â,γ-Dihydroxy R-Amino Acid-Derived Peptides
J . Org. Chem., Vol. 66, No. 12, 2001 4185
in CH2Cl2 (6 mL) while the temperature was kept below -70
°C. The resulting mixture was stirred at -78 °C for 5 min,
and after removal of the cold bath, stirring was continued for
an additional 2 h at room temperature. The reaction mixture
was washed with 1 M HCl and a saturated solution of NaCl.
The resulting solution was dried over MgSO4 and the solvent
evaporated under reduced pressure to give an oily product that
was used as indicated in method A without further purifica-
tion.
Da ta for 2a : yield 0.355 g (88%); mp 132-134 °C; [R]20
)
D
+24.8 (c ) 1, CH2Cl2); IR (KBr) 1745.3 cm-1 (CO); H NMR
(CDCl3, δ) 7.37-7.15 (m, 15H), 4.98 (d, 1H, J ) 11.50 Hz),
4.85 (d, 1H, J ) 15.37 Hz), 4.68 (d, 1H, J ) 11.58 Hz), 4.65 (d,
1H, J ) 4.81 Hz), 4.62 (d, 1H, J ) 5.18 Hz), 4.27 (d, 1H, J )
15.34 Hz), 3.91 (t, 1H, J ) 4.94 Hz), 3.65 (t, 1H, J ) 4.85 Hz);
13C NMR (CDCl3, δ) 168.7, 137.2, 136.2, 129.5, 129.4, 129.3,
129.0, 128.9, 128.8, 128.5, 128.4, 127.4, 81.6, 75.5, 74.1, 73.9,
57.8, 45.9. Anal. Calcd. for C25H25NO4 (403.48): C, 74.42; H,
6.24; N, 3.47. Found: C, 74.50; H, 6.35; N, 3.49.
1
Da ta for 11e: yield 7.32 g (84%); oil; [R]20D ) -3.65 (c ) 1,
CH2Cl2); IR (KBr) 1759.0 cm-1 (CO); 1H NMR (CDCl3, δ) 7.40-
6.94 (m, 15H), 5.12 (d, 1H, J ) 15.63 Hz), 4.97 (d, 1H, J )
11.56 Hz), 4.76 (d, 1H, J ) 11.50 Hz), 4.64 (d, 1H, J ) 5.12
Hz), 4.22 (dd, 1H, J ) 2.00 Hz, J ′ ) 4.86 Hz), 4.14 (dd, 1H, J
) 2.02 Hz, J ′ ) 5.08 Hz), 3.99 (d, 1H, J ) 15.80 Hz), 3.76 (m,
1H), 3.07 (d, 1H, J ) 11.97 Hz), 2.05 (dd, 1H, J ) 12.75 Hz, J ′
) 11.06 Hz), 0.99 and 0.69 (s, 9H), 0.11, 0.07, -0.24, and -0.71
(s, 3H). 13C NMR (CDCl3, δ) 169.1, 139.7, 137.4, 136.8, 130.2,
129.2, 128.9, 128.8, 128.7, 128.5, 128.4, 128.0, 126.6, 81.3, 76.6,
73.4, 73.3, 70.1, 54.7, 45.8, 38.3, 26.5, 26.2, 18.6, 18.3, -3.9,
-4.3, -4.5, -5.3.
Keta liza tion of 15a a n d 2a . To a solution of diol 15a or
2a (4.5 mmol) in benzene (34 mL) were added 2,2-dimethoxy-
propane (0.68 mL, 9 mmol) and p-toluenesulfonic acid mono-
hydrate (0.043 g, 0.2 mmol). The mixture was stirred at reflux
for 30 min, and then it was distilled until 24 mL of liquid was
collected. Additional 2,2-dimethoxypropane (0.15 mL, 1.2
mmol) and benzene (15 mL) were added, the mixture was kept
at reflux for 30 min again, and a further 10 mL of distillate
was collected. To the resulting residue were added Et2O and
a saturated aqueous solution of NaHCO3. The organic phase
was separated and washed with a saturated solution of
NaHCO3 and brine. The organic solution was dried over
MgSO4 and the solvent removed under reduced pressure. The
crude product was purified by column chromatography (eluent
hexane/ethyl acetate 3:1).
