Organocatalytic Entry to Chiral Bicyclo[3.n.1]alkanones via
Direct Asymmetric Intramolecular Aldolization
Noriaki Itagaki, Mari Kimura, Tsutomu Sugahara, and Yoshiharu Iwabuchi
Graduate School of Pharmaceutical Sciences, Tohoku University Aobayama, Sendai 980-8578, Japan
Fax: +81-22-795-6845 E-mail: [email protected]
Supporting Information
Table of Contents 1. General S-2 2. Experimental Procedures(1) Preparation of substrates for the aldol reactions S-2
(2) Typical procedures for the asymmetric aldol reactions S-6
(3) Conversion of (–)- 2a to known (–)- 6 and determination of
the absolute structure S-8
(4) Preparation of the catalysts for the aldol reaction S-10
(5) Preparation of _–branched ketoaldehyde 1c S-14
3. References S-16
1. General.
IBX1 and Dess-Martin periodinane2 were prepared according to the literature procedures. Other chemicals and solvents were purchased from commercial suppliers or purified by standard techniques. All reactions were stirred magnetically, under an argon atmosphere, unless otherwise noted, and
monitored with analytical TLC (Merck Kieselgel 60 F254). Column
chromatography was carried out with silica gel 60 particle size 0.063-0.210 mm. Melting points were taken with Yazawa BY-2 and are uncorrected. NMR spectra were measured in JEOL JNM-AL400 (400 MHz). Chemical shifts were reported in theb scale relative to tetramethylsilane (TMS) as 0.00 ppm for 1H (CDCl
3) and residual CHCl3 (7.26 ppm for
1H and 77.00 ppm for 13C), as internal reference. The infrared (IR) spectra were recorded on JASCO IR-700 or JASCO FT/IR-410. Mass spectra were measured on JEOL JMS-DX303 (for low resolution MS) and JMS-AX500 or JMS-700 (for high resolution MS) instruments. The specific rotations were measured on JASCO DIP-370. Elemental analyses utilized Yanaco CHN CORDER MT-6. HPLC utilized Gilson Model 307 or Gilson Model 305 with Gilson Model 112 or Gilson Model 119 as UV-detector (254 nm).
2. Experimental procedures.
(1) Preparation of substrates for the aldol reactions
3-(4-hydroxycyclohexyl)propionic acid ethyl ester: 5% (w/w) Rh/C (5.5 g) was added to a solution of ethyl p-hydroxycinnamate (55.94 g, 291.2 mmol) in ethyl acetate (310 ml) and the mixture was stirred under atmospheric pressure of H2 for 10 days at room temperature. Then, the reaction mixture was filtered through a Celite pad eluting with ethyl acetate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [hexane-AcOEt (3:1 v/v)] to afford hydroxyester (58.20 g, 100 %, cis:trans = 1:1) as a colorless oil. cis–isomer : IR (neat): 3439, 1736 cm-1;1H-NMR (400 MHz, CDCl 3)b: 4.11 (q, 2H, J = 7.1 Hz), 3.96 (br.s, 1H), 2.31 (t, 2H, J = 7.8 Hz), 1.75-1.48 (m, 9H), 1.44-1.30 (m, 3H). 1.25 (t, 3H, J = 7.2 Hz); 13C-NMR (100 MHz, CDCl 3)b: 173.9, 66.4, 60.0, 35.6, 31.83, 31.78, 30.8, 26.4, 14.0; MS m/z : 182 (M+-H 2O), 136 (100%); HRMS Calcd. C11H18O2 (M +-H 2O): 182.1306. Found: 182.1306.
trans–isomer : IR (neat): 3408, 1733 cm-1;1H-NMR (400 MHz, CDCl 3)b: 4.11 (q, 2H, J = 7.2 Hz), 3.50 (m, 1H), 3.22 (br.s, 1H), 2.30 (t, 2H, J = 7.8 Hz), 1.95 (m, 2H), 1.76 (m, 2H), 1.52 (q, 2H, J = 7.6 Hz), 1.28-1.15 (m, 3H). 1.25 (t, 3H, J = 7.2 Hz), 0.95 (qd, 3H, J = 7.2 Hz); 13C-NMR (100 MHz, CDCl 3) b: 173.7, 70.2, 59.9, 35.9, 34.8, 31.8, 31.2, 30.6, 13.8; MS m/z : 200 (M+), 136 (100%); HRMS Calcd. C11H20O3: 200.1411. Found: 200.1404
4-(3-hydroxypropyl)cyclohexanol: LiAlH4(193 mg, 5.09 mmol) was added to a stirred solution of 3-(4-hydroxycyclohexyl)propionic acid ethyl ester (1.06 g, 5.29 mmol, cis: trans = 2:1) in THF at 0 °C and the mixture was stirred for 4 h at room
temperature. Then, H2O (0.20 ml) and 15% aqueous NaOH (0.20 ml) was
dropped to the reaction mixture at 0 °C, and stirring was continued for 10 min at the same temperature. Additional H2O (0.60 ml) was dropped to the reaction mixture and further stirring was continued for 30 min at 0 °C. After MgSO4 was added, the reaction mixture was filtered through a Celite pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [hexane-AcOEt (1:1 v/v)] to afford diol (800 mg, 96 %) as a colorless solid. mp 90-91°C. IR (CHCl3 solution): 3348 cm -1;1H-NMR (400 MHz, CDCl 3) b: 3.92 (s, 0.67H), 3.58 (s, 2H), 3.52 (m, 0.34H), 2.78 (br.s, 2H), 1.95 (d, 0.66H J = 12.7 Hz), 1.80-1.15 (m, 11.7H), 0.94 (q, 0.67H, J = 11.5 Hz); MS m/z : 158 (M+), 81 (100%); HRMS Calcd. C9H18O2: 158.1306. Found: 158.1271.
3-(4-oxocyclohexyl)propionaldehyde (1a):N-methylmorpholine N-oxide (2.28 g, 19.4 mmol) was added to a mixture of 4-(3-hydroxypropyl)cyclohexanol (1.00 g, 6.32 mmol) and molecular sieves 4Å (1.30 g) in CH2Cl2 (33 ml) and the mixture was stirred for 10 min at room temperature. Then, tetrapropylammonium perruthenate (114 mg, 0.324 mmol) was added to the reaction mixture at 0 °C and stirring was continued for 2 h at room temperature. The reaction mixture was filtered through a Celite pad and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography [hexane-AcOEt (17:3 v/v)] to afford ketoaldehyde 1a (695 mg, 71 %) as a colorless oil.
