Palladium-catalyzed mono-N-allylation of unprotected amino acids with 1,1-dimethylallyl alcohol in water

Article abstract of DOI:10.1039/c1ob05238a

Palladium-catalyzed N-allylation of unprotected amino acids with 1,1-dimethylallyl alcohol were carried out. The reaction in the presence of Pd(OAc)₂ (5 mol%), sodium diphenylphosphinobenzene-3-sulfonate (TPPMS, 10 mol%), and AcONa (2 equiv) in

Full text of DOI:10.1039/c1ob05238a

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PAPER
Palladium-catalyzed mono-N-allylation of unprotected amino acids with
1,1-dimethylallyl alcohol in water†
Hidemasa Hikawa* and Yuusaku Yokoyama*
Received 15th February 2011, Accepted 23rd March 2011
DOI: 10.1039/c1ob05238a
Palladium-catalyzed N-allylation of unprotected amino acids with 1,1-dimethylallyl
alcohol were carried out. The reaction in the presence of Pd(OAc)2 (5 mol%), sodium
diphenylphosphinobenzene-3-sulfonate (TPPMS, 10 mol%), and AcONa (2 equiv) in water
at 120 ◦C for 16 h in a sealed tube gave only mono-N-allylated amino acids in good yield.
synthesis of clavicipitic acid, palladium-catalyzed N-allylation of
unprotected 4-bromotryptophan with 1,1-dimethylallyl alcohol
Introduction
Biologically active natural products containing N-1,1-dimethyl-
was observed. In general, palladium-catalyzed allylations with
allylated amino acids such as fumitremorgin B,1 fumitremorgin
allylic alcohols are difficult because the reactivity of allylic alcohols
C,2 (+)-austamide,3 okaramine N4 and aeruginosamide5 have been
towards Pd(0) is poor, and compared with allylic carbonates
reported (Fig. 1). Reductive amination1–4 and N-alkylation5 of
ester 1 were used for formation of N-1,1-dimethylallylated amino
acids (Scheme 1).
or acetates, the reaction does not easily lead to the formation
of the p-allyl complex. Therefore, Lewis acids,7 cationic PdII
catalysts,8 Pt catalysts,9 or Pd-P(OPh)3 catalysts10 were used for
N-allylations with allylic alcohols in organic solvents. On the
other hand, recent studies indicated that palladium-catalyzed N-
allylation with allylic alcohols proceeded in water, which played an
important role in the activation of the allylic alcohol to form the
p-allyl complex.11 In these reports, hydrophobic substrates were
often tested on the N-allylation in a two-phase system. However,
there has been no investigation of water-soluble starting materials
such as amino acids using only water as a solvent. We have already
reported the palladium-catalyzed chemoselective reaction of 4-
bromotryptophan or haloanilines with 1,1-dimethylallyl alcohol
in aqueous media.6,11c Changing the pH affected which site in
the molecule was reactive: N-allylation occurred under weakly
basic conditions, while the Heck reaction occurred selectively
under strongly basic conditions. It should be emphasized that this
reaction only occurred when water was used as the solvent. It is
very interesting that pH plays a critical role in the chemoselectivity
of palladium-catalyzed reactions in aqueous media.
Fig. 1 Biologically active natural products.
Herein, we report a palladium-catalyzed mono-N-allylation of
unprotected amino acids with 1,1-dimethylallyl alcohol in water.
Scheme 1 Formation of N-allylated amino acids.
Results and discussion
Since 1999, we have been investigating the total synthesis
of ergot alkaloids from tryptophan derivatives.6 During the
To evaluate the N-allylation of unprotected amino acids with 1,1-
dimethylallyl alcohol 2a, we treated a mixture of tryptophan 1a
and 2a (5 equiv) in the presence of Pd(OAc)2 (5 mol%), sodium
diphenylphosphinobenzene-3-sulfonate (TPPMS, 10 mol%), and
AcONa (2 equiv) in water at 120 ◦C for 16 h in a sealed tube.
