The Journal of Organic Chemistry
Note
OMe), 2.24 (s, 3H, SMe), 1.88 (m, 2H, alkyl), 1.69 (m, 2H, alkyl),
gradient from 80:20 to 75:25) to yield 69.7 mg (66%) of the anti-6d as
1.47 (m, 1H, alkyl), 1.28−1.21 (m, 5H, alkyl), 1.02 (m, 1H, alkyl); 13
C
a red resin: TLC, Rf = 0.20 (petroleum ether/EtOAc = 70:30); [α]20
D
NMR (75 MHz, CDCl3) δ 168.4 (Cq), 151.3 (2Cq), 146.5 (CH),
142.9 (Cq), 135.5 (Cq), 129.9 (CH), 128.8 (2CH), 128.5 (CH),
128.4 (2CH), 120.6 (Cq), 119.5 (CH), 115.5 (CH), 111.6 (CH), 68.1
(CH2), 64.6 (CH), 58.8 (CH), 55.9 (CH3), 43.0 (CH), 31.0 (CH2),
30.5 (CH2), 26.4 (CH2), 26.1 (CH2), 26.0 (CH2), 18.7 (CH3); ESI-
MS m/z 503.30 [M + Na]+ (calcd 503.20 [M + Na]+). Anal. Calcd for
C27H32N2O4S: C, 67.47; H, 6.71; N, 5.83 Found: C, 67.22; H, 6.75; N,
5.84. Chiral HPLC: (1′S,5R)-6a, tR 21.82 min (97.0%); (1′R,5S)-6a, tR
29.14 min (3.0%) (Whelk-O1, hexane/EtOH = 80:20, 0.9 mL/min,
254 nm).
(R)-1-(Benzyloxycarbonyl)-5-[(S)-1-[4-methoxy-2-
(methylthio)phenylamino]-2-methylpropyl]-1H-pyrrol-2(5H)-
one (anti-6b). Prepared according to the representative procedure,
utilizing aldehyde 2c (19.2 μL, 0.21 mmol), aniline 3c (35.5 mg, 0.21 mmol),
and pyrrole 1e (90.0 mg, 0.31 mmol). The diastereomeric ratio of the
addition products was determined to be >95:5 by 1H NMR analysis of
the crude reaction mixture. The crude residue was purified by silica gel
flash chromatography (petroleum ether/EtOAc = 70:30) to yield
69.4 mg (75%) of the anti-6b as a red resin: TLC, Rf = 0.40
(petroleum ether/EtOAc = 70:30); [α]20D = +202.7 (c = 0.7, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.40−7.32 (m, 5H, Cbz), 7.27 (dd, J =
7.3, 2.0 Hz, 1H, H4), 6.91 (d, J = 2.8 Hz, 1H, H3″), 6.53 (dd, J = 8.9,
2.9 Hz, 1H, H5″), 6.34 (d, J = 8.5 Hz, 1H, H6″), 6.30 (dd, J = 6.1, 1.4
Hz, 1H, H3), 5.30 (d, J = 12.4 Hz, 1H, Cbz), 5.17 (d, J = 12.4 Hz, 1H,
Cbz), 5.09 (s, 1H, H5), 4.04 (dd, J = 9.1, 2.5 Hz, 1H, H1′), 3.68 (s,
3H, OMe), 2.25 (s, 3H, SMe), 1.77 (m, 1H, H2′), 1.17 (d, J = 6.7 Hz,
3H, CH3), 1.03 (d, J = 6.6 Hz, 3H, CH3); 13C NMR (75 MHz,
CDCl3) δ 168.3 (Cq), 151.3 (2Cq), 146.4 (CH), 142.8 (Cq), 135.4
(Cq), 130.0 (CH), 128.8 (2CH), 128.5 (CH), 128.3 (2CH), 120.6
(Cq), 119.4 (CH), 115.5 (CH), 111.6 (CH), 68.1 (CH2), 64.9 (CH),
60.3 (CH), 55.9 (CH3), 33.7 (CH), 21.0 (CH3), 20.2 (CH3), 18.8
(CH3); ESI-MS m/z 463.30 [M + Na]+ (calcd 463.18 [M + Na]+).
