Syntheses of α-amino squaric acids using an aminomalonate equivalent bearing a squaryl group

Article abstract of DOI:10.1055/s-2005-872109

The synthesis of an amino acid analogue bearing a squaryl group as a carboxylic acid surrogate (sq-AA; 2) has been developed. Aminomalonate equivalent 6 was used as a nucleophilic synthon whose alkylation or conjugate addition reaction followed by deprote

Full text of DOI:10.1055/s-2005-872109

PAPER
2723
Syntheses of a-Amino Squaric Acids Using an Aminomalonate Equivalent
Bearing a Squaryl Group
a
-Amino Squar
o
U
sin
s
g
a
n
A
m
h
i
E
quiva
k
lent Bearing
a
a
Squaryl
G
z
roup u Ishida, Tetsuro Shinada,* Yasufumi Ohfune*
Graduate School of Science, Osaka City University, Sugimoto, Sumiyoshi 558-8585, Japan
E-mail: shinada@sci.osaka-cu.ac.jp; E-mail: ohfune@sci.osaka-cu.ac.jp
Received 6 April 2005; revised 2 May 2005
would suffer problems since addition to 4 with a dianion
enolate from Asp or Glu occurs non-selectively at the a-
position and the b- or g-position.13
Abstract: The synthesis of an amino acid analogue bearing a squar-
yl group as a carboxylic acid surrogate (sq-AA; 2) has been devel-
oped. Aminomalonate equivalent 6 was used as a nucleophilic
synthon whose alkylation or conjugate addition reaction followed
by deprotection and decarboxylation reaction gave sq-AAs.
To compliment method A, we planned a new method us-
ing an aminomalonate equivalent 613 (method B)
(Scheme 1) that resembles the classical acetamidoma-
lonate method for the synthesis of a-amino acids.14 The
methine proton in 6 would be acidic enough to generate a
carbanion in the presence of a mild base owing to the dual
electron-withdrawing effects of the carboxylate and sq
groups. In this regard, this carbanion can be viewed as a
versatile nucleophilic synthon for an alkylation or a
conjugate addition reaction to give various sq-AAs.
Key words: amino acids, squaric acid, malonate, alkylations, addi-
tion reactions
a-Amino acid analogues bearing other acidic functional
groups, e.g., sulfonic acid,1 phosphonic acid,2 boronic
acid,3 and tetrazole,4 as a carboxylic acid surrogate are an
important probe in the area of biological and medicinal
chemistries. We have recently developed a novel ana-
logue 2 (sq-AA) of a-amino acids where the carboxylic
acid moiety of a-amino acids 1 is replaced by a 4-hy-
droxy-2,3-dioxocyclobut-1-enyl (sq) group (Figure 1).5,6
O
O
Oi-Pr
Oi-Pr
R
CO2t-Bu
R
O
O
Ot-Bu
M
BocHN
BocN
M
4
O
R
i-PrO
Method A
3
O
O
R
OH
O
5
dianion enolate
H2N
from amino acids
deprotection
H2N
CO2H
decarboxylation
HO
OH
CO2t-Bu
Method B
alkylation or
Michael addition
O
R
1
squaric acid
O
O
2
BocHN
O
H
H2N
Figure 1
active
methine
proton
i-PrO
HO
O
6
2
Squaric acid is a kind of oxocarbon.7 In view of its unique
physicochemical properties, e.g., strong acidity, aromatic-
ity, ring strain, electron deficiency, and metal chelating
ability, many applications have been initiated in the fields
of medicinal chemistry,5,6 bioconjugate chemistry,8 mate-
rials science,9 organic chemistry,10 and inorganic
chemistry11 since the first synthesis by Cohen.12
Scheme 1
Since carbon–carbon bond forming reaction using 6 was
unprecedented, we attempted a model study using a ben-
zylation reaction of 6 (Table 1). Treatment of 6 with BnBr
(1.5 equiv) in the presence of an amine base (Et3N, 1.2
equiv or EtNi-Pr2, 1.5 equiv) at room temperature afford-
ed the desired adduct 5a in moderate yield (entries 1, 2).
In the course of our studies regarding a carbon–carbon
bond forming reaction of a sq group, we have established
a facile synthetic method to access 2 via an addition of a
di-anion enolate 3 derived from easily available N-Boc
amino acid esters to diisopropyl squarate 4 followed by
concomitant deprotection and decarboxylation reactions
(method A).5 Although various amino acids are commer-
cially available, the number of sq-AAs provided by meth-
od A is dependent upon the number of available a-amino
acids. Moreover, the synthesis of sq-Asp and sq-Glu
1
Analysis of H and 13C NMR data of 5a and the corre-
sponding sq-AA confirmed that the alkylation occurred
chemoselectively to form a quaternary amino carbon cen-
ter. Undesired N-alkylation reaction was not observed at
all, due probably to the steric bulkiness of the Boc group.
The yield was raised to 50% by using K2CO3 as a base in
MeCN (entry 3). However, further improvement in yields
was not obtained in spite of a systematic survey of the
bases and solvents. Monitoring of this benzylation reac-
tion indicated that the alkylation reaction was found to be
slow. Moreover, 6 was completely decomposed by treat-
ment with K2CO3 in the absence of benzyl bromide for 12
SYNTHESIS 2005, No. 16, pp 2723–2729
x
x.
x
x
.