After work-up, the mixture was subjected to ODS silica gel
chromatography to give the desired product 3a in 70% yield
along with recovery of starting material 1a (entry 1 in Table 1,
Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba
274-8510, Japan. E-mail: hidemasa.hikawa@phar.toho-u.ac.jp; Fax: +81-
47-472-1595; Tel: +81-47-472-1591
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra of the new products and HPLC analytical data of (S)-3a methyl
ester. See DOI: 10.1039/c1ob05238a
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Table 1 Effects of catalyst, additive and solvent on N-allylation of 1a
Yield (%)
Entry
Catalysts
Additive (equiv)
Solvent
3a
Recov. of 1a
1
Pd(OAc)2/TPPMS
Pd(OAc)2/TPPMS
Pd2dba3/TPPMS
Pd(tppts)3
Pd(OAc)2/Ligand A
None
AcONa (2)
AcONa (2)
AcONa (2)
AcONa (2)
AcONa (2)
AcONa (2)
AcONa (2)
AcONa (2)
None
H2O
H2O
H2O
H2O
H2O
H2O
DMF
70
85
69
48
27
trace
25
28
32
2a
3
4
5
6
7
8
9
10
11
53
No reaction
No reaction
No reaction
32
PdCl2(PPh3)2
Pd(OAc)2/TPPMS
Pd(OAc)2/TPPMS
Pd(OAc)2/TPPMS
Pd(OAc)2/TPPMS
DMF, DMSO or EtOH
H2O
H2O
H2O
33
68
K2CO3 (2)
AcOH (2)
20
No reaction
a Method B: Amino acid 1, Pd(OAc)2 (5 mol%), TPPMS (10 mol%), AcONa (2 equiv) and 2a (5 equiv) in H2O, 120 ◦C, 14 h. Then, Pd(OAc)2 (5 mol%),
TPPMS (10 mol%) and 2a (5 equiv) were added, 120 ◦C, 1 d.
method A). The reaction did not go to completion, because the
p-allyl palladium intermediate may be unstable in our catalytic
system.12
water-soluble ligand, the reaction did not occur in DMF (entry
7). Using a water-soluble ligand, the use of organic solvents such
as DMF, DMSO or EtOH also resulted in no reaction (entry
8), most likely due to the insolubility of the amino acid in the
organic solvent. In addition, water may play an important role
for the smooth generation of the p-allylpalladium species by
hydration of the hydroxyl group. With regard to the additive,
the absence of AcONa or switching to K2CO3 gave lower yields
of 3a (entries 9 and 10). AcOH also suppressed the N-allylation
(entry 11).
Table 2 summarizes the results of N-allylation of tryp-
tophan derivatives with allylic alcohol 2a. At first, we
tested the N-allylation of 5-hydroxytryptophan derivatives. 5-
Hydroxytryptophan (5-HTP) is known as a chemical precursor
as well as a metabolic intermediate in the biosynthesis of the
neurotransmitters serotonin and melatonin from tryptophan. 5-
HTP 1b afforded only the N-allylated product 3b in 57% yield
(entry 1). O-Protected 5-HTP such as 5-benzyloxytryptophan 1c
and 5-methoxytryptophan 1d gave the corresponding allylated
products 3c and 3d in 70% and 80% yields, respectively (entries
2 and 3). Other tryptophans such as 5-methyltryptophan 1e
Therefore, after the N-allylation of 1a with 1,1-
dimethylallylalcohol 2a under the same reaction conditions
as entry 1 for 14 h, fresh catalyst [Pd(OAc)2 (5 mol%) and
TPPMS(10 mol%)] and allylic alcohol 2a (5 equiv) were added to
the resulting solution. After 1 d, the yield improved up to 85%
yield (entry 2, method B). It is noted that only mono-N-allylated
product 3a was obtained in good yield in spite of the possibility of
forming by-products 4 and 5. Thus, the reaction was considered
sufficient for synthetic purposes. With regard to the catalyst, the
use of Pd2(dba)3/TPPMS also resulted in the formation of 3a in
69% yield (entry 3). Using Pd(tppts)3 (tppts: triphenylphosphine-
3,3¢,3¢¢-trisulfonic acid trisodium salt) or Pd(OAc)2 with ligand
A (ligand A: sodium 2¢-dicyclohexylphosphino-2,6-dimethoxy-
1,1¢-biphenyl-3-sulfonate hydrate), the reaction proceeded slowly
to give 3a in 48–53% yield (entries 4 and 5). Since the reaction
did not proceed without the palladium catalyst (entry 6), a
SN2¢ type reaction mechanism was excluded in the formation
of the N-allylated product. Using PdCl2(PPh3)2 instead of a
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Table 2 N-Allylation of tryptophans 1 with allylic alcohol 2a
Yield (%)
Entry
1
Tryptophan 1
Product 3
Methoda
B
3
Recov. of SM 1
b
5-Hydroxy tryptophan 1b
57
70
80
71
—
2
3
4
5-Benzyloxy tryptophan 1c
5-Methoxy tryptophan 1d
5-Methyl tryptophan 1e
A
B
21
Trace
A
19
5
6
6-Fluoro tryptophan 1f
5-Bromo tryptophan 1g
B
86
58
Trace
A
32
a Method A: Amino acid 1, Pd(OAc)2 (5 mol%), TPPMS (10 mol%), AcONa (2 equiv) and 2a (5 equiv) in H2O, 120 ◦C, 16 h. Method B: Amino acid 1,
Pd(OAc)2 (5 mol%), TPPMS (10 mol%), AcONa (2 equiv) and 2a (5 equiv) in H2O, 120 ◦C, 14 h. Then, Pd(OAc)2 (5 mol%), TPPMS (10 mol%) and 2a
(5 equiv) were added, 120 ◦C, 1 d. b Yield not determined.
