194 J ournal of Natural Products, 2003, Vol. 66, No. 2
Nieman et al.
mmol); TFA salt of ethyl (2E,4S)-4-amino-2,5-dimethylhex-2-
enoate (0.822 mmol, prepared from N-Bocvaline by General
Procedures 6-9 (69% yield to end of General Procedure 8));
CH2Cl2 (1.5 mL); and DIEA (0.464 mL, 2.66 mmol). The crude
product was purified by radial column chromatography (2 mm
plate, 3:7 diethyl ether/petroleum ether, loaded with chloro-
form), affording 0.328 g (0.822 mmol, quantitative yield) of a
colorless oil. 65: 1H NMR (400 MHz, CDCl3) 0.88 (d, 3H, J )
6.8 Hz), 0.91 (d, 3H, J ) 6.8 Hz), 0.95 (3, 9H), 1.27 (t, 3H, J )
14.3 Hz), 1.40 (s, 9H), 1.78 (octet, 1H, J ) 6.8 Hz), 1.91 (d,
3H, J ) 1.1 Hz), 3.72 (bd, 1H, J ) 9.7 Hz), 4.17 (q, 2H, J ) 7.1
Hz), 4.55 (bq, 1H, J ) 8.5 Hz), 5.16 (bs, 1H), 5.67 (bs, 1H),
6.47 (d, 1H, J ) 9.7 Hz); HREIMS m/z 398.2778 (calcd for
(t, 3H, J ) 7.1 Hz), 1.40 (s, 2H), 1.82-1.92 (m, 1H), 1.86 (d,
3H, J ) 1.2 Hz), 2.72 (s, 1H), 2.80 (s, 2H), 2.88 (s, 1H), 2.96 (s,
2H), 3.01-3.2 (m, 1H), 3.26-3.48 (m, 1H), 3.67 (s, 3H), 4.17
(q, 2H, J ) 7.3 Hz), 4.79 (t, 0.6H, J ) 9.0 Hz), 4.86-5.09 (m,
1.5H), 6.60 (d, 1H, J ) 9.0 Hz), 6.81 (bs, 1H), 7.02-7.25 (m,
3H), 7.55 (m, 1H); HRCIMS m/z 627.4138 (calcd for C36H57N4O6
(M + H), 627.4121).
E t h yl (S)-Nr-ter t-Bu t oxyca r b on ylt r yp t op h a n yl-(S)-
ter t-leu cyl-(2E,4S)-N-m eth yl-4-a m in o-2,5-d im eth ylh ex-2-
en oa te (69). Following the general procedure 13, ester 69 was
prepared with the following: NR-Boc-tryptophan (40 mg, 0.13
mmol); DIEA (70 µL, 0.40 mmol); DMAP (10 mg, 0.08 mmol);
PyBrop (62 mg, 0.13 mmol); TFA salt of ethyl (S)-tert-leucine-
(2E,4S)-N-methyl-4-amino-2,5-dimethylhex-2-enoate (crude from
General Procedure 9 with 50 mg (0.12 mmol) of 59); and CH2-
Cl2 (2 mL). Purification of the crude product by silica gel
column chromatography (1:1 diethyl ether/petroleum ether)
afforded 43 mg (59% yield) of 69: 1H NMR (200 MHz, CDCl3)
0.76 (d, 3H, J ) 6.6 Hz), 0.83 (d, 3H, J ) 6.6 Hz), 0.84 (s, 9H),
1.27 (t, 3H, J ) 7.1 Hz), 1.37 (s, 9H), 1.82-1.90 (m, 1H), 1.86
(d, 3H, J ) 1.5 Hz), 2.93 (s, 3H), 3.17 (d, 1H, J ) 6.8 Hz), 4.17
(q, 2H, J ) 7.3 Hz), 4.42 (q, 1H, J ) 7.1 Hz), 7.75 (d, 1H, J )
9.5 Hz), 5.00 (t, 1H, J ) 9.5 Hz), 5.10 (d, 0.5H, J ) 7.8 Hz),
6.62 (dd, 1H, J ) 1.5 and 9.5 Hz), 7.04-7.20 (m, 4H), 7.31
(dd, 1H, J ) 1.2 and 6.7 Hz), 7.67 (d, 1H, J ) 7.1 Hz), 8.3 (s,
1H); HRCIMS m/z 599.3806 (calcd for C33H51N4O6 (M + H),
599.3808).
