A short synthesis of optically active γ,γ-dimethylallyltryptophan (DMAT)

Article abstract of DOI:10.1055/s-2000-6246

A short synthesis (4 steps) of optically active γ,γ- dimethylallyltryptophan (1, DMAT) was accomplished from N(α)-tert- butoxycarbonyl(Boc)-4-(3-hydroxy-3-methyl-1-buten-1-yl)-1-tosyl-tryptophan methyl ester (5) prepared by Heck reaction of N(α)-Boc-4-bro

Full text of DOI:10.1055/s-2000-6246

214
SHORT PAPER
A Short Synthesis of Optically Active g,g-Dimethylallyltryptophan (DMAT)
Hidemasa Hikawa, Yuusaku Yokoyama,* Yasuoki Murakami*
School of Pharmaceutical Sciences, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan
Fax +81(47)4721589; E-mail: yokoyama@phar.toho-u.ac.jp
Received 17 September 1999; revised 20 October 1999
synthesis of optically active DMAT 1 starting from 5 in
combination with the abnormal reactivity of the C4-dime-
thylallyl side chain of 5.
Abstract:
g,g-dimethylallyltryptophan (1, DMAT) was accomplished
from Na-tert-butoxycarbonyl(Boc)-4-(3-hydroxy-3-methyl-1-
A short synthesis (4 steps) of optically active
buten-1-yl)-1-tosyl-tryptophan methyl ester (5) prepared by Heck
reaction of Na-Boc-4-bromo-1-tosyltryptophan methyl ester (4)
with 1,1-dimethylallylalcohol.
OH
CO2Me
CO2Me
H
OH
Key words: 4-bromotryptophan, g,g-dimethylallyltryptophan
(DMAT), optically active synthesis, Heck reaction
BocHN
H
BocHN
Br
Pd(0),
N
Ts
g,g-Dimethylallyltryptophan (1, DMAT) was first
proposed1 as a biosynthetic key-intermediate for ergot al-
kaloids such as clavicipitic acid 2 or lysergic acid 3. The
structure of this hypothesized compound was subsequent-
ly confirmed by its isolation from claviceps bioorganism
under anaerobic conditions2 as well as by feeding
experiment3 using synthetic DMAT 1. DMAT 1 is not
only important in the biosynthetic pathway but also attrac-
tive as a potential synthetic intermediate for ergot alka-
loids. The first total synthesis of DL-1 was reported4 in
1963 by Plieninger’s group starting from 4-formylindole.
This synthesis has played an important role in the supply
of DL-1 for biosynthetic research until Nettekoven’s
group5 developed the synthesis of optically active DMAT
(S)-1 by enzymatic kinetic resolution of the phenacyl
amide of DL-1 in 1995.
N
Heck Reaction
Ts
4
5
X
CO2Me
H2N
H
Deprotection
Clavicipitic
Acid (2)
1) HCl/EtOAc
2) Et3N
N
Ts
6
Scheme 1
The key compound 5 was prepared by palladium cata-
lyzed vinylation (Heck reaction) of (S)-N-Boc-4-bromo-
1-tosyltryptophan methyl ester (4) with 1,1-dimethylallyl-
alcohol according to the reported method.6 At first, the de-
hydration of 5 was carried out by treatment with SOCl2/
Et3N in toluene at 0 °C to give the rather unstable diene 7
in as high as 82% yield. Since the yield was not reproduc-
ible, milder conditions were attempted. After several at-
tempts, we finally found that treatment of 5 with 3
equivalents of TsOH in benzene at room temperature gave
the diene 7 in good yield (83%) consistently.
1,4-Reduction and reductive detosylation occurred simul-
taneously upon treatment of 7 with Mg/MeOH to di-
rectly give N-Boc-DMAT methyl ester 8 (Scheme 2).
Figure 1
We previously reported6 the first total synthesis of optical-
ly active clavicipitic acid 2 from optically active 4-bro-
motryptophan (4) (Scheme 1). The key step in this
synthesis was the one-pot cyclization of Nα-tert-butoxy-
carbonyl(Boc)-4-(3-hydroxy-3-methyl-1-buten-1-yl)-1-
tosyltryptophan methyl ester (5) by deprotection of the
Boc group with acid and subsequent neutralization with
Et3N at the stage of 6. Thus, compound 5 was regarded as
a synthetic equivalent of DMAT 1 from the view-point of
the biosynthetic pathway. In this paper, we report the total
CO2Me
CO2Me
BocHN
H
BocHN
H
TsOH
Mg
5
Benzene
r.t., 1 h
MeOH
0 °C, 30 min
N
Ts
7
83%
N
H
72%
8
Scheme 2
Synthesis 2000, No. 2, 214–216 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
A Short Synthesis of Optically Active g,g-Dimethylallyltryptophan (DMAT)
215
1,4-Reduction7 of a diene and reductive elimination8 of Thus, we accomplished the total synthesis of optically ac-
the tosyl group from indole nitrogen by treatment with tive DMAT 1 in 4 steps from 5 (total yield 49%). During
Mg/MeOH has previously been reported. Since the optical this study, unexpected high reactivity of the double bond
purity of 5 was 93% ee and that of 8 was 91% ee, racem- of 4-dimethylallyl group became apparent. This is inter-
ization was considered negligible in those steps.
esting for considering the biosynthesis of ergot alkaloids
from DMAT. We are now investigating the total synthesis
of ergot alkaloids using DMAT or its precursor.
We then turned our attention to remove the protecting
groups of 8. Simultaneous removal of the Boc and ester
