The Journal of Organic Chemistry
Note
in an ice bath, and H2O (12.5 mL), together with saturated NaHCO3
(aq) (6.25 mL), was added to the cold reaction. The resulting mixture
was washed with EtOAc (2 × 10 mL). The aqueous phase was
acidified to pH 2−3 with 1 M KHSO4 (aq) and extracted with EtOAc
(3 × 50 mL). The combined organic phases were dried over MgSO4,
and the solvent was removed in vacuo.
added dropwise. After complete addition, the reaction was stirred for
6 h at −20 °C under a N2 atmosphere. The suspension was filtered,
and the solvent was evaporated in vacuo. The residue was redissolved
in 3 mL dry DME and stirred at −40 °C. TFAA (3.0 mmol) and 2,6-
lutidine in dry DME (2 mL) were added dropwise under a N2
atmosphere. After complete addition, the temperature was raised to
−20 °C, and the reaction was stirred for 1 h. The solvent was
evaporated in vacuo. The residue was redissolved in EtOAc (10 mL)
and washed with H2O (5 mL), 20% citric acid (aq) (3 × 5 mL), and
brine (5 mL). The organic phase was dried over MgSO4 and
evaporated in vacuo. The residue was purified on silica gel by VLC
eluting with a stepwise gradient of pure PE to 1:1 PE/EtOAc.
(S)-tert-Butyl 1-(4-Cyanothiazol-2-yl)ethylcarbamate (Boc-L-
Ala-TzN) (13a). Starting from Boc-L-Ala(S)-NH2 (12a) (205 mg,
1.0 mmol) and following the general procedure E, we obtained Boc-L-
Ala-TzN (13a) as a white solid (172 mg, 68%): Rf = 0.5 (2:1 PE:/
EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 5.27−4.96 (m,
2H), 1.62 (d, J = 6.9 Hz, 3H), 1.46 (s, 9H); 13C NMR (101 MHz,
CDCl3) δ 176.3, 154.9, 130.4, 126.5, 113.9, 80.6, 48.8, 28.3, 21.1.
HRMS-TOF (m/z): [M + Na]+ calcd for C11H15N3NaO2S+,
276.0783; found, 276.0775.
(R)-2-[2-[(R)-1-(tert-Butoxycarbonylamino)ethyl]thiazol-4-
yl]-4-methyl-4,5-dihydrothiazole-4-carboxylic Acid (Boc-D-Ala-
Tz-Tzin-OH) (10a) from Boc-D-Ala-TzN. Starting from Boc-D-
Ala-TzN (9a) (253 mg, 1.0 mmol) following the general procedure
D, we isolated Boc-D-Ala-Tz-Tzin-OH (10a) as a white solid (370 mg,
1
99%): H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 5.20 (br, 1H),
5.10 (br, 1H), 3.87 (d, J = 11.6 Hz, 1H), 3.35 (d, J = 11.6 Hz, 1H),
1.68 (s, 3H), 1.61 (d, J = 6.9 Hz, 3H), 1.46 (s, 9H); 13C NMR (101
MHz, CDCl3) δ 175.5, 174.7, 165.3, 155.0, 147.7, 122.4, 84.0, 80.4,
48.8, 41.0, 28.3, 24.1, 21.6. HRMS-TOF (m/z): [M + H]+ calcd for
+
C15H22N3O4S2 , 372.1052; found, 372.1046.
(R)-2-[2-[(R)-1-(tert-Butoxycarbonylamino)ethyl]thiazol-4-
yl]-4-methyl-4,5-dihydrothiazole-4-carboxylic Acid (Boc-D-Ala-
Tz-Tzin) Acid (10a) from Boc-D-Ala-Tz(NH)-OMe. Boc-D-Ala-
Tz(NH)-OMe (15) (51.4 mg, 0.18 mmol) and (R)-α-methylcysteine
hydrochloride (50.0 mg, 0.30 mmol) were dissolved in MeOH
(0.5 mL), and the mixture was stirred at 50 °C for 3 h. The reaction
was cooled to 0 °C, and saturated NaHCO3 (aq) (5 mL) was added.
