Synthesis of Enantiomerically Enriched Dimers of Vinylphenols by Tandem Action of Laccases and Lipases
water phase was extracted with AcOEt. Following drying by
sodium sulfate addition, the solvent was evaporated under
reduced pressure and the crude residue was purified by
flash chromatography (mobile phase: petroleum ether-
AcOEt 8:2) to give the product 6; isolated yield: 249 mg
45.78, 18.29, 17.91; butanoyl mojety: 171.57, 35.86, 18.51,
13.53; MS (ESI): m/z=419 Da (M+Na+).
6c: isolated yield: 559 mg (1.10 mmol, 60%); 1H NMR
(CDCl3): d=7.07 (1H, d, J=1.5 Hz, H-6’), 7.01 (1H, d, J=
8.0 Hz, H-3’), 6.98 (1H, dd, J1 =1.5 Hz, J2 =8.0 Hz, H-2’),
6.80 (1H, s, H-4), 6.77 (1H, s, H-6), 6.37 (1H, dq, J1 =
2.0 Hz, J2 =16.0 Hz, H-1’’), 6.11 (1H, dq, J1 =6.5 Hz, J2 =
16.0 Hz, H-2’’), 5.17 (1H, d, J=9.0 Hz, H-2), 3.92 (3H, s,
OMe), 3.82 (3H, s, OMe), 3.47 (1H, dq, J1 =7.0 Hz, J2 =
9.0 Hz, H-3), 1.88 (3H, dd, J1 =2.0 Hz, J2 =6.5 Hz, CH3vin),
1.42 (3H, d, J=7.0 Hz, CH3aliph), dodecanoyl mojety: 2.58
(2H, t, J=7.0 Hz, CH2CO), 1.77 (2H, quintet, J=7.0 Hz,
CH2), 1.28 [16H, mult, -(CH2)8-], 0.90 (3H, t, J=7.0 Hz,
CH3); 13C NMR (CDCl3): d=151.66, 146.91, 144.51, 140.21,
139.52, 133.44, 132.76, 131.28, 123.79, 123.01, 118.94, 113.76,
110.73, 110.04, 93.40, 56.38, 56.25, 46.12, 18.56, 18.27, dodec-
anoyl mojety: 172.03, 34.35, 32.19, 29.89, 29.79, 29.60, 29.57,
29.36, 25.33, 22.95, 14.34; MS (ESI): m/z=531 (M+Na+);
509 Da (M+H+).
1
(0.76 mmol, 41.5%). H NMR (CDCl3): d=6.99 (1H, d, J=
1.5 Hz, H-6’), 6.92 (1H, dd, J1 =1.5 Hz, , J2 =8.0 Hz, H-2’),
6.90 (1H, d, J=8.0 Hz, H-3’), 6.80 (1H, s, H-4), 6.78 (1H, s,
H-6), 6.337 (1H, dq, J1 =1.5 Hz, J2 =15.5 Hz, H-1’’), 6.12
(1H, dq, J1 =6.5 Hz, J2 =15.5 Hz, H-2’’), 5.12 (1H, d, J=
9.5 Hz, H-2), 3.91 (3H, s, OMe), 3.89 (3H, s, OMe), 3.46
(1H, dq, J1 =7.0 Hz, J2 =9.5 Hz, H-3), 1.89 (3H, dd, J1 =
1.5 Hz, J2 =6.5 Hz, CH3vin), 1.40 (3H, d, J=7.0 Hz,
CH3aliph);13C NMR (CDCl3): d=146.70, 146.62, 145.82,
144.18, 133.31, 132.23, 132.13, 130.97, 123.50, 119.99, 114.11,
113.35, 109.31, 108.96, 93.81, 55.99, 45.65, 18.39, 17.60; ME
(EI): m/z=326 Da.
6d: isolated yield: 571 mg (1.29 mmol, 70%); 1H NMR
(CDCl3): d=7.05 (1H, d, J=2.0 Hz, H-6’), 6.99 (1H, d, J=
8.5 Hz, H-3’), 6.96 (1H, dd, J1 =2.0 Hz, , J2 =8.5 Hz, H-2’),
6.80 (1H, s, H-4), 6.76 (1H, s, H-6), 6.37 (1H, dq, J1 =
1.5 Hz, J2 =15.5 Hz, H-1’’), 6.11 (1H, dq, J1 =6.5 Hz, J2 =
15.5 Hz, H-2’’), 5.15 (1H, d, J=9.0 Hz, H-2), 3.91 (3H, s,
OMe), 3.77 (3H, s, OMe), 3.44 (1H, dq, J1 =7.0 Hz, J2 =
9.0 Hz, H-3), 1.88 (3H, dd, J1 =1.5 Hz, J2 =6.5 Hz, CH3vin),
1.41 (3H, d, J=7.0 Hz, CH3aliph), phenylacetyl mojety: 7.41
(2H, d, J=7.5 Hz), 7.37 (2H, t, J=7.5 Hz), 7.30 (1H, t, J=
7.5 Hz), aromatic protons: 3.89 (2H, s, CH2); 13C NMR
(CDCl3): d=151.73, 146.99, 144.64, 140.29, 139.84, 133.53,
132.90, 131.39, 124.01, 123.03, 119.08, 113.86, 110.88, 110.00,
93.53, 56.48, 56.38, 46.31, 18.79, 18.37, phenylacetyl mojety:
169.95, 134.10, 129.83, 129.00, 127.63, 41.44; MS (ESI):
m/z=467 (M+Na+), 445 Da (M+H+).
