electronic supplementary information: towards cialis
TRANSCRIPT
Electronic Supplementary Information:
Highly stereoselective one-pot construction of trisubstituted tetrahydro--carboline-fused diketopiperazines: A synthetic route towards cialis analogues
Mouhamad Jida,* Dirk Tourwé and Steven Ballet*
Research Group of Organic Chemistry, Departments of Chemistry and Bio-engineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, [email protected] and [email protected]
Contents
1. General information..................................................................................................................12. General procedure for the synthesis of THBC-based DKPs (8a-n) .........................................23. Characterization of compounds 8a-o........................................................................................34. NOESY studies of 8a and 8l ....................................................................................................85. NMR Spectra.......................................................................................................................9-265. 2D NMR Spectra (COSY, NOESY, HSQC) and HPLC of 8a .........................................27-30
NH
HN
OOH
R3 NC
R1 NH2R2 CHO
Boc
NH
N
R4
NR1O
O
R2
( R3 = Cy, Bn, tBu)
1) Ugi-4CR2) Boc-deprotection
3) Pictet-Spengler
4) Cyclisationup to > 98% de
15 examples up to 81% yield
one-pot
*
*
R4 CHO
Electronic Supplementary Material (ESI) for RSC Advances.This journal is © The Royal Society of Chemistry 2014
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1. General information1H and 13C NMR spectra (25°C) were recorded at 250 MHz and 63 MHz on a Bruker Avance
DRX 250 spectrometer or at 500 MHz and 126 MHz respectively on a Bruker Avance II 500
spectrometer. Chemical shifts are in parts per million (ppm). The assignments were made using
one dimensional (1D) 1H and 13C spectra or two-dimensional (2D) HSQC and COSY spectra.
HRMS data was recorded with a Micromass QTOF-micro system. Mass spectra were recorded
with a LCMS-MS triple-quadrupole system. Analytical HPLC was performed on an Agilent 1100
Series system with a Supelco Discovery BIO Wide Pore RP column (25 cm × 4.6 mm, 5 μm).
Flow rates of 1 ml/min were used and detection was done at 215 nm. The solvent system
consisted of 0.1% TFA in water (A) and 0.1% TFA in acetonitrile (B). The gradient consisted of
a 26 min. run from 3% B to 100% B. Flash chromatography was performed with silica gel 60
(Davisil, 0.040-0.063 mm) from Merck. Glass plates with silica gel 60 F254 (Merck) were used
for thin layer chromatography. Visualization of the products on TLC plates was realized using
UV light (254 nm), KMnO4 spray. Melting points were determined on a Büchi B-540 apparatus
and are uncorrected. Reactions were performed using a Biotage® Initiator+ Microwave
Synthesizer. All commercial reagents and solvents were used without further purification.
Specific rotations were measured on a polarimeter polartronic M Schmidt-Haenschusing a 5 cm
cell in standard conditions (20°C / 589.3 nmair / 589.44 nmvac).
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2. General procedure for one-pot tandem Ugi-4CR/Boc-deprotection/Pictet-Spengler/Cyclisation sequence (8a-n).
In a capped 5 mL microwave-vessel containing a stirring bar, the N-Boc protected (L/D)-
tryptophan (0.5 mmol), the aldehyde (0.5 mmol) and the amine (0.5 mmol) were dissolved and
mixed in methanol (3 mL). The solution was stirred at room temperature for 30 min. Isocyanide
(0.5 mmol) was then added, and the resulting mixture was stirred at room temperature. After 18h,
total conversion was determined from LC-MS analysis and the solvent was removed in vacuo.
The crude Ugi-4CR product was dissolved in 30% TFA in DCM (3 mL) and the resulting
mixture was stirred at room temperature for 3 hours. After completion of the N-Boc deprotection
step (monitored by HPLC and LC-MS), the solvent was evaporated in vacuo. Next, the crude
deprotected Ugi product was dissolved in a mixture of TFA (1.5 mmol) in DCM (3 mL) and the
corresponding aldehyde (0.55 mmol) was then added, and the resulting mixture was stirred
overnight at room temperature. Total conversion was observed from HPLC and LC-MS analysis
and the solvent was removed under reduced pressure.
The crude Ugi Pictet-Spengler product was dissolved in glacial acetic acid (3 mL) and the
reaction vessel was capped. The reaction mixtures was heated at 180°C under microwave
irradiation for 80 minutes using the Biotage initiator+ microwave reactor (average effective ramp
time =1 min), the power was set at 400 W and the pressure was set at 30 bar (average effective
pressure = 5 bar). After completion of the reaction as indicated by LC-MS, the solvent was
evaporated under reduced pressure and the residue was dissolved in EtOAc (20 mL). The organic
layer was washed with sat. NaHCO3 (3 X 10 mL), 1N HCl (3 X 10 mL), sat. NaCl (3 X 10 mL),
dried over MgSO4 and the solvent was removed under reduced pressure.The crude products were
purified by flash chromatography. The resulting products (8a-n) were isolated in good purity and
yields as a single diastereomer. Purity (%) was determined by reversed phase HPLC, using UV
detection (215 nM).
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3. Characterization of compounds (8a-n).
(6R,12aS)-2-benzyl-6-phenyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione (8a):
8aNH
N
NO
O
Chemical Formula: C27H23N3O2Exact Mass: 421.18
Yield (171 mg, 81%); pale yellow solid; mp= 263-265 °C; [α]D = -30.0 ° (c 0.6, CHCl3); 1H NMR (250 MHz, CDCl3) δ 7.92 (br s, 1H, NH), 7.56 (d, J = 8.0 Hz, 1H), 7.40-7.14 (m, 13H), 7.04 (s, 1H), 4.87 (d, J = 14.75 Hz, 1H), 4.43 (dd, J = 12.0, 4.0 Hz, 1H), 4.34 (d, J = 14.5 Hz, 1H), 4.00 (d, J = 18.25 Hz, 1H), 3.95 (d, J = 18.25 Hz, 1H), 3.62 (dd, J = 16.0, 4.0 Hz, 1H), 2.99 (dd, J = 16.0, 12.0 Hz, 1H); 13C NMR (63 MHz, CDCl3) δ 165.46, 162.07, 137.99, 136.34, 134.74, 129.56, 129.07, 128.96, 128.83, 128.54, 128.33, 126.23, 122.78, 120.13, 118.44, 111.19, 108.95, 52.67, 52.19, 49.45, 48.78, 27.83; TLC: Rf = 0.55 (EtOAc /Hexane 9/1, v/v); rt(HPLC) = 17.20 min; HRMS-ESI (m/z): [M+Na]+ calcd for C27H23N3O2Na444.1682; found 444.1660.
