Reduction of 1-nitrospiro[2.2]pentanecarboxylates: Convenient synthesis of novel polyspirocyclic cyclopropane amino acids

Article abstract of DOI:10.1055/s-2005-918514

A facile method for the preparation of a series of racemic spiropentane amino acids is described. An approach involving sequential catalytic cyclopropanation of polycyclic methylenecyclopropanes with nitrodiazoesters and reduction of the nitro group is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918514

PAPER
279
Reduction of 1-Nitrospiro[2.2]pentanecarboxylates: Convenient Synthesis of
Novel Polyspirocyclic Cyclopropane Amino Acids
Spiropentane
A
min
i
o Acid
k
s
olai V. Yashin, Elena B. Averina, Yuri K. Grishin, Tamara S. Kuznetsova,* Nikolai S. Zefirov
Moscow State University, Chemistry Department, Leninskie gory, 119992 Moscow, Russia
Fax +7(495)9390290; E-mail: kuzn@org.chem.msu.ru
Received 27 May 2005; revised 17 August 2005
method for synthesis of spiropentane amino acids via the
Abstract: A facile method for the preparation of a series of racemic
spiropentane amino acids is described. An approach involving se-
quential catalytic cyclopropanation of polycyclic methylenecyclo-
propanes with nitrodiazoesters and reduction of the nitro group is
described.
reduction of a nitro group is of particular interest due to
the presence of a rather sensitive spiropentane moiety in
substrates to be reduced. There are only two examples of
the reduction of nitro cyclopropanecarboxylates.6,7 The
first example was reported by Seebach and Häner6 using
Pd/C–H2 (1 atm) system for reduction of 1-nitrocarb-
ethoxycyclopropane, while the second example was re-
cently reported by Wurz and Charette7 about reducing a
diverse series of aryl nitrocyclopropyl carboxylates using
Zn/HCl in i-PrOH.
Key words: [1+2] cycloaddition, reductions, spiropentane a-amino
acids, carbenes/diazo compounds
Most of the known amino acids containing a cyclopropyl
group are an integral part of many biologically active
compounds.1 These compounds are of growing biological
interest, particularly as source for plant hormone ethylene
or, on the contrary, inhibitors of ethylene-forming enzyme
(1-aminocyclopropanecarboxylic acid or its derivatives).1
Cyclopropane amino acids have received extensive atten-
tion over the two last decades as conformationally restrict-
ed analogues of natural amino acids.2
It is also noteworthy to mention the absence of reports in
the literature for the reduction of nitrocarbalkoxyspiro-
pentanes.
Our approach to the synthesis of a-amino spiro[2.2]pen-
tane carboxylic acids includes as initial stage the
preparation of base precursors, 1-nitro-ethoxycarbonyl-
spiropentanes (2a–e, Table 1) from methylenecyclopro-
panes 1a–e and nitrodiazoacetate by known dirhodium(II)
tetraacetate-catalyzed cyclopropanation.5,8,9
The more strained polyspirocyclopropane amino acids are
even more reactive and might show important physiolog-
ical properties in their own right. Few precedents of bio-
active substances incorporating the spiropentane moiety
are known.3 Recently, the synthesis of amino acids con-
taining the spiropentyl group such as (+)-spiropentylgly-
cine and (+)-1-aminospiropentane carboxylic acid has
been reported.4 For instance, racemic 1-amino-
spiro[2.2]pentane carboxylic acid was prepared by the
rhodium-catalyzed cycloaddition of dimethyl diazoma-
lonate to methylenecyclopropane followed by Curtius re-
arrangement with the resulting carboxylic acid.4
The reaction of methylenecyclopropanes 1a–d with
ENDA in the presence of catalytic amounts of dirhodium
tetraacetate afforded ethyl nitrospiro[2.2]pentane carbox-
ylates 2a–d in good yields (Table 1). Only cyclic methyl-
enecyclopropane 1e gave a different result (Scheme 1).
The expected adduct 2e was obtained as by-product and
the main product was ester of hydroxamic acid 2f which
was formed as a result of the rearrangement of nitrocar-
bene into acylnitrosoacetate followed by addition to olefin
1e that was analogous to previously reported data.8b
The present work is a continuation of our program to pre-
pare the representative series of polyspirocyclopropane
amino acids. We have recently reported the synthetic pro-
tocol affording spirohexane amino acids using ammoni-
um formate in the presence of palladium on charcoal as a
‘H2’ source for the reduction of spirohexane nitrocarbox-
ylates.5 We now wish to report our results on the synthesis
The crucial stage in the synthesis of polyspirocyclic ami-
no acids is the reduction of nitro esters 2a–e into amino es-
ters 3a–e. The choice of an effective reducing agent is
important because spiropentane fragment is a strained
moiety and undergoes ring opening under the action of
various reagents.
Previously we have found that the most suitable system
for the reduction of 1-nitrospiro[2.3]hexanecarboxylates
is ammonium formate in the presence of catalytic amounts
of palladium on charcoal.5 However only nitroesters 2d
and 2e containing cyclooctane ring were reduced with this
system in good yields to give the corresponding amino es-
ters 3d,e. Nitroesters 2a and 2b under these conditions
gave complex reaction mixtures of products of small rings
opening. The results of the reduction of nitroesters 2a and
of novel polycyclic amino acids containing
a
spiro[2.2]pentane framework by the rhodium-catalyzed
[1+2] cycloaddition of ethyl nitrodiazoacetate (ENDA) to
a series of methylenecyclopropanes followed by reduc-
tion of nitrocarbethoxy adducts and subsequent hydroly-
sis. In fact, the development of an efficient and expedient
SYNTHESIS 2006, No. 2, pp 0279–0284
x
x
.
x
x
.2
0
0
5
Advanced online publication: 21.12.2005
DOI: 10.1055/s-2005-918514; Art ID: Z10305SS
© Georg Thieme Verlag Stuttgart · New York

280
N. V. Yashin et al.
PAPER
Table 1 Syntheses of Spiropentane Amino Acidsa
R4
R4 EtO2C
R4 EtO2C
R4 HO2C
NH2
NO2
NH2
ENDA
[H]
NaOH
R1
Rh2(OAc)4
A or B
EtOH
48 h
R3
R3
R3
R3
R1
R2
1 a–e
R1
R1
R2
R2
R2
4 a–e
3 a–e
2 a–e
Entry Methylene-
cyclopropane 1
Nitroester 2
Yield Amino ester 3
Method Yield
(%)
Amino acid (4)
Yield
(%)
(%)b
859
B
89
NH2
87
CO2Et
a
NH2
CO2H
CO2Et
NO2
b
CO2Et
859
dr = 3:1
CO2Et
B
91
dr = 4:1
90
dr 3:1
CO2H
NH2
NO2
NH2
c
85
dr = 3:1
B
76
dr = 8:1
85c
CO2Et
NO2
CO2Et
NH2
CO2H
NH2
d
e
24
dr = 4:1
A
A
68
dr = 5:1
70c
NO2
NH2
CO2Et
EtO2C
NH2
CO2Et
CO2H
70c
89c
87c
EtO2C
HO2C
NO2
NH2
NH2
a Reagents and conditions: A: HCO2NH4, Pd/C (10%), MeOH. B: Zn–AcOH–i-PrOH.
b Yields refer to the isolated pure products after column chromatography.
c A single diastereomer was obtained.