The aqueous solution was washed with EtOAc (2 × 2 mL). The
aqueous phase was acidified with 20% citric acid (aq) (5 mL) and
extracted with EtOAc (3 × 5 mL). The combined organic phases were
washed with brine (3 mL) and dried over MgSO4. The solvent was
evaporated in vacuo to yield the pure thiazoline (5a) as a pale yellow
(S)-tert-Butyl 1-(4-Cyanothiazol-2-yl)-2-methylpropylcarba-
mate (Boc-L-Val-TzN) (13b). Starting from Boc-L-Val(S)-NH2
(12b) (210 mg, 0.9 mmol) and following the general procedure E,
we obtained Boc-L-Val-TzN (13b) as a white solid (137 mg, 54%):
1
Rf = 0.6 (2:1 PE/EtOAc); H NMR (400 MHz, CDCl3) δ 7.93 (s,
1H), 5.22 (d, J = 7.1 Hz, 1H), 4.94−4.84 (m, 1H), 2.44−2.31 (m,
1H), 1.46 (s, 9H), 0.99 (d, J = 6.8 Hz, 3H), 0.93 (d, J = 6.9 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 174.7, 155.4, 130.0, 126.7, 113.9, 80.5,
1
58.0, 33.1, 28.3, 19.2, 17.3. HRMS-TOF (m/z): [M + Na]+ calcd for
solid (60.2 mg, 90%): H NMR identical to the above-described data.
C13H19N3NaO2S+, 304.1096; found, 304.1088.
(R)-2-[2-[(R)-1-(tert-Butoxycarbonylamino)-2-methylpropyl]-
thiazol-4-yl]-4-methyl-4,5-dihydrothiazole-4-carboxylic Acid
(Boc-D-Val-Tz-Tzin-OH) (10b). Starting from Boc-D-Val-TzN
(9b) (310 mg, 1.10 mmol) and following the general procedure D,
we isolated Boc-D-Val-Tz-Tzin-OH (10b) as a white solid (436 mg,
(S)-tert-Butyl 1-(4-Cyanothiazol-2-yl)-2-phenylethylcarba-
mate (Boc-L-Phe-TzN) (13c). Starting from Boc-L-Phe(S)-NH2
(12c) (281 mg, 1.0 mmol) and following the general procedure E, we
obtained Boc-L-Phe-TzN (13c) as a white solid (214 mg, 65%): Rf =
1
1
99%): H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 5.27−5.18 (m,
0.6 (2:1 PE/EtOAc); H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H),
1H), 4.92−4.84 (m, 1H), 3.85 (d, J = 11.5 Hz, 1H), 3.35 (d, J = 11.6
Hz, 1H), 2.44−2.35 (m, 1H), 1.68 (s, 3H), 1.46 (s, 9H), 1.00 (d, J =
6.8 Hz, 3H), 0.93 (d, J = 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
175.0, 173.1, 165.6, 155.4, 148.1, 121.4, 84.3, 80.3, 57.9, 40.7, 33.2,
28.3, 24.3, 19.4, 17.4. HRMS-TOF (m/z): [M + H]+ calcd for
7.31−7.23 (m, 3H), 7.12−7.07 (m, 2H), 5.30−5.10 (m, 2H), 3.34−
3.26 (m, 2H), 1.40 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 174.5,
154.9, 135.7, 130.4, 129.4, 128.8, 127.2, 126.7, 113.9, 80.7, 53.9, 41.1,
28.2. HRMS-TOF (m/z): [M + Na]+ calcd for C17H19N3NaO2S+,
352.1096; found, 352.1093.
+
C17H26N3O4S2 , 400.1359; found, 400.1359.
(R)-2-[2-[(S)-1-(tert-Butoxycarbonylamino)ethyl]thiazol-4-
yl]-4-methyl-4,5-dihydrothiazole-4-carboxylic Acid (Boc-L-Ala-
Tz-Tzin-OH) (14a). Starting from Boc-L-Ala-TzN (12a) (370 mg,
1.5 mmol) and following the general procedure D, we isolated Boc-L-
Ala-Tz-Tzin-OH (14a) as a white solid (494 mg, 91%): 1H NMR (400
MHz, CDCl3) δ 7.98 (s, 1H), 5.28 (bs, 1H), 5.08 (bs, 1H), 3.89 (d, J =
11.5 Hz, 1H), 3.32 (d, J = 11.5 Hz, 1H), 1.68 (s, 3H), 1.60 (d, J = 6.9
Hz, 3H), 1.45 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 175.5, 174.6,
165.1, 155.0, 147.9, 122.0, 84.2, 80.3, 48.7, 41.0, 28.3, 24.2, 21.6.