Esterification of 6 to 6a–d Derivatives
To 600 mg (1.84 mmol) of 6 dissolved in 10 mL of anhydrous
THF, 10 equiv. of TEA (2.56 mL, 1.86 g, 18.4 mmol) and
5 mg (0.04 mmol) of DMAP were added. The mixture was
cooled at 08C and 5 equiv. of either acetic anhydride, buty-
ric anhydride, dodecanoyl chloride or phenylacetyl chloride
were added under stirring. Conversions were monitored by
TLC (mobile phase: petroleum ether-AcOEt 8:2, in the case
of acylation with dodecanoyl chloride petroleum ether-
AcOEt 9:1) after 12 h. Products 6a–d were recovered by sol-
vent evaporation, resuspended in 20 mL of AcOEt and
washed with H2O, 5% (w/v) NaHCO3 solution, and again
H2O (10 mL each). Following drying by sodium sulfate addi-
tion, the solvent was evaporated under reduced pressure
and the crude residues were purified by flash chromatogra-
phy (mobile phase: petroleum ether-AcOEt; 6a and 6b, 9:1;
6c, 97:3; 6d, 8:2).
6a: isolated yield: 564 mg (1.53 mmol, 83%); 1H NMR Screening of Lipases for the Alcoholysis of the Esters
(CDCl3): d=7.08 (1H, d, J=2.0 Hz, H-6’), 7.03 (1H, d, J=
8.0 Hz, H-3’), 6.98 (1H, dd, J1 =2.0 Hz, J2 =8.0 Hz, H-2’),
6.80 (1H, s, H-4), 6.78 (1H, s, H-6), 6.37 (1H, dq, J1 =
2.0 Hz, J2 =15.5 Hz, H-1’’), 6.12 (1H, dq, J1 =6.5 Hz, J2 =
15.5 Hz, H-2’’), 5.17 (1H, d, J=9.0 Hz, H-2), 3.92 (3H, s,
OMe), 3.84 (3H, s, OMe), 3.47 (1H, dq, J1 =7.0 Hz, J2 =
9.0 Hz, H-3), 1.89 (3H, dd, J1 =2.0 Hz, J2 =6.5 Hz, CH3 vin),
1.43 (3H, d, J=7.0 Hz, CH3aliph), acetyl moiety: 2.32 (3H, s,
CH3); 13C NMR (CDCl3): d=151.58, 146.85, 144.51, 140.03,
139.67, 133.40, 132.76, 131.23, 123.90, 122.99, 119.01, 113.73,
110.69, 109.85, 93.41, 56.36, 56.30, 46.12, 18.65, 18.31, acetyl
mojety: 169.25, 20.96; MS (ESI): m/z=391 Da (M+Na+).
6b: isolated yield: 580 mg (1.46 mmol, 79%); 1H NMR
(CDCl3): d=7.07 (1H, d, J=2.0 Hz, H-6’), 7.02 (1H, d, J=
8.5 Hz, H-3’), 6.98 (1H, dd, J1 =2.0 Hz, J2 =8.5 Hz, H-2’),
6.80 (1H, s, H-4), 6.78 (1H, s, H-6), 6.37 (1H, dq, J1 =
1.5 Hz, J2 =16.0 Hz, H-1’’), 6.12 (1H, dq, J1 =6.5 Hz, J2 =
16.0 Hz, H-2’’), 5.17 (1H, d, J=9.0 Hz, H-2), 3.92 (3H, s,
OMe), 3.83 (3H, s, OMe), 3.47 (1H, dq, J1 =7.0 Hz, J2 =
9.0 Hz, H-3), 1.89 (3H, dd, J1 =1.5 Hz, J2 =6.5 Hz, CH3vin),
1.43 (3H, d, J=7.0 Hz, CH3aliph), butanoyl moiety: 2.57 (2H,
t, J=7.5 Hz, CH2CO), 1.81 (2H, sextet, J=7.5 Hz, CH2),
1.07 (3H, t, J=7.5 Hz, CH3);13C NMR (CDCl3): d=151.27,
146.51, 144.15, 139.79, 139.15, 133.07, 132.39, 130.89, 123.52,
122.66, 118.65, 113.37, 110.34, 109.50, 93.10, 55.99, 55.91,
6a–d
To a solution of ester 6a–d (5 mg; 6a, 0.014 mmol; 6b,
0.013 mmol; 6c, 0.010 mmol; 6d, 0.011 mmol) in tert-butyl
methyl ether (MTBE, 1 mL), n-butanol (n-BuOH, 0.05 mL,
0.545 mmol) and the respective lipase preparation were
added (Novozym 435 and Lipolase, 5 mg; Lipozyme, 10 mg;
lipase CV, 50 mg; all other lipases, 25 mg; screening on 6c
was carried out using a triplicate amount of each enzyme).
The mixtures were incubated at 308C and 185 rpm and
monitored by TLC (mobile phase: petroleum ether-AcOEt;
6a, 6b, and 6d, 8:2; 6c, 9:1) and HPLC (mobile phase: petro-
leum ether-AcOEt; 6a and 6b, 9:1; 6c, 7:3; 6d, 95:5) at
scheduled times (see Supporting Information for details). E
values of the respective reactions were evaluated from the
conversion and the enantiomeric excess of products (ee).[13]
Preparative Alcoholysis of 6b Catalyzed by Lipase
CE
To a solution of 6b (313 mg, 0.79 mmol) in 25 mL of MTBE,
3 mL of n-BuOH (32.7 mmol) and 9 g of lipase CE were
added. The mixture was incubated at 308C and 250 rpm and
monitored by TLC (mobile phase: petroleum ether-AcOEt,
8:2) and HPLC [mobile phase: petroleum ether-AcOEt, 9:1;
Adv. Synth. Catal. 2011, 353, 2421 – 2430
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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