Synthesis of (±)-(2-methylenecyclopropyl)glycine and (±)-4-[amino(carboxymethyl)]spiro[2.2]pentane-1-carboxylie acid

Article abstract of DOI:10.1055/s-2006-926320

A facile method for the preparation of racemic cyclopropylglycines is described, involving oxidation of cyclopropylcarbinols followed by a Bucherer-Berg reaction with sequential hydrolysis of the hydantoins obtained. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926320

880
PAPER
Synthesis of ( )-(2-Methylenecyclopropyl)glycine and ( )-4-[(Amino(carboxy-
methyl)]spiro[2.2]pentane-1-carboxylic Acid
Synthesis of
(
)
l
-(2-Me
e
thylenecyc
n
aine B. Averina, Nikolai V. Yashin, Yurii K. Grishin, Tamara S. Kuznetsova,* Nikolai S. Zefirov
Moscow State University, Chemistry Department, Leninskie gory, 119992 Moscow, Russia
Fax +7(95)9390290; E-mail: kuzn@org.chem.msu.ru
Received 1 September 2005
Recently we have reported the synthesis of amino acid 1
Abstract: A facile method for the preparation of racemic cyclopro-
pylglycines is described, involving oxidation of cyclopropyl-
carbinols followed by a Bucherer–Berg reaction with sequential
hydrolysis of the hydantoins obtained.
based on methylenecyclopropane.8 Here we report a facile
total synthesis of cyclopropylglycines from cyclopro-
panecarbinols. To the best of our knowledge only one ex-
ample of an eight-step synthesis of glycine 1 was known9
before our investigation, while the amino acid 2 had not
yet been synthesized.
Key words: [1+2] cycloaddition, Bucherer–Berg reaction, cyclo-
propylglycines, carbenes, diazo compounds
The starting compound in both syntheses was 2-methyl-
enecyclopropylcarbinol 3, which may be readily prepared
from methylenecyclopropane10 or 2-bromopropene.11 Ox-
idation of alcohol 3 under standard Swern reaction condi-
tions furnished a-methylenecyclopropanal 4.12 This rather
unstable compound was used in subsequent steps
(Scheme 1).
Cyclopropylglycines form a vast group of natural cyclo-
propane-derived amino acids as well as non-natural ana-
logues, some of which exhibit interesting biological
properties.1 For instance, they have been used as probes
for radical or cationic intermediates in the study of meta-
bolic mechanisms.2a–c Some substituted cyclopropylgly-
cine derivatives are antibacterial compounds and
conformationally restricted analogues of L-glutamate (L-
Glu).2c–g
Hydantoins are convenient intermediates for a-amino acid
synthesis from aldehydes or ketones.13 We obtained hy-
dantoin 5 by the reaction of aldehyde 4 with (NH4)2CO3
and KCN under Bucherer–Berg reaction conditions in
good yield. Hydrolysis of hydantoin 5 in the presence of
Ba(OH)2 after three days gave amino acid 1 in moderate
yield. According to NMR data both hydantoin 5 and ami-
no acid 1 were formed as a mixture of two diastereomers.8
(2-Methylenecyclopropyl)glycine 1, a cyclopropyl amino
acid isolated from lychee fruits,3 exhibits a strong
hypoglycemic
effect.
4-[Amino(carboxy)meth-
yl]spiro[2.2]pentane-1-carboxylic acid 2 is a novel con-
formationally constrained analogue of L-Glu. These two
compounds were chosen as target compounds (Figure 1)
in the proposed synthetic route.
The introduction of the additional carboxycyclopropyl
moiety into the molecule of methylenecyclopropane 1
forming dicarboxylic acid 2 is especially fascinating, as
amino acid 2 which possesses a glutamate-like backbone
is a promising ligand of metabothropic L-Glu receptors.
H2N
CO2H
NH2
CO2H
For this purpose we used the [1+2] cycloaddition of ethyl
diazoacetate (EDA) to the double bond of alcohol 3 or al-
dehyde 4 with protected functional groups which served
as synthetic precursors of 2.
1
HO2C
2
Figure 1
Diethyl acetal 6 derived from aldehyde 4 failed to undergo
cycloaddition with EDA. Tetrahydropyranyl and trimeth-
ylsilyl derivatives of methylenecyclopropylcarbinol 3
were employed in the addition reaction with EDA. This
reaction in the case of 7 gave adduct 8 in a low yield even
after multiple treatment of the reaction mixture with EDA
in the presence of Rh2(OAc)4. The addition of EDA to tri-
methylsilyl derivative 9 was more successful.