and 6-fluorotryptophan 1f afforded desired products 3e and
3f in 71% and 86% yields, respectively (entries 4 and 5). N-
Allylation of 5-bromotryptophan 1g occurred to give N-allylated
5-bromotryptophan 3g in 58% yield selectively (entry 6). N-
Allylated 3g should be converted to the 5-substituted product
using cross-coupling.13
We then investigated the scope and limitations of differ-
ent amino acids 1 (Table 3). Phenylglycine 1h afforded the
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Table 3 N-Allylation of several amino acids 1
Entry
1
Amino acid 1
Product 3
Methoda
B
Yield (%)b
60
Phenylglycine 1h
2
3
Leucine 1i
Valine 1j
B
43
58
A
a Method A: Amino acid 1, Pd(OAc)2 (5 mol%), TPPMS (10 mol%), AcONa (2 equiv) and 2a (5 equiv) in H2O, 120 ◦C, 16 h. Method B: Amino acid 1,
Pd(OAc)2 (5 mol%), TPPMS (10 mol%), AcONa (2 equiv) and 2a (5 equiv) in H2O, 120 ◦C, 14 h. Then, Pd(OAc)2 (5 mol%), TPPMS (10 mol%) and 2a
(5 equiv) were added, 120 ◦C, 1 d. b Incomplete conversion.
corresponding product 3h in 60% yield (entry 1). Aliphatic amino
acids such as leucine 1i and valine 1j gave the desired products 3i
and 3j in 43% and 58% yields, respectively (entries 2 and 3). In all
cases, the reaction did not go to completion, and starting material
1 was detected by TLC.
that racemization did not occur during the Heck reaction of (S)-
4-bromotryptophan with 1,1-dimethylallyl alcohol 2a in spite of
the strong basic conditions (3 equiv. of K2CO3, 130 ◦C, 8 h in
H2O),6 and water suppressed the racemization and decomposition
of amino acids.15 Thus, this reaction will be applicable to the
synthesis of optically active N-allylated amino acids.
As shown in Scheme 2, allyl alcohol itself (2b) also gave the
N-allylated product 6 in 68% yield.
A
possible mechanism for the formation of N-1,1-
dimethylallylamino acid 3 from amino acid 1 and 1,1-dimethylallyl
alcohol 2a is illustrated in Scheme 4. Oxidative addition of alcohol
2a to a Pd(0) species affords the p-allyl palladium complex, and
water may play an important role for the smooth generation of the
p-allylpalladium species 7 by hydration of the hydroxyl group.11a
Next, the ligand exchange of the p-allyl system with the amino
Scheme 2 N-Allylation of tryptophan with allyl alcohol 2b.
As shown in Scheme 3, N-allylation of (S)-1a occurred to give
(S)-3a (>99% ee)14 in 72% yield. In our previous report, we found
Scheme 4 A possible mechanism for the formation of N-1,1-dimethyl-
allylamino acid 3.
Scheme 3 N-Allylation of (S)-tryptophan.
