Synthesis of 2-azaspiro[3.3]heptane-derived amino acids: Ornitine and GABA analogues

Article abstract of DOI:10.1007/s00726-009-0467-9

Synthesis of 6-amino-2-azaspiro[3.3]heptane-6-carboxylic acid and 2-azaspiro[3.3]heptane-6-carboxylic acid was performed. Both four-membered rings in the spirocyclic scaffold were constructed by subsequent ring closure of corresponding 1,3-bis-electrophil

Full text of DOI:10.1007/s00726-009-0467-9

Amino Acids (2010) 39:515–521
DOI 10.1007/s00726-009-0467-9
ORIGINAL ARTICLE
Synthesis of 2-azaspiro[3.3]heptane-derived amino acids:
ornitine and GABA analogues
•
Dmytro S. Radchenko Oleksandr O. Grygorenko
•
Igor V. Komarov
Received: 18 November 2009 / Accepted: 24 December 2009 / Published online: 27 January 2010
Ó Springer-Verlag 2010
Abstract Synthesis of 6-amino-2-azaspiro[3.3]heptane-
6-carboxylic acid and 2-azaspiro[3.3]heptane-6-carboxylic
acid was performed. Both four-membered rings in the
spirocyclic scaffold were constructed by subsequent ring
closure of corresponding 1,3-bis-electrophiles at 1,1-C- or
1,1-N-bis-nucleophiles. The two novel amino acids were
added to the family of the sterically constrained amino
acids for the use in chemistry, biochemistry, and drug
design.
principle be much more efficient and selective ligands for
various biological targets, thus displaying pronounced
biological activity (Mann 2008). Recent studies showed that
this view of the ligand–target interaction is too simplified
(Martin 2007); nevertheless, molecular rigidity is widely
regarded as one of the most important property of approved
drugs (Feher and Schmidt 2003). Sterically constrained
amino acids are especially popular for the design of pepti-
domimetic drugs. The principles of such design were for-
mulated long ago (Shemyakin et al. 1969; Hruby et al. 1990;
Cowell et al. 2004) and have been intensively used since
then. As the result, a number of the approved drugs or
clinical candidates contain residues of sterically constrained
amino acids. It is interesting to note that many natural
amino acids are sterically constrained; the Nature has been
practicing the concept of rigidification of the biologically
important molecules for millions of years.
Keywords Tailor-made amino acids Á Spiro azetidines Á
Ornitine analogues Á GABA analogues Á Molecular rigidity
Introduction
The amino acids which possess sterically constrained
molecular framework occupy a distinctive class of organic
compounds which arouse much interest of chemists and
biologists in the last decade. A number of tailor-made ste-
rically constrained or rigid amino acids were synthesized to
Natural and synthetic rigid amino acids are either steri-
cally congested or cyclic (polycyclic). This is illustrated in
Fig. 1 by three amino acids which occur in Nature: 2-ami-
noisobutyric acid (1), 2-azetidinecarboxylic acid (2), and
2,4-methanoproline (3). Rigid spirocyclic scaffolds have
great potential in providing wide variation of spatial dis-
position of the functional groups. However, spirocyclic
aminoacids are very rare, both among natural and tailor-
made amino acids. There are only a few reports in the lit-
erature on spirocyclic analogues of natural amino acids
(Weatherhead et al. 2009; Radchenko et al. 2008; Pellicciari
et al. 2002; de Meijere et al. 1999; Tamm et al. 1999).
In this paper, we report syntheses of compounds 4 and
5—2-azaspiro[3.3]heptane-derived amino acids, spirocyclic
rigidified analogues of two natural amino acids, ornitine
and c-aminobutyric acid. To the best of our knowledge,
spirocyclic analogues of these biologically important amino
acids are not described in the literature to date. The
´
date (for recent reviews see Cativiela and Ordon˜ez 2009;
Trabocchi et al. 2008; Komarov et al. 2004). The main
driving force of the activity in this area is the quest for new
drugs. In general, due to pre-organization of functional
groups, the sterically constrained compounds can in
D. S. Radchenko Á O. O. Grygorenko Á I. V. Komarov
Enamine Ltd., Aleksandra Matrosova Street,
23, Kyiv 01103, Ukraine
D. S. Radchenko Á O. O. Grygorenko (&) Á I. V. Komarov
Department of Chemistry,
Kyiv National Taras Shevchenko University,
Volodymyrska Street, 64, Kyiv 01033, Ukraine
e-mail: gregor@univ.kiev.ua
123

