Isothiourea-Catalysed Acylation
FULL PAPER
1H), 7.49–7.54 (m, 2H), 7.81–7.89 (m, 3H), 7.99 ppm (d, J=1.9 Hz, 1H);
13C NMR (75 MHz, CDCl3): d=8.4, 28.9, 29.1, 32.1, 44.8, 68.3, 82.7,
124.1, 125.9, 126.9, 126.9, 127.7, 128.4, 129.5, 132.6, 133.4, 136.2, 172.9,
0.650 mmol, 1.3 equiv) at À788C to RT gave a product distribution con-
taining 39. Purification of the residue by flash column chromatography
on silica gel (silica, Et2O/40–60 petrol 5:95) gave 39 as a white solid
(113 mg, 76%), which was shown by chiral HPLC [Daicel CHIRALCEL
204.4 ppm; nmax (film): 2979, 1754, 1716, 1598, 1507 cmÀ1; MS (NSI+) m/z
+
(%): 297 [M+H]+ (100); HRMS (NSI+): m/z calcd for C19H21O3
297.1485 [M+NH4]+; found: 297.1480 (À1.8 ppm).
:
OD-H, 4.6ꢂ250 mm, 2-propanol/hexane 1:99, 0.5 mLminÀ1
, retention
times of enantiomers: 14.47 (minor), 17.01 min (major)] to have 94% ee;
[a]2D5 = +268.0 (c=0.5 in CH2Cl2); m.p. 70–728C; 1H NMR (400 MHz,
CDCl3): d=0.85 (t, J=7.2 Hz, 3H), 1.17 (s, 3H), 1.54 (s, 3H), 1.90 (dq,
J=7.2, 19.0 Hz, 1H), 2.33 (d, J=13.3 Hz, 1H), 2.95 (dq, J=7.2, 19.0 Hz,
1H), 3.83 (d, J=13.3 Hz, 1H), 7.36 (dd, J=1.0, 8.2 Hz, 1H), 7.43–7.52
(m, 3H), 7.75 (dd, J=1.1, 7.3 Hz, 1H), 7.85 (d, J=8.3 Hz, 1H), 7.88–
7.92 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=8.2, 29.4, 29.4, 32.7,
44.5, 69.0, 83.2, 123.4, 125.5, 126.1, 126.3, 127.2, 129.3, 129.7, 130.2, 134.8,
Preparation of (S)-3-(2-chlorophenyl)-5,5-dimethyl-3-propionyldihydro-
furan-2(3H)-one (36): Following the general procedure, compound 26
ACHTUNGTRENNUNG
(15 mg, 0.0500 mmol, 10 mol%), compound 55 (148 mg, 0.500 mmol,
1.0 equiv), in CH2Cl2 (4 mL) at À788C and (EtCO)2O (0.08 mL,
0.650 mmol, 1.3 equiv) at À788C to RT gave a product distribution con-
taining 36. Purification of the residue by flash column chromatography
on silica gel (silica, Et2O/40–60 petrol 5:95) gave 36 as a colourless oil
(101 mg, 72%), which was shown by chiral HPLC [Daicel CHIRALPAK
135.9, 173.1, 207.1 ppm; nmax (KBr)=3055, 2980, 1717, 1598, 1509 cmÀ1
;
MS (NSI+): m/z (%): 314 [M+NH4]+ (100); HRMS (NSI+): m/z calcd
for C19H24NO3+: 314.1751 [M+NH4]+; found: 314.753 (+0.7 ppm).
AD-H, 4.6ꢂ250 mm, 2-propanol/hexane 1:99, 0.5 mLminÀ1
, retention
times of enantiomers: 15.30 (minor), 18.35 min (major)] to have 86% ee.
[a]2D5 = +202.0 (c=0.5 in CH2Cl2); 1H NMR (300 MHz, CDCl3): d=0.94
(t, J=7.1 Hz, 3H), 1.18 (s, 3H), 1.47 (s, 3H), 2.10–2.24 (m, 2H), 2.73 (dq,
J=7.1, 19.0 Hz, 1H), 3.58 (d, J=13.8 Hz, 1H), 7.21–7.30 (m, 2H), 7.35–
7.38 (m, 1H), 7.49–7.52 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=
8.2, 29.0, 29.6, 32.7, 44.2, 68.8, 83.5, 127.6, 129.5, 129.6, 131.1, 133.0, 138.2,
172.4, 203.9 ppm; nmax (film)=3069, 2979, 2878, 1755, 1722, 1591,
1570 cmÀ1; MS (NSI+): m/z (%): 298 [M+NH4]+ (100); HRMS (NSI+):
m/z calcd for C15H21ClNO3+: 298.1204 [M+NH4 ]+; found: 298.1207
(+0.8 ppm).