(6R,12aS)-2-methyl-6-phenyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione (8b):
8bNH
N
NO
O
Chemical Formula: C21H19N3O2Exact Mass: 345.15
Yield (121 mg, 70%); brown solid; mp= 288-290 °C; [α]D = -73.3 ° (c 0.5, CHCl3); 1H NMR (250 MHz, CDCl3) δ 8.14 (br s, 1H, NH), 7.53 (d, J = 7.75 Hz, 1H), 7.32-7.12 (m, 8H), 7.06 (s, 1H), 4.32 (dd, J = 11.75, 4.5 Hz, 1H), 4.12 (d, J = 17.5 Hz, 1H), 3.95 (d, J = 17.75 Hz, 1H), 3.55 (dd, J = 15.25, 4.5 Hz, 1H), 3.01-2.89 (m, 1H), 2.96 (s, 3H); 13C NMR (63 MHz, CDCl3) δ 165.46, 161.64, 138.24, 136.36, 129.63, 128.89, 128.78, 126.26, 122.70, 120.06, 118.41, 111.18, 109.07, 52.55, 52.08, 51.42, 33.40, 27.65; TLC: Rf = 0.42 (EtOAc /Hexane 9/1, v/v); rt(HPLC) = 14.22 min; HRMS-ESI (m/z): [M+H]+ calcd for C21H20N3O2 346.1550; found 346.1558.
(6R,12aS)-2-methyl-6-(m-tolyl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione (8c):
8cNH
N
NO
O
Chemical Formula: C22H21N3O2Exact Mass: 359.16
Yield (136 mg, 76%); yellow oil; [α]D = -176.8 ° (c 1, CHCl3); 1H NMR (250 MHz, CDCl3) δ 7.88 (br s, 1H, NH), 7.55 (d, J = 8.0 Hz, 1H), 7.33-7.10 (m, 7H), 7.03 (s, 1H), 4.39 (dd, J = 12.5, 4.5 Hz, 1H), 4.15 (d, J = 17.5 Hz, 1H), 3.98 (d, J = 17.5 Hz, 1H), 3.57 (dd, J = 15.0, 4.5 Hz, 1H), 3.04-2.91 (m, 1H), 3.00 (s, 3H), 2.29 (s, 3H); 13C NMR (63 MHz, CDCl3) δ 165.53, 161.56, 138.83, 138.08, 136.31, 129.84, 129.71, 129.31, 128.81, 125.96, 122.70, 120.08, 118.43, 111.15, 109.12, 52.60, 52.06, 51.48, 33.40, 27.67, 21.38; TLC: Rf = 0.51 (EtOAc /Hexane 9/1, v/v); rt(HPLC) = 14.85 min; HRMS-ESI (m/z): [M+H]+ calcd for C22H22N3O2 360.1707; found 360.1695.
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(6R,12aS)-2-methyl-6-(naphthalen-2-yl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione (8d):
8dNH
N
NO
O
Chemical Formula: C25H21N3O2Exact Mass: 395.16
Yield (141 mg, 71%); brown solid; mp= 165-167 °C; [α]D = -87.5 ° (c 0.7, CHCl3); 1H NMR (250 MHz, CDCl3) δ 8.28 (br s, 1H, NH), 7.78-7.70 (m, 1H), 7.62-7.55 (m, 3H), 7.50-7.39 (m, 3H), 7.33-7.15 (m, 5H), 4.34 (dd, J = 12.0, 4.5 Hz, 1H), 4.05 (d, J = 17.5 Hz, 1H), 3.86 (d, J = 17.5 Hz, 1H), 3.57 (dd, J = 15.5, 4.5 Hz, 1H), 3.00-2.90 (m, 1H), 2.86 (s, 3H); 13C NMR (63 MHz, CDCl3) δ 165.40, 161.76, 136.43, 135.73, 133.32, 132.97, 129.73, 128.91, 128.14, 127.95, 127.61, 126.76, 126.63, 126.33, 126.22, 122.68, 120.04, 118.45, 111.31, 109.14, 52.54, 52.24, 51.35, 33.28, 27.69; TLC: Rf = 0.47 (EtOAc /Hexane 8/2, v/v); rt(HPLC) = 15.76 min; HRMS-ESI (m/z): [M+H]+ calcd for C25H22N3O2 396.1707; found 396.1706.
(6R,12aS)-6-isobutyl-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione (8e):
8eNH
N
NO
O
Chemical Formula: C19H23N3O2Exact Mass: 325.18
Yield (119 mg, 73%); yellow oil; [α]D = -29.2 ° (c 0.5, CHCl3); 1H NMR (250 MHz, MeOD) δ 7.42 (d, J = 8.75 Hz, 1H), 7.29 (d, J = 8.75 Hz, 1H), 7.10-6.94 (m, 2H), 6.43 (d, J = 16.5 Hz, 1H), 6.21 (dd, J = 16.5, 6.75 Hz, 1H), 4.23 (br s, 1H), 3.49-3.11 (m, 5H), 2.58-2.25 (m, 2H), 2.50 (s, 3H), 1.16 (d, J = 6.5 Hz, 3H), 1.15 (d, J = 6.5 Hz, 3H); 13C NMR (126 MHz, MeOD) δ 167.40, 165.77, 137.00, 136.39, 135.25, 128.41, 121.69, 118.65, 118.17, 115.59, 110.00, 105.29, 56.42, 50.01, 32.53, 31.58, 28.69, 21.43; TLC: Rf = 0.32 (EtOAc /Hexane 9/1, v/v); rt(HPLC) = 13.04 min; HRMS-ESI (m/z): [M+H]+ calcd for C19H24N3O2 326.1863; found 326.1871.
