Hydrolysis of the 1,2- and 2,3-Peptide Bonds in Teicoplanin
J . Org. Chem., Vol. 61, No. 6, 1996 2149
After being stirred at room temperature for 72 h, the reaction
mixture was worked up as described above, yielding 5.6 g of
BOC-TDHP A. This compound was dissolved at room tem-
perature in 50 mL of dry TFA. After 5 min of stirring, the
solvent was evaporated and the oily residue was slurried with
50 mL of EtOAc and then with 150 mL of Et2O. The solid
which separated was chromatographed under the usual condi-
tions, yielding 4.9 g of pure TDHP A.
P r ep a r a tion of TDHP O via In ter m ed ia te CBZ-TDH-
P A. A stirred solution of 10.7 g (∼8 mmol) of CBZ-TD in 300
mL of a EtOH/H2O 9/1 mixture was treated with 60 g of NaBH4
as described above. After 48 h, the reaction mixture was
divided into two portions of 150 mL each. One portion was
worked up as usual to yield 1.7 g of pure CBZ-TDHP A. The
other aliquot was allowed to react for additional 72 h until
CBZ-TDHP A completely transformed into TDHP O, which
was recovered and chromatographed,47 obtaining 1.4 g of pure
title compound.
Syn th esis of VAHP fr om BOC-VA. (a ) P r ep a r a tion of
BOC-VA. A stirred solution of 1.15 g (∼1 mmol) of VA in 25
mL of a dioxane/water 1/1 mixture was adjusted at pH 6.5 with
solid NaHCO3, and then a solution of di-tert-butyl dicarbonate
in 3 mL of dioxane was added dropwise in 15 min. After being
stirred at room temperature for 24 h, the reaction mixture was
adjusted at pH 3 with 1 N HCl and 50 mL of H2O was added.
Extraction with 50 mL of a 1-BuOH/EtOH 1/1 mixture and
evaporation of the organic solvents yielded 1.2 g of BOC-VA
pure enough for the next step.
(b) Red u ctive Hyd r olysis of BOC-VA. The compound
(BOC-VA, 1.2 g) was dissolved in 50 mL of a EtOH/H2O 8/2
(or 2/8) mixture and then treated with 6 g of NaBH4 as
described above for the reductive hydrolysis of BOC-TD,
yielding 0.85 g of pure title compound.
Syn th esis a n d Red u ctive Hyd r olysis of Ac-VAHP . The
compound was prepared (98%) by reaction of 1 mmol of VAHP
with 1.1 mmol of MeCOCl in 20 mL of DMF at room
temperature (4 h), in the presence of 1 mmol of TEA. Then it
was submitted to reductive hydrolysis (reaction time: 35 h)
under the same conditions described above for BOC-VA,
yielding48 VAHP (36%) and Ac-RH-VAHP (24%).
Syn th esis of RC-1 a n d RC-2. Step a : BOC-Ac-1 a n d
BOC-Ac-2. To a stirred solution of 1.3 g (∼1 mmol) of BOC-
TDHP A and of 84 mg of NaHCO3 in 30 mL of a Me2CO/H2O
1/1 mixture was added dropwise a solution of 1 mmol of
bromoacetyl (for BOC-Ac-1) or 3-bromopropionyl (for BOC-
Ac-2) chloride in 2 mL of Me2CO with cooling to 0-3 °C. After
15 min, the reaction mixture was poured into 40 mL of H2O,
and after the pH was adjusted to 4.5 with glacial AcOH, the
resulting mixture was extracted with 100 mL (2 × 50 mL) of
EtOAc (or 1-BuOH). The organic layer was washed with 25
mL of H2O, and then it was concentrated at 35 °C (or 45 °C)
under reduced pressure to a small volume (∼5 mL). On
addition of Et2O (∼50 mL), the precipitated solid was collected
and dried in vacuo at room temperature overnight, yielding
BOC-Ac-1 (0.79 g) or BOC-Ac-2 (1.3 g).
Step b: Ac-1 a n d Ac-2. A solution of 0.7 mmol of one of
the above BOC-acyl derivatives in 10 mL of dry TFA was
stirred at room temperature for 10 min, and then the solvent
was evaporated (30 °C, reduced pressure). The oily residue
was redissolved in 50 mL of H2O, and the resulting solution
was adjusted at pH 7 with 1 N NaOH then extracted with 50
mL of 1-BuOH. The organic layer was washed with 15 mL of
H2O and concentrated at 40 °C under reduced pressure to a
small (∼5 mL) volume. Upon addition of 50 mL of Et2O, the
precipitated solid was collected, washed with 20 mL of Et2O,
and then dried in vacuo at room temperature overnight,
yielding (100%) Ac-1 or Ac-2.
