Electronic Supplementary Material (ESI) for RSC Advances. This journal is © The Royal Society of Chemistry 2014
Conformationally restricted glutamic acid
analogues: stereoisomers of
1-aminospiro[3.3]heptane-1,6-dicarboxylic acid
Anton V. Chernykh, a, b Dmytro S. Radchenko, a, c Oleksandr O. Grygorenko, c
Dmitriy M. Volochnyuk, b Svitlana V. Shishkina, d Oleg V. Shishkin d and Igor V. Komarov c, *
a Enamine Ltd., Alexandra Matrosova Street 23, Kyiv 01103, Ukraine
b Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska 5, Kyiv
02660, Ukraine
c Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine
E-mail: [email protected]
d STC “Institute for Single Crystals”, National Academy of Sciences of Ukraine, 60 Lenina ave.,
61001 Kharkiv, Ukraine
S1
Table of contents.
1. 1H NMR spectrum of the compound 8 S5
2. 13 C NMR spectrum of the compound 8 S6
3. 1H NMR spectrum of the compound 13 S7
4. 13 C NMR spectrum of the compound 13 S8
5. 31 P NMR spectrum of the compound 13 S9
6. 1H NMR spectrum of the compound 15 S10
7. 13 C NMR spectrum of the compound 15 S11
8. 1H NMR spectrum of the compound 9 S12
9. 13 C NMR spectrum of the compound 9 S13
10. 1H NMR spectrum of the compound 11a S14
11. 13 C NMR spectrum of the compound 11a S15
12. NOE spectrum of the compound 11a S16
13. HMBC spectrum of the compound 11a S17
14. 1H-1H COSY spectrum of the compound 11a S18
15. NOESY spectrum of the compound 11a S19
16. NOESY spectrum of the compound 11a (fragment) S20
17. 1H NMR spectrum of the compound 11b S21
18. 13 C NMR spectrum of the compound 11b S22
19. NOE spectrum of the compound 11b S23
20. 1H-1H COSY spectrum of the compound 11b S24
21. HMBC spectrum of the compound 11b S25
22. NOESY spectrum of the compound 11b S26
23. NOESY spectrum of the compound 11b (fragment) S27
24. 1H NMR spectrum of the compound 16a S28
25. 13 C NMR spectrum of the compound 16a S29
S2
26. 1H NMR spectrum of the compound 16b S30
27. 13 C NMR spectrum of the compound 16b S31
28. 1H NMR spectrum of the compound 16c S32
29. 13 C NMR spectrum of the compound 16c S33
30. 1H NMR spectrum of the compound 16d S34
31. 13 C NMR spectrum of the compound 16d S35
32. 1H NMR spectrum of the compound 1a ⋅HCl S36
33. 13 C NMR spectrum of the compound 1a ⋅HCl S37
34. 1H NMR spectrum of the compound 1b ⋅HCl S38
35. 13 C NMR spectrum of the compound 1b ⋅HCl S39
36. 1H NMR spectrum of the compound 1c ⋅HCl S40
37. 13 C NMR spectrum of the compound 1c ⋅HCl S41
38. 1H NMR spectrum of the compound 1d ⋅HCl S42
39. 13 C NMR spectrum of the compound 1d ⋅HCl S43
40. 1H NMR spectrum of the compound 18a S44
41. 13 C NMR spectrum of the compound 18a S45
42. 1H NMR spectrum of the compound 18b S46
43. 13 C NMR spectrum of the compound 18b S47
44. 1H NMR spectrum of the compound 18c S48
45. 13 C NMR spectrum of the compound 18c S49
46. 1H NMR spectrum of the compound 18d S50
47. 13 C NMR spectrum of the compound 18d S51
48. 13 C DEPT spectrum of the compound 18d S52
49. 1H NMR spectrum of the compound 19 c S53
50. 13 C NMR spectrum of the compound 19 c S54
51. Stereochemical assignments of 1a -d S55
S3
52. Table S1. Crystallographic data and experimental parameters S56
for the compound 13 and 18a-c
53. ORTEP diagrams of the compounds 18a–c S57
S4
1H NMR spectrum of the compound 8
S5
13С NMR spectrum of the compound 8
S6
1H NMR spectrum of the compound 13
S7
13С NMR spectrum of the compound 13
S8
31 P NMR spectrum of the compound 13
S9
1H NMR spectrum of the compound 15
S10
13C NMR spectrum of the compound 15
S11
1H NMR spectrum of the compound 9
S12
13С NMR spectrum of the compound 9
S13
1H NMR spectrum of the compound 11a
S14
13C NMR spectrum of the compound 11a
S15
NOE spectrum of the compound 11a
S16
HSQC spectrum of the compound 11a
S17
1H-1H COSY spectrum of the compound 11a
S18
NOESY spectrum of the compound 11a
S19
NOESY spectrum of the compound 11a (fragment)
S20
1H NMR spectrum of the compound 11b
S21
13C NMR spectrum of the compound 11b
S22
NOE spectrum of the compound 11b
S23
1H-1H COSY spectrum of the compound 11b
S24
HSQC spectrum of the compound 11b
S25
NOESY spectrum of the compound 11b
S26
NOESY spectrum of the compound 11b (fragment)
S27
1H NMR spectrum of the compound 16a
S28
13C NMR spectrum of the compound 16a
S29
1H NMR spectrum of the compound 16b
S30
13C NMR spectrum of the compound 16b