IR (neat): 1719 cm-1;1H-NMR (400 MHz, CDCl 3)b: 9.80 (t, 1H, J = 1.6 Hz), 2.53 (td, 2H, J = 7.4, 1.5 Hz), 2.45-2.28 (m, 4H), 2.06 (m, 2H), 1.80-1.65 (m, 3H), 1.43 (m, 2H); 13C-NMR (100 MHz, CDCl 3)b: 211.1, 201.6, 41.3, 40.2, 35.1, 32.1, 27.2; MS m/z : 154 (M+), 55 (100%); HRMS Calcd. C 9H14O2: 154.0993. Found: 154.0998. 8-ethoxycarbonylmethylidene-1,4-dioxaspiro[4.5]decane: Triethylphospho-noacetate (14.0 ml, 70.57 mmol) was added to a suspension of NaH (60 %) (2.83 g, 70.8 mmol) in THF (270 ml) at 0 °C and the mixture was stirred for 30 min at the same temperature. Then, to the mixture was dropped 1,4-cyclohexanedione monoethylene acetal (10.05 g, 64.35 mmol) in THF (65 ml) at 0 °C and stirring was continued for 40 min at the same temperature. After addition of H2O, the mixture was extracted with Et2O. The aqueous layer was extracted with AcOEt and the combined organic solution was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography [hexane-AcOEt (9:1 v/v)] to afford _,`-unsaturated ester (14.63 g, 100 %) as a colorless oil.
IR (neat): 1731 cm-1;1H-NMR (400 MHz, CDCl 3)b: 5.66 (s, 1H), 4.15 (q, 2H, J = 7.2 Hz), 3.98 (s, 4H), 3.00 (t, 2H, J = 6.6 Hz), 2.37 (t, 2H, J = 6.6 Hz), 1.76 (m, 4H), 1.27 (t, 3H, J = 7.1 Hz); 13C-NMR (100 MHz, CDCl 3) b: 166.4, 160.0, 114.2, 107.9, 64.4, 59.6, 35.7, 35.0, 34.6, 26.0, 14.3; MS m/z : 226 (M+), 226 (100%); HRMS Calcd. C12H18O4: 226.1205. Found: 226.1185. 8-ethoxycarbonylmethyl-1,4-dioxaspiro[4.5]decane: 10% (w/w) Pd/C (285
mg) was added to a solution of
8-ethoxycarbonylmethylidene-1,4-dioxaspiro[4.5]decane (2.85 g, 12.6 mmol) in AcOEt (25 ml) and the mixture was stirred under atmospheric pressure of H2for 2 h at room temperature. Then, the reaction mixture was filtered through a Celite pad eluting with AcOEt, and concentrated under reduced pressure to afford ester (2.87 g, 100 %) as a colorless oil. IR (neat): 1718 cm-1;1H-NMR (400 MHz, CDCl 3)b: 4.12 (q, 2H, J = 7.2 Hz), 3.94 (s, 4H), 2.20 (d, 2H, J = 7.1 Hz), 1.84 (m, 1H), 1.74 (m, 4H), 1.55 (td, 2H, J = 13.7, 3.7 Hz), 1.32 (m, 2H), 1.25 (t, 3H, J = 7.1 Hz); 13C-NMR (100 MHz, CDCl 3)
b: 172.8, 108.5, 64.2, 60.2, 41.0, 34.3, 33.5, 30.0, 14.3; MS m/z : 228 (M+), 99 (100%). HRMS Calcd. C12H20O4 : 228.1362. Found : 228.1355.
8-(2-hydroxyethyl)-1,4-dioxaspiro[4,5]decane: A solution of 8-ethoxycarbonylmethyl-1,4-dioxaspiro[4.5]decane (1.30 g, 5.71 mmol) in THF (13.0 ml) was dropped to a stirred suspention of LiAlH4 (163 mg, 4.30 mmol) in THF (10.0 ml) at 0 °C and the mixture was stirred for 4 h at room temperature. Then, H2O (0.2 ml) and 15% aq.NaOH (0.6 ml) was dropped to the reaction mixture at 0 °C, and stirring was continued for 10 min at the same temperature. Additional H2O (0.6 ml) was dropped to the reaction mixture and further stirring was continued for 30 min at 0 °C . After the addition of MgSO4, the reaction mixture was filtered through a Celite pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [hexane-AcOEt (2:1-1:1 v/v)] to afford ketalalcohol (1.07 g, 100 %) as a colorless oil.
4-(2-hydroxyethyl)cyclohexanone: 10% aq.HCl (4.6 ml) was dropped to a solution of 8-(2-hydroxyethyl)-1,4-dioxaspiro[4,5]decane (566 mg, 3.03 mmol) in THF (9.2 ml) at 0 °C and the mixture was stirred for 24 h at room temperature. After neutralization with K2CO3, the reaction mixture was extracted with AcOEt. The aqueous layer was extracted with AcOEt and the combined organic solution was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography [hexane-AcOEt (4:1 v/v)] to afford hydroxyketone (418 mg, 97 %) as a colorless oil.
(4-oxocyclohexyl)acetaldehyde (1b): To a solution of oxalyl chloride (1.90 ml, 1.31 mmol) in CH2Cl2 (80.0 ml) was added a solution DMSO (3.0 ml, 42.3 mmol) in CH2Cl2(10.0 ml) at –78 °C and the mixture was stirred for 5 min at the same temperature. A solution of 4-(2-hydroxyethyl)cyclohexanone (1.00 g, 7.04 mmol) in CH2Cl2 (20.0 ml) was added to the reaction mixture at –78 °C and stirring was continued for 15 min at the same temperature. To the mixture was added Et3N (8.8 ml, 63.1 mmol), and the mixture was further stirred for 30 min at the same temperature. Then, the reaction mixture was warmed to room temperature and H2O was added, and the mixture was extracted with AcOEt.
The aqueous layer was extracted with AcOEt and the combined organic solution was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography [hexane-AcOEt (9:1-4:1 v/v)] to afford ketoaldehyde 1b (782 mg, 80 %) as a colorless oil. IR (neat): 1712 cm-1; 1H-NMR (400 MHz, CDCl 3) b: 9.81 (t, 1H, J = 1.5 Hz), 2.50-2.35 (m, 7H), 2.10 (m, 2H), 1.49 (m, 2H); 13C-NMR (100 MHz, CDCl 3) b: 210.6, 200.9, 49.3, 40.5, 32.4, 30.5; MS m/z : 140 (M+), 96 (100%); HRMS Calcd. C8H12O2: 140.0837. Found: 140.0807.
(2) Typical procedures for the asymmetric aldol reactions
(1S,5R,8R)-8-hydroxybicyclo[3.3.1]nonan-2-one [(–)-2a]: A solution of ketoaldehyde 1a (100 mg, 0.648 mmol) in MeCN (2.6 ml) was added dropwisely to a stirred solution of tetrabutylammonium 4-TBDPSoxy-L-prolinate (21.5 mg,
0.033mmol) in MeCN (2.6 ml) at room temperature. The reaction mixture was stirred for 3 h at room temperature. Then, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography [hexane-AcOEt (4:1 v/v)] to afford hydroxyketone (–)-2a (77 mg, 77 %) as colorless needles. An aliquot sample was recrystallized from diisopropyl ether-hexane.
mp 131-133 °C; [_]D
31 = –3.57° (c 0.8, CHCl 3). [lit.