(6R,12aS)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione {12a-epi-Cialis }(8f):
8fNH
N
NO
O
O
O
Chemical Formula: C22H19N3O4Exact Mass: 389.14
Yield (133 mg, 68%); pale yellow solid; mp= 291-293 °C (lit.1 mp = 287-289 °C); [α]D = -297.8 ° (c 1, CHCl3) {lit.2[α]D = -293.4 ° (c 1.2, CHCl3)}; 1H NMR (250 MHz, CDCl3) δ 8.00 (br s, 1H, NH), 7.53 (d, J = 7.5 Hz, 1H), 7.33-7.12 (m, 3H), 6.97 (s, 1H), 6.81 (s, 1H), 6.70 (s, 2H), 5.92 (s, 2H), 4.34 (dd, J = 12.0, 4.5 Hz, 1H), 4.14 (d, J = 17.5 Hz, 1H), 3.98 (d, J = 17.5 Hz, 1H), 3.55 (dd, J = 15.5, 4.5 Hz, 1H), 2.99 (s, 3H), 2.96-2.89 (m, 1H); 1H NMR (500 MHz, DMSO-d6) δ 11.02 (br s, 1H, NH), 7.47 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), ), 6.99 (t, J = 7.5 Hz, 1H), 6.85-6.80 (m, 2H), 6.74 (s, 1H), 6.58 (d, J = 8.0 Hz, 1H), 5.97 (d, J = 7.0 Hz, 2H), 4.22 (d, J = 18.0 Hz, 1H), 4.05 (dd, J = 11.5, 4.0 Hz, 1H), 4.01 (d, J = 18.0 Hz, 1H), 3.24 (dd, J = 15.5, 4.0 Hz, 1H), 2.93 (dd, J = 15.5, 11.5 Hz, 1H), 2.82 (s, 3H); 13C NMR (63 MHz, CDCl3) δ 165.46, 161.53, 148.15, 148.05, 136.32, 132.05, 129.71, 126.23, 122.77, 122.48, 120.10, 118.45, 111.15, 109.14, 108.31, 101.36, 52.42, 51.81, 51.47, 33.40, 27.60; TLC: Rf = 0.45 (EtOAc /Hexane 8/2, v/v); rt(HPLC) = 14.21 min; HRMS-ESI (m/z): [M+Na]+ calcd for C22H19N3O4Na 412.1268; found 412.1284.
(2) Daugan, A. C. –M. U.S. Patent 5, 859, 006.
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(6S,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione{6-epi-Cialis } (8g):
8gNH
N
NO
O
O
O
Chemical Formula: C22H19N3O4Exact Mass: 389.14
Yield (142 mg, 73%); off-white solid; mp= 289-291 °C (lit.1mp = 287-288 °C); [α]D = +288.4 ° (c 1, CHCl3) {lit.20d [α]D
28 = +278 ° (c 1.03, CHCl3)};1H NMR (500 MHz, DMSO-d6) δ 11.02 (br s, 1H, NH), 7.47 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), ), 6.99 (t, J = 7.5 Hz, 1H), 6.85-6.81 (m, 2H), 6.75 (s, 1H), 6.59 (d, J = 8.0 Hz, 1H), 5.97 (d, J = 6.0 Hz, 2H), 4.22 (d, J = 18.0 Hz, 1H), 4.06 (dd, J = 12.0, 4.0 Hz, 1H), 4.01 (d, J = 18.0 Hz, 1H), 3.24 (dd, J = 15.5, 4.0 Hz, 1H), 2.93 (dd, J = 15.5, 12.0 Hz, 1H), 2.82 (s, 3H); 13C NMR (126 MHz, DMSO-d6) δ 165.13, 162.74, 148.11, 147.73, 136.75, 133.38, 130.83, 126.39, 122.19, 122.15, 119.36, 118.59, 111.80, 108.83, 108.62, 107.99, 101.73, 52.49, 51.33, 51.15, 33.09, 27.17; TLC: Rf = 0.45 (EtOAc /Hexane 8/2, v/v); rt(HPLC) = 14.20 min; HRMS-ESI (m/z): [M+Na]+ calcd for C22H19N3O4Na 412.1268; found 412.1288.
(6R,12aS)-2-benzyl-6-(4-bromophenyl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione (8h):
8hNH
N
NO
O
Br
Chemical Formula: C27H22BrN3O2Exact Mass: 499.09
Yield (185 mg, 74%); pale yellow oil; [α]D = -80.0 ° (c 0.5, CHCl3); 1H NMR (250 MHz, CDCl3) δ 8.23 (br s, 1H, NH), 7.54 (d, J = 10.0 Hz, 1H), 7.40-7.21 (m, 8H), 7.13-7.03 (m, 4H), 6.95 (s, 1H), 4.82 (d, J = 14.25 Hz, 1H), 4.32 (d, J = 14.25 Hz, 1H), 4.31 (dd, J = 12.0, 4.5 Hz, 1H), 3.96 (d, J = 18.0 Hz, 1H), 3.86 (d, J = 18.0 Hz, 1H), 3.59 (dd, J = 16.0, 4.5 Hz, 1H), 2.95 (dd, J = 16.0, 12.0 Hz, 1H); 13C NMR (63 MHz, CDCl3) δ 165.17, 161.94, 137.22, 136.39, 134.81, 132.04, 130.40, 129.07, 128.52, 128.32, 126.19, 123.05, 122.88, 120.18, 118.49, 111.25, 109.15, 52.65, 51.45, 49.39, 48.78, 27.75; TLC: Rf = 0.56(EtOAc /Hexane 9/1, v/v); rt(HPLC) = 18.33 min; HRMS-ESI (m/z): [M+H]+ calcd for C27H23BrN3O2 500.0968; found 500.0976.
