6880 J . Org. Chem., Vol. 64, No. 18, 1999
Notes
Ta ble 1. Syn th esis of Dip ep tid es 3 via Boc2O-Med ia ted Cou p lin g of th e Am in o Acid Der iva tives 1 a n d 2
N-Boc-amino acid 1a
amino acid ester 2a
dipeptide 3
time (h)
yield (%)
b
c
d
e
f
Boc-Pro-OH
Boc-Phe-OH
Boc-Ala-OH
Boc-Val-OH
NR,Nꢀ-Boc-Lys-OH
Boc-Thr(OTBDMS)-OH
H2N-Phe-OMe
H2N-Ala-OMe
D-H2N-Phg-OMe
D-H2N-Phg-OMe
H2N-Ala-OMe
H2N-Val-OMe
Boc-Pro-Phe-OMe
Boc-Phe-Ala-OMe
Boc-Ala-D-Phg-OMe
Boc-Val-D-Phg-OMe
NR,Nꢀ-Boc-Lys-Ala-OMe
Boc-Thr(OTBDMS)-Val-OMe
4
6
5
5
7
6
91
74
75
81
67
79
g
a
L-Amino acid, unless stated otherwise.
6.52 (br s, 1H), 7.22 (m, 5H); 13C NMR (CDCl3) δ 171.7, 171.4,
155.8, 135.8, 128.9, 128.2, 126.7, 80.2, 60.2, 52.7, 51.9, 46.6, 37.8,
28.0, 23.6; HRMS (FAB+) calcd for C20H28N2O5 376.1998 (M+),
found 376.2007. Anal. Calcd for C20H28N2O5 (376.45): C, 63.81;
H, 7.49: N, 7.44. Found: C, 64.19; H, 7.44; N, 7.78.
diastereomeric purity. A variety of amino acid combina-
tions were similarly subjected to dipeptide formation
affording the products 3c-g (Table 1) in good yields and
high diastereomeric purity.
3c: white solid; mp (CH2Cl2) 94-95 °C (lit.7 mp 98 °C); HPLC
retention time ) 16.8 min; [R]D ) -21.5 (c ) 0.4, MeOH); IR
(neat) 3335, 1750, 1693, 1655 cm-1; 1H NMR (CDCl3) δ 1.35 (d,
J ) 6.8 Hz, 3H), 1.43 (s, 9H), 3.05 (m, 2H), 3.7 (s, 3H), 4.3 (m,
1H), 4.47 (m, 1H), 4.96 (br s, 1H), 6.34 (br d, J ) 7.2 Hz, 1H),
7.23 (m, 5H); 13C NMR (CDCl3) δ 172.3, 171.6, 155.2, 135.7,
129.1, 128.3, 126.9, 79.8, 53.1, 52.1, 50.0, 37.7, 28.1, 18.2; HRMS
(FAB+) calcd for C18H26N2O5 350.1841 (M+), found 350.1844.
Anal. Calcd for C18H26N2O5 (350.42): C, 61.69; H, 7.48: N, 7.99.
Found: C, 61.35; H, 7.82; N, 8.18.