2
0
0
5
Advanced online publication: 04.08.2005
DOI: 10.1055/s-2005-872109; Art ID: F06605SS
© Georg Thieme Verlag Stuttgart · New York

2724
T. Ishida et al.
PAPER
Table 1 Benzylation of Compound 6
CO2t-Bu
O
CO2t-Bu
Bn
O
O
BnBr
BocHN
BocHN
solvent, r.t.
i-PrO
O
i-PrO
6
5a
Entry
Base (equiv)
i-Pr2NEt (1.5)
Et3N (1.2)
BnBr (equiv)
Additive (equiv) Solvent
Time (h)
Yield (%)
1
2
3
4
5
1.5
1.5
1
-
CH2Cl2
CH2Cl2
MeCN
MeCN
MeCN
9
9
26
38
50
70
90
-
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
-
12
1
1
TBAI (1)
TBAI (3)
3
0.5
h.15 These results suggested that the benzylation reaction Table 2 Alkylation and Conjugate Addition Reaction of 6
competed with decomposition of 6 under the reaction con-
R
ditions. To accelerate the desired alkylation, tetrabutyl-
b
c
d
e
f
g
h
i
-CH2CO2t-Bu
allyl
2-propenyl
cinnamyl
(1H-indol-3-yl)methyl
Me
i-Pr
-(CH2)2C(=O)Me
-(CH2)2CN
-(CH2)2CO2Me
-(CH2)2CO2t-Bu
electrophile
ammonium iodide (TBAI),16 known as a phase-transfer
reagent as well as a reagent for halogen exchange reaction
from bromide to more reactive iodide in situ, was tested as
an additive. As expected, the benzylation reaction using 1
equiv of TBAI proceeded smoothly (1 h) to afford 5a in
70% yield (entry 4). The best result was obtained when 6
was treated with K2CO3 (1.5 equiv), BnBr (3 equiv), and
TBAI (3 equiv) in MeCN to give 5a in 90% yield in 0.5 h
(entry 5).
5b–l
6
K2CO3 (1.5 equiv)
MeCN, r.t.
j
k
l
Entry
Electrophile
Equiv Time (h) Product Yield (%)
Having the optimal conditions in hand, the addition reac-
tions with various electrophiles were examined (Table 2).
Alkylation reactions using allylic bromides, an ammoni-
um salt derived from gramine, methyl iodide, and bromo
acetate smoothly provided the corresponding adducts in
good to moderate yields, except in the case of i-PrI (en-
tries 1–7). Michael addition reactions of 6 with unsaturat-
ed ketone, ester, and nitrile gave the corresponding
adducts in good to moderate yields (entries 8–11). It is
noteworthy that the sterically congested methine carbon
was alkylated with different kinds of electrophiles.
Br
CO2t-Bu
1
2
3
3a
3a
3a
0.5
0.5
0.5
5b
5c
5d
86
77
82
Br
Br
4
5
3a
5
0.5
2.5
5e
5f
quant
62
Br
Ph
I Me3N
N
H
6
7
MeI
30
12
5g
5h
5i
66
–
These adducts were converted to sq-AAs 7–14 (Table 3).
Adducts 5a–c,g,l were treated with concd HCl which al-
lowed concomitant removal of all protecting groups and
decarboxylation to give sq-Phe 7, sq-Asp 8, sq-Allylgly 9,
sq-Ala 13, and sq-Glu 14, respectively (entries 1–3, 7, and
8). Thus, sq-AAs 8 and 14, which could not be synthe-
sized by method A, were obtained. Sq-Norvaline 10, sq-
Leu 11, and sq-Phenylethylgly 12 were provided by an
initial reduction of the carbon–carbon double bond of 5c–
e using H2/Pd-C and subsequent decarboxylation reaction
(entries 4–6).
i-PrI
30
5
12
5
8
52
33
35
12
COMe
CN
9
30
30
30
12
12
12
5j
5k
5l
10
11
CO2Me
CO2t-Bu
a TBAI (3 equiv) was added.
glutamate receptors as well as its incorporation into bio-
logically active peptides are being further studied.
In summary, we have developed a new approach to access
sq-AAs by an operationally simple alkylation or conju-
gate addition reaction of the aminomalonate equivalent 6.
Complementary use of methods A5 and B would extend
the scope for the synthesis of a variety of sq-AAs. Biolog-
ical activities of sq-Glu and sq-Asp as a novel ligand to
Reagents, solvents, and anhydrous solvents were purchased from
either Aldrich Chemical Company, Inc., Merck & Co., Inc., Nacalai
Tesque Company, Ltd., Peptide Institute, Tokyo Kasei Kogyo Co.,
Ltd., or Wako Pure Chemical Industries, Ltd., and used without
Synthesis 2005, No. 16, 2723–2729 © Thieme Stuttgart · New York

PAPER
a-Amino Squaric Acids Using an Aminomalonate Equivalent Bearing a Squaryl Group
2725
1H NMR (300 MHz, CDCl3): d = 5.55 (br d, J = 8.0 Hz, 3/5 H),
5.37 (br d, J = 8.0 Hz, 2/5 H), 4.87 (sept, J = 6.2 Hz, 2 H), 4.59 (d,
J = 8.0 Hz, 1 H), 4.44 (br s, 1 H), 1.49–1.18 (m, 30 H).
13C NMR (75 MHz, CDCl3): d = 181.6, 168.3, 166.8, 163.7, 155.5,
134.3, 132.5, 82.6, 78.6, 76.9, 73.4, 73.3, 57.5, 50.0, 45.4, 28.0,
27.5, 22.5, 22.4, 22.2, 22.1, 22.0, 21.9.
Table 3 Conversion of 5a–e,g,l to sq-AAs 7–14
R
concd HCl–acetone
O
(1/1)
H3N
5a, b, c, g, l
r.t., 12 h
O
O
7–14
HRMS (CI): m/z calcd for C21H36NO8 (M + H)+: 430.2440; found:
430.2412.
1) Pd/C (20–70 w%)
5c, d, e
2) concd HCl–acetone (1/1)
r.t., 12 h
To a solution of the adduct described above (6.73 g, 15.7 mmol) in
CH2Cl2 (200 mL) was added HCl (12 M; 13 mL) at r.t. The mixture
was stirred for 4 h, diluted with sat. aq NaHCO3 (200 mL), and ex-
tracted with EtOAc (3 × 200 mL). The combined organic phases
were washed with brine (200 mL), dried (MgSO4), and concentrated
in vacuo. The residue was purified by flash chromatography (silica
gel; EtOAc–hexane, 1:9–1:2) to give 6.
Entry
Substrate
Product
R
Yield (%)
72
1
2
3
4
5
6
7
8
5a
5b
5c
5c
5d
5e
5g
5l
7
Bn
8
CH2CO2H
allyl
n-Pr
81
Yield: 4.87 g (84%); sticky pale yellow oil.
