3888 J . Org. Chem., Vol. 62, No. 12, 1997
Bastiaans et al.
2(S)-[(ter t-Bu t yloxyca r b on yl)a m in o]-3-[4-(ter t-b u t yl-
oxy)p h en yl]p r op a n a l (29). To a stirred solution of 28 (8.79
g, 25.0 mmol) in CH2Cl2 (250 mL) at -70 °C was added
DIBALH (1 N in hexanes, 62.5 mL, 62.5 mmol) over 15 min,
after which time the reaction was usually complete (monitored
by TLC). Subsequently, a solution of EtOH/36% HClaq (9:1,
6.0 mL) was added slowly (the temperature was kept below
-65 °C). The reaction mixture was added to a vigorously
stirred solution of HClaq (1 N, 400 mL) at 0 °C. The layers
were separated, and the aqueous layer was extracted with ice-
cold CH2Cl2 (2 × 150 mL). The combined organic layers were
washed with ice-cold HClaq (1 N, 2 × 150 mL), ice-cold H2O (2
× 150 mL), and ice-cold brine, dried (Na2SO4), and concen-
trated in vacuo at ambient temperature, to give aldehyde 29
as a colorless oil that was used as such without delay (8.04 g;
100% crude yield): 1H NMR (CDCl3) 1.31 (s, 9 H), 1.42 (s, 9
H), 3.07 (bd, J ) 6.7, 2 H), 4.43 (m, 1 H), 5.06 (bd, J ) 8.1, 1
H), 6.91, 7.01 (AB-system, J ) 9.2, 4 H), 9.61 (s, 1 H).
E t h yl 4(S)-[(ter t-Bu t yloxyca r b on yl)a m in o]-5-[4-(ter t-
bu tyloxy)p h en yl]p en t-2(E)-en oa te (30). A dispersion of
NaH (60% in mineral oil, 2.00 g, 50.0 mmol) was washed with
Et2O (2×). THF (130 mL) was added. The stirred suspension
was cooled with an ice bath, and triethyl phosphonoacetate
(10.5 mL, 52.5 mmol) was carefully added (H2 evolution!).
Subsequently, the reaction mixture was stirred at room
temperature for 10 min. The resulting solution was placed
again in an ice bath and added dropwise to a solution of 29
(8.04 g, max 25.0 mmol) in THF (200 mL) at -50 °C. After
an additional 30 min at -50 °C, the reaction mixture was
warmed to 10 °C in 2.5 h. The resulting yellow solution was
added to a vigorously stirred mixture of aqueous NaHCO3 (5%)/
EtOAc (500 mL, 2:3), the layers were separated, and the
aqueous layer was extracted with EtOAc (2 × 150 mL). The
combined organic layers were washed with H2O (2×) and
brine, dried (Na2SO4), filtered, and concentrated in vacuo to
give, after purification by LC (EtOAc/PE, 1:4), 30 as a slightly
yellow oil (9.09 g, 93.7%): 1H NMR (CDCl3) 1.25 (t, J ) 6.7, 3
H), 1.30 (s, 9 H), 1.39 (s, 9 H), 2.80 (m, 2 H), 4.16 (q, J ) 6.7,
2 H), 4.39-4.62 (m, 2 H), 5.80 (dd, J ) 16.7, 1.5, 1 H), 6.67
(dd, J ) 16.7, 5.0, 1 H), 6.90, 7.02 (AB-system, J ) 9.2, 4 H);
FAB-HRMS calcd for [C22H33NO5 + H]+ 392.2437, found
392.2460.
15.6, 1 H), 5.90 (m, 1 H), 6.30 (bs, 1 H), 6.79 (dd, J ) 15.6, 4.9,
1 H), 6.90 and 7.06 (AB-system, J ) 8.4, 4 H) , 7.05 (m
overlapping, 1 H); 13C NMR (CDCl3) 22.6, 28.0, 28.5, 40.0, 40.9,
52.4, 53.1, 66.1, 78.0, 79.3, 119.7, 122.6, 123.8, 129.5, 131.1,
131.4, 144.0, 153.7, 154.9, 166.5, 170.0, 170.6; FAB-HRMS
calcd for [C28H41N3O7 + H]+ 532.3023, found 532.3042.
Allyl 2(S)-(Acetylam in o)-3-[[4(S)-[[2(R)-[[2(R,S)-h ydr oxy-
3(S)-[[[1-(a llyloxyca r bon yl)p yr r olid in -2(S)-yl]ca r bon yl]-
a m in o]-6-[[[(ter t-b u t yloxyca r b on yl)im in o][(ter t-b u t yl-
oxyca r b on yl)a m in o]m et h yl]a m in o]h exa n oyl]a m in o]-3-
ph en ylpr opan oyl]am in o]-5-[4-(ter t-bu tyloxy)ph en yl]pen t-
2-(E)-en oyl]a m in o]p r op a n oa te (35). To a vigorously stirred
solution of dipeptide 32 (1.06 g, 2.00 mmol) and 2,6-lutidine
(1.17 mL, 10.0 mmol) in CH2Cl2 (4.0 mL) at 0 °C was added
trimethylsilyl riflate (1.60 mL, 8.00 mmol). After 15 min, the
ice bath was removed, and stirring was continued for 95 min.