(6R,12aS)-6-phenyl-2-((S)-1-phenylethyl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione (8i):
8iNH
N
NO
O
Chemical Formula: C28H25N3O2Exact Mass: 435.19
Yield (158 mg, 73%); yellow oil; [α]D = -184.4 ° (c 0.6, CHCl3); 1H NMR (250 MHz, CDCl3) δ 7.97 (br s, 1H, NH), 7.55 (d, J = 9.0 Hz, 1H), 7.38-7.12 (m, 13H), 7.00 (s, 1H), 6.01 (q, J = 7.0 Hz, 1H), 4.44 (dd, J = 12.25, 4.5 Hz, 1H), 4.01 (d, J = 18.0 Hz, 1H), 3.65 (d, J = 18.0 Hz, 1H), 3.62 (dd, J = 16.0, 4.5 Hz, 1H), 3.00 (dd, J = 16.0, 12.25 Hz, 1H), 1.58 (d, J = 6.5 Hz, 3H); 13C NMR (63 MHz, CDCl3) δ 165.49, 162.92, 137.82, 137.38, 136.65, 129.46, 128.99, 128.94, 128.41, 127.82, 127.40, 126.83, 126.21, 122.96, 120.31, 118.47, 111.26, 52.83, 52.39, 50.92, 43.64, 27.59, 15.08; TLC: Rf = 0.35 (EtOAc /Hexane 1/1, v/v); rt(HPLC) = 17.66 min; HRMS-ESI (m/z): [M+H]+ calcd for C28H26N3O2 436.2020; found 436.2018.
(20d)Vedantham, R.; Shanmugam, S.; Vetukuri, P.V.N.K.V.; Khagga, M.; Bandichhor, R. Arkivoc2013, 22.
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(6S,12aR)-6-phenyl-2-((S)-1-phenylethyl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione (8j):
8jNH
N
NO
O
Chemical Formula: C28H25N3O2Exact Mass: 435.19
Yield (163 mg, 75%); pale yellow solid; mp= 195-197 °C; [α]D = +75. 7 ° (c 0.6, CHCl3); 1H NMR (250 MHz, CDCl3) δ 7.80 (br s, 1H, NH), 7.56 (d, J = 7.75 Hz, 1H), 7.39-7.14 (m, 13H), 7.03 (s, 1H), 6.09 (q, J = 7.5 Hz, 1H), 4.45 (dd, J = 12.0, 3.75 Hz, 1H), 3.90 (d, J = 18.0 Hz, 1H), 3.63 (dd, J = 15.5, 3.75 Hz, 1H), 3.53 (d, J = 18.0 Hz, 1H), 2.94 (dd, J = 15.5, 12.0 Hz, 1H), 1.55 (d, J = 6.75 Hz, 3H); 13C NMR (63 MHz, CDCl3) δ 165.26, 162.58, 138.08, 136.41, 129.59, 128.93, 128.88, 128.75, 128.28, 127.44, 126.21, 122.78, 120.10, 118.42, 111.17, 108.93, 52.79, 52.18, 50.26, 43.82, 27.72, 14.54; TLC: Rf = 0.47 (EtOAc /Hexane 6/4, v/v); rt(HPLC) = 17.65 min; HRMS-ESI (m/z): [M+H]+ calcd for C28H26N3O2 436.2020; found 436.2010.
(6R,12aS)-6-phenyl-2-((R)-1-phenylethyl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione (8k):
8kNH
N
NO
O
Chemical Formula: C28H25N3O2Exact Mass: 435.19
Yield (171mg, 79%); pale yellow solid; mp= 200-203 °C; [α]D = -82.4 ° (c 0.55, CHCl3); 1H NMR (250 MHz, CDCl3) δ 8.28 (br s, 1H, NH), 7.52 (d, J = 7.75 Hz, 1H), 7.40-7.09 (m, 13H), 6.96 (s, 1H), 6.02 (q, J = 7.0 Hz, 1H), 4.33 (dd, J = 12.5, 4.5 Hz, 1H), 3.81 (d, J = 18.0 Hz, 1H), 3.55 (dd, J = 15.5, 4.5 Hz, 1H), 3.46 (d, J = 18.0 Hz, 1H), 2.86 (dd, J = 15.5, 12.5 Hz, 1H), 1.49 (d, J = 7.5 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 165.20, 162.30, 138.27, 136.40, 129.75, 128.98, 128.89, 128.83, 128.21, 127.35, 126.31, 122.64, 120.01, 118.41, 111.19, 108.90, 52.85, 52.07, 50.10, 43.91, 27.76, 14.61; TLC: Rf = 0.48 (EtOAc /Hexane 6/4, v/v); rt(HPLC) = 17.65 min; HRMS-ESI (m/z): [M+H]+ calcd for C28H26N3O2 436.2020; found 436.2027.
(3R,6R,12aS)-2-benzyl-3,6-diphenyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione (8l):
8lNH
N
NO
O
Ph
Chemical Formula: C33H27N3O2Exact Mass: 497.21
Yield (178 mg, 72%); white solid; mp= 267-269 °C; [α]D = -26.6 ° (c 0.3, CHCl3); 1H NMR (250 MHz, DMSO-d6) δ 11.04 (br s, 1H, NH), 7.58 (d, J = 7.25 Hz, 1H), 7.35-7.01 (m, 18H), 6.90 (s, 1H), 5.05 (d, J = 14.50 Hz, 1H), 5.02 (s, 1H), 4.53 (dd, J = 11.25, 4.75 Hz, 1H), 3.59 (dd, J = 16.0, 4.75 Hz, 1H), 3.56 (d, J = 14.50 Hz, 1H), 3.10 (dd, J = 16.0, 11.25 Hz, 1H); 13C NMR (126 MHz, DMSO-d6) δ 165.70, 163.56, 139.66, 138.02, 136.90, 136.23, 130.42, 129.63, 129.28, 129.05, 128.99, 128.73, 128.16, 128.13, 128.03, 127.86, 126.40, 122.17, 119.42, 118.72, 111.84, 107.38, 63.48, 52.42, 52.07, 47.16, 28.91; TLC: Rf = 0.53 (EtOAc /Hexane 3/7, v/v); rt(HPLC) = 19.25 min; HRMS-ESI (m/z): [M+Na]+ calcd for C23H27N3O2Na520.1995; found 520.2089.