Preparation of (S)-3-propionyl-3-(2-(trifluoromethyl)phenyl)dihydrofur-
an-2ACTHNUGRTENUNG(3H)-one (40): Following the general procedure, compound 26
(15 mg, 0.0500 mmol, 10 mol%), compound 59 (151 mg, 0.500 mmol,
1.0 equiv), in CH2Cl2 (4 mL) at À788C and (EtCO)2O (0.08 mL,
0.650 mmol, 1.3 equiv) at À788C to RT gave a product distribution con-
taining 40. Purification of the residue by flash column chromatography
on silica gel (silica, Et2O/40–60 petrol 30:70) gave 40 as a colourless oil
(22 mg, 15%), which was shown by chiral HPLC [Daicel CHIRALPAK
AD-H, 4.6ꢂ250 mm, 2-propanol/hexane 1:99, 0.5 mLminÀ1
, retention
times of enantiomers: 18.92 (minor), 21.48 min (major)] to have 62% ee;
Preparation of (S)-3-(2-methoxyphenyl)-5,5-dimethyl-3-propionyldihy-
drofuran-2ACHTUNGTRENNUNG(3H)-one (37): Following the general procedure, compound 26
1
[a]2D5 = +186.0 (c=0.05 in CH2Cl2); H NMR (500 MHz, CDCl3): d=0.89
(t, J=7.1 Hz, 3H), 2.11 (dq, J=6.8, 19.3 Hz, 1H), 2.21–2.26 (m, 1H),
2.58 (dq, J=7.0, 19.2 Hz, 1H), 3.50 (dt, J=8.3, 13.5 Hz, 1H), 4.02 (q, J=
8.1 Hz, 1H), 4.34 (dt, J=4.4, 8.5 Hz, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.51 (t,
J=7.6 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.68 ppm (d, J=7.8 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=7.7, 33.3, 33.6, 66.1, 66.2, 124.3, 127.9,
128.9, 129.5, 130.1, 132.8, 135.1, 173.9, 203.8 ppm; nmax (film)=2983, 2942,
1763, 1724, 1605, 1581 cmÀ1; MS (ES+): m/z (%): 309 [M+Na]+ (100);
HRMS (ES+): m/z calcd for C14H13F3NaO3+: 309.0714 [M+Na]+; found:
309.0710 (À1.6 ppm).
(15 mg, 0.0500 mmol, 10 mol%), compound 56 (146 mg, 0.500 mmol,
1.0 equiv) in CH2Cl2 (4 mL) at À788C and (EtCO)2O (0.08 mL,
0.650 mmol, 1.3 equiv) at À788C to RT gave a product distribution con-
taining 37. Purification of the residue by flash column chromatography
on silica gel (silica, Et2O/40–60 petrol 20:80) gave 37 as a colourless oil
(113 mg, 82%), which was shown by chiral HPLC [Daicel CHIRALCEL
AS-H, 4.6ꢂ250 mm, 2-propanol/hexane 1:99, 0.5 mLminÀ1
, retention
times of enantiomers: 19.85 (minor), 25.00 min (major)] to have 53% ee.
[a]2D5 = +84.0 (c=0.5 in CH2Cl2); 1H NMR (400 MHz, CDCl3): d=0.96
(t, J=7.2 Hz, 3H), 1.26 (s, 3H), 1.46 (s, 3H), 2.02 (d, J=13.6 Hz, 1H),
2.23 (dq, J=7.2, 18.7 Hz, 1H), 2.71 (dq, J=7.2, 18.7 Hz, 1H), 3.50 (d, J=
13.6 Hz, 1H), 3.74 (s, 3H), 6.89 (dd, J=0.9, 8.5 Hz, 1H), 6.97 (td, J=1.1,
7.6 Hz, 1H), 7.28–7.34 ppm (m, 2H); 13C NMR (400 MHz, CDCl3): d=
8.3, 29.1, 29.6, 31.8, 43.8, 55.2, 66.5, 83.3, 111.3, 121.1, 128.2, 129.3, 129.5,
156.1, 173.6, 205.0 ppm; nmax (film)=2978, 2939, 1754, 1721, 1599,
Preparation of (S)-5,5-dimethyl-3-propionyl-3-(thiophen-2-yl)dihydrofur-
an-2ACTHNUGRTENUNG(3H)-one (41): Following the general procedure, compound 27
(18 mg, 0.0500 mmol, 10 mol%), compound 60 (134 mg, 0.500 mmol,
1.0 equiv), in CH2Cl2 (4 mL) at À788C and (EtCO)2O (0.08 mL,
0.650 mmol, 1.3 equiv) at À788C to RT gave a product distribution con-
taining 41. Purification of the residue by flash column chromatography
on silica gel (silica, Et2O/40–60 petrol 5:95) gave 41 as a colourless oil
(88 mg, 70%), which was shown by chiral HPLC [Daicel CHIRALCEL
1586 cmÀ1; MS (NSI+): m/z (%): 294 [M+NH4]+ (100); HRMS (NSI+):
+
m/z calcd for C16H24NO4
(À2.3 ppm).