In conclusion, the described reaction constitutes a
convenient method for the synthesis of peptides under
mild, nonracemizing reaction conditions. The method also
eliminates some commonly encountered problems associ-
ated with peptide coupling, such as separation of product
from reagent derived coproducts, racemization, poor
recovery of product, high cost, instability of the reagent,
etc. Incidentally, because of its extensive use for N-
protection in amino acid/peptide related-chemistry, Boc2O
is already a familiar and commonly available reagent to
researchers involved in this area of research, thus adding
to its utility for the present method. It is hoped that the
above reaction will be a useful addition to the existing
methodologies for dipeptide formation. Further applica-
tion toward synthesizing higher peptides and in solid-
phase synthesis is currently under investigation.8
3d : white solid; mp (CH2Cl2) 115-117 °C; HPLC retention
time ) 14.9 min; [R]D ) -125.1 (c ) 1.2, MeOH); IR (neat) 3298,
1
1750, 1719, 1663 cm-1; H NMR (CDCl3) δ 1.34 (d, J ) 8.2 Hz,
3H), 1.41 (s, 9H), 3.67 (s, 3H), 4.24 (br s, 1H), 5.17 (br d, J ) 6.8
Hz, 1H), 5.5 (br d, J ) 7.7 Hz, 1H), 7.32 (br s, 6H); 13C NMR
(CDCl3) δ 172.2, 171.1, 155.8, 136.2, 128.9, 128.5, 127.2, 127.1,
80.1, 56.4, 52.7, 28.2, 19.2; HRMS (FAB+) calcd for C17H25N2O5
337.1763 (MH+), found 337.1773. Anal. Calcd for C17H24N2O5
(336.39): C, 60.70; H, 7.19: N, 8.32. Found: C, 60.35; H, 7.22;
N, 8.68.
Exp er im en ta l Section 9
3e: white solid; mp (CH2Cl2) 91-93 °C; HPLC retention time
) 11.9 min; [R]D ) -98.8 (c ) 1, MeOH); IR (neat) 3330, 1743,
1692, 1654 cm-1; 1H NMR (CDCl3) δ 0.9 (br t, J ) 11.7 Hz, 6H),
1.44 (s, 9H), 2.3 (m, 1H), 3.74 (s, 3H), 3.97 (m, 1H), 5.07 (d, J )
8.2 Hz, 1H), 5.51 (d, J ) 7.2 Hz, 1H), 7.08 (br d, J ) 6.3 Hz,
1H), 7.34 (br s, 5H); 13C NMR (CDCl3) δ 171.2, 171.1, 155.8,
136.2, 128.8, 128.4, 127.2, 79.8, 59.5, 56.3, 52.6, 30.8, 28.2, 19.1,
17.5; MS (FAB+) 365 (MH+). Anal. Calcd for C19H28N2O5
(364.44): C, 62.62; H, 7.74: N, 7.68. Found: C, 62.98; H, 7.87;
N, 8.05.
Typ ica l Exp er im en ta l P r oced u r e. A room-temperature
solution of the N-Boc-amino acid 1 (1 mmol), pyridine (1.1 mmol),
and a catalytic amount of 4-(dimethylamino)pyridine (20 mg)
in anhydrous THF (10 mL) under N2 atmosphere was treated
with a solution of di-tert-butyl dicarbonate (1 mmol) dissolved
in anhydrous THF (2 mL) and the mixture stirred for 20-30
min. To this mixture was added in one lot a solution of the amino
acid ester 2 (1.1 mmol) in anhydrous THF (3 mL), and stirring
was continued at room temperature. After completion of reaction
(TLC monitoring), solvent was removed under vacuum, and the
residue was dissolved in ethyl acetate (50 mL) and washed
sequentially with ice-cooled 10% aqueous HCl (2 × 20 mL),
saturated aqueous NaHCO3 solution (2 × 20 mL), and brine.
Drying over anhydrous Na2SO4, removal of solvent under
vacuum, and purification of the residue by silica gel column
chromatography (hexane/ethyl acetate 9/1 f 5/1) afforded the
pure product 3. Enantiomeric purity of the products formed was
verified by HPLC analysis. HPLC conditions: column, CHIRAL-
CEL (OD); mobile phase, 10% i-PrOH in n-hexane; flowrate, 1
mL/min; UV detection at 225 nm.
3f: viscous liquid; HPLC retention time ) 17.5 min; [R]D
)
-13.4 (c ) 1, MeOH); 1H NMR (CDCl3) δ 1.27-1.8 (m, 27H),
3.07 (m, 2H), 3.7 (s, 3H), 4.23 (m, 1H), 4.56 (br s, 1H), 5.07 (br
d, J ) 8.2 Hz, 1H); 13C NMR (CDCl3) δ 173.1, 171.8, 156.1, 155.6,
79.9, 79.0, 54.1 52.3, 47.9, 39.9, 32.0, 29.5, 28.4, 28.3, 22.4, 18.0;
EIMS 431 (M+). Anal. Calcd for C20H37N3O7 (431.53): C, 55.67;
H, 8.64: N, 9.74. Found: C, 55.98; H, 8.90; N, 10.11.