Step c: RC-1 a n d RC-2. To a stirred solution of 0.5 mmol
of one of the above compounds in 40 mL of DMF was added
100 mg (∼0.8 mmol) of K2CO3, and the resulting suspension
was stirred at room temperature for 2 h. Then the reaction
mixture was poured into 100 mL of H2O. The resulting
solution was adjusted at pH 3 with 1 N HCl, and then it was
extracted with 70 mL of 1-BuOH. The organic layer was
washed with 50 mL of H2O, and then it was concentrated at
35 °C under reduced pressure to a small (∼10 mL) volume.
On addition of 50 mL of Et2O, the precipitated solid was
collected and purified by reversed-phase chromatography
under the usual conditions, yielding pure RC-1 (85%) or RC-2
(90%).
NMR Da ta (DMSO-d6, δ in p p m ) for Som e Rep r esen ta -
tive Com p ou n d s. RH-TD: 1H NMR δ 2.67 (m, 1H), 2.87
(m, 1H), 3.51 (br s, 2H), 3.96 (m, 1H), 4.17 (br s, 1H), 4.20 (dd,
1H), 4.33 (br s, 1H), 4.38 (d, 1H), 4.59 (br s, 1H), 5.11 (s, 1H),
5.49 (s, 1H), 5.65 (d, 1H), 5.83 (s, 1H), 6.36 (s, 1H), 6.39 (s,
1H), 6.45 (s, 3H), 6.58 (d, 1H), 6.62 (s, 1H), 6.70 (d, 2H), 6.77
(d, 1H), 6.83 (d, 1H), 6.93 (d, 1H), 6.96 (d, 1H), 7.16 (d, 2H),
7.23 (s, 1H), 7.42 (d, 1H), 7.74 (d, 1H), 7.89 (s, 1H), 8.39 (d,
1H), 8.62 (br s, 1H), 8.64 (d, 1H).
BOC-RH-TD (‚TFA): 1H NMR δ 1.38 (s, 9H), 2.70 (m, 1H),
2.90 (m, 1H), 3.40-3.50 (m, 2H), 4.00 (m, 1H), 4.23 (dd, 1H),
4.42 (d, 1H), 4.62 (br s, 1H), 4.85 (br s, 1H), 4.92 (br s, 1H),
5.11 (s, 1H), 5.50 (s, 1H), 6.32 (s, 1H), 6.75 (br s, 1H), 7.18 (s,
1H), 7.31 (br s, 1H), 7.42 (d, 1H), 7.89 (s, 1H), 8.60 (d, 1H, and
NH3+), 8.90 (br s, 1H), 9.20 (d, 1H).
CBZ-RH-TD (‚TFA): 1H NMR δ 2.75 (m, 1H), 2.90 (m, 1H),
3.38-3.48 (dd, 2H), 4.00 (m, 1H), 4.28 (dd, 1H), 4.46 (d, 1H),
4.65 (br s, 1H), 4.90 (br s, 1H), 5.00 (br s, 1H), 5.05 (br s, 2H),
5.14 (s, 1H), 5.50 (s, 1H), 5.64 (d, 1H), 6.00 (s, 1H), 6.32 (s,
1H), 6.48 (s, 1H), 6.70 (s, 1H), 6.80 (br s, 1H), 7.35 (m, 5H),
7.45 (d, 1H), 7.85 (br s, 1H), 7.90 (s, 1H), 8.60 (d, 1H, and
NH3+), 8.88 (br s, 1H), 9.22 (d, 1H).
TDHP A: 1H NMR δ 2.74 (dd, 1H), 3.21 (dd, 1H), 3.58 (d,
1H), 3.62 (d, 1H), 3.71 (m, 1H), 4.10 (m, 1H), 4.12 (dd, 1H),
4.37 (d, 1H), 4.42 (d, 1H), 5.08 (d, 1H), 5.25 (s, 1H), 5.48 (d,
2H), 5.96 (d, 2H), 6.26 (s, 2H), 6.35 (s, 1H), 6.40 (s, 1H), 6.63
(d, 1H), 6.68 (d, 1H), 6.72 (d, 1H), 6.94 (d, 1H), 7.07 (s, 1H),
7.10 (d, 1H), 7.12 (d, 2H), 7.16 (s, 1H), 7.28 (d, 1H), 7.43 (d,
1H), 8.42 (d, 1H), 8.42 (br s, 1H), 8.52 (br s, 1H); 13C NMR δ
39.72 (t), 54.14 (d), 54.70 (d), 55.99 (d), 56.36 (d), 57.29 (d),
58.03 (d), 62.09 (d), 63.76 (t), 71.89 (d), 102.40 (d), 102.95 (d),
104.80 (d), 106.47 (d), 107.36 (d), 107.69 (d), 116.64 (d), 117.56
(d), 118.49 (s), 121.63 (d), 123.36 (d), 124.96 (d), 125.69 (s),
125.88 (d), 126.25 (s), 127.36 (d), 127.54 (s), 127.91 (d), 128.64
(s), 131.24 (d), 134.39 (s), 135.28 (s), 136.45 (s), 136.73 (d),
137.90 (s), 142.15 (s), 148.31 (s), 149.73 (s), 150.47 (s), 155.46
(s), 156.76 (s), 157.68 (s), 158.56 (s), 159.16 (s), 161.56 (s),
167.85 (s), 168.96 (s), 169.33 (s), 169.63 (s), 172.84 (s), 173.03
(s); 15N NMR δ 87.7 (d), 95.8 (d), 105.2 (d), 107.5 (d).