3 for the enantiomer [_] D 20 = +3.6° (c 0.65, CHCl3)]; IR (CHCl3solution): 3520, 1700 cm -1;1H-NMR (400 MHz, CDCl3)b: 3.78 (m, 1H), 2.79 (br. s, 1H), 2.66 (s, 1H), 2.54 (m, 1H), 2.37 (m, 1H), 2.18-2.05 (m, 3H), 1.97 (m, 1H) 1.69 (m, 4H), 1.38 (m, 1H); 13C-NMR (100 MHz, CDCl3)b: 216.3, 71.6, 51.6, 39.0, 31.0, 30.7, 29.7, 26.7, 24.9; MS m/z : 154 (M +), 70 (100%); HRMS Calcd. C9H14O2: 154.0993. Found: 154.0983; Anal. Calcd. for C9H14O2: C, 70.10; H, 9.15. Found: C, 70.05; H, 9.13.
The diastereomeric purity of this aldol product 2a was determined to be 98% de by 400 MHz 1H-NMR spectra. The signals used for the analysis were the signals due to the C8-bonding protons of the diastereomers. Chemical shifts of the peaks appears as follows; endo-alcohol b : 3.80 (m, 1H), exo-alcohol b : 4.06 (m, 1H).
spectra using Mosher’s method4and (b) chiral HPLC analysis after conversion of 2a to the corresponding benzoyl ester.
(a) Mosher’s method: Hydroxyketone (–)-2a was converted into the
corresponding (S)-MTPA ester by treatment with (R)-MTPA chloride and pyridine in CH2Cl2 with a small amount of 4-dimethylaminopyridine as catalyst and analyzed by the 400 MHz 1H-NMR spectroscopy in CDCl
3. The signals used for the analysis of the MTPA ester of (–)-2a were the signals due to the methoxy protons of the corresponding (S)-MTPA ester. Chemical shifts of the peaks used were as follows; (R)-MTPA ester of (–)-2ab: 3.57 (d, 3H, J = 1.0 Hz), (S)-MTPA ester of (–)-2ab : 3.48 (d, 3H, J = 1.0 Hz).
(b) Chiral HPLC analysis: Hydroxyketone (–)-2a was converted into the corresponding benzoyl ester by treatment with benzoyl chloride and Et3N in CH2Cl2 with a small amount of 4-dimethylaminopyridine as catalyst and analyzed by HPLC using DAICEL CHIRALCEL OD. The conditions used for the analysis of the benzoyl ester of (–)-2a and the retention time were as follows; Solvent: i-PrOH-hexane (3:97). Flow rate: 0.5 ml/min. Retention time: benzoyl ester of (1S,5R,8R)-2a; 20.6 min, benzoyl ester of (1R,5S,8S)-2a; 23.5 min
(1S,5R,7R)-7-hydroxy-bicyclo[3.2.1]octan-2-one (2b): A solution of ketoaldehyde 1b (50.0mg, 0.36 mmol) in DMSO (1.9 ml) was added dropwisely to a stirred solution of tetrabutylammonium -L-aspartate (34 mg, 0.090 mmol) in
DMSO (1.0 ml) at room temperature and stirring was continued for 24 h at the same temperature. Then, the reaction mixture was diluted with Et2O and the organic solution was washed by H2O. The aqueous layer was extracted with Et2O several times and the combined organic solution was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [hexane-AcOEt (17:3 v/v)] to afford hydroxyketone 2b (20.0 mg, 40 %) as a colorless solid.
mp 121-122 °C; IR (CHCl3 solution): 3406, 1695 cm -1; 1H-NMR (400 MHz, CDCl3) b: 4.61 (m, 1H), 3.40 (br. s, 1H), 2.78 (t, 1H, J = 5.1 Hz), 2.62 (m, 1H), 2.47-2.25 (m, 3H), 1.94-1.67 (m, 4H), 1.57 (m, 1H); 13C-NMR (100 MHz, CDCl 3) b:212.5, 74.0, 57.8, 36.5, 36.4, 36.1, 33.5, 31.6; MS m/z : 140 (M+), 80 (100%); HRMS Calcd. C8H12O2: 140.0837. Found: 140.0807.
The diastereomeric purity of this aldol product 2b was determined to be 98% de by 400 MHz 1H-NMR spectra. The signals used for the analysis were the signals due to the C7-bonding protons of the diastereomers. Chemical shifts of the peaks appears as follows; endo-alcohol b : 4.61 (m, 1H), exo-alcohol b : 4.40 (m, 1H).
The enantiomeric purity of 2b was determined to be 33% ee by 400 MHz 1
H-NMR spectra using Mosher’s method4 as described above. The absolute
configuration of 2b was determined to be (1S,5R,7R) by comparison of the specific optical rotation after conversion of 2b to a known bicyclooctenone 135as shown in the following scheme.
Scheme 1 O HO MOMCl i-Pr2EtN O MOMO MOMO O CH2Cl2 (85 %) 55-75 °C (75 %) 2b 13 [_]D26 = 72.4° (c 0.1, CHCl3). [lit.5 [_]D29= 204° (c 0.7, CHCl3)] IBX toluene -DMSO
(3) Conversion of (–)-2a to known (–)-66 and determination of the absolute structure
(1S,5S,8R)-8-hydroxybicyclo[3.3.1]non-3-en-2-one (4): TBDPSCl (0.593 ml, 2.28 mmol) and imidazole (310 mg, 4.55 mmol) were added to a solution of alcohol (–)-endo-2a (293 mg, 1.90 mmol, >99% ee) in DMF (3.8 ml) at room temperature. The reaction mixture was stirred for 18 h at the same temperature. Then, the reaction mixture was diluted with Et2O and washed with H2O. The aqueous layer was extracted with Et2O and the combined organic extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography [hexane-AcOEt (19:1 v/v)] to afford TBDPS ether as a colorless oil. To a solution of this TBDPS ether in toluene-DMSO (20 ml, 2:1 v/v) was added IBX (2.13 g, 7.60 mmol) . The mixture was heated to 55-75 °C and stirred for 16 h. After cooling, the reaction mixture was diluted with Et2O, filtered through a Celite pad, and the organic solution was washed with saturated aqueous NaHCO3 and H2O. The aqueous layer was extracted with Et2O and the combined organic solution was washed with brine, dried over MgSO4, and concentrated under reduced pressure.
The crude mixture was purified by silica gel column chromatography [hexane-AcOEt (19:1 v/v)] to afford enone as a colorless oil. Next, 1.0 M TBAF in THF (5.7 ml, 5.7 mmol) was added dropwisely to a solution of this enone in THF (5.0 ml) at room temperature and the mixture was stirred for 20 h at the same temperature. After removal of the solvent under reduced pressure, AcOEt was added to this residue, and the organic solution was washed with H2O. The aqueous layer was extracted with AcOEt and the combined organic solution was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography [hexane-AcOEt (4:1 v/v)] to afford hydroxyenone 4 as a colorless solid (130 mg, 45 %).
