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Hydroxy[4-(propan-2-yl)phenyl]acetic acid rac-2d. 1. H NMR Spectrum of rac-2d (400 MHz, CDCl3). 13. C NMR Spectrum of rac-2d (100 MHz, CDCl3) ...

Eur. J. Org. Chem. 2017 · ISSN 1099–0690 https://doi.org/10.1002/ejoc.201700161 SUPPORTING INFORMATION Title: Chemoenzymatic Preparation of Enantiomerically Enriched (R)-(–)-Mandelic Acid Derivatives: Application in the Synthesis of the Active Agent Pemoline Author(s): Marcin Poterała,* Maciej Dranka, Paweł Borowiecki*

Table of contents X-ray diffraction data (Table S1)…………………………………............………………… S2 Table S2. Analytical separation conditions of different compounds by Chiralcel OD-H (Diacel) chiral column …………………………………………...………....................… S3-S4 Copies

of

NMR,

HRMS,

IR,

UV/VIS

spectra

and

HPLC

chromatograms

……….……………………………………..……………………………………....….. S5-S37

S1

X-ray crystallography

Table S1. Crystal data and structure refinement parameters for (R)-(–)-11. Compound Chemical formula M /g·mol−1 Crystal size /mm3 T /K Crystal system

(R)-(–)-11 C20H26F6NO3P 473.39 0.32 × 0.15 × 0.1 100.0(1) orthorhombic

Space group P212121 a /Å 6.11283(16) b /Å 10.7206(3) c /Å 32.3877(5) α,β,γ /° 90 3 V /Å 2122.47(8) Z 4 −3 Dcalc /g·cm 1.481 Radiation, λ/ Å CuKα (λ = 1.5418) −1 μ /mm 1.841 F(000) 984.0 2Θ Range /° 8.68–133.22° Reflections collected 17547 Independent refln. 3752 Rint 0.0352 Parameters/restraints 284/0 S (F2)[a] 1.053 [b] R1, wR2 (I>2σ(I)) 0.0270, 0.0661 R1, wR2 (all data) 0.0290, 0.0673 −3 Δρmin/max/eÅ +0.15/−0.28 Flack parameter −0.004(18) [a] Goodness-of-fit S={[w(Fo2−Fc2)2]/(n−p)}1/2 where n is the reflections number and p is the parameters number; [b] R1=||Fo|−|Fc||/|Fo|, wR2={[w(Fo2−Fc2)2]/[w(Fo2)2]}1/2.

S2

Table S2. Analytical separation conditions of different compounds by Chiralcel OD-H (Diacel) chiral column. Compound

Ratio of n-hexane to 2-propanol

Elution velocity [mL/min]

Retention time [min]

0.8

8.939 (S) and 14.612 (R)

0.4

22.997 (S) and 24.383 (R)

0.8

9.185 (S) and 12.946 (R)

0.25

34.677 (S) and 36.610 (R)

90:10a

0.8

8.939 (S) and 14.612 (R)

99:1a

0.25

21.782 (S) and 23.480 (R)

95:5a

0.8

11.062 (S) and 13.837 (R)

99:1a

0.4

18.176 (S) and 19.740 (R)

95:5a

0.8

10.437 (S) and 12.668 (R)

90:10

99:1

a

90:10

99:1

a

a

a

S3

99:1a

0.4

17.587 (S) and 19.371 (R)

90:10a

0.7

14.707 (S) and 24.420 (R)

0.4

22.440 (S) and 27.504 (R)

90:10a

0.8

14.588 (S) and 17.379 (R)

98:2a

0.2

55.647 (S) and 61.512 (R)

N.R.b

N.R.b

N.R.b

N.R.b

N.R.b

N.R.b

0.8

32.816 (R) and 40.669 (S)

96:4

a

90:10

c

a

The samples were carried out at 254 nm and at 30 °C. Not resolvable. c The samples were carried out at 215 nm and at 30 °C. b

S4

Hydroxy(4-methylphenyl)acetic acid rac-2b

1

H NMR Spectrum of rac-2b (400 MHz, CDCl3)

13

C NMR Spectrum of rac-2b (100 MHz, CDCl3)

S5

Hydroxy(3-methylphenyl)acetic acid rac-2c

1

H NMR Spectrum of rac-2c [500 MHz, (CD3)2SO]

13

C NMR Spectrum of rac-2c [126 MHz, (CD3)2SO]

S6

Hydroxy[4-(propan-2-yl)phenyl]acetic acid rac-2d

1

H NMR Spectrum of rac-2d (400 MHz, CDCl3)

13

C NMR Spectrum of rac-2d (100 MHz, CDCl3)

S7

(4-Tert-butylphenyl)(hydroxy)acetic acid rac-2e

1

H NMR Spectrum of rac-2e (400 MHz, CDCl3)

13

C NMR Spectrum of rac-2e (100 MHz, CDCl3)

S8

Hydroxy(4-methoxyphenyl)acetic acid rac-2f 1

H NMR Spectrum of rac-2f [500 MHz, (CD3)2SO]

13

C NMR Spectrum of rac-2f [126 MHz, (CD3)2SO]

S9

Hydroxy(naphthalen-2-yl)acetic acid rac-2g 1

H NMR Spectrum of rac-2g (400 MHz, CD3COCD3)

13

C NMR Spectrum of rac-2g (100 MHz, CD3COCD3)

S10

Hydroxy(naphthalen-1-yl)acetic acid rac-2h 1

H NMR Spectrum of rac-2h [500 MHz, (CD3)2SO]

13

C NMR Spectrum of rac-2h [126 MHz, (CD3)2SO]