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group of 1 takes place to generate intermediate 8, followed by
reductive elimination to give only the mono-N-allylated product
3. On the other hand, N-alkylation with prenylbromide gives the
di-N-allylated product in organic solvents.5 In our catalytic system,
N-allylated compound 3 does not react any further with the p-allyl
complex 7, because water suppresses the nucleophilicity of 3 by the
hydration of the amino group. In addition, our method succeeds in
the presence of AcONa as a base in good yield. AcOH suppressed
the nucleophilicity of 1a by protonation of the amino group. In
strong basic conditions, the p-allyl palladium intermediate 7 is
unstable.12 Therefore, pH plays a critical role in the palladium-
catalyzed N-allylation and the outcome of the N-allylation can be
controlled simply by changing the basicity of the reaction media.
Overall, water plays a key role as a solvent in our catalytic system.
and subjected to ODS silica gel column chromatography. A solvent
gradient, starting with H2O and with increasing proportions of
MeOH, was used as the eluent.
Method B. A mixture of amino acid 1 (0.5 mmol), palla-
dium(II) acetate (6 mg, 0.025 mmol), TPPMS (18 mg, 0.05 mmol),
AcONa·3H2O (136 mg, 1.0 mmol) and 2a (260 mL, 2.5 mmol)
in H2O (2 mL) was heated at 120 ◦C for 14 h in a sealed tube.
Next, palladium(II) acetate (6 mg, 0.025 mmol), TPPMS (18 mg,
0.05 mmol) and 2a (260 mL, 2.5 mmol) were added to the resulting
◦
solution, which was heated at 120 C for 1 d. The work-up and
isolation were carried out as above.
Characterization of N-allylated amino acid 3a–j and 6
dl-N-(3-Methyl-2-buten-1-yl)tryptophan (3a) (Table 1, entries 1
◦
and 2). Off-white solid; mp 238–240 C; IR (KBr) (cm-1) 3419,
Conclusions
1618; 1H NMR (400 MHz, CD3OD+DCl): d 1.63 (s, 3H), 1.76 (s,
3H), 3.48 (d, J = 6.1 Hz, 2H), 3.64 (d, J = 7.8 Hz, 2H), 4.23 (t,
J = 6.1 Hz, 1H), 5.20 (t, J = 7.8 Hz, 1H), 7.04 (ddd, J = 7.8, 7.1,
1.0 Hz, 1H), 7.12 (ddd, J = 8.0, 7.1, 1.0 Hz, 1H), 7.25 (s, 1H), 7.38
(d, J = 8.0 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H); 13C NMR (400 MHz,
CD3OD + DCl): d 18.2, 26.0, 27.2, 45.6, 60.1, 107.5, 112.6, 114.7,
119.1, 120.3, 122.9, 125.7, 128.3, 138.3, 144.7, 171.2; FAB-MS:
m/z 273 [M + H]+; Anal. Calcd for C16H20N2O2·0.3H2O: C, 69.19;
H, 7.48; N, 10.09. Found: C, 68.87; H, 7.24; N, 9.86%.
In summary, we developed a methodology for achieving a
palladium-catalyzed mono-N-allylation of unprotected amino
acids 1 with 1,1-dimethylallyl alcohol 2a in water. This method-
ology offers a new synthetic strategy for the chemical modifi-
cation of amino acids into unnatural derivatives containing a
1,1-dimethylallyl moiety using the Tsuji–Trost reaction without
activation of allylic alcohols in water. Water may play a key role as
a solvent in the development of new synthetic reactions involving
free amino acids. We are currently working on the development
of new reactions involving water-soluble compounds in aqueous
media.
