Synthesis of (±)-Homohistidine

Full text of DOI:10.1021/jo991630q

J . Org. Chem. 2000, 65, 2229-2230
2229
Sch em e 1
Syn th esis of (()-Hom oh istid in e
Michael C. Pirrung* and Tao Pei
Department of Chemistry, Levine Science Research Center,
Box 90317, Duke University,
Durham, North Carolina 27708-0317
Received October 19, 1999
For a program studying the inhibition of histidine
kinases,1 we required quantities of several histidine
analogues in forms suitable for solid-phase synthesis.
Methods for the generation of the histidine homologue
homohistidine have been earlier reported.2 The most
recent synthesis of homohistidine was achieved in
nine steps with an overall yield of 40%, starting from
Z-glutamic acid. Here is described a preparation of
homohistidine from the readily available urocanic acid,
and conversion to its BOC derivatives (Scheme 1).
Urocanic acid was esterified and hydrogenated. While
in earlier work3 the N-H of the imidazole was left
unprotected for the following reduction step, the solubility
properties of 2 are sufficiently poor as to limit the
synthesis scale. As reported by Browne,4 tritylation
significantly improves its solubility in ethereal solvents,
permitting DIBAL-H reduction in quantity to the alde-
hyde. Strecker reaction gives an aminonitrile whose
hydrolysis also causes removal of the trityl group,
producing homohistidine (6) in 73% overall yield.
The protection of histidines with activated BOC de-
rivatives can a priori protect either or both nitrogens. The
R-amino group is expected to be more nucleophilic/
reactive, but it did not prove possible to derivatize
selectively this site with stoichiometric BOC protection
reagents. It has been reported that treatment of histidine
with excess BOC-N3 gives the bis-BOC derivative, which
can be further treated in refluxing methanol to form the
R-amino BOC derivative.5 Treatment of homohistidine
with an excess of BOC2O derivatizes both nitrogens,
producing the bis-BOC-homohistidine (8) in 17% yield.
We attribute this low yield to the reactivity of the BOC-
imidazolide toward aqueous reaction conditions, as some
R-BOC derivative was also isolated. That suggested a
method to obtain selectively the mono-BOC derivative
by use of an excess of BOC2O, followed by an extended
reaction time in water to hydrolyze the imidazolide. This
produces the target R-BOC-homohistidine (7) in 56%
yield.
added to the reaction, which was heated at reflux for 30 h. The
solid Na2SO4 was filtered off, and the solvent was removed in
vacuo. The remaining white solid was dissolved in a small
amount of water and neutralized with saturated NaHCO3/H2O
until no gas was evolved. The cloudy aqueous solution was
extracted with ethyl acetate. The organic layer was dried over
Na2SO4, and the solvent was removed in vacuo. A white solid
remained (15.36 g, 99%). mp 92-94 °C; MS: MH+ ) 153. 1H
NMR (CDCl3): δ 7.69 (s, 1H), 7.59 (d, J ) 15.6 Hz, 1H), 7.27 (s,
1H), 6.45 (d, J ) 15.6 Hz, 1H), 5.24 (b, 1H), 3.76 (s, 3H). 13C
NMR (DMSO-d6): δ 165.6, 136.6, 129.2, 128.3, 121.7, 119.8, 51.9.
All data were consistent with literature.6
Meth yl 3-(Im id a zol-4-yl)p r op ion a te (2). Urocanic acid
methyl ester (1) (14.73 g, 96.9 mmol) was dissolved in 125 mL
of methanol and 1.5 g of palladium on activated carbon (10%)
was added. The reaction was stirred under H2 at room-temper-
ature overnight, whereupon TLC showed the reaction was
complete. The solid was filtered off, and the methanol was
removed in vacuo. A white solid remained (14.32 g, 96%). mp
1
95-97 °C; H NMR showed adequate purity for the next step.
1
MS: MH+ ) 155. H NMR (CDCl3): δ 8.56 (b, 1H), 7.53 (d, J )
1.2 Hz, 1H), 6.78 (d, J ) 1.2 Hz, 1H), 3.65 (s, 3H), 2.91 (t, J )
7.2 Hz, 2H), 2.65 (t, J ) 7.2 Hz, 2H). 13C NMR (CDCl3) δ 173.8,
135.2, 134.5, 117.7, 51.8, 33.9, 21.9. This is a known compound.7
Meth yl 3-(1-Tr itylim id a zol-4-yl)p r op ion a te (3). A litera-
ture procedure was used.4 To a solution of 2 (4.62 g, 30.0 mmol)
and triethylamine (8.40 mL, 60.0 mmol) in 30 mL of anhydrous
DMF was added triphenylchloromethane (9.39 g, 33.0 mmol) in
25 mL of anhydrous DMF. The mixture turned cloudy after
addition and generated heat. The reaction mixture was stirred
overnight at room temperature as it became cloudy and yellowish
and was poured onto 300 g of ice. A white solid precipitated,
which was collected on a filter and washed with water and small
amount of ether. A white powder was obtained (10.88 g, 92%).
