Acid catalyzed monodehydro-2,5-diketopiperazine formation from N-α-ketoacyl amino acid amides

Article abstract of DOI:10.1016/j.tet.2009.02.058

We have developed a new synthetic method for monodehydro-2,5-diketopiperazines (monodehydroDKPs), which is based on an acid catalyzed cyclization of N-α-ketoacyl amino acid amides. Using this cyclization reaction, monodehydroDKP was formed with no or slight racemization in case that N-α-ketoacyl amino acid amides with β-aliphatic-α-ketoacyl groups and sterically unhindered N-substituting groups at the C-terminal amide nitrogen were used in the presence of catalytic amount of p-TsOH (3-5 mol %) or 10% TFA. In the case of β-aryl-α-ketoacyl amino acid derivatives, in which an enol form predominantly exists by conjugation with the aromatic ring, racemization could be minimized by optimizing the reaction conditions (5 mol % p-TsOH, reflux for 6 h), although the chemical yield could not be dramatically improved. However, this reaction condition was successfully applied to the synthesis of a tubulin depolymerization agent, (-)-tert-butyl-oxa-phenylahistin, with no racemization.

Full text of DOI:10.1016/j.tet.2009.02.058

Tetrahedron 65 (2009) 3688–3694
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Acid catalyzed monodehydro-2,5-diketopiperazine formation
from N-a-ketoacyl amino acid amides
,
Yuri Yamazaki a, Yuki Mori a, Akiko Oda b, Yuka Okuno b, Yoshiaki Kiso b, Yoshio Hayashi a
*
a Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan
b Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, 21st Century COE program, Kyoto Pharmaceutical University, Kyoto 607-8412, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed
dehydroDKPs), which is based on an acid catalyzed cyclization of N-
a
new synthetic method for monodehydro-2,5-diketopiperazines (mono-
-ketoacyl amino acid amides. Using
this cyclization reaction, monodehydroDKP was formed with no or slight racemization in case that N-
ketoacyl amino acid amides with -aliphatic- -ketoacyl groups and sterically unhindered N-substituting
groups at the C-terminal amide nitrogen were used in the presence of catalytic amount of p-TsOH
(3–5 mol %) or 10% TFA. In the case of -aryl- -ketoacyl amino acid derivatives, in which an enol form
Received 19 January 2009
Received in revised form 23 February 2009
Accepted 24 February 2009
Available online 3 March 2009
a
a-
b
a
b
a
predominantly exists by conjugation with the aromatic ring, racemization could be minimized by
optimizing the reaction conditions (5 mol % p-TsOH, reflux for 6 h), although the chemical yield could not
be dramatically improved. However, this reaction condition was successfully applied to the synthesis of
a tubulin depolymerization agent, (ꢀ)-tert-butyl-oxa-phenylahistin, with no racemization.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
onto the DKP ring with a chiral side chain at the opposite a-
position (Fig. 1, compound 1).8 In order to develop a new
method that reduces such unfavorable racemization and to
provide a new efficient synthetic route of monodehydroDKPs,
we focused our work on Gladiali et al.’s report that the re-
Monodehydro-2,5-diketopiperazine (monodehydroDKP, 1) is
a cyclic dipeptide with a dehydrated structure on one side of the
ring. Many naturally occurring derivatives of the monodehydroDKP
possessing varied biological activity have been discovered such as
phenylahistin with microtubule depolymerization activity,1 cyclo
action of
a-ketoester and Boc-NH2 in the presence of a cata-
lytic amount of p-TsOH resulted in the formation of
dehydroamino acid as shown in Scheme 1A.9 It was thought
that, if this acid catalyzed reaction was applied to an intra-
molecular reaction, monodehydroDKPs would be formed with
no racemization (Scheme 1B). Hence, we applied Gladiali’s
method to corresponding precursors of monodehydroDKPs,
(dehydroAla-L-Leu) with a
-glucosidase inhibitory activity,2 barettin
with selective 5HT-ligand activity,3 neoechinulin A with cytopro-
tection activity,4 cristatin A with immunosuppressive activity,5 and
golmaenone with radical scavenging activity,6 etc. Among these
compounds, phenylahistin was recognized as a new lead com-
pound for anticancer agents. Recently, we developed a phenyl-
ahistin derivative NPI-2358 with highly potent cytotoxic and
vascular disrupting activities and this compound is currently in the
Phase I clinical trials for anticancer drug in the US as a vascular
disrupting agent (VDA)7 that would afford an important contribu-
tion in the future cancer therapy (Fig. 1). Additionally, mono-
dehydroDKPs are useful building blocks and templates for
combinatorial chemistry.
i.e., N-
method based on an acid catalyzed cyclization of N-
amino acid amides to facilitate the synthesis of mono-
dehydroDKPs. The limitation of this method in the use of N-
aryl- -ketoacyl amino acid amides was also discussed.
a
-ketoacyl amino acid amides. Here, we describe a new
a
-ketoacyl
b
-
a
2. Results and discussion
In the synthesis of monodehydroDKPs, racemization at the
-position of a-amino acids is often observed during base
2.1. Acid catalyzed monodehydroDKP formation
a
catalyzed cyclization of the corresponding dipeptide units, or
during base catalyzed introduction of the dehydro-moiety
To examine the acid catalyzed formations of mono-
dehydroDKPs 4 from -ketoacyl amino acid amides 3, a series of
3 as starting materials were firstly prepared by the coupling
between -ketocarboxylic acid 1 and amino acid amides 2 using
a
a
an EDC–HOBt method. As Table 1 shows, although the chemical
yields of 3 were moderate, the obtained 3 was refluxed in
* Corresponding author. Tel.: þ81 042 676 3275; fax: þ81 042 676 3279.
E-mail address: yhayashi@ps.toyaku.ac.jp (Y. Hayashi).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.058

Y. Yamazaki et al. / Tetrahedron 65 (2009) 3688–3694
3689
O
O
O
toluene in the presence of a catalytic amount of p-TsOH (3–
5 mol %). Enantiomeric excess of the product was determined by
chiral HPLC using a CHIRALCEL OD column eluted with n-hex-
ane/ethanol (5:1). As shown in entries a–c (Table 1), the acid
R
1
NH
NH
N
NH
HN
HN
R
2
HN
O
R
3
catalyzed cyclization of pyruvoyl- or b-aliphatic-a-ketoacyl-Phe-
NH2 was successfully proceeded to give corresponding mono-
dehydroDKPs with a good chemical yield. During reaction no
racemization was observed in these compounds. Therefore, an
idea of monodehydroDKPs formation via acid catalyzed intra-
molecular cyclization based on Gladiali’s method was realized.