C
21H38N2O5, 398.2782).
N16-ter t-Bu toxyca r bon ylh em ia ster lin Eth yl Ester (66).
Following general procedure 13, ester 66 was prepared with
the following: (S)-NR-Boc-NR,N1,â,â-tetramethyltryptophan 13
(50 mg, 0.14 mmol); DIEA (72 µL, 0.41 mmol); DMAP (10 mg,
0.08 mmol); PyBroP (65 mg, 0.14 mmol); TFA salt of ethyl (S)-
tert-leucyl-(2E,4S)-N-methyl-4-amino-2,5-dimethylhex-2-
enoate (crude from General Procedure 9 with 74 mg (0.18
mmol) of 59); and CH2Cl2 (2 mL). Purification of the crude
product by silica gel column chromatography (3:7 diethyl ether/
petroleum ether) afforded 48 mg of 66 (53% yield): 1H NMR
(400 MHz, CDCl3, mixture of rotamers) 0.42 (s, 6H), 0.46 (s,
3H), 0.82 (t, 3H, J ) 6.7 Hz), 0.86 (d, 3H, J ) 6.4 Hz), 1.26 (t,
3H, J ) 7.3 Hz), 1.40 (s, 1H), 1.42 (s, 1H), 1.49 (s, 6H), 1.51 (s,
2H), 1.52 (s, 3H), 1.54 (s, 2H), 1.84 (d, 3H, J ) 1.2 Hz), 1.80-
1.90 (m, 1H), 2.92 (s, 3H), 2.99 (s, 3H), 3.72 (s, 2H), 3.73 (s,
1H), 4.09 (q, 0.3H, J ) 7.0 Hz), 4.16 (q, 0.7H, J ) 7.0 Hz),
4.37 (d, 0.7H, J ) 8.6 Hz), 4.45 (d, 0.3H, J ) 8.8 Hz), 5.02 (t,
1H, J ) 10.4 Hz), 5.64 (s, 0.3H), 5.97 (s, 0.7H), 6.12 (d, 0.3H,
J ) 8.6 Hz), 6.18 (d, 0.7H, J ) 8.5 Hz), 6.60 (dd, 1H, J ) 1.2
and 9.0 Hz), 7.05 (s, 0.3H), 7.06 (s, 0.7H), 7.16-7.30 (m, 3H),
7.95 (d, 0.3H, J ) 8.2 Hz), 8.27 (d, 0.7H, J ) 7.6 Hz); 13C NMR
(100 MHz, CDCl3, mixture of rotamers) 13.8, 14.2, 18.8, 19.4,
24.1, 24.3, 25.9, 27.7, 28.4, 28.6, 29.7, 30.1, 30.3, 31.1, 32.6,
32.7, 33.8, 34.1, 34.4, 34.7, 39.5, 39.6, 54.8, 55.2, 55.9, 60.8,
63.0, 64.2, 77.2, 79.5, 80.6, 109.3, 109.7, 118.8, 119.7, 120.7,
121.4, 121.6, 121.9, 121.9, 122.1, 124.9, 125.0, 126.6, 126.8,
132.4, 132.5, 138.0, 138.8, 139.0, 156.3, 157.3, 167.7, 169.7,
170.4, 171.3, 171.4; HRCIMS m/z 655.4423 (calcd for C37H59N4O6
(M + H), 655.4434); anal. calcd for C37H58N4O6, C 67.86%; H
8.93%; N 8.56%; found, C 67.98%; H 8.70%; N 8.34%.
