL, 1.25 mmol, 5.00 equiv) to give (+)-24 as a brown oil; yield: 110 mg (78%). 1H NMR (300 MHz, CDCl3, δ): 8.58 (d, J = 4.6 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.82 (td, J = 7.7, 1.6 Hz, 1H), 7.52 – 7.41 (m, 5H), 7.32 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 6.34 (d, J = 9.3 Hz, 1H), 4.35 (d, J = 9.2 Hz, 1H), 3.42 (s, 3H), 3.09 – 3.02 (m, 1H), 2.75 – 2.62 (m, 4H). 13C NMR (75 MHz, CDCl3, δ): 171.2, 157.5, 149.9, 143.6, 143.3, 138.1, 129.7, 129.6, 128.8 (q, J = 32.5 Hz), 128.7 (q, J = 32.3 Hz), 126.9, 125.4 (q, J = 3.8 Hz), 125.3 (q, J = 3.8 Hz), 124.4 (q, J = 271.9 Hz), 124.2 (q, J = 271.8 Hz), 58.3, 52.5, 45.6, 36.4, 35.4. 19F NMR (282 MHz, CDCl3, δ): -62.5, -62.6.
HRMS-ESI (m/z): calcd. for C23H23F6N2O4S (M+H+): 561.1256; Found: 561.1277.
IR (νmax/cm): 1735, 1323, 1103. [α]D20: +73 (c = 1.0; CH2Cl2).
(S)-Methyl 3-(3-methylbenzyl)-2-(pyridine-2-sulfonamido)-4-(m-tolyl)butanoate ((+)-25). Compound (+)-25 was prepared following the general protocol from L-valine derivative (+)-I and 3-iodotoluene (160 μL, 1.25 mmol, 5.00 equiv) to give (+)-25 as a yellow oil;
yield: 71.8 mg (63%). 1H NMR (300 MHz, CDCl3, δ): 8.60 (d, J = 4.7 Hz, 1H), 7.88 – 7.80 (m, 2H), 7.43 (ddd, J = 6.6, 4.7, 1.7 Hz, 1H), 7.19 – 7.10 (m, 2H), 7.01 – 6.97 (m, 4H), 6.89 – 6.88 (m, 2H), 5.56 (d, J = 9.3 Hz, 1H), 4.35 (d, J = 9.3 Hz, 1H), 3.39 (s, 3H), 2.89 – 2.81 (m, 1H), 2.65 – 2.50 (m, 4H), 2.32 (s, 3H), 2.29 (s, 3H). 13C NMR (75 MHz, CDCl3, δ): 171.6, 157.7, 149.9, 139.6, 139.1, 138.0, 130.3, 130.1, 128.4, 128.3, 127.2, 127.1, 126.7, 126.4, 126.3, 122.0, 58.5, 52.3, 45.8, 36.8,
S16 35.6, 21.5, 21.5. HRMS-ESI (m/z): calcd. for C25H29N2O4S (M+H+): 443.1827; Found:
443.1842. IR (νmax/cm): 1733, 1336, 1172. [α]D20: +71 (c = 1.0; CH2Cl2).
(S)-Methyl 2-(pyridine-2-sulfonamido)-3-(3-(trifluoromethyl)benzyl)-4-(3-(trifluoro methyl)phenyl)butanoate ((+)-26). Compound (+)-26 was prepared following the general protocol from L-valine derivative (+)-I (68.1 mg, 0.25 mmol, 1.00 equiv) and 3- iodobenzotrifluoride (180 μL, 1.25 mmol, 5.00 equiv) to give (+)-26 as a light brown oil; yield: 85.5 mg (61%).