mp 142-143 °C; MS: MH+ ) 397. 1H NMR (CDCl3): δ 7.32 (m,
10H), 7.12 (m, 6H), 6.54 (s, 1H), 3.62 (s, 3H), 2.87 (t, J ) 7.8
Hz, 2H), 2.65 (t, J ) 7.87 Hz, 2H). 13C NMR (CDCl3): δ 173.4,
142.4, 139.9, 138.3, 129.7, 127.9, 117.9, 51.5, 33.9, 24.0. All data
were consistent with literature.
(2) Altman, J .; Wilchek, M. Synth. Comm. 1989, 19, 2069-2076.
Bloemhoff, W.; Kerling, K. E. T. J . R. Neth. Chem. Soc. 1975, 183.
(3) Iizuka, K.; Akahane, K.; Momose, D.; Nakazawa, M.; Tanouchi,
T.; Kawamura, M.; Ohyama, I.; Kajiqara, I.; Iguchi, Y.; Okada, T.;
Taniguchi, K.; Miyamoto, T.; Hayashi, M. J . Med. Chem. 1981, 24,
1139-1148.
Exp er im en ta l Section
(4) Browne, L. J .; Gude, C.; Rodriguez, H.; Steele, R. E.; Bhatnagar,
A. J . Med. Chem. 1991, 34, 725-736.
Meth yl Ur oca n a te (1). Urocanic acid (14.08 g, 101.9 mmol)
and anhydrous Na2SO4 (2.0 g) were added to 150 mL of
anhydrous methanol. Concentrated sulfuric acid (8 mL) was
(5) Flouret, G.; Morgan, R.; Gendrich, R.; Wilber, J .; Siebel, M. J .
Med. Chem. 1973, 16, 113.
(6) Viguerie, N. L.; Sergueeva, N.; Damiot, M.; Mawlawi, H.; Riviere,
M.; Lattes, A. Heterocycles 1994, 37, 1561.
(1) Pirrung, M. C. Chem. Biol. 1999, 6, R167.
(7) Schunack, W.; Arch. Pharm. 1974, 307, 517.
10.1021/jo991630q CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/16/2000

2230 J . Org. Chem., Vol. 65, No. 7, 2000
Notes
3-(1-Tr itylim id a zol-4-yl)p r op ion a ld eh yd e (4). A modifica-
tion of a known procedure was used.4 To a solution of 4 (3.97 g,
10.0 mmol) in 50 mL of anhydrous dichloromethane was added
DIBAL-H (1.5 M in toluene) (13.5 mL, 20.3 mmol) at -78 °C.
The reaction was kept stirring at this temperature for 45 min
before it was quenched by adding 5 mL of methanol and 35 mL
of water. After the reaction mixture rose to room temperature,
the organic layer was separated and dried over Na2SO4. After
removal of solvent in vacuo, a slight yellowish white solid was
obtained (3.90 g, 100%). mp 84-86 °C; MS: MH+ ) 367. 1H
NMR (CDCl3): δ 9.81 (t, J ) 1.5 Hz, 1H), 7.32 (m, 9H), 7.23 (s,
1H), 7.12 (m, 6H), 6.56 (s, 1H), 2.87 (m, 2H), 2.80 (m, 2H). 13C
NMR (CDCl3) δ 202.1, 142.3, 139.6, 138.5, 129.6, 127.9, 118.0,
43.3, 21.3. IR (film) 3060, 3030, 1722 cm-1. All data were
consistent with literature.