N16-ter t-Bu toxycar bon yl-21-desm eth ylh em iaster lin Eth -
yl Ester (70). Following the general procedure 13, ester 70
was prepared with the following: (S)-NR-Boc-NR,N1,â,â-tet-
ramethyltryptophan 13 (5 mg, 0.014 mmol); DIEA (7.2 µL,
0.041 mmol); DMAP (1 mg, 0.008 mmol); PyBrop (7.1 mg, 0.014
mmol); TFA salt of ethyl (S)-valyl-(2E,4S)-N-methyl-4-amino-
2,5-dimethylhex-2-enoate (crude from General Procedure 9
with 6.8 mg (0.016 mmol) of 60); and CH2Cl2 (1 mL). Purifica-
tion of the crude product by silica gel column chromatography
(3:7 diethyl ether/petroleum ether) afforded 4.4 mg (51% yield)
of 70: 1H NMR (400 MHz, CDCl3) 0.22 (d, 1H, J ) 6.7 Hz),
0.30 (d, 0.5H, J ) 6.7 Hz), 0.54 (d, 1H, J ) 6.7 Hz), 0.59 (d,
0.5H, J ) 6.7 Hz), 0.69-0.94 (m, 9H), 1.23 (s, 9H), 1.27 (t,
3H, J ) 7.3 Hz), 1.48 (s, 2H), 1.50 (s, 2H), 1.57 (s, 1H), 1.60 (s,
1H), 1.82 (s, 2H), 1.87 (d, 1H, J ) 1.5 Hz), 1.95-2.08 (m, 1H),
2.81 (s, 2H), 2.83 (s, 1H), 2.96 (s, 2H), 2.97 (s, 1H), 3.45 (q,
0.8H, J ) 7.0 Hz), 3.74 (s, 3H), 4.13-4.21 (m, 1.5H), 4.32 (t,
0.6H, J ) 7.0 Hz), 4.41 (t, 0.4H, J ) 7.0 Hz), 4.76 (dd, 0.6H, J
) 6.0 and 10.0 Hz), 4.93-5.00 (m, 1.5H), 5.53 (bs, 0.4H), 5.83
(s, 0.6H), 6.12 (d, 0.5H, J ) 7.9 Hz), 6.57-6.63 (m, 1H), 7.02
(s, 0.4H), 7.05 (s, 0.6H), 7.14-7.29 (m, 3H), 7.91 (d, 0.4H, J )
8.2 Hz), 8.19 (d, 0.6H, J ) 8.2 Hz); HRCIMS m/z 641.4284
(calcd for C36H57N4O6 (M + H), 641.4278).
N16-ter t-Bu t oxyca r b on yl-N16-d esm et h ylh em ia st er lin
Eth yl Ester (67). Following the general procedure 13, ester
67 was prepared with the following: (S)-NR-Boc-N1,â,â-trim-
ethyltryptophan 32 (30 mg, 0.08 mmol); DIEA (45 µL, 0.26
mmol); DMAP (6.2 mg, 0.05 mmol); PyBroP (40 mg, 0.08
mmol); TFA salt of ethyl (S)-tert-leucyl-(2E,4S)-N-methyl-4-
amino-2,5-dimethylhex-2-enoate (crude from General Proce-
dure 9 with 32 mg (0.08 mmol) of 59); and CH2Cl2 (2 mL).