2c under different conditions are presented in the of oxime 6 accompanied by the hydrogenolysis of the C–
Schemes 2 and 3. C bond of small ring (Scheme 3).
Dispirononane 2c gives hydroxylamine 5 under the action Spiropentylcarbinol 7 was the only product of the reduc-
of the reducing agent. Hydroxylamine 5 was isolated in a tion of nitro ester 2a via NaBH4–Pd/C system. Clearly, the
good yield. The increase of the reaction time provides ring reduction of nitrocarbethoxyspiropentanes 2a–d was
opening. The introduction of the compounds 5 in the reac- problematic using catalytic systems on the base of palla-
tion mixture also gave the product of the ring opening.
dium.
Use of other catalytic systems containing Pd was not suc- We turned our attention to zinc–HCl system due to its suc-
cessful. Thus, the catalytic hydrogenation of nitrospiro- cess in the reduction of phenyl substituted 1-nitrocyclo-
pentane 2a in the presence of Pd/C resulted in a formation propanecarboxylates.6 Under these conditions opening of
the substituted small ring of nitroester 2a is found to take
place forming 1,1-disubstituted cyclopropane
(Scheme 3).
8
NO2
ENDA
CO2Et
O
+
NO2
NHOH
CO2Et
Rh2(OAc)4
Pd/C–HCO2NH4
CO2Et
N
MeOH
2 h, r.t.
CO2Et
HO
2f, 49 % (dr 1:1)
1e
2e, 24% (dr 4:1)
2c
5, 74% (dr 5:1)
Scheme 1
Scheme 2
Synthesis 2006, No. 2, 279–284 © Thieme Stuttgart · New York

PAPER
Spiropentane Amino Acids
281
Preparation of Compounds 2a–e; General Procedure
Me
H2–10% Pd/C
MeOH
Ethyl nitrodiazoacetate (1 mmol) was slowly added to a stirred mix-
ture of alkene 1 (5 mmol) and Rh2(OAc)4 (0.03 mmol) at 0–5 °C.
Then the reaction mixture was warmed to r.t. and stirred at r.t. for 1
h. An excess of alkene was removed under reduced pressure, the
catalyst was filtered through silica gel and the product (a colorless
oil) was purified by flash column chromatography (Et2O–PE as the
eluent, 0–30%).
CO2Et
NOH
6, 62%
EtO2C
NaBH4–10% Pd/C
THF
NO2
NO2
1-Nitrodispiro[2.0.3.1]octane-1-carboxylic Acid Ethyl Ester
(2c)
Yield: 0.191 g (85%); mixture of stereoisomers (3:1); colorless oil;
HOH2C
7, 70%
2a
Rf 0.60 (PE–EtOAc, 4:1).
2
a b
1H NMR (400 MHz, CDCl3): d (major isomer) = 1.08 (d, JH H
=
CH2Cl
CO2Et
5.7 Hz, 1 H, CHaHb), 1.22 (d, 2JH a = 5.7 Hz, 1 H, CHaHb), 1.29 (t,
b
Zn–HCl–EtOH
H
3J = 7.1 Hz, 3 H, CH3,), 1.87–2.30 (m, 6 H, cy-Bu), 1.94 (d,
2JH Hb = 5.4 Hz, 1 H, CHaHb), 2.40 (d, 2JH a = 5.4 Hz, 1 H, CHaHb),
a
b
H
4.28 (m, 3J = 7.1 Hz, 2 H, CH2O).
NO2
2
a b
1H NMR (400 MHz, CDCl3): d (minor isomer) = 1.13 (d, JH H
=
8, 63%
5.9 Hz, 1 H, CHaHb), 1.16 (d, 2JH a = 5.9 Hz, 1 H, CHaHb), 1.32 (t,
b
H
a
Scheme 3
3J = 7.1 Hz, 3 H, CH3), 1.87 (d, 2JH Hb = 5.3 Hz, 1 H, CHaHb), 1.87–
2.30 (m, 6 H, cy-Bu), 2.16 (d, JH = 5.4 Hz, 1 H, CHaHb), 4.27
2
b
a
H
(m, 3J = 7.1 Hz, 2 H, CH2O).
We succeeded in the reduction of nitrospiropentane esters
2a–c using system Zn–AcOH–i-PrOH and obtained ami-
no esters 3a–c in high yields (Table 1).
13C NMR (100 MHz, CDCl3): d (major isomer) = 13.69 (1JCH= 127
Hz, CH3), 16.78 (1JCH = 138 Hz, CH2, cy-Bu), 18.09 (1JCH = 163 Hz,
CH2, cy-Pr), 21.58 (1JCH = 168 Hz, CH2, cy-Pr), 25.19 (1JCH = 138
Hz, CH2, cy-Bu), 27.97 (Cspiro, cy-Pr, cy-Pr), 28.28 (1JCH = 135 Hz,
CH2, cy-Bu), 32.57 (Cspiro, cy-Bu, cy-Pr), 62.13 (1JCH = 149 Hz,
OCH2), 70.28 (C), 164.03 (CO2Et).
13C NMR (100 MHz, CDCl3): d (minor isomer) = 13.68 (CH3),
16.51 (CH2, cy-Bu), 17.62 (CH2, cy-Pr), 21.57 (CH2, cy-Pr), 27.11
(CH2, cy-Bu), 27.63 (CH2, cy-Bu), 28.29 (Cspiro, cy-Pr, cy-Pr), 33.63
(Cspiro, cy-Bu, cy-Pr), 62.29 (OCH2), 70.38 (C), 164.85 (CO2Et).
Finally, the amino esters 3a–e were converted into amino
acids 4a–e by saponification of ester group according to
the previously reported methods.5,8,9 The polyspiro amino
acids synthesized are shown in Table 1.