dl-5-Hydroxy-N-(3-methyl-2-buten-1-yl)tryptophan (3b) (Ta-
◦
ble 2, entry 1). White solid; mp 195–196 C; IR (KBr) (cm-1)
3323, 1618; 1H NMR (400 MHz, CD3OD): d 1.53 (s, 3H), 1.68 (s,
3H), 3.12 (dd, J = 15.2, 9.1 Hz, 1H), 3.30–3.60 (m, 3H), 3.81 (d, J =
9.1, 4.4 Hz, 1H), 4.90–5.10 (m, 1H), 6.69 (dd, J = 8.6, 2.0 Hz, 1H),
Experimental
7.01 (d, J = 2.0 Hz, 1H), 7.14 (s, 1H), 7.18 (d, J = 8.6 Hz, 1H); 13
C
All reagents and anhydrous solvents were purchased from com-
mercial suppliers and used without further purification. Melting
points were determined on a Yanagimoto micro-melting hot stage
apparatus and were uncorrected. IR spectra were recorded on a
JASCO FT/IR-230 spectrometer. NMR spectra were recorded
on a JEOL GX-400 (400 MHz) spectrometer. For 1H NMR,
CD3OD (d = 3.30) or tetramethylsilane (TMS) (d = 0) served
as an internal standard. For 13C NMR, CD3OD (d = 49.00) or
tetramethylsilane (TMS) (d = 0) served as an internal standard.
Preparation of NMR samples for 1H NMR and 13C NMR:
compound 3 and 6 (5 mg) were dissolved in CD3OD (500 mL) and
20% DCl in D2O (10 mL). FAB mass spectra were measured with
a JEOL JMS-600H spectrometer. EI mass spectra were measured
with a JEOL GCmate spectrometer. Separations were performed
using ODS DM1020T (Fuji Silysia Chemical Ltd.) for silica gel
column chromatography. Thin layer chromatography (TLC) was
performed on precoated plates of silica gel 60F254 (Merck).
NMR (400 MHz, CD3OD + DCl): d 18.2, 26.0, 27.3, 45.6, 59.9,
106.7, 113.0, 113.1, 114.7, 126.3, 128.9, 133.1, 144.8, 151.7, 171.2;
FAB-MS: m/z 289 [M + H]+; Anal. Calcd for C16H20N2O3·1.1H2O:
C, 62.36; H, 7.26; N, 9.09. Found: C, 62.18; H, 7.10; N, 8.71%.
dl-5-Benzyloxy-N-(3-methyl-2-buten-1-yl)tryptophan (3c) (Ta-
◦
ble 2, entry 2). White solid; mp 236–238 C; IR (KBr) (cm-1)
3420, 3033, 1612; 1H NMR (400 MHz, CD3OD + DCl): d 1.63 (s,
3H), 1.76 (s, 3H), 3.44 (d, J = 6.1 Hz, 2H), 3.63 (d, J = 7.5 Hz,
2H), 4.20 (t, J = 6.1 Hz, 1H), 5.10 (s, 2H), 5.21 (t, J = 7.5 Hz,
1H), 6.87 (dd, J = 8.7, 2.0 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H),
7.22 (s, 1H), 7.25–7.35 (m, 2H), 7.36 (t, J = 7.3 Hz, 1H), 7.46 (d,
J = 7.3 Hz, 1H); 13C NMR (400 MHz, CD3OD + DCl): d 18.2,
26.0, 27.2, 45.6, 60.0, 72.1, 107.3, 113.3, 113.8, 114.8, 126.5, 128.7,
128.8, 129.5, 133.7, 139.3, 144.7, 154.4, 171.2; FAB-MS: m/z 379
[M + H]+; Anal. Calcd for C23H26N2O3: C, 72.99; H, 6.92; N, 7.40.
Found: C, 72.89; H, 7.00; N, 7.25%.
General procedure for the synthesis of N-allylated amino acids
3a–j, 6 and (S)-3a.