Well-known approaches to cyclopropylglycines are the
following: (a) cyclopropanation of the derivatives of b,g-
dehydroamino acids by carbenes4 or sulfur ylides;5 (b) cy-
clization of glycine anion equivalents;6 and (c) transfor-
mation of suitably functionalized cyclopropanes to
cyclopropyl amino acids.7 These methods are rather labo-
rious and reported yields of cyclopropylglycines are often
low. Thus, elaboration of an efficient route to cyclopro-
pylglycines and its derivatives is important.
Spiropentane 10 was then used in the synthesis of acid 2
(Scheme 2). It has been reported that the Corey method,14
excluding the distillation during the isolation of aldehyde,
is preferable to the Swern reagent. Aldehyde 11 was con-
verted to the corresponding amino acid 2 according to the
above-mentioned synthetic protocol used for the prepara-
tion of amino acid 1. Both hydantoin 12 and dicarboxylate
SYNTHESIS 2006, No. 5, pp 0880–0884
x
x
.
x
x
.2
0
0
6
Advanced online publication: 07.02.2006
DOI: 10.1055/s-2006-926320; Art ID: Z16305SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of ( )-(2-Methylenecyclopropyl)glycine
881
CH(OEt)2
OEt
OEt
N2CHCO2Me
CH(OEt)3
EtOH
Rh2(OAc)4, CH2Cl2
CO2Me
6, 50%
O
NH2
CO2H
NH
CHO
KCN, (NH4)2CO3
H2O-EtOH, 60 °C
O
Ba(OH)2
Cl(CO)2Cl
DMSO
N
H
H2O, reflux
4, 75%
5, 53%
1, 38%
CH2OTHP
CH2OTHP
N2CHCO2Me
CH2OH
O
Rh2(OAc)4, CH2Cl2
PPTS, CH2Cl2
CO2Me
3
8,
10%
7, 93%
CH2OTMS
CH2OTMS
N2CHCO2Me
Rh2(OAc)4, CH2Cl2
HMDS
CO2Me
10, 49%
Imidazole
9, 80%
Scheme 1
1-(Diethoxymethyl)-2-methylenecyclopropane (6)
H
N
CO2H
NH2
O
NH4NO3 (0.020 g, 0.25 mmol) was added to a solution of aldehyde
4 (0.503 g, 6.1 mmol) and CH(OEt)3 (1.098 g, 7.4 mmol) in anhyd
EtOH (1 mL) and the resulting mixture was stirred at 50 °C for 12
h. Then Na2CO3 (0.150 g, 1.4 mmol) was added, the solvent was
evaporated, and the residue was purified by ‘bulb-to-bulb’ distilla-
tion (50–55 °C, 2 Torr). The distillate was used in the next step
without further purification.
CHO
O
KCN,
(NH4)2CO3
N
H
Ba(OH)2
PCC
CH2Cl2
10
H2O,
reflux
EtOH–H2O,
60 °C
CO2Me
CO2Me
CO2H
2, 80%
11, 98%
12, 64%
Scheme 2
Yield: 0.476 g (50%); colorless oil.
1H NMR (400 MHz, CDCl3): d = 0.97–1.03 (m, 1 H, c-Pr), 1.05–
1.15 (m, 6 H, 2 × CH3), 1.16–1.22 (m, 1 H, c-Pr), 1.67–1.77 (m, 1
H, c-Pr), 3.38–3.62 (m, 4 H, 2 × OCH2), 4.02 (d, 1 H, CHO, 3J = 6.4
Hz), 5.30–5.42 (m, 2 H, =CH2).
13C NMR (100 MHz, CDCl3): d = 6.71 (c-Pr-CH2), 15.16 (2 ×
CH3), 18.56 (c-Pr-CH), 60.98 (CH2O), 61.22 (CH2O), 103.41 (CH),
104.25 (=CH2), 131.21 (=C).
2 were obtained in good yields as a mixture of eight dia-
stereomers.
In conclusion, we have developed a novel synthetic ap-
proach to cyclopropylglycines along with the syntheses of
two challenging amino acids in this family, namely (2-
methylenecyclopropyl)glycine and 4-[amino(carboxy-
methyl)]spiro[2.2]pentane-1-carboxylic acid.
2-[(2-Methylenecyclopropyl)methoxy]tetrahydro-2H-pyran (7)
Alcohol 3 (30 mmol, 2.524 g) was added to a solution of 3,4-dihy-
dro-2H-pyran (45 mmol, 3.780 g) and PPTS (3 mmol, 0.710 g) in
anhyd CH2Cl2 (200 mL). The resulting mixture was stirred under Ar
for 4 h at r.t. The reaction mixture was washed with brine (3 ×
50 mL), the organic layer was dried over MgSO4, the solvent was
removed under reduced pressure, and the residue was distilled.