(R)-2-[2-[(R)-1-(tert-Butoxycarbonylamino)-2-phenylethyl]-
thiazol-4-yl]-4-methyl-4,5-dihydrothiazole-4-carboxylic Acid
(Boc-D-Phe-Tz-Tzin-OH) (10c). Starting from Boc-D-Phe-TzN
(9c) (300 mg, 0.9 mmol) and following the general procedure D,
we obtained Boc-D-Phe-Tz-Tzin-OH (10c) as a pale yellow solid (410
24
1
mg, 99%): H NMR as described. HRMS-TOF (m/z): [M + H]+
+
calcd for C21H26N3O4S2 , 448.1365; found, 448.1360.
(S)-tert-Butyl 1-Amino-1-thioxopropan-2-ylcarbamate (Boc-
L-Ala(S)-NH2) (12a). Starting from Boc-L-Ala-OH (5.0 g, 26.4 mmol)
and following the general procedure A (doubling all amounts), we
HRMS: HRMS-TOF (m/z): [M + H]+ calcd for C15H22N3O4S2 ,
+
372.1052; found, 372.1042.
1
obtained Boc-L-Ala(S)-NH2 (12a) as a white solid (4.4 g, 82%): H
(R)-2-[2-[(S)-1-(tert-Butoxycarbonylamino)-2-methylpropyl]-
thiazol-4-yl]-4-methyl-4,5-dihydrothiazole-4-carboxylic Acid
(Boc-L-Val-Tz-Tzin-OH) (14b). Starting from Boc-L-Val-TzN
(12b) (338 mg, 1.2 mmol) and following the general procedure D,
we isolated Boc-L-Val-Tz-Tzin-OH (14b) as a white solid (465 mg,
NMR as described.48
(S)-tert-Butyl 1-Amino-3-methyl-1-thioxobutan-2-ylcarba-
mate (Boc-L-Val(S)-NH2) (12b). Starting from Boc-L-Val-OH (5.0 g,
23.0 mmol) and following the general procedure A (doubling all
amounts), we obtained Boc-L-Val(S)-NH2 (12b) as white solid (4.7 g,
1
97%): H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 5.25 (d, J = 8.7
49
1
88%): H NMR as described.
Hz, 1H), 4.93−4.84 (m, 1H), 3.89 (d, J = 11.6 Hz, 1H), 3.34 (d, J =
11.6 Hz, 1H), 2.45−2.34 (m, 1H), 1.69 (s, 3H), 1.46 (s, 9H), 0.99 (d,
J = 6.8 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 175.3, 173.0, 165.4, 155.4, 148.0, 121.7, 84.2, 80.2, 57.9,
40.8, 33.2, 28.3, 24.2, 19.3, 17.3. HRMS-TOF (m/z): [M + H]+ calcd
(S)-tert-Butyl 1-Amino-3-phenyl-1-thioxopropan-2-ylcarba-
mate (Boc-L-Phe(S)-NH2) (12c). Starting from Boc-L-Phe-OH (5.0
g, 18.8 mmol) and following the general procedure A (doubling all
amounts), we obtained Boc-L-Phe(S)-NH2 (12c) as white solid (4.5 g,
35
1
+
85%): H NMR as described.
for C17H26N3O4S2 , 400.1365; found 400.1360.
General Procedure E: Synthesis of Thiazole-4-carbonitriles
from Thioamides. Bromoacetyl bromide (383 mg, 1.9 mmol) was
added dropwise to TMS cyanide (198 mg, 2.0 mmol) under a N2
atmosphere, and the resulting mixture was heated to 70 °C for 1.5 h to
form the cyclization agent (11). The thioamide (see below) was
dissolved in dry DME (3 mL), and KHCO3 (5.0 mmol) was added.
The mixture was stirred at −40 °C while the cyclization agent was
(R)-2-[2-[(S)-1-(tert-Butoxycarbonylamino)-2-phenylethyl]-
thiazol-4-yl]-4-methyl-4,5-dihydrothiazole-4-carboxylic Acid
(Boc-L-Phe-Tz-Tzin-OH) (14c). Starting from Boc-L-Phe-TzN
(12c) (329 mg, 1.0 mmol) and following the general procedure D,
we isolated Boc-L-Phe-Tz-Tzin-OH (14c) as a white solid (443 mg,
99%): H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.33−7.18 (m,
3H), 7.16−7.10 (m, 2H), 5.26 (bs, 2H), 3.90 (d, J = 11.6 Hz, 1H),
1
9849
dx.doi.org/10.1021/jo201675r|J. Org. Chem. 2011, 76, 9845−9851