A Novel Allylic Anchor in Solid Phase Synthesis
J . Org. Chem., Vol. 62, No. 4, 1997 821
) 7.71 (d, 2H), 7.57 (d, 2H), 7.39-7.30 (m, 4H), 5.84-5.77 (m,
2H), 5.55 (d, 1H, VNH, J ) 9.1), 4.60 (d, 2H, J ) 4.1), 4.38-
4.19 (m, 4H, VR, CH2-, H-9-Fmoc), 3.97 (d, 2H, J ) 3.6), 3.67
(t, 2H, J ) 6.6), 3.60-3.57 (m, 12H), 2.46 (t, 2H, J ) 6.6), 2.16
CDCl3) δ ) 7.74 (d, 2H), 7.58 (d, 2H), 7.41-7.13 (m, 5H), 5.86-
5.80 (m, 2H), 5.40 (d, 1H, VNH, J ) 9.2), 4.62 (d, 2H, J ) 4.2),
4.40-4.17 (m, 4H, VR, CH2-, H-9-Fmoc), 4.01 (d, 2H, J ) 3.8),
3.74 (t, 2H, H-3, J ) 6.2), 3.62-3.57 (m, 12H), 2.60 (t, 2H,
H-2, J ) 6.2), 2.33-2.06 (m, 1H, Vâ), 0.95, 0.88 (2 × d, 6H,
Vγa, Vγb, J a ) J b ) 6.8).
(mc, 1H, Vâ), 1.41 (s, 9H), 0.94, 0.87 (2 × d, 6H, Vγa, Vγb, J a
)
J b ) 6.8). 50.3 MHz 13C-NMR (CDCl3) δ ) 171.50, 170.57,
156.00, 143.64, 143.45, 140.97, 131.49, 127.39, 126.77, 125.50,
124.80, 119.66, 80.10, 70.37, 70.27, 70.18, 70.05, 69.37, 66.67,
66.57, 64.69, 58.80 (VR), 46.89, 35.96, 30.94 (Vâ), 27.79, 18.75
(Vγa), 17.33 (Vγb).
(E)-17-(N-(9-F lu or en ylm eth oxyca r bon yl)-O-ter t-bu tyl-
L-th r eon yloxy)-4,7,10,13-tetr a oxa -15-h ep ta d ecen oic Acid
P h en a cyl Ester (12a ). Yield: 83% (cor). Rf : 0.32 (petroleum
ether/EtOAc, 1:2). 200 MHz 1H-NMR (CDCl3) δ ) 7.88 (dd,
2H, o-Pac), 7.74 (d, 2H, J ) 7.3), 7.65-7.24 (m, 9H, H-1-, H-8-,
H-2-, H-7-, H-3-, H-6-Fmoc, m-, p-Pac), 5.86-5.81 (m, 2H), 5.61
(d, 1H, TNH), 5.33 (s, 2H), 4.64-4.22 (m, 7H, Tâ, H-17, TR, CH2-,
H-9-Fmoc), 3.99 (d, 2H), 3.80 (t, 2H, J ) 6.6), 3.63-3.55 (m,
12H), 2.78 (t, 2H, J ) 6.6), 1.22 (d, 3H, Tγ, J ) 6.6), 1.11 (s,
9H).
(E)-17-(N-(9-F lu or en ylm eth oxyca r bon yl)-O-ter t-bu tyl-
L-th r eon yloxy)-4,7,10,13-tetr a oxa -15-h ep ta d ecen oic Acid
(12b). To a stirred solution of 12a (2.62 g, 3.13 mmol)cor in 40
mL of glacial acetic acid was added 3.5 g of freshly activated
zinc. After 2 h zinc was removed by filtration over Hyflo
followed by distillation of the filtrate. The residue was
dissolved in dichloromethane and washed with 0.5 M HCl. The
aqueous layer was reextracted with dichloromethane. The
combined organic layers were dried over MgSO4, and the
solvent was removed by distillation. The residue was purified
by chromatography (EtOAc/AcOH, 100:1). Coevaporation with
toluene yielded 2.11 g (97%, cor) of a clear and colorless, highly
viscous oil. Rf: 0.11 (EtOAc/AcOH, 100:1). [R]22 ) 1.54 (c )
D
1
1.0, toluene). 200 MHz H-NMR (CDCl3) δ ) 7.74 (d, 2H, J )
Gen er a l P r oced u r e for Syn th esis of An ch or -Con ju -
ga tes 8b-11b. The tert-butyl esters 8a -11a were treated
with TFA for 45 min. After evaporation of TFA in vacuo, the
residue was dissolved in chloroform. The solution was washed
with 1 M HCl. The aqueous phase was extracted twice with
chloroform. The combined organic layers were washed with
brine and dried over Na2SO4 prior to removal of the solvent.
The residue is purified by chromatography. The eluents
usually contain small amounts of acetic acid, which were
removed by coevaporation with toluene.