However, when N-phenylpyruvoyl derivative (entry d in Table 1)
was used as a substrate, this substrate remained after 18 h
reflux, the chemical yield of desired product was lowered, and
partial racemization was observed. This low reactivity, resulting
in the racemization, will be discussed in Sections 2.3 and 2.5. In
entries b and d (Table 1), energetically favored Z-configuration
was selectively obtained.
phenylahistin
1
O
NH
O
NH
NH
H N
N
NH
HN
2
H
Br
O
cyclo(dehydroAla-L-Leu)
O
barettin
O
O
O
NH
NH
O
HN
NH
HN
HN
R
Next, we examined the effect of an alkyl-substitution on the C-
terminal amide nitrogen in 3e–h (entries e–h in Table 1). In spite
of the electron donating effect of the alkyl groups, the chemical
yields of the corresponding monodehydroDKPs were lowered
except for the allyl group (entry h, 92% yield), but no racemization
was observed. Since the derivative with a bulky isopropyl group
showed the lowest yield (entry f, 20% yield), the steric factor
seemed to be more influenced than the electron donating effect of
the alkyl group in this cyclization reaction. Therefore, unhindered
groups such as an allyl group can favorably be inserted at this
position for obtaining molecular diversity in the future combina-
torial synthesis.
O
O
R
neoechinulin A (R= H)
golmaenone
cristatin A (R= dimethylallyl)
O
NH
N
NH
HN
O
NPI-2358 (vascular disrupting agent, Phase I)
Figure 1. Chemical structures of naturally occurring monodehydroDKPs and DKP an-
Furthermore, fixing the substituting group on the C-ter-
minal amide nitrogen to the allyl group, monodehydroDKPs
ticancer agent NPI-2358.
with
-Phe residue (entries i and j in Table 1). Similar chemical yield
to the -Phe derivative was obtained in the case of -Leu de-
rivative, while -Ser(Bzl) derivative needed longer reaction
time and showed moderate chemical yield probably due to
some steric effect. No racemization was observed in both
cases.
L-Leu and L-Ser(Bzl) were also synthesized in place of the
A
O
L
cat.p-TsOH
OMe
Boc NH2
L
L
+
Boc N
H
OMe
Δ
O
L
O
trichloroethylene
O
B
R2
O
R3
R4
H
R3
HN
+
N
cat. H
N
R1
O
N
H
R4
As a comparative study, HCl$H-
methanol in the presence of triethylamine (2.5 equiv) for 12 h.
Racemization (93% ee) at the -position of the Phe residue was
observed (see Supplementary data).
L-Phe-DAla-OMe was refluxed in
R1
R2
O
O
a
Scheme 1. (A) Gladiali’s method for the synthesis of dehydroamino acid derivatives.
(B) A new synthetic strategy of monodehydroDKP based on A.
Table 1
Synthesis of monodehydroDKPs by acid catalyzed cyclization of N-a-ketoacyl amino acid amides
O
O
Step 1
Step 2
R2
O
R3
R2
O
R3
R3
HN
R4
R2
H
N
H
N
N
EDC, HOBt
DMF or CH2Cl2
cat. p-TsOH
+
R1
OH
H2N
R4
R1
N
H
R4
R1
Δ
toluene
O
O
O
O
1
2
3a-j
4a-j
Entry
R1
R2
R3
R4
Yield (%), step 1
p-TsOH (mol %)
Time (h)
Yield (%), step 2
E/Za
ee (%)b
a
b
c
d
e
f
g
h
i
H
H
H
Me
H
H
H
H
H
H
H
Bzl
Bzl
Bzl
Bzl
Bzl
Bzl
Bzl
Bzl
i-Bu
H
H
H
H
Bn
i-Pr
i-Bu
Allyl
Allyl
Allyl
65
94
74
66
64
73
57
40
63
86
5
5
5
5
3
5
3
3
5
5
18
17
18
18
24
72
72
20
10
40
96
86
94
35
53
20
43
92
96
69
d
>99c
>99c
>99c
74
Me
Me
Ph
H
H
H
H
H
H
1/25
d
1/>99d
d
>99c
>99c
>99c
>99c
>99c
>99c
d
d
d
d
j
CH2-O-Bzl
d
a
E/Z ratio was determined by NMR.
Enantiomeric excess values were determined by chiral HPLC using CHIRALCEL OD column eluted with n-hexane/ethanol (5:1).
No another enantiomer was detected.
The E-form was not detected.
b
c
d

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Y. Yamazaki et al. / Tetrahedron 65 (2009) 3688–3694
Table 3
2.2. Effect of acids on the cyclization reaction
MonodehydroDKP formation from a
b
-phenyl-
a
-keto acid derivative
To understand the effect of acids, which were required in the
cyclization reaction, a model substrate pyruvoyl-Phe-NH-allyl 3h
was refluxed in the presence of a variety of acids. As shown in
Table 2, the reaction did not proceed with a catalytic amount
(3 mol %) of TFA (pKa¼ꢀ0.25) or MSA (pKa¼ꢀ2.6). However, in the
catalytic use of stronger acids p-TsOH (pKa¼ꢀ6.57) and TFMSA
(pKa¼ꢀ14), monodehydroDKP 4h was produced with no racemi-
zation. Especially, the use of p-TsOH resulted in the highest
chemical yield (92%) of desired product. Alternatively, the effect of
the large amount of TFA or AcOH as a weaker acid was evaluated.
TFA solution (1%) (corresponding to 50 mol %) in toluene, promoted
the production of 4h in 26% yield and a higher chemical yield of 62%
was obtained in 10% TFA. AcOH (10%, pKa¼4.76) was not effective in
this cyclization reaction. As a result, the catalytic use of p-TsOH with
a pKa value of ꢀ6.57 was suitable for this cyclization reaction.
O
NH
O
cat. p-TsOH
NH2
HN
Δ
N
H
toluene
O
O
O
3d
4d
Entry
p-TsOH (mol %)
Time (h)
Yield (%)a
ee (%)b
1
2
3
4
5
6
1
1
5
5
10
10
18
48
6
18
3
20
31
34
35
5
>99c
>99c
>99c
74
>99c
59
6
38
a
Isolated yield.
b
Enantiomeric excess values were determined by chiral HPLC using CHIRALCEL
OD column eluted with n-hexane/ethanol (5:1).
