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DOI: 10.1055/s-0028-1087510
Controlled Ring Opening of N-Sulfinyl- and N-Silyl-N-carboxyanhydrides (NCA): One-Pot Synthesis of Dipeptides and Unsymmetrical Peptidyl Ureas from Unprotected NCA
Publication History
Publication Date:
15 January 2009 (online)
Abstract
We report herein new labile protecting groups of N-carboxyanhydrides (NCA) useful to prevent polymerization during coupling reactions with nitrogen nucleophiles. Thus, N-sulfinyl-NCA 1 and N-silyl-NCA 2 were prepared in situ and involved, without being isolated, in coupling reactions with various α-amino esters to furnish dipeptides 3 and unsymmetrical peptidyl ureas 4, respectively, in good yields.
Key words
N-protected carboxyanhydrides (NCA) - peptidyl ureas - dipeptides
- 1 For an excellent review on the main
applications of NCA, see:
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J. Am. Chem. Soc. 2004, 126: 8134 - 13 The formation of ureas from the
reaction of unprotected NCA with silylated amines has been reported
previously and was explained by the formation of an isocyanate as intermediate:
Kricheldorf HR.Greber G. Chem. Ber. 1971, 104: 3168 -
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References and Notes
Val-NCA and Leu-NCA were generously gifted by ISOCHEM company.
8After elimination of the triethylamine hydrochloride salt by filtration and evaporation of THF, the major diastereomer could be isolated by precipitation in Et2O. Selected data of the major diastereomer: ¹H NMR (300 MHz, CDCl3): δ = 7.69 (m, 5 H), 3.77 (d, 1 H, J = 3.4 Hz), 2.45 (m, 1 H), 1.02 (d, 3 H, J = 6.8 Hz), 0.95 (d, 3 H, J = 7.1 Hz). ¹³C NMR (75 MHz, CDCl3): δ = 16.0, 17.9, 31.7, 65.8, 125.3, 130.5, 133.6, 139.7, 150.8, 165.2. IR (KBr): 1853, 1787 cm-¹.
11
General Procedure
for the One-Pot Synthesis of Dipeptides 3a-f
To
a solution of Val-NCA or Leu-NCA (7 mmol) in dry THF (20 mL) at
0 ˚C was added dropwise Et3N (1 mL,
7 mmol) followed by tert-butylsulfinyl
chloride (0.98g, 7 mmol). The resultant solution was stirred at
this temperature for 5 h before adding the amino ester hydrochloride
(7 mmol) and Et3N (7 mmol). After stirring for 5 h at
r.t., the solvent was evaporated under reduced pressure. Ethanol
(20 mL) and dry HCl (4 M) in dioxane (3.5 mL) were added at 0 ˚C.
The solution was stirred for 2 h at 0 ˚C and then
concentrated under vacuum. Dipeptides 3a-f were obtained as white solids after precipitation
from EtOH with Et2O.
H-Val-Phe-OEt (3a): ¹H NMR (300 MHz,
CDCl3): δ = 8.23 (d, 1 H, J = 7.1 Hz),
7.92 (s, 2 H), 6.92 (m, 5 H), 4.38 (m,
1 H), 3.78 (q,
2 H, J = 7.1
Hz), 3.43 (d, 1 H, J = 5.3
Hz), 2.73 (m, 2 H), 1.85 (m, 1 H), 0.86 (t, 3 H, J = 7.1
Hz), 0.66 (m, 6 H). ¹³C NMR (75 MHz,
CDCl3): δ = 14.2, 17.7, 18.6, 30.4, 37.5,
54.1, 58.2, 61.3, 126.9, 128.6, 129.5, 136.8, 168.7, 171.2. IR (KBr)
1721, 1692 cm-¹. HRMS: m/z calcd for C16H25N2O3 [MH+]:
293.1865; found: 293.1864.
[α]D
²0 +21.1
(c 0.75, EtOH).
H-Leu-Phe-OEt
(3b): ¹H NMR (300 MHz,
CDCl3): δ = 8.38 (d, 1 H, J = 7.5 Hz),
7.89 (s, 2 H), 6.77 (m, 5 H), 4.17 (m,
1 H), 3.61 (q,
2 H, J = 7.0
Hz), 3.40 (m, 1 H), 2.60 (m, 3.5 H), 1.19 (m, 3 H), 0.89 (t, 1.5
H, J = 7.4
Hz), 0.70 (t, 3 H, J = 7.0
Hz), 0.45 (m, 6 H). ¹³C NMR (75 MHz,
CDCl3): δ = 8.7, 14.1, 22.2, 22.8,
24.0, 37.3, 45.9, 51.6, 54.2, 61.1, 126.8, 128.4, 129.4, 136.8,
169.4, 171.0. IR (KBr): 1732, 1667 cm-¹.