NMR spectra were recorded on a ‘Bruker DPX-400’ spectrometer
at r.t., referenced to the residual solvent peak (1H: CDCl3, d = 7.24
ppm; 13C: CDCl3, d = 77.13 ppm). MS were taken on a Finnigan
MAT 95 XL (70 eV) by EI and GC-MS coupling. MALDI-TOF MS
were performed on a Bruker Daltonics Autoflex II. Analytical TLC
was carried out with Silufol silica gel plates (supported on alumi-
num) and visualized by UV light (254 and 365 nm) and chemical
staining (iodine vapor). Mps were determined on a Electrothermal
9100 capillary apparatus and are uncorrected. Column chromatog-
raphy was performed using silica gel 60 (230–400 mesh, Merck).
Petroleum ether (PE) used refers to the 40–60 °C boiling point frac-
tion. All reagents, except commercial products of satisfactory qual-
ity were purified by literature procedures prior to use. Compounds
obtained as mixtures of diastereomers were not separated into single
isomers.
Yield: 4.694 g (93%); diastereomeric ratio 1:1; colorless oil; bp 64–
65 °C/2 Torr.
1H NMR (400 MHz, CDCl3): d = 0.88–0.96 (m, 2 H), 1.23–1.34 (m,
2 H), 1.42–1.89 (m, 14 H), 3.22 (dd, 2J = 10.5 Hz, 3J = 7.8 Hz, 1 H,
CH2O), 3.39–3.50 (m, 4 H, 2 × CH2OTHP), 3.66 (dd, 2J = 10.5 Hz,
3J = 6.5 Hz, 1 H, CH2O), 3.75–3.88 (m, 2 H, CH2O), 4.56–4.63 (m,
2 H, 2 × OCHO), 5.32–5.43 (m, 4 H, 2 × CH2=).
13C NMR (100 MHz, CDCl3): d = 8.42 (1JC-H = 161 Hz, c-Pr-CH2),
8.68 (1JC-H = 161 Hz, c-Pr-CH2), 15.31 (1JC-H = 168 Hz, 2 × c-Pr-
CH), 19.32 (1JC-H = 127 Hz, THP-CH2), 19.44 (1JC-H = 127 Hz,
THP-CH2), 25.35 (1JC-H = 126 Hz, 2 × THP-CH2), 30.50
(1JC-H = 127 Hz, THP-CH2), 30.54 (1JC-H = 127 Hz, THP-CH2),
61.87 (1JC-H = 131 Hz, CH2O), 62.03 (1JC-H = 131 Hz, CH2O), 69.70
2-Methylenecyclopropylcarbinol 310 and 2-methylenecyclopro-
panecarbaldehyde 412 were synthesized by known procedures.
Synthesis 2006, No. 5, 880–884 © Thieme Stuttgart · New York

882
E. B. Averina et al.
PAPER
(1JC-H = 136 Hz, CH2O), 69.84 (1JC-H = 136 Hz, CH2O), 98.06
(1JC-H = 162 Hz, 2 × OCHO), 103.83 (1JC-H = 164 Hz, CH2=),
103.93 (1JC-H = 164 Hz, CH2=), 132.89 (c-PrC=), 133.28 (c-PrC=).
Isomer B
13C NMR (100 MHz, CDCl3): d = –0.68 (3 × SiMe3), 9.80 (c-Pr-
CH2), 12.35 (c-Pr-CH2), 19.40 (c-Pr-CH), 20.04 (CH, c-Pr), 22.66
(Cspiro), 51.06 (OCH3), 65.02 (CH2O), 174.45 (CO2Me).
Trimethyl(2-methylenecyclopropylmethoxy)silane (9)
Isomer C
HMDS (12 mmol, 1.930 g) and imidazole (0.2 mmol, 0.014 g) were
added to a solution of alcohol 3 (20 mmol, 1.682 g) in benzene (5
mL). The reaction mixture was refluxed for 8 h and then the solvent
was removed under reduced pressure. PE (15 mL) was added to the
residue and resulting solution was washed with H2O (3 × 5 mL).
The organic layer was dried over MgSO4, the solvent was removed
under reduced pressure, and the residue was distilled.
13C NMR (100 MHz, CDCl3): d = –0.74 (3 × SiMe3), 9.53 (c-Pr-
CH2), 14.06 (c-Pr-CH2), 17.52 (c-Pr-CH), 19.80 (c-Pr-CH), 22.84
(Cspiro), 51.09 (OCH3), 64.96 (CH2O), 173.68 (CO2Me).