516
D. S. Radchenko et al.
IR spectra are given for the main absorption bands. HPLC–
MS analyzes were done on an Agilent 1100 LCMSD SL
instrument [chemical ionization (CI)] and Agilent 5890
Series II 5972 GCMS instrument [electron impact ioniza-
tion (EI)]. Elemental analyzes were performed on Ele-
mentar Vario MICRO Cube CHNS/O analyzer.
Methanesulfonic acid 1-methanesulfonyloxymethyl-
3,3-dimethoxycyclobutylmethyl ester 11
To a solution of 10 (4.81 g, 27.4 mmol) in chloroform
(50 mL), triethylamine (11.46 mL, 82.2 mmol) was added.
The resulting solution was cooled to -30°C, and mesyl
chloride (5.09 mL, 65.8 mmol) was added dropwise. After
the addition was complete, the reaction mixture was heated
to ambient temperature, stirred for 1 h and washed with
water (1 9 25 mL), 10% aqueous citric acid (1 9 25 mL)
and brine (1 9 25 mL). Drying of solution with sodium
sulfate and evaporation at reduced pressure led to 11
(9.10 g, 100%): mp 96°C (EtOH). MS (m/z, CI)
333 (MH?). Anal. calcd for C10H20O8S2 C 36.14, H 6.06,
S 19.29. Found C 36.19, H 6.31, S 19.04. IR (KBr, cm-1):
Fig. 1 Natural sterically constrained amino acids (1–3) and com-
pounds with 2-azaspiro[3.3]heptane scaffold (4–6)
2-azaspiro[3.3]heptane scaffold has recently captured
attention of synthetic and medicinal chemists—compound 6
was suggested as an entry to structural surrogates of
4-substituted piperidines, building blocks for drug design
(Meyers et al. 2009). It should also be noted that compounds
4 and 5 are non-chiral; the former being an example of a non-
chiral analogue of the chiral natural amino acid, ornitine (for
some other examples of non-chiral bicyclic amino acids see
Avenoza et al. 2001; Rammeloo et al. 2002; Radchenko
et al. 2009).
1
1,355 (mas(SO2)), 1,174 (ms(SO2)). H NMR (DMSO-d6) d
4.20 (s, 4H, CH2OMs), 3.20 (s. 6H), 3.05 (s, 6H), 2.04 (s,
4H, C(CH2)2C); 13C NMR (DMSO-d6) d 98.7 (C(OMe)2),
72.0 (CH2OMs), 48.4, 37.1, 36.2, 32.6.
6,6-Dimethoxy-2-(toluene-4-sulfonyl)-2-azaspiro[3.3]
heptane 12
A solution of 11 (9.1 g, 27.4 mmol), potassium carbonate
(18.9 g, 137 mmol) and tosyl amide (4.91 g, 28.7 mmol) in
DMSO (50 mL) was heated at 85°C for 30 h. After cool-
ing, water (100 mL) was added, and the product was
extracted with dichloromethane (3 9 50 mL). The com-
bined organic phases were washed with 10% aqueous citric
acid (50 mL) and brine (3 9 50 mL). Drying of the solu-
tion with sodium sulfate and evaporation in vacuo led to 12
(5.03 g, 59%) pure enough for the next step. Mp 114°C
(EtOH). MS (m/z, CI) 312 (MH?), 280. IR (KBr, cm-1):