Anal. Calcd for C24H28N2O4S: C, 65.43; H, 6.41; N, 6.36. Found: C,
65.20; H, 6.49; N, 6.39. Chiral HPLC: (1′S,5R)-6b, tR 22.47 min
(97.7%); (1′R,5S)-6b, tR 27.97 min (2.3%) (Whelk-O1, hexane/EtOH =
80:20, 0.9 mL/min, 254 nm).
(R)-1-(Benzyloxycarbonyl)-5-[(S)-1-[4-methoxy-2-
(methylthio)phenylamino]ethyl]-1H-pyrrol-2(5H)one (anti-
6c). Prepared according to the representative procedure, utilizing
aldehyde 2d (11.8 μL, 0.21 mmol), aniline 3c (35.5 mg, 0.21 mmol),
and pyrrole 1e (90.0 mg, 0.31 mmol). The diastereomeric ratio of the
addition products was determined to be >95:5 by 1H NMR analysis of
the crude reaction mixture. The crude residue was purified by silica gel
flash chromatography (petroleum ether/EtOAc = 70:30−60:40) to
yield 59.8 mg (69%) of the anti-6c as a red resin: TLC, Rf = 0.20
(petroleum ether/EtOAc = 70:30); [α]20D = +240.7 (c = 0.7, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.43−7.28 (m, 6H, Cbz, H4), 6.94 (d,
J = 2.9 Hz, 1H, H3″), 6.61 (dd, J = 8.85, 3.0 Hz, 1H, H5″), 6.41 (d, J =
8.9 Hz, 1H, H6″), 6.33 (dd, J = 6.1, 1.4 Hz, 1H, H3), 5.34 (1/2 ABq, J
= 12.4 Hz, 1H, Cbz), 5.27 (1/2 ABq, J = 12.4 Hz, 1H, Cbz), 4.86 (s,
1H, H5), 4.45 (m, 1H, H1′), 3.71 (s, 3H, OMe), 2.25 (s, 3H, SMe),
1.34 (d, J = 6.6 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ 168.3
(Cq), 151.8 (Cq), 151.5 (Cq), 146.7 (CH), 141.5 (Cq), 135.5 (Cq),
129.6 (CH), 128.8 (2CH), 128.5 (CH), 128.3 (2C), 122.0 (Cq),
119.3 (CH), 115.3 (CH), 112.3 (CH), 68.3 (CH2), 67.2 (CH), 56.0
(CH3), 49.6 (CH), 18.8 (CH3), 18.3 (CH3); ESI-MS m/z 435.20 [M +
Na]+ (calcd 435.15 [M + Na]+). Anal. Calcd for C22H24N2O4S: C,
64.06; H, 5.86; N, 6.79. Found: C, 64.11; H, 5.90; N, 6.73. Chiral
HPLC: (1′S,5R)-6c, tR 30.01 min (97.8%); (1′R,5S)-6c, tR 36.09 min
(2.2%) (Whelk-O1, hexane/EtOH = 80:20, 0.9 mL/min, 254 nm).