(1S,5S)-bicyclo[3.3.1]non-3-ene-2,8-dione [(+)-5]: Dess-Martin periodinane (725 mg) was added to a solution of alcohol 4 (120 mg, 0.788 mmol) in CH2Cl2 (5.3 ml) at room temperature and the mixture was stirred for 2 h at the same temperature. Then, the reaction mixture was diluted with Et2O, filtered through a Celite pad, and the organic solution was washed with saturated aqueous
NaHCO3 and H2O. The aqueous layer was extracted with Et2O and the
combined organic solution was washed with brine, dried over MgSO4, and
concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography [hexane-AcOEt (4:1 v/v)] to afford enedione (+)-5 (99 mg, 84 %) as a colorless solid. mp 64.5-65.5 ˚C;. [_]D 28 = +312.5˚ (c 1.36, CHCl 3); IR (CHCl3 solution): 1750, 1705 cm-1.1H-NMR (400 MHz, CDCl 3)b: 7.18 (m, 1H), 6.21 (d, 1H, J = 10.0 Hz), 3.42 (d, 1H, J = 1.5 Hz), 2.86 (m, 1H), 2.67-2.57 (m, 2H), 2.46 (dd, 1H, J = 16.1, 5.4 Hz), 2.27-2.17 (m, 2H), 2.09 (m, 1H); 13C-NMR (100 MHz, CDCl 3) b: 202.4, 193.1, 152.4, 129.0, 63.0, 35.7, 34.7, 29.7, 28.1.; MS m/z : 150 (M+), 55 (100%). HRMS Calcd. C9H10O2 : 150.0680. Found : 150.0700.
(R)-3-(4-Oxocyclohex-2-enyl)propionic acid ethyl ester [(–)-6]: A solution of 0.26 M NaOEt in EtOH (0.615 ml, 0.160 mmol) was added dropwisely to a solution of enedione (+)-5 (20.0 mg, 0.133 mmol) in EtOH (1.0 ml) at –30 °C and the mixture was stirred for 45 min at the same temperature. Then, the reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted
with Et2O. The aqueous layer was extracted with Et2O and the combined organic solution was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [hexane-AcOEt (9:1 v/v)] to afford ester (–)-6 (23.0 mg, 88 %) as a colorless oil. [_]D 32 = –88.2˚ (c 0.25, CHCl 3) [lit. 6 [_] D= –81.9˚ (c 1.15, CHCl3)]; IR (neat): 1733, 1681 cm-1.1H-NMR (400 MHz, CDCl 3)b: 6.83 (m, 1H), 6.00 (dd, 1H, J = 10.2, 2.4 Hz), 4.16 (q, 2H, J = 7.2 Hz), 2.54-2.32 (m, 5H), 2.13 (m, 1H), 1.88 (m, 1H), 1.80-1.65 (m, 2H), 1.27 (t, 3H, J = 7.2 Hz); 13C-NMR (100 MHz, CDCl 3)b: 199.4, 173.0, 153.6, 129.5, 60.6, 36.7, 35.3, 31.5, 29.5, 28.2, 14.2; MS m/z : 196 (M+), 109 (100%). HRMS Calcd. C11H16O3 : 196.1099. Found : 196.1089.
(4) Preparation of the catalysts for the aldol reaction Schme 2 N H OH O HO N H OH O TBDPSO N Cbz OBn O HO N Cbz OBn O TBDPSO ref. 7 TBDPSClimidazole DMF (100 %) H2, Pd/C MeOH (99 %) trans-4-hydroxy-L-proline 14 15 7 (2S,4R)-4-(tert-butyldiphenylsiloxy)pyrrolidine-1,2-dicarboxylic acid dibenzyl ester [(–)-15]: TBDPSCl (10.8 ml, 41.6 mmol) and imidazole (5.67 g, 82.3 mmol) were added to a solution of alcohol 14 (12.36 g, 34.8 mmol) in DMF (35 ml) at room temperature. The reaction mixture was stirred for 12 h at the same temperature. Then, the reaction mixture was diluted with Et2O and the organic solution was washed with H2O. The aqueous layer was extracted with Et2O and the combined organic solution was washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The crude mixture was
purified by silica gel column chromatography [hexane-AcOEt (19:1 v/v)] to afford silyl ether (–)-15 (20.77 g, 100 %) as a colorless oil.
[_]D
29 = –18.9° (c 0.8, CHCl
3); IR (neat): 1745, 1711 cm
CDCl3)b: 7.63-7.10 (m, 20H), 5.20-5.02 (m, 3Hrotamer), 4.95 (d, 0.5Hrotamer, J = 12.2 Hz), 4.88 (d, 0.5Hrotamer, J = 12.4 Hz), 4.62 and 4.53 (each t, total 1Hrotamer, each J = 7.7 Hz), 4.41 (br.s, 1H,), 3.63-3.42 (m, 2H), 2.26 (m, 1H), 1.89 (m, 1H), 1.03 and 1.01 (each s, total 9Hrotamer);
13C-NMR (100 MHz, CDCl 3) (rotamer) b: 172.2, 172.0, 154.9, 154.1, 136.4, 136.3, 135.4, 135.2, 133.2, 133.1, 133.0, 132.9, 129.78, 129.77, 129.74, 128.33, 128.27, 128.23, 128.12, 128.0, 127.93, 127.89, 127.78, 127.76, 127.67, 127.65, 127.62, 77.3, 71.4, 70.6, 67.0, 66.7, 66.6, 58.2, 58.0, 54.9, 54.5, 39.5, 38.6, 26.8, 26.7, 19.0; MS m/z : 536 (M+–C 4H9), 492 (100%). HRMS Calcd. C32H30NO5Si (M +–C 4H9) : 536.1891. Found : 536.1912. (4R)-4-(tert-butyldiphenylsilyloxy)-L-proline [(–)-7]: 10% (w/w) Pd/C (1.20 g)
was added to a solution of estercarbamate (–)-15 (11.99 g, 20.2 mmol) in MeOH (110 ml) and the mixture was stirred under atmospheric pressure of H2for 12 h at room temperature. Then, the reaction mixture was filtered through a Celite pad eluting with MeOH, and concentrated under reduced pressure to afford amino acid (–)-7 (7.38 g, 99 %) as a colorless solid. An aliquot sample was recrystallized from MeOH-Et2O-hexane to provide colorless needles .
mp 214-215 ˚C;. [_]D28 = –36.3˚ (c 0.8, CH 3OH). [lit. 8 [ _]D23 = –33.3˚ (c 1.08, CH3OH)]; IR (nujol): 3458, 1613 cm -1. 1H-NMR (400 MHz, CD 3OD) b: 7.67-7.63 (m, 4H), 7.49-7.40 (m, 6H), 4.60 (br.s, 1H), 4.27 (dd, 1H, J = 10.5, 7.6 Hz), 3,34-3.30 (m, 1H), 3.20 (dd, 1H, J = 12.2, 1.5 Hz), 2.34 (dd, 1H, J = 13.7, 7.3 Hz), 1.94 (ddd, 1H, J = 14.1, 10.5, 3.9 Hz), 1.09 (s, 9H); 13C-NMR (100 MHz, CD 3OD) b: 173.6, 136.7, 133.9, 131.2, 128.9, 74.0, 61.5, 54.5, 40.0, 27.4, 19.8; MS m/z : 312 (M+–C 4H9), 312 (100%). HRMS Calcd. C17H18NO3Si (M +–C 4H9) : 312.1055. Found : 312.1039; Anal. Calcd. for C21H27NO3Si: C, 68.26; H, 7.36; N, 3.79. Found: C, 67.88; H, 7.31; N, 3.75.