Isomer D
13C NMR (100 MHz, CDCl3): d = –0.78 (3 × SiMe3), 10.00 (c-Pr-
CH2), 13.73 (c-Pr-CH2), 19.08 (c-Pr-CH), 19.55 (c-Pr-CH), 21.06
(Cspiro), 51.10 (OCH3), 63.29 (CH2O), 173.61 (CO2Me).
MS (EI, 70 eV): m/z (%) = 227 ([M – 1]+, 1), 213 ([M – Me]+, 8),
181 (4), 169 ([M – CO2Me]+, 14), 138 (5), 125 ([M – CH2OSiMe3]+,
37), 89 ([OSiMe3]+, 64), 79 (29), 75 (27), 73 ([SiMe3]+, 100), 59
(22), 45 (12).
Yield: 2.500 g (80%); colorless liquid; bp 45–50 °C/20 Torr.
1H NMR (400 MHz, CDCl3): d = –0.15 (s, 9 H, CH3), 0.57–0.64 (m,
1 H, c-Pr), 0.97–1.56 (m, 1 H, c-Pr), 1.38–1.49 (m, 1 H, c-Pr), 3.30
3
(dd, 1 H, CH2O, 2J = 12.0 Hz, J = 9.1 Hz), 3.64 (dd, 1 H, CH2O,
2J = 12.0 Hz, 3J = 6.2 Hz), 5.38 (m, 2 H, CH2=).
13C NMR (100 MHz, CDCl3: d = –0.40 (3 × CH3), 8.55 (c-Pr-CH2),
18.02 (c-Pr-CH), 65.42 (CH2O), 103.82 (CH2=), 133.35 (C=).
Anal. Calcd for C11H20O3Si: C, 57.85; H, 8.83. Found: C, 57.90; H,
8.85.
Anal. Calcd for C8H16OSi: C, 61.48; H, 10.24. Found: C, 61.40; H,
10.32.
Methyl 4-Formylspiro[2.2]pentane-1-carboxylate (11)
A solution of ester 10 (10 mmol, 2.284 g) in anhyd CH2Cl2 (10 mL)
was added to a stirred suspension of PCC (15 mmol, 3.233 g) in an-
hyd CH2Cl2 (20 mL). The resulting mixture was stirred at r.t. for 6
h, then the mixture was concentrated, and filtered through a short
column of silica gel (CH2Cl2). The solvent was evaporated under re-
duced pressure and the residue was used in the next step without fur-
ther purification.
Methyl Cyclopropane Carboxylates; General Procedure
EDA (1.23 M; 21 mmol, 17 mL) was added dropwise over 24 h to
a solution of olefin (24 mmol) and Rh2(OAc)4 (0.5 mol%, 0.044 g)
in anhyd CH2Cl2 (10 mL). The reaction mixture was concentrated
and passed through a short column of silica gel (CH2Cl2), the sol-
vent was evaporated under reduced pressure, and the residue was
purified by column chromatography (8) or distilled (10).
Yield 1.510 g (98%); diastereomeric ratio 3.5:3:2.5:1; colorless oil.
1H NMR (400 MHz, CDCl3): d = 1.15–1.52 (m, 16 H, c-Pr, isomers
A–D), 1.77–2.05 (m, 8 H, c-Pr, isomers A–D), 3.34 (s, 3 H, OCH3,
isomer D), 3.39 (s, 3 H, OCH3, isomer B), 3.42 (s, 3 H, OCH3, iso-
mer A), 3.44 (s, 3 H, OCH3, isomer C), 8.75 (d, 3J = 6.1 Hz, 1 H,
CHO, isomer C), 8.76 (d, 3J = 6.2 Hz, 1 H, CHO, isomer A), 8.79
Methyl 4-[(Tetrahydro-2H-pyran-2-yloxy)meth-
yl]spiro[2.2]pentane-1-carboxylate (8)
Yield: 0.505 g (10%); diastereomeric ratio 3:2:1.5:1; a colorless liq-
uid; Rf 0.70 (PE–EtOAc, 5:1).
1H NMR (400 MHz, CDCl3): d = 0.66–2.00 (m, 48 H), 3.30–3.93
(m, 28 H), 4.46–4.63 (m, 4 H, OCHO).
13C NMR (100 MHz, CDCl3): d = 10.22, 10.32, 10.48, 10.94, 12.08,
12.19, 12.86, 13.03, 13.11, 14.28, 14.55, 14.64, 16.46 (CH), 16.68
(CH), 17.47 (CH), 17.56 (CH), 17.78 (CH), 17.91 (CH), 17.97
(CH), 18.09 (CH), 19.45, 19.56, 19.62, 19.68, 25.49 (4 C), 30.70 (4
C), 51.56 (4 × OMe), 62.01 (2 × CH2O), 62.28 (2 × CH2O), 69.71
(CH2O), 70.07 (CH2O), 70.21 (CH2O), 70.30 (CH2O), 98.10
(OCHO), 98.55 (OCHO), 98.68 (OCHO), 98.80 (OCHO), 173.90
(COOMe), 174.00 (COOMe), 174.06 (COOMe), 174.24
(COOMe).