(R)-1-(Benzyloxycarbonyl)-5-[(S)-1-[4-methoxy-2-
(methylthio)phenylamino]-3-phenylpropyl]-1H-pyrrol-2(5H)-
one (anti-6d). Prepared according to the representative procedure,
utilizing aldehyde 2e (27.7 μL, 0.21 mmol), aniline 3c (35.5 mg, 0.21
mmol), and pyrrole 1e (90.0 mg, 0.31 mmol). The diastereomeric
ratio of the addition products was determined to be >95:5 by 1H NMR
analysis of the crude reaction mixture. The crude residue was purified
by silica gel flash chromatography (petroleum ether/EtOAc elution
= +154.9 (c = 0.7, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.36−7.23
(m, 10H, Cbz, Ph), 7.17 (d, J = 7.1 Hz, H4), 6.92 (d, J = 2.9 Hz, 1H,
H3″), 6.50 (dd, J = 8.9, 2.9 Hz, 1H, H5″), 6.30 (m, 2H, H6″ and H3),
5.27 (d, J = 12.4 Hz, 1H, Cbz), 5.17 (d, J = 12.3 Hz, 1H, Cbz), 4.87 (s,
1H, H5), 4.38 (m, 1H, H1′), 3.68 (s, 3H, OMe), 2.85 (m, 1H, H3′),
2.71 (m, 1H, H3′), 2.27 (s, 3H, SMe), 2.07 (m, 1H, H2′), 1.84 (m, 1H,
H2′); 13C NMR (100 MHz, CDCl3) δ 168.0 (Cq), 151.4 (Cq), 151.1
(Cq), 146.2 (CH), 142.1 (Cq), 141.1 (Cq), 135.2 (Cq), 129.7 (CH),
128.6 (4CH), 128.4 (2CH), 128.3 (CH), 128.2 (2CH), 126.2 (CH),
121.1 (Cq), 119.1 (CH), 115.1 (CH), 111.8 (CH), 68.0 (CH2), 66.5
(CH), 55.7 (CH3), 53.9 (CH), 36.3 (CH2), 33.0 (CH2); 18.5 (CH3);
ESI-MS m/z 525.21 [M + Na]+ (calcd 525.19 [M + Na]+). Anal. Calcd
for C29H30N2O4S: C, 69.30; H, 6.02; N, 5.57. Found: C, 69.05; H,
6.04; N, 5.58. Chiral HPLC: (1′S,5R)-6d, tR 30.03 min (96.8%);
(1′R,5S)-6d, tR 36.91 min (3.2%) (Whelk-O1, hexane/EtOH = 80:20,
0.9 mL/min, 254 nm).
(R)-1-(Benzyloxycarbonyl)-5-[(S)-1-[4-methoxy-2-
(methylthio)phenylamino]octyl]-1H-pyrrol-2(5H)one (anti-
6e). Prepared according to the representative procedure, utilizing
aldehyde 2f (32.8 μL, 0.21 mmol), aniline 3c (35.5 mg, 0.21 mmol),
and pyrrole 1e (90.0 mg, 0.31 mmol). The diastereomeric ratio of the
addition products was determined to be >95:5 by 1H NMR analysis of
the crude reaction mixture. The crude residue was purified by silica gel
flash chromatography (petroleum ether/EtOAc = 75:25−70:30) to
yield 82.4 mg (79%) of the anti-6e as a red resin: TLC, Rf = 0.30
(petroleum ether/EtOAc = 70:30); [α]20D = +151.5 (c = 0.7, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.43−7.33 (m, 5H, Cbz), 7.29 (dd, J =
6.2, 2.1 Hz, 1H, H4), 6.92 (d, J = 2.9 Hz, 1H, H3″), 6.56 (dd, J = 8.9,
2.9 Hz, 1H, H5″), 6.39 (brd, J = 8.7 Hz, 1H, H6″), 6.31 (dd, J = 6.2,
1.6 Hz, 1H, H3), 5.32 (d, J = 12.4 Hz, 1H, Cbz), 5.21 (d, J = 12.4 Hz,
1H, Cbz), 4.91 (brs, 1H, H5), 4.33 (m, 1H, H1′), 3.69 (s, 3H, OMe),
2.25 (s, 3H, SMe), 1.68 (m, 2H, H2′), 1.50 (m, 2H, H3′), 1.28 (m, 8H,
H4′, H5′, H6′, H7′), 0.89 (dd, J = 7.0, 6.5 Hz, 3H, H8′); 13C NMR (75
MHz, CDCl3) δ 168.3 (Cq), 151.6 (Cq), 151.4 (Cq), 146.7 (CH),
142.8 (Cq), 135.4 (Cq), 129.7 (CH), 128.8 (2CH), 128.5 (CH),
128.4 (2CH), 120.6 (Cq), 119.3 (CH), 115.4 (CH), 111.6 (CH), 68.2
(CH2), 66.5 (CH), 55.9 (CH3), 53.5 (CH), 33.7 (CH2), 31.9 (CH2),
29.6 (CH2), 29.3 (CH2), 26.9 (CH2), 22.8 (CH2), 18.6 (CH3), 14.3
(CH3); ESI-MS m/z 519.20 [M + Na]+ (calcd 519.24 [M + Na]+).