Schme 3 N H OH O HO N H OH O TBDPSO N Cbz OBn O HO N Cbz OBn O TBDPSO ref. 9 TBDPSClimidazole DMF (98 %) H2, Pd/C MeOH (100 %) cis-4-hydroxy-D-proline 16 17 8 (76 % for 2 steps in our handle) (2R,4R)-4-(tert-butyldiphenylsiloxy)pyrrolidine-1,2-dicarboxylic acid dibenzyl ester [(+)-17]: TBDPSCl (1.54 ml, 5.92 mmol) and imidazole (804 mg, 11.8 mmol) were added to a solution of alcohol 16 (1.75 g, 34.8 mmol) in DMF (5.0 ml) at room temperature. The reaction mixture was stirred for 24 h at the same temperature. Then, the reaction mixture was diluted with Et2O and the organic solution was washed with H2O. The aqueous layer was extracted with Et2O and the combined organic solution was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [hexane-AcOEt (97:3 v/v)] to afford silyl ether (+)-17 (2.852 g, 98 %) as a colorless oil.
[_]D
28 = +26.5° (c 0.84, CHCl
3); IR (neat): 1798, 1747 cm
-1;1H-NMR (400 MHz, CDCl3)b: 7.62-7.23 (m, 20H), 5.19-4.97 (m, total 4Hrotamer), 4.50 (dd, 0.5Hrotamer, J = 8.8, 3.4 Hz), 4.40 (dd, 0.5Hrotamer, J = 8.8, 3.9 Hz), 4.32 (m, 1H), 3.57 (d, 1H, J = 4.4 Hz), 3.49 (m, 1H), 2.28-2.12 (m, 2H), 1.03 and 1.02 (each s, total 9Hrotamer);
13C-NMR (100 MHz, CDCl 3) (rotamer) b: 171.5, 171.2, 154.7, 154.2, 136.5, 136.3, 135.6, 135.5, 135.4, 133.2, 133.1, 133.0, 129.8, 129.7, 128.39, 128.37, 128.3, 128.2, 128.1, 128.0, 127.9, 127.80, 127.76, 127.72, 127.7, 127.68, 127.64, 127.6, 71.6, 70.7, 67.03, 66.95, 66.9, 66.8, 58.02, 57.77, 54.9, 54.4, 39.3, 38.4, 26.7, 19.0; MS m/z : 536 (M+–C 4H9), 91 (100%). HRMS Calcd. C32H30NO5Si (M+–C
4H9) : 536.1891. Found : 536.1899; Anal. Calcd. for C36H39NO5Si: C, 72.82; H, 6.62; N, 2.36. Found: C, 72.75; H, 6.51; N, 2.40.
(2R,4R)-4-(tert-butyldiphenylsilyloxy)-D-proline [(+)-8]: 10% (w/w) Pd/C (255
mg) was added to a solution of ester-carbamate (+)-17 (2.550 g, 4.29 mmol) in MeOH (23.3 ml) and the mixture was stirred under atmospheric pressure of H2
for 48 h at room temperature. Then, the reaction mixture was filtered through a Celite pad, and concentrated under reduced pressure to afford amino acid (+)-8 (1.583 g, 100 %) as a colorless solid. mp 137-138.5 ˚C;. [_]D 27 = +3.85˚ (c 0.7, CH 3OH); IR (nujol): 3404, 1714 cm -1. 1H-NMR (400 MHz, CD 3OD)b: 7.67-7.63 (m, 4H), 7.48-7.39 (m, 6H), 4.50 (br.s, 1H), 4.24 (m, 1H), 3,34 (d, 1H, J = 12.2 Hz), 3.18 (q, 1H, J = 12.2, 3.7 Hz), 2.39 (m, 1H), 2.29 (m, 1H), 1.05 (s, 9H); 13C-NMR (100 MHz, CD 3OD) b: 172.7, 136.93, 136.87, 134.1, 133.9, 131.29, 131.27, 129.1, 129.0, 72.9, 60.4, 54.9, 39.4, 27.2, 19.8; MS m/z : 312 (M+–C 4H9), 234 (100%). HRMS Calcd. C17H18NO3Si (M +–C 4H9) : 312.1055. Found : 312.1022.
tetrabutylammonium L-prolinate (9): 10.7% (w/v) tetrabutylammonium
hydroxide in MeOH (4.73 ml, 1.95 mmol) was added to a stirred solution of L
-proline (230 mg, 2.00 mmol) in MeOH (2.0 ml) at room temperature and stirring was continued for 30 min at the same temperature. Then, the mixture was concentrated in vacuo to give ammonium salt 9 as a colorless oil.
tetrabutylammonium (4R)-4-(tert-butyldiphenylsilyloxy)-L-prolinate (10):
10.7% (w/v) (concentration was determined by neutralization titration) tetrabutylammonium hydroxide in MeOH (1.20 ml, 0.496 mmol) was added to a stirred solution of amino acid (–)-7 (200 mg, 0.541 mmol) in MeOH (2.2 ml) at room temperature and stirring was continued for 30 min at the same temperature. Then, the mixture was concentrated in vacuo to give ammonium salt 10 (320 mg, 100 %) as a colorless oil.
tetrabutylammonium (4R)-4-(tert-butyldiphenylsilyloxy)-D-prolinate (11):
10.0% (w/v) (concentration was determined by neutralization titration) tetrabutylammonium hydroxide in MeOH (0.63 ml, 0.243 mmol) was added to a stirred solution of amino acid (+)-8 (100 mg, 0.271 mmol) in MeOH (2.0 ml) at room temperature and stirring was continued for 30 min at the same temperature. Then, the mixture was concentrated in vacuo to give ammonium salt 11 (159 mg, 100 %).
Tetrabutylammonium L-aspartate (12): 10.7% (w/v) tetrabutylammonium
hydroxide in MeOH (0.48 ml, 0.20 mmol) was added to a stirred mixture of L
-aspartic acid (26 mg, 0.20 mmol) in MeOH (0.2 ml) at room temperature and stirring was continued for 30 min at the same temperature. Then, the mixture was concentrated in vacuo to give ammonium salt 12.
(5) Preparation of _–branched ketoaldehyde 1c
1c was synthesized according to the reported procedure3 as shown in the following scheme. Scheme 4 CO2Et OH CO2Et O LiAlH4 THF CH2OH OH Me CHO O Me (COCl)2 DMSO CO2Et N CO2Et O Me PCC MS4Å CH2Cl2 (98%) pyrrolidine MS4Å benzene reflux MeI benzene reflux (30%) (91%) CH 2Cl2 (55%) 18 19 20 21 1c
oxocyclohexyl)propionic acid ethyl ester (18): A solution of 3-(4-hydroxycyclohexyl)propionic acid ethyl ester (1.824 g, 9.11 mmol) in CH2Cl2 (9.0 ml) was added dropwisely to a mixture of PCC (3.93 g, 18.2 mmol) and molecular sieves 4Å (9.7 g) in CH2Cl2 (46.0 ml) at 0 °C and the mixture was stirred for 1 h at room temperature. The reaction mixture was filtered through a Celite pad and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography [hexane-AcOEt (17:3 v/v)] to afford ketoester 18 (1.763 g, 98 %) as a colorless oil.
