Notes
Eth yl 2-Ch lor o-3-oxo-4,4-d im eth yl-5-h exen oa te (11). A
J . Org. Chem., Vol. 65, No. 24, 2000 8405
(-)-P h en yla h istin (1). To a mixture solution of 3 (100 mg,
0.61 mmol) and diacetyl-cyclo(l-Phe-Gly)5 (351 mg, 1.28 mmol)
in dry DMF (5 mL) was added Cs2CO3 (198 mg, 0.61 mmol), and
the mixture was stirred at room temperature for 16 h. To the
reaction mixture was added 5 mL of 28% aqueous NH4OH. After
being stirred at room temperature for 12 h, the reaction mixture
was neutralized with AcOH at 4 °C, and the resultant solution
was purified by preparative reverse phase (RP) HPLC with a
column (µBondasphere 5C18 100 A, 19 × 150 mm) employing a
linear gradient from 24 to 33% CH3CN in 0.1% aqueous TFA
over 18 min at a flow rate of 12 mL/min to give 60 mg (21%) of
1 (TFA salt) as a white fluffy powder. However, since almost
complete racemization was observed in purified 1, the (-)-form
of 1 was isolated by HPLC using a chiral column (CHIRALCEL
OD, 10 × 250 mm) eluted with a mixture of hexane and ethanol
(5:1) at a flow rate of 3.0 mL/min. 7% yield (15 mg) from 3: white
solid, mp 229-231 °C; [R]23D -268° (c ) 0.1, MeOH); IR (CHCl3)
1670, 1640, 1430 cm-1; 1H NMR (300 MHz, CDCl3) δ 12.0 (br s,
1H, NH), 8.96 (br s, 1H, NH), 7.55 (s, 1H), 7.22-7.38 (m, 5H),
6.88 (s, 1H), 6.03 (dd, J ) 11, 17 Hz, 1H), 5.69 (br s, 1H, NH),
5.21 (dd, J ) 1, 11 Hz, 1H), 5.16 (dd, J ) 1, 17 Hz, 1H), 4.33
(ddd, J ) 2, 3, 10 Hz, 1H), 3.47 (dd, J ) 3, 14 Hz, 1H), 2.93 (dd,
J ) 10, 14 Hz, 1H), 1.51 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
164.7, 159.9, 144.6, 136.6, 135.5, 132.3 (2C), 129.5, 129.1, 127.4,
123.9, 113.5, 105.3, 57.2, 41.3, 37.6, 27.9 (2C). HRMS (EI) m/z
350.1736 (M+) (calcd for C20H22N4O2: 350.1743). Anal. Calcd
for C20H22N4O2‚CF3COOH‚H2O: C, 54.77; H, 5.22, N, 11.61.
Found: C, 54.62, H, 5.00, N, 11.23.
10.25 g (55.6 mmol) amount of 5 in 40 mL of CHCl3 was treated
with 4.7 mL (58.4 mmol) of sulfuryl chloride at 4 °C. The reaction
mixture was stirred for 30 min at room temperature and then
refluxed for 2 h. On cooling, the clear solution was washed with
water, 5% NaHCO3, water, and saturated NaCl, dried over Na2-
SO4, and concentrated in vacuo. The residual oil was purified
by column chromatography on silica (3.2 × 20 cm) using
hexane-EtOAc (400:1 to 75:1) as an eluant to give an oil of 11
(9.39 g, 77%): IR (CHCl3) 1725, 1760 cm-1; 1H NMR (270 MHz,
CDCl3) δ 5.96 (dd, J ) 11, 17 Hz, 1H), 5.294 (d, J ) 11 Hz, 1H),
5.288 (d, J ) 17 Hz, 1H), 5.19 (s, 1H), 4.24 (q, J ) 7 Hz, 2H),
1.35 (s, 3H), 1.33 (s, 3H), 1.29 (t, J ) 7 Hz, 3H); 13C NMR (67.5
MHz, CDCl3) δ 201.1, 165.1, 140.5, 116.5, 63.0, 55.2, 51.6, 23.7,
23.4, 13.9. HRMS (EI) m/z 218.0698 (M+) (calcd for C10H15O3
Cl: 218.0710).