9
80
IR (neat): 3390, 2990, 2940, 1800, 1760, 1600, 1510, 1390, 1370,
1150, 1100, 1050 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.70 (br d, J = 7.5 Hz, 1 H), 5.47
(sept, J = 6.2 Hz, 1 H), 5.36 (d, J = 7.5 Hz, 1 H), 1.49 (d, J = 6.4 Hz,
3 H), 1.48 (d, J = 6.4 Hz, 3 H), 1.48 (s, 9 H), 1.45 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 196.3, 193.6, 191.4, 175.3, 165.3,
154.7, 84.2, 80.5, 80.1, 51.1, 28.1, 27.7, 22.7, 22.6.
10
11
12
13
14
40a
2-methylpropyl
(CH2)3Ph
Me
20a
42a
65
(CH2)2CO2H
67
HRMS (CI): m/z calcd for C18H28NO7 (M + H)+: 370.1866; found:
a Two steps.
370.1890.
tert-Butyl 1-(tert-Butoxycarbonyl)-1-(2-isopropoxy-3,4-dioxo-
cyclobut-1-enyl)-2-phenylethylcarbamate (5a)
further purification unless otherwise indicated. CH2Cl2 was distilled
from P2O5. All reactions were monitored by TLC, carried out on
2 × 5 cm precoated TLC plates (Merck Kieselgel gel 60F-254; layer
thickness, 0.25 mm). Silica gel (DAISO-GEL IR-60-40/63W) was
used for column chromatography. Reversed phase chromatography
was performed on Cosmosil® 140C18-PREP. 1H and 13C NMR spec-
tra were recorded on JEOL JNM-LA400 or JEOL JNM-LA-300 in-
struments. Chemical shifts of 1H NMR were reported as d values in
ppm relative to CHCl3 (d = 7.26) in CDCl3, or Me2SO (d = 2.49) in
(CD3)2SO. Chemical shifts of 13C NMR were reported as d values
in ppm relative to CHCl3 (d = 77.0) in CDCl3, or Me2SO (d = 39.5)
in (CD3)2SO. IR were measured on a JASCO FT/IR-420 spectro-
photometer (neat conditions) and reported in wave numbers (cm–1).
HRMS were obtained on either a JEOL JMS-D300 or a JEOL JMS-
AX500 spectrometer for electron ionization (EI), chemical ioniza-
tion (CI) or fast atom bombardment ionization (FAB). Compounds
7–14 were recrystallized from MeOH–H2O. Melting points were
determined with a Yanaco MP-21 melting point apparatus and were
uncorrected.
To a solution of 6 (0.102 g, 0.28 mmol) in MeCN (2.8 mL) was add-
ed K2CO3 (0.06 g, 0.42 mmol) at r.t. The mixture was stirred at r.t.
for 5 min. To the mixture was added BnBr (0.099 mL, 0.84 mmol)
and TBAI (0.31 g, 0.84 mmol) at r.t. The mixture was stirred for 30
min at r.t., filtered through a Celite pad, and concentrated in vacuo.
The residue was purified by flash column chromatography (silica
gel; n-hexane–EtOAc, 9:1–1:1) to give 5a.
Yield: 0.114 g (90%); pale yellow oil.
IR (neat): 3429 (br), 2980, 2935, 1795, 1760, 1738, 1715, 1595,
1484, 1390, 1370, 1152, 1097, 1074 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.27 (m, 3 H), 7.12 (m, 2 H), 5.74
(br s, 1 H), 5.49, (sept, J = 6.21 Hz, 1 H), 3.82 (d, J = 13.7 Hz, 1 H),
3.63 (d, J = 13.7 Hz, 1 H), 1.5–1.39 (m, 24 H).
13C NMR (75 MHz, CDCl3): d = 195.5, 193.96, 191.0, 179.2,
166.5, 153.9, 134.5, 130.2, 128.2, 127.4, 84.6, 80.0, 79.9, 63.5,
38.1, 28.3, 27.8, 22.8, 22.7.
HRMS (FAB): m/z calcd for C25H34NO7 ([M + H]+): 460.2335;
found: 460.2334.
tert-Butyl (tert-Butoxycarbonyl)(2-isopropoxy-3,4-dioxocyclo-
but-1-enyl)methylcarbamate (6)
tert-Butyl 1,2-Di-(tert-butoxycarbonyl)-1-(2-isopropoxy-3,4-di-
oxocyclobut-1-enyl)ethylcarbamate (5b)
According to the procedure for the synthesis of 5a, 6 (0.109 g, 0.29
mmol) was treated with K2CO3 (0.061 g, 0.44 mmol), BrCH2CO2t-
Bu (0.13 mL, 0.88 mmol), and TBAI (0.33 g, 0.88 mmol). The
crude product was purified by flash column chromatography (silica
gel; n-hexane–EtOAc, 9:1–1:1) to give 5b.
To a solution of N-Boc glycine tert-butyl ester (4.66 g, 20.1 mmol)
in THF (100 mL) was added LDA (42.0 mmol) in THF (100 mL)
under argon at –78 °C. The mixture was stirred for 0.5 h. To the
mixture was added a solution of 4 (3.71 g, 18.8 mmol) in THF (30
mL) at –78 °C. The mixture was stirred for 1 h, diluted with sat. aq
NH4Cl (100 mL), and extracted with EtOAc (3 × 100 mL). The
combined organic phases were washed with brine (100 mL), dried
(MgSO4), and concentrated in vacuo. The residue was purified by
flash chromatography (silica gel; EtOAc–hexane, 1:9–1:3) to give
an adduct.
Yield: 0.12 g, 86%; pale yellow oil.
IR (neat): 3429 (br), 2935, 1797, 1745, 1731, 1597, 1483, 1391,
1369, 1155, 1096, 1046 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.2 (br s, 1 H), 5.45 (sept, J = 6.21
Hz, 1 H), 3.46 (d, J = 16.3 Hz, 1 H), 3.38 (d, J = 16.3 Hz, 1 H),
1.46–1.38 (m, 33 H).
Yield: 6.22 g (72%); diastereomer ratio, 2:3; pale yellow oil.