1H NMR (300 MHz, CDCl3, δ): 8.58 (ddd, J = 4.7, 1.6, 0.9 Hz, 1H), 7.90 (dt, J = 7.8, 1.1 Hz, 1H), 7.83 (td, J = 7.7, 1.7 Hz, 1H), 7.46 – 7.25 (m, 9H), 6.14 (d, J = 9.1 Hz, 1H), 4.38 (dd, J = 9.1, 2.0 Hz, 1H), 3.42 (s, 3H), 3.11 – 3.02 (m, 1H), 2.76 – 2.64 (m, 4H). 13C NMR (75 MHz, CDCl3, δ): 171.2, 157.6, 149.9, 140.3, 140.0, 138.1, 132.9, 132.8, 130.8 (q, J = 32.1 Hz), 130.7 (q, J = 32.1 Hz), 129.1, 129.0, 126.9, 126.0 (q, J = 3.9 Hz), 125.7 (q, J = 3.8 Hz), 124.2 (q, J = 272.2 Hz), 124.1 (q, J = 272.5 Hz), 122.0, 58.5, 52.5, 45.6, 36.7, 35.4. 19F NMR (282 MHz, CDCl3, δ): -62.7, -62.8. HRMS-ESI (m/z): calcd. for C25H23F6N2O4S (M+H+): 561.1283; Found: 561.1277. IR (νmax/cm): 1736, 1323, 1159. [α]D20: +68 (c = 1.0; CH2Cl2).
(S)-Methyl 3-(2-fluorobenzyl)-4-(2-fluorophenyl)-2-(pyridine-2- sulfonamido)butanoate ((+)-27). Compound (+)-27 was prepared following the general protocol from L-valine derivative (+)-I (68.1 mg, 0.25 mmol, 1.00 equiv) and 2-fluoroiodobenzene (146 μL, 1.25 mmol, 5.00 equiv) to give (+)-27 as a yellow oil;
yield: 65.9 mg (57%). [α]D20: +13 (c = 1.0; CH2Cl2).
1H NMR (300 MHz, CDCl3, δ): 8.59 – 8.57 (m, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.84 (td, J = 7.7, 1.7 Hz, 1H), 7.43 (ddd, J = 7.5, 4.7, 1.2 Hz, 1H), 7.36 (td, J = 7.6, 1.7 Hz, 1H), 7.21 – 7.06 (m, 4H), 7.03 – 6.90 (m, 3H), 5.71 (d, J = 9.6 Hz, 1H), 4.43 (dd, J = 9.6, 1.9 Hz, 1H), 3.33 (s, 3H), 2.92 (dd, J = 13.2, 6.4 Hz, 1H), 2.82 – 2.69 (m, 3H), 2.54 (dd, J = 16.1, 9.3 Hz, 1H). 13C NMR (75 MHz, CDCl3, δ): 171.4, 161.5 (d, J = 245.6 Hz), 161.4 (d, J = 244.9 Hz), 157.7, 149.8, 138.1, 131.8 (d, J = 26.7 Hz), 131.8 (d, J = 26.6 Hz), 128.3 (d, J = 3.3 Hz), 128.2 (d, J = 3.2 Hz), 126.8, 126.4 (d, J = 15.1 Hz), 125.8 (d, J = 15.3 Hz), 124.1 (d, J = 3.5 Hz), 123.9 (d, J = 3.5 Hz), 121.9, 115.4, 115.1, 58.6, 52.4, 42.7, 31.1 (d, J = 1.6 Hz), 28.9 (d, J = 1.9 Hz). 19F NMR (282 MHz, CDCl3, δ): -117.5, -117.7. HRMS-ESI (m/z): calcd. for C23H23F2N2O4S (M+H+): 461.1341; Found: 461.1331. IR (νmax/cm): 1739, 1330, 1178.
[α]D20: +80 (c = 1.0; CH2Cl2).
(2S,3R)-Methyl 3-(4-methylbenzyl)-2-(pyridine-2-sulfonamido)-4-(4- (trifluoromethyl)phenyl)butanoate ((+)-(2S,3R)-29).