3
3
(d, J = 5.0 Hz, 1 H, CHO, isomer D), 8.92 (d, J = 5.5 Hz, 1 H,
CHO, isomer B).
Isomer A
13C NMR (100 MHz, CDCl3): d = 12.71 (c-Pr-CH2), 13.92 (c-Pr-
CH2), 18.28 (CHCHO), 25.37 (Cspiro), 29.34 (CHCO2Me), 52.03
(OCH3), 172.49 (CO2Me), 200.21 (CHO).
Isomer B
13C NMR (100 MHz, CDCl3): d = 13.03 (c-Pr-CH2), 13.80 (c-Pr-
CH2), 18.17 (CHCHO), 24.98 (Cspiro), 27.73 (CHCO2Me), 52.38
(OCH3), 172.30 (CO2Me), 200.30 (CHO).
Methyl 4-(Trimethylsilanyloxymethyl)spiro[2.2]pentane-1-car-
boxylate (10)
Yield: 2.346 g (49%); diastereomeric ratio 3.5:3:2:1; colorless liq-
Isomer C
13C NMR (100 MHz, CDCl3): d = 12.23 (c-Pr-CH2), 12.83 (c-Pr-
CH2), 18.35 (CHCHO), 24.94 (Cspiro), 29.22 (CHCO2Me), 52.08
(OCH3), 172.60 (CO2Me), 200.20 (CHO).
uid; bp 67–70 °C/2 Torr.
1H NMR (400 MHz, CDCl3): d = –0.78 [s, 9 H, Si(CH3)3, isomer D],
–0.72 [s, 9 H, Si(CH3)3, isomer B), –0.70 [s, 9 H, Si(CH3)3, isomer
C], –0.68 [s, 9 H, Si(CH3)3, isomer A], 1.08–1.27 (m, 4 H, c-Pr, iso-
mers A–D), 1.44–1.98 (m, 16 H, c-Pr, isomers A–D), 2.32–2.47 (m,
4 H, c-Pr-CH, isomers A–D), 3.45–4.39 (m, 20 H, OCH2, OCH3,
isomers A–D).
Isomer D
13C NMR (100 MHz, CDCl3): d = 13.48 (c-Pr-CH2), 14.11 (c-Pr-
CH2), 18.90 (CHCHO), 25.78 (Cspiro), 27.79 (CHCO2Me), 51.98
(OCH3), 172.90 (CO2Me), 199.78 (CHO).
MS (EI, 70 eV): m/z (%) = 154 ([M]+, 1), 153 ([M – 1]+, 5), 139 ([M
– Me]+, 8), 125 ([M – CHO]+, 77), 123 (25), 111 ([M – Me – C2H4]+,
Isomer A
12), 95 ([M
67 (45), 55 (79), 39 (61)
–
CO2Me]+, 100), 94 (78), 81 (12),
13C NMR (100 MHz, CDCl3): d = –0.72 (3 × SiMe3), 11.74 (c-Pr-
CH2), 12.38 (c-Pr-CH2), 18.71 (c-Pr-CH), 19.19 (c-Pr-CH), 21.67
(Cspiro), 51.07 (OCH3), 64.79 (CH2O), 174.47 (CO2Me).
Hydantoins; General Procedure
To a solution of aldehyde (2 mmol) in aq EtOH (50%; 150 mL),
KCN (3.2 mmol, 0.208 g), and ammonium carbonate (7.8 mmol,
0.749 g) were added. The resulting mixture was stirred for 24 h at
Synthesis 2006, No. 5, 880–884 © Thieme Stuttgart · New York

PAPER
Synthesis of ( )-(2-Methylenecyclopropyl)glycine
883
58–60 °C, and then the solvent was removed under reduced pres-
sure. The residue was extracted with MeOH (30 mL) and the insol-
uble solid was filtered off. The filtrate was evaporated to give pure
hydantoins.
Isomer F
13C NMR (100 MHz, CD3OD): d = 8.46 (c-Pr-CH2), 14.83 (c-Pr-
CH2), 17.66 (c-Pr-CH), 18.18 (c-Pr-CH), 21.93 (Cspiro), 50.94
(OCH3), 60.99 (CHNH), 170.34 (CO), 174.42 (CO2Me), 184.75
(CO).
