Solid Phase Synthesis of Vancomycin Mimics
FULL PAPER
volitile components were removed in vacuo and the remaining
aqueous phase was extracted with EtOAc (3 ϫ 80 mL). The organic
fractions were combined and extracted with 5% NaHCO3 (3 ϫ
100 mL), acidified with concd. HCl (15 mL), and extracted with
EtOAc (3 ϫ 100 mL). The organic fractions were washed with
brine, dried with Na2SO4, and the solvents were removed in vacuo
to yield pure (؉/-)-13 in quantitative yield. (1.74 g). All data
matched 14 (below).
then washed with water, brine, and dried with Na2SO4. The solvent
was removed in vacuo and the residue was purified with column
chromatography (eluent: CH2Cl2/MeOH/AcOH, 20:0:0.1 gradient
to 20:1:0.1). Lyophilization gave 382 mg (76%) of compound 17 as
a white powder, m.p. 85 °C (dec.). Rf ϭ 0.6 (CH2Cl2/MeOH, 3:1).
[α]D ϭ Ϫ48.3 (c ϭ 0.18, MeOH). Chiral HPLC analysis: 80% ee
1
Rt: 5.4 min (S), Rt: 18.6 min (R). H NMR (CD3OD): δ ϭ 0.19 [s,
6 H, Si(CH3)2], 0.98 [s, 9 H, SiC(CH3)3], 4.22 (t, J ϭ 6 Hz, 1 H,
CH-Fmoc), 4.30, 4.32 (2 H, CH2-Fmoc), 5.17 (s, 1 H, Hα), 6.78
(dd, J ϭ 8.5, J ϭ 1.5 Hz, 1 H, ArH), 6.94 (s, 1 H, ArH), 7.02 (d,
J ϭ 8 Hz, 1 H, ArH), 7.21 (t, J ϭ 8 Hz, 1 H, ArH), 7.29 (t, J ϭ
6.6 Hz, 2 H, ArH-Fmoc), 7.38 (t, J ϭ 6.6 Hz, 2 H, ArH-Fmoc),
7.65 (d, J ϭ 7.5 Hz, 1 H, ArH-Fmoc), 7.78 (d, J ϭ 7.5 Hz, 2 H,
ArH-Fmoc) ppm. 13C NMR (CD3OD): δ ϭ Ϫ4.5, 18.1, 25.6, 46.8,
47.0, 57.7, 58.1, 67.3, 68.3, 99.9, 118.8, 119.1, 119.9, 120.4, 124.9,
125.0, 127.1, 127.7, 129.7, 130.0, 137.1, 138.7, 141.1, 141.2, 143.3,
143.5, 143.6, 143.7, 155.5, 156.0, 157.2, 173.2, 175.1 ppm. ES-MS:
m/z ϭ 504.4 [M ϩ H]ϩ, 526.3 [M ϩ Na]ϩ. C29H33NO5Si (503.21):
calcd. C 69.16, H 6.60, N 2.78; found C 69.28, H 6.53, N 2.85.
