Yang et al.
JOCArticle
was concentrated under vacuum, 3% sodium carbonate solution
(10 mL) was added. The resultant solution was then extracted
with ether (3 ꢀ 20 mL), andthe combined organic layer wasdried
over anhydrous sodium sulfate and concentrated to afford the
crude product, which was directly used in the next step.
was washed sequentially with aqueous saturated NaHCO3
solution and dilute hydrochloric acid. It was then dried over
anhydrous MgSO4. After removal of the solvent, the residue
obtained was purified by flash column chromatography to
afford the pure product.
Deprotection of the C-tert-Butyl Group of Protected Aminoxy
Characterization Data of Compounds 1-9. Piv-OAcc-NHiBu
(1): white solid; mp 100-101 ꢀC; Rf = 0.3 (EtOAc/hexane =1:1);
1H NMR (400 MHz, CDCl3) δ 8.74 (br, 1H), 8.47 (br, s, 1H), 3.10
(dd, J = 6.4, 6.2 Hz, 2H), 1.84-1.79 (m, 1H), 1.43-1.41 (m, 2H),
1.23-1.20 (m, 11H), 0.92 (d, J = 6.7 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ 178.7, 170.6, 68.0, 47.4, 38.3, 28.5, 27.2, 20.3, 15.4;
IR (CH2Cl2) 3250, 3097, 1674 cm-1; EI-MS (20 eV) m/z 156 (100),
256 (Mþ, 3); HRMS-EI m/z for C13H24N2O3 (Mþ) calcd 256.1787,
found 256.1793.
Acid (or Oligopeptide) with 2,2,2-Trifluoroacetic Acid (TFA)11.
A
solution of C-tert-butyl-protected aminoxy acid (or
oligopeptide) (1.73 mmol) in dichloromethane (5 mL) in an ice
bath was treated with trifluoroacetic acid (5 mL). After being
stirred at room temperature for 1 h, the reaction mixture was
concentrated under vacuum and azeotroped with toluene. The
crude product thus obtained was directly used in the next step.
Deprotection of the C-Methyl Group of the Protected Aminoxy
Acid (or Oligopeptide) with LiOH/THF/H2O. To a solution of
C-methyl-protected aminoxy acid (or oligopeptide) (1.5 mmol)
in THF (8 mL) and water (1 mL) was added LiOH (190 mg,
4.5 mmol). The reaction mixture was stirred at room tempera-
ture for 2 h. When the reaction was complete as monitored by
TLC, the mixture was concentrated and then diluted with
deionized water (5 mL). The resultant aqueous solution was
then acidified with 10% HCl aqueous solution to pH ∼2,
followed by extraction with ethyl acetate (15 mL ꢀ 2). The
combined organic layer was dried over anhydrous MgSO4 and
concentrated to afford the crude product, which was directly
used in the next step.
Coupling of N-Deprotected Aminoxy Acid (or Oligopeptide)
with Isobutyric Acid or Pivalic Acid. Isobutyric acid or pivalic
acid (3 mmol) was added to a solution of N-deprotected
aminoxy acid (or oligopeptide) in CH2Cl2 (10 mL). To this
mixture were added HOAt (612 mg, 4.50 mmol) and EDCI (891
mg, 3 mmol). The reaction mixture was stirred overnight. When
the reaction was complete, the mixture was washed sequentially
with aqueous saturated NaHCO3 solution and dilute hydro-
chloric acid. The organic layer was separated and then dried
over anhydrous MgSO4. After removal of the solvent, the
residue obtained was purified by flash column chromatography
to afford the pure product.
Coupling of N-Deprotected Aminoxy Acid (or Oligopeptide)
with Pivaloyl Chloride11. The N-deprotected aminoxy acid (or
oligopeptide) (0.8 mmol) was dissolved in CH2Cl2 (5 mL).