In summary, we have outlined the synthesis of unnatural
racemic spiropentane a-amino acids, containing ACC-
fragment via the [1+2]-cycloaddition of nitrodiazoacetic
ester to methylenecyclopropanes followed by the reduc-
tion of 1-nitrocarbethoxyspiropentanes. This facile and
Anal. Calcd for C11H15NO4: C, 58.66; H, 6.71. Found: C, 58.91; H,
6.62.
convenient method may be extended to a variety of 2-Nitrotricyclo[7.1.0.01,3]decane-2-carboxylic Acid Ethyl Ester
polyspirocyclopropane amino acids. Development of the
stereoselective version of this method is underway now.
(2d)
Yield: 0.061 g (24%); mixture of stereoisomers (4:1); colorless oil;
Rf 0.70 (PE–EtOAc, 4:1).
a
b
1H NMR (400 MHz, CDCl3): d (major isomer) = 0.90 (dd, 2JH H
=
NMR spectra were recorded on Bruker DPX-400 spectrometer at
r.t.; the chemical shifts (d) were measured in ppm with respect to
solvent (1H: CDCl3, d = 7.24; 13C: CDCl3, d = 77.13). Mass spectra
were taken on Finnigan MAT 95 XL instrument at 70 eV using elec-
tron impact ionization (EI) and GC–MS coupling. Analytical TLC
was carried out with Silufol silica gel plates (supported on alumi-
num); the detection was done by UV lamp (254 and 365 nm) and
chemical staining (I2 vapor). Melting points were determined on a
Electrothermal 9100 capillary apparatus and are uncorrected. Col-
umn chromatography was performed using silica gel 60 (230–400
mesh, Merck). Petroleum ether (PE) used refers to the 40–60 °C bp
fraction. All reagents except commercial products of satisfactory
quality were purified with literature procedures prior to use. Mi-
croanalyses were performed on a Karlo Erba 1106 instrument.
Compounds obtained as mixtures of diastereomers were not sepa-
rated into the single isomers. 1-Methylenespiro[2.2]pentane (1b),10
1-methylenespiro[2.3]hexane (1c),10 bicyclo[6.1.0]non-1-ene
a
b
5.5 Hz, 3JH Hc = 5.8 Hz, 1 H, CHcCHaHbCspiro), 1.02 (dd, 2JH a = 5.5
H
b
Hz, 3JH c = 9.1 Hz, 1 H, CHcCHaHbCspiro), 1.31 (t, 3J = 7.1 Hz, 3 H,
H
3
b
CH3), 2.30–1.35 (m, 11 H, cy-Oct), 2.89 (dd, JHH = 5.3 Hz,
3JHHa = 7.6 Hz, 1 H, CCHCHaHb), 4.12–4.28 (m, 2 H, OCH2).
a
b
1H NMR (400 MHz, CDCl3): d (minor isomer) = 0.81 (dd, 2JH H
=
a
b
5.5 Hz, 3JH Hc = 5.6 Hz, 1 H, CHcCHaHbCspiro), 1.04 (dd, 2JH a = 5.5
H
Hz, 3JH c = 9.5 Hz, 1 H, CHcCHaHbCspiro), 1.27 (t, 3J = 7.1 Hz, 3 H,
b
H
3
a
CH3), 1.35–2.30 (m, 11 H, cy-Oct), 2.48 (dd, JHH = 6.3 Hz,
3JHHb = 6.4 Hz, 1 H, C-CHCHaHb), 4.12–4.28 (m, 2 H, OCH2).
13C NMR (100 MHz, CDCl3): d (major isomer) = 10.40 (1JCH = 165
Hz, CH2, cy-Pr), 14.02 (1JCH = 127 Hz, CH3), 18.54 (1JCH = 160 Hz,
CH, cy-Pr), 20.25 (1JCH = 130 Hz, CH2, cy-Oct), 24.14 (CH2, cy-
Oct), 25.42 (CH2, cy-Oct), 27.89 (CH2, cy-Oct), 31.19 (CH2, cy-
Oct), 32.55 (Cspiro), 34.12 (1JCH = 164 Hz, CH, cy-Pr), 62.24 (1JCH
148 Hz, OCH2), 72.93 (C), 163.29 (CO2Et).
=
13C NMR (100 MHz, CDCl3): d (minor isomer) = 10.17 (CH2, cy-
Pr), 14.03 (CH3), 18.54 (CH, cy-Pr), 20.12 (CH2, cy-Oct), 24.30
(CH2, cy-Oct), 25.93 (CH2, cy-Oct), 27.67 (CH2, cy-Oct), 31.20
(CH2, cy-Oct), 32.56 (Cspiro), 33.09 (CH, cy-Pr), 62.61 (OCH2),
73.84 (C), 165.57 (CO2Et).
(1d),11
9-methylenebicyclo[6.1.0]nonane
(1e),12
1-nitro-
spiro[2.2]pentane-1-carboxylic acid ethyl ester (2a),9 1-nitro-
dispiro[2.0.2.1]heptane-1-carboxylic acid ethyl ester (2b)9 and
ethyl nitrodiazoacetate13 were synthesized by known procedures.
Methylenecyclopropane (1a) is commercially available.
Anal. Calcd for C13H19NO4: C, 61.64; H, 7.56. Found: C, 61.54; H,
7.58.
Synthesis 2006, No. 2, 279–284 © Thieme Stuttgart · New York

282
N. V. Yashin et al.
PAPER
1-Nitrospiro(cyclopropane-2,9¢-bicyclo[6.1.0]nonane)-1-car-
boxylic Acid Ethyl Ester (2e)
(1JCH = 161 Hz, CH2, cy-Pr), 23.77 (Cspiro), 40.08 (C), 60.66 (1JCH
149 Hz, OCH2), 175.43 (CO2Et).
=
A single diastereomer of 2e was obtained.
MS (EI, 70 eV): m/z (%) = 155 (1) [M]+, 140 (1) [M – CH3]+, 127
(12) [M – C2H4]+, 126 (100) [M – C2H5]+, 115 (9), 108 (16) [M –
NH2 – C2H5]+, 98 (17) [M – C2H4 – C2H5] +, 82 (54) [M –
CO2C2H5]+, 80 (26), 71 (8), 55 (24), 42 (14).
Yield: 0.187 g (70%); colorless oil; Rf 0.70 (PE–EtOAc, 4:1).
1H NMR (400 MHz, CDCl3): d = 0.95–1.14 (m, 2 H, cy-Oct), 1.25–
1.65 (m, 10 H, cy-Oct), 1.29 (t, 3J = 7.1 Hz, 3 H, CH3), 1.70–1.85
2
a b
(m, 2 H, cy-Oct), 1.94 (d, JH H = 5.5 Hz, 1 H, CHaHb), 2.17 (d,
1-Aminodispiro[2.0.2.1]heptane-1-carboxylic Acid Ethyl Ester
(3b)
Yield: 0.165 g (91%); mixture of diastereomers (4:1); yellow oil.
b
2JH a = 5.5 Hz, 1 H, CHaHb), 4.10–4.30 (m, 2 H, OCH2).