Da ta for 11f: yield 8.38 g (95% crude); oilo [R]20 ) +2.5 (c
D
) 1, CH2Cl2); IR (KBr) 1758.8 cm-1 (CO); 1H NMR (CDCl3, δ)
7.32-7.10 (m, 10H), 4.97 (d, 1H, J ) 15.75 Hz), 4.89 (d, 1H, J
) 11.39 Hz), 4.68 (d, 1H, J ) 11.39 Hz), 4.52 (d, 1H, J ) 5.08
Hz), 4.06 (dd, 1H, J ) 2.22 Hz, J ′ ) 4.60 Hz), 3.88 (d, 1H, J )
15.75 Hz), 3.87 (m, 1H), 3.48 (m, 1H), 1.09 (m, 12H), 0.83 and
0.75 (s, 9H), -0.01, -0.06, -0.07, and -0.09 (s, 3H); 13C NMR
(CDCl3, δ) 169.4, 137.6, 137.1, 129.2, 129.0, 128.9, 128.8, 128.7,
128.4, 128.0, 81.3, 74.9, 73.4, 70.2, 55.1, 45.8, 32.4, 31.5, 30.2,
29.8, 27.0, 26.6, 26.4, 23.3, 18.6, 14.8, -3.8, -3.9, -4.4.
Dep r otection of 10 to 2. To a solution of the corresponding
â-lactam 10 (5 mmol) in a mixture of THF (20 mL) and water
(10 mL) was added p-toluenesulfonic acid monohydrate (0.32
g, 1.65 mmol), and the resulting mixture was stirred at reflux
for 16 h. The mixture was then cooled to room temperature,
and a saturated solution of sodium bicarbonate was added
until all the acid was neutralized (pH neutral). The aqueous
phase was extracted with ethyl acetate, the combined organic
phase was dried over MgSO4, and the solvent was removed
under reduced pressure to give 2, which exhibited the same
characterization data as the products obtained from dihy-
droxylation of 3, vide infra.
Da ta for 16: yield 1.53 g (77%); oil; [R]20 ) -5.0 (c ) 1,
D
CH2Cl2); IR (KBr) 1756 cm-1 (CO); 1H NMR (CDCl3, δ) 7.43-
7.26 (m, 13H), 7.16-7.11 (m, 2H), 4.88 (d, 1H, J ) 8.1 Hz),
4.76 (d, 1H, J ) 5.1 Hz), 4.74 (d, 1H, J ) 11.7 Hz), 4.68 (d,
1H, J ) 15.2 Hz), 4.63 (d, 1H, J ) 11.7 Hz), 4.46 (dd, 1H, J )
6.6 Hz, J ′ ) 8.1 Hz), 3.78 (dd, 1H, J ) 5.1 Hz, J ′ ) 6.6 Hz),
3.44 (d, 1H, J ) 15.2 Hz), 1.48 (s, 6H); 13C NMR (CDCl3, δ)
168.6, 137.7, 137.3, 135.6, 129.6, 129.5, 129.3, 129.0, 128.6,
128.5, 109.9, 82.7, 81.4, 80.2, 73.8, 59.1, 45.3, 27.8, 27.7.
Da ta for 18: yield 1.61 g (80%); mp 98-101 °C; [R]20
)
D
-4.19 (c ) 1, CH2Cl2); IR (KBr) 1743.3 cm-1 (CO); H NMR
(CDCl3, δ) 7.34-6.99 (m, 15H), 4.89 (d, 1H, J ) 14.83 Hz),
4.68 (d, 1H, J ) 7.14 Hz), 4.54 (d, 1H, J ) 12.05 Hz), 4.52 (d,
1H, J ) 4.90 Hz), 4.35 (d, 1H, J ) 12.04 Hz), 4.30 (t, 1H, J )
7.10 Hz), 4.08 (d, 1H, J ) 14.87 Hz), 3.67 (dd, 1H, J ) 4.94
Hz, J ′ ) 6.81 Hz), 1.48, 1.40 (s, 3H); 13C NMR (CDCl3, δ) 168.1,
138.1, 137.3, 136.1, 129.3, 129.1, 128.9, 128.8, 128.7, 128.4,
128.3, 127.7, 110.5, 82.2, 82.1, 81.3, 73.1, 57.8, 45.6, 28.2, 28.0.
Anal. Calcd. for C28H29NO4 (443.54): C, 75.82; H, 6.59; N, 3.16.
Found: C, 75.66; H, 6.50; N, 3.07.