2.3. MonodehydroDKP formation from a
-keto acid derivative
b-aryl-
c
No another enantiomer was detected.
a
To improve the observed low reactivity of N-phenylpyruvoyl
compound by using acid catalyzed intramolecular cyclization of
derivative 3d (entry d in Table 1 or entry 4 in Table 3), optimization
of the reaction conditions was conducted. As Table 3 shows, by
increasing the amount of p-TsOH or reaction time, racemization at
the corresponding
a key step. To obtain this key amino acid intermediate, as shown
in Scheme 2, we first synthesized N-tert-butoxycarbonyl- -dime-
thylphosphonoglycine-tert-butyl ester from tert-butyl-P,P-
b-aryl-a-ketoacyl amino acid derivative as
a
the a-position of the Phe residue was increased and the chemical
6
yield was not well improved, suggesting that a longer exposure to
the acid might enhance racemization at the non-reactive site in the
monodehydroDKP formation. The best reaction condition obtained
among these experiments was 5 mol % p-TsOH and 6 h reflux,
resulted in desired 4d in 34% yield with no racemization (entry 3 in
Table 3). The results also suggested that the use of 1 mol % p-TsOH
could induce no racemization even in a longer time reaction
(entries 1 and 2 in Table 3).
dimethylphosphonoacetate 5 in two steps by using the known
procedure.11,12 Briefly, compound 5 was diazotized with tosyl
azide (TsN3) in the presence of NaH, and then the obtained diazo
compound was refluxed with Boc–NH2 in the presence of
Rh2(OAc)4 catalyst in toluene to give desired 6 (51% yield in two
steps). tert-Butyl-1-(tert-butoxycarbonyl)-2-(5-tert-butyloxazol-4-
yl)vinylcarbamate 8 was then synthesized from compound 6 by
Horner–Emmons reaction with 5-tert-butyl-4-oxazolecarbox-
aldehyde 7, which were prepared from ethyl isocyanoacetate in
three steps.13 In this reaction, only Z isomer was obtained from
the NMR analysis.14 Then, compound 8 was treated with 4 M HCl/
2.4. Application: synthesis of tert-butyl-oxa-phenylahistin
As one of the chiral monodehydroDKPs, we focused on tert-
butyl-oxa-phenylahistin 11, a derivative of natural microtubule
depolymerization agent, phenylahistin,1 and synthesized this
OMe
O
O
P
MeO
P
O
OMe
OMe
a
c
b
d
N
O
Table 2
O
Boc
N
H
Effect of acids on cyclization reaction
O
O
5
6
N
acid
Δ
toluene
O
H
N
HN
N
H
O
O
O
O
O
N
OH
3h
4h
O
O
N
OH
Boc
N
H
a
Entry
Acid
Amount
pKa
Time (h)
Yield (%)
ee (%)b
O
N.D. (0.3)e
N.D. (1)e
92
N.D.
8
9
1
2
3
4
5
6
7
8
9
TFA
3 mol %
3 mol %
3 mol %
3 mol %
0.5%d
1%d
ꢀ0.25
ꢀ2.6
24
24
20
24
24
24
24
24
24
MSA
p-TsOH
TFMSA
TFA
TFA
TFA
N.D.
>99c
>99c
N.D.
O
ꢀ6.57
ꢀ14
41 (85)e,f
N.D. (1)e
26 (47)e
42 (76)e
62 (85)e
N.D. (7)e
NH
ꢀ0.25
ꢀ0.25
ꢀ0.25
ꢀ0.25
4.76
e
O
>99c
>99c
>99c
N.D.
HN
O
NH2
5%d
N
H
O
O
TFA
AcOH
10%d
N
OH
10
O
10%d
(-)-tBu-oxa-phenylahistin (11)
phenylahistin derivative 11 ((ꢀ)-tert-butyl-oxa-phenyl-
a
See Ref. 10.
b
Enantiomeric excess values were determined by chiral HPLC using CHIRALCEL
Scheme 2. Synthesis of
a
OD column eluted with n-hexane/ethanol (5:1).
ahistin) via acid catalyzed monodehydroDKP synthesis. Reagents and conditions; (a) (i)
NaH, TsN3, rt, 2 h, (ii) Boc-NH2, cat. Rh2(OAc)4, toluene, reflux, 1 h, 51% in two steps; (b)
5-tert-butyl-4-oxazolecarboxaldehyde 7, Cs2CO3, DMF, rt, 14 h, 47%; (c) 4 M HCl/di-
oxane, rt, 1 h, 76%; (d) HCl$H-Phe-NH2, EDC$HCl, HOBt$H2O, Et3N, DMF, rt, 14 h, 43%;
(e) 5 mol % p-TsOH, toluene, reflux, 6 h, 20%.
c
No another enantiomer was detected.
v/v % in toluene.
The values in the parenthesis indicate HPLC yield. N.D.: not determined.
The chemical yield decreased due to the existence of inseparable impurity.
d
e
f

Y. Yamazaki et al. / Tetrahedron 65 (2009) 3688–3694
3691
3. Conclusion
We have developed
a
new synthetic method for mono-
O
O
dehydroDKPs with no or slight racemization, which was based on
an acid catalyzed intramolecular cyclization of N- -ketoacyl amino
acid amides. The catalytic use of p-TsOH (3–5 mol %) with a pKa
value of ꢀ6.57 was superior for this cyclization reaction. In case
aliphatic- -ketoacyl amino acid amides were used as starting ma-
terials, no racemization was observed. In case of a -aryl- -ketoacyl
phenylalanine amide, corresponding monodehydroDKP could be
obtained by optimizing the reaction condition (5 mol % p-TsOH,
reflux for 6 h) although the chemical yield was mild. We applied
this optimized reaction condition to the synthesis of (ꢀ)-tert-butyl-
oxa-phenylahistin, which is a derivative of natural anti-microtu-
bule agent phenylahistin, and successfully synthesized it. These
findings suggest that this method is beneficial for the convenient
synthesis of monodehydroDKPs. It is likely to be applied to com-
binatorial synthesis of monodehydroDKP derivatives in the future.
H+
NH2
O
NH2
N
H
N
H
O
a
O
N
O
O
N
O
O
H
b
-
a
b
a
H+
NH
N
O
HN
O
Scheme 3. Keto–enol tautomerism of
b
-aryl-a-keto acid derivative.
dioxane to produce corresponding acid 9.15 This
hydroxyacrylic acid 9 was then condensed with H-Phe-NH2 by the
EDC–HOBt method to afford N-( -aryl)- -hydroxyacryloyl-Phe-
b-aryl-a-
b
a
NH2 10. Finally, the acid catalyzed intramolecular cyclization
reaction in the presence of 5 mol % p-TsOH for 6 h was performed
to give desired (ꢀ)-tert-butyl-oxa-phenylahistin 11 with no race-
mization (>99% ee), although the chemical yield of the final step
was low (20%). Total yield of 11 from commercially available
starting material 5 was 2%. Compound 11 exhibited mild cytotoxic
activity with IC50 value of 924 nM against HT-29 human colon
cancer cell lines.
