The Journal of Organic Chemistry
NOTE
(1H,d, J= 2.3 Hz), 1.48 (3H, d, J=7.2Hz);13C NMR (100 MHz, CDCl3) δ
196.4, 172.6, 156.7, 140.5, 137.8, 137.4, 132.5, 131.6, 130.4, 130.0 (2), 129.5,
128.8, 128.5, 128.4, 128.3 (2), 124.2, 120.4, 110.5, 79.9, 75.1, 60.9, 55.3, 45.2,
18.2; IR (thin film) 3286, 2939, 2125, 1736, 1655 cmꢀ1; HRMS (ESI) m/z
calcd for C26H23O4 ([M þ H]þ) 399.1596, found 399.1590. 12b: Rf 0.33
(1:4 EtOAc:hexanes); [R]D ꢀ17.2 (c 0.7, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.75ꢀ7.24 (11H, m), 6.90 (1H, dt, J = 0.7, 7.6 Hz), 6.80 (1H, d,
J = 8.3 Hz), 7.72 (1H, d, J = 2.2 Hz), 3.76 (1H, q, J = 7.2 Hz), 3.70 (3H, s),
2.44 (1H, d, J = 2.2 Hz), 1.46 (3H, d, J = 7.2 Hz); 13C NMR (100 MHz,
CDCl3) δ 196.5, 172.7, 156.7, 140.4, 137.8, 137.5, 132.5, 131.6, 130.5, 130.1
(2), 129.4, 128.9, 128.7, 128.5, 128.3 (2), 124.3, 120.6, 110.7, 79.8, 75.0, 60.8,
55.5, 45.2, 18.5; IR (thin film) 3288, 2250, 1736, 1655, 1493 cmꢀ1; HRMS
(ESI) m/z calcd for C26H23O4 ([M þ H]þ) 399.1596, found 399.1587.
(S)-2-(((R)-1-(2-Methoxyphenyl)prop-2-yn-1-yl)oxy)-2-oxo-1-
phenylethyl Benzoate (13a) and (R)-2-(((R)-1-(2-Methoxyphe-
nyl)prop-2-yn-1-yl)oxy)-2-oxo-1-phenylethyl Benzoate (13b).
Purification by three successive column chromatography steps (10% EtOAc
in hexane) gave 13a (168 mg, 42%) and 13b (172 mg, 43%) as colorless oils.
13a: Rf 0.41 (1:4 EtOAc:hexanes); [R]D þ7.8 (c 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 8.04 (2H, d, J = 7.6 Hz), 7.56ꢀ7.24 (10H, m), 6.89
(1H, t, J = 7.5 Hz), 6.81 (1H, d, J = 8.2 Hz), 6.78 (1H, d, J = 2.2 Hz), 6.15
(1H, s),3.72(3H, s), 2.44(1H, d,J=2.2Hz);13C NMR (100 MHz, CDCl3)
δ167.4, 165.6, 156.9, 133.8, 133.4, 130.7, 130.0 (2), 129.4, 129.2, 128.8, 128.7
(2), 128.4 (2), 127.9 (2), 123.7, 120.4, 110.7, 79.1, 75.4, 74.6, 61.7, 55.5; IR
(thin film) 3286, 2128, 1758, 1723, 1493 cmꢀ1; HRMS (ESI) m/z calcd for
C25H21O5 ([M þ H]þ) 401.1389, found 401.1381. 13b: Rf 0.37 (1:4
EtOAc:hexanes); [R]D ꢀ55.0 (c 0.9, CHCl3); 1H NMR (400 MHz,
CDCH3, δ 8.04 (2H, dd, J = 1.2, 8.2 Hz), 7.52ꢀ7.15 (10H, m), 6.78 (1H,
dt, J = 0.8, 7.6 Hz), 6.72 (1H, d, J = 2.2 Hz), 6.64 (1H, d, J = 8.3 Hz), 6.13
(1H, m), 3.40 (3H, s), 2.59 (1H, d, J = 2.3 Hz); 13C NMR (100 MHz,
CDCl3) δ 167.5, 165.7, 156.7, 133.9, 133.4, 130.5, 130.0 (2), 129.3, 129.1,
128.6 (2), 128.4 (3), 127.8 (2), 123.7, 120.3, 110.3, 79.2, 75.9, 74.7, 61.9, 55.1;
IR (thin film) 1760, 1725, 1494, 1110 cmꢀ1; HRMS (ESI) m/z calcd for
C25H21O5 ([M þ H]þ) 401.1389, found 401.1376.