IR (neat): 1735, 1714, 1235 cm-1.1H-NMR (400 MHz, CDCl
3)b: 4.08 (t, 2H, J = 6.7 Hz), 2.42-2.28 (m, 4H), 2.09-2.03 (m, 5H), 1.79-1.66 (m, 3H), 1.46-1.35 (m,
4H); 13C-NMR (100 MHz, CDCl
3) b: 211.7, 171.0, 64.5, 40.7, 35.7, 32.6, 31.8, 26.4, 21.0; MS m/z : 198 (M+), 43 (100%). HRMS Calcd. C
11H18O3 : 198.1255. Found : 198.1225.
3-(3-methyl-4-oxocyclohexyl)propionic acid ethyl ester (20): Pyrrolidine (1.02 ml, 12.2 mmol) was added to a mixture of ketoester 18 (1.72 g, 8.68 mmol) and molecular sieves 4Å (9.7 g) in benzene (26.3 ml) and the mixture was refluxed with removal of water using a Dean-Stark apparatus for 6 h. After cooling, the solvent and excess pyrrolidine were removed in vacuo to give a cude product 19. Benzene (14.0 ml) and iodomethane (0.580 ml, 9.32 ml) were added to this and the mixture was refluxed for 15 h. After cooling to room temperature, H2O (6.5 ml) and silica gel (650 mg) were added and the mixture was stirred for 3 h. Then, this mixture was poured into H2O and extracted with Et2O several times. The combined organic solution was washed with brine, dried
over MgSO4, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography [hexane-AcOEt (19:1-9:1 v/v)] to afford ester 20 (562 mg, 30 %) as a colorless oil and recover starting ketoester 18 (600 mg, 35 %).
IR (neat): 1738, 1711, 1247 cm-1.1H-NMR (400 MHz, CDCl
3) b: 4.10 (t, 2H, J = 6.7 Hz), 2.52 (m, 1H), 2.36 (m, 2H), 2.06 (s, 3H), 1.98-1.86 (m, 2H), 1.81-1.63 (m, 5H), 1.50 (m, 2H), 1.10 and 1.01 (each d, total 3H, J = 6.8 and 6.6 Hz); MS m/z : 212 (M+), 43 (100%). HRMS Calcd. C
12H20O3 : 212.1411. Found : 212.1404.
4-(3-hydroxypropyl)-2-methylcyclohexanol (21): A solution of ketoester 20 (462 mg, 2.18 mmol) in THF (7.5 ml) was dropped to a stirred suspention of LiAlH4 (207 mg, 5.44 mmol) in THF (8.6 ml) at 0 °C and the mixture was stirred for 12 h at room temperature. Then, H2O (5.4 ml) and 15% aqueous NaOH (5.4 ml) was added to the reaction mixture at 0 °C, and stirring was continued for 10 min at the same temperature. Additional H2O (16.2 ml) was added to the reaction mixture and further stirring was continued for 30 min at 0 °C . After addition of MgSO4, the mixture was filtered through a Celite pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [hexane-AcOEt (1:1 v/v)] to afford diol 21 (341 mg, 91 %) as a colorless oil.
IR (neat): 3348 cm-1;1H-NMR (400 MHz, CDCl
3)b: 3.71-3.02 (m, total 5H), 2.03-0.64 (m, total 15H); MS m/z : 172 (M+), 95 (100%). HRMS Calcd. C
10H20O2 : 172.1462. Found : 172.1437.
3-(3-methyl-4-oxocyclohexyl)propionaldehyde (1c): A solution of diol 21 (158 mg, 0.917 mmol) in CH2Cl2 (1.3 ml) was added to a stirred suspension of PCC (858 mg, 3.98 mmol) and molecular sieves 4Å (1.30 g) in CH2Cl2(6.7 ml) at 0 °C and the mixture was stirred for 1 h at room temperature. Then, Florisil® was added to the reaction mixture and stirring was continued for 10 min. After dilution with Et2O, the mixture was filtered through Florisil
® and concentrated under
reduced pressure. The residue was purified by silica gel column chromatography [hexane-AcOEt (17:3 v/v)] to afford ketoaldehyde 1c (85 mg, 55 %) as a colorless oil.
IR (neat): 1707 cm-1; 1H-NMR (400 MHz, CDCl
3) b: 9.82 and 9.80 (each t, total 1H, each J = 1.5 Hz), 2.56-2.34 (m, total 5H), 2.08-1.62 (m, total 7H), 1.10 and 1.01 (each t, total 3H, J = 7.1, 6.6 Hz) ; MS m/z : 168 (M+), 55 (100%). HRMS Calcd. C10H16O2 : 168.1149. Found : 168.1133.
3. References
(1) (a) Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537.(b) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596. (c) Nicolaou, K. C.; Montagnon, T.; Baran, P. S. Angew. Chem. Int. Ed. 2002, 41, 993.
(2) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4156. (b) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
(3) Mori, K.; Takayama, S.; Kido, M. Bioorg. Med. Chem. 1994, 2, 395. (4) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
(5) Nagata, H.; Miyazawa, N.; Ogasawara, K. Synthesis 2000, 2013. (6) Elliott, M. L.; Urban, F. J. J. Org. Chem. 1985, 50, 1752.
(7) Tamaki, M.; Han, G.; Hruby, V. J. J. Org. Chem. 2001, 66, 1038.