Enzymatic Resolution of (14): (؉/؊)-13 (0.41 g, 1.56 mmol) was dis-
solved in phosphate buffer (40 mL, pH 7) and CoCl2·6H2O (0.5 mg
2.1 µmol) and NaN3 (0.8 mg, 13 µmol) were added to it. After
addition of ‘‘Amano 30000’’ (0.144 g) the reaction was stirred for
5 d at 25 °C. The mixture was then acidified to pH 2Ϫ3 with a
citric acid solution and extracted with EtOAc (3 ϫ 100 mL). The
organic layer was filtered through celite and washed with brine (2
ϫ 150 mL). The organic solvents were removed in vacuo and co-
evaperated with CHCl3 (2 ϫ) to yield a white solid. The solid was
then dissolved in H2O (4 mL) and lyophilized giving 14 in 45%
yield (185 mg) with an ee of 82% (based on rotation of 15, see
below) [α]D ϭ Ϫ161 (c ϭ 0.39, MeOH). Rf ϭ 0.31 (hexane/EtOAc/
Synthesis of Receptor 18: Synthesis was performed on Fmoc-Rink-
Argogel with a loading of 0.335 mmol/g. 0.5 g Resin was depro-
tected (see Fmoc Deprotection) and then coupled (see Amino Acid
Coupling) with sequentially: Fmoc-Ala-OH, 17, Fmoc-Leu-OH,
and 7. After cyclization, deprotection, and cleavage (see below), the
crude material was purified using preparative HPLC to obtain a
white solid in 30% yield (27 mg). Rt: 18.0 min. 1H NMR (CD3OH):
δ ϭ 0.94 [d, J ϭ 5.5 Hz, 6 H, Leu(CH3)2), 1.30 (d3, J ϭ 7.0 Hz, 3
H, AlaCH), 1.60 (m, 2 H, LeuβCH2), 1.69 (m, 1 H, LeuγCH), 2.14
(s, 2 H, NH2), 3.10 (dd, J ϭ 14.5, J ϭ 5.5 Hz, 1 H, PheβCH), 3.53
(dd, J ϭ 14.5, J ϭ 4.0 Hz, 1 H, PheβCH), 4.24 (m, 3 H, 3NH),
5.10 (d, J ϭ 5.5 Hz, 1 H, PhgαH), 6.06 (s, 1 H, PhgC2H], 7.02,
7.56 (s, 2 H, NH2), 7.07 (d, J ϭ 7.0 Hz, 1 H, ArH), 7.13 (d, J ϭ
8.5 Hz, 1 H, ArH), 7.19 (d, J ϭ 7.5 Hz, 1 H, ArH), 7.37 (t, J ϭ
7.5 Hz, 1 H, ArH), 7.57 (s, 1 H, ArH), 7.99 (s, 1 H, ArH), 8.24 (d,
J ϭ 6.5 Hz, 1 H, NH), 8.31 (d, J ϭ 4.5 Hz, 1 H, NH) ppm. ES-
MS: m/z ϭ 541.3 [M ϩ H]ϩ, 563.3 [M ϩ Na]ϩ.
1
AcOH, 1:1:0.05). H NMR (CD3OD): δ ϭ 5.43 (s, 1 H, Hα), 6.78
(d, J ϭ 8 Hz, 1 H, ArH), 6.90 (m, 2 H, ArH), 7.19 (t, J ϭ 8 Hz, 1
H, ArH) ppm. 13C NMR (CD3OD): δ ϭ 58.3, 116.0, 116.7, 120.1,
130.9, 117.4 (q, JC,F ϭ 286 Hz), 137.9, 159.0, 158.6 (q, JCCF
ϭ
45 Hz), 172.3 ppm. C10H8F3NO4 (263.17): calcd. C 45.64, H 3.06,
N 5.32; found C 45.38, H 3.11, N 5.26.
(3-Hydroxy)phenylglycine·HCl (15): To 14 (0.1 g, 0.4 mmol) was ad-
ded aqueous HCl (6 , 4 mL) and acetic acid (4 mL) in a round
bottom flask fitted with a condenser. The mixture was heated to
65 °C overnight and then evaporated to dryness to quantitatively
yield the free amino acid hydrochloride salt (0.08 g) after lyophiliz-
ation. [α]D ϭ Ϫ128 (c ϭ 0.13, 6 HCl), 82% ee, (ref.[49] [α]D
Ϫ151 (97% ee, c ϭ 0.13, 6 HCl).
ϭ
Fmoc-(3-Hydroxy)phenylglycine
(16):
(3-Hydroxy)phenyl-
glycine·HCl (15, 0.245 g, 1.2 mmol) was dissolved in water (4 mL)
and the pH was adjusted to 9 with NEt3 (20 drops). Fmoc-OSu
(0.410 g, 1.2 mmol) was dissolved in acetonitrile (4 mL) and added
all at once to the stirred solution. The reaction was stirred at room
temperature for 30 min and the pH was kept at 8.5 with NEt3. The
clear light-beige reaction mixture was neutralized with HCl and the
acetonitrile was removed in vacuo. 1 KHSO4 (50 mL) was added
and then extracted with EtOAc (3 ϫ 100 mL). The organic solvents
were then combined, washed with brine, and dried with Na2SO4.