Compound (+)-(2S,3R)-29 was prepared following the general protocol from (2S,3S)-methyl 3-methyl-2-(pyridine-2- sulfonamido)-4-(p-tolyl)butanoate ((+)-1) (90.6 mg, 0.25 mmol, 1.00 equiv) and 4-iodobenzotrifluoride (183 μL, 1.25 mmol, 5.00 equiv) to give (+)-(2S,3R)-29 as a colorless oil; yield:
95.1 mg (75%). 1H NMR (300 MHz, CDCl3, δ): 8.59 – 8.58 (m, 1H), 7.90 – 7.82 (m, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.47 – 7.42
S17 (m, 1H), 7.31 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 7.7 Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H), 5.47 (d, J = 9.4 Hz, 1H), 4.34 (dd, J = 9.3, 2.1 Hz, 1H), 3.41 (s, 3H), 2.95 (dd, J = 14.0, 7.2 Hz, 1H), 2.71 – 2.48 (m, 4H), 2.30 (s, 3H). 13C NMR (75 MHz, CDCl3, δ): 171.5, 157.7, 149.9, 149.8, 144.0, 138.1, 136.2, 135.6, 129.8, 129.5 (q, J = 29.1 Hz), 129.3, 129.1, 126.9, 124.5 (q, J = 271.8 Hz), 58.3, 52.6, 45.9, 36.3, 35.2, 21.2. IR (νmax/cm): 1741, 1325, 1120. [α]D20: +49 (c = 1.0; CH2Cl2).
(2S,3S)-Methyl 3-(4-methylbenzyl)-2-(pyridine-2-sulfonamido)-4-(4- (trifluoromethyl)phenyl)butanoate ((+)-(2S,3S)-29).
Compound (+)-(2S,3S)-29 was prepared following the general protocol from (2S,3S)-methyl 3-methyl-2-(pyridine-2- sulfonamido)-4-(4-(trifluoromethyl)phenyl)-butanoate ((+)-V) (104 mg, 0.25 mmol, 1.00 equiv) and 4-iodotoluene (272 mg, 1.25 mmol, 5.00 equiv) to give (+)-(2S,3S)-29 as a colorless oil;
yield: 82.2 mg (65%). 1H NMR (300 MHz, CDCl3, δ): 8.58 (d, J = 4.6 Hz, 1H), 7.87 – 7.80 (m, 2H), 7.48 (d, J = 8.2 Hz, 2H), 7.45 – 7.42 (m, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.08 (bs, 4H), 5.60 (d, J = 8.8 Hz, 1H), 4.29 (dd, J = 8.8, 2.6 Hz, 1H), 3.42 (s, 3H), 2.91 (dd, J = 13.5, 5.9 Hz, 1H), 2.67 – 2.57 (m, 3H), 2.49 (dd, J = 13.5, 6.7 Hz, 1H). 13C NMR (75 MHz, CDCl3, δ): 171.4, 157.6, 149.9, 143.6, 138.1, 136.1, 129.7, 129.3, 129.3, 128.7 (q, J = 32.3 Hz), 126.9, 125.3 (q, J = 3.7 Hz), 124.3 (q, J = 271.8 Hz), 122.1, 58.3, 52.5, 46.0, 36.5, 35.5, 21.1. 19F NMR (282 MHz, CDCl3, δ): -62.6. HRMS-ESI (m/z): calcd. for C25H26F3N2O4SNa (M+Na+): 529.1379; Found: 529.1380. IR (νmax/cm): 1741, 1325, 1120. [α]D20: +6 (c = 1.0; CH2Cl2).
(R)-N-(3-(4-Methylbenzyl)-4-(p-tolyl)butan-2-yl)pyridine-2-sulfonamide ((+)-49).