7.3), 7.65-7.59 (m, 2H), 7.41-7.25 (m, 4H), 5.86-5.80 (m, 2H),
5.68 (d, 1H, TNH, J ) 9.6), 4.65-4.22 (m, 7H, Tâ, H-17, TR,
CH2-, H-9-Fmoc), 4.00 (d, 2H, J ) 3.6), 3.73 (t, 2H, J ) 6.3),
3.67-3.59 (m, 12H), 2.60 (t, 2H, H-2, J ) 6.3), 1.22 (d, 3H, Tγ,
J ) 6.2), 1.12 (s, 9H). 50.3 MHz 13C-NMR (CDCl3) δ ) 175.03,
170.64 (TCO), 156.63, 143.74, 143.49, 140.98, 131.37, 127.43,
126.83, 125.64, 124.98, 124.92, 119.68, 73.89, 70.42, 70.26,
70.18, 70.06, 69.34, 67.14 (Tâ), 67.00, 66.26, 64.94, 59.66 (TR),
46.88, 34.53 (C-2), 28.12, 20.63 (Tγ).
(E)-17-(N-(9-F lu or en ylm eth oxyca r bon yl)-L-a la n yloxy)-
4,7,10,13-tetr a oxa -15-h ep ta d ecen oyl-â-a la n in e P h en a cyl
Ester (13). A solution of DCC (1.06 g, 5.14 mmol) in 10 mL
of dichloromethane was added to a solution of 8b (3.53 g, 4.67
mmol)korr and HONSu (0.54 g, 4.70 mmol) in 25 mL of
dichloromethane and was stirred for 25 min. The resulting
solution was combined with a mixture of â-alanine phenacyl
ester hydrochloride (1.13 g, 4.67 mmol) and diisopropylethyl-
amine (DIEA, 0.80 mL, 4.67 mmol) in 20 mL of dry ethyl
acetate, which had been stirred for 15 min. The urea precipi-
tated after 17 h and was filtered off. The filtrate was
concentrated in vacuo. The residue was dissolved in 100 mL
of acetone and cooled to 0 °C for 16 h. The mixture was filtered
again prior to removal of the solvent in vacuo. The residue
was dissolved in chloroform and washed with saturated
NaHCO3 and 1 M HCl solution and brine. After each extrac-
tion the aqueous layers were reextracted two to three times.
The combined organic layers were dried over Na2SO4, and the
solvent was evaporated in vacuo. The residue was purified
by chromatography (EtOAc/EtOH, 9:1), which yielded 3.17 g
(82%, cor) of a clear, yellowish and viscous oil. Rf: 0.29
(E)-17-(N-(9-F lu or en ylm eth oxyca r bon yl)-L-a la n yloxy)-
4,7,10,13-tetr aoxa-15-h eptadecen oic Acid (8b). Yield: 84%
(cor). Rf : 0.27 (EtOAc/AcOH, 100:1). [R]22 ) 6.0 (c ) 1.00,
D
toluene). 200 MHz 1H-NMR (CDCl3) δ ) 7.75 (d, 2H), 7.59 (d,
2H), 7.43-7.14 (m, 4H), 5.94-5.80 (m, 2H), 5.47 (d, 1H, J )
7.7), 4.64 (d, 2H, J ) 3.7), 4.43-4.30 (m, 3H, AR, CH2-Fmoc),
4.21 (t, 1H, J ) 6.8), 4.02 (d, 2H, J ) 3.3), 3.75 (t, 2H, H-3, J
) 6.2), 3.65-3.52 (m, 12H), 2.60 (t, 2H, H-2, J ) 6.2), 1.43 (d,
3H, Aâ, J ) 7.2). 50.3 MHz 13C-NMR (CDCl3) δ ) 175.25
(COOH), 172.69 (ACO), 155.62, 143.73, 143.58, 141.10, 131.26,
127.54, 126.91, 125.79, 124.91, 119.81, 70.52, 70.37, 70.28,
70.20, 70.13, 69.45, 66.82, 66.27, 65.02, 49.52 (AR), 46.93, 34.70
(C-2), 18.38 (Aâ).
(E)-17-(N-(9-F lu or en ylm et h oxyca r b on yl)glycyloxy)-
4,7,10,13-tetr aoxa-15-h eptadecen oic Acid (9b). Yield: 88%.
1
Rf : 0.37 (EtOAc/AcOH, 100:1). 200 MHz H-NMR (CDCl3) δ
) 7.73 (d, 2H), 7.58 (d, 2H), 7.41-7.24 (m, 4H), 5.85-5.78 (m,
2H), 5.50 (d, 1H, GNH, J ) 5.5), 4.63 (d, 2H, J ) 4.1), 4.38 (d,
2H, J ) 7.0), 4.20 (t, 1H, J ) 7.0), 4.00-3.90 (m, 4H, H-14,
GR), 3.75 (t, 2H, H-3, J ) 6.2), 3.61-3.54 (m, 12H), 2.58 (t,
2H, H-2, J ) 6.2). 100.6 MHz 13C-NMR (CDCl3) δ ) 175.03
(COOH), 169.74 (GCO), 156.34, 143.68, 141.12, 131.45, 127.56,
126.93, 125.72, 124.94, 119.81, 70.49, 70.37, 70.29, 70.19,
70.14, 69.48, 67.02, 66.32, 64.97, 46.96, 42.59 (GR), 34.72 (C-
2).