4. Experimental
4.1. General procedures
Melting points were measured on a Yanagimoto micro hot-stage
apparatus and are uncorrected. Proton (1H) NMR spectra were
recorded on either a JEOL JNM-AL300 spectrometer operating at
300 MHz for proton. Chemical shifts were recorded as
d values in
parts per million (ppm) downfield from tetramethylsilane (TMS).
Low- and high-resolution mass spectra were recorded on a JEOL
JMS-GCmate (EI, CI) or a Micromass LCT (ESI). Optical rotations
were measured with a Horiba High-speed Accurate Polarimeter
SEPA-300 at the sodium-D line (589 nm) at the concentrations (c, g/
100 mL). The measurements were carried out between 22 and
2.5. Low reactivity in
derivatives
b-aryl-a-ketoacyl amino acid
Observed low reactivity in
surely caused by keto-enol tautomerism at the
with -aromatic ring (Scheme 3), i.e., an unfavorable enol form for
b-aryl-
a-keto acid derivative was
a
-keto acid moiety
28 ꢁC in a cell with path length (l) of 0.5 dm. Specific rotations [
a]
D
b
are given in 10ꢀ1 deg cm2 gꢀ1. Preparative HPLC was performed
the cyclization was stabilized by conjugation with the aromatic
ring. Actually, from the NMR analysis, it was indicated that these
substrates existed as enol forms with conjugation to the
using a C18 reverse-phase column (19ꢂ100 mm; SunFireÔ Prep
b-aryl
C18 OBDÔ 5 mm) with binary solvent system: linear gradient of
groups (for example, compounds 9 and 10, see Experimental).
These enol forms are inconvenient to accept a nucleophilic attack of
the amide nitrogen (Scheme 3), hence, resulted in the observed low
reactivity. Elongated reaction time in the presence of acids
CH3CN in 0.1% aqueous TFA at a flow rate of 15 mL/min, detected at
UV 230 nm. Analytical HPLC was performed using a C18 reverse-
phase column (4.6ꢂ150 mm; YMC Pack ODS AM302) with a binary
solvent system: (a linear gradient of CH3CN and aq TFA (0.1%) at
a flow rate of 0.9 mL minꢀ1), detected at 230 nm. The tR given for
the target compounds are obtained from analytical HPLC. Solvents
used for HPLC were of HPLC grade and all other chemicals were of
analytical grade or better.
enhanced the racemization at the
a-position of the amino acid.
Furthermore, catalytic amount of acid not only promotes the
monodehydroDKP formation, but also would accelerate the enol
formation through protonation to the
a-carbonyl oxygen in the
b
-aryl- -keto acid moiety. Reaction conditions that are able to ac-
a
celerate the keto formation might be effective to solve this problem,
which should be considered in the future study.
4.1.1. N-2-Oxo-propanoyl-
method for the synthesis of N-
L
-phenylalanine amide (3a) (general
-ketoacyl amino acid amides, 3a–d)
a
However, it is certain that this method is beneficial for the
A suspension of HCl$H-Phe-NH2 (1.0 g, 4.98 mmol) in DCM
(49 mL) was neutralized with Et3N (0.69 mL, 4.98 mmol) at 4 ꢁC. To
this mixture were added HOBt$H2O (0.76 g, 4.98 mmol), pyruvic
acid (0.52 mL, 7.47 mmol), and EDC$HCl (1.05 g, 5.47 mmol), and
the mixture was stirred at 4 ꢁC for 30 min and at room temperature
for 2 h. After removal of the solvent in vacuo, the residue was dis-
solved in AcOEt, successively washed with 10% citric acid, 5%
NaHCO3, and saturated NaCl for three times, dried over Na2SO4, and
concentrated in vacuo to obtain 0.76 g (65%) of the title compound
as a white solid. Mp 138–140 ꢁC; 1H NMR (300 MHz, DMSO-d6)
synthesis of monodehydroDKPs from
b-aliphatic-a-ketoacyl
amino acid derivatives, likely to be applied to combinatorial
synthesis of monodehydroDKP derivatives in the future. Addi-
tionally, 6-methylene-2,5-piperazinedione 12 derivatives (Fig. 2)
synthesized in this new synthetic method would be a valuable key
synthon for the synthesis of naturally occurring mono-
dehydroDKPs based on the derivatization from the exo-methylene
structure.
d
8.34 (d, J¼8.6 Hz,1H), 7.52 (s,1H), 7.24–7.19 (m, 6H), 4.45–4.37 (m,
O
1H), 3.11 (dd, J¼4.2, 13.8 Hz, 1H), 2.96 (dd, J¼9.5, 13.8 Hz, 1H), 2.26
R1
HN
R2
(s, 3H); HRMS (EI): m/z 234.1008 (Mþ) (calcd for C12H14N2O3:
N
25
234.1004); [
a
]
ꢀ14.8 (c 1.03, CHCl3).
D
O
12
4.1.2. N-2-Oxo-butanoyl-L-phenylalanine amide (3b)
The title compound was prepared according to the same pro-
Figure 2. MonodehydroDKP synthon with an exo-olefin structure.
cedure as described in example 3a using 2-oxobutanoic acid

3692
Y. Yamazaki et al. / Tetrahedron 65 (2009) 3688–3694
instead of pyruvic acid. White solid (94%); mp 121–123 ꢁC; 1H NMR
(300 MHz, DMSO-d6)
7.46–7.13 (m,10H), 6.33 (s,1H), 4.36 (m,1H), 3.15 (dd, J¼3.9,13.4 Hz,
d
8.35 (d, J¼8.5 Hz, 1H), 7.53 (s, 1H), 7.24–7.19
1H), 2.95 (dd, J¼4.9, 13.4 Hz, 1H); HRMS (EI): m/z 292.1211 (Mþ)
25
(m, 6H), 4.43 (ddd, J¼4.4, 8.5, 9.6 Hz, 1H), 3.10 (dd, J¼4.5, 13.8 Hz,
1H), 2.96 (dd, J¼9.6, 13.8 Hz, 1H), 2.72 (q, J¼7.2 Hz, 2H), 0.92
(calcd for C18H16N2O2: 292.1212); [
a
]
D
ꢀ316.2 (c 0.62, DMSO).
Enantiomeric excess was determined to be 73% using chiral HPLC
with a CHIRALCEL OD column.
(t, J¼7.2 Hz, 3H); HRMS (EI): m/z 248.1157 (Mþ) (calcd for
25
C13H16N2O3: 248.1161); [
a
]
ꢀ22.9 (c 1.02, CHCl3).