H-Val-Thr-OEt
(3c): ¹H NMR (300 MHz,
DMSO): δ = 11.12 (s, 1 H), 9.12 (d, 1 H, J = 6.6 Hz),
8.33 (s, 3 H), 7.61 (d, 1 H, J = 7.7
Hz), 7.47 (d, 1 H, J = 7.9
Hz), 7.19 (s, 1 H), 7.13 (m, 2 H), 4.65 (dd, 1 H, J = 6.6,
7.7 Hz), 4.51 (s, 1 H), 4.12 (q,
2 H, J = 7.2
Hz), 3.81 (s, 1 H), 3.27-3.15 (m, 2 H), 2.26 (m, 1 H),
1.18-1.06 (m, 6 H). ¹³C NMR
(75 MHz, DMSO): δ = 14.2, 17.9, 18.6, 27.2, 30.2,
39.0, 40.4, 53.8, 56.4, 57.3, 61.0, 109.2, 111.8, 118.2, 121.3,
124.5, 127.3, 136.4, 168.5, 171.6. IR (KBr): 1728, 1672 cm-¹.
Anal. Calcd for C18H26ClN3O3:
H, 7.48; N, 10.75. Found: H, 7.46; N, 10.72. Mp 152 ˚C. [α]D
²0 -125.1
(c 0.51, EtOH).
H-Val-Pro-OEt
(3d): ¹H NMR (300 MHz,
DMSO): δ = 8.34 (s, 1 H), 4.35 (m, 1 H), 4.08
(q, 2 H, J = 7.0
Hz), 3.99 (d,
1 H, J = 5.5
Hz), 3.79 (m, 1 H), 3.50 (m, 1 H), 2.23-2.11 (m, 2 H),
1.89 (m, 3 H), 1.17 (t, 3 H, J = 7.0
Hz), 0.99 (dd, 6 H, J = 6.8, J = 6.6 Hz). ¹³C
NMR (75 MHz, DMSO): δ = 14.3, 17.6, 18.5, 25.1,
29.0, 29.8, 47.6, 55.8, 59.2, 61.0, 167.4, 171.6. IR (KBr): 1739,
1652 cm-¹. HRMS: m/z calcd
for C12H22N203 [MH+]:
243.1705; found: 243.1708. [α]D
²0 -47.7 (c 1.01, EtOH).
H-Val-Met-OEt
(3e): ¹H NMR (300 MHz,
CDCl3): δ = 7.89 (d, 1 H, J = 7.7 Hz),
4.68 (m, 1 H), 4.20 (q, 2 H, J = 7.2
Hz), 3.28 (d, 1 H, J = 4.0
Hz), 2.49 (m, 2 H), 2.30-1.95 (m, 6 H), 1.28 (t, 3 H, J = 7.2 Hz),
0.99 (d, 3 H, J = 7.0
Hz), 0.84 (d,
3 H, J = 7.0
Hz). ¹³C NMR (75 MHz, CDCl3): δ = 14.6,
15.9, 16.6, 20.0, 30.4, 31.2, 32.4, 51.6, 60.5, 61.9, 172.4, 174.6.
IR (KBr): 1720, 1650 cm-¹. HRMS: m/z calcd for C12H24N203S [MH+]:
277.1508; found: 277.1510.
H-Val-Ala-OEt (3f): ¹H
NMR (300 MHz, CDCl3): δ = 7.75 (d,
1 H, J = 6.0
Hz), 4.55 (m, 1 H), 4.15 (q, 2 H, J = 7.2
Hz), 3.23 (d, 1 H, J = 4.0
Hz), 2.25 (m, 1 H), 1.39 (d, 3 H, J = 7.2 Hz),
1.26 (t, 3 H, J = 7.0
Hz), 0.97 (d, 3 H, J = 7.0
Hz), 0.81 (d, 3 H, J = 7.0
Hz). ¹³C NMR (75 MHz, CDCl3): δ = 14.5, 16.4,
18.5, 20.0, 31.3, 48.1, 60.4, 61.7, 173.5, 174.5. IR (KBr): 1745,
1636 cm-¹. HRMS: m/z calcd
for C10H20N203 [MH+]:
217.1556; found: 217.1552.