IR (neat): 3420 (br), 2980, 2940, 1770, 1720, 1630, 1500, 1460,
1390, 1320, 1220, 1150, 1100, 1060, 1030 cm–1.
Synthesis 2005, No. 16, 2723–2729 © Thieme Stuttgart · New York

2726
T. Ishida et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 195.3, 193.6, 191.0, 178.3, 168.7,
165.9, 153.9, 84.3, 83.0, 81.7, 80.1, 62.3, 38.6, 28.2, 27.9, 27.6,
22.8, 22.7.
HRMS (FAB): m/z calcd for C27H36NO7 ([M + H]+): 486.2492;
found: 486.2505.
tert-Butyl 1-(tert-Butoxycarbonyl)-2-(1H-indol-3-yl)-1-(2-iso-
propoxy-3,4-dioxocyclobut-1-enyl)ethylcarbamate (5f)
According to the procedure for the synthesis of 5a, 6 (0.66 g, 1.8
mmol) was treated with K2CO3 (0.37 g, 2.7 mmol) and N,N,N-tri-
methyl-1H-indole-3-methanaminium iodide (2.3 g, 7.2 mmol). The
crude product was purified by flash column chromatography (silica
gel; n-hexane–EtOAc, 9:1–1:1) to give 5f.
HRMS (FAB): m/z calcd for C24H38NO9 ([M + H]+): 484.2547;
found: 484.2554.
tert-Butyl 1-(tert-Butoxycarbonyl)-1-(2-isopropoxy-3,4-dioxo-
cyclobut-1-enyl)but-3-enylcarbamate (5c)
According to the procedure for the synthesis of 5a, 6 (0.096 g, 0.26
mmol) was treated with K2CO3 (0.054 g, 0.39 mmol), allyl bromide
(0.07 mL, 0.78 mmol), and TBAI (0.29 g, 0.78 mmol). The crude
product was purified by flash column chromatography (silica gel; n-
hexane–EtOAc, 9:1–1:1) to give 5c.
Yield: 0.55 g (62%); pale yellow oil.
IR (neat): 3419, 2980, 2935, 1794, 1758, 1738, 1714, 1590, 1486,
1457, 1391, 1369, 1152, 1096, 1001 cm–1.
Yield: 0.082 g (77%); pale yellow oil.
1H NMR (400 MHz, CDCl3): d = 8.27 (br s, 1 H), 7.6 (d, J = 8.04
Hz, 1 H), 7.34 (d, J = 8.04 Hz, 1 H), 7.17 (t, J = 8.04 Hz, 1 H), 7.09
(t, J = 8.04 Hz, 1 H), 7.03 (s, 1 H), 5.87 (br s, 1 H), 5.46 (sept,
J = 6.36 Hz, 1 H), 3.95 (d, J = 14.7 Hz, 1 H), 3.83 (d, J = 14.7 Hz,
1 H), 1.46 (s, 9 H), 1.43 (d, J = 6.36 Hz, 3 H), 1.4 (d, J = 6.36 Hz,
3 H), 1.37 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 195.6, 193.9, 191.5, 180.3,
166.98, 154.1, 135.7, 128.2, 123.5, 122.1, 119.5, 118.9, 111.1,
108.7, 84.3, 80.1, 79.9, 63.97, 28.6, 28.3, 27.6, 22.8, 22.7.
IR (neat): 3427, 2981, 2935, 1795, 1758, 1738, 1718, 1596, 1485,
1391, 1370, 1157, 1097, 1074 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.78 (br s, 1 H), 5.62 (dddd,
J = 15.3, 11.5, 7.3, 7.3 Hz, 1 H), 5.46 (sept, J = 6.24 Hz, 1 H), 5.17
(d, J = 15.3 Hz, 1 H), 5.17 (d, J = 11.5 Hz, 1 H), 3.23 (dd, J = 14.1,
7.3 Hz, 1 H), 2.99 (dd, J = 14.1, 7.3 Hz, 1 H), 1.46–1.4 (m, 24 H).
13C NMR (75 MHz, CDCl3): d = 195.4, 194.1, 191.1, 179.6, 166.9,
153.8, 130.4, 120.6, 84.3, 80.02, 79.8, 62.1, 37.5, 28.2, 27.7, 22.8,
22.7.
HRMS (FAB): m/z calcd for C27H35N2O7 ([M + H]+): 499.2444;
found: 499.2423.
HRMS (FAB): m/z calcd for C21H32NO7 ([M + H]+): 410.2179;
found: 410.2155.
tert-Butyl 1-(tert-Butoxycarbonyl)-1-(2-isopropoxy-3,4-dioxo-
cyclobut-1-enyl)ethylcarbamate (5g)
tert-Butyl 1-(tert-Butoxycarbonyl)-1-(2-isopropoxy-3,4-dioxo-
cyclobut-1-enyl)-3-methylbut-3-enylcarbamate (5d)
According to the procedure for the synthesis of 5a, 6 (0.103 g, 0.28
mmol) was treated with K2CO3 (0.058 g, 0.42 mmol), methallyl bro-
mide (0.085 mL, 0.84 mmol), and TBAI (0.31 g, 0.84 mmol). The
crude product was purified by flash column chromatography (silica
gel; n-hexane–EtOAc, 9:1–1:1) to give 5d.
According to the procedure for the synthesis of 5a, 6 (0.52 g, 1.41
mmol) was treated with K2CO3 (0.31 g, 2.1 mmol) and MeI (2.6
mL, 42.3 mmol). The crude product was stirred for 12 h at r.t., fil-
tered through a Celite pad, and concentrated in vacuo. The residue
was purified by flash column chromatography (silica gel; n-hex-
ane–EtOAc, 9:1–1:1) to give 5g.
Yield: 0.35 g (66%); pale yellow oil.
Yield: 0.097 g (82%); pale yellow oil.
IR (neat): 3392, 2981, 2935, 1796, 1756, 1739, 1734, 1717, 1594,
1390, 1368, 1286, 1255, 1160, 1089 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.77 (br s, 1 H), 5.45 (sept,
J = 6.24 Hz, 1 H), 1.82 (s, 3 H), 1.44–1.37 (m, 24 H).