H
13C NMR (100 MHz, CDCl3): d = 13.94 (CH3), 19.37 (CH2, cy-Pr),
22.20 (CH), 22.85 (CH), 24.08 (CH2, cy-Oct), 24.22 (CH2, cy-Oct),
26.35 (2 × CH2, cy-Oct), 28.49 (CH2, cy-Oct), 28.54 (CH2, cy-Oct),
34.39 (Cspiro), 61.93 (OCH2), 70.23 (C), 164.78 (CO2Et).
1H NMR (400 MHz, CDCl3): d (for major isomer) = 0.51–0.78 (m,
2 H, CH2, cy-Pr), 0.78–1.02 (m, 2 H, CH2, cy-Pr), 0.82–0.95 (m, 2
3
H, CspiroCH2Cspiro, cy-Pr), 1.14 (t, J = 7.2 Hz, 3 H, CH3), 1.19 (d,
a
b
2JH Hb = 3.5 Hz, 1 H, CHaHb), 1.69 (d, 2JH a = 3.5 Hz, 1 H, CHaHb),
Anal. Calcd for C14H21NO4: C, 62.90; H, 7.92. Found: C, 62.84; H,
7.89.
H
2.26 (br s, 2 H, NH2), 3.97–4.18 (m, 2 H, CH2O).
1H NMR (400 MHz, CDCl3): d (for minor isomer) = 0.51–0.78 (m,
N-Bicyclo[6.1.0]non-2-en-1-yl-N-hydroxyoxalamic Acid Ethyl
Ester (2f)
Yield: 0.124 g (49%); mixture of stereoisomers (1.1:1); colorless
oil; Rf 0.15 (PE–EtOAc, 4:1).
2 H, CH2, cy-Pr), 0.78–1.02 (m, 2 H, CH2, cy-Pr), 0.82–0.95 (m, 2
3
H, CspiroCH2Cspiro, cy-Pr), 1.13 (t, J = 7.2 Hz, 3 H, CH3), 1.25 (d,
a
b
2JH Hb = 4.0 Hz, 1 H, CHaHb), 1.58 (d, 2JH a = 4.0 Hz, 1 H, CHaHb),
H
2.26 (br s, 2 H, NH2), 3.97–4.18 (m, 2 H, CH2O).
a
b
1H NMR (400 MHz, CDCl3): d (major isomer) = 0.50 (dd, 2JH H
=
13C NMR (100 MHz, CDCl3): d (for major isomer) = 3.36 (CH2, cy-
Pr), 4.81 (CH2, cy-Pr), 12.96 (CH2, cy-Pr), 14.22 (CH3), 15.41
(Cspiro), 22.89 (CH2, cy-Pr), 28.06 (Cspiro), 41.48 (C), 60.63 (OCH2),
175.21 (CO2Et).
13C NMR (100 MHz, CDCl3): d (for minor isomer) = 4.23 (CH2, cy-
Pr), 4.84 (CH2, cy-Pr), 10.36 (CH2, cy-Pr), 14.39 (CH3), 16.17
(Cspiro), 22.90 (CH2, cy-Pr), 29.13 (Cspiro), 40.23 (C), 60.54 (OCH2),
175.19 (CO2Et).
MS (EI, 70 eV): m/z (%) = 181 (1) [M]+, 166 (2) [M – CH3]+, 154
(2) [M – C2H4]+, 152 (10) [M – C2H5]+, 134 (3), 124 (6) [M – C2H4
– C2H5]+, 109 (7), 108 (100) [M – CO2C2H5]+, 106 (17), 93 (11), 91
(7), 81 (11), 79 (14).
a
6.5 Hz, 3JH Hc = 7.6 Hz, 1 H, CHcCHaHbC), 1.05–0.85 (m, 1 H, cy-
3
Pr), 1.38 (t, J = 7.1 Hz, 3 H, CH3), 1.45–2.30 (m, 8 H, cy-Oct),
2.61–2.82 (m, 1 H, cy-Oct), 4.26 (m, 2 H, CH2O), 5.64 (d, 3J = 11.8
Hz, 1 H, CHa=CHC), 8.1 (br s, 1 H, NOH).
a
b
1H NMR (400 MHz, CDCl3): d (minor isomer) = 0.57 (dd, 2JH H
=
a
6.1 Hz, 3JH Hc = 6.6 Hz, 1 H, CHcCHaHbC), 1.05–0.85 (m, 1 H, cy-
3
Pr), 1.32 (t, J = 7.1 Hz, 3 H, CH3), 1.45–2.30 (m, 8 H, cy-Oct),
2.61–2.82 (m, 1 H, cy-Oct), 4.37 (m, 3J = 7.1 Hz, 2 H, CH2O), 5.72
3
a
(d, JHH = 11.6 Hz, 1 H, CHa=CHC), 5.81–5.96 (m, 1 H,
CH2CH=CH), 8.1 (br s, 1 H, NOH).
13C NMR (100 MHz, CDCl3): d (major isomer) = 14.08 (1JCH = 129
Hz, CH3), 20.90 (1JCH = 162 Hz, CH2, cy-Pr), 22.77 (1JCH = 125 Hz,
CH2, cy-Oct), 26.04 (1JCH = 159, CH, cy-Pr), 28.26 (1JCH = 125 Hz,
1-Aminodispiro[2.0.3.1]octane-1-carboxylic Acid Ethyl Ester
(3c)
Yield: 0.148 g (76%); mixture of diastereomers (8:1); yellow oil.
CH2, cy-Oct), 29.53 (1JCH = 123 Hz, CH2, cy-Oct), 29.65 (1JCH
=
123 Hz, CH2, cy-Oct), 42.14 (C), 62.78 (1JCH = 149 Hz, OCH2),
121.93 (1JCH = 161 Hz, CH=), 137.58 (1JCH = 152 Hz, CH=), 157.14
(C=O), 161.62 (C=O).
1H NMR (400 MHz, CDCl3): d (for major isomer) = 0.70 (d,
a
b
2JH Hb = 5.2 Hz, 1 H, CHaHb), 0.73 (d, 2JH a = 5.2 Hz, 1 H, CHaHb),
13C NMR (100 MHz, CDCl3): d (minor isomer) = 13.99 (1JCH = 127
Hz, CH3), 20.74 (CH2, cy-Pr), 23.96 (CH2, cy-Oct), 26.33 (CH, cy-
Pr), 28.58 (CH2, cy-Oct), 29.54 (CH2, cy-Oct), 29.64 (CH2, cy-Oct),
41.62 (C), 62.30 (1JCH = 150 Hz, OCH2), 122.29 (1JCH = 161 Hz,
CH=), 137.16 (1JCH = 145 Hz, CH=), 160.97 (C=O), 163.65 (C=O).