5-(2-Methylenecyclopropyl)imidazolidine-2,4-dione (5)8
Yield: 0.161 g (53%); diastereomeric ratio 1:1; brown oil.
Amino Acids; General Procedure
1H NMR (400 MHz, CD3OD): d = 1.14 (m, 1 H, c-Pr-CH2), 1.28 (m,
1 H, c-Pr-CH2), 1.34 (m, 1 H, c-Pr-CH2), 1.44 (m, 1 H, c-Pr-CH2),
To a solution of Ba(OH)2·8H2O (2.8 mmol, 0.882 g) in H2O (10 mL)
hydantoin (1 mmol) was added. The reaction mixture was refluxed
for 3 d, then (NH4)2CO3 (5.6 mmol, 0.538 g) was added, and the re-
sulting mixture was refluxed for 12 h. After cooling the solid was
filtered off and the filtrate was evaporated under reduced pressure.
The residue was dissolved in distilled H2O (2 mL), passed through
a Dowex 50 ion-exchange column, eluted with a solution of NH3
(0.9 M), the solvent was evaporated, and the crystalline residue was
recrystallized (EtOH–H2O, 1:1).
3
1.83 (m, 2 H, c-Pr-CH), 3.81 (d, J = 6.4 Hz, 1 H, CH), 3.90 (d,
3J = 6.4 Hz, 1 H, CH), 5.50 (m, 1 H, =CH2), 5.53 (m, 1 H, =CH2),
5.58 (m, 1 H, =CH2), 5.66 (m, 1 H, =CH2).
13C NMR (100 MHz, CD3OD): d = 6.89 (c-Pr-CH2), 7.60 (c-Pr-
CH2), 17.78 (2 × c-Pr-CH), 61.73 (CH), 62.10 (CH), 105.58
(=CH2), 106.32 (=CH2), 132.15 (=C), 132.57 (=C), 168.61 (CO),
168.88 (CO), 185.43 (CO), 186.15 (CO).
MS (EI, 70 eV): m/z (%) = 152 ([M]+, 4), 113 (47), 100 (9), 81
(100), 66 (14), 53 (41), 44 (96).
(2-Methylenecyclopropyl)glycine (1)8
Yield: 0.048 g (38%); diastereomeric ratio 1:1; white crystalline
solid; mp 246 °C (dec.) [lit.9 mp 250 °C (dec.)].
Methyl 4-(2,5-Dioxoimidazolidin-4-yl)spiro[2.2]pentane-1-car-
boxylate (12)
1H NMR (400 MHz, D2O): d = 1.35 (m, 1 H, c-Pr-CH2), 1.47 (m, 1
H, c-Pr-CH2), 1.70 (m, 2 H, c-Pr-CH2), 2.03 (m, 2 H, c-Pr-CH), 3.46
(d, 3J = 9.9 Hz, 1 H, CH), 3.60 (d, 3J = 9.8 Hz, 1 H, CH), 5.73 (m, 2
H, CH2), 5.79 (m, 2 H, CH2).
13C NMR (100 MHz, D2O): d = 8.31 (c-Pr-CH2), 8.77 (c-Pr-CH2),
15.39 (c-Pr-CH), 15.45 (c-Pr-CH), 57.33 (CH), 57.57 (CH), 105.98
(=CH2), 106.15 (=CH2), 130.59 (=C), 130.62 (=C), 173.47 (CO2H),
173.67 (CO2H).
Yield: 0.287 g (64%); diastereomeric ratio 4:3.5:3:2.5:2:1.5:1:1;
brown oil.
Complete assignment of the signals of two minor isomers in the 1H
and 13C NMR spectra was not possible due to the low solubility of
hydantoin 12.
1H NMR (400 MHz, CD3OD): d = 0.87–1.72 (m, 30 H, c-Pr, iso-
mers A–F), 1.97–2.41 (m, 6 H, c-Pr, A–F), 3.66 (s, 3 H, OCH3, iso-
mer C), 3.67 (s, 3 H, OCH3, isomer A), 3.67 (s, 3 H, OCH3, isomer
E), 3.68 (s, 3 H, OCH3, isomer B), 3.69 (s, 3 H, OCH3, isomer D),
3.66 (s, 3 H, OCH3, isomer F), 3.70 (d, 3J = 6.5 Hz, 1 H, HNCH, iso-
4-[Amino(carboxy)methyl]spiro[2.2]pentane-1-carboxylicAcid
(2)
Yield: 0.148 g (80%); diastereomeric ratio 4:3.5:3:2.5:2:1.5:1.2:1;
3
mer B), 3.71 (d, J = 7.8 Hz, 1 H, HNCH, isomer A), 3.74 (d,
white crystalline solid; mp 222–224 °C (dec.)