dl-5-Methoxy-N-(3-methyl-2-buten-1-yl)tryptophan (3d) (Ta-
ble 2, entry 3). Pale yellow solid; mp 235–236 ◦C; IR (KBr) (cm-1)
3353, 3056, 1627; 1H NMR (400 MHz, CD3OD+DCl): d 1.63 (s,
3H), 1.76 (s, 3H), 3.46 (d, J = 6.2 Hz, 2H), 3.66 (d, J = 7.4 Hz,
2H), 3.83 (s, 3H), 4.20 (t, J = 6.2 Hz, 1H), 5.24 (t, J = 7.4 Hz, 1H),
6.77 (dd, J = 8.8, 2.2 Hz, 1H), 7.10 (d, J = 2.2 Hz, 1H),7.24 (s, 1H),
7.28 (d, J = 8.8 Hz, 1H); 13C NMR (400 MHz, CD3OD+DCl):
d 18.2, 26.0, 27.2, 45.6, 56.4, 60.0, 101.2, 107.2, 113.2, 113.3,
114.8, 126.4, 128.6, 133.4, 144.7, 155.4, 171.2; FAB-MS: m/z 303
Method A. A mixture of amino acid 1 (0.5 mmol), pal-
ladium(II) acetate (6 mg, 0.025 mmol), sodium diphenylphos-
phinobenzene-3-sulfonate (TPPMS, 18 mg, 0.05 mmol),
AcONa·3H2O(136 mg, 1.0 mmol) and 2-methyl-3-buten-2-ol 2a or
prop-2-en-1-ol 2b (2.5 mmol) in H2O (2 mL) was heated at 120 ◦C
for 16 h in a sealed tube. The solvent was removed under reduced
pressure, and the resulting residue was dissolved in AcOH (1 mL)
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[M + H]+; Anal. Calcd for C17H22N2O3·0.5H2CO3: C, 63.05; H,
3.60–3.80 (m, 2H), 3.80 (d, J = 3.6 Hz, 1H), 5.31 (t, J = 6.8 Hz,
1H); 13C NMR (400 MHz, CD3OD+DCl): d 17.5, 18.2, 19.5, 19.6,
26.0, 30.7, 46.2, 65.4, 114.7, 145.0, 170.2; FAB-MS: m/z 186 [M +
H]+; Anal. Calcd for C10H19NO2·0.1H2O: C, 64.21; H, 10.35; N,
7.49. Found: C, 63.85; H, 10.12; N, 7.44%.
6.95; N, 8.40. Found: C, 63.32; H, 6.97; N, 8.08%.
dl-5-Methyl-N-(3-methyl-2-buten-1-y◦l)tryptophan (3e) (Table 2,
entry 4). Off-white solid; mp 240–242 C; IR (KBr) (cm-1) 3238,
3034, 1616; 1H NMR (400 MHz, CD3OD + DCl): d 1.62 (s, 3H),
1.75 (s, 3H), 2.41 (s, 3H), 3.40–3.50 (m, 2H), 3.60–3.70 (m, 2H),
4.22 (t, J = 6.3 Hz, 1H), 5.19 (t, J = 7.3 Hz, 1H), 6.96 (d, J = 8.3 Hz,
1H), 7.20 (s, 1H), 7.26 (d, J = 8.3 Hz, 1H), 7.37 (s, 1H); 13C NMR
(400 MHz, CD3OD + DCl): d 18.1, 21.7, 26.0, 27.2, 45.6, 60.0,
107.0, 112.3, 114.8, 118.7, 124.6, 125.7, 128.5, 129.5, 136.6, 144.7,
171.2; FAB-MS: m/z 287 [M + H]+; Anal. Calcd for C17H22N2O2:
C, 71.30; H, 7.74; N, 9.78. Found: C, 70.90; H, 7.68; N, 9.53%.
dl◦-N-Allyltryptophan (6) (Scheme 2). White solid; mp 226–
229 C (Lit.,16 247 ◦C); IR (KBr) (cm-1) 3411 (OH), 1625 (C O);
1H NMR (400 MHz, CD3OD+DCl): d 3.50 (d, J = 6.0 Hz, 2H),
3.65 (d, J = 6.8 Hz, 2H), 4.26 (t, J = 6.0 Hz, 1H), 5.41 (dd, J =
7.8, 1.2 Hz, 1H), 5.44 (s, 1H), 5.80–5.95 (m, 1H), 7.04 (ddd, J =
8.0, 7.0, 1.2 Hz, 1H), 7.12 (dd, J = 8.0, 7.0, 1.2 Hz, 1H), 7.26 (s,
1H), 7.38 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H); 13C NMR
(400 MHz, CD3OD+DCl): d 26.9, 60.4, 107.4, 112.6, 119.1, 120.3,
122.9, 124.9, 125.7, 128.3, 128.8, 138.2, 171.0; FAB-MS: m/z 245
[M + H]+; Anal. Calcd for C14H16N2O2·0.2H2O: C, 67.83; H, 6.67;
N, 11.30. Found: C, 67.68; H, 6.54; N, 11.06%.
