Enzymatic Synthesis of Enantiopure Precursors of Chiral Bidentate and Tridentate Phosphorus Catalysts
uct 13 as a diastereomer mixture; yield: 6.189 g (98%).
31P NMR (CDCl3): d=32.50, 32.89, 33.08. The crude product
was used in the ensuing reaction.
Synthesis of (+)-(S)-19: A mixture of (+)-(S)-18 (291 mg,
0.735 mmol) and sodium iodide (441 mg, 2.939 mmol) in
acetone (10 mL) was stirred overnight at room temperature
(TLC control: CH2Cl2:acetone 3:2). Acetone was removed
under vacuum, the residue was dissolved in dichloromethane
and washed with H2O and an aqueous solution of Na2S2O3.
The organic layer was dried with MgSO4 and evaporated.
The crude product was purified by preparative TLC
(CH2Cl2:acetone 3:2) to give pure 19; yield: 179 mg (57%);
[a]D: +24.51 (c 1.22, CHCl3); ee=86%. 31P NMR (CDCl3):
Synthesis of Bis-(2-hydroxymethylphenyl)methyl-
phosphine Oxide (14)
To 13 (6.397 g, 0.0144 mol) was added BH3/Me2S (2M in
THF, 29.4 mL, 0.3312 mol; 23 equiv.) and the solution was
stirred at room temperature for 50 h. The reaction was
quenched by a slow addition of 5% K2CO3 (12 mL). The or-
ganic solvents were evaporated, water was added and the
mixture was extracted with chloroform (3ꢂ50 mL). The
combined organic layers were dried over MgSO4, the sol-
vent was evaporated and the residue was purified by column
chromatography using dichloromethane/acetone in gradient
from 10:1 to 1:1 to afford 14; yield: 2.39 g (60%); white
powder; m.p. 153–1558C. 1H NMR (CDCl3): d=1.2 (br. s,
2H), 2.16 (d, J=13.22 Hz, 3H), 4.60–4.80 (AB, 4H), 7.23–
7.69 (m, 8H, Ar-H); 31P NMR (CDCl3): d=42.49; MS (CI):
m/z=277 (M+H); HR-MS (FAB): m/z=277.09893, calcd.
for C15H18PO3 (M+H), 277.099358; anal. calcd. for
C15H17O3P: C 65.22, H 6.16, P 11.23, O 17.39; found: C
65.03, H 6.11, P 10.97, O 17.51.
1
d=34.17; H NMR (CDCl3): d=1.88 (s, 3H, Ac), 2.18 (d,
J=13.24 Hz, 3H, P-Me), 4.97 (AB, 2H, CH2I), 5.34 (d, J=
2.52 Hz, 2H, CH2OAc), 7.30–7.68 (m, 8H, aromat.); MS
(CI): m/z=429 (M+H); HR-MS: m/z=429.011653, calcd.
for C17H19IPO3: 429.01055.
Synthesis of (À)-(R)-20: A mixture of (+)-(S)-19 (164 mg,
0.735 mmol), AIBN (a few milligrams) and Bu3SnH
(133 mg, 0.460 mmol) in dry benzene (20 mL) was refluxed
for 6 days [TLC (CH2Cl2:acetone 3:2) and 31P NMR con-
trol]. After evaporation of the solvent the residue was puri-
fied by preparative chiral HPLC [CYCLOBOND DMT
hexane (i-PrOH-EtOH 4:1) 15%; flow 3.6 mLminÀ1] to give
pure 20; yield: 46 mg (40%); [a]D: À7.31 (c 1.34, CHCl3);
1
ee=100%. 31P NMR (CDCl3): d=32.76; H NMR (CDCl3):
1
Spirophosphorane 15: H NMR (CDCl3): d=1.96 (d, J=
d=1.93 (s, 3H, Ac), 2.11 (d, J=13.12 Hz, 3H, P-Me), 2.34
(s, 3H, CH3), 5.29 (AB, 2H, CH2OAc), 7.30–7.68 (m, 8H,
aromat.); MS (CI): m/z=303 (M+H); HR-MS: m/z=
303.115008, calcd. for C17H20PO3 303.11598.
16.33 Hz, 3H), 4.88–5.22 (m, 4H), 7.25–7.56 (m, 6H, Ar-H),
8.08 (m, 2H); 31P NMR (CDCl3): d=À30.19; MS (CI): m/
z=259 (M+H).