D
4.1.7. N-2-Oxo-propanoyl-
A solution of HCl$H-Phe-NH-benzyl (215 mg, 0.85 mmol) in
DMF was neutralized with Et3N (122
L, 0.85 mmol) at 4 ꢁC. To
L-phenylalanine benzylamide (3e)
4.1.2.1. N-2-Oxo-3-methylbutanoyl-L-phenylalanine amide (3c). The
title compound was prepared according to the same procedure as
described in example 3a using 3-methyl-2-oxobutanoic acid in-
stead of pyruvic acid. White solid (74%); mp 166–168 ꢁC; 1H NMR
m
this mixture were added HOBt$H2O (129 mg, 0.85 mmol), pyruvic
acid (116 mg, 1.26 mmol), and EDC$HCl (242 mg, 1.26 mmol), and
the mixture was stirred at room temperature for 2 h. After re-
moval of the solvent in vacuo, the residue was dissolved in AcOEt,
successively washed with 10% citric acid, 5% NaHCO3, and satu-
rated NaCl for three times, dried over Na2SO4, and concentrated in
vacuo to obtain 175 mg (64%) of the title compound as a off white
(300 MHz, DMSO-d6)
d
8.41 (d, J¼8.7 Hz, 1H), 7.55 (s, 1H), 7.24–7.19
(m, 6H), 4.50 (ddd, J¼4.2, 8.7, 9.9 Hz, 1H), 3.23 (dq, J¼6.9, 6.9 Hz,
1H), 3.10 (dd, J¼4.2, 13.6 Hz, 1H), 2.92 (dd, J¼9.9, 13.6 Hz, 1H), 0.96
(d, J¼6.9 Hz, 3H), 0.87 (d, J¼6.9 Hz, 3H); HRMS (EI): m/z 262.1311
25
(Mþ) (calcd for C14H18N2O3: 262.1317); [
a
]
ꢀ13.8 (c 1.03, CHCl3).
D
solid. Mp 122–124 ꢁC; 1H NMR (300 MHz, CDCl3)
d 7.52
4.1.3. N-2-Oxo-3-phenylpropanoyl-
L
-phenylalanine amide (3d)
(d, J¼8.4 Hz, 1H), 7.27–7.03 (m, 10H), 5.80 (br s, 1H), 4.48–4.58 (m,
The title compound was prepared according to the same pro-
cedure as described in example 3a using 3-phenyl-2-oxobutanoic
acid instead of pyruvic acid. White solid (66%); mp 123–125 ꢁC; 1H
1H), 4.24–4.41 (m, 2H), 3.01–3.18 (m, 2H), 2.49 (s, 3H); HRMS (EI):
26
m/z 324.1470 (Mþ) (calcd for C19H20N2O3: 324.1474); [
(c 1.06, CHCl3).
a
]
ꢀ13.3
D
NMR (300 MHz, CDCl3)
d
7.57 (d, J¼7.7 Hz, 1H), 7.34–7.01 (m, 10H),
5.83 (s, 1H), 5.75 (s, 1H), 4.61 (ddd, J¼6.9, 6.9, 7.7 Hz, 1H), 4.15
(s, 2H), 3.08 (dd, J¼2.0, 6.9 Hz, 2H); HRMS (EI): m/z 310.1318 (Mþ)
(calcd for C18H18N2O3: 310.1317).
4.1.8. N-2-Oxo-propanoyl-L-phenylalanine isopropylamide (3f)
The title compound was prepared according to example 3e
using HCl$H-Phe-NH-isopropyl. Yield 73%. Off white solid; mp 138–
141 ꢁC; 1H NMR (300 MHz, CDCl3)
d
7.57 (d, J¼7.2 Hz, 1H), 7.21–7.34
4.1.3.1. (S)-3-Benzyl-6-methylenepiperazine-2,5-dione (4a). Using
a Dean–Stark trap whose trap part was filled with molecular sieves
(m, 5H), 5.09 (d, J¼7.0 Hz 1H), 4.36–4.45 (m, 1H), 3.88–4.01 (m, 1H),
3.13 (dd, J¼5.9, 13.4 Hz, 1H), 2.97 (dd, J¼9.0, 13.4 Hz, 1H), 2.46 (s,
3 Å, a solution of N-2-oxo-propanoyl-L-phenylalanine amide from
3H), 1.03 (d, J¼6.6 Hz, 3H), 0.91 (d, J¼6.6 Hz, 3H); HRMS (EI): m/z
25
example 3a (100 mg, 0.427 mmol) in toluene (20 mL) was refluxed
in the presence of p-TsOH$H2O (4.37 mg, 0.023 mmol, 0.05 equiv)
for 18 h. After removal of the solvent, the residue was triturated in
ether to obtain 89 mg (96%) of the title compound as a white solid.
276.1472 (Mþ) (calcd for C15H20N2O3: 276.1474); [
CHCl3).
a]
ꢀ14.8 (c 1.05,
D
4.1.9. N-2-Oxo-propanoyl-L-phenylalanine isobutylamide (3g)
The title compound was prepared according to example 3e
using HCl$H-Phe-NH-isobutyl. Yield 57%. Brown solid; mp 114–
Mp 175–177 ꢁC (decomp.); 1H NMR (300 MHz, DMSO-d6)
d
10.36 (s,
1H), 8.41 (s, 1H), 7.24–7.11 (m, 5H), 4.90 (s, 1H), 4.50 (s, 1H), 4.40–
4.37 (m, 1H), 3.15 (dd, J¼3.8, 13.5 Hz, 1H), 2.91 (dd, J¼5.0, 13.5 Hz,
118 ꢁC; 1H NMR (300 MHz, CDCl3)
d
7.52 (d, J¼8.1 Hz, 1H), 7.20–7.34
1H); HRMS (EI): m/z 216.0891 (Mþ) (calcd for C12H12N2O2:
(m, 5H), 5.46 (br s, 1H), 4.47 (ddd, J¼6.3, 8.1, 8.4 Hz, 1H), 3.12 (dd,
J¼6.3, 13.5 Hz, 1H), 3.04 (dd, J¼8.4, 13.5 Hz, 1H), 2.89–3.04 (m, 2H),
2.45 (s, 3H), 1.54–1.67 (m, 1H), 0.76 (d, J¼6.8 Hz, 3H), 0.74 (d,
26
216.0899); [
a
]
D
ꢀ40.0 (c 1.08, DMSO). Enantiomeric excess was
determined to be >99% using chiral HPLC with a CHIRALCEL OD
column.
J¼6.8 Hz, 3H); HRMS (EI): m/z 290.1636 (Mþ) (calcd for C16H22N2O3:
26
290.1630); [
a]
ꢀ23.9 (c 1.03, CHCl3).