H
1.29 (t, 3J = 7.1 Hz, 3 H, CH3), 1.16 (d, 2JH Hb = 3.4 Hz, 1 H, CHaHb),
a
1.41 (d, 2JH = 3.4 Hz, 1 H, CHaHb), 1.55–2.32 (m, 6 H, cy-Bu),
b
a
H
2.65 (br s, 2 H, NH2), 3.91–4.17 (m, 2 H, CH2O).
1H NMR (400 MHz, CDCl3): d (for minor isomer) = 0.42 (d,
2JH Hb = 5.0 Hz, 1 H, CHaHb), 0.59 (d, 2JH a = 5.0 Hz, 1 H, CHaHb),
a
b
H
Anal. Calcd for C13H19NO4: C, 61.64; H, 7.56; N, 5.53. Found: C,
61.56; H, 7.86; N, 5.69.
1.29 (t, 3J = 7.1 Hz, 3 H, CH3), 1.38 (d, 2JH Hb = 4.1 Hz, 1 H, CHaHb),
a
b
a
1.53 (d, 2JH = 4.1 Hz, 1 H, CHaHb), 1.55–2.32 (m, 6 H, cy-Bu),
H
2.65 (br s, 2 H, NH2), 3.91–4.17 (m, 2 H, CH2O).
Reduction for Preparation of Amino Esters 3a–c via Zn–AcOH
System; General Procedure
13C NMR (100 MHz, CDCl3): d (for major isomer) = 14.22 (CH3),
16.83 (CH2, cy-Bu), 18.51 (CH2, cy-Pr), 22.27 (CH2, cy-Pr), 27.08
(CH2, cy-Bu), 27.46 (Cspiro, cy-Pr, cy-Pr), 29.09 (CH2, cy-Bu), 31.87
(Cspiro, cy-Bu, cy-Pr), 42.28 (C), 60.61 (OCH2), 175.37 (CO2Et).
13C NMR (100 MHz, CDCl3): d (for minor isomer) = 14.06 (CH3),
16.57 (CH2, cy-Bu), 18.97 (CH2, cy-Pr), 22.74 (CH2, cy-Pr), 27.08
(CH2, cy-Bu), 27.67 (Cspiro, cy-Pr, cy-Pr), 28.08 (CH2, cy-Bu), 34.29
(Cspiro, cy-Bu, cy-Pr), 40.46 (C), 60.75 (OCH2), 172.83 (CO2Et).
To the stirred mixture of 1-nitrocyclopropanecarboxylate (1 mmol),
AcOH (2.5 mL), i-PrOH (5 mL) and zinc dust (1.95 g, 30 mmol)
were added. The resulting mixture was stirred for 6 h at r.t., treated
with sat. NaHCO3 solution to pH 7 and then filtered. The filtrate was
extracted with CH2Cl2 (2 × 10 mL) and the organic extract was dried
over MgSO4. After removing the solvent, pure amino esters (> 90%
pure according to 1H and 13C NMR data) were obtained.
MS (EI, 70 eV): m/z (%) = 195 (1) [M]+, 180 (1) [M – CH3]+, 167
(20) [M – C2H4]+, 166 (35) [M – C2H5]+, 138 (94) [M – C2H4 –
C2H5] +, 124 (10), 122 (71) [M – CO2C2H5] +, 120 (73), 106 (22), 94
(100), 93 (32), 79(28), 77 (23), 67 (20), 42 (26), 29 (21).
1-Aminospiro[2.2]pentane-1-carboxylic Acid Ethyl Ester (3a)
Yield: 0.138 g (89%); yellow oil.
1H NMR (400 MHz, CDCl3): d = 0.78–1.02 (m, 4 H, 2 × CH2, cy-
Pr), 1.24 (t, 3J = 7.1 Hz, 3 H, CH3), 1.31 (d, 2JH Hb = 4.9 Hz, 1 H,
a
CHaHb), 1.80 (d, 2JH a = 4.9 Hz, 1 H, CHaHb), 2.30 (br s, 2 H, NH2),
b
H
Reduction for Preparation of Compounds 3d,e and 5 via
HCO2NH4–Pd/C System; General Procedure
Ammonium formate (10 mmol) was added to a stirred mixture of 1-
4.07–4.27 (m, 2 H, CH2O).
13C NMR (100 MHz, CDCl3): d = 4.98 (1JCH = 163 Hz, CH2, cy-Pr),
7.17 (1JCH = 162 Hz, CH2, cy-Pr), 14.30 (1JCH = 127 Hz, CH3), 22.81
nitrocylopropanecarboxylate (1 mmol) and 10% Pd/C (10 mol%) in
Synthesis 2006, No. 2, 279–284 © Thieme Stuttgart · New York

PAPER
Spiropentane Amino Acids
283
b
anhyd EtOH (10 mL). The reaction mixture was stirred for 40 h at
r.t. and the catalyst was removed by filtering. Then the solvent was
evaporated under reduced pressure and pure amino esters were ob-
tained.
1.88 (dd, 2JH a = 4.9Hz, 1 H, CHaHb), 1.90–2.36 (m, 6 H, cy-Bu),
H
4.10–4.35 (m, 2 H, CH2O).
13C NMR (100 MHz, CD3OD): d (for major isomer) = 13.53 (CH3),
16.24 (CH2, cy-Bu), 18.26 (CH2, cy-Pr), 19.27 (CH2, cy-Pr), 27.20
(CH2, cy-Bu), 27.95 (Cspiro, cy-Pr, cy-Pr), 28.59 (CH2, cy-Bu), 33.54
(Cspiro, cy-Bu, cy-Pr), 50.84 (C), 60.84 (OCH2), 173.33 (CO2Et).
MS (EI, 70 eV): m/z (%) = 211 (2) [M]+, 194 (1) [M – OH]+, 183 (8)
[M – C2H4]+, 182 (42) [M – C2H5]+, 166 (48) [M – C2H4 – OH]+, 148
(11), 138 (26) [M – CO2C2H5]+, 120 (76), 110 (29), 93 (52), 79 (34),
77 (23), 71 (48), 41 (43), 29 (100).
2-Aminotricyclo[7.1.0.01,3]decane-2-carboxylic Acid Ethyl
Ester (3d)
Yield: 0.152 g (68%); mixture of diastereomers (5:1); yellow oil.