Bis-BOC-h om oh istid in e (7). Homohistidine (6) (0.29 g, 1.7
mmol) was dissolved in a minimum amount of water. Saturated
NaHCO3/H2O was added to pH 9. A solution of (BOC)2O (1.30
g, 5.8 mmol) in dichloromethane was added followed by tetra-
butylammonium bromide. The reaction was stirred overnight
and acidified to pH 3 with 1 N HCl/H2O. The resulting solution
was extracted with chloroform, and the organic layer was
dried over Na2SO4. After removal of solvent, the product was
purified by flash column chromatography (0.11 g, 17%), Rf
(0.3, CHCl3:MeOH ) 5:1). MS: MH+ ) 370.18. HRMS calcd for
C
17H28N3O6: MH+ ) 370.1978, found MH+) 370.1978. 1H NMR
(CDCl3) δ 11.94 (b, 1H), 8.11 (s, 1H), 7.14 (s, 1H), 5.40 (d, J )
7.5 Hz, 1H), 4.31 (m, 1H), 2.66 (m, 2H), 2.11 (m, 2H), 1.58 (s,
9H), 1,41 (s, 9H). 13C NMR (CDCl3) δ 174.3, 155.2, 146.3, 141.0,
136.2, 113.6, 86.2, 79.6, 52.9, 32.8, 28.4, 27.9, 23.1. IR (film) 3303,
4-(1-Tr itylim id a zol-4-yl)-2-a m in obu tyr on itr ile (5). To a
solution of 4 (2.38 g, 6.5 mmol) in methanol was added NH4Cl
(1.25 g, 23.3 mmol) in 20 mL of ammonia/H2O. The reaction
mixture was stirred at room temperature for 40 min, and KCN
(0.76 g, 11.7 mmol) was added. The reaction was kept stirring
at room temperature for 18 h followed by removal of the solvent
in vacuo. The solid was redissolved in ethyl acetate and water.
The organic layer was dried over Na2SO4 and evaporated to a
slight yellowish residue. The product was recrystallized from
CH2Cl2/hexane to provide a white solid after filtration (2.15 g,
84%). mp 111-113 °C; MS: MH+ ) 393.22. HRMS calcd for
3065, 1772, 1711, 1692, 1649 cm-1
.
BOC-h om oh istid in e (8). Homohistidine (6) (1.80 g, 10.6
mmol) was dissolved in a minimum amount of water and
adjusted to pH 9 with saturated NaHCO3/H2O. (BOC)2O (4.62
g, 21.2 mmol) in dioxane was added, and the reaction was
refluxed overnight. After cooling to room temperature, most of
the solvent was removed and the residue was acidified to pH 3
with 1 N HCl/H2O. The cloudy mixture was extracted with
chloroform. The aqueous layer was evaporated in vacuo, and the
solid was redissolved in methanol. Chloroform was added to
induce precipitation. After filtration of the solid, the solute was
evaporated in vacuo. A slight yellowish sticky oil was obtained
(1.60 g, 56%). MS: MH+ ) 270. HRMS calcd for C12H20N3O4:
MH+ ) 270.1454, found MH+ ) 270.1454.1H NMR (CDCl3) δ
8.44 (s, 1H), 7.10 (s, 1H), 3.85 (m, 1H), 2.70 (t, J ) 7.35 Hz,
2H), 2.07 (m, 1H), 1.88 (m, 1H), 1.27 (s, 9H). 13C NMR (CDCl3)
δ 173.5, 155.4, 133.7, 133.3, 115.8, 78.0, 52.7, 29.9, 28.2, 21.6.
C
26H24N4: M ) 392.2001, found M ) 392.2080. 1H NMR (CDCl3)
δ 7.38 (s, 1H), 7.27 (m, 9H), 7.11 (m, 6H), 6.58 (s, 1H), 3.71 (t, J
) 7.2 Hz, 1H), 2.75 (m, 2H), 2.38 (b, 2H), 2.10 (m, 2H). 13C NMR
(CDCl3) δ 142.2, 139.0, 138.4, 129.6, 127.9, 118.5, 118.3, 42.7,
34.9, 24.2. IR (film) 3384, 3153, 3089, 3062, 2251 cm-1
.
Hom oh istid in e (6). A modification of a literature procedure
was used.8 To 20 mL of concentrated HCl was added 5 (1.2 g,
3.05 mmol), and the reaction mixture was refluxed overnight.
The solution was twice extracted with ether. The aqueous layer
was evaporated in vacuo, and a white solid was obtained (0.55
g, 100%). Further purification was accomplished on Dowex
cation-exchange resin, eluting with 1 N ammonia. mp 222-224
°C; MS: MH+ ) 170.13. 1H NMR (D2O) δ 7.63 (s, 1H), 6.85 (s,
1H), 3.62 (t, J ) 6.0 Hz, 1H), 2.61 (t, J ) 8.1 Hz, 2H), 2.06 (m,
2H). IR (film) 3372, 3048, 1732 cm-1. All data were consistent
with literature.2
IR (KBr) 3397, 3134, 1754, 1691 cm-1
.
Ack n ow led gm en t. Financial support provided by
NIH AI-42151. The assistance of L. LaBean in admin-
istrative support of this work is greatly appreciated.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra for 5,
7, and 8. This material is available free of charge via the
Internet at http://www.pubs.acs.org.
(8) Harada, K.; Okawara, T. J . Org. Chem. 1973, 38, 707.
J O991630Q