(8) Ohtake, H.; Imada, Y.; Murahashi, S. Bull. Chem. Soc. Jpn. 1999, 72, 2737. (9) (a) Remuzon, P.; Massoudi, M.; Bouzard, D.; Jacquet, J.-P. Heterocycles
PPM 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 2.33 1.00 2.28 9.89 7.45 7.2650 4.1493 4.1310 4.1133 4.0956 3.9638 2.3328 2.3139 2.2937 1.7226 1.7098 1.6994 1.6884 1.6170 1.6012 1.5810 1.5621 1.5389 1.5206 1.5084 1.4968 1.4236 1.4120 1.3992 1.3894 1.3687 1.3607 1.3412 1.3186 1.2857 1.2729 1.2546 1.2369 0.0000 -0.0024 OH CO 2Et H
PPM 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 OH CO2Et H S-19
PPM 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 2.00 0.97 1.00 1.98 1.97 2.01 2.03 6.02 2.03 4.1418 4.1235 4.1058 4.0875 3.5148 3.5038 3.4934 3.4763 3.2201 2.3186 2.2997 2.2795 1.9593 1.9361 1.7714 1.7549 1.7391 1.5506 1.5329 1.5128 1.4939 1.2669 1.2511 1.2493 1.2310 1.2200 1.2120 1.1870 1.0065 0.9986 0.9723 0.9656 0.9357 OH CO 2Et H
PPM 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 OH CO2Et H S-21
PPM 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.67 2.34 2.02 0.66 11.81 0.66 7.3089 3.9204 3.5898 3.5788 3.5190 2.7797 1.9611 1.9294 1.7781 1.7452 1.7000 1.6671 1.5530 1.5433 1.5329 1.5256 1.4841 1.3853 1.3621 1.3322 1.2999 1.2840 1.2407 1.2139 0.9851 0.9528 0.9241 CH 2OH OH
PPM 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 77.3210 77.0000 76.6790 70.8110 66.9099 62.8524 62.7784 36.4256 35.8824 35.2898 32.5492 31.9895 31.8414 31.1418 30.1789 30.0802 26.9033 CH 2OH OH
PPM 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 0.86 5.88 2.00 3.04 2.08 9.8077 9.8040 9.7997 7.2754 2.5512 2.5476 2.5323 2.5286 2.5140 2.5103 2.3694 2.3358 2.3224 2.3010 2.2864 2.0728 2.0655 2.0460 1.7604 1.7415 1.7153 1.6982 1.6799 1.6622 1.6445 1.4376 1.4096 0.0000 O CH O
PPM 220.0 210.0 200.0 190.0180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0
O
CHO
PPM 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 0.95 2.12 4.00 1.97 1.99 4.29 3.61 7.2656 5.6620 4.1731 4.1554 4.1377 4.1194 3.9760 3.9413 3.0156 2.9997 2.9826 2.3920 2.3761 2.3590 1.7952 1.7744 1.7616 1.7549 1.7384 1.6536 1.2942 1.2924 1.2765 1.2747 1.2588 1.2070 0.0000 -0.0024 CO 2Et O O
PPM 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0.0 166.3665 160.0062 114.2051 107.9025 77.3217 77.0000 76.6865 64.4031 59.5771 35.7444 34.9524 34.5812 26.0348 14.3122 CO 2Et O O
PPM 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 2.00 3.94 1.99 5.01 2.03 5.01 7.2650 4.1512 4.1329 4.1152 4.0975 3.9516 3.9376 3.9333 3.9284 2.2303 2.2126 1.8397 1.7513 1.7275 1.6445 1.6054 1.5926 1.5694 1.5597 1.5371 1.5279 1.3571 1.3498 1.3266 1.3205 1.2948 1.2832 1.2723 1.2546 1.2363 0.0000 CO 2Et O O
PPM 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0.0 CO2Et O O S-29
PPM 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 0.91 7.00 2.09 2.03 9.8138 9.8101 9.8064 7.2662 7.2650 2.4896 2.4872 2.4731 2.4688 2.4328 2.4127 2.4097 2.4054 2.3999 2.3901 2.3779 2.3627 2.1210 2.1168 2.1125 2.1094 2.1052 2.1009 2.0948 2.0795 2.0765 2.0722 2.0643 1.6390 1.5139 1.5084 1.4883 1.4785 1.4590 0.0000 O CHO
PPM 220.0 210.0 200.0 190.0180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0
O
CHO
PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 1.00 1.98 2.18 4.28 5.04 1.09 7.2625 3.8052 3.7911 3.7765 3.7625 2.7880 2.6617 2.5750 2.5555 2.5335 2.5152 2.5079 2.4926 2.3993 2.3853 2.3792 2.3657 2.3560 2.3486 2.3419 2.3364 2.3218 2.1711 2.1564 2.1326 2.1094 2.0673 1.9923 1.9831 1.9770 1.9654 1.9545 1.9453 1.7391 1.7287 1.7232 1.7146 1.7104 1.6982 1.6957 1.6835 1.6799 1.6750 1.6713 1.6634 1.6585 1.6494 1.4413 1.4248 1.4114 1.3943 1.3784 1.3644 1.3601 1.3485 1.3302 0.0000 O OH
PPM 220.0 210.0 200.0 190.0180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0
O OH
PPM 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 1.00 1.00 0.98 1.22 3.22 4.43 1.07 7.2998 4.6247 4.6137 4.6100 4.5990 4.5874 4.5728 3.4513 3.3976 2.7935 2.7807 2.7678 2.6812 2.6580 2.6507 2.6385 2.6281 2.6153 2.6086 2.5854 2.5683 2.4695 2.4512 2.4438 2.4347 2.4328 2.4255 2.4237 2.4170 2.4145 2.3926 2.3749 2.3505 2.3328 2.2669 2.2614 2.2498 2.0429 1.9441 1.9374 1.9307 1.9172 1.9111 1.9062 1.8971 1.8886 1.8257 1.8214 1.8092 1.7964 1.7897 1.7787 1.7744 1.7726 1.7568 1.7397 1.7262 1.7201 1.6951 1.6890 1.6677 1.5938 1.5871 1.5828 1.5761 1.5590 1.5493 1.5420 1.2576 0.0000 O OH
PPM 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 212.5059 212.4316 77.3217 77.0000 76.6865 73.9889 57.7787 36.5528 36.5363 36.4373 36.1239 33.4510 31.5784 O OH
PPM 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 1.00 0.97 0.96 1.02 3.22 3.27 7.2760 7.1967 7.1918 7.1802 7.1753 7.1710 7.1668 7.1552 7.1503 6.2225 6.1975 3.4233 3.4196 2.8731 2.8651 2.8584 2.8572 2.8505 2.6724 2.6638 2.6565 2.6480 2.6437 2.6406 2.6315 2.6230 2.6126 2.6034 2.5906 2.5717 2.4894 2.4759 2.4491 2.4357 2.2704 2.2588 2.2570 2.2448 2.2381 2.2356 2.2332 2.2246 2.2112 2.2045 2.2002 2.1929 2.1911 2.1795 2.1209 2.1136 2.1093 2.1020 2.0941 2.0898 2.0868 2.0825 2.0746 2.0673 2.0599 2.0551 2.0483 1.6878 0.0000 O O
PPM 220.0 210.0 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 202.3507 193.1443 152.4084 152.3589 129.0047 77.3135 77.0000 76.6783 63.0336 63.0089 35.7774 35.7279 34.7792 34.7215 34.6637 29.7800 29.7388 28.1796 28.1219 O O