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(S)-2'-benzyl-2',3',12',12a'-tetrahydro-4'H-spiro[cyclohexane-1,6'-pyrazino[1',2':1,6]pyrido[3,4-b]indole]-1',4'(7'H)-dione (8m):
8mNH
N
NO
O
Chemical Formula: C26H27N3O2Exact Mass: 413.21
Yield (166 mg, 80%); white solid; mp= 281-283 °C; 1H NMR (500 MHz, DMSO-d6) δ 10.83 (br s, 1H, NH), 8.04 (s, 1H); 7.46 (d, J = 8.0 Hz, 1H), 7.31-7.22 (m, 4H), 7.05-7.02 (m, 3H), 6.95 (t, J = 8.0 Hz, 1H), 6.00 (s, 1H), 4.60 (d, J = 15.0 Hz, 1H), 4.10-4.07 (m, 1H); 3.91 (d, J = 15. 0 Hz, 1H), 3.31-3.21 (m, 3H), 3.05 (d, J = 17.0 Hz, 1H), 2.40-2.35 (m, 2H), 2.20-2.14 (m, 2H), 1.75-1.68 (m, 2H), 1.66-1.59 (m, 2H); 13C NMR (126 MHz, DMSO-d6) δ 166.99, 165.07, 139.45, 136.55, 135.65, 130.43, 129.13, 129.04, 128.17, 127.96, 127.85, 121.40, 118.97, 111.17, 104.68, 56.72, 48.92, 48.72, 29.81, 27.96, 25.69, 22.88, 22.00; TLC: Rf = 0.31 (EtOAc /Hexane 8/2, v/v); rt(HPLC) = 15.72 min; HRMS-ESI (m/z): [M+Na]+ calcd for C26H27N3O2Na436.1996; found 436.1970.
(S)-2-benzyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione (8n):
8nNH
N
NO
O
Chemical Formula: C21H19N3O2Exact Mass: 345.15
Yield (130 mg, 75%); off-white solid; mp= 185-188 °C;1H NMR (500 MHz, CDCl3) δ 7.93 (br s, 1H, NH), 7.50 (d, J = 7.0 Hz, 1H), 7.41-7.22 (m, 6H), 7.21-7.13 (m, 2H), 5.62 (d, J = 17.50 Hz, 1H), 4.74 (d, J = 14.0 Hz, 1H), 4.66 (d, J = 14. 0 Hz, 1H), 4.45 (d, J = 10.50 Hz, 1H), 4.21 (d, J = 16.50 Hz, 1H), 4.02 (s, 2H), 3.59 (d, J = 15.0 Hz, 1H), 2.96 (t, J = 13.5 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 165.44, 163.06, 136.22, 134.84, 129.09, 128.53, 128.83, 128.33, 128.02, 126.65, 122.58, 120.20, 118.20, 111.00, 107.44, 56.88, 49.49, 48.68, 40.05, 27.41; TLC: Rf = 0.45 (EtOAc /Hexane 19/1, v/v); rt(HPLC) = 14.95 min; HRMS-ESI (m/z): [M+H]+ calcd for C21H20N3O2346.1550; found 346.1553.
7
S
4. NOESY Studies of 8a and 8l
The relative configuration of the THBC-based DKP 8a was confirmed by NOESY studies. As
shown in Figure 3, the configuration of the trans isomer 8a was determined by the presence of a
nOe between the proton at position C-12a and the aryl ortho protons at position C-6, thus
confirming a trans-stereochemistry for 8a. Since the C-12a configuration was known (L-
tryptophan was used as starting material) the absolute configuration of the major isomers
corresponds to (6R,12aS).
NH
N
NO
O
THBC-based DKP (8a)
H
HH
NO NOENOE
6
12a
d = 4.0 A°
d = 2.8 A°
Figure 1. Identification of the relative configuration of 8a by 2D NOESY experiments
The relative configuration of the THBC-based DKP 8l was confirmed by NOESY studies. As
shown in Figure 4, the configuration of the trans isomer 8l was determined by the presence of a
nOe between the proton at position C-12a and the aryl ortho protons at position C-3, thus
confirming a trans-stereochemistry for 8l. Since the C-12a configuration was known (L-
tryptophan was used as starting material) the absolute configuration of the major isomers
corresponds to (3R, 6R,12aS).
NH
N
NO
O
THBC-based DKP (8l)
HNO NOE
6
12a
d = 4.0 A°H
NOEd = 2.7 A°
3H
Figure 2. Identification of the relative configuration of 8l by 2D NOESY experiments
8
S
5. NMR Spectra (8a): 1H NMR (250 MHz, CDCl3)
1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5 ppm
2.932
2.982
2.997
3.043
3.584
3.599
3.646
3.663
3.876
3.948
3.965
4.039
4.304
4.362
4.402
4.420
4.451
4.467
4.840
4.899
7.039
7.136
7.403
7.543
7.575
7.923
1.0
1.1
2.1
1.0
1.0
1.0
1.1
13.31.1
1.0
(8a): 13C NMR (63 MHz, CDCl3)
190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm
27.83
48.78
49.45
52.19
52.67
76.53
77.04
77.55
108.95
111.19
118.44
120.13
122.78
126.23
128.33
128.54
128.83
128.96
129.07
129.56
134.74
136.34
137.99
162.07
165.46
9
C
DC
l 3
8aNH
N
NO
O
Chemical Formula: C27H23N3O2
S
(8b): 1H NMR (250 MHz, CDCl3)
1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5 ppm
2.895
2.962
3.015
3.512
3.531
3.573
3.592
3.914
3.983
4.081
4.152
4.289
4.307
4.336
4.354
7.059
7.124
7.320
7.522
7.553
8.137
4.1
1.1