Compound (+)-49 was prepared following the general protocol from (R)-N-(3-methylbutan-2-yl)pyridine-2-sulfonamide ((+)-IV) (57.1 mg, 0.25 mmol, 1.00 equiv) and 4-iodotoluene (272 mg, 1.25 mmol, 5.00 equiv) to give (+)-49 as a dark brown oil; yield:
35.7 mg (35%). 1H NMR (300 MHz, CDCl3, δ): 8.68 (d, J = 4.4 Hz, 1H), 7.84 – 7.75 (m, 2H), 7.44 (ddd, J = 6.3, 4.7, 1.4 Hz, 1H), 7.09 (d, J = 8.0 Hz, 2H), 7.05 – 7.03 (m, 4H), 6.92 (d, J = 7.9 Hz, 2H), 5.44 (d, J = 7.9 Hz, 1H), 3.51 – 3.41 (m, 1H), 2.83 (dd, J = 13.6, 6.2 Hz, 1H), 2.58 – 2.51 (m, 1H), 2.47 – 2.37 (m, 2H), 2.33 (s, 6H), 2.22 – 2.07 (m, 1H), 1.06 (d, J = 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3, δ): 157.7, 149.9, 137.7, 137.3, 136.8, 135.3, 135.2, 129.0, 128.9, 128.6, 126.4, 122.3, 50.8, 47.4, 35.6, 34.7, 20.9, 17.0. HRMS-ESI (m/z): calcd. for C24H29N2O2S (M+H+): 409.1950; Found: 409.1936. IR (νmax/cm): 1332, 1174. [α]D20: +49 (c = 1.0;
CH2Cl2).
S18 2.3. Synthesis of the N-(2-pyridyl)sulfonyl protected 2-benzylcyclohexanamines4
Step 1. Synthesis of 2-benzylcyclohexanone oxime (IX). In a 100 mL round bottom flask, 2-benzylcyclohexanone (IX)(0.92 mL, 5.00 mmol, 5.00 equiv) and NH2OH.HCl (69.5 mg, 1.00 mmol, 1.00 equiv) were weighed and then a 5:1 mixture of EtOH/H2O (60.0 mL) were added via syringe. In a 0 °C bath (ice- water), NaOAc (1.23 g, 15.0 mmol, 15.0 equiv) was added in short portions.
Then the reaction was heated to 60 °C for 4 h. After that time, EtOH was removed in vacuo and the aqueous phase was extracted with Et2O. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The crude oxime was used in the next step without further purification.
Step 2. Synthesis of 2-benzylcyclohexanamine (X). The crude oxime obtained in Step 1 was dissolved in THF (39.5 mL), and then LiAlH4 1M in THF (10.5 mL, 10.5 mmol, 10.5 equiv) was added via syringe under Ar atmosphere. The resulting mixture was then heated to 80 °C for 12 h. After the reaction time was complete, the solvent was removed in vacuo, and the crude mixture was stirred with Et2O and a saturated solution of sodium tartrate for 6 h. Once that time has passed, the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to obtain the corresponding 1:1 mixture of diasteromers (determined by 1H NMR) of 2-benzylcyclohexanamines which will be used without further purification in the next step.
Step 3. Synthesis of N-SO2Py protected 2-benzylcyclohexanamines (±)-51 and (±)-52. The crude amine obtained in Step 2 was used following the general protocol for the synthesis of N-SO2Py protected amino acid derivatives using 2-pyridylsulfonyl chloride (178 mg, 1.00 mmol, 1.00 equiv), to give a mixture of diasteromers trans-51 and cis-52 in a 1:1 ratio with an overall yield of 78%. The purification of the crude by flash column chromatography (CH2Cl2-Et2O 30:1) allowed the isolation and characterization of both diasteromers.
S19 N-((1R*,2S*)-2-Benzylcyclohexyl)pyridine-2-sulfonamide ((±)-51). White solid; yield:
127 mg (39%); mp = 125-126 °C. 1H NMR (300 MHz, CDCl3, δ): 8.80 (d, J = 4.7 Hz, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.99 (td, J = 7.7, 1.7 Hz, 1H), 7.56 (ddd, J = 7.6, 4.7, 1.0 Hz, 1H), 7.36 – 7.30 (m, 2H), 7.26 – 7.24 (m, 1H), 7.19 – 7.16 (m, 2H), 5.42 (d, J = 9.0 Hz, 1H), 3.32 (dd, J = 13.6, 3.5 Hz, 1H), 3.28 – 3.17 (m, 1H), 2.17 (dd, J = 13.6, 10.3 Hz, 1H), 1.83 – 1.50 (m, 4H), 1.35 – 1.20 (m, 2H), 1.15 – 0.93 (m, 2H).