1H NMR (400 MHz, CDCl3): d (for major isomer) = 0.65 (dd,
b
c
2
a b
3JH
= 5.0 Hz, JH
= 4.7 Hz, 1 H, CH2, cy-Pr), 0.89 (dd,
H
H
b
a
3JH c = 8.5 Hz, 2JH Hb = 4.7 Hz, 1 H, CH2, cy-Pr), 1.26 (t, 3J = 7.1
H
Hz, 3 H, CH3), 1.29–1.93 (m, 14 H, cy-Oct, NH2), 4.05–4.22 (m, 2
H, OCH2).
Hydrolysis for Preparation of Amino Esters 4a–e; General
Procedure
1H NMR (400 MHz, CDCl3): d (for minor isomer) = 0.70 (dd,
1-Aminocyclopropanecarboxylate (1 mmol) was added to a 1 M
EtOH solution of NaOH (2 mL). The resulting mixture was stirred
for 48 h at r.t. and then acidified with 0.2 M HCl to pH 3. The sol-
vent was evaporated under reduced pressure; the residue was dis-
solved in the distilled water (2 mL), put on a Dowex 50 ion-
exchange column and eluted with a 0.9 N NH3 solution. The solvent
was evaporated and crystalline residue was recrystallized from
EtOH–H2O (1:1).
a
a
2JH Hb = 4.2 Hz, 3JH Hc = 4.4 Hz, 1 H, CH2, cy-Pr), 0.81–0.86 (m, 1
H, CH2, cy-Pr), 1.27 (t, 3J = 7.1 Hz, 3 H, CH3), 1.29–1.93 (m, 14 H,
cy-Oct, NH2), 4.05–4.22 (m, 2 H, OCH2).
13C NMR (100 MHz, CDCl3): d (for major isomer) = 8.28 (CH2, cy-
Pr), 14.51 (CH3), 18.06 (CH, cy-Oct, cy-Pr), 20.50 (CH2, cy-Oct),
24.43 (CH2, cy-Oct), 24.79 (Cspiro), 26.45 (CH2, cy-Oct), 27.83
(CH2, cy-Oct), 31.14 (CH2, cy-Oct), 37.90 (CH, cy-Oct, cy-Pr),
42.53 (C), 60.63 (OCH2), 174.46 (CO2Et).
13C NMR (100 MHz, CDCl3): d (for minor isomer) = 7.89 (CH2, cy-
Pr), 14.71 (CH3), 18.75 (CH, cy-Oct, cy-Pr), 20.23 (CH2, cy-Oct),
24.27 (CH2, cy-Oct), 26.60 (CH2, cy-Oct), 29.65 (CH2, cy-Oct),
31.16 (CH2, cy-Oct), 35.27 (CH, cy-Oct, cy-Pr), 43.72 (C), 62.49
(OCH2).
In the 13C NMR spectrum of minor isomer of 3d the signals of Cspiro
and CO2Et carbon atoms are not observed.
MS (EI, 70 eV): m/z (%) = 223 (2) [M]+, 195 (1), 194 (61) [M –
C2H5]+, 180 (4), 176 (8), 166 (4) [M – C2H4 – C2H5]+, 152 (12), 150
(100) [M – CO2C2H5]+, 149 (25), 148 (55), 128 (13), 120 (12), 112
(11), 106 (34), 100 (12), 94 (30), 91 (36), 79 (33), 67 (30), 54 (34),
41 (45), 28 (35).
1-Aminospiro[2.2]pentane-1-carboxylic Acid (4a)
Yield: 0.111 g (87%); a white crystalline; mp 152–154 °C (Lit.4 mp
156 °C).
1H NMR (400 MHz, D2O): d = 1.32–1.47 (m, 4 H, 2 × CH2, cy-Pr),
a
a
1,29 (d, 2JH Hb = 6.1 Hz, 1 H, CHaHb), 2.12 (d, 2JH Hb = 6.1 Hz, 1 H,
CHaHb).
13C NMR (100 MHz, D2O): d = 5.97 (1JCH = 163 Hz, CH2, cy-Pr),
6.80 (1JCH = 169 Hz, CH2, cy-Pr), 19.64 (1JCH = 168 Hz, CH2, cy-
Pr), 22.53 (Cspiro), 39.08 (C), 172.81 (COOH).
1-Aminodispiro[2.0.2.1]heptane-1-carboxylic Acid (4b)
Yield: 0.138 g (90%); mixture of stereoisomers (3:1); white crys-
tals; mp 156–158 °C.
1H NMR (400 MHz, D2O): d (for major isomer) = 0.85–1.20 (m, 6
2-Aminotricyclo[7.1.0.01,3]decane-2-carboxylic Acid Ethyl
Ester (3e)
Yield: 0.211 g (89%); yellow oil.
a
b
b a
H, cy-Pr), 1.85 (d, 2JH H = 6.3 Hz, 1 H, CHaHb), 2,16 (d, 2JH
=
H
6.3 Hz, 1 H, CHaHb).
1H NMR (400 MHz, D2O): d (for minor isomer) = 0.85–1.20 (m, 6
1H NMR (400 MHz, CDCl3): d = 0.85–2.03 (m, 16 H, cy-Oct, NH2),
a
b
b a
H
H, cy-Pr), 1.97 (d, 2JH H = 6.2 Hz, 1 H, CHaHb), 2.07 (d, 2JH
=
a
1.26 (t, 3J = 7.2 Hz, 3 H, CH3), 1.54 (d, 2JH Hb = 5.5 Hz, 1 H, CHaHb),
6.2 Hz, 1 H, CHaHb).
b
1.72 (d, 2JH a = 5.5 Hz, 1 H, CHaHb), 4.10–4.40 (m, 2 H, OCH2).
H
13C NMR (100 MHz, D2O): d (for major isomer) = 4.73 (CH2, cy-
Pr), 4.99 (CH2, cy-Pr), 12.67 (CH2, cy-Pr), 15.21 (Cspiro), 18.98
(CH2, cy-Pr), 26.64 (Cspiro), 39.93 (C), 172.55 (COOH).
13C NMR (100 MHz, D2O): d (for minor isomer) = 3.68 (CH2, cy-
Pr), 4.89 (CH2, cy-Pr), 10.70 (CH2, cy-Pr), 15.38 (Cspiro), 18.73
(CH2, cy-Pr), 26.49 (Cspiro), 38.77 (C), 172.56 (COOH).
13C NMR (100 MHz, CDCl3): d = 14.90 (CH3), 17.53 (CH2, cy-Pr),
21.90 (CH, cy-Oct, cy-Pr), 23.07 (CH, cy-Oct, cy-Pr), 25.55 (CH2,
cy-Oct), 25.65 (CH2, cy-Oct), 27.71 (CH2, cy-Oct), 27.82 (CH2, cy-
Oct), 30.10 (2 × CH2, cy-Oct), 32.35 (Cspiro), 40.50 (C), 62.99
(OCH2), 172.17 (CO2Et).