General Procedure
for the Preparation of N-Silylated-NCA 2a-c
To
a solution of Val-NCA or Leu-NCA (7 mmol) in dry THF (20 mL) at -30 ˚C,
were added dropwise Et3N (7 mmol) and then Me3SiCl
or TBSCl (10.5 mmol). The resulting solution was stirred at this
temperature for 5 h. The reaction mixture was filtered under a nitrogen
atmosphere and evaporated in vacuo at r.t. to give N-trialkylsilyl-NCA 2a-c in
95-99% yields as white solids without further
purification.
Selected Data for
N
-TMS-Val-NCA
2a
¹H NMR (300 MHz, CDCl3): δ = 4.07
(d, 1 H, J = 3.4
Hz), 2.08 (m, 1 H), 1.19 (d, 3 H, J = 7.1
Hz), 0.94 (d, 3 H, J = 7.1 Hz),
0.39 (s, 9 H). ¹³C NMR (75 MHz, CDCl3): δ = 15.0, 16.5,
18.2, 32.4, 66.1, 154.2, 169.7. IR (KBr): 1840, 1785 cm-¹.
Selected Data for
N
-TBS-Val-NCA 2b
¹H
NMR (300 MHz, CDCl3): δ = 3.87 (d,
1 H, J = 3.4
Hz), 2.19 (m, 1 H), 0.99 (d, 3 H, J = 6.8
Hz), 0.90 (s, 9 H), 0.84 (d, 3 H, J = 6.8
Hz), 0.27 (s, 3 H), 0.26 (s, 3 H). ¹³C
NMR (75 MHz, CDCl3): δ = 3.4, 3.5,
17.9, 18.2, 19.2, 21.5, 26.9, 27.2, 32.4, 33.2, 64.7, 65.8, 128.9,
154.3, 171.3, 172.7. IR (KBr): 2258, 1857, 1786, 1733 cm-¹.
Selected Data for
N
-TMS-Leu-NCA 2c
¹H
NMR (300 MHz, CDCl3): δ = 4.19 (dd,
0.5 H, J = 3.8,
9.8 Hz), 3.96 (dd, 0.5 H, J = 6.8,
7.9 Hz), 1.99 (m, 0.5 H), 1.85-1.61 (m, 3.5 H), 0.96 (m,
6 H), 0.39 (s, 4.5 H), 0.32 (s, 0.5 H). ¹³C
NMR (75 MHz, CDCl3): δ = 0.01, 0.39,
21.5, 21.8, 23.3, 24.2, 25.5, 42.4, 42.9, 57.4, 59.4, 68.4, 127.0,
154.8, 171.5, 172.5. IR (KBr): 2255, 1845, 1780, 1720 cm-¹.
General Procedure
for the One-Pot Preparation of Unsymmetrical Peptidyl Ureas 4a-j
To
a solution of Val-NCA or Leu-NCA (7 mmol) in dry THF (20 mL) maintained
at -30 ˚C were dropwise added Et3N
(1
mL, 7 mmol) and TMSCl (1.33 mL, 10.5 mmol). The resultant solution
was stirred at this temperature for 4.5 h before adding the amine
nucleophile (7 mmol) and Et3N
(2 mL, 14 mmol).
After stirring for 2 h at 0 ˚C, the solution was
acidified to pH 4.0 with HCl (4 M) in dioxane. The precipitate
was then filtered and dried to afford peptidyl ureas 4d,h,i. Ureas 4a-c,e,f,g,j were isolated
as followed. After acidification of the solution to pH 4
with HCl (4 M in dioxane), solvents were evaporated and the resulting
residue was dissolved in CH2Cl2. The CH2Cl2 layer
was washed with brine and evaporated in vacuo to provide pure ureas 4a-c,
e,f,g,j.