1
(EtOAc/EtOH, 9:1). 200 MHz H-NMR (CDCl3) δ ) 7.88 (dd,
2H), 7.74 (d, 2H, J ) 7.7), 7.60-7.23 (m, 9H), 7.11 (m, 1H,
â-AlaNH), 5.84-5.79 (m, 2H), 5.41 (d, 1H, ANH), 5.37 (s, 2H),
4.62 (d, 2H), 4.41-4.34 (m, 3H, AR, CH2-Fmoc), 4.21 (t, 1H, J
) 6.9), 3.98 (d, 2H, J ) 3.5), 3.74 (t, 2H, J ) 6.0), 3.65-3.56
(m, 14H, (CH2CH2O)3, â-Alaâ), 2.68 (t, 2H, â-AlaR, J ) 6.0),
2.50 (t, 2H, H-2, J ) 6.0), 1.42 (d, 3H, Aâ, J ) 7.2). 50.3 MHz
13C-NMR (CDCl3) δ ) 192.10, 172.50, 171.32, 155.50, 143.68,
143.53, 141.00, 133.87, 133.62, 131.23, 128.68, 127.52, 127.46,
126.83, 125.59, 124.83, 119.72, 70.44, 70.30, 70.25, 70.07,
69.99, 69.85, 69.40 (C-14), 66.90, 66.67, 65.86, 64.88, 49.45,
46.85, [36.68, 34.79, 34.04 (C-2, â-AlaR, â-Alaâ)], 18.24.
(E)-17-(N-(9-F lu or en ylm eth oxyca r bon yl)-L-p r olyloxy)-
4,7,10,13-tetr a oxa -15-h ep ta d ecen oic Acid (10b). Yield:
85% (cor). Rf: 0.25 (EtOAc/AcOH, 100:1). [R]22 ) -15.83 (c
D
1
) 1.05, toluene). 200 MHz H-NMR (CDCl3, signal doubling
due to Pro-(E,Z)-isomers) δ ) 7.74 (d, 2H), 7.60-7.56 (m, 2H),
7.42-7.03 (m, 4H), 5.83-5.75 (m, 2H), 4.63, 4.54 (2 × d, 2H,
H-17, J 1 ) 3.4, J 2 ) 4.4), 4.44-4.28 (m, 4H, PR, CH2-, H-9-
Fmoc), 4.01 (d, 1.1H, H-14, J ) 3.9), 3.91 (d, 0.9H, H-14, J )
4.3), 3.74 (t, 2H, H-3, J ) 6.2), 3.62-3.51 (m, 14H, Pδ, (CH2-
CH2O)3), 2.60 (t, 2H, H-2, J ) 6.2), 2.32-2.15 (m, 1H, Pâ1),
2.08-1.96 (m, 3H, Pâ2, Pγ). 100.6 MHz 13C-NMR (CDCl3, signal
doubling due to Pro-(E,Z)-isomers) δ ) 175.30 (COOH), 172.12
(PCO), 154.82, 154.39, 143.94, 143.67, 143.54, 141.10, 131.15,
130.80, 128.85, 128.05, 127.52, 126.88, 126,29, 125.90, 125.12,
125.02, 119.79, 70.61, 70.48, 70.33, 70.19, 70.11, 69.33, 67.41,
66.26, 64.74, [59.10, 58.70 (2 × PR)], 47.09, 47.01, [46.84, 46.34
(2 × Pδ)], 34.68 (C-2), [30.88, 29.74 (2 × Pâ)], [24.18, 23.21 (2
× Pγ)].
(E)-17-Br om o-4,7,10,13-t et r a oxa -15-h ep t a d ecen oyl-â-
a la n in e P h en a cyl E st er (14). To a solution of 5 (9.74 g,
27.42 mmol) in 150 mL of dichloromethane HONSu (3.15 g,
27.37 mmol) was added. At 0 °C DCC (5.94 g, 28.79 mmol)
was added. After stirring for 30 min, the mixture was allowed
to warm up to room temperature. Urea was removed by
filtration. For completion of precipitation the filtrate was
concentrated in vacuo and triturated with acetone. After 14
h at 0 °C the solution was filtered and concentrated to dryness.
The residue was dissolved in a mixture of ethyl acetate (190
mL) and ethanol (50 mL). The resulting solution was com-
bined with a mixture of â-alanine phenacyl ester hydrochloride
(6.67 g, 27.4 mmol) and DIEA (4.7 mL, 27.4 mmol) in 160 mL
of ethyl acetate, which already had been stirred for 10 min.
(E)-17-(N-(9-F lu or en ylm eth oxyca r bon yl)-L-va lyloxy)-
4,7,10,13-tetr a oxa -15-h ep ta d ecen oic Acid (11b). Yield:
57%. Rf : 0.39 (EtOAc/AcOH, 100:1). 1H-NMR (200 MHz,