3
3J = 7.1 Hz, 1 H, HNCH, isomer C), 3.75 (d, J = 6.8 Hz, 1 H,
1H NMR (400 MHz, D2O): d = 0.76–1.70 (m, 30 H, c-Pr, isomers
A–F), 1.75–2.10 (m, 6 H, c-Pr, isomers A–F), 3.02 (d, 3J = 10.6 Hz,
1 H, H2NCH, isomer F), 3.18 (d, 3J = 10.1 Hz, 1 H, H2NCH, isomer
B), 3.23 (d, 3J = 10.3 Hz, 1 H, H2NCH, isomer C), 3.27 (d, 3J = 10.3
Hz, 1 H, H2NCH, isomer A), 3.29 (d, 3J = 8.4 Hz, 1 H, H2NCH, iso-
mer D), 3.52 (d, 3J = 8.6 Hz, 1 H, H2NCH, isomer E); CHNH2 for
two minor isomers was not observed.
3
HNCH, isomer D), 3.76 (d, J = 7.1 Hz, 1 H, HNCH, isomer F),
3.79 (d, 3J = 7.1 Hz, 1 H, HNCH, isomer E).
Isomer A
13C NMR (100 MHz, CD3OD): d = 7.98 (c-Pr-CH2), 13.47 (c-Pr-
CH2), 19.34 (c-Pr-CH), 19.35 (c-Pr-CH), 21.80 (Cspiro), 50.99
(OCH3), 61.25 (CHNH), 167.99 (CO), 174.43 (CO2Me), 186.27
(CO).
Isomer A
13C NMR (100 MHz, D2O): d = 9.93 (c-Pr-CH2), 12.45 (c-Pr-CH2),
18.94 (c-Pr-CH), 21.35 (c-Pr-CH), 23.11 (Cspiro), 58.25 (CHNH2),
173.78 (COOH), 180.27 (COOH).
Isomer B
13C NMR (100 MHz, CD3OD): d = 8.16 (c-Pr-CH2), 13.37 (c-Pr-
CH2), 19.16 (c-Pr-CH), 19.26 (c-Pr-CH), 21.82 (Cspiro), 51.06
(OCH3), 60.87 (CHNH), 170.21 (CO), 174.63 (CO2Me), 184.84
(CO).
Isomer B
13C NMR (100 MHz, D2O): d = 10.06 (c-Pr-CH2), 12.73 (c-Pr-
CH2), 18.65 (c-Pr-CH), 21.18 (c-Pr- CH), 22.91 (Cspiro), 57.37
(CHNH2), 173.95 (COOH), 180.88 (COOH).
Isomer C
13C NMR (100 MHz, CD3OD): d = 9.26 (c-Pr-CH2), 12.62 (c-Pr-
CH2), 19.51 (c-Pr-CH), 19.98 (c-Pr- CH), 21.13 (Cspiro), 51.12
(OCH3), 58.97 (CHNH), 170.11 (CO), 174.42 (CO2Me), 186.21
(CO).
Isomer C
13C NMR (100 MHz, D2O): d = 10.23 (c-Pr-CH2), 12.63 (c-Pr-
CH2), 18.82 (c-Pr-CH), 21.22 (c-Pr-CH), 22.49 (Cspiro), 57.72
(CHNH2), 173.61 (COOH), 179.37 (COOH).
Isomer D
13C NMR (100 MHz, CD3OD): d = 8.63 (c-Pr-CH2), 12.22 (c-Pr-
CH2), 19.53 (c-Pr-CH), 20.01 (c-Pr-CH), 20.85 (Cspiro), 51.03
(OCH3), 60.76 (CHNH), 170.02 (CO), 174.64 (CO2Me), 186.70
(CO).
Isomer D 13C NMR (100 MHz, D2O): d = 11.44 (c-Pr-CH2), 12.34
(c-Pr-CH2), 19.13 (c-Pr-CH), 20.09 (c-Pr-CH), 22.53 (Cspiro), 57.88
(CHNH2), 173.55 (COOH), 180.57 (COOH).
Isomer E
Isomer E
13C NMR (100 MHz, D2O): d = 10.17 (c-Pr-CH2), 13.32 (c-Pr-
CH2), 19.86 (c-Pr-CH), 22.29 (c-Pr-CH), 23.02 (Cspiro), 57.11
(CHNH2), 173.08 (COOH), 179.07 (COOH).
13C NMR (100 MHz, CD3OD): d = 7.67 (c-Pr-CH2), 13.26 (c-Pr-
CH2), 18.45 (c-Pr-CH), 18.92 (c-Pr-CH), 21.24 (Cspiro), 51.43
(OCH3), 61.62 (CHNH), 170.64 (CO), 174.41 (CO2Me), 186.12
(CO).