Another 5 mL of 5% aqueous NaHCO3 solution (or pyridine,
1.9 mmol) was added. The mixture was vigorously stirred while
pivaloyl chloride (0.20 mL, 1.60 mmol) was added dropwise at
0 ꢀC. The resulting mixture was stirred overnight at room
temperature and diluted with CH2Cl2 (50 mL). This organic
solution was washed with brine and dried over anhydrous
MgSO4. After removal of the solvent, the residue obtained
was purified by flash column chromatography to afford the
pure product.
Coupling of C-Deprotected Aminoxy Acid (or Oligopeptide)
with Isobutylamine10b. Isobutylamine (1.73 mmol) was added to
a solution of C-deprotected aminoxy acid (or oligopeptide) (1.73
mmol) in CH2Cl2 (10 mL). To this mixture were added HOAt
(354 mg, 2.60 mmol) and EDCI (668 mg, 2.25 mmol). The
reaction mixture was stirred overnight. When the reaction was
completed, the mixture was washed sequentially with aqueous
saturated NaHCO3 solution and dilute hydrochloric acid. It was
then dried over anhydrous MgSO4. After removal of the solvent,
the residue obtained was purified by flash column chromato-
graphy to afford the pure product.
iPrCO-D-OVal-OAcc-NHiBu (2): white solid; mp 132-133 ꢀC;
Rf = 0.5 (acetone in CH2Cl2 = 5%); [R]20D þ44.5 (c 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) δ 11.89 (s, 1H), 8.51 (br, s, 1H), 8.43
(s, 1H), 4.08 (d, J = 3.2 Hz, 1H), 3.16-2.96 (m, 2H), 2.34-2.25
(m, 2H), 1.85-1.78 (m, 1H), 1.55-1.33 (m, 4H), 1.18 (d, J = 6.9
Hz, 3H), 1.17 (d, J = 6.9 Hz, 3H), 1.08 (d, J = 6.9 Hz, 3H),
0.95-0.91 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 178.5, 171.0,
169.6, 91.5, 68.0, 47.4, 32.4, 30.7, 28.6, 20.3, 19.3, 19.1 (2), 16.9,
16.1, 14.9; IR (CH2Cl2) 3263, 1675, 1640 cm-1; EI-MS (20 eV) m/z
130 (100), 357 (Mþ, 3); HRMS (EI) m/z for C17H31N3O5 (Mþ)
calcd 357.2264, found 357.2261.
Piv-OAcc-D-OVal-NHiBu (3): colorless oil; Rf = 0.5 (acetone
in CH2Cl2 = 10%); [R]20D þ28.8 (c 1.0, CHCl3); 1H NMR (400
MHz, CDCl3) δ 12.13 (s, 1H), 8.35 (s, 1H), 8.24 (br, s, 1H), 4.08
(d, J = 3.2 Hz, 1H), 3.18-2.99 (m, 2H), 2.36-2.33 (m, 1H),
1.84-1.77 (m, 1H), 1.46-1.27 (m, 4H), 1.22 (s, 9H), 1.17 (d, J =
7.3 Hz, 3H), 0.95 (d, J = 7.3 Hz, 3H), 0.92-0.90 (m, 6H); 13C
NMR (100 MHz, CDCl3) δ 179.8, 170.6, 169.9, 91.6, 67.8, 46.6,
38.4, 30.7, 28.5, 27.1, 20.3(2), 19.3, 16.9, 16.2, 15.6; IR (CH2Cl2)
3246, 2964, 1651 cm-1; EI-MS (20 eV) m/z 131 (100), 371 (Mþ,
3); HRMS (EI) m/z for C18H33N3O5 (Mþ) calcd 371.2420, found
371.2401.