and 15b (168 mg, 39%) as a white solid. 15a: Rf 0.34 (1:3 EtOAc:
hexanes); [R]D ꢀ20.5 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ
7.68 (1H, dd, J = 1.7, 7.6 Hz), 7.36ꢀ7.10 (6H, m), 6.99 (1H, td, J = 0.9,
7.6 Hz), 6.88 (1H, d, J = 0.7 Hz), 6.87 (1H, d, J = 2.2 Hz), 5.86ꢀ5.80
(1H, m), 5.51 (1H, d, J = 10.0 Hz), 4.53 (1H, d, J = 14.7), 4.42 (1H, d, J =
14.7 Hz), 3.81 (3H, s), 3.39ꢀ3.34 (1H, m), 3.05ꢀ2.98 (2H, m),
2.85ꢀ2.76 (1H, m), 2.74ꢀ2.64 (1H, m), 2.57 (1H, d, J = 2.3 Hz),
2.51ꢀ2.29 (2H, m), 2.01ꢀ1.89 (1H, m), 1.83ꢀ1.72 (1H, m); 13C NMR
(100 MHz, CDCl3) δ 172.4, 168.9, 156.7, 137.4, 130.0, 129.1, 128.5,
128.4 (2), 127.9 (2), 127.7, 127.1, 125.3, 120.4, 110.8, 81.1, 74.0, 60.3,
55.6, 49.9, 43.8, 42.6, 41.4, 34.4, 27.3, 23.7; IR (thin film) 3285, 1737,
1635, 1493, 1251 cmꢀ1; HRMS (ESI) m/z calcd for C27H28NO4 ([M þ
H]þ) 430.2018, found 430.2011. 15b: Rf 0.31 (1:3 EtOAc:hexanes); mp
149ꢀ151 °C; [R]D ꢀ30.6 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 7.69 (1H, dd, J = 1.7, 7.6 Hz), 7.36ꢀ7.14 (6H, m), 6.99 (1H, dt, J = 0.9,
7.5 Hz), 6.91 (1H, d, J = 2.2 Hz), 6.89 (1H, d, J = 8.2 Hz), 5.84ꢀ5.80
(1H, m), 5.49 (1H, d, J = 10.0 Hz), 4.79 (1H, d, J = 14.7 Hz), 4.31 (1H, d,
J = 14.7 Hz), 3.84 (3H, s), 3.47ꢀ3.42 (1H, m), 3.07ꢀ2.62 (4H, m), 2.58
(1H, d, J = 2.3 Hz), 2.50ꢀ1.65 (4H, m); 13C NMR (100 MHz, CDCl3)
δ 172.2, 169.0, 156.7, 137.3, 130.0, 129.0, 128.5, 128.4 (2), 127.9 (2), 127.8,
127.1, 125.6, 120.5, 110.8, 80.7, 74.2, 60.3, 55.7, 50.2, 43.9, 42.6, 41.3, 34.3,
27.3, 23.8; IR (thin film) 3285, 1736, 1634, 1492, 1250 cmꢀ1; HRMS (ESI)
m/z calcd for C27H28NO4 ([M þ H]þ) 430.2018, found 430.2005.