13C NMR (75 MHz, CDCl3): d = 195.3, 194.1, 191.5, 180.5, 168.2,
153.9, 84.1, 80.2, 79.6, 58.9, 28.3, 27.6, 22.8, 22.7, 21.8.
IR (neat): 3430, 2980, 2935, 1795, 1760, 1737, 1718, 1645, 1595,
1390, 1370, 1154, 1098, 1049 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.86 (br s, 1 H), 5.47 (sept,
J = 6.24 Hz, 1 H), 4.92 (s, 1 H), 4.81 (s, 1 H), 3.26 (d, J = 13.9 Hz,
1 H), 3.02 (d, J = 13.9 Hz, 1 H), 1.72 (s, 3 H), 1.5–1.3 (m, 24 H).
13C NMR (75 MHz, CDCl3): d = 195.2, 194.0, 190.6, 180.4, 167.3,
153.8, 139.5, 116.7, 84.4, 79.98, 79.7, 62.5, 40.4, 28.3, 27.7, 23.2,
22.8, 22.7.
HRMS (FAB): m/z calcd for C19H30NO7 ([M + H]+): 384.2022;
found: 384.2003.
HRMS (FAB): m/z calcd for C22H34NO7 ([M + H]+): 424.2335;
found: 424.2360.
tert-Butyl 1-(tert-Butoxycarbonyl)-1-(2-isopropoxy-3,4-dioxo-
cyclobut-1-enyl)-4-oxopentylcarbamate (5i)
To a solution of 6 (0.107 g, 0.29 mmol) in MeCN (2.9 mL) was add-
ed K2CO3 (0.06 g, 0.43 mmol) at r.t. The mixture was stirred at r.t.
for 5 min. To the mixture was added methyl vinyl ketone (0.12 mL,
1.45 mmol) at r.t. The mixture was stirred for 5 h at r.t., filtered
through a Celite pad, and concentrated in vacuo. The residue was
purified by flash column chromatography (silica gel; n-hexane–
EtOAc, 9:1–1:1) to give 5i.
tert-Butyl (3E)-1-(tert-Butoxycarbonyl)-1-(2-isopropoxy-3,4-di-
oxocyclobut-1-enyl)-4-phenylbut-3-enylcarbamate (5e)
According to the procedure for the synthesis of 5a, 6 (0.108 g, 0.29
mmol) was treated with K2CO3 (0.061 g, 0.44 mmol), cinnamyl bro-
mide (0.13 mL, 0.88 mmol), and TBAI (0.33 g, 0.88 mmol). The
crude product was purified by flash column chromatography (silica
gel; n-hexane–EtOAc, 9:1–1:1) to give 5e.
Yield: 0.066 g (52%); pale yellow oil.
Yield: 0.12 g (quantitative); pale yellow oil.
IR (neat): 3383, 2980, 2935, 1795, 1757, 1737, 1718, 1593, 1484,
1391, 1368, 1254, 1154, 1096 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.90 (br s, 1 H), 5.47 (sept, J = 6.1
Hz, 1 H), 2.69 (m, 1 H), 2.53 (m, 2 H), 2.35 (m, 1 H), 2.14 (s, 3 H),
1.48–1.38 (m, 24 H).
13C NMR (100 MHz, CDCl3): d = 206.9, 195.6, 193.9, 191.2, 179.6,
167.2, 153.9, 84.6, 79.9, 61.99, 37.7, 29.9, 28.3, 27.7, 27.6, 22.8,
22.7.
IR (neat): 3429, 2980, 2935, 1795, 1758, 1736, 1716, 1594, 1484,
1390, 1369, 1153, 1095, 1005 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.27–7.10 (m, 5 H), 6.48 (d,
J = 15.9 Hz, 1 H), 5.95 (ddd, J = 15.9, 7.56, 7.56 Hz, 1 H), 5.79 (br
s, 1 H), 5.44 (sept, J = 6.1 Hz, 1 H), 3.36 (dd, J = 13.9, 7.56 Hz, 1
H), 3.12 (dd, J = 13.9, 7.56 Hz, 1 H), 1.44–1.34 (m, 24 H).
13C NMR (75 MHz, CDCl3): d = 195.5, 194.1, 191.2, 180.0, 166.9,
153.9, 136.7, 135.3, 128.5, 127.7, 126.3, 121.7, 84.4, 80.1, 79.8,
62.5, 37.0, 28.3, 27.8, 22.8, 22.7.
Synthesis 2005, No. 16, 2723–2729 © Thieme Stuttgart · New York

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a-Amino Squaric Acids Using an Aminomalonate Equivalent Bearing a Squaryl Group
2727
HRMS (FAB): m/z calcd for C22H34NO8 ([M + H]+): 440.2284;
HRMS (FAB): m/z calcd for C25H40NO9 ([M + H]+): 498.2703;
found: 440.2260.
found: 498.2715.
tert-Butyl 1-(tert-Butoxycarbonyl)-3-cyano-1-(2-isopropoxy-
3,4-dioxocyclobut-1-enyl)propylcarbamate (5j)
According to the procedure for the synthesis of 5i, 6 (0.53 g, 1.44
mmol) was treated with K2CO3 (0.4 g, 2.88 mmol) and acrylonitrile
(2.84 mL, 43.2 mmol). The crude product was purified by flash col-
umn chromatography (silica gel; n-hexane–EtOAc, 9:1–1:1) to give
5j.
3-(1-Amino-2-phenylethyl)-4-hydroxycyclobut-3-ene-1,2-dione
(7)
To a solution of 5a (0.147 g, 0.32 mmol) in acetone (0.5 mL) was
added aq HCl (12 N; 0.5 mL). The mixture was stirred for 12 h at
r.t. and concentrated in vacuo. The residue was purified by flash col-
umn chromatography on Cosmosil® (H2O–MeOH, 9:1–1:1) to give
7.
Yield: 0.198 g (33%); pale yellow oil.
Yield: 0.051 g (72%); as a white solid; mp 220–221 °C (decomp.).
IR (neat): 3401, 2981, 2936, 2249, 1796, 1759, 1737, 1716, 1595,
1483, 1391, 1370, 1255, 1153 cm–1.