The reaction mixture was placed again in an ice bath, and ice-
cold saturated NH4Claq (16 mL) was added. Subsequently, the
quenched reaction mixture was extracted with EtOAc (2× 30
mL). The combined organic extracts were washed with
saturated aqueous NaHCO3 and brine, dried (Na2SO4), filtered,
and concentrated under reduced pressure to give amine 34
(contaminated with some 2,6-lutidine) as a viscous oil (1.00 g,
essentially quantitative): 1H NMR (CDCl3) 1.30 (s, 3 H), 2.01
(s, 3 H), 2.31 (bs, 2 H), 2.60 (dd, J ) 4.9, 17.9, 1 H), 2.88 (dd,
J ) 8.4, 17.9, 1 H), 3.61-3.82 (m, 3 H), 4.58-4.71 (m, 3 H),
5.30 (m, 2 H), 5.89 (m, 1 H), 5.92 (dd, J ) 15.4, 1.5, 1 H), 6.51
(bt, 1 H), 6.72 (dd, J ) 15.5, 5.1, 1 H), 6.88 (bs, 1 H), 6.92 and
7.08 (AB-system, J ) 8.2, 4 H); FAB-HRMS calcd for
[C23H33N3O5 + H]+ 431.2420, found 431.2441.
To a stirred solution of dipeptide 34 (206 mg, 0.400 mmol
+ lutidine) and tripeptide 24 (267 mg, 0.365 mmol) in CH2Cl2
(10 mL) was added DIPEA (140 mL, 0.804 mmol) followed by
TBTU (129 mg, 0.402 mmol). After 3 h, the reaction mixture
was diluted with EtOAc (100 mL), sequentially washed with
H2O (3×), aqueous NaHCO3 (5%, 3×), H2O, aqueous KHSO4
(6%, 3×), H2O (2×), and brine, dried (Na2SO4), filtered, and
concentrated in vacuo to give, after preparative TLC (EtOAc/
CH2Cl2, 6:4), 35 as a white foam (356 mg, 85.3%), pure
according to analytical TLC: 1H NMR (DMSO-d6, 400.1 MHz)
1.07-1.43 (m, 4 H), 1.19 (s, 9 H), 1.39 (s, 9 H), 1.47 (s, 9 H),
1.67-1.80 (m, 3 H), 1.81 (s, 3 H), 1.97 (m, 1 H), 2.53-2.72 (m,
3 H), 2.82 (m, 1 H), 3.19 (m, 2 H), 3.27-3.40 (m, 3 H), 3.51
(m, 1 H), 3.82 (m, 1 H), 3.90 (m, 1 H), 4.18 (m, 1 H), 4.31-
4.60 (m, 7 H), 5.03-5.32 (m, 4 H), 5.73-5.92 (m, 4 H), 6.60
(dd, J ) 15.2, 5.3, 1 H), 6.87 (part of AB-system, J ) 8.4), 6.89-
6.97 (m, 2 H), 7.08-7.24 (m, 5 H), 7.47-7.59 (m, 2 H), 8.14-
8.29 (m, 4 H), 11.50 (bs, 1 H); 13C NMR (CDCl3) 22.7, 24.5,
25.6, 28.0, 28.2, 28.7, 29.5, 31.1, 38.4, 39.4, 40.6, 40.8, 46.9,
51.1, 51.6, 53.2, 54.8, 60.8, 66.2, 66.4, 71.8, 78.2, 79.2, 83.0,
117.7, 118.7, 122.4, 123.9, 127.0, 128.5, 129.3, 129.8, 131.2,
131.5, 132.5, 136.5, 143.2, 153.1, 154.0, 154.8, 155.4, 156.1,
163.3, 167.7, 170.4, 170.4, 171.2, 172.4, 172.6.