Urea 4a: ¹H NMR (300 MHz,
CDCl3): δ = 6.58 (s, 1 H), 3.84 (m,
2 H), 2.22-2.05 (m, 3 H), 1.80 (d, 2 H, J = 12.8
Hz), 1.62 (d, 3 H), 1.35-1.16 (m, 3 H), 1.01 (d, 3 H, J = 6.9 Hz),
0.86 (d, 3 H, J = 6.8
Hz). ¹³C NMR (75 MHz, CDCl3): δ = 16.0, 19.1,
25.4, 26.1, 26.2, 29.5, 29.8, 30.7, 51.7, 61.9, 158.9, 174.1. IR
(KBr): 1641, 1565 cm-¹. Anal. Calcd
for C18H26N2O5: C, 59.48;
H, 9.15; N, 11.56. Found: C, 59.64; H, 9.32; N, 11.58. Mp 94 ˚C. [α]D
²0 -75.9
(c 0.7, EtOH).
Urea 4b: ¹H NMR (300 MHz,
CDCl3): δ = 4.45 (m, 1 H), 3.57 (m,
1 H), 1.92-1.55 (m, 5 H), 1.52-1.30 (m, 3 H),
1.35-1.16 (m, 5 H), 1.01 (m, 6 H). ¹³C
NMR (75 MHz, CDCl3):
δ = 20.1,
21.9, 22.3, 22.5, 22.9, 28.0, 33.3, 33.4, 39.8, 49.5, 54.3, 157.6,
174.8. IR (KBr): 1638, 1565 cm-¹. Anal.
Calcd for C13H24N2O3:
C, 60.91; H, 9.44; N, 10.93. Found: C, 60.96; H, 9.48; N, 10.94. [α]D
²0 -80.0
(c 0.7, EtOH).
Urea 4c: ¹H NMR (300 MHz,
CDCl3): δ = 7.99 (s, 1 H), 7.66 (s,
1 H), 7.15 (t, 2 H, J = 7.9
Hz), 6.72 (d, 3 H, J = 8.7
Hz), 6.25 (d, 1 H, J = 9.0
Hz), 4.07 (dd, 1 H, J = 4.9,
9.0 Hz), 2.03 (m, 1 H), 0.84 (d, 3 H, J = 6.8
Hz), 0.77 (d, 3 H, J = 6.8
Hz). ¹³C NMR (75 MHz, CDCl3): δ = 17.9,
19.5, 30.8, 57.5, 112.7, 129.1, 158.9, 174.0. IR (KBr): 1703, 1621,
1563
cm-¹. Anal. Calcd for
C12H17N3O3: C, 57.36;
H, 6.82; N, 16.72. Found: C, 57.46; H, 6.90; N, 16.94. [α]D
²0 +24.0
(c 0.58, EtOH).
Urea 4d: ¹H NMR (300 MHz,
CDCl3): δ = 7.28 (m, 5 H), 5.11 (m,
2 H), 4.37 (m, 1 H), 4.25 (m, 1 H), 2.15 (m, 1 H), 1.54 (m, 3 H),
0.85 (m, 12 H). ¹³C NMR (75 MHz, CDCl3): δ = 16.4,
17.8, 20.8, 21.6, 23.7, 30.0, 40.5, 51.1, 57.4, 66.5, 127.2, 127.5,
127.6, 134.0, 157.5, 173.7, 175.2. IR (KBr): 1715, 1644, 1566 cm-¹.
HRMS: m/z calcd for C19H28N205 [MH+]:
365.1998; found: 365.2006. [α]D
²0 -14.5
(c 1.0, EtOH).
Urea 4e: ¹H NMR (300 MHz,
CDCl3): δ = 7.09 (m, 2 H), 4.47 (m,
1 H), 4.35 (m, 1 H), 3.77 (s, 3 H), 3.70 (s, 3 H), 2.47 (m, 2 H),
2.20 (m, 2 H), 2.06 (m, 1 H), 0.98 (m, 6 H). ¹³C NMR
(75 MHz, CDCl3): δ = 17.8, 19.1, 27.8,
30.4, 31.4, 52.7, 53.2, 53.3, 58.8, 158.8, 173.9, 175.1, 176.7.
IR (KBr): 1720, 1655, 1561 cm-¹. HRMS: m/z calcd for C13H22N207 [MH+]:
318.1427; found: 318.1430. [α]D
²0 +4.3
(c 0.58, EtOH).
Urea 4f: ¹H NMR (300 MHz,
CDCl3): δ = 4.33 (m, 2 H), 3.77 (s,
3 H), 2.21 (m, 2 H), 1.87 (m, 1 H), 1.41 (m,1 H), 1.18 (m, 1 H),
0.95 (m, 12 H). ¹³C NMR (75 MHz, CDCl3): δ = 11.8, 15.7,
18.0, 19.2, 25.4, 31.5, 38.5, 52.9, 58.8, 68.3, 158.8, 174.7, 175.6.