IR (neat): 3338–2346 (br), 1769, 1712, 1600, 1571, 1566, 1459,
1377, 1176 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.99 (br s, 1 H), 5.48 (sept,
J = 6.21 Hz, 1 H), 2.91 (ddd, J = 14.8, 8.4, 6.6 Hz, 1 H), 2.6 (ddd,
J = 15.4, 8.4, 6.6 Hz, 1 H), 2.44 (ddd, J = 14.8, 8.1, 6.6 Hz, 1 H),
2.28 (ddd, J = 15.4, 8.6, 6.6 Hz, 1 H), 1.5–1.35 (m, 24 H).
13C NMR (75 MHz, CDCl3): d = 195.7, 193.1, 190.8, 177.3, 166.1,
153.8, 118.5, 85.7, 80.9, 80.6, 61.7, 28.6, 28.2, 27.6, 22.8, 22.7,
11.9.
1H NMR (300 MHz, DMSO-d6): d = 8.39 (br s, 3 H), 7.27 (m, 5 H),
4.25 (br s 1 H), 3.26 (dd, J = 13.0, 9.3 Hz, 1 H), 3.13 (dd, J = 13.0,
4.8 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 217.5, 197.6, 176.0, 136.4,
129.1, 128.5, 126.9, 47.3, 36.1.
HRMS (FAB): m/z calcd for C12H10NO3 ([M – H]–): 216.0661;
found: 216.0636.
HRMS (FAB): m/z calcd for C21H31N2O7 ([M + H]+): 423.2131;
found: 423.2162.
3-Amino-3-(2-hydroxy-3,4-dioxocyclobut-1-enyl)propanoic
Acid (8)
tert-Butyl 1-(tert-Butoxycarbonyl)-3-(methoxycarbonyl)-1-(2-
isopropoxy-3,4-dioxocyclobut-1-enyl)propylcarbamate (5k)
According to the procedure for the synthesis of 5i, 6 (0.542 g, 1.47
mmol) was treated with K2CO3 (0.41 g, 2.94 mmol) and methyl
acrylate (3.97 mL, 44.1 mmol). The crude product was purified by
flash column chromatography (silica gel; n-hexane–EtOAc, 9:1–
1:1) to give 5k.
According to the procedure for the synthesis of 7, to a solution of 5b
(0.188 g, 0.39 mmol) in acetone (0.6 mL) was added aq HCl (12 N;
0.6 mL). The crude product was purified by flash column chroma-
tography on Cosmosil® (H2O) to give 8.
Yield: 0.058 g (81%); white solid; mp 186–187 °C (decomp.).
IR (neat): 3691–2500 (br), 1783, 1723, 1574, 1403, 1221 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.25 (br s, 3 H), 4.39 (br s 1
H), 3.0 (dd, J = 17.04, 6.4 Hz, 1 H), 2.78 (dd, J = 17.04, 6.4 Hz, 1
Yield: 0.23 g (35%); pale yellow oil.
IR (neat): 3379, 2980, 2936, 1797, 1756, 1740, 1719, 1595, 1391,
1370, 1154, 1097, 1054 cm–1.
H).
13C NMR (75 MHz, DMSO-d6): d = 217.1, 196.8, 175.5, 171.0,
43.6, 34.6.
HRMS (FAB): m/z calcd for C7H6NO5 ([M – H]–): 184.0246; found:
184.0234.
1H NMR (300 MHz, CDCl3): d = 5.92 (br s, 1 H), 5.47 (sept,
J = 6.24 Hz, 1 H), 3.62 (s, 3 H), 2.79 (ddd, J = 15.9, 9.7, 6.4 Hz, 1
H), 2.6 (ddd, J = 15.6, 9.2, 6.1 Hz, 1 H), 2.37 (ddd, J = 15.6, 9.2,
6.24 Hz, 1 H), 2.21 (ddd, J = 15.9, 9.7, 6.03 Hz, 1 H), 1.47–1.36 (m,
24 H).
3-(1-Aminobut-3-enyl)-4-hydroxycyclobut-3-ene-1,2-dione (9)
According to the procedure for the synthesis of 7, 5c (0.153 g, 0.37
mmol) in acetone (0.6 mL) was treated with aq HCl (12 N; 0.6 mL).
The crude product was purified by flash column chromatography on
Cosmosil® (H2O–MeOH, 9:1–1:1) to give 9.
13C NMR (75 MHz, CDCl3): d = 195.5, 193.4, 190.99, 179.3, 172.7,
166.97, 153.8, 84.7, 80.3, 79.97, 61.97, 51.9, 28.5, 28.24, 28.2,
27.7, 22.8, 22.7.
HRMS (FAB): m/z calcd for C22H34NO9 ([M + H]+): 456.2234;
found: 456.2213.
Yield: 0.0544 g (80%); pale orange solid; mp 198–199 °C (de-
comp.).
IR (neat): 3545–2935 (br), 1774, 1714, 1566, 1493, 1444 cm–1.
tert-Butyl 1,3-Di(tert-butoxycarbonyl)-1-(2-isopropoxy-3,4-di-
oxocyclobut-1-enyl)propylcarbamate (5l)
1H NMR (300 MHz, DMSO-d6): d = 8.05 (br s, 3 H), 5.67 (dddd,
J = 17.0, 10.1, 6.96, 6.96 Hz, 1 H), 5.06 (d, J = 17.0 Hz, 1 H), 5.00
(d, J = 10.1 Hz, 1 H), 4.07 (br t, J = 6.03 Hz, 1 H), 2.66–2.38 (m, 2
H).
13C NMR (75 MHz, DMSO-d6): d = 217.2, 196.9, 176.2, 132.7,
119.02, 46.6, 35.2.
According to the procedure for the synthesis of 5i, 6 (0.51 g, 1.4
mmol) was treated with K2CO3 (0.29 g, 2.1 mmol) and tert-butyl
acrylate (6.1 mL, 42 mmol). The crude product was purified by
flash column chromatography (silica gel; n-hexane–EtOAc, 9:1–
1:1) to give 5l.
Yield: 0.083 g (12%); pale yellow oil.
HRMS (CI): m/z calcd for C8H9NO3 (M+): 167.0582; found:
167.0571.