MS (EI, 70 eV): m/z (%) = 237 (2) [M]+, 210 (1), 209 (12), 208
(100) [M – C2H5]+, 191 (5), 190 (8), 180 (4) [M – C2H4 – C2H5]+,
165 (9), 164 (53) [M – CO2C2H5] +, 152 (5), 134 (6), 120 (13), 106
(12), 94 (22), 79 (28), 71 (11), 67 (24), 55 (30), 41 (24).
Anal. Calcd for C8H11NO2: C, 62.73; H, 7.24. Found: C, 62.59; H,
7.11.
1-Aminodispiro[2.0.3.1]octane-1-carboxylic Acid (4c)
Only major isomer of amino ester 3c was put into the hydrolysis.
1-Hydroxyaminodispiro[2.0.3.1]octane-1-carboxylicAcidEthyl
Ester (5)
Yield: 0.156 g (74%); mixture of diastereomers (5:1); yellow oil.
Yield: 0.142 g (85%); white crystals; mp 168–170 °C.
2
a b
1H NMR (100 MHz, D2O): d = 1.38 (d, JH H = 5.6 Hz, 1 H,
1H NMR (400 MHz, CD3OD): d (for major isomer) = 0.84 (d,
b
a
CHaHb), 1.49 (d, 2JH a = 5.6 Hz, 1 H, CHaHb), 1.96 (d, 2JH Hb = 6.1
H
a
b
2JH Hb = 5.2 Hz, 1 H, CHaHb,), 0.90 (d, 2JH a = 5.2 Hz, 1 H, CHaHb),
b
Hz, 1 H, CHaHb), 2.07 (d, 2JH a = 6.1 Hz, 1 H, CHaHb), 2.10–2.55
H
H
1.22 (t, 3J = 7.1 Hz, 3 H, CH3), 1.57 (d, 2JH Hb = 4.1 Hz, 1 H, CHaHb),
a
(m, 6 H, cy-Bu).
1.72 (d, 2JH = 4.1 Hz, 1 H, CHaHb), 1.90–2.36 (m, 6 H, cy-Bu),
b
a
H
13C NMR (100 MHz, D2O): d = 15.79 (CH2), 17.95 (CH2), 18.36
(CH2), 26.84 (CH2, cy-Bu), 27.49 (Cspiro), 27.91 (CH2, cy-Bu),
28.61 (Cspiro), 39.63 (C), 171.97 (COOH).
4.10–4.35 (m, 2 H, CH2O).
1H NMR (400 MHz, CD3OD): d (for minor isomer) = 0.99 (d,
a
b
2JH Hb = 5.6 Hz, 1 H, CHaHb), 1.02 (d, 2JH a = 5.6 Hz, 1 H, CHaHb),
H
1.34 (t, 3J = 7.1 Hz, 3 H, CH3), 1.46 (d, 2JH Hb = 4.9 Hz, 1 H, CHaHb),
a
Anal. Calcd for C9H13NO2: C, 64.65; H, 7.84. Found: C, 64.79; H,
7.46.
Synthesis 2006, No. 2, 279–284 © Thieme Stuttgart · New York

284
N. V. Yashin et al.
PAPER
2-Aminotricyclo[7.1.0.01,3]decane-2-carboxylic Acid (4d)
Yield: 0.137 g (70%); white crystals; mp 195–197 °C;
yield crude 8 (0.198 g), which was than isolated by column chroma-
tography (SiO2, PE–EtOAc, 4:1).
1H NMR (400 MHz, D2O–CF3CO2H, 40:1): d = 0.76 (dd, 2JH H
=
Yield: 0.139 g (63%); slightly yellow oil; Rf 0.45 (PE–EtOAc, 4:1).
a
b
a
5.0 Hz, 3JH Hc = 5.2, 1 H, cy-Pr), 0.98–1.60 (m, 13 H, cy-Oct, cy-Pr).
1H NMR (400 MHz, CDCl3): d = 0.83–0.95 (m, 2 H, CH2, cy-Pr),
It was not possible to register 13C NMR spectrum and establish iso-
mer ratio of amino acid 4d owing to its poor solubility.
1.03–1.09 (m, 1 H, CH2, cy-Pr), 1.12–1.21 (m, 1 H, CH2, cy-Pr),
3
2
a
b
1.31 (t, J = 7.2 Hz, 3 H, CH3), 3.61 (d, JH = 12.3 Hz, 1 H,
H
CHaHbCl), 3.80 (d, 2JH a = 12.3 Hz, 1 H, CHaHbCl), 4.18–4.36 (m,
b
H
Anal. Calcd for C12H19NO2: C, 67.66; H, 8.78. Found: C, 67.52; H,
8.91.
2 H, CH2O), 5.07 (s, 1 H, CH).
13C NMR (100 MHz, CDCl3): d = 13.30 (1JCH = 165 Hz, CH2, cy-
Pr), 13.69 (1JCH = 128 Hz, CH3), 14.05 (1JCH = 166 Hz, CH2, cy-Pr),
23.00 (C), 49.84 (1JCH = 149 Hz, CH2Cl), 63.26 (1JCH = 149 Hz,
OCH2), 90.36 (1JCH = 151 Hz, CH), 163.23 (CO2Et).
1-Aminospiro[cyclopropane-2,9¢-bicyclo[6.1.0]nonane]-1-car-
boxylic Acid (4e)
Yield: 0.182 g (87%); white crystals; mp 189–190 °C.
1H NMR (400 MHz, D2O–CF3CO2H, 10:1): d = 0.98–1.60 (m, 14
Anal. Calcd for C8H12NO4Cl: C, 43.35; H, 5.46. Found: C, 43.21;
H, 5.30.
a
b a
H, cy-Oct), 1.51 (d, 2JH Hb = 5.9 Hz, 1 H, CHaHb), 1.75 (d, 2JH
=
H
5.9 Hz, 1 H, CHaHb).
13C NMR (100 MHz, D2O–CF3CO2H, 10:1): d = 16.62 (CH2, cy-
Pr), 21.21 (cy-Oct), 22.08 (cy-Oct), 24.08 (cy-Oct), 24.55 (cy-Oct),
26.52 (cy-Oct), 26.64 (cy-Oct), 28.83 (cy-Oct), 28.94 (cy-Oct),
31.30 (Cspiro), 39.61 (C), 173.58 (COOH).
Acknowledgment
This work was supported by the Russian Foundation of Basic
Research (Project 05-03-32906-a) and the Ministry of Education
and Science of Russian Federation (Project MK-3156.2005.3).
Anal. Calcd for C12H19NO2: C, 68.87; H, 9.15. Found: C, 68.52; H,
8.91.