dl-5-Fluoro-N-(3-methyl-2-buten-1-yl)tryptophan (3f) (Table 2,
◦
entry 5). White solid; mp 248–250 C; IR (KBr) (cm-1) 3256,
3033, 1617; 1H NMR (400 MHz, CD3OD + DCl): d 1.65 (s, 3H),
1.77 (s, 3H), 3.46 (t, J = 6.1 Hz, 2H), 3.65 (d, J = 7.6 Hz, 2H),
4.22 (t, J = 6.1 Hz, 1H), 5.22 (t, J = 7.6 Hz, 1H), 6.80–6.86 (m,
1H), 7.08 (dd, J = 9.8, 2.2 Hz, 1H), 7.20 (s, 1H), 7.54 (dd, J =
8.8, 5.1 Hz, 1H); 13C NMR (400 MHz, CD3OD + DCl): d 18.1,
21.7, 26.0, 27.2, 45.6, 60.0, 107.0, 112.3, 114.8, 118.7, 124.6, 125.7,
128.5, 129.5, 136.6, 144.7, 171.2; FAB-MS: m/z 291 [M + H]+;
Anal. Calcd for C16H19FN2O2: C, 65.38; H, 6.65; N, 9.53. Found:
C, 65.31; H, 6.53; N, 9.31%.
(S)-N-(3-Methyl-2-buten-1-yl)tryptophan (S)-3a6b (Scheme 3).
Off-white solid; mp 228–229 ◦C (Lit. mp 224–225 ◦C); IR (KBr)
(cm-1) 3276, 3057, 1611; 1H NMR (400 MHz, CD3OD + DCl): d
1.63 (s, 3H), 1.76 (s, 3H), 3.48 (d, J = 6.4 Hz, 2H), 3.64 (d, J =
7.8 Hz, 2H), 4.23 (t, J = 6.4 Hz, 1H), 5.20 (t, J = 7.8 Hz, 1H), 7.04
(ddd, J = 7.8, 7.1, 1.0 Hz, 1H), 7.12 (ddd, J = 8.0, 7.1, 1.0 Hz, 1H),
7.24 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H); 13
C
dl-5-Bromo-N-(3-methyl-2-buten-1-yl)tryptophan (3g) (Table 2,
NMR (400 MHz, CD3OD + DCl): d 18.1, 26.0, 27.2, 45.6, 60.1,
107.5, 112.6, 114.7, 119.1, 120.3, 122.9, 125.6, 128.3, 138.3, 144.7,
171.2; FAB-MS: m/z 273 [M + H]+.
◦
entry 6). White solid; mp 251–253 C; IR (KBr) (cm-1) 3418,
1626; 1H NMR (400 MHz, CD3OD+DCl): d 1.67 (s, 3H), 1.78 (s,
3H), 3.44 (t, J = 6.1 Hz, 2H), 3.67 (d, J = 7.8 Hz, 2H), 4.21 (t, J =
6.1 Hz, 1H), 5.23 (t, J = 7.8 Hz, 1H), 7.20 (dd, J = 8.5, 1.7 Hz,
1H), 7.29 (s, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 1.7 Hz,
1H); 13C NMR (400 MHz, CD3OD + DCl): d 18.2, 26.0, 26.9,
45.7, 60.1, 107.4, 113.5, 114.3, 114.7, 121.7, 125.7, 127.3, 130.2,
136.8, 144.8, 171.1; FAB-MS: m/z 351 [M + H]+, 353 [M + H +
2]+; Anal. Calcd for C16H19BrN2O2·0.3CH3CH2OH: C, 54.62; H,
5.74; N, 7.67. Found: C, 54.64; H, 5.41; N, 7.30%.
Determination of optical purity of (S)-3a. A mixture of (S)-
3a (20 mg, 0.073 mmol), MeOH (160 mL), AcOEt (625 mL)
and TMSCHN2 (600 mL, 0.36 mmol) was stirred at room
temperature for 12 h. The solvent was removed under reduced
pressure, and the resulting residue was purified by preparative
TLC (hexane : AcOEt = 2 : 1) to give (S)-N-(3-methyl-2-buten-1-
yl)tryptophan methyl ester (16 mg, 77%) as a colorless oil, whose
optical purity was >99% ee as determined by HPLC analysis
[CHIRALCEL AD-H, n-hexane/EtOH = 97/3, 1.0 mL min-1,
220 nm (UV), t (minor) = 23 min, t (major) = 29 min).