groups by heating with 50% aqueous HOAc (130 °C for
7 hours in a sealed tube) or stepwise deprotection with
HCl/EtOAc (0 °C, 1 hour) followed by mild alkaline hy-
Mps were determined on a Yanagimoto micro-melting hot stage ap-
paratus and were uncorrected. IR spectra were recorded in Nujol
drolysis (1% KOH/MeOH, room temperature, 2 days) mulls (unless otherwise stated) on a JASCO FT/IR-230 spectrome-
ter. NMR spectra were recorded on a JEOL GX-400 (400 MHz)
spectrometer with TMS as internal reference. Mass spectra were
measured with a JEOL JMS-01SG-2 spectrometer using direct inlet
system. Optical rotations were measured with JASCO DIP-1000.
For column chromatography, Kieselgel 60 (70−230 mesh, Merck),
and for TLC, Kieselgel GF 254, were used.
gave a mixture of DMAT 1 and alcohol 9 which were dif-
ficult to separate. Treatment of 8 with HCl/ EtOAc caused
the addition of HCl to the double bond to form 10. There-
fore, deprotection of the Boc group was carried out in the
absence of strong nucleophiles such as chloride ions.
(S)-Nα-Boc-4-(g,g-dimethylallyl)tryptophan Methyl Ester (8)
A mixture of (S)-Nα-Boc-4-(2-methyl-2-butene-4-yl)tryptophan
methyl ester (5, 542 mg, 0.974 mmol, 93% ee) and p-TsOH (601.3
mg, 3.1 mmol) in benzene (30 mL) was stirred for 1 h at r.t.. Then,
the mixture was directly subjected to Al2O3 column chromatogra-
phy (benzene:EtOAc, 20:1) to give (S)-Nα-Boc-4-(3-methyl-1,3-
butadiene-1-yl)tryptophan methyl ester (7) as pale a yellow amor-
phous solid (436 mg, 83%), which was used in the next reaction
without further purification.
OH
Cl
H2N
CO2H
Cl H3N
CO2Me
N
H
N
H
9
10
After the generation of H2 gas began from a mixture of Mg turnings
(611 mg, 25.1 mmol) and MeOH (8.0 mL) at r.t., the mixture was
cooled to 0 °C. A solution of 7 (436 mg, 0.809 mmol) in MeOH (10
mL) was slowly added to the mixture and vigorously stirred for 30
min at the same temperature. The reaction mixture (gray slimy
mass) was quenched with sat. NH4Cl, and extracted with CH2Cl2.
The organic layer was washed with sat. NaHCO3 and sat. NaCl, and
dried (MgSO4). After evaporation of the solvent, the resulting pale
brown residue was subjected to silica gel column chromatography
(benzene:EtOAc, 20:1) to give 225 mg of (S)-Nα-Boc-4-(g,g-dime-
thylallyl)tryptophan methyl ester (8) as a pale yellow solid (60%
yield from 5), which was recrystallized from EtOH to give colorless
needles. The optical purity was measured by HPLC using a chiral
column (SUMICHIRAL OA-4500, hexane:EtOH, 30:1). The opti-
cal purity of crude 8 was 91% ee and that of recrystallized 8 was in-
Figure 2
After alkaline hydrolysis of the optically active ester 8
(94% ee) (10% KOH/MeOH in dioxane, room tempera-
ture, 3.5 hours), deprotection of the Boc group of the re-
sulting acid 11 was accomplished by heating in 50%
aqueous HOAc (80 °C, 3 hours). Finally, the desired
DMAT 1 was obtained as a single product in good yield
without any racemization (94% ee) (Scheme 3). When
glacial HOAc was used as a solvent, a higher temperature
was required to make the reaction proceed (140 °C, 4
hours, 79% yield) and the resultant DMAT 1 was racem- creased to 94% ee.
ized seriously (15% ee). At lower temperature (100 °C,
3.5 hours) in the same solvent, the reaction did not pro-
ceed sufficiently (24% yield and 53% starting material re-
covery) and racemization still occurred (71% ee). Other
acids such as CF3COOH, dilute H2SO4, and HCO2H gave
unknown products or complex mixtures. We noted that
the presence of H2O lowered the reaction temperature re-
quired, and suppressed the racemization, although the rea-
son for this is not clear at the present time.
Mp: 133−134 °C.
[a]20 : −35.7 (c = 0.48, MeOH).
D
IR (KBr) : nmax = 3384, 3298 1734, 1686 cm-1.
1H NMR (400 MHz, DMSO-d6, 100 °C): d = 1.32 (s, 9H), 1.71 (s,
6H), 3.12 (dd, 1H, J = 16, 9 Hz), 3.31 (dd, 1H, J = 16, 5 Hz), 3.60
(s, 3H), 3.67 (d, 2H, J = 7 Hz), 4.28 (dt, 1H, J = 9, 5 Hz), 5.32 (t-
like, 1H, J = 7 Hz), 6.67 (br s, 1H), 6.73 (d, 1H, J = 8 Hz), 6.93 (t,
1H, J = 8 Hz), 7.05 (d, 1H, J = 2 Hz), 7.16 (d, 1H, J = 8 Hz), 10.55
(br s, 1H).
ET-MS: m/z = 386 (M+, 3.1%), 198 (100%).
Anal. Calcd. for C22H30N2O4: C, 68.37, H, 7.82, N, 7.25. Found: C,
68.82, H, 8.12, N, 7.30.
CO2H
BocHN
H
(S)-Nα-Boc-4-(g,g-dimethylallyl)tryptophan (11)
10% KOH/MeOH
in Dioxane
A mixture of (S)-8 (49 mg, 0.127 mmol, 94% ee.), 10% KOH/
MeOH (0.6 mL), and 1,4-dioxane (0.8 mL) was stirred for 3.5 h at
r.t.. Then the mixture was poured into H2O and extracted with
EtOAc. The aqueous layer was acidified with HOAc and extracted
with EtOAc. The organic layer was washed with H2O and dried
50% aq. AcOH
8
1
r.t., 3.5 h
92%
80 °C, 3 h
N
H
91%
11
Scheme 3
Synthesis 2000, No. 2, 214–216 ISSN 0039-7881 © Thieme Stuttgart · New York