Materials and methods
General
Solvents were purified according to the standard proce-
dures. (3,3-dimethoxycyclobutane-1,1-diyl)dimethanol 10
(Radchenko et al. 2008) and 2-phenyl-5,5-di(bromo-
methyl)-1,3-dioxane 16 (Allinger and Tushaus 1965) were
prepared using the procedures reported in the literature. All
other starting materials were purchased from Acros, Merck,
and Fluka. Melting points were measured on MPA100
OptiMelt automated melting point system. Analytical TLC
was performed using Polychrom SI F254 plates. Column
chromatography was performed using Kieselgel Merck 60
(230–400 mesh) as the stationary phase. 1H, 13C NMR, and
all 2D NMR spectra were recorded on a Bruker 170 Avance
500 spectrometer (at 499.9 MHz for protons, 124.9 MHz
for carbon-13) and Varian Unity Plus 400 spectrometer (at
400.4 MHz for protons, 100.7 MHz for carbon-13).
Chemical shifts are reported in ppm downfield from TMS
(1H, 13C) as an internal standard. IR spectra were obtained
on Nicolet Nexus 470 spectrometer. mmax (cm-1) values in
1
1,339 (mas(SO2)), 1,280, 1,157 (ms(SO2)), 1,107, 1,042. H
NMR (DMSO-d6) d 7.67 (d, J = 8.0 Hz, 2H), 7.48 (d,
J = 8.0 Hz, 2H), 3.64 (s, 4H, C(CH2)2N), 2.93 (s, 6H,
C(OCH3)2), 2.42 (s, 3H, C6H5CH3), 2.02 (s, 4H,
C(CH2)2C); 13C NMR (DMSO-d6) d 144.4, 131.2, 130.4,
128.7, 99.2 (C(OMe)2), 62.2, 48.6, 42.2, 28.8, 21.6.
2-(Toluene-4-sulfonyl)-2-azaspiro[3.3]
heptan-6-one 13
Compound 12 (3 g, 9.64 mmol) was mixed with 3 N HCl
(100 mL) and stirred vigorously for 12 h. The solid formed
was filtered and dried on air to yield 13 (2.41 g, 94%): mp
123

Synthesis of 2-azaspiro[3.3]heptane-derived amino acids
517
180–182°C (EtOH); MS (m/z) 266 (MH?). Anal. calcd for
C13H15NO3S C 58.85, H 5.70, N 5.28, S 12.08. Found
C 58.99, H 5.45, N 5.03, S 11.87. IR (KBr, cm-1): 1,785
(m(C=O)), 1,338 (mas(SO2)), 1,158 (ms(SO2)). 1H NMR
2 h. Water was evaporated in vacuo, the residue was
purified by ion-exchange chromatography using Amberlite
IR-120(plus) ion-exchange resin (25 g) as the stationary
phase and 5% aqueous ammonia as an eluent yielding the
amino acid 4 (45 mg, 54% from 15): mp [ 250°C, dec.
(EtOH–H2O). Anal. calcd for C7H12N2O2 C 53.83, H 7.74,
N 17.94. Found C 53.99, H 7.95, N 18.04 IR (KBr, cm-1):
3,479 and 3,430 (m(NH2)), 1,633 (mas(COO-)), 1,590
(DMSO-d6)
d 7.69 (d, J = 7.5 Hz, 2H), 7.49 (d,
J = 7.5 Hz, 2H), 3.85 (s, 4H, C(CH2)2N), 3.07 (s, 4H,
C(CH2)2C), 2.42 (s, 3H, C6H5CH3); 13C NMR (DMSO-d6)
d 205.8, 144.5, 131.5, 130.4, 128.7, 61.5, 57.0, 27.8, 21.6.
1
(d(NH2?), 1,397 (ms(COO-)). H NMR (D2O) d 4.22 (s,
2-(Toluene-4-sulfonyl)-2,7,9-triaza-
2H) 4.06 (s, 2H), 2.73 (d, J = 14.5 Hz, 2H), 2.53 (d,
J = 14.5 Hz, 2H); 13C NMR (D2O) d 176.9, 58.3, 56.1,
53.7, 40.8, 34.3.
dispiro[3.1.4.1]undecane-8,10-dione 14
Ketone 13 (0.8 g, 3.02 mmol), potassium cyanide (0.3 g,
4.61 mmol) and ammonium carbonate (0.87 g, 9.05 mmol)
were dissolved in a mixture of EtOH (8 mL) and water
(3.3 mL). The mixture was stirred at 50°C for 2 days and
acidified with 1 N HCl to pH = 1. The precipitate formed
was filtered and dried to yield 0.62 g (61%) of 14 as a
white solid: mp 241°C (EtOH); MS (m/z, CI) 336 (MH?),
311. Anal. calcd for C15H17N3O4S C 53.72, H 5.11,
N 12.53, S 9.56. Found C 53.93, H 5.11, N 12.72, S 9.69.