Eth yl 5-(1,1-Dim eth yl-2-p r op en yl)im id a zole-4-ca r boxy-
la te (12). A mixture of 7.83 g (35.81 mmol) of 11, 14.2 mL (0.358
mol) of formamide, and 1.29 mL (71.6 mmol) of water was
refluxed at 145 °C for 4 h. On cooling, to the reaction mixture
was added 100 mL of CHCl3, and it was washed with 10% Na2-
CO3 and saturated NaCl three times, dried over Na2SO4, and
concentrated in vacuo. The residual oil was purified by column
chromatography on silica (3.2 × 20 cm) using CHCl3-MeOH (50:
1) as an eluant to give 4.29 g (48%) of a white solid 12: mp 88-
90 °C; IR (CHCl3) 1705 cm-1; 1H NMR (270 MHz, CDCl3) δ 7.82
(br, 1H), 7.54 (s, 1H), 6.28 (dd, J ) 10, 18 Hz, 1H), 5.08 (dd, J
) 1, 18 Hz, 1H), 5.05 (dd, J ) 1, 10 Hz, 1H), 4.33 (q, J ) 7 Hz,
2H), 1.57 (s, 6H), 1.34 (t, J ) 7 Hz, 3H); 13C NMR (67.5 MHz,
CDCl3) δ 161.3, 149.1, 145.2, 133.3, 122.6, 111.8, 60.6, 38.5,
26.6 (2C), 14.4. HRMS (EI) m/z 208.1221 (M+) (calcd for
Au r a n tia m in e (2). This compound was prepared according
to the same procedure described for 1 starting from aldehyde 3
(100 mg) and diacetyl-cyclo (L-Val-Gly) in the presence of Cs2-
CO3. After the reaction, the resultant solution was purified using
RP-HPLC with the same conditions described for the purification
of 1 except for a column (YMC-Pac ODS-AM 120 A, 20 × 250
mm) and a linear gradient from 21 to 24% CH3CN over 12 min
to give 89 mg (35%) of 2 (TFA salt) as a white fluffy powder.
Since purified 2 contained 31% of a racemized compound with
D-valine (38% ee), further purification by HPLC with a chiral
column was performed using the same procedure described for
the purification of 1 with a mixture of hexane and ethanol (8:1)
as an eluant. 20% (36 mg) yield from 3; white solid, mp 237-
C
11H16N2O2: 208.1212). Anal. Calcd for C11H16N2O2: C, 63.44;
H, 7.74, N, 13.45. Found: C, 63.38, H, 7.82, N, 13.28.
(5-(1,1-Dim eth yl-2-pr open yl)im idazol-4-yl)m eth an ol (13).
To a solution of 12 (3.0 g, 14.4 mmol) in toluene (60 mL) was
added 47.5 mL of 1.0 M DIBALH dropwise in toluene at -50 °C
under argon atmosphere, and the mixture was stirred, allowing
the temperature rise up to -20 °C for 1 h. This solution was
recooled to -30 °C, and then 30 mL of a mixture of MeOH and
AcOH (2:1) was added slowly. After the mixture was stirred for
30 min at 0 °C, 50 mL of water, 50 mL of EtOAc, and 10% Na2-
CO3 up to pH 10 were added, and the resulting precipitate was
removed by filtration. To the filtrate was added NaCl up to
saturation, and the organic layer was washed with 10% Na2-
CO3 (once) and saturated NaCl (three times), dried over Na2-
SO4, and concentrated in vacuo. The residual solid was recrys-
tallized from ether to obtain 1.18 g (50%) of white crystals 13:
mp 171-173 °C; IR (KBr) 3460, 2980, 1460, 1015 cm-1; 1H NMR
(270 MHz, CD3OD) δ 7.49 (s, 1H), 6.11 (dd, J ) 11, 17 Hz, 1H),
5.04 (dd, J ) 1, 17 Hz, 1H), 5.02 (dd, J ) 1, 11 Hz, 1H), 4.58 (s,
2H), 1.44 (s, 6H); 13C NMR (67.5 MHz, CD3OD) δ 147.6, 138.5,
134.0, 131.4, 111.4, 57.2, 39.0, 28.4 (2C). HRMS (EI) m/z
166.1105 (M+) (calcd for C9H14N2O: 116.1106). Anal. Calcd for
C9H14N2O: C, 65.03; H, 8.49, N, 16.85. Found: C, 65.20, H,8.67,
N, 16.56.