1
Dep r otection of 11 to 2. To a solution of 11 (5 mmol) in
THF (20 mL) was added a 1.1 M solution of tetrabutylammo-
nium fluoride in THF (13.63 mL, 15 mmol), and the resulting
solution was stirred at room temperature for 2 h. The reaction
mixture was then filtered through a short pad of silica gel,
and the pad was thoroughly eluted with dicloromethane. The
resulting solution was dried over MgSO4 and the solvent
removed under reduced pressure to give 2, which exhibited
the same characterization data as the products obtained from
dihydroxylation of 3, vide infra.
Gen er a l P r oced u r e for th e Dih yd r oxyla tion of 4-Alk -
en yl â-La cta m s 3. To a mixture of AD-mix-R (1.4 g, 1 mol %)
or AD-mix-â (1.4 g, 1 mol %) and methanesulfonylamine (0.095
g, 1 mmol) in tert-butyl alcohol (5 mL) and H2O (5 mL) was
added at 0 °C the corresponding â-lactam 3 (1 mmol). The
resulting mixture was stirred at the temperature specified in
Table 2 for 16 h. Then it was cooled at 0 °C, and Na2SO3 (1.5
g) was added. After bein stirred for 60 min, the reaction
mixture was extracted with CH2Cl2 the combined organic
phase dried over MgSO4, and the solvent evaporated under
reduced pressure. From this reaction crude product, the
isomeric diols were separated by column chromatography.
P r ep a r a tion of NCAs 17, 19, a n d 20. To a solution of the
corresponding 3-benzyloxy â-lactam 16, 18, or 3a (1 mmol) in
methanol (15 mL) for 3a , or ethyl acetate (15 mL) for 16 and
18, was added 10% palladium on charcoal (0.05 g), and the
mixture was kept under hydrogen (1 atm). The reaction
mixture was stirred at room temperature until the dissap-
pearance of the starting material as monitored by TLC (ca.16
h). The suspension was then filtered through a pad of Celite
and evaporated to yield the debenzylated product, which was
purified by column chromatography (see the Supporting
Information for data). To a magnetizally stirred solution of the
hydrogenated product in 15 mL of methylene chloride were
added 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) (0.003 g,
0.01 mmol) and a solution of potassium bromide (0.012 g, 0.1
mmol) in water (0.25 mL) at room temperature. The solution
was cooled to -5-0 °C (ice-salt bath), and aqueous sodium
hypochlorite (Aldrich, 23,930-5) (10 mL) buffered at pH 7 (0.6
g of sodium hydrogen carbonate for 30 mL of a concentrate
buffer solution phosphate, Aldrich 22,358-1) was added. The
resulting reaction mixture was stirred at 0 °C for 1-3 min.
The organic layer was separated and washed with 15 mL of
10% HCl containing 0.75 g of KI, a 10% solution of Na2S2O3,
and water. The resulting solution was dried over MgSO4, and
the solvent was evaporated under reduced pressure to afford
the corresponding NCA, which was recristalized only for
analytical purposes.
Da ta for 15a : yield 0.34 g (85%); mp 76-79 °C; [R]20
)
D
+122.4 (c ) 1, CH2Cl2); IR (KBr) 1734.7 cm-1 (CO); H NMR
(CDCl3, δ) 7.39-7.04 (m, 15H), 4.98 (d, 1H, J ) 11.54 Hz),
4.75 (d, 1H, J ) 11.53 Hz), 4.68 (d, 1H, J ) 4.94 Hz), 4.61 (d,
1H, J ) 6.00 Hz), 4.55 (d, 1H, J ) 15.23 Hz), 4.18 (d, 1H, J )
15.20 Hz), 3.87 (t, 1H, J ) 5.14 Hz), 3.45 (t, 1H, J ) 4.62 Hz);
13C NMR (CDCl3, δ) 167.8, 140.8, 136.7, 135.7, 129.4, 129.2,
129.0, 128.9, 128.8, 128.5, 128.4, 126.9, 82.0, 74.9, 74.8, 73.9,
57.6, 45.3. Anal. Calcd. for C25H25NO4 (403.48): C, 74.42; H,
6.24; N, 3.47. Found: C, 74.55; H, 6.38; N, 3.40.
1
Da ta for 17: yield 0.352 g (96%); mp 110-112 °C; [R]20
)
D
+16.5 (c ) 1, CH2Cl2); IR (KBr) 1848, 1780 cm-1 (CO); 1H NMR
(CDCl3, δ) 7.38-7.15 (m, 8H), 7.02-6.98 (m, 2H), 5.25 (d, 1H,
J ) 8.7 Hz), 4.84 (d, 1H, J ) 15.0 Hz), 4.20 (d, 1H, J ) 15.0