IR (KBr, cm-1): 1,758 and 1,710 (m(C=O)), 1,402, 1,340
Diisopropyl 7-phenyl-6,8-dioxaspiro[3.5]nonane-2,2-
dicarboxylate 17
To a suspension of NaH (60% in mineral oil, 67 g, 1.67 mol)
in dry DMF (700 mL), diisopropyl malonate (286 g,
1.52 mmol) was added dropwise (the temperature being
maintained below 70°C) followed by 2-phenyl-5,5-di(bro-
momethyl)-1,3-dioxane 16 (266 g, 0.76 mol). The resulting
reaction mixture was heated at 140°C for 15 h. After cool-
ing, saturated NH4Cl solution (1.5 L) was added, and the
product was extracted with hexanes (3 9 500 mL). The
combined organic extracts were dried over sodium sulfate
and concentrated in vacuo. A crystalline product formed was
separated from a liquid residue by filtration, washed with
hexane (2 9 100 mL) and dried to yield pure 17 (195 g,
72%) as a white solid: mp 90°C (Hexanes); MS (m/z, EI):
375 (M?–H), 333, 317, 291. Anal. calcd. for C12H14Br2O2
C 41.17, H 4.03, Br 45.65. Found C 41.32, H 3.89,
Br 45.58. IR (KBr, cm-1): 1,740, 1,720 (m(C=O)). 1H NMR
(CDCl3) d 7.47 (m, 2H), 7.36 (m, 3H), 5.41 (s, 1H, PhCH),
5.07 (m, J = 6.5 Hz, 2H, CH(CH3)2), 4.15 (d, J = 11 Hz,
2H), 3.75 (d, J = 11 Hz, 2H), 2.76 (s, 2H), 2.19 (s, 2H), 1.25
(d, 6.5 Hz); 13C NMR (CDCl3) d 171.3, 138.1, 129.0, 128.3,
126.1, 101.4, 75.4, 69.1, 47.3, 37.5, 31.6, 31.3, 21.6.
1
(mas(SO2)), 1,161 (ms(SO2)). H NMR (DMSO-d6) d 10.56
(s, 1H, NH), 8.1 (s, 1H, NH), 7.69 (d, J = 6.5 Hz, 2H),
7.48 (d, J = 6.5 Hz, 2H), 3.76 (br s, 2H), 3.66 (br s, 2H),
2.41 (s, 3H), 2.24 (m, 4H); 13C NMR (DMSO-d6) d 178.6,
156.4, 144.5, 131.3, 130.4, 128.7, 63.0, 61.1, 57.6, 42.2,
30.2, 21.6.
6-amino-2-azaspiro[3.3]heptane-6-carboxylic acid 4
Compound 14 (200 mg, 0.57 mmol) was added to solid
sodium amalgam (3.9 g) in methanol (15 mL). The reac-
tion mixture was heated at reflux for 6 h. The solution was
decanted from the liquid amalgam, and the residue was
washed with methanol (10 mL). The solvent was evapo-
rated in vacuo and the residue was dissolved in DME
(4 mL). Boc2O (0.68 g, 3.1 mmol), NEt3 (0.25 mL,
1.79 mmol) and DMAP (2 mg, 0.016 mmol) were added in
succession. Reaction mixture was stirred overnight at
ambient temperature and concentrated in vacuo. The resi-
due was taken up in CH2Cl2 (15 mL), washed with 1 N
HCl (2 9 5 mL), saturated aqueous Na2CO3 (1 9 5 mL)
and brine (1 9 5 mL), dried over Na2SO4, filtered and
concentrated to yield 15 as a yellowish oil, 0.254 g (93%,
Diisopropyl 3,3-bis(hydroxymethyl)cyclobutane-1,1-
dicarboxylate 18
To a solution of 17 (10 g, 26.6 mmol) in MeOH (100 mL),
10% Pd/C (2 g) was added, and the resulting suspension
was hydrogenated at 5 atm and ambient temperature upon
stirring for 48 h. Filtration of the catalyst and removal of
the solvent in vacuo yielded 18 (7.4 g, 96%) as a colorless
oil which was used in the next step without further puri-
1
[90% purity by H NMR), which was used in the next
step without further purification.