S31
1H NMR spectrum of the compound 16c
S32
13C NMR spectrum of the compound 16c
S33
1H NMR spectrum of the compound 16d
S34
13C NMR spectrum of the compound 16d
S35
1H NMR spectrum of the compound 1a ⋅HCl
S36
13C NMR spectrum of the compound 1a ⋅HCl
S37
1H NMR spectrum of the compound 1b⋅HCl
S38
13C NMR spectrum of the compound 1b⋅HCl
S39
1H NMR spectrum of the compound 1c⋅HCl
S40
13C NMR spectrum of the compound 1c⋅HCl
S41
1H NMR spectrum of the compound 1d⋅HCl
S42
13C NMR spectrum of the compound 1d⋅HCl
S43
1H NMR spectrum of the compound 18a
S44
13C NMR spectrum of the compound 18a
S45
1H NMR spectrum of the compound 18b
S46
13C NMR spectrum of the compound 18b
S47
1H NMR spectrum of the compound 18c
S48
13C NMR spectrum of the compound 18c
S49
1H NMR spectrum of the compound 18d
S50
13C NMR spectrum of the compound 18d
S51
13C DEPT spectrum of the compound 18d
S52
1H NMR spectrum of the compound 19c
S53
13C NMR spectrum of the compound 19c
S54
Stereochemical assignments of 1a-d
The stereochemical assignment of the final compounds 1a-d was done basing on several experiments: 1D- and 2D-NOESY for compounds 11a ,b (see above) and X-ray diffractional studies of three purposely synthesized compounds 18a -c.
Before performing the NOE studies, we assigned the NMR signals in the spectra of 11a ,b using APT, HSQC, H,H-COSY experiments (see the spectra above). The H2 proton (which gives NMR signal at 3.15 ppm for 11a, 3.08 ppm for 11b ), assigned reliably by its correlation with the C2 in the HSQC (the only tertiary carbon atom, 32.8 ppm for 11a, 31.9 ppm for 11b) was irradiated; NOE effect was observed for the proton with the chemical shift 2.54 ppm for 11a and 2.19-2.34 ppm for 11b . At the same time, strong NOE correlation was observed in the 2D-NOESY spectra for H7 (1.97 ppm (11 а) and 2.11 ppm ( 11b)): with the signals H1b in 11a (2.33 ppm) and H3b in 11b (2.19-2.34 ppm). From these data we concluded that signals at 2.54 ppm ( 11 а) and 2.63-2.77 ppm ( 11b) correspond to Н1а and Н3а. Hence, the keto-ester 11a is the trans -isomer, because its H2 proton reveals strong NOE with Н1а and Н3а. Compound 11b is the cis -isomer, because its H2 proton shows strong NOE with Н1b and Н3b.
The crystallographic data, experimental parameters and CCDB deposition numbers are listed in Table S1. ORTEP diagrams of the compounds 18a–c illustrate the absolute configuration of the stereocenters in these compounds.
Ideally, X-Ray analysis of all the four derivatives 18a -d would give us enough information regarding the stereochemistry of 1a -d, because compounds 16a -d bear chiral auxiliary with the defined absolute configuration and transformed both into 1a -d and 18a -d without racemization at the stereocenters. However, compound 18d did not give crystals suitable for the X-Ray study. Its absolute stereoconfiguration was deduced using the following reasoning. Compound 18d is the only diastereomer of the four possible (the chiral auxiliary group was derived from the S-α-phenylglycinol for all the diastereomers); its absolute configuration at one of the stereocenter C2 (2 S) should be the same as in its precursor 11b , determined by 1D- and 2D-NOESY experiments. The other stereocenter C5 must have the stereoconfiguration reverse to that in its diastereomer 18c , thus, 5 S.
S55
Table S1 Crystallographic data and experimental parameters for the compound 13 and 18a–c
Parameter 13 18a 18b 18c a, Å 8.9199(4) 6.0940(5) 6.1255(6) 10.260(3) b, Å 18.9724(8) 15.418(2) 11.218(1) 5.820(2) c, Å 17.167(1) 17.637(2) 24.188(2) 14.060(4) α, deg 90.0 90.0 90.0 90.0 β, deg 100.522(5) 90.0 90.0 98.37(3) γ, deg 90.0 90.0 90.0 90.0 V, Å 3 2856.4(3) 1657.1(3) 1662.1(3) 830.6(5) T, K 293(2) 293(2) 293(2) 293(2) F(000) 1132 672 672 336 Crystal system Monoclinic Rhombic Rhombic Monoclinic
Space group P21/n Р212121 Р212121 Р21 Z 2 4 4 2 µ, mm -1 0.307 0.089 0.089 0.089 3 dcalc , g/cm 1.256 1.264 1.260 1.261
2Θmax , deg 50 60 60 60 Reflection measured 19720 8562 13719 7469 Reflections independent 5018 4455 4755 4370
Rint 0.023 0.071 0.102 0.155 Reflections with F>4 σ(F) 3827 1524 1883 836
R1 0.098 0.048 0.055 0.066
wR 2 0.285 0.064 0.084 0.159 S 1.227 0.793 0.840 0.696 CCDC deposition number 962474 962475 962476 962477
S56
ORTEP diagrams of the compounds 18a–c
18a 18b 18c
S57