1.0
1.0
1.0
1.1
8.3
1.0
1.0
(8b): 13C NMR (63 MHz, CDCl3)
220 200 180 160 140 120 100 80 60 40 20 0 ppm
27.65
33.40
51.42
52.08
52.55
76.54
77.05
77.55
109.07
111.18
118.41
120.06
122.70
126.26
128.78
128.89
129.63
136.36
138.24
161.64
165.46
(8c): 1H NMR (250 MHz, CDCl3)
10
C
DC
l 3
8bNH
N
NO
O
Chemical Formula: C21H19N3O2
S
1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5 ppm
2.292
2.910
2.996
3.038
3.533
3.551
3.592
3.612
3.958
4.029
4.116
4.184
4.350
4.367
4.399
4.417
7.033
7.104
7.334
7.535
7.564
7.881
3.0
4.2
1.2
1.2
1.2
1.1
8.5
1.0
1.0
(8c): 13C NMR (63 MHz, CDCl3)
102030405060708090100110120130140150160170180190 ppm
21.38
27.67
33.40
51.48
52.06
52.60
76.51
77.02
77.53
109.12
111.15
118.43
120.08
122.70
125.96
128.81
129.31
129.71
129.84
136.31
138.08
138.83
161.56
165.53
11
C
DC
l 3
8cNH
N
NO
O
Chemical Formula: C22H21N3O2
S
(8d): 1H NMR (250 MHz, CDCl3)
1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5 ppm
2.859
2.896
3.008
3.533
3.550
3.595
3.611
3.821
3.893
4.010
4.080
4.311
4.328
4.358
4.375
7.152
7.325
7.391
7.502
7.547
7.623
7.705
7.785
8.284
2.9
1.0
0.9
1.0
0.9
1.0
5.0
3.1
3.1
1.3
0.9
(8d): 13C NMR (63 MHz, CDCl3)
102030405060708090100110120130140150160170 ppm
27.69
33.28
51.35
52.24
52.54
76.56
77.06
77.57
109.14
111.31
118.45
120.04
122.68
126.22
126.33
126.63
126.76
127.61
127.95
128.14
128.91
129.73
132.97
133.32
135.73
136.43
161.76
165.40
12
C
DC
l 3
8dNH
N
NO
O
Chemical Formula: C25H21N3O2
S
(8e): 1H NMR (250 MHz, MeOD)
8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
1.146
1.151
1.172
1.178
2.245
2.499
2.577
3.111
3.494
4.193
4.261
6.172
6.198
6.237
6.264
6.397
6.463
6.944
7.100
7.270
7.305
7.405
7.440
6.0
5.1
5.0
1.2
0.9
0.8
2.1
1.0
1.1
(8e): 13C NMR (63 MHz, MeOD)
190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm
21.431
28.695
31.582
32.530
46.471
46.812
47.151
47.491
47.831
48.170
48.510
50.009
56.425
105.295
110.004
115.592
118.174
118.646
121.693
128.409
135.251
136.394
137.002
165.777
167.402
13
8eNH
N
NO
O
Chemical Formula: C19H23N3O2
S
(8f): 1H NMR (250 MHz, CDCl3)
1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5 ppm
2.886
2.957
2.994
3.507
3.525
3.569
3.587
3.946
4.017
4.102
4.169
4.316
4.332
4.362
4.380
5.923
6.703
6.806
6.972
7.124
7.328
7.515
7.545
8.002
1.1
3.0
1.0
1.2
1.2
1.0
2.1
2.1
1.0
1.1
3.5
1.1
0.8
(8f): 13C NMR (63 MHz, CDCl3)
102030405060708090100110120130140150160170180190 ppm
27.60
33.40
51.47
51.81
52.42
76.52
77.03
77.53
101.36
108.31
109.14
111.15
118.45
120.10
122.48
122.77
126.23
129.71
132.05
136.32
148.05
148.15
161.53
165.46
14
C
DC
l 3
8fNH
N
NO
O
O
O
Chemical Formula: C22H19N3O4
S
(8f): 1H NMR (500 MHz, (CD3)2SO)
11 10 9 8 7 6 5 4 3 2 1 ppm
2.822
2.906
2.926
2.936
2.957
3.218
3.226
3.248
3.256
3.992
4.028
4.031
4.041
4.056
4.064
4.199
4.234
5.967
5.981
6.577
6.593
6.735
6.801
6.835
6.850
6.976
6.991
7.006
7.062
7.078
7.092
7.279
7.295
7.464
7.482
11.024
3.0
1.2
1.0
2.0
1.0
2.0
1.0
1.0
1.1
1.0
1.2
1.1
1.1
1.0
1.0
15
8fNH
N
NO
O
O
O
Chemical Formula: C22H19N3O4
Water
DMSO-d6
S
(8g): 1H NMR (500 MHz, (CD3)2SO)
11 10 9 8 7 6 5 4 3 2 1 ppm
2.823
2.906
2.930
2.935
2.960
3.226
3.234
3.257
3.265
3.994
4.029
4.044
4.052
4.068
4.075
4.201
4.237
5.968
5.980
6.585
6.601
6.746
6.813
6.833
6.849
6.978
6.993
7.008
7.064
7.079
7.094
7.285
7.301
7.468
7.484
11.024
3.0
1.1
1.0
2.1
1.0
2.1
1.0
1.0
2.0
1.0
1.0
1.0
1.0
0.7
(8g): 13C NMR (126 MHz, (CD3)2SO)
190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm
27.17
33.09
39.51
39.68
39.85
40.01
40.18
40.35
40.51
51.15
51.33
52.49
101.73
107.99
108.62
108.83
111.80
118.59
119.36
122.15
122.19
126.39
130.83
133.38
136.75
147.73
148.11
162.74
165.13
16
8gNH
N
NO
O
O
O
Chemical Formula: C22H19N3O4
S
(8h): 1H NMR (250 MHz, CDCl3)
8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
2.899
2.946
2.961
3.010
3.552
3.567
3.614
3.631
3.824
3.896
3.920
3.987
4.267
4.288
4.313
4.333
4.345
4.788
4.847
6.950
7.028
7.112
7.128
7.215
7.405
7.521
7.561
8.235
0.9
0.9
1.9
1.9
0.9
1.0
2.0
1.9
8.3