3g: white solid; mp (CH2Cl2) 64-66 °C; HPLC retention time
) 7.6 min; [R]D ) -6.5 (c ) 0.6, MeOH); IR (neat) 3365, 1738,
1710, 1675 cm-1; 1H NMR (CDCl3) δ 0.18 and 0.2 (2s, 6H), 0.95
(br s, 15H), 1.14 (d, J ) 6.4 Hz, 3H), 1.48 (s, 9H), 2.14 (m, 1H),
3.74 (s, 3H), 4.11 (br s, 1H), 4.24 (m, 1H), 4.51 (m, 1H), 5.51 (br
d, J ) 6.1 Hz, 1H), 7.32 (br d, J ) 7.8 Hz, 1H); 13C NMR (CDCl3)
δ 171.7, 169.9, 155.6, 79.8, 68.5, 58.6, 57.3, 51.7, 30.9, 28.2, 25.7,
18.9, 17.9, 17.8, 17.6, -4.8, -5.1; HRMS (FAB+) calcd for
3a : white solid; mp (CH2Cl2) 112-113 °C (lit.7 mp 114-115
°C); HPLC retention time ) 21.0 min; [R]D ) -13.5 (c ) 1,
MeOH); IR (neat) 3340, 1744, 1696, 1665 cm-1; 1H NMR (CDCl3)
δ 1.4 (s, 9H), 3.02 (m, 4H), 3.66 (s, 3H), 4.28 (dd, J ) 6.4, 12.4
Hz, 1H), 4.74 (dd, J ) 6.5, 12.9 Hz, 1H), 4.94 (br s, 1H), 6.21 (br
d, J ) 7.6 Hz, 1H), 6.95 (m, 2H), 7.25 (m, 8H); 13C NMR (CDCl3)
δ 171.3, 170.8, 155.1, 136.5, 135.6, 129.8, 129.1, 128.5, 128.4,
127.0, 126.8, 80.0, 55.7, 53.2, 52.1, 38.2, 37.9, 28.2; MS (FAB+)
427 (MH+). Anal. Calcd for C24H30N2O5 (426.51): C, 67.58; H,
7.09; N, 6.57. Found: C, 67.89; H, 7.44; N, 6.96.
C
21H43N2SiO6 447.2890 (MH+), found 447.2885. Anal. Calcd for
C21H42N2SiO6 (446.65): C, 56.47; H, 9.48; N, 6.27. Found: C,
56.75; H, 9.87; N, 6.60.
Ack n ow led gm en t. The authors thank Dr. M. K.
Gurjar for his support and encouragement. D.K.M. also
thanks UGC, New Delhi, for a research fellowship
(SRF).
3b: white solid; mp (CH2Cl2) 65-66 °C; HPLC retention time
) 21.6 min; [R]D ) -50.4 (c ) 1.4, MeOH); IR (neat) 3300, 1754,
1
1694, 1662 cm-1; H NMR (CDCl3) δ 1.48 (s, 9H), 1.74-2.2 (m,
1
4H), 3.05 (dd, J ) 7.3, 13.6 Hz, 1H), 3.22 (dd, J ) 6.9, 13.6 Hz,
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
1H), 3.34 (br s, 2H), 3.77 (s, 3H), 4.25 (br s, 1H), 4.86 (br s, 1H),
spectra and HPLC chromatograms for dipeptide 3a and its
epimeric mixture. This material is available free of charge via
the Internet at http://pubs.acs.org.
(8) IICT Communication No. 4022.
(9) For general experimental details, see: Mohapatra, D. K.; Datta,
A. J . Org. Chem. 1998, 63, 642-646.
J O982229R