The solvent was removed in vacuo and purified using column chro-
matography (eluent: CH2Cl2/MeOH/AcOH, 10:1:0.1) yielding
0.448 g (96%) of 16 as a white powder, m.p. 173Ϫ174 °C. Rf ϭ 0.49
(CH2Cl2/MeOH/AcOH, 5:1:0.1). 1H NMR (CD3CN): δ ϭ 4.22 (m,
1 H, CH-Fmoc), 4.32 (d, 2 H, CH2-Fmoc), 5.17 (d, 1 H, NH), 6.48
(d, 1 H, αCH), 6.79 (dd, 1 H, ArH), 6.75 (m, 2 H, ArH), 7.21 (t,
1 H, ArH), 7.28Ϫ7.43 (m, 4 H, ArH-Fmoc), 7.66 (d, 2 H, ArH-
Fmoc), 7.81 (d, 2 H, ArH-Fmoc) ppm. 13C NMR (CD3CN): δ ϭ
47.9, 58.8, 67.5, 115.4, 116.3, 119.9, 121.0, 126.2, 128.4, 131.0,
142.1, 144.9, 158.1, 172.3 ppm. MS: m/z ϭ 390.1 [M ϩ H]ϩ, 412.1
[M ϩ Na]ϩ. C23H19NO5 (389.13): calcd. C 70.94, H 4.92, N 3.60;
found C 71.04, H 4.86, N 3.51.
Fmoc Deprotection: To the resin was added 20% piperidine in NMP
(3 ϫ 8 min) and agitated by bubbling nitrogen through the solution.
The resin was washed with NMP (3 ϫ 2 min) and CH2Cl2 (3 ϫ 2
min). The ‘‘Kaiser test’’[50] was performed on a small portion of
beads for elucidation of the free amine terminus.
Amino Acid Coupling: To the reaction vessel containing the depro-
tected resin (500 mg) was added sequentially the appropriate amino
acid (4 equivalents, 0.67 mmol) in NMP (3 mL), BOP (296 mg,
0.67 mmol) in NMP (3 mL) and DIPEA (233 µL, 1.34 mmol). The
reaction mixture was agitated by bubbling nitrogen through the
solution for 75 min. For amino acids 7 and 17, 2.5 equivalents were
used with reaction times of 150 min. The beads were then washed
with NMP (3 ϫ 2 min) and CH2Cl2 (3 ϫ 2 min) and the ‘‘Kaiser
test’’ was performed on a small portion of beads. The negative test
provided evidence for successful coupling.
On-bead Cyclization: TBAF·3H2O (1.29 g, 4.1 mmol) was dissolved
˚
in DMF (45 mL) and dried with molecular sieves (4 A, 3 h). The
TBAF solution in DMF (11 mL) was then added to the resin and
shaken (40 h). The resin was washed exhaustively with NMP,
CH2Cl2, NMP, CH2Cl2, 3% AcOH in dioxane, Et2O, NMP, and
CH2Cl2. (each 2 ϫ 2 min).
Fmoc-(3-TBDMSO)phenylglycine (17): 16 (390 mg, 1.0 mmol) was
dissolved in pyridine (1.5 mL) and then a solution of TBDMS-Cl
(380 mg, 2.5 mmol) in pyridine (2 mL) was added. The solution
was fitted with a condenser, and stirred overnight at 70 °C. The
solvent was removed in vacuo, then 1 KHSO4 (30 mL) and
EtOAc (80 mL) were added to the residue. The organic phase was
Deprotection and Cleavage from the Resin: The resin was treated
with (TFA/water/TIS, 95:2.5:2.5) for 3 h. The resin was washed
with TFA (1 mL, 2 ϫ 2 min) and the organic solvents were removed
Eur. J. Org. Chem. 2003, 3131Ϫ3138
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3137