epi-TDHP A: 1H NMR δ 2.69 (dd, 1H), 3.42 (dd, 1H), 3.60
(m, 1H), 3.67 (dd, 2H), 4.11 (dd, 1H), 4.14 (br s, 1H), 4.31 (d,
1H), 4.42 (d, 1H), 4.85 (s, 1H), 5.12 (br s, 2H), 5.51 (s, 1H),
5.87 (d, 1H), 5.92 (s, 1H), 6.00 (d, 1H), 6.19 (s, 2H), 6.25 (s,
1H), 6.47 (s, 1H), 6.65 (d, 1H), 6.71 (d, 2H), 6.80 (br s, 1H),
6.94 (d, 1H), 6.97 (d, 1H), 7.06 (d, 1H), 7.12 (d, 3H), 7.24 (d,
1H), 7.43 (d, 1H), 7.82 (s, 1H), 7.84 (s, 1H), 8.31 (br s, 1H),
8.48 (br s, 1H), 8.59 (d, 1H), 8.95 (d, 1H); 13C NMR δ 36.58 (t),
53.22 (d), 54.11 (d), 54.33 (d), 56.92 (d), 60.25 (d), 62.09 (d),
63.02 (t), 71.71 (d), 102.58 (d), 103.69 (d), 104.25 (d), 105.91
(d), 106.10 (d), 107.58 (d), 109.24 (d), 116.45 (d), 117.38 (d),
118.12 (s), 121.44 (d), 123.48 (d), 124.96 (d), 125.14 (s), 125.70
(s), 125.76 (d), 126.06 (s), 126.44 (s), 127.54 (d), 127.91 (d),
128.47 (s), 131.43 (d), 131.98 (d), 134.20 (s), 134.94 (s), 136.05
(d), 136.23 (s), 137.90 (s), 142.52 (s), 147.51 (s), 148.25 (s),
149.18 (s), 149.55 (s), 150.10 (s), 155.28 (s), 156.76 (s), 157.50
(s), 158.97 (s), 158.98 (s), 165.03 (s), 167.85 (s), 168.40 (s),
169.22 (s), 172.43 (s); 15N NMR δ 21.0 (t), 22.5 (t), 87.0 (d),
100.2 (d), 103.0 (d), 106.5 (d), 107.3 (d).
BOC-TDHP A: 1H NMR δ 1.34 (s, 9H), 2.70 (dd, 1H), 3.22
(dd, 1H), 3.42 (m, 2H), 3.69 (m, 1H), 4.12 (dd, 1H), 4.38 (d,
1H), 4.40 (m, 2H), 5.10 (d, 1H), 5.26 (s, 1H), 5.47 (s, 1H), 5.51
(d, 1H), 5.90 (s, 1H), 5.96 (d, 1H), 6.22 (s, 1H), 6.30 (s, 1H),
6.55 (d, 1H), 7.81 (s, 1H), 8.35 (br s, 1H), 8.43 (d, 1H), 8.50 (br
s, 1H).
TDHP O: 1H NMR δ 2.76 (dd, 1H), 3.21 (dd, 1H), 3.69 (m,
1H), 3.94 (m, 1H), 4.12 (dd, 1H), 4.39 (d, 2H), 4.58-4.80 (dd,
2H), 5.09 (s, 1H), 5.26 (s, 1H), 5.47 (s, 1H), 5.50 (d, 1H), 5.70
(d, 1H), 5.92 (s, 1H), 6.24 (s, 1H), 6.33 (s, 1H), 6.63 (d, 1H),
(47) Purification yield, ∼60%.
(48) Overall yields from VAHP .