Anal. Calcd for C28H36N2O4S: C, 67.71; H, 7.31; N, 5.64. Found: C,
67.65; H, 7.33; N, 5.62. Chiral HPLC: (1′S,5R)-6e, tR 15.93 min
(97.0%); (1′R,5S)-6e, tR 19.38 min (3.0%) (Whelk-O1, hexane/EtOH =
80:20, 0.9 mL/min, 254 nm).
(R)-1-(Benzyloxycarbonyl)-5-[(R)-1-[4-methoxy-2-
(methylthio)phenylamino]-2-(tert-butyldimethylsilyl)-
oxyethyl]-1H-pyrrol-2(5H)one (anti-6f). Prepared according to the
representative procedure, utilizing aldehyde 2g (38.8 μL, 0.21 mmol),
aniline 3c (35.5 mg, 0.21 mmol), and pyrrole 1e (90.0 mg, 0.31 mmol).
The diastereomeric ratio of the addition products was determined to
1
be >95:5 by H NMR analysis of the crude reaction mixture. The
crude residue was purified by silica gel flash chromatography
(petroleum ether/EtOAc 70:30) to yield 58.1 mg (51%) of the anti-
6f as a yellow resin: TLC, Rf = 0.38 (petroleum ether/EtOAc =
1
70:30); [α]20 = +106.9 (c = 0.57, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 7.48 (dd, J = 6.2, 2.1 Hz, 1H, H4), 7.43−7.40 (m, 2H, Cbz),
7.38−7.30 (m, 3H, Cbz), 6.92 (d, J = 2.9 Hz, 1H, H3″), 6.55 (dd, J =
8.9, 2.9 Hz, 1H, H5″), 6.40 (brd, J = 9.0 Hz, 1H, H6″), 6.21 (dd, J =
6.2, 1.6 Hz, 1H, H3), 5.34 (d, J = 12.4 Hz, 1H, Cbz), 5.26 (d, J = 12.4
Hz, 1H, Cbz), 5.09 (brs, 1H, H5), 4.46 (dt, J = 5.6, 2.8, 2.8 Hz, 1H,
H1′), 3.89 (dd, J = 10.6, 2.2 Hz, 1H, H2′), 3.74 (dd, J = 10.6, 5.8 Hz,
t
1H, H2′) 3.70 (s, 3H, OMe), 2.23 (s, 3H, SMe), 0.92 (s, 9H, Bu),
0.06 (s, 3H, CH3), 0.05 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ
168.5 (Cq), 151.5 (Cq), 151.2 (Cq), 148.2 (CH), 141.3 (Cq), 135.3
(Cq), 128.6 (2CH), 128.3 (CH), 128.2 (CH), 128.1 (2CH), 121.6
(Cq), 119.4 (CH), 115.2 (CH), 111.7 (CH), 67.9 (CH2), 65.8 (CH),
63.7 (CH2), 55.8 (CH3), 54.6 (CH), 25.9 (CH3), 18.1 (Cq), 18.1
(CH3), −5.6 (2CH3); ESI-MS m/z 565.30 [M + Na]+ (calcd 565.23
[M + Na]+). Anal. Calcd for C28H38N2O5SSi: C, 61.96; H, 7.06; N, 5.16.
10295
dx.doi.org/10.1021/jo201875a | J. Org. Chem. 2011, 76, 10291−10298