dl-N-(3-Methyl-2-buten-1-yl)phenylglycine (3h) (Table 3, entry
◦
1). White solid; mp 224–226 C; IR (KBr) (cm-1) 3422, 3063,
1579; 1H NMR (400 MHz, CD3OD+DCl): d 1.63 (s, 3H), 1.81 (s,
3H), 3.50–3.70 (m, 2H), 4.95–5.05 (m, 1H), 5.29 (t, J = 7.3 Hz, 1H),
7.40–7.60 (m, 5H); 13C NMR (400 MHz, CD3OD+DCl): d 18.2,
26.0, 45.0, 63.4, 114.6, 129.8, 130.7, 131.5, 132.2, 144.6, 170.2;
FAB-MS: m/z 220 [M + H]+; Anal. Calcd for C13H17NO2·0.1H2O:
C, 70.63; H, 7.84; N, 6.34. Found: C, 70.66; H, 7.80; N, 6.23%.
(S)-N-(3-Methyl-2-buten-1-yl)tryptophan methyl ester1c. IR
1
(neat) (cm-1) 3408, 2923, 1735; H NMR (400 MHz, CDCl3): d
1.56 (s, 3H), 1.66 (s, 3H), 1.95 (brs, 1H), 3.11 (dd, J = 13.2, 6.8 Hz,
1H), 3.15 (d, J = 6.4 Hz, 1H), 3.16 (d, J = 6.4 Hz, 1H), 3.21 (dd,
J = 13.0, 6.8 Hz, 1H), 3.62 (s, 3H), 3.66 (t, J = 6.4 Hz, 1H), 5.16 (t,
J = 6.8 Hz, 1H), 7.04 (d, J = 2.2 Hz, 1H), 7.11 (ddd, J = 7.8, 6.8,
1.0 Hz, 1H), 7.18 (ddd, J = 7.8, 6.8, 1.0 Hz, 1H), 7.33 (d, J = 7.8 Hz,
1H), 7.59 (d, J = 7.8 Hz, 1H), 8.15 (brs, 1H); 13C NMR (400 MHz,
CDCl3): d 17.8, 25.7, 29.3, 45.6, 51.7, 61.4, 111.1, 111.3, 118.8,
119.4, 122.1, 122.3, 122.8, 127.5, 135.1, 136.2, 175.4; EI-MS: m/z
286 (M+, 22%), 130 (BP).
dl-N-(3-Methyl-2-buten-1-yl)leucine (3i) (Table 3, entry 2).
◦
White solid; mp 197–200 C; IR (KBr) (cm-1) 3448, 2956, 1577;
1H NMR (400 MHz, CD3OD+DCl): d 0.99 (d, J = 6.6 Hz, 3H),
1.00 (d, J = 6.6 Hz, 3H), 1.65–1.90 (m, 3H), 1.76 (s, 3H), 1.82 (s,
3H), 3.30–3.45 (m, 2H), 3.68 (d, J = 7.6 Hz, 2H), 3.89 (dd, J =
8.3, 5.4 Hz, 1H), 5.31 (t, J = 7.6 Hz, 1H); 13C NMR (400 MHz,
CD3OD+DCl): d 18.3, 21.9, 23.3, 25.9, 26.0, 40.1, 45.3, 58.7,
114.8, 144.9, 171.5; FAB-MS: m/z 200 [M + H]+; Anal. Calcd for
C11H21NO2: C, 66.29; H, 10.62; N, 7.03. Found: C, 65.99; H, 10.51;
N, 6.93%.
Acknowledgements
We are grateful to the “Open Research Center Project” for private
universities and a matching fund subsidy from the Ministry
of Education, Sports, Culture, Science, and Technology, Japan
(MEXT). And this work was supported by a Grant-in-Aid for
Scientific Research (C) (No. 20590014).
dl-N-(3-Methyl-2-buten-1-yl)valine (3j) (Table 3, entry 3).
White solid; mp 206–209 ◦C; IR (KBr) (cm-1) 3422, 2967, 1578; 1H
NMR (400 MHz, CD3OD+DCl): d 1.05 (d, J = 7.1 Hz, 3H), 1.13
(d, J = 7.1 Hz, 3H), 1.74 (s, 3H), 1.82 (s, 3H), 2.20–2.40 (m, 1H),
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