216
H. Hikawa et al.
SHORT PAPER
FAB-MS: m/z = 273 [(M+H)+, 90%], 198 (100%).
(MgSO4). After evaporation of the solvent, the resulting residue was
subjected to silica gel chromatography (CH2Cl2:MeOH, 10:1) to
give (11) as a colorless solid (43.5 mg, 92.1% yield).
Anal. Calcd for C16H20N2O2∑0.7H2O: C, 67.44, H, 7.57, N, 9.83.
Found: C, 67.37, H, 7.31, N, 9.53.
Mp: 96−100 °C.
[a]20 : −37.0 (c = 0.85, MeOH).
IR (KBr): nmax = 3411, 1687 cm-1.
1H NMR (400 MHz, CD3OD): d = 1.00 (s) and 1.36 (s) (total 9H),
1.74 (s, 6H), 3.18 (dd, 1H, J = 15, 8 Hz), 3.48 (dd, 1H, J = 15, 5
Hz), 3.76 (m, 2H), 4.34 (t-like, 1H, J = 5 Hz), 5.32 (m, 1H), 6.74
(d, 1H, J = 7 Hz), 6.95 (t, 1H, J = 7 Hz), 7.08 (br s, 1H), 7.14 (d,
1H, J = 7 Hz).
D
Acknowledgement
This work was supported by a Grant-in-Aid (08672452) for Scien-
tific Research from the Ministry of Education, Science and Culture
of Japan.
References
Anal. Calcd. for C21H28N2O4 H2O: C, 64.60, H, 7.74, N, 7.17.
Found: C, 64.38, H, 7.44, N, 7.05.
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(S)-γ,γ-Dimethylallyltryptophan (1)
A solution of (S)-11 (42.5 mg, 0.114 mmol, 94% ee) in 50% aq
HOAc (8 mL) was heated at 80 °C for 3h. Then the mixture was
poured into H2O and extracted with EtOAc. The organic layer was
extracted with 5% HOAc 3 times and the combined aqueous layer
was evaporated to dryness. The residue was purified by ODS col-
umn chromatography (H2O:MeOH, 2:1~3:1), and the resulting sol-
id was successively trituated with EtOAc and EtOH to give (S)-
DMAT (1) as a colorless solid (28.2 mg, 91% yield). The optical pu-
rity (94% ee) was measured by HPLC using a chiral column (SUM-
ICHIRAL OA-4500, hexane:EtOH, 50:1) after converting to 8.
Mp: 204−209 °C.
[a]20 : −45.7 (c = 0.23, MeOH:1N HCl, 99:1) [Lit.5 [a]D: −48.5
D
(MeOH:1N-HCl, 99:1)].
IR (KBr): nmax = 3418, 1627 cm-1.
(8) Muratake, H.; Natsume, M. Heterocycles 1989, 29, 783.
1H NMR (400 MHz, CD3OD): d = 1.75 (s, 3H), 1.76 (s, 3H), 3.16
(dd, 1H, J = 16, 10 Hz), 3.75−3.88 (m, 4H), 5.34 (tt, 1H, J = 6, 1
Hz), 6.78 (d, 1H, J = 8 Hz), 7.00 (t, 1H, J = 8 Hz), 7.18 (s, 1H),
7.20 (d, 1H, J = 8 Hz).
Article Identifier:
1437-210X,E;2000,0,02,0214,0216,ftx,en;F06199SS.pdf
Synthesis 2000, No. 2, 214–216 ISSN 0039-7881 © Thieme Stuttgart · New York