238 °C; [R]24 -111° (c ) 0.1, MeOH); IR (CHCl3) 1670, 1640,
D
1430 cm-1
;
1H NMR (300 MHz, CDCl3) δ 12.0 (br s, 1H, NH),
9.07 (br s, 1H, NH), 7.55 (s, 1H), 6.93 (s, 1H), 6.04 (dd, J ) 11,
17 Hz, 1H), 6.00(br s, 1H, NH), 5.21 (d, J ) 11 Hz, 1H), 5.17 (d,
J ) 17 Hz, 1H), 4.05 (dd, J ) 2, 3 Hz, 1H), 2.47 (dhept, J ) 3,
7 Hz, 1H), 1.52 (s, 6H), 1.06 (d, J ) 7 Hz, 3H), 0.96 (d, J ) 7 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 165.0, 160.7, 144.6, 136.5.
132.3 (2C), 123.8, 113.5, 105.1, 61.2, 37.6, 33.0, 28.0 (2C), 18.7,
15.9. HRMS (EI) m/z 302.1749 (M+) (calcd for C16H22N4O2:
302.1743). Anal. Calcd for C16H22N4O2‚CF3COOH‚0.5MeOH: C,
51.39; H, 5.83, N, 12.96. Found: C, 51.72, H, 6.02, N, 13.25.
Ack n ow led gm en t. This work was supported by
grants from the Ministry of Education, Science and
Culture of J apan and Frontier Research Program of the
Ministry of Education, Science and Culture of J apan.
The authors are grateful to Dr. Hiroshi Kanzaki (Labo-
ratory of Bioresources Chemistry, Faculty of Agricul-
ture, Okayama University) for helpful suggestions and
discussions.
5-(1,1-Dim e t h yl-2-p r op e n yl)im id a zole -4-ca r b oxa ld e -
h yd e (3). To a solution of 13 (0.3 g, 1.80 mmol) in acetone (70
mL) was added 1.6 g of MnO2, and the mixture was stirred at
room temperature for 1 h. After filtration to remove MnO2, the
solvent was removed by evaporation, and the residual white
powder was purified by column chromatography on silica (1.6
× 20 cm) using CHCl3-MeOH (200:1 to 25:1) as an eluant to
give 280 mg (95%) of white crystalline 12: mp 109-111 °C; IR
(CHCl3) 1650, 1340 cm-1 1H NMR (270 MHz, CDCl3) δ 10.02
;
Su p p or tin g In for m a tion Ava ila ble: Copies of both 1H
and 13C NMR spectra of compounds 1-3, 12, and 13. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(s, 1H), 8.01 (br, 1H), 7.80 (s, 1H), 6.22 (dd, J ) 11, 18 Hz, 1H),
5.20 (dd, J ) 1, 18 Hz, 1H), 5.16 (dd, J ) 1, 11 Hz, 1H), 1.56 (s,
6H); 13C NMR (67.5 MHz, CDCl3) δ 181.5, 156.8, 146.2, 137.4,
128.6, 112.3, 39.8, 28.5 (2C). HRMS (EI) m/z 164.0944 (M+) (calcd
for C9H12N2O: 164.0950). Anal. Calcd for C9H12N2O: C, 65.83;
H, 7.37, N, 17.06, Found: C, 65.65, H, 7.40, N, 16.73.
J O0012905