:
294.1700 [M+NH4]+; found: 294.1693
AS-H, 4.6ꢂ250 mm, 2-propanol/hexane 1:99, 0.5 mLminÀ1
, retention
times of enantiomers: 19.25 (major), 21.92 min (minor)] to have 35% ee;
[a]2D5 = +70.0 (c=0.5 in CH2Cl2); 1H NMR (400 MHz, CDCl3): d=0.95
(t, J=7.2 Hz, 3H), 1.33 (s, 3H), 1.40 (s, 3H), 2.38 (d, J=13.4 Hz, 1H),
2.58 (dq, J=7.2, 18.7 Hz, 1H), 2.78 (dq, J=7.2, 18.7 Hz, 1H), 3.39 (d, J=
13.4 Hz, 1H), 6.98 (dd, J=3.6, 5.2 Hz, 1H), 7.12 (dd, J=1.2, 3.6 Hz, 1H),
7.28 ppm (dd, J=1.2, 5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=8.4,
28.5, 29.1, 31.3, 45.5, 64.6, 83.1, 126.2, 126.6, 127.4, 140.8, 172.6,
203.2 ppm; nmax (film)=3109, 2980, 1760, 1716 cmÀ1; MS (NSI+): m/z
(%): 270 [M+NH4]+ (100); HRMS (NSI+): m/z calcd for C13H20NO3S+:
270.1158 [M+NH4]+; found: 270.1162 (+1.3 ppm).
Preparation of (S)-5,5-dimethyl-3-propionyl-3-(o-tolyl)dihydrofuran-2-
ACHTUNGTRENNUNG(3H)-one (38): Following the general procedure, compound 26 (15 mg,
0.0500 mmol, 10 mol%), compound 57 (138 mg, 0.500 mmol, 1.0 equiv),
in CH2Cl2 (4 mL) at À788C and (EtCO)2O (0.08 mL, 0.650 mmol,
1.3 equiv) at À788C to RT gave a product distribution containing 38. Pu-
rification of the residue by flash column chromatography on silica gel
(silica, Et2O/40–60 petrol 10:90) gave 38 as a colourless oil (79 mg, 61%),
which was shown by chiral HPLC [Daicel CHIRALCEL OD-H, 4.6ꢂ
250 mm, 2-propanol/hexane 1:99, 0.5 mLminÀ1, retention times of enan-
tiomers: 12.34 (minor), 14.50 min (major)] to have 98% ee; [a]2D5 = +
1
210.0 (c=0.5 in CH2Cl2); H NMR (400 MHz, CDCl3): 0.99 (t, J=7.2 Hz,
Preparation of (R)-3-benzyl-3-propionyldihydrofuran-2ACTHNUTRGENUGN(3H)-one (42):
3H), 1.25 (s, 3H), 1.51 (s, 3H), 2.05 (s, 3H), 2.08 (d, J=13.2 Hz, 1H),
2.16 (dq, J=7.2, 19.1 Hz, 1H), 2.93 (dq, J=7.2, 19.1 Hz, 1H) 3.60 (d, J=
13.2 Hz, 1H), 7.18–7.23 (m, 1H), 7.24–7.28 (m, 2H), 7.46–7.50 ppm (m,
1H); 13C NMR (100 MHz, CDCl3): d=8.3, 20.2, 29.3, 29.5, 32.7, 43.9,
69.2, 82.9, 126.8, 127.9, 128.2, 132.5, 135.3, 138.7, 173.1, 206.1 ppm; nmax
(film)=2979, 2938, 1754, 1717 cmÀ1; MS (NSI+): m/z (%): 261 ([M+H]+,
Following the general procedure, compound 27 (18 mg, 0.0500 mmol,
10 mol%), compound 61 (124 mg, 0.500 mmol, 1.0 equiv) in CH2Cl2
(4 mL) at À788C and (EtCO)2O (0.08 mL, 0.650 mmol, 1.3 equiv) at
À788C to RT gave a product distribution containing 42. Purification of
the residue by flash column chromatography on silica gel (silica, Et2O/
40–60 petrol 10:90) gave 42 as a colourless oil (61 mg, 53%), which was
shown by chiral HPLC [Daicel CHIRALCEL OD-H, 4.6ꢂ250 mm, 2-
propanol/hexane 10:90, 1.0 mLminÀ1, retention times of enantiomers:
11.19 (major), 12.63 min (minor)] to have 56% ee; [a]2D5 =-4.0 (c 0.5 in
CH2Cl2); 1H NMR (400 MHz, CDCl3): d=1.01 (t, J=7.2 Hz, 3H), 2.05
(dt, J=8.4, 13.1 Hz, 1H), 2.64–2.83 (m, 3H), 3.05 (d, J=14.0 Hz, 1H),
3.36 (d, J=14.0 Hz, 1H), 3.72 (td, J=4.2, 8.8 Hz, 1H), 3.96–4.03 (m,
+
41%); HRMS (NSI+): m/z calcd for C16H21O3 [M+H]+: 261.1485;
found: 261.1481 (À1.6 ppm).
Preparation of (S)-5,5-dimethyl-3-(naphthalen-1-yl)-3-propionyldihydro-
furan-2ACHTUNGTRENNUNG(3H)-one (39): Following the general procedure, compound 27
(18 mg, 0.0500 mmol, 10 mol%), compound 58 (156 mg, 0.500 mmol,
1.0 equiv) in CH2Cl2 (4 mL) at À788C and (EtCO)2O (0.08 mL,
Chem. Eur. J. 2011, 17, 11060 – 11067
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11065