Synthesis of (À)-(R)-21: To a solution of (À)-(R)-20
(22 mg, 0.073 mmol) in MeOH (2 mL) was added NaOMe
(a few milligrams in methanol) and the mixture was stirred
at room temperature for several minutes until the substrate
disappeared (TLC control: CH2Cl2:acetone 3:2). After evap-
oration of the solvent the residue was purified by prepara-
tive TLC (CH2Cl2:acetone 3:2) to give pure 21; yield:12 mg
(60%); [a]D: À9.56 (c 1.13, CHCl3); ee=100%. 31P NMR
(CDCl3): d=38.54; 1H NMR (CDCl3): d=2.10 (d, J=
13.10 Hz, 3H, P-Me), 2.43 (s, 3H, CH3), 4.71(d, J=7.5 Hz,
2H, CH2OH), 5.82 (t, J=7.52 Hz, 1H, OH), 7.18–7.75 (m,
8H, aromat.); MS (CI): m/z=261 (M+H); HR-MS: m/z=
261.104444, calcd. for C15H18PO2: 261.10391.
Enzymatic Desymmetrization of Bis-(2-hydroxy-
methylphenyl)methylphosphine Oxide (14)
To the diol 14 (2.12 g, 7.69 mmol), dissolved in CH2Cl2
(50 mL), were added pyridine (1.86 mL, 23.07 mmol,
3 equiv), CAL-B (immobilized, Novozym 435; 500 mg) and
vinyl acetate (5 mL). The mixture was stirred at room tem-
perature and the reaction was monitored by 31P NMR. After
5 days the enzyme was filtered off, the solvents were evapo-
rated and the crude reaction mixture was purified by
column chromatography using CH2Cl2/acetone in gradient
from 10:1 to 1:1 to give pure (À)-(R)-17 as an oil; yield:
1.96 g (80%); [a]D: À6.6; ee> 98% (for other examples see
Table 2). 1H NMR (CDCl3): d=1.88 (s, 3H), 2.13 (d, J=
13.24 Hz, 3H), 4.55–4.73 (m, 2H), 5.39–5.51 (m, 2H), 7.26–
7.55 (m, 8H, Ar-H); 31P NMR (CDCl3): d=38.62; MS (CI):
m/z=319 (M+H); HR-MS (CI): m/z=319.109170, calcd.
for C17H20PO4 (M+H): 319.109923.
Crystallographic Data
See Supporting Information. Crystallographic data for (À)-
(S)-6 and (À)-(R)-21 have been deposited with the Cam-
bridge Crystallographic Data Centre as entries CCDC
785937 and CCDC 810782, respectively. These data can be
obtained free of charge from The Cambridge Crystallo-
cif.
Chemical Correlations
Synthesis of (+)-(S)-18: To
a
solution of (À)-(R)-17
(263 mg,0.826 mmol, [a]D: À5.88 (c 1.7, acetone; ee=86%)
in dichlorometane (10 mL) were added methanesulfonic an-
hydride (288 mg, 1.653 mmol) and triethylamine (167 mg,
1.653 mmol) and the mixture was stirred at room tempera-
ture for 3 h [TLC (CH2Cl2:acetone 3:2) and 31P NMR con-
trol]. Then the solution was washed with water and dried
with MgSO4. The solvent was evaporated to give pure 18;
yield: 311 mg (95%); [a]D: +24.75 (c 1.6, CHCl3); ee=86%.
Acknowledgements
1
31P NMR (CDCl3): d=35.44; H NMR (CDCl3): d=1.85 (s,
Financial support by the Polish Ministry of Science and
Higher Education, grant No N204 131 140 (for P. K.), is
gratefully acknowledged. J.B. would like to thank Dr. Grze-
3H, Ac), 2.14 (d, J=13.23 Hz, 3H, P-Me), 2.99 (s, 3H,
CH3SO2), 5.37 (s, 2H, CH2OAc), 5.68 (AB, 2H, CH2OMs),
7.31–7.62 (m, 8H, aromat.).
´
gorz M. Salamonczyk (CMMS PAS) for helpful discussions.
Adv. Synth. Catal. 2011, 353, 2446 – 2454
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2453