1
Compound 15 (0.25 g) was dissolved in DME (5 mL),
and 1 N NaOH (5 mL) was added. The mixture was stirred
overnight at ambient temperature. The resulting solution
was partitioned between Et2O (5 mL) and water (10 mL),
the aqueous layer was washed with Et2O (1 9 5 mL),
acidified with 3 N HCl to adjust pH = 1 and stirred for
fication. MS (m/z, CI) 289 (MH?). H NMR (CDCl3) d
5.04 (m, J = 6.0 Hz, 2H, CH(CH3)2), 3.70 (br. s, 4H,
CH2OH), 2.66 (br. s, 2H, CH2OH), 2.37 (s, 4H, C(CH2)2C),
1.22 (d, J = 6.0 Hz, 12H, CH(CH3)2); 13C NMR (CDCl3)
d 171.6 (COOiPr), 69.2, 68.5, 47.2 (C(COOiPr)2), 37.9
(C(CH2OH)2), 32.7 (C(CH2)2C), 21.5 (CH(CH3)2).
123

518
D. S. Radchenko et al.
Diisopropyl 3,3-bis(((methylsulfonyl)oxy)
with 2 N HCl to pH = 2. Extraction of the resulting mix-
ture with diethyl ether (3 9 5 mL), drying of the combined
organic extracts over magnesium sulfate and evaporation
of the solvent afforded dicarboxylic acid 21 (0.614 g, 93%)
as a white solid: mp 231°C (EtOH); MS (m/z): 340 (MH?).
Anal. calcd for C15H17NO6S C 53.09, H 5.05, N 4.13,
S 9.45. Found C 52.97, H 5.12, N 4.01, S 9.77. IR (KBr,
cm-1): 2,860–3,500 (m(O–H)), 1,708 (m(C=O)), 1,338
methyl)cyclobutane-1,1-dicarboxylate 19
To a solution of 18 (6.96 g, 24 mmol) in dichloromethane
(100 mL), triethylamine (10 mL, 72 mmol) was added.
The resulting mixture was cooled to -30°C, and mesyl
chloride (4.49 mL, 58 mmol) was added dropwise. After
the addition was complete, the reaction mixture was heated
to ambient temperature and stirred for 1 h, then washed
with water (1 9 50 mL), 10% aqueous citric acid
(1 9 50 mL) and brine (1 9 50 mL). The organic phase
was dried over sodium sulfate and evaporated at reduced
pressure to give dimesylate 19 (10.7 g, 100%) as a white
solid. Mp 87°C (EtOH). MS (m/z, CI) 445 (MH?). Anal.
calcd for C16H28O10S2 C 43.23, H 6.35, S 14.43. Found
C 43.07, H 6.18, S 14.51. IR (KBr, cm-1): 1,720
(m(C=O)), 1,365 (mas(SO2)), 1,274, 1,176 (ms(SO2)). 1H
NMR (CDCl3) d 5.07 (sept, J = 6.0 Hz, 2H, CH(CH3)2),
4.28 (s, 4H, CH2OSO2CH3), 3.06 (s, 6H, CH2OSO2CH3),
2.51 (s, 4H, C(CH2)2C), 1.25 (d, J = 6.0 Hz, 12H,
CH(CH3)2); 13C NMR (CDCl3) d: 170.6 (COOiPr), 70.5,
69.7, 37.4, 35.7, 32.2, 21.5 (CH(CH3)2).