1.0
0.8
(8h): 13C NMR (63 MHz, CDCl3)
190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm
27.75
48.78
49.39
51.45
52.65
76.56
77.06
77.57
109.15
111.25
118.49
120.18
122.88
123.05
126.19
128.32
128.52
129.07
130.40
132.04
134.81
136.39
137.22
161.94
165.17
17
C
DC
l 3
8hNH
N
NO
O
Br
Chemical Formula: C27H22BrN3O2
S
(8i): 1H NMR (250 MHz, CDCl3)
8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
1.566
1.592
2.955
2.996
3.011
3.063
3.566
3.582
3.624
3.644
3.696
3.970
4.042
4.410
4.430
4.459
4.479
5.970
5.999
6.028
6.054
7.007
7.124
7.385
7.532
7.568
7.976
3.0
1.0
2.1
1.0
1.0
1.1
1.1
13.31.1
0.9
(8i): 13C NMR (63 MHz, CDCl3)
190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm
15.08
27.59
43.64
50.92
52.39
52.83
76.53
77.19
77.63
111.26
118.47
120.31
122.96
126.21
126.83
127.40
127.82
128.41
128.94
128.99
129.46
136.65
137.38
137.82
162.92
165.49
18
C
DC
l 3
8iNH
N
NO
O
Chemical Formula: C28H25N3O2
S
(8j): 1H NMR (250 MHz, CDCl3)
1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5 ppm
1.537
1.564
2.892
2.941
2.956
3.004
3.487
3.559
3.595
3.609
3.655
3.671
3.860
3.932
4.415
4.430
4.463
4.478
6.045
6.071
6.100
6.130
7.029
7.140
7.229
7.277
7.387
7.549
7.580
7.803
2.9
1.0
1.0
1.2
1.0
1.0
1.0
1.2
2.1
11.41.1
1.0
(8j): 13C NMR (63 MHz, CDCl3)
190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm
14.54
27.72
43.82
50.26
52.18
52.79
76.56
77.07
77.59
108.93
111.17
118.42
120.10
122.78
126.21
127.44
128.28
128.75
128.88
128.93
129.59
136.41
137.99
138.08
162.58
165.26
19
C
DC
l 3
8jNH
N
NO
O
Chemical Formula: C28H25N3O2
S
(8k): 1H NMR (250 MHz, CDCl3)
8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
1.476
1.506
2.814
2.865
2.877
2.922
3.418
3.490
3.510
3.528
3.572
3.588
3.770
3.841
4.298
4.316
4.348
4.366
5.981
6.009
6.037
6.065
6.958
7.093
7.165
7.180
7.405
7.482
7.549
8.284
3.1
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
11.21.0
1.0
(8k): 13C NMR (126 MHz, CDCl3)
200 180 160 140 120 100 80 60 40 20 0 ppm
14.61
27.76
43.91
50.10
52.07
52.85
76.85
77.11
77.36
108.90
111.19
118.41
120.01
122.64
126.31
127.35
128.21
128.83
128.89
128.98
129.75
136.40
138.27
162.30
165.20
20
C
DC
l 3
8kNH
N
NO
O
Chemical Formula: C28H25N3O2
S
(8l): 1H NMR (250 MHz, (CD3)2SO)
11 10 9 8 7 6 5 4 3 2 1 ppm
3.041
3.092
3.108
3.152
3.532
3.551
3.570
3.591
3.614
3.635
4.498
4.517
4.543
4.561
5.026
5.081
6.898
7.014
7.180
7.222
7.351
7.567
7.596
11.040
1.0
2.1
1.0
2.1
1.1
8.4
10.71.1
1.0
(8l): 13C NMR (126 MHz, (CD3)2SO)
200 180 160 140 120 100 80 60 40 20 0 ppm
28.91
39.52
39.69
39.86
40.02
40.19
40.36
40.52
47.16
52.07
52.42
63.48
107.38
111.84
118.72
119.42
122.17
126.40
127.86
128.03
128.13
128.16
128.73
128.99
129.05
129.28
129.63
130.42
136.23
136.90
138.02
139.66
163.56
165.70
21
8lNH
N
NO
O
Ph
Chemical Formula: C33H27N3O2
S
(8m): 1H NMR (500 MHz, (CD3)2SO)
11 10 9 8 7 6 5 4 3 2 1 ppm
1.594
1.663
1.681
1.744
2.137
2.204
2.346
2.403
3.035
3.069
3.208
3.310
3.894
3.924
4.072
4.100
4.582
4.612
6.000
6.934
6.948
6.964
7.021
7.052
7.222
7.306
7.450
7.466
8.038
10.826
2.1
2.1
2.0
2.0
1.0
3.1
1.0
1.0
1.0
1.0
1.1
3.0
4.1
1.0
1.0
0.9
(8m): 13C NMR (126 MHz, (CD3)2SO)
190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm
22.00
22.88
25.69
27.96
29.81
39.52
39.68
39.85
40.02
40.18
40.35
40.52
48.72
48.92
56.72
104.68
111.17
118.97
121.40
127.85
127.96
128.17
129.04
129.13
130.43
135.65
136.55
139.45
165.07
166.99
22
8mNH
N
NO
O
Chemical Formula: C26H27N3O2
S
(8n): 1H NMR (500 MHz, CDCl3)
1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5 ppm
2.935
2.961
2.988
3.575
3.605
4.021
4.198
4.231
4.440
4.461
4.642
4.670
4.730
4.758
5.601
5.636
7.135
7.149
7.165
7.196
7.212
7.225
7.323
7.411
7.495
7.509
7.930
1.3
1.0
1.9
0.9
1.0
1.0
1.0
1.0
1.1
1.2
6.5
1.0
0.9
(8n): 13C NMR (126 MHz, CDCl3)
190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm
27.41
40.05
48.68
49.49
56.88
107.44
111.00
118.20
120.20
122.58
126.65
128.02
128.33
128.53
129.09
134.84
136.22
163.06
165.44
23
C
DC
l 3
8nNH
N
NO
O