(4aS,8R,8aS)-1-((R)-Phenylprop-2-yn-1-yl)-2-benzyl-1-oxo-
1,2,3,4,4a,7,8,8a octahydroisoquinoline-8-carboxylate (16a)
and (4aR,8S,8aR)-1-((R)-Phenylprop-2-yn-1-yl)-2-benzyl-1-
oxo-1,2,3,4,4a,7,8,8a-octahydroisoquinoline-8-carboxylate
(16b). Purification by three successive column chromatography steps
(10% EtOAc in hexane) gave 16a (190 mg, 48%) and 16b (192 mg,
48%) as white foams. 16a: Rf 0.58 (1:3 EtOAc:hexanes); [R]D ꢀ37.0 (c
1
1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 7.70ꢀ7.60 (2H, m),
7.40ꢀ7.10 (8H, m), 6.63 (1H, d, J = 2.2 Hz), 5.90ꢀ5.83 (1H, m), 5.51
(1H, dd, J = 10.0, 1 Hz), 4.64 (1H, d, J = 14.7 Hz), 4.38 (1H, d, J = 14.7
Hz), 3.34 (1H, dd, J = 5.4, 3.3 Hz), 3.10ꢀ2.98 (2H, m), 2.85- 2.76 (1H,
m), 2.74ꢀ2.65 (1H, m), 2.69 (1H, d, J = 2.2 Hz), 2.46ꢀ2.38 (2H, m),
1.98ꢀ1.86 (1H, m), 1.84ꢀ1.74 (1H, m); 13C NMR (100 MHz, CDCl3)
δ 172.6, 169.0, 137.3, 136.5, 129.1, 128.6, 128.5 (2), 128.4 (2), 127.9
(2), 127.8 (2), 127.6, 127.2, 80.5, 75.5, 65.0, 50.1, 43.8, 42.5, 41.1, 34.2,
27.3, 23.6; IR (thin film) 2122, 1737, 1630, 1356 cmꢀ1; HRMS (ESI) m/
z calcd for C26H26NO3 ([M þ H]þ) 400.1913, found 400.1902. 16b: Rf
0.52 (1:3 EtOAc:hexanes); [R]D ꢀ15.0 (c 1.0, CHCl3); 1H NMR (400
MHz, CDCl3) δ 7.70ꢀ7.60 (2H, m), 7.40ꢀ7.15 (8H, m), 6.62 (1H, d, J
= 2.2 Hz), 5.85ꢀ5.78 (1H, m), 5.50 (1H, dd, J = 10.0, 1.6 Hz), 4.75 (1H,
d, J = 14.7 Hz), 4.36 (1H, d, J = 14.7 Hz), 3.47 (1H, dd, J = 5.4, 3.2 Hz),
3.10ꢀ3.00 (2H, m), 2.85ꢀ2.60 (2H, m), 2.65 (1H, d, J = 2.2 Hz),
2.48ꢀ2.28 (2H, m), 2.05ꢀ1.95 (1H, m), 1.82ꢀ1.77 (1H, m); 13C NMR
(100 MHz, CDCl3) δ 172.6, 169.1, 137.2, 137.0, 129.0, 128.7, 128.5 (2),
128.4 (2), 127.9 (2), 127.8, 127.7 (2), 127.2, 80.5, 75.3, 65.3, 50.3, 43.8,
(1R,2R)-(R)-1-(2-Methoxyphenyl)prop-2-yn-1-yl-2-benzoyl-
cyclohexanecarboxylate (14a) and (1S,2S)-(R)-1-(2-Methox-
yphenyl)prop-2-yn-1-yl-2-benzoylcyclohexanecarboxylate
(14b). Purification by three successive column chromatography steps
(10% EtOAc in hexane) gave 14a (154 mg, 41%) and 14b (141 mg,
38%) as colorless oils. 14a: Rf 0.41 (1:4 EtOAc:hexanes); [R]D ꢀ15.2 (c
1
1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 8.02ꢀ7.95 (2H, m),
7.62ꢀ7.41 (4H, m), 7.32 (1H, dt, J = 1.7, 8.2 Hz), 6.95 (1H, dt, J = 0.8,
7.6 Hz), 6.86 (1H, d, J = 8.3 Hz), 6.68 (1H, d, J = 2.2 Hz), 3.79 (3H, s),
3.70ꢀ3.60 (1H, m), 3.02ꢀ2.92 (1H, m), 2.51 (1H, d, J = 2.2 Hz),