1
(mas(SO2)), 1,160 (ms(SO2)). H NMR (DMSO-d6) d 12.77
(br s, 2H, COOH), 7.68 (d, J = 7.5 Hz, 2H), 7.48 (d,
J = 7.5 Hz, 2H), 3.65 (s, 4H, C(CH2)2N), 2.42 (s, 3H,
C6H4CH3), 2.31 (s, 4H, C(CH2)2C); 13C NMR (DMSO-d6)
d 172.9, 144.4, 131.6, 130.3, 128.6, 62.5, 48.0, 38.9, 32.5,
21.54.
2-[(4-methylphenyl)sulfonyl]-2-azaspiro[3.3]heptane-
6-carboxylic acid 22
Dicarboxylic acid 21 (1.58 g, 4.66 mmol) was dissolved in
pyridine (20 mL) and heated at reflux for 8 h. Then most of
the solvent was evaporated in vacuo, 2 N HCl was added to
adjust pH = 1, and the product was extracted with diethyl
ether (3 9 20 mL). The combined organic extracts were
dried over magnesium sulfate and evaporated in vacuo to
give 22 (1.29 g, 94%) as a white solid: mp 136°C (EtOH);
MS (m/z, CI) 296 (MH?). Anal. calcd for C14H17NO4S
C 56.93, H 5.80, N 4.74, S 10.86. Found C14H17NO4S
C 56.76, H 5.83, N 4.59, S 11.00. IR (KBr, cm-1): 2,560–
3,070 (m(O–H)), 1,705 (m(C=O)), 1,343 (mas(SO2)), 1,158
(ms(SO2)). 1H NMR (DMSO-d6) d 12.10 (br s, 1H, COOH),
7.67 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 3.67 (s,
2H, C(CH2)(CH2)N), 3.59 (s, 2H, C(CH2)(CH2)N), 2.78
(m, 1H, CHCOOH), 2.42 (s, 3H, C6H4CH3), 2.05 (m, 4H,
CH(CH2)2C); 13C NMR (DMSO-d6) d 176.1, 144.4, 131.4,
130.3, 128.7, 62.7, 62.2, 35.2, 34.3, 32.4, 21.6.
Diisopropyl 2-((4-methylphenyl)sulfonyl)-2-
azaspiro[3.3]heptane-6,6-dicarboxylate 20
A solution of 19 (9.17 g, 20.6 mmol), potassium carbonate
(14.2 g, 103 mmol), and tosylamide (3.7 g, 21.7 mmol) in
DMSO (50 mL) was heated at 85°C for 12 h. After cool-
ing, water (100 mL) was added, and the product was
extracted with EtOAc (3 9 50 mL). The combined organic
phases were washed with 10% aqueous citric acid (50 mL)
and brine (3 9 50 mL), dried over sodium sulfate and
evaporated in vacuo to yield 20 (8.3 g, 81%) pure enough
for the next step: mp 70°C (EtOH); MS (m/z, CI): 424
(MH?), 382, 340. IR (KBr, cm-1): 1,744, 1,722 (m(C=O)),
1
1,341 (mas(SO2)), 1,279, 1,159 (ms(SO2)), 1,102, 1,080. H
2-azaspiro[3.3]heptane-6-carboxylic acid 5
NMR (CDCl3) d 7.70 (d, J = 7.5 Hz, 2H), 7.35 (d,
J = 7.5 Hz, 2H), 4.99 (sept, J = 6.0 Hz, 2H, CH(CH3)2),
3.74 (s, 4H, C(CH2)2N), 2.61 (s, 2H, CH2), 2.49 (s, 3H,
C6H4CH3), 2.45 (s, 2H, CH2), 1.19 (d, J = 6 Hz, 12H,
CH(CH3)2); 13C NMR (CDCl3) d 170.6, 144.1, 131.6,
129.7, 128.4, 69.2, 62.1, 48.3, 41.0, 39.0, 32.5, 21.6, 21.5.
Carboxylic acid 22 (1.29 g, 4.37 mmol) was dissolved in
methanol (100 mL), and solid sodium amalgam (15 g) was
added to the solution in one portion. The reaction mixture
was refluxed for 8 h and then cooled. The solution was
decanted from the liquid amalgam, and the residue was
washed with methanol (30 mL). The solvent was evapo-
rated in vacuo, the residue was dissolved in water, and 3 N
HCl was added to adjust pH = 1. The resulting aqueous
solution was washed with diethyl ether and evaporated.