Purification of the crude product by silica gel column chroma-
tography (2:3 diethyl ether/petroleum ether) afforded 21 mg
of 67 (42% yield): 1H NMR (200 MHz, CDCl3) 0.41 (s, 9H),
0.85 (d, 3H, J ) 6.6 Hz), 0.86 (d, 3H, J ) 6.6 Hz), 1.14 (s, 3H),
1.26 (t, 3H, J ) 7.1 Hz), 1.46 (s, 9H), 1.79-1.90 (m, 1H), 1.84
(d, 3H, J ) 1.5 Hz), 2.95 (s, 3H), 3.76 (s, 3H), 4.16 (q, 1H, J )
7.1 Hz), 4.98 (t, 1H, J ) 10.2 Hz), 5.12 (d, 1H, J ) 8.3 Hz),
5.39 (d, 1H, J ) 8.3 Hz), 5.69 (d, 1H, J ) 8.1 Hz), 6.61 (dd,
1H, J ) 1.5 and 9.5 Hz), 6.99 (s, 1H), 7.11-7.31 (m, 3H), 8.13
(d, 1H, J ) 8.1 Hz); HRCIMS m/z 641.4280 (calcd for
N16-ter t-Bu toxycar bon yl-21,21′-bisdesm eth ylh em iaster -
lin Eth yl Ester (71). Following the general procedure 13,
ester 71 was prepared with the following: (S)-NR-Boc-NR,N1,â,â-
tetramethyltryptophan 13 (5 mg, 0.014 mmol); DIEA (7.1 µL,
0.41 mmol); DMAP (1 mg, 0.008 mmol); PyBrop (7.1 mg, 0.014
mmol); TFA salt of ethyl (S)-2-aminobutanoyl-(2E,4S)-N-
methyl-4-amino-2,5-dimethylhex-2-enoate (crude from General
Procedure 9 with 6.2 mg (0.016 mmol) of 61); and CH2Cl2 (1
mL). Purification of the crude product by silica gel column
chromatography (3:7 diethyl ether/petroleum ether) afforded
4.0 mg (46% yield) of 71: 1H NMR (400 MHz, CDCl3) 0.41 (t,
2H, J ) 7.3 Hz), 0.47 (t, 1H, J ) 7.3 Hz), 0.77 (d, 3H, J ) 6.5
Hz), 0.86 (d, 3H, J ) 6.7 Hz), 1.18 (t, 1H, J ) 7.0 Hz), 1.27 (t,
2H, J ) 7.0 Hz), 1.47 (s, 9H), 1.51 (s, 1H), 1.59 (s, 4H), 1.61 (s,
1H), 1.79-1.85 (m, 1H), 1.80 (s, 3H), 2.74 (s, 2H), 2.77 (s, 1H),
2.97 (s, 2H), 2.99 (s, 1H), 3.45 (q, 0.7H, J ) 7.0 Hz), 3.74 (s,
3H), 4.16 (q, 1.3H, J ) 7.0 Hz), 4.45 (q, 0.6H, J ) 6.5 Hz),
4.52 (q, 0.4H, J ) 6.5 Hz), 4.91 (t, 1H, J ) 9.3 Hz), 5.43 (bs,
0.6H), 5.73 (s, 0.6H), 6.10 (d, 0.4H, J ) 7.6 Hz), 6.16 (d, 0.6H,
J ) 8.8 Hz), 6.58 (d, 1H, J ) 7.6 Hz), 6.99 (s, 0.4H), 7.01 (s,
0.6H), 7.12-7.28 (m, 3H), 7.89 (d, 0.4H, J ) 8.2 Hz), 8.14 (d,
0.6H, J ) 7.6 Hz); HRCIMS m/z 627.4138 (calcd for C35H55N4O6
(M + H), 627.4121).
C
36H57N4O6 (M + H), 641.4278).
N16-ter t-Bu toxycar bon yl-11,11′-bisdesm eth ylh em iaster -
lin Eth yl Ester (68). Following the general procedure 13,
ester 68 was prepared with the following: (S)-NR-Boc-NR,N1-
dimethyltryptophan 58 (44 mg, 0.13 mmol); DIEA (70 µL, 0.40
mmol); DMAP (10 mg, 0.08 mmol); PyBroP (62 mg, 0.13 mmol);
TFA salt of ethyl (S)-tert-leucyl-(2E,4S)-N-methyl-4-amino-2,5-
dimethylhex-2-enoate (crude from General Procedure 9 with
50 mg (0.12 mmol) of 59); and CH2Cl2 (2 mL). Purification of
the crude product by silica gel column chromatography (1:1
diethyl ether/petroleum ether) afforded 45 mg (54% yield) of
68: 1H NMR (200 MHz, CDCl3) 0.67-0.89 (m, 6H), 0.91 (s,
9H), 1.13 (s, 1H), 1.15 (s, 1H), 1.21 (s, 4H), 1.22 (s, 1H), 1.28
Met h yl
m et h ylt r yp t op h a n yl-(S)-ter t-leu cyl-N-m et h yl-4-a m in o-
(S)-Nr-ter t-Bu t oxyca r b on yl-NR,N1,â,â-t et r a -