2.34ꢀ1.20 (8H, m); 13C NMR (100 MHz, CDCl3) δ 202.8, 173.9,
156.8, 136.4, 132.8, 130.3, 128.5 (3), 128.4 (2), 124.3, 120.4, 110.7, 80.2,
74.5, 60.4, 55.5, 46.7, 44.3, 29.9, 28.9, 25.6, 25.5; IR (thin film) 3285,
1732, 1679, 1493, 1167 cmꢀ1; HRMS (ESI) m/z calcd for C24H25O4
([M þ H]þ) 377.1753, found 377.1747. 14b: Rf 0.35 (1:4 EtOAc:
hexanes); [R]D ꢀ30.5 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ
7.90ꢀ7.85 (2H, m), 7.57 (1H, dd, J = 1.7, 7.6 Hz), 7.55ꢀ7.23 (4H, m),
6.90 (1H, dt, J = 0.9, 7.6 Hz), 6.71 (1H, d, J = 8.2 Hz), 6.68 (1H, d, J = 2.2
Hz), 3.67 (3H, s), 3.63ꢀ3.55 (1H, m), 3.03ꢀ2.94 (1H, m), 2.54 (1H, d,
J = 2.3 Hz), 2.22ꢀ1.15 (8H, m); 13C NMR (100 MHz, CDCl3) δ 202.6,
173.6, 156.6, 136.3, 132.7, 130.2, 128.5 (2), 128.4, 128.3 (2), 124.5,
120.4, 110.4, 80.0, 74.9, 60.4, 55.3, 46.7, 44.4, 29.9, 29.0, 25.6, 25.5; IR
(thin film) 3285, 1732, 1678 cmꢀ1; HRMS (ESI) m/z calcd for
C24H25O4 ([M þ H]þ) 377.1753, found 377.1739.
42.8, 41.4, 34.3, 27.3, 23.6; IR (thin film) 2123, 1734, 1630, 1356 cmꢀ1
;
HRMS (ESI) m/z calcd for C26H26NO3 ([M þ H]þ) 400.1913, found
400.1908.
General Procedure for Removal of Propargylic Esters:
N-Boc-D-Proline ((R)-5. To the propargyl ester 11b (108 mg, 0.30
mmol) and CuCl (3 mg, 0.03 mmol) in a 10 mL flask was added 3.0 mL
of MeOH (degassed with Ar). The reaction solution was degassed with
Ar for 5 min and then heated for 2 h at 40 °C with constant stirring. The
reaction was cooled, concentrated, and chromatographed with
20ꢀ100% EtOAc in hexane to give (R)-5 (53 mg, 82% yield) as a white
solid. The er (97:3) of (R)-5 was determined by converting it into
phenyl amide (EDCl, DMAP-mediated coupling with aniline in
CH2Cl2) and then using analytical HPLC (Chiralcel OD-H, 0.5 mL/
min, 10% i-PrOH/hexane).
(4aS,8R,8aS)-(R)-1-Phenylprop-2-yn-1-yl-2-benzyl-1-oxo-1,
2,3,4,4a,7,8,8a-octahydroisoquinoline-8-carboxylate (15a)
and (4aR,8S,8aR)-(R)-1-(2-Methoxyphenyl)prop-2-yn-1-yl-2-
benzyl-1-oxo-1,2,3,4,4a,7,8,8a-octahydroisoquinoline-8-carboxyl-
ate (15b). Purification by three successive column chromatography
steps (20% EtOAc in hexane) gave 15a (181 mg, 42%) as a colorless oil
(R)-Ketoprofen ((R)-6) and (S)-Ketoprofen ((S)-6). The er values
of (R)- and (S)-6 were determined by converting them into phenyl amides
4171
dx.doi.org/10.1021/jo200433w |J. Org. Chem. 2011, 76, 4168–4172