Purification of the residue by ion-exchange chromatogra-
phy (Amberlite IR-120(plus) ion-exchange resin (50 g),
5% aqueous ammonia as an eluent) yielded amino acid 5
(0.48 g, 77%): mp 297°C, dec. (EtOH–H2O). Anal. calcd
for C7H11NO2 C 59.56, H 7.85, N 9.92. Found C 59.65,
H 7.88, N 10.01. IR (KBr, cm-1): 3,459 (m(N–H)), 1,621
2-((4-methylphenyl)sulfonyl)-2-azaspiro[3.3]heptane-
6,6-dicarboxylic acid 21
To a solution of 20 (0.824 g, 1.95 mmol) in ethanol
(5 mL), a solution of sodium hydroxide (0.26 g, 6.5 mmol)
in ethanol (5 mL) was added. The resulting mixture was
refluxed for 2 h, then cooled, filtered and washed with
ethanol (2 9 2 mL) to give dipotassium salt of 21. It was
dissolved in water (5 mL), and the solution was acidified
123

Synthesis of 2-azaspiro[3.3]heptane-derived amino acids
519
Scheme 1 Retrosynthetic
analysis of amino acids 4 and 5
Scheme 2 Synthesis of amino
acid 4
(mas(COO-)), 1,569 (d(NH2?), 1,394 (ms(COO-)). 1H NMR
(D2O) d 4.07 (s, 2H, 1-CH2), 3.96 (s, 2H, 3-CH2), 2.80
(quint, J = 8.5 Hz, 1H, CHCOO), 2.39 (t, J = 11.0 Hz,
2H, 5-CHH and 7-CHH), 2.26 (t, J = 11.0 Hz, 2H, 5-CHH
and 7-CHH); 13C NMR (D2O) d 183.9 (COO), 58.0
(1-CH2), 57.2 (3-CH2), 36.8, 35.8, 34.6.
The syntheses are outlined in the Schemes 2 and 3. To
obtain the ornitine analogue 4, the dibromide 7 was
transformed to dimesylate 11 analogously to the method
reported previously by our group (Radchenko et al. 2008).
Reaction of 11 with tosyl amide under mild basic condi-
tions resulted in the construction of 2-azaspiro[3.3]heptane
ring system. Deprotection of 12 led to the formation of
ketone 131 which underwent Bucherer–Lieb reaction giv-
ing the dispirocyclic hydantoine 14. Hydrolysis of 14 by
heating with excess of the strong alkali was unsuccessful
and led to the formation of many unidentified by-products,
probably due to the azetidine ring opening. On other hand,
relatively mild condition of the hydrolysis (heating to 60°C
with 3.5 equivalents of 10% aqueous NaOH) resulted in no
reaction. Therefore, we transformed 14 to the tris-Boc-
derivative 15; compounds of that type are known to
hydrolyze under mild conditions (Wysong et al. 1996).
Indeed, two-step hydrolysis of 15 afforded the amino acid 4
Results and discussion
The construction of the 2-azaspiro[3.3]heptane core in both
4 and 5 was done by consequent closure of the cyclobutane
and azetidine rings using bis-alkylation of malonate and
tosylamide, respectively. Nevertheless, the origin of the
bis-electrophile necessary for the azetidine ring construc-
tion was different. Whereas in the case of 4 the corre-
sponding C(CH2X)2 unit originated from the malonate, in
the case of 5 the fragment was already present in the
starting molecule. Thus, isomeric dibromides 7 and 8 were
suggested to be the appropriate starting compounds for the
synthesis of 4 and 5, respectively (Scheme 1).
1
While the manuscript was in the preparation, an alternative
synthesis of 6-oxo-2-azaspiro[3.3]heptane derivative was reported
(Meyers et al. 2009).
123

520
D. S. Radchenko et al.
Scheme 3 Synthesis of amino
acid 5
which was isolated by ion-exchange chromatography
(Scheme 2).
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