D
4.1.4. (S,Z)-3-Benzyl-6-ethylidenepiperazine-2,5-dione (4b)
The title compound was prepared according to example 4a us-
ing the compound of example 3b. White solid (86%); mp 219–
4.1.10. N-2-Oxo-propanoyl-L-phenylalanine allylamide (3h)
The title compound was prepared according to example 3e us-
ing HCl$H-Phe-NH-allyl. Yield 40%. Brown solid; mp 104–106 ꢁC;
221 ꢁC (decomp.); 1H NMR (300 MHz, DMSO-d6)
d 9.75 (s, 1H), 8.20
(s, 1H), 7.25–7.12 (m, 5H), 5.50 (q, J¼7.5 Hz, 1H), 4.32–4.29 (m, 1H),
1H NMR (300 MHz, CDCl3)
5H), 5.71–5.55 (m, 1H), 5.58 (br s, 1H), 5.09–4.96 (m, 2H), 4.55–4.47
d
7.51 (br d, J¼8.4 Hz, 1H), 7.34–7.19 (m,
3.12 (dd, J¼4.2, 13.5 Hz, 1H), 2.90 (dd, J¼5.0, 13.5 Hz, 1H), 1.52 (d,
J¼7.5 Hz, 3H); HRMS (EI): m/z 230.1057 (Mþ) (calcd for C13H14N2O2:
(m, 1H), 3.81–3.75 (m, 2H), 3.17–3.02 (m, 2H), 2.44 (s, 3H); HRMS
26
26
230.1055); [
a
]
D
ꢀ111.1 (c 1.03, DMSO). Enantiomeric excess was
(EI): m/z 274.1325 (Mþ) (calcd for C15H18N2O3: 274.1317); [
ꢀ26.1 (c 1.00, CHCl3).
a]
D
determined to be >99% using chiral HPLC with a CHIRALCEL OD
column.
4.1.11. N-2-Oxo-propanoyl-L-leucine allylamide (3i)
4.1.5. (S)-3-Benzyl-6-(propan-2-ylidene)piperazine-2,5-dione (4c)
The title compound was prepared according to example 4a
using the compound of example 3c. White solid (94%); mp 255–
The title compound was prepared according to example 3e
using HCl$H-Leu-NH-allyl. White solid (63%); mp 114–116 ꢁC; 1H
NMR (300 MHz, CDCl3)
d 7.27 (br s, 1H), 6.01 (br s, 1H), 5.88–5.75
257 ꢁC (decomp.); 1H NMR (300 MHz, DMSO-d6)
d
9.26 (s, 1H), 7.97
(m, 1H), 5.21–5.13 (m, 2H), 4.39–4.32 (m, 1H), 3.90–3.86 (m, 2H),
(d, J¼3.3 Hz, 1H), 7.56–7.10 (m, 5H), 4.04 (m, 1H), 3.00 (dd, J¼4.4,
2.48 (s, 3H), 1.78–1.60 (m, 3H), 0.95 (d, J¼5.2 Hz, 3H), 0.93 (d,
13.5 Hz, 1H), 2.85 (dd, J¼5.3, 13.5 Hz, 1H), 1.8 (s, 3H), 1.49 (s, 3H);
J¼5.2 Hz, 3H); HRMS (ESI): m/z 241.1530 (MþHþ) (calcd for
26
HRMS (EI): m/z 244.1210 (Mþ) (calcd for C14H16N2O2: 244.1212);
C12H21N2O3: 241.1552); [
a]
ꢀ8.1 (c 1.00, CHCl3).
D
26
[
a]
ꢀ112.8 (c 0.50, DMSO). Enantiomeric excess was determined
D
to be >99% using chiral HPLC with a CHIRALCEL OD column.
4.1.12. N-2-Oxo-propanoyl-
L
-serine(Bzl) allylamide (3j)
The title compound was prepared according to example 3e us-
4.1.6. (S,Z)-3-Benzyl-6-benzylidenepiperazine-2,5-dione (4d)
The title compound was prepared according to example 4a
using the compound of example 3c. Off white solid (35%); mp 275–
ing HCl$H-Ser(Bzl)-NH-allyl. Yield 86%. Yellow oil; 1H NMR
(300 MHz, CDCl3)
(br s, 1H), 5.74–5.87 (m, 1H), 5.11–5.19 (m, 2H), 4.46–4.63 (m, 3H),
d
7.73 (d, J¼6.4 Hz, 1H), 7.29–7.36 (m, 5H), 6.37
276 ꢁC; 1H NMR (300 MHz, DMSO-d6)
d
9.75 (s, 1H), 8.46 (s, 1H),
3.88–3.93 (m, 3H), 3.56 (dd, J¼7.4, 9.1 Hz, 1H), 2.47 (s, 3H); HRMS

Y. Yamazaki et al. / Tetrahedron 65 (2009) 3688–3694
3693
25
(ESI): m/z 305.1526 (MþHþ) (calcd for C16H21N2O4: 305.1501); [
ꢀ1.4 (c 0.79, CHCl3).
a
]
4.1.18. (S)-1-Allyl-3-(benzyloxy)methyl-6-methylenepiperazine-
2,5-dione (4j)
D
The title compound was prepared according to example 4e us-
ing the compound from example 3j. Yield 69%. Brown solid; mp 78–
4.1.13. (S)-1,3-Dibenzyl-6-methylenepiperazine-2,5-dione (4e)
Using a Dean–Stark trap whose trap part was filled with mo-
lecular sieves 4 Å, a solution of N-2-oxo-propanoyl- -phenylalanine
81 ꢁC; 1H NMR (300 MHz, CDCl3)
d 7.24–7.37 (m, 5H), 6.76 (br s,1H),
L
5.81 (d, J¼1.4 Hz,1H), 5.68–5.79 (m,1H), 5.18–5.20 (m,1H), 5.15 (dd,
benzylamide from example 3e (100 mg, 0.31 mmol) in toluene
(20 mL) was refluxed in the presence of p-TsOH$H2O (1.8 mg,
0.0093 mmol, 0.03 equiv) for 24 h. After removal of the solvent, the
residue was purified by a silica gel chromatography to yield 50 mg
(53%) of title compound as a white solid. Mp 124–127 ꢁC; 1H NMR
J¼6.5, 0.9 Hz, 1H), 4.95 (s, 1H), 4.53 (s, 2H), 4.47–4.50 (m, 1H), 4.32–
4.34 (m, 1H), 4.20–4.27 (m, 1H), 3.75–3.85 (m, 2H); HRMS (ESI): m/z
26
287.1400 (MþHþ) (calcd for C16H19N2O3: 287.1396); [
a]
ꢀ107.4 (c
D
0.25, CHCl3). Enantiomeric excess was determined to be >99%
using chiral HPLC with a CHIRALCEL OD column.