4(S)-[(ter t-Bu t yloxyca r b on yl)a m in o]-5-[4-(ter t-b u t yl-
oxy)p h en yl]p en t-2(E)-en oic Acid (31). To stirred solution
of 30 (9.00 g, 23.0 mmol) in 1,4-dioxane/H2O (390 mL, 35:4)
was added aqueous NaOH (1 N, 23.0 mL) over a period of 2 h
so as to maintain the pH at approximately 12. The reaction
mixture was stirred overnight (the reaction was complete as
checked by TLC), acidified to pH ≈ 2.5 with aqueous 6%
KHSO4, diluted with H2O (100 mL), and extracted with EtOAc
(3 × 250 mL). The combined organic extracts were washed
with H2O and brine, dried (Na2SO4), filtered, and concentrated
under reduced pressure to give, after purification by LC
(CHCl3/MeOH, 98:2), acid 31 as a colorless crystalline solid
(8.15 g, 97.5%). The crude product could also be crystallized
N-E t h ylm or p h olin iu m 2(S)-(Acet yla m in o)-3-[[4(S)-
[[2(R )-[[2-(R ,S )-h yd r oxy-3(S )-[[[1-(a llyloxyca r b on yl)-
p yr r olid in -2(S)-yl]ca r b on yl]a m in o]-6-[[[(ter t-b u t yloxy-
ca r bon yl)im in o][(ter t-bu tyloxyca r bon yl)a m in o]m eth yl]-
a m in o]h exa n oyl]a m in o]-3-p h en ylp r op a n oyl]a m in o]-5-[4-
(t er t -b u t y lo x y )p h e n y l]p e n t -2(E )-e n o y l]a m in o ]p r o -
p a n oa te (36). To a stirred solution of 35 (316 mg, 0.270
mmol) and morpholine (1.18 mL, 13.5 mmol) in THF (38 mL)
was added Pd(PPh3)4 (20.1 mg, 0.017 mmol). After 45 min,
the volatiles were evaporated in vacuo. Purification by
preparative TLC (CH2Cl2/MeOH/NEM, 85:15:10) gave 36 as
an off-white powder (224 mg; 72.9%): 1H NMR (DMSO-d6) 0.99
(t, J ) 6.7, 3 H), 1.05-2.00 (m, 8 H), 1.20 (s, 9 H), 1.38 (s, 9
H), 1.48 (s, 9 H), 2.23-2.89 (m, 6 H), 1.81 (s, 3 H), 2.55-3.05
(m, 4 H), 3.07-3.61 (m, 10 H), 3.70 (m, 1 H), 3.81-4.00 (m, 2
H), 4.08 (m, 1 H), 4.41-4.63 (m, 2 H), 5.92 (bd, J ) 15.3, 1 H),
6.02 (bs, 1 H), 6.59 (dd, J ) 15.3, 4.7, 1 H), 6.87 (part of AB-
system, J ) 8.2, 2 H), 6.90-7.00 (m, 2 H), 7.03-7.28 (m, 5 H),
7.60 (d, J ) 8.2, 1 H), 7.79 (d, J ) 7.0, 1 H), 7.96 (bt, J ) 6.0,
1 H), 8.08 (d, J ) 8, 1 H), 8.18-8.45 (bt, 2 H), 11.49 (bs, 1 H);
FAB-HRMS calcd for [C51H75N9O13 + H]+ 1022.5563, found
1022.5546.
from CHCl3/hexane: mp 133-135 °C dec; [R]30 +9.2° (c ) 1,
D
1
CHCl3); H NMR (CDCl3, 400.1 MHz) 1.31 (s, 9 H), 1.39 (s, 9
H), 2.84 (m, 2 H), 4.46-4.70 (m, 2 H), 5.83 (dd, J ) 15.7, 1.6,
1 H), 6.94 and 7.02 (AB-system, J ) 8.3, 4 H), 6.99 (dd, J )
15.7, 5.1, 1 H); 13C NMR (CDCl3) 28.1, 28.6, 39.9, 52.3, 77.3,
78.3, 120.3, 124.1, 129.6, 131.0, 150.0, 154.1, 154.9, 170.7; FAB-
HRMS calcd for [C20H29NO5 + H]+ 364.2124, found 364.2139.
Allyl 2(S)-Acetyla m in o-3-[[4(S)-[(ter t-bu tyloxyca r bon -
yl)a m in o]-5-[4-(ter t-b u t yloxy)p h en yl]p en t -2(E)-en oyl]-
a m in o]p r op a n oa te (32). To a stirred solution of acid 31
(2.00 g, 5.50 mmol) and amine 27 (1.33 g, 5.97 mmol) in CH2Cl2
(50 mL) was added DIPEA (2.09 mL, 12.0 mmol) followed by
TBTU (1.92 g, 6.00 mmol). The reaction was complete after
1.5 h (checked by TLC). The reaction mixture was diluted with
EtOAc (200 mL) and sequentially washed with H2O (3×),
aqueous NaHCO3 (5%, 3×), H2O, aqueous KHSO4 (6%, 3×),
H2O (2×) and brine, dried (Na2SO4), filtered, and concentrated
in vacuo to give 32 as a colorless glass (2.89 g, 98.8%): mp
134-135 °C; [R]30 -49.2° (c ) 1, CHCl3); 1H NMR (CDCl3)
D
1.30 (s, 3 H), 1.39 (s, 9 H), 2.01 (s, 3 H), 2.79 (m, 2 H), 3.70 (t,
J ) 5.8, 2 H), 4.44-4.71 (m, 5 H), 5.30 (m, 2 H), 5.79 (d, J )