Chemical Formula: C21H19N3O2
S
(8i/8i’ : 70/30 dr): 1H NMR (250 MHz, CDCl3)
1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5 ppm
1.473
1.501
1.526
1.555
2.788
2.843
2.858
2.896
2.940
2.955
3.003
3.395
3.463
3.499
3.520
3.566
3.579
3.636
3.809
3.882
3.897
3.969
4.340
4.359
4.388
4.405
5.887
6.055
6.919
6.953
7.113
7.385
7.453
7.590
8.260
8.319
1.0
2.4
0.2
0.9
0.2
0.7
1.4
0.3
0.9
1.1
1.2
0.3
0.8
16.11.9
0.3
0.8
(8i/8i’ : 70/30 dr): 13C NMR (63 MHz, CDCl3)
190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm
14.57
15.10
23.24
27.61
43.64
44.83
50.41
50.81
52.29
52.83
56.30
56.54
76.65
77.16
77.67
106.17
108.60
109.69
111.30
118.43
120.07
122.38
122.73
126.24
126.77
127.39
127.74
128.37
128.77
128.94
129.64
132.84
136.42
137.51
138.39
141.15
162.74
165.40
166.61
167.86
24
C
DC
l 3
8i/8i' (70/30 dr)
NH
N
NO
ONH
N
NO
O
S
(8i/8j : 40/60 dr): 1H NMR (500 MHz, CDCl3)
1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5 ppm
1.524
1.539
1.559
1.573
2.907
2.932
2.937
2.962
2.999
3.024
3.497
3.531
3.581
3.596
3.605
3.619
3.627
3.635
3.864
3.898
3.938
3.973
4.401
5.999
6.013
6.027
6.047
6.062
6.076
7.016
7.138
7.146
7.152
7.160
7.168
7.175
7.189
7.203
7.216
7.230
7.240
7.253
7.273
7.287
7.300
7.315
7.324
7.334
7.351
7.365
7.381
7.537
7.552
7.788
7.804
3.0
2.0
1.7
1.0
2.2
0.9
0.6
1.5
0.6
0.9
1.5
4.3
16.70.7
0.7
0.8
0.5
(8i/8j : 40/60 dr): 13C NMR (126 MHz, CDCl3)
190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm
14.58
15.06
27.67
27.76
29.69
43.72
43.90
50.20
50.56
52.13
52.17
52.89
76.75
77.01
77.26
109.10
109.17
111.14
118.45
120.19
122.82
126.29
127.34
127.72
128.24
128.89
128.97
129.62
129.71
136.34
137.72
137.95
138.02
138.15
162.53
162.62
165.20
165.26
25
C
DC
l 3
NH
N
NO
O
8i/8j (40/60 dr)
NH
N
NO
O
S
(7i : 53/47 dr): 1H NMR (250 MHz, CDCl3)
8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
1.136
1.258
1.489
1.517
1.738
1.766
2.861
3.265
3.327
3.375
3.879
3.899
3.922
3.945
4.039
4.101
4.344
4.360
4.381
4.408
5.182
5.283
5.422
5.446
5.472
5.502
6.103
6.128
6.156
6.189
6.270
7.101
7.424
7.507
7.531
7.640
9.0
8.2
3.5
3.0
8.0
1.9
1.2
1.0
1.2
0.9
1.0
3.3
8.0
23.22.5
1.0
(7i : 53/47 dr):13C NMR (126 MHz, CDCl3)
220 200 180 160 140 120 100 80 60 40 20 0 ppm
16.11
18.27
25.18
26.15
28.36
28.60
47.87
48.10
50.89
51.37
51.74
54.52
55.08
55.34
57.99
58.51
109.33
111.06
111.17
118.11
118.22
119.58
119.66
122.08
122.18
127.05
127.17
127.25
127.82
128.03
128.13
128.49
128.62
128.70
128.84
129.02
129.15
134.17
134.40
136.24
139.24
139.99
140.34
140.53
168.35
168.78
173.35
173.78
26
NH
NH
NO
O
NH
Ph
7i (95%, 53/47 dr)Chemical Formula: C32H36N4O2
S
(7a : 75/25 dr): 1H NMR (500 MHz, CDCl3 at 293 K) (4rotamers : 34/32/20/14)
1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0 ppm
0.905
1.172
1.231
1.289
3.054
3.500
3.556
3.718
3.886
3.960
3.997
4.114
4.202
4.258
4.355
4.392
4.546
4.704
4.741
4.890
5.536
5.931
6.052
6.149
6.996
7.152
7.188
7.215
7.230
7.244
7.258
7.286
7.301
7.322
7.337
7.353
7.368
7.383
7.398
7.492
7.990
8.436
8.938
5.7
9.0
8.8
3.1
1.7
5.0
1.9
2.8
0.6
1.6
2.6
1.8
0.7
1.7
0.8
1.3
6.0
32.50.9
0.6
0.6
(7a : 75/25 dr): 1H NMR (500 MHz, CDCl3 at 323 K)
9 8 7 6 5 4 3 2 1 ppm
1.001
1.233
1.310
2.976
3.860
4.051
4.232
4.343
4.473
4.624
4.916
5.650
5.830
6.182
6.976
7.529
7.962
8.233
8.786
9.0
2.7
3.2
1.1
0.8
1.1
1.9
0.3
1.9
17.50.4
0.3
0.2
0.2
27
7a ( 75/25 dr)
NH
NH
N
O
O
HN
Chemical Formula: C31H34N4O2
S
(8a): COSY
ppm
9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm9
8
7
6
5
4
3
2
1
ppm
2.83.03.23.43.63.84.04.24.44.64.85.05.25.4 ppm
2.6
2.8
3.0
3.2
3.4
3.6
3.8
4.0
4.2
4.4
4.6
4.8
5.0
5.2
5.4
28
S
(8a): NOESY
ppm
3.03.54.04.55.05.56.06.57.07.58.0 ppm
3.0
3.5
4.0
4.5
5.0
5.5
6.0
6.5
7.0
7.5
8.0
ppm
2.83.03.23.43.63.84.04.24.44.64.85.05.25.4 ppm
2.6
2.8
3.0
3.2
3.4
3.6
3.8
4.0
4.2
4.4
4.6
4.8
5.0
5.2
5.4
29
S
(8a): HSQC
ppm
9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm
180
160
140
120
100
80
60
40
20
ppm
3.03.54.04.55.05.56.06.57.07.58.08.59.0 ppm
25
30
35
40
45
50
55
30
S
(8a): HPLC
31