(300 MHz, CDCl3)
d 7.01–7.35 (m, 10H), 6.84 (br s, 1H), 5.60 (s, 1H),
5.01 (d, J¼15.7 Hz,1H), 4.85 (d, J¼15.7 Hz,1H), 4.76 (s,1H), 4.49–4.52
4.1.19. N-tert-Butoxycarbonyl-a-dimethylphosphonoglycine-
tert-butyl ester (6)
(m, 1H), 3.36 (dd, J¼3.7, 13.6 Hz, 1H), 3.12 (dd, J¼7.7, 13.6 Hz, 1H);
HRMS (EI): m/z 306.1369 (Mþ) (calcd for C19H18N2O2: 306.1368);
The solution of tert-butyl-P,P-dimethylphosphonoacetate
(12.5 mL, 63 mmol, 1.0 equiv) in THF (20 mL) was added dropwise
to a solution of NaH (60% NaH, 2.7 g, 69.3 mmol, 1.1 equiv) in an-
hydrous THF (300 mL) at 0 ꢁC. After the mixture was stirred for
45 min at the same temperature, a solution of TsN3 (12.4 g,
63 mmol,1.0 equiv) in THF (10 mL) was added dropwise at 0 ꢁC. The
cooling bath was removed and the mixture was stirred for 2 h at
room temperature. The reaction was quenched by the addition of
ether/H2O (1:1, 200 mL) at 4 ꢁC. After the resultant organic phase
was washed with water, 10% NaHCO3, and saturated NaCl, dried
over Na2SO4, and concentrated in vacuo. The residual oil was pu-
rified by a silica gel column chromatography to yield 9.9 g (63%) of
diazo phoaphonoacetate as a yellow oil. This oil was used in the
next reaction. Boc–NH2 (18.3 g, 156 mmol, 4.0 equiv) was added to
a solution of diazo compound (9.8 g, 39 mmol, 1.0 equiv) in toluene
(200 mL), and the mixture was refluxed in the presence of
Rh2(OAc)4 (346 mg, 0.78 mmol, 0.02 equiv) for 1 h using a Dean–
Stark trap. After removal of the solvent, the residue was dissolved in
AcOEt, successively washed with 10% citric acid, 5% NaHCO3, and
saturated NaCl for three times, dried over Na2SO4, and concentrated
in vacuo. The residual oil was purified by a silica gel column
chromatography to yield 11 g (81%) of a title compound as colorless
26
[
a]
ꢀ433.1 (c 0.19, CHCl3). Enantiomeric excess was determined to
D
be >99% using chiral HPLC with a CHIRALCEL OD column.
4.1.14. (S)-3-Benzyl-1-isopropyl-6-methylenepiperazine-
2,5-dione (4f)
The title compound was prepared according to example 4e us-
ing the compound from example 3f. Yield 20%. Mp 141–142 ꢁC; 1H
NMR (300 MHz, CDCl3)
d 7.30–7.27 (m, 3H), 7.18–7.16 (m, 2H), 5.87
(br s, 1H), 5.61 (s, 1H), 4.90 (s, 1H), 4.47–4.38 (m, 1H), 4.29–4.22 (m,
1H), 3.23 (dd, J¼5.7, 13.6 Hz, 1H), 3.00 (dd, J¼5.7, 13.6 Hz, 1H), 1.41
(dd, J¼5.0, 7.0 Hz, 6H); HRMS (ESI): m/z 259.1464 (MþHþ) (calcd for
26
C15H19N2O2: 259.1447); [
a]
ꢀ122.7 (c 0.18, CHCl3). Enantiomeric
D
excess was determined to be >99% using chiral HPLC with a CHIR-
ALCEL OD column.
4.1.15. (S)-3-Benzyl-1-isobutyl-6-methylenepiperazine-
2,5-dione (4g)
The title compound was prepared according to example 4e us-
ing the compound from example 3g. Yield 43%. 1H NMR (300 MHz,
CDCl3)
d
7.17–7.36 (m, 5H), 5.91 (br s,1H), 5.73 (d, J¼1.5 Hz,1H), 4.84
(s, 1H), 4.30–4.37 (m, 1H), 3.65 (dd, J¼8.1, 13.8 Hz, 1H), 3.55 (dd,
J¼6.9, 13.8 Hz, 1H), 3.37 (dd, J¼3.6, 13.8 Hz, 1H), 2.93 (dd, J¼9.0,
13.5 Hz, 1H), 1.98–2.13 (m, 1H), 0.92 (d, J¼5.7 Hz, 3H), 0.90 (d,
oil. 1H NMR (300 MHz, CDCl3)
J¼9.2, 21.7 Hz, 1H), 3.82 (dd, J¼1.8, 11.0 Hz, 6H), 1.51 (s, 9H), 1.45 (s,
9H); HRMS (CI): m/z 340.1526 (Mþ) (calcd for C13H27NO7:
340.1525).
d
5.31 (d, J¼8.4 Hz, 1H), 4.76 (dd,
J¼5.7 Hz, 3H); HRMS (EI): m/z 324.1470 (Mþ) (calcd for C19H20N2O3:
26
324.1474); [
a]
ꢀ93.5 (c 0.48, CHCl3). Enantiomeric excess was
D
determined to be >99% using chiral HPLC with a CHIRALCEL OD
column.
4.1.20. tert-Butyl 1-(tert-butoxycarbonyl)-2-(5-tert-
butyloxazol-4-yl)vinylcarbamate (8)
4.1.16. (S)-1-Allyl-3-benzyl-6-methylenepiperazine-2,5-dione (4h)
The title compound was prepared according to example 4e us-
ing the compound from example 3h. Yield 92%. Mp 102–110 ꢁC; 1H
To a solution of N-(tert-butoxycarbonyl)-a-dimethylphospho-
noglycine-tert-butyl ester 6 (11.8 g, 34.68 mmol) and 5-tert-buty-
loxazole-4-carboxaldehyde 7 (6.9 g, 45.08 mmol) in DMF (50 mL)
was added Cs2CO3 (12.4 g, 38.15 mmol) under an argon atmosphere
at room temperature. The reaction mixture was stirred for 14 h at
room temperature. After removal of solvent in vacuo, the residue
was dissolved in AcOEt, successively washed with 10% citric acid, 5%
NaHCO3, and saturated NaCl for three times, dried over Na2SO4, and
concentrated in vacuo. The residual oil was purified by a silica gel
column chromatography to yield 6.0 g (47%) of title compound as
NMR (300 MHz, CDCl3)
d 7.16–7.35 (m, 5H), 6.48 (br s, 1H), 5.63–
5.77 (m, 1H), 5.65 (s, 1H), 5.21 (d, J¼10.2 Hz, 1H), 5.10 (d, J¼17.4 Hz,
1H), 4.84 (s, 1H), 4.36–4.48 (m, 2H), 4.25 (br d, J¼16.2 Hz, 1H), 3.27–
3.38 (m, 1H), 2.94–3.08 (m, 1H); HRMS (EI): m/z 256.1210 (Mþ)
25
(calcd for 15H16N2O2: 256.1212); [
a]
ꢀ320.6 (c 0.15, CHCl3). En-
D
antiomeric excess was determined to be >99% using chiral HPLC
with a CHIRALCEL OD column.
a white solid. Mp 170–172 ꢁC; 1H NMR (300 MHz, CDCl3)
d 7.74 (s,
4.1.17. (S)-1-Allyl-3-(iso-butyl)-6-methylenepiperazine-
2,5-dione (4i)
1H), 6.55 (s, 1H), 1.54 (s, 9H), 1.49 (s, 9H), 1.38 (s, 9H); HRMS (EI):
m/z 366.2159 (Mþ) (calcd for C19H30N2O5: 366.2154).