13C NMR (75 MHz, CDCl3, δ): 158.7, 150.1, 140.7, 138.1, 129.3, 128.2, 126.6, 125.8, 121.9, 58.3, 45.9, 39.1, 34.4, 30.6, 25.2, 24.9.
HRMS-ESI (m/z): calcd. for C18H23N2O2S (M+H+): 331.1480; Found:
331.1467. IR (νmax/cm): 1323, 1174.
N-((1R*,2R*)-2-Benzylcyclohexyl)pyridine-2-sulfonamide ((±)-52). White solid; yield:
128 mg (39%); mp = 120-122 °C. 1H NMR (300 MHz, CDCl3, δ): 8.69 (d, J = 4.6 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.87 (td, J = 7.8, 1.6 Hz, 1H), 7.47 – 7.43 (m, 1H), 7.22 (t, J = 7.1 Hz, 2H), 7.14 (t, J = 7.2 Hz, 1H), 7.06 (d, J = 6.9 Hz, 2H), 5.51 (d, J = 8.7 Hz, 1H), 3.70 – 3.67 (m, 1H), 2.67 (dd, J = 13.6, 5.0 Hz, 1H), 2.44 (dd, J = 13.6, 9.7 Hz, 1H), 1.83 – 1.74 (m, 1H), 1.58 – 1.33 (m, 6H), 1.24 – 1.10 (m, 2H).
13C NMR (75 MHz, CDCl3, δ): 158.4, 150.0, 140.4, 137.9, 129.0, 128.1, 126.5, 125.7, 121.9, 54.3, 42.3, 37.4, 30.7, 26.2, 23.8, 21.1.
HRMS-FAB(m/z): calcd. for C18H23N2O2S (M+H+): 331.1480; Found:
331.1483. IR (νmax/cm): 1329, 1176.
S20 2.4. Typical procedure for the synthesis of 2-aryltryptophane NSO2Py derivatives
Step 1. Protection of the acid group. To a suspended mixture of L-tryptophan (XI) (3.10 g, 15.2 mmol, 1.00 equiv) in MeOH (30.5 mL) at 0 °C, thionyl chloride (1.22 mL, 16.7 mmol, 1.10 equiv) was added dropwise under Ar atmosphere. Once the thionyl chloride was added, the solution was refluxed for 16 h. After this time the volatiles were removed in vacuo affording the pure aminoester hydrochloride XII, which was used without further purification.
Step 2. Protection of the amino group as an acetyl. To a three-necked round- bottomed flask fitted with a reflux condenser and purged with Ar, was added methyl (2S)-2-amino-3-(1H-indol-3-yl)propanoate (XII) (300 mg, 1.38 mmol, 1.00 equiv). To this solid, dry THF (15.0 mL) and triethylamine (0.20 mL) were added. The mixture was cooled to 0 °C, and acetic anhydride (143 μl, 154 mg, 1.51 mmol, 1.10 equiv) was added in one portion. The reaction was then stirred for 2 h at 80 °C. After the corresponding time, water (40.0 mL) was added and the crude mixture was extracted with EtOAc (3 x 50.0 mL). The organic layers were combined and washed sequentially with 1 M aq. HCl (1 x 40.0 mL), sat. aq. NaHCO3 (40.0 mL) and brine (1 x 40.0 mL). The organic layer was collected and dried over Na2SO4, filtered and concentrated in vacuo. The resulted residue was purified by flash column chromatography (cyclohexane:AcOEt 6:1 to 2:1) to obtain the pure N-acetyl tryptophan methyl ester (XIII) as a white solid, yield: 391 mg (91%).