Piv-D-OLeu-OGly-NHiBu (4): yellow oil; [R]20D þ60.8 (c 1.0,
CH3CH2OH); 1H NMR (400 MHz, CDCl3) δ 12.05 (s, 1H), 9.40
(s, 1H), 8.35 (s, 1H), 4.42-4.29 (m, 3H), 3.10-3.13 (m, 2H),
1.66-1.89 (m, 4H), 1.21 (s, 9H), 0.97-0.92 (m, 12H); 13C NMR
(100 MHz, CDCl3) δ 180.0, 171.8, 167.2, 85.6, 76.0, 46.6, 41.0,
28.3, 27.1, 24.6, 23.2, 21.7, 20.2; IR (CH2Cl2) 3380, 3162, 1677
cm-1; ESI-MS, m/z 360 (Mþ þ 1, 100); HRMS (EI) for
C17H33N3O5 (Mþ) calcd 359.2420, found 359.2416.
Piv-OGly-D-OLeu-NHiBu (5): white solid; mp 91-93 ꢀC;
[R]20 þ54.9 (c 1.00, CH3CH2OH); 1H NMR (300 MHz,
D
CDCl3) δ 12.09 (s, br, 1H), 9.57 (s, br, 1H), 8.05 (s, br, 1H),
4.39 (AB, J = 16.3 Hz, 2H), 4.31 (dd, J = 8.9, 6.6 Hz, 1H),
3.13-3.02 (m, 2H), 1.95-1.67 (m, 4H), 1.21 (s, 9H), 1.03-0.90
(m, 12H); 13C NMR (75 MHz, CDCl3) δ 180.2, 172.0, 167.6,
86.2, 76.2, 47.0, 41.2, 28.8, 27.4, 25.2, 23.6, 22.0, 20.5;
IR (CH2Cl2) 3380, 3168, 1673, 1605 cm-1; ESI-MS m/z 360
(Mþ þ 1, 100); HRMS (EI) for C17H33N3O5 (Mþ) calcd
359.2420, found 359.2408.
iPrCO-D-OLeu-(OAcc)2-NHiBu (6): colorless oil; Rf = 0.5
(acetone in CH2Cl2 = 10%); [R]20D þ133.1 (c 1.0, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 12.10 (s, 1H), 11.98 (s, 1H), 8.67 (s,
1H), 8.62 (br, s, 1H), 4.31 (dd, J = 8.2, 5.0 Hz, 1H), 3.10-3.07
(m, 2H), 2.36-2.29 (m, 1H), 1.81-1.69 (m, 4H), 1.60-1.42 (m,
8H), 1.18 (d, J=6.0 Hz, 3H), 1.16 (d, J = 6.4 Hz, 3H), 0.98-
0.95 (m, 6H), 0.90 (d, J = 6.9 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 178.9, 171.7, 170.8, 170.1, 85.5, 68.0, 67.6, 47.4, 40.7,
32.4, 28.4, 24.6, 23.3, 21.6, 20.3, 19.3, 19.1, 17.3, 16.1, 16.0, 15.7;
IR (CH2Cl2) 3293, 3149, 1654 cm-1; EI-MS (20 eV) m/z 145
(100), 471 (Mþ, 3); HRMS (EI) m/z for C22H38N4O7 (Mþ) calcd
470.2740, found 470.2724.
Coupling of N-Deprotected Aminoxy Acid (or Oligopeptide)
with C-Deprotected Aminoxy Acid (or Oligopeptide)11. N-De-
protected aminoxy acid (or oligopeptide) (2 mmol) was added to
the solution of C-deprotected aminoxy acid (2 mmol) in CH2Cl2
(10 mL). To this mixture were added HOAt (362 mg, 2.66 mmol)
and EDCI (772 mg, 2.60 mmol). The reaction mixture was
stirred overnight. When the reaction was completed, the mixture
Piv-D-OLeu-(OAcc)3-NHiBu (7): colorless oil; Rf = 0.4
1
(acetone in CH2Cl2 = 10%); [R]20 þ54.2 (c 1.0, CHCl3); H
D
4804 J. Org. Chem. Vol. 75, No. 14, 2010