The title compound was prepared according to example 4e us-
ing the compound from example 3i. Yield 96%. Yellow oil; 1H NMR
4.1.21. 3-(5-tert-Butyloxazol-4-yl)-2-hydroxyacrylic acid (9)
(300 MHz, CDCl3)
d
7.02 (br s, 1H), 5.73–5.85 (m, 1H), 5.8 (d,
The compound from example 8 (6.0 g, 16.3 mmol) was treated
with 4 M HCl/dioxane (64 mL) for 1 h at room temperature. After
removal of the solvent, the residue was dissolved in AcOEt, washed
with 5% citric acid, and saturated NaCl, dried over Na2SO4, and
concentrated in vacuo to obtain 2.6 g (76%) of the title compound as
J¼1.3 Hz, 1H), 5.24 (dd, J¼16, 1.2 Hz, 1H), 5.19 (dd, J¼24, 1.2 Hz, 1H),
5.00 (s, 1H), 4.49–4.56 (m, 1H), 4.26 (dd, J¼5.2, 16 Hz, 1H), 4.13–4.20
(m, 1H), 1.66–1.83 (m, 3H), 0.98 (d, J¼6.0 Hz, 3H), 0.97 (d, J¼6.0 Hz,
3H); HRMS (ESI): m/z 223.1457 (MþHþ) (calcd for C12H19N2O2:
26
223.1447); [
a]
ꢀ122.7 (c 0.18, CHCl3). Enantiomeric excess was
a white solid. Mp 153–155 ꢁC; 1H NMR (300 MHz, CDCl3)
d 7.87 (s,
D
determined to be >99% using chiral HPLC with a CHIRALCEL OD
1H), 6.78 (s, 1H), 1.41 (s, 9H); HRMS (EI): m/z 211.0841 (Mþ) (calcd
column.
for C10H13NO4: 211.0844).

3694
Y. Yamazaki et al. / Tetrahedron 65 (2009) 3688–3694
4.1.22. 3-(5-tert-Butyloxazol-4-yl)-N-((S)-1-carbamoyl-2-
phenylethyl)-2-hydroxyacrylamide (10)
20390036. We are grateful to Ms. K. Oda and Ms. I. Takao for mass
spectra measurements. We thank Dr. J.-T. Nguyen for valuable help
during manuscript preparation.
To a solution of the compound from example 9 (2.61 g,
12.3 mmol) in DMF were added HOBt$H2O (2.26 g, 14.76 mmol),
EDC$HCl (2.8 g, 14.76 mmol), HCl$H-Phe-NH2 (3.16 g, 14.76 mmol),
and Et3N (1.72 mL, 12.3 mmol), and the reaction mixture was stir-
red for 14 h at room temperature. After removal of the solvent, the
residue was dissolved in AcOEt, successively washed with 10% citric
acid, 5% NaHCO3, and saturated NaCl for three times, dried over
Na2SO4, and concentrated in vacuo to obtain the title compound.
Supplementary data
Supplementary data include the monodehydroDKP formation
by base-catalyzed method and chiral HPLC charts of the acid cat-
alyzed reaction from compound 3d. Supplementary data associated
with this article can be found in the online version, at doi:10.1016/
j.tet.2009.02.058.
Yield 2.26 g (43%); mp 50–53 ꢁC; 1H NMR (300 MHz, CDCl3)
d 11.04
(s, 1H), 7.81 (d, J¼0.6 Hz 1H), 7.74–7.21 (m, 5H), 6.62 (d, J¼0.7 Hz,
1H), 6.00 (s, 1H), 5.52 (s, 1H), 4.79–4.72 (m, 1H), 3.24–3.11 (m, 2H),
1.38 (s, 9H); HRMS (EI): m/z 357.1689 (Mþ) (calcd for C19H23N3O4:
357.1688).
References and notes
1. Kanoh, K.; Kohno, S.; Asari, T.; Harada, T.; Katada, J.; Muramatsu, M.; Kawa-
shima, H.; Sekiya, H.; Uno, I. Bioorg. Med. Chem. Lett. 1997, 7, 2847–2852.
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benzylpiperazine-2,5-dione (11)
Using a Dean–Stark trap whose trap part was filled with mo-
lecular sieves 3 Å, a solution of the compound from example 10
(50 mg, 0.14 mmol) in toluene (5 mL) was refluxed in the presence
of p-TsOH (1.3 mg, 0.007 mmol) for 6 h. After removal of the sol-
vent, the residue was purified by HPLC to obtain the title compound
as a white powder. Yield 8.1 mg (20%), mp 52–56 ꢁC; 1H NMR
(300 MHz, DMSO-d6) d 10.65 (s, 1H), 8.60 (s, 1H), 8.47 (s, 1H), 7.24–
7.13 (m, 5H), 6.37 (s, 1H), 4.52 (m, 1H), 3.20 (dd, J¼3.7, 13.6 Hz, 1H),
2.95 (dd, J¼5.0, 13.6 Hz, 1H), 1.31 (s, 9H); HRMS (EI): m/z 339.1584
25
(Mþ) (calcd for C19H21N3O3: 339.1583); [
a
]
ꢀ128.9 (c 0.27, DMSO).
D
Enantiomeric excess was determined to be >99% using chiral HPLC
with a CHIRALCEL OD column.
Acknowledgements
This research was supported by various grants from MEXT
(Ministry of Education, Culture, Sports, Science, and Technology),
Japan, including the 21st Century COE Program of Kyoto Pharma-
ceutical University and Grant-in Aid for Scientific research (B)
14. Schiavi, B. M.; Richard, D. J.; Joulli, M. M. J. Org. Chem. 2002, 67, 620–624.
15. Nagasaki, A.; Adachi, Y.; Yonezawa, Y.; Shin, C. Heterocycles 2003, 60, 321–335.