IR (neat): 3429, 2980, 2935, 1796, 1758, 1735, 1720, 1596, 1483,
1391, 1369, 1252, 1154 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.93 (br s, 1 H), 5.47 (sept, J = 6.1
Hz, 1 H), 2.70 (ddd, J = 14.4, 9.5, 6.4 Hz, 1 H), 2.53 (ddd, J = 14.9,
9.3, 6.1 Hz, 1 H), 2.30 (ddd, J = 16.1, 9.04, 6.4 Hz, 1 H), 2.11 (ddd,
J = 15.8, 9.5, 6.1 Hz, 1 H), 1.46–1.41 (m, 33 H).
13C NMR (100 MHz, CDCl3): d = 195.5, 193.99, 191.1, 179.7,
171.6, 167.1, 153.9, 84.4, 83.5, 80.9, 79.9, 62.2, 29.9, 28.3, 28.0,
27.7, 22.8, 22.7, 21.4.
3-(1-Aminobutyl)-4-hydroxycyclobut-3-ene-1,2-dione (10)
To a solution of 5c (0.106 g, 0.26 mmol) in MeOH (1.06 mL) was
added 10% Pd–C (0.027 g) at r.t. The mixture was stirred under H2
for 2 h at r.t., filtered through a Celite pad, and concentrated in vac-
uo. The residue was purified by flash column chromatography (sil-
ica gel; n-hexane–EtOAc, 9:1–1:1) to give tert-butyl 1-(tert-
butoxycarbonyl)-1-(2-isopropoxy-3,4-dioxocyclobut-1-enyl)butyl-
carbamate.
Synthesis 2005, No. 16, 2723–2729 © Thieme Stuttgart · New York

2728
T. Ishida et al.
PAPER
Yield: 0.086 g (78%); pale yellow oil.
1H NMR (300 MHz, CDCl3): d = 7.41–7.21 (m, 5 H), 5.95 (br s, 1
H), 5.56 (sept, J = 6.24 Hz, 1 H), 2.85–2.56 (m, 3 H), 2.44 (ddd,
J = 16.5, 11.9, 4.4 Hz, 1 H), 1.79 (m, 1 H), 1.6–1.45 (m, 25 H).
13C NMR (75 MHz, CDCl3): d = 195.4, 194.1, 191.1, 180.1, 167.3,
153.8, 141.5, 128.4, 128.3, 125.9, 84.2, 80.0, 79.6, 62.6, 35.3, 32.4,
28.3, 27.6, 25.2, 22.8, 22.7.
IR (neat): 3429, 2978, 2935, 2875, 1795, 1759, 1735, 1718, 1594,
1484, 1390, 1369, 1159, 1095, 1073 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.79 (br s, 1 H), 5.46 (sept,
J = 6.24 Hz, 1 H), 2.43 (ddd, J = 13.9, 13.9, 4.6 Hz, 1 H), 2.23 (ddd,
J = 13.9, 11.5, 4.6 Hz, 1 H), 1.46–1.05 (m, 26 H), 0.91 (t, J = 5.5
Hz, 3 H).
HRMS (FAB): m/z calcd for C27H38NO7 ([M + H]+): 488.2648;
found: 488.2625.
13C NMR (75 MHz, CDCl3): d = 195.3, 194.2, 191.3, 180.1, 167.6,
153.8, 84.1, 79.9, 79.6, 62.7, 35.1, 28.3, 27.7, 22.8, 22.7, 16.8, 13.9.
According to the procedure for the synthesis of 7, the product (0.101
g, 0.21 mmol) described above was treated with aq HCl (12 N; 0.5
mL). The crude product was purified by flash column chromatogra-
phy on Cosmosil® (H2O–MeOH, 9:1–1:1) to give 12.
HRMS (FAB): m/z calcd for C21H34NO7 ([M + H]+): 412.2335;
found: 412.2337.
According to the procedure for the synthesis of 7, the product (0.1
g, 0.24 mmol) described above in acetone (0.4 mL) was treated with
aq HCl (12 N; 0.4 mL). The crude product was purified by flash col-
umn chromatography on Cosmosil® (H2O–MeOH, 9:1–1:1) to give
10.
Yield: 0.032 g (60%); pale orange solid; mp 189–190 °C (decomp.).
IR (neat): 2925, 2855, 1775, 1710 (br), 1591, 1556, 1463, 1377,
1172 (br) cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.1 (br s, 3 H), 7.3–7.1 (m, 5
H), 4.1 (dd, J = 6.5, 5.5 Hz, 1 H), 2.57 (t, J = 7.3 Hz, 2 H), 1.9–1.5
(m, 4 H).
13C NMR (75 MHz, DMSO-d6): d = 216.9, 197.1, 177.0, 141.6,
128.3, 128.2, 125.8, 47.1, 34.7, 31.1, 26.8.
Yield: 0.021 g (52%); pale yellow solid; mp 186–187 °C (decomp.).
IR (neat): 2952, 2925, 2855, 1711 (br), 1460, 1377, 1172 (br) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.06 (br s, 3 H), 4.07 (dd,
J = 7.86, 5.85 Hz, 1 H), 1.76 (m, 2 H), 1.32 (m, 2 H), 0.86 (t, J = 7.3
Hz, 3 H).
HRMS (FAB): m/z calcd for C14H14NO3 ([M – H]–): 244.0974;
found: 244.0975.
13C NMR (75 MHz, DMSO-d6): d = 217.0, 197.1, 177.1, 46.97,
33.4, 18.2, 13.6.
3-(1-Aminoethyl)-4-hydroxycyclobut-3-ene-1,2-dione (13)
According to the procedure for the synthesis of 7, 5g (0.109 g, 0.28
mmol) was treated with aq HCl (12 N; 0.5 mL). The crude product
was purified by flash column chromatography on Cosmosil® (H2O–
MeOH, 9:1–1:1) to give 13.
HRMS (FAB): m/z calcd for C8H10NO3 ([M – H]–): 168.0661;
found: 168.0654.
3-(1-Amino-3-methylbutyl)-4-hydroxycyclobut-3-ene-1,2-di-
one (11)
Yield: 0.025 g (65%); white solid; mp 231–232 °C (decomp.).