S11

Methyl hydroxy(phenyl)acetate rac-3a 1

H NMR Spectrum of rac-3a (400 MHz, CDCl3)

13

C NMR Spectrum of rac-3a (100 MHz, CDCl3)

S12

Methyl hydroxy(4-methylphenyl)acetate rac-3b 1

H NMR Spectrum of rac-3b (400 MHz, CDCl3)

13

C NMR Spectrum of rac-3b (100 MHz, CDCl3)

S13

Methyl hydroxy(3-methylphenyl)acetate rac-3c 1

H NMR Spectrum of rac-3c (400 MHz, CDCl3)

13

C NMR Spectrum of rac-3c (100 MHz, CDCl3)

S14

Methyl hydroxy[4-(propan-2-yl)phenyl]acetate rac-3d 1

H NMR Spectrum of rac-3d (400 MHz, CDCl3)

13

C NMR Spectrum of rac-3d (100 MHz, CDCl3)

S15

Methyl (4-tert-butylphenyl)(hydroxy)acetate rac-3e 1

H NMR Spectrum of rac-3e (400 MHz, CDCl3)

13

C NMR Spectrum of rac-3e (100 MHz, CDCl3)

S16

Methyl hydroxy(4-methoxyphenyl)acetate rac-3f 1

H NMR Spectrum of rac-3f (500 MHz, CDCl3)

13

C NMR Spectrum of rac-3f (100 MHz, CDCl3)

S17

Methyl hydroxy(naphthalen-2-yl)acetate rac-3g 1

H NMR Spectrum of rac-3g (500 MHz, CDCl3)

13

C NMR Spectrum of rac-3g (126 MHz, CDCl3)

S18

Methyl hydroxy(naphthalen-1-yl)acetate rac-3h 1

H NMR Spectrum of rac-3h (400 MHz, CDCl3)

13

C NMR Spectrum of rac-3h (100 MHz, CDCl3)

S19

Methyl (acetyloxy)(phenyl)acetate rac-4a 1

H NMR Spectrum of rac-4a (500 MHz, CDCl3)

13

C NMR Spectrum of rac-4a (126 MHz, CDCl3)

S20

Methyl (acetyloxy)(4-methylphenyl)acetate rac-4b 1

H NMR Spectrum of rac-4b (400 MHz, CDCl3)

13

C NMR Spectrum of rac-4b (100 MHz, CDCl3)

S21

Methyl (acetyloxy)(3-methylphenyl)acetate rac-4c 1

H NMR Spectrum of rac-4c (400 MHz, CDCl3)

13

C NMR Spectrum of rac-4c (100 MHz, CDCl3)

S22

Methyl (acetyloxy)[4-(propan-2-yl)phenyl]acetate rac-4d 1

H NMR Spectrum of rac-4d (400 MHz, CDCl3)

13

C NMR Spectrum of rac-4d (100 MHz, CDCl3)

S23

Methyl (acetyloxy)(4-tert-butylphenyl)acetate rac-4e 1

H NMR Spectrum of rac-4e (500 MHz, CDCl3)

13

C NMR Spectrum of rac-4e (126 MHz, CDCl3)

S24

Methyl (acetyloxy)(4-methoxyphenyl)acetate rac-4f 1

H NMR Spectrum of rac-4f (400 MHz, CDCl3)

13

C NMR Spectrum of rac-4f (100 MHz, CDCl3)

S25

Methyl (acetyloxy)(naphthalen-2-yl)acetate rac-4g 1

H NMR Spectrum of rac-4g (500 MHz, CDCl3)

13

C NMR Spectrum of rac-4g (126 MHz, CDCl3)

S26

Methyl (acetyloxy)(naphthalen-1-yl)acetate rac-4h: 1

H NMR Spectrum of rac-4h (500 MHz, CDCl3)

13

C NMR Spectrum of rac-4h (126 MHz, CDCl3)

S27

2-Imino-5-phenyl-1,3-oxazolidin-4-one (Pemoline) rac-5b: 1

H NMR Spectrum of rac-5b [500 MHz, (CD3)2SO)]

13

C NMR Spectrum of rac-5b [126 MHz, (CD3)2SO)]

S28

HRMS spectrum of (R)-(+)-5 (ESI-TOF)

IR spectrum of rac-5 (Mineral oil, Nujol)

130

100

%T 50

0 4000

3000

2000

Wavenumber [cm-1] S29

1000

596

UV spectra of rac-5

Wavelength (nm) Abs ________________________________ 223.00 4.172 221.00 4.365 217.00 4.389 215.00 4.549 211.00 4.405 209.00 4.256

S30

HPLC analytical separation for both enantiomers of rac-5

HPLC chromatogram of optically active pemoline (R)-(+)-5 (98% ee)

S31

HPLC chromatogram of enantiomerically pure pemoline (R)-(+)-5 (>99% ee) obtained after two recrystallizations from EtOH

HPLC chromatograms of the optimization of the synthesis of pemoline (R)-(+)-5

S32

S33

S34

HPLC chromatograms of (R)-(+)-5 methanolic solution stored for 1, 4, and 8 days

S35

S36

1‐(2‐{[(2R)‐2‐(4‐Tert‐butylphenyl)‐2‐methoxyacetyl]oxy}ethyl)pyridin‐1‐ium hexafluoro-phosphate (R)-(-)-11: 1

H NMR Spectrum of (R)-(-)-11 (400 MHz, CD3COCD3)

13

C NMR Spectrum of (R)-(-)-11 (100 MHz, CD3COCD3)

S37