IR (KBr): 1721, 1640, 1566 cm-¹. HRMS: m/z calcd for C13H24N205 [MH+]:
289.1762; found: 289.1763. [α]D
²0 +10.1
(c 0.89, EtOH).
Urea 4g: ¹H NMR (300 MHz,
CDCl3): δ = 5.98 (m, 2 H), 4.54 (m,
1 H), 4.33 (m, 1 H), 4.19 (q, 2 H, J = 7.1
Hz), 2.50 (m, 2 H), 2.16-1.91 (m, 6 H), 1.26 (t, 3 H, J = 7.1 Hz),
0.94 (d, 3 H, J = 6.8
Hz), 0.88 (d, 3 H, J = 6.8
Hz). ¹³C NMR (75 MHz, CDCl3): δ = 14.5,
15.7, 18.1, 19.4, 30.3, 31.5, 32.7, 52.8, 58.6, 62.2, 158.5, 174.1,
176.3. IR (KBr): 1740, 1704, 1634 cm-¹.
Mp 118 ˚C. Anal. Calcd for C13H24N2O5S:
C, 48.73; H, 7.55; N, 8.74. Found: C, 48.79; H, 7.58; N, 8.65. [α]D
²0 +7.6
(c 0.8, EtOH).
Urea 4h: ¹H NMR (300 MHz,
CDCl3): δ = 7.13 (m, 3 H), 7.00 (m,
2 H), 5.87 (d, 1 H, J = 8.7
Hz), 5.73 (d, 1 H, J = 7.9 Hz),
4.70 (m, 1 H), 4.30 (m, 1 H), 3.98 (m, 2 H), 3.02 (m,
2
H), 2.07 (m, 1 H), 1.09 (t, 3 H, J = 7.1
Hz), 0.87 (d, 3 H, J = 6.8
Hz), 0.79 (d, 3 H, J = 6.8
Hz). ¹³C NMR (75 MHz, CDCl3): δ = 14.2,
17.9, 19.2, 31.1, 54.6, 58.5, 81.8, 127.1, 128.6, 129.6, 136.2,
158.0, 176.1. IR (KBr): 1733, 1637, 1562 cm-¹.
Anal. Calcd for C17H24N2O5:
C, 60.7; H, 7.1; N, 8.3. Found: C, 60.31; H, 7.2; N, 8.3. Mp 102.6 ˚C. [α]D
²0 +34.5
(c 0.70, EtOH).
Urea 4i: ¹H NMR (300 MHz,
CDCl3): δ = 7.28 (m, 5 H), 5.11 (m,
2 H), 4.37 (m, 1 H), 4.25 (m, 1 H), 2.15 (m, 1 H), 1.54 (m, 3 H),
0.85 (m, 12 H). ¹³C NMR (75 MHz, CDCl3): δ = 16.4,
17.8, 20.8, 21.6, 23.7, 30.0, 40.5, 51.1, 57.4, 66.5, 127.2, 127.5,
127.6, 134.0, 157.5, 173.7, 175.2. IR (KBr): 1715, 1644, 1566 cm-¹.
HRMS: m/z calcd for C19H25N305 [MH+]:
375.1794; found: 375.1799. [α]D
²0 +34.0
(c 0.15, EtOH).
Urea 4j: ¹H NMR (300 MHz,
CDCl3): δ = 7.11 (m, 3 H), 7.01 (m,
2 H), 5.77 (s, 1 H), 5.66 (d, 1 H, J = 7.5
Hz), 4.69 (m,
1 H), 4.31 (m, 1 H), 3.96 (m, 2 H), 2.98
(m, 2 H), 1.57 (m,
2 H), 1.37 (m, 1 H), 1.08 (t, 3 H, J = 7.1 Hz),
0.81 (d, 6 H, J = 5.7
Hz). ¹³C NMR (75 MHz, CDCl3): δ = 14.4,
22.3, 23.3, 25.1, 39.8, 42.1, 52.7, 54.6, 61.8, 127.2, 136.5, 160.5, 173.3.
IR (KBr): 1740, 1644, 1557 cm-¹. Anal.
Calcd for C18H26N2O5:
C, 61.7; H, 7.48; N, 7.99. Found: C, 61.66; H, 7.46; N, 8.04. [α]D
²0 +1.2
(c 0.4, EtOH).