To a solution of 5d (0.154 g, 0.36 mmol) in MeOH (3.6 mL) was
added 10% Pd–C (0.36 g) at r.t. The mixture was stirred under H2
for 5 h at r.t., filtered through a Celite pad, and concentrated in vac-
uo. The residue was purified by flash column chromatography (sil-
ica gel; n-hexane–EtOAc, 9:1–1:1) to give an inseparable mixture
of tert-butyl 1-(tert-butoxycarbonyl)-1-(2-isopropoxy-3,4-dioxo-
cyclobut-1-enyl)-3-methylbutylcarbamate and 5d (9:1; 0.085 g). To
a solution of the mixture (0.085 g) in acetone (0.4 mL) was added
aq HCl (12 N; 0.4 mL). The mixture was stirred for 12 h at r.t. and
concentrated in vacuo. The residue was purified by flash column
chromatography on Cosmosil® (H2O–MeOH, 9:1–1:1) to give 11.
IR (neat): 3430–2361 (br), 1770, 1712, 1462, 1455, 1377, 1239,
1183 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.21 (br s, 3 H), 4.21 (br s, 1
H), 1.40 (d, J = 6.6 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 215.5, 196.8, 177.95, 43.5,
16.8.
HRMS (FAB): m/z calcd for C6H6NO3 ([M – H]–): 140.0348; found:
140.0352.
4-Amino-4-(2-hydroxy-3,4-dioxocyclobut-1-enyl)butanoic Acid
(14)
According to the procedure for the synthesis of 7, 5k (0.079 g, 0.18
mmol) was treated with aq HCl (12 N; 0.3 mL). The crude product
was purified by flash column chromatography on Cosmosil® (H2O)
to give 14.
Yield: 0.013 g (20%; 2 steps); pale orange solid; mp 213–214 °C
(decomp.).
IR (neat): 3417–2956 (br), 1774, 1715, 1574, 1567, 1557 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.07 (br s, 3 H), 4.06 (dd,
J = 9.5, 5.7 Hz, 1 H), 1.89–1.49 (m, 3 H), 0.86 (d, J = 6.0 Hz, 6 H).
Yield: 0.025 g (71%); pale yellow solid; mp 209–210 °C (decomp.).
13C NMR (75 MHz, DMSO-d6): d = 217.3, 197.1, 177.2, 45.2, 24.2,
22.8, 21.7.
IR (neat): 3033, 2925, 2855, 1775, 1732, 1712, 1703, 1562, 1498,
1290, 1198, 1165 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.24 (br s, 3 H), 4.16 (dd,
J = 10.8, 5.5 Hz, 1 H), 2.35 (m, 2 H), 2.04 (m, 2 H).
HRMS (FAB): m/z calcd for C9H12NO3 ([M – H]–): 182.0817;
found: 182.0808.
3-(1-Amino-4-phenylbutyl)-4-hydroxycyclobut-3-ene-1,2-di-
one (12)
13C NMR (75 MHz, DMSO-d6): d = 216.7, 197.0, 176.2, 173.6,
46.5, 29.6, 26.6.
To a solution of 5e (0.26 g, 0.53 mmol) in MeOH (5.3 mL) was add-
ed 10% Pd–C (0.065 g) at r.t. The mixture was stirred under H2 for
2 h at r.t., filtered through a Celite pad, and concentrated in vacuo.
The residue was purified by flash column chromatography (silica
gel; n-hexane–EtOAc, 9:1–1:1) to give tert-butyl 1-(tert-butoxycar-
bonyl)-1-(2-isopropoxy-3,4-dioxocyclobut-1-enyl)-4-phenylbutyl-
carbamate.
HRMS (FAB): m/z calcd for C8H8NO5 ([M – H]–): 198.0402; found:
198.0420.
Conversion of tert-Butyl Ester 5l to 14
According to the procedure for the synthesis of 7, 5l (0.062 g, 0.12
mmol) was treated with aq HCl (12 N; 0.3 mL). The crude product
was purified by flash column chromatography on Cosmosil® (H2O)
to give 14. The physical data was identical with those of 14 derived
from 5k.
Yield: 0.18 g (70%); pale yellow oil.
IR (neat): 3429, 2980, 2934, 1795, 1758, 1736, 1718, 1593, 1483,
1454, 1390, 1369, 1153, 1097, 1013 cm–1.
Yield: 0.016 g (67%); pale yellow solid.
Synthesis 2005, No. 16, 2723–2729 © Thieme Stuttgart · New York

PAPER
a-Amino Squaric Acids Using an Aminomalonate Equivalent Bearing a Squaryl Group
2729
K.; Shock, A.; Taylor, R. J.; Warrellow, G. J.; Alexander, R.
P.; Langham, B. Bioorg. Med. Chem. Lett. 2002, 12, 1051.
(c) Bergh, A.; Magnusson, B.-G.; Ohlsson, J.; Wellmar, U.;
Nilsson, U. J. Glycoconjugate J. 2001, 18, 615.
Acknowledgment
This study was supported by a grant from the Research for the Fu-
ture Program (99L01204) and Grant-in-Aid (No. 15510178) from
the Japan Society for the Promotion of Science (JSPS).
(9) For recent examples, see: (a) Block, M. A. B.; Khan, A.;
Hecht, S. J. Org. Chem. 2004, 69, 184. (b) Bueschel, M.;
Ajayaghosh, A.; Arunkumar, E.; Daub, J. Org. Lett. 2003, 5,
2975. (c) Pham, W.; Weissleder, R.; Tung, C.-H.
Tetrahedron Lett. 2003, 44, 3975. (d) Jiao, G.-S.; Loudet,
A.; Lee, H. B.; Kalinin, S.; Johansson, L. B.-A.; Burgess, K.
Tetrahedron 2003, 59, 3109.
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(12) Cohen, S.; Lacher, J. R.; Park, J. D. J. Am. Chem. Soc. 1959,
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(15) The Sq group is sensitive to strongly basic or acidic
conditions, giving a complex mixture.
(16) Charette, A. B. In Encyclopedia of Reagents for Organic
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