PPM 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 0.98 0.93 2.00 5.10 1.04 3.30 3.24 7.2760 6.8508 6.8471 6.8441 6.8404 6.8252 6.8215 6.8185 6.8148 6.0182 6.0114 5.9919 5.9858 4.1827 4.1644 4.1467 4.1284 2.5357 2.5235 2.5052 2.4936 2.4814 2.4741 2.4674 2.4613 2.4503 2.4387 2.4192 2.4088 2.4003 2.3777 2.3655 2.3540 2.3350 2.3228 2.1618 2.1581 2.1490 2.1459 2.1368 2.1283 2.1246 2.1154 2.1124 1.9209 1.9044 1.8849 1.8684 1.8129 1.7934 1.7739 1.7586 1.7482 1.7385 1.7244 1.7141 1.7049 1.6921 1.6824 1.2907 1.2730 1.2547 O CO 2Et
PPM 220.0 210.0 200.0 190.0180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0
O
CO2Et
PPM 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 4.14 16.19 4.06 1.00 1.00 2.47 1.00 0.99 9.11 7.6055 7.5975 7.5896 7.5817 7.5780 7.5725 7.5695 7.5524 7.4364 7.4181 7.4114 7.4029 7.3998 7.3840 7.3687 7.3504 7.3345 7.3217 7.3107 7.3053 7.2943 7.2833 7.2766 7.2699 7.2613 7.2448 7.1509 7.1460 7.1375 5.1989 5.1677 5.1287 5.1049 5.0701 5.0567 4.9645 4.9340 4.9005 4.8694 4.6363 4.6173 4.5978 4.5478 4.5289 4.5093 4.4062 4.1249 4.1072 3.5904 3.5434 3.5318 3.5147 3.5044 3.5001 3.4824 3.4647 3.4580 3.4470 2.2809 2.2711 2.2608 2.2510 2.2394 2.2303 2.0387 1.9038 1.8867 1.8733 1.5859 1.2729 1.2552 1.2369 1.2228 1.2051 1.1880 1.0257 1.0141 0.0000 N Cbz CO 2Bn TB D PSO
PPM 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 172.2154 172.0422 154.8750 154.1326 136.4210 136.3137 135.3815 135.1753 133.2037 133.0717 133.0304 132.9067 129.7884 129.7719 129.7471 128.3365 128.2705 128.2375 128.1220 128.0395 127.9322 127.8910 127.7755 127.7590 127.6683 127.6518 127.6188 77.3217 77.0000 76.6865 71.3739 70.5902 66.9851 66.7377 66.6057 58.1912 57.9602 54.9327 54.4954 39.5144 38.6235 26.7772 26.7360 18.9897 N Cbz CO 2Bn TB D PSO
PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 4.22 6.14 1.24 1.00 3.91 1.00 1.00 9.31 7.6666 7.6550 7.6507 7.6470 7.6391 7.6354 7.4859 7.4676 7.4609 7.4530 7.4499 7.4457 7.4371 7.4194 7.4030 4.8706 4.5936 4.2867 4.2672 4.2623 4.2428 3.3330 3.3232 3.3037 3.3000 3.2957 3.2152 3.2115 3.1847 3.1810 2.3444 1.9374 1.0899 N H CO 2H TB D PSO
PPM 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 173.5755 136.6590 136.6425 133.8954 133.8377 131.1896 128.9293 73.9547 61.5310 54.4859 49.6352 49.4290 49.2145 49.0000 48.7855 48.5793 48.3648 39.7936 27.3864 19.8463 N H CO 2H TB D PSO
PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 20.11 4.00 1.99 2.00 2.00 9.00 7.6230 7.6206 7.6151 7.6121 7.6035 7.6005 7.5950 7.4413 7.4376 7.4248 7.4193 7.4077 7.4041 7.3790 7.3699 7.3595 7.3510 7.3424 7.3284 7.3168 7.3040 7.2967 7.2845 7.2802 7.2705 7.2656 7.2625 7.2509 7.2430 7.2351 5.1910 5.1630 5.1471 5.1318 5.1148 5.1020 5.0812 5.0037 4.9720 4.5042 4.4914 4.4224 4.4127 4.4005 4.3907 4.3279 4.3193 4.3096 3.5794 3.5684 3.5032 3.4959 3.4849 3.4721 2.2564 2.2466 2.2368 2.2283 2.2167 2.2069 2.1941 2.1740 1.6397 1.0303 1.0236 0.0000 N Cb z TB D P S O CO 2Bn
PPM 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 171.4565 171.1512 154.6770 154.1986 136.5282 136.3055 135.5630 135.5300 135.4228 133.1707 133.1212 132.9644 129.7801 129.6894 128.3942 128.3695 128.2870 128.2375 128.0807 127.9900 127.9322 127.8003 127.7590 127.7178 127.6930 127.6765 127.6435 127.5940 77.3217 77.2062 77.0000 76.6865 71.6048 70.6562 67.0346 66.9521 66.9109 66.7789 58.0262 57.7705 54.8502 54.4459 39.2587 38.3595 26.7442 19.0145 N Cb z TB D P S O CO 2Bn
PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 4.15 6.10 1.00 0.90 1.82 0.98 1.95 9.20 7.6645 7.6608 7.6584 7.6547 7.6450 7.6407 7.6346 7.4797 7.4760 7.4614 7.4577 7.4479 7.4437 7.4400 7.4321 7.4284 7.4138 7.4101 7.3973 7.3930 4.8732 4.5029 4.2504 4.2327 3.3549 3.3244 3.3085 3.3043 3.3000 3.2963 3.2921 3.1951 3.1859 3.1646 3.1554 2.9340 2.4039 2.3692 2.3204 2.3100 2.2850 1.0558 1.0467 1.0131 N H TB D P S O CO 2H
PPM 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 172.2556 136.7580 136.7168 133.8377 133.6562 131.1814 131.1566 128.9045 72.8905 60.0543 54.9809 49.6435 49.4290 49.4042 49.2145 49.1897 49.0000 48.9753 48.7855 48.7608 48.5793 48.5545 48.3648 48.3400 38.9521 27.2791 19.8133 19.7968 N H TB D PSO CO 2 H
PPM 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 2.00 4.06 4.98 3.25 3.99 7.2808 4.0932 4.0767 4.0596 2.3682 2.3554 2.3377 2.3242 2.0838 2.0765 2.0576 2.0435 1.7330 1.7159 1.6970 1.6890 1.6762 1.4291 1.4157 1.4083 1.3900 1.3693 1.3516 0.0000 O CO 2Et
PPM 220.0 210.0 200.0 190.0180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0
O
CO2Et
PPM 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 2.00 3.02 3.14 7.04 1.88 3.02 7.3046 4.1133 4.0968 4.0798 4.0700 2.5476 2.5305 2.5134 2.4963 2.3822 2.3669 2.3627 2.3480 2.3334 2.0625 2.0545 1.9728 1.9532 1.9423 1.9258 1.9136 1.9038 1.8977 1.8867 1.8794 1.8696 1.8593 1.8062 1.7921 1.7738 1.7580 1.7433 1.7269 1.7067 1.6994 1.6866 1.6707 1.6524 1.6353 1.5291 1.5115 1.4992 1.4889 1.4724 1.1087 1.0916 1.0172 1.0007 0.0000 O CO 2Et
PPM 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 5.00 14.71 7.3681 3.7051 3.6947 3.6825 3.6679 3.6575 3.5764 3.5605 3.5447 3.5276 3.2525 2.0130 1.7556 1.7183 1.6824 1.6421 1.6189 1.6110 1.6006 1.5622 1.5427 1.5280 1.5036 1.4737 1.3554 1.3383 1.3164 1.2999 1.2273 1.2120 1.1870 1.1730 1.1504 0.9912 0.9748 0.9607 0.9430 0.9394 0.9211 CH 2OH OH
PPM 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 0.82 4.81 6.97 3.00 9.8272 9.8235 9.8199 7.2668 2.5604 2.5567 2.5415 2.5232 2.5195 2.5110 2.3895 2.3749 2.3700 2.3627 2.3602 2.3590 2.3554 2.3444 1.9575 1.9465 1.9435 1.9288 1.9142 1.8965 1.8855 1.8782 1.8684 1.8172 1.7982 1.7805 1.7690 1.7659 1.7629 1.7519 1.7378 1.7348 1.7208 1.7177 1.7098 1.7067 1.7012 1.6976 1.6902 1.6872 1.6774 1.6579 1.6439 1.6249 1.1087 1.0910 1.0227 1.0062 0.0000 O CH O