Synthesis 2006, No. 5, 880–884 © Thieme Stuttgart · New York

884
E. B. Averina et al.
PAPER
Isomer F
(4) (a) Ma, D.; Zhu, W. J. Org. Chem. 2001, 66, 348.
(b) Hallinan, K. O.; Crout, D. H. G.; Errington, W. J. Chem.
Soc., Perkin Trans. 1 1994, 3537. (c) Ma, D.; Ma, Z.; Jian,
J.; Zheng, C. Tetrahedron: Asymmetry 1997, 8, 889.
(d) Shimamoto, K.; Ishida, M.; Shinozaki, H.; Ohfune, J. J.
Org. Chem. 1991, 56, 4167. (e) Pelliciari, R.; Natalini, B.;
Marinozzi, M.; Monahan, J. B.; Snyder, J. S. Tetrahedron
Lett. 1990, 3, 139. (f) Pellicciari, R.; Marinozzi, M.;
Constantino, G.; Natalini, B.; Moroni, F.; Pellegrini-
Giampietro, D. J. Med. Chem. 1999, 42, 2716.
13C NMR (100 MHz, D2O): d = 10.77 (c-Pr-CH2), 13.90 (c-Pr-
CH2), 19.64 (c-Pr-CH), 23.02 (c-Pr-CH), 26.01 (Cspiro), 58.68
(CHNH2), 172.87 (COOH), 181.17 (COOH).
Isomer G
13C NMR (100 MHz, D2O): d = 10.01 (c-Pr-CH2), 13.46 (c-Pr-
CH2), 19.29 (c-Pr-CH), 20.49 (c-Pr-CH), 22.39 (Cspiro), 58.64
(CHNH2), 173.65 (COOH), 180.49 (COOH).
Isomer H
(g) Shimamoto, K.; Ohfune, Y. J. Med. Chem. 1996, 39, 407.
(5) (a) Demir, A. S.; Tanyeli, C.; Cagir, A.; Tahir, M. N.; Ulku,
D. Tetrahedron: Asymmetry 1998, 9, 1035. (b) Ma, D.; Ma,
Z. Tetrahedron Lett. 1997, 38, 7599. (c) Monn, J. A.; Valli,
M. J.; Massey, S. M.; Wright, R. A.; Salhoff, C. R.; Jonson,
B. G.; Howe, T.; Alt, C. A.; Rhodes, C. A.; Robey, R. L.;
Criffey, K. R.; Tizzano, J. P.; Kallman, M. J.; Helton, D. R.;
Schoepp, D. D. J. Med. Chem. 1997, 40, 528. (d) Ma, D.;
Jiang, Y. Tetrahedron: Asymmetry 2000, 11, 3727. (e) Ma,
D.; Cao, Y.; Wu, W.; Jiang, J. Tetrahedron 2000, 56, 7447.
(6) (a) Chavan, S. P.; Venkatraman, M. S.; Sharma, A. K.;
Chittiboyina, A. G. Tetrahedron Lett. 1996, 37, 2857.
(b) Joucla, M.; el Goumzili, M.; Fouchet, B. Tetrahedron
Lett. 1986, 27, 1677. (c) Zindel, J.; de Meijere, A. Synthesis
1994, 190. (d) Mazon, A.; Pedregal, C.; Prowse, W.
Tetrahedron 1999, 55, 7057. (e) Shibuya, A.; Kurishita, M.;
Ago, C.; Taguchi, T. Tetrahedron 1996, 52, 271.
13C NMR (100 MHz, D2O): d = 10.70 (c-Pr-CH2), 13.57 (c-Pr-
CH2), 18.11 (c-Pr-CH), 20.53 (c-Pr-CH), 22.12 (Cspiro), 58.58
(CHNH2), 173.07 (COOH), 179.28 (COOH).
MS (EI, 70 eV): m/z (%) = 185 ([M]+, 3), 167 ([M – H2O]+, 5), 141
([M – CO2]+, 7), 111 ([M – CH(NH2)COOH]+, 7), 95 ([M – 2
COOH]+, 12), 71 (54), 43 (61), 38 (68), 36 (100).
MALDI-TOF (dithranol): m/z = 186.0 [M + H]+.
Acknowledgment
This work was supported by the Russian Foundation of Basic Re-
search (Project 05-03-32906-a) and the Ministry of Education and
Science of Russian Federation (Project MK-3156.2005.3).
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Synthesis 2006, No. 5, 880–884 © Thieme Stuttgart · New York