References
Hydroxyimino(1-methylcyclopropyl)acetic Acid Ethyl Ester (6)
A mixture of nitroester 2a (180 mg, 1 mmol) and 10% Pd/C in an-
hyd MeOH(15 mL) was stirred at r.t. under H2 (1 atm) for 24 h. The
catalyst was filtered, the solvent was evaporated under reduced
pressure and the colorless oil obtained was purified by column chro-
matography (SiO2, PE–EtOAc, 2:1).
(1) (a) Salaun, J.; Baird, M. S. Curr. Med. Chem. 1995, 2, 511.
(b) Pirrung, M. C.; McGeehan, G. M. Angew. Chem., Int. Ed.
Engl. 1985, 24, 1044; Angew. Chem. 1985, 97, 1074.
(c) Mitchell, R. E.; Pirrung, M. C.; McGeehan, G. M.;
Gerard, M. S. Phytochemistry 1987, 26, 2695. (d)Stammer,
C. H. Tetrahedron 1990, 46, 2231. (e) Burgess, K.; Lim, D.;
Ho, K.-K.; Ke, C.-Y. J. Org. Chem. 1994, 59, 2179.
(2) Pellicciari, R.; Marinozzi, M.; Camaioni, E.; Nunez, M.;
Costantino, G.; Gasparini, F.; Giorgi, G.; Macchiarulo, A.;
Subramanian, N. J. Org. Chem. 2002, 67, 5497.
(3) (a) Tserng, K. Y.; Jin, S.-J.; Hoppel, C. L. Biochemistry
1991, 30, 10755. (b) Li, D.; Zhou, H.-Q.; Dakoji, S.; Shin,
I.; Oh, E.; Liu, H.-W. J. Am. Chem. Soc. 1998, 120, 2008.
(c) Guan, H.-P.; Ksebati, M. B.; Cheng, Y.-C.; Drach, J. C.;
Kern, E. R.; Zemlichka, J. J. Org. Chem. 2000, 65, 1280.
(4) de Meijere, A.; Ernst, K.; Zuck, B.; Brandl, M.;
Kozhushkov, S. I.; Tamm, M.; Yufit, D. S.; Howard, J. A.;
Labahn, T. Eur. J. Org. Chem. 1999, 3105.
Yield: 0.106 g (62%); white crystals; mp 45 °C; Rf 0.10 (SiO2, PE–
EtOAc, 4:1).
1H NMR (400 MHz, CDCl3): d = 0.62–0.71 (m, 2 H, CH2, cy-Pr),
0.77–0.84 (m, 2 H, CH2, cy-Pr), 1.29 (s, 3 H, CH3), 1.34 (t, 3J = 7.1
3
Hz, 3 H, CH3), 4.28 (q, J = 7.1 Hz, 2 H, CH2), 9.8 (br s, 1 H,
=NOH).
13C NMR (100 MHz, CDCl3): d = 13.62 (2 × CH2, cy-Pr), 14.26
(CH3CH2), 21.67 (CH3C), 22.88 (C), 61.71 (OCH2), 154.03 (C=N),
163.42 (CO2Et).
Anal. Calcd for C8H13NO3: C, 56.13; H, 7.65; N, 8.18. Found: C,
56.00; H, 7.40; N, 8.12.
(5) Yashin, N. V.; Averina, E. B.; Gerdov, S. M.; Kuznetsova,
T. S.; Zefirov, N. S. Tetrahedron Lett. 2003, 44, 8241.
(6) Seebach, D.; Häner, R. Chimia 1985, 39, 356.
(7) Wurz, R. P.; Charette, A. B. J. Org. Chem. 2004, 69, 1262.
(8) (a) O’Bannon, P. E.; Dailey, W. P. Tetrahedron Lett. 1989,
30, 4197. (b) O’Bannon, P. E.; Dailey, W. P. Tetrahedron
1990, 46, 7341. (c) O’Bannon, P. E.; Dailey, W. P. J. Org.
Chem. 1989, 54, 3096.
(9) Ivanova, O. A.; Yashin, N. V.; Averina, E. B.; Grishin, Y.
K.; Kuznetsova, T. S.; Zefirov, N. S. Russ. Chem. Bull. 2001,
2101.
(10) Zefirov, N. S.; Lukin, K. A.; Kozhushkov, S. I.; Kuznetsova,
T. S.; Domarev, A. M.; Sosonkin, I. M. Zh. Org. Khim. 1989,
25, 312; Chem. Abstr. 1989, 111, 194165.
(11) Osborn, C. L.; Shields, T. C.; Shoulders, B. A.; Krause, J. F.;
Cortes, H. V.; Gardner, P. D. J. Am. Chem. Soc. 1965, 87,
3158.
(12) Kuznetsova, T. S.; Averina, E. B.; Kokoreva, O. V.; Zefirov,
A. N.; Grishin, Y. K.; Zefirov, N. S. Russ. J. Org. Chem.
2000, 36, 205.
(1-Nitrospiro[2.2]pent-1-yl)methanol (7)
To the mixture of nitroester 2a (130 mg, 0.75 mmol) and 10% Pd/C
(30 mg, 10 mol%) in THF (4 mL) at 0 °C NaBH4 (70 mg, 1.75
mmol) was added. The resulting mixture was stirred for 2 h. Then
the catalyst was filtered and the solvent was evaporated under re-
duced pressure.
Yield: 0.075 g (70%); yellow oil.
1H NMR (400 MHz, CDCl3): d = 0.91–0.99 (m, 1 H, CH2, cy-Pr),
1.01–1.05 (m, 1 H, CH2, cy-Pr), 1.17–1.32 (m, 2 H, CH2, cy-Pr),
a
b
1.81 (d, 2JH Hb = 5.4 Hz, 1 H, CHaHbCspiro), 2.34 (d, 2JH a = 5.4 Hz,
H
a
1 H, CHaHbCspiro), 3.96 (d, 2JH Hb = 13.8 Hz, 1 H, CHaHbOH), 4.29
b
(d, 2JH a = 13.8 Hz, 1 H, CHaHbOH).
H
13C NMR (100 MHz, CDCl3): d = 6.98 (CH2, cy-Pr), 7.86 (CH2, cy-
Pr), 23.25 (CCH2Cspiro), 27.76 (Cspiro), 63.07 (CH2OH), 71.70 (C).
(1-Chloromethylcyclopropyl)nitroacetic Acid Ethyl Ester (8)
To the mixture of nitroester 2a (0.185 g, 1 mmol), EtOH (5 mL),
20% aq HCl (0.44 g, 2.4 mmol) and zinc dust (1.3 g, 20 mmol) were
slowly added. The reaction mixture was stirred for 2 h at r.t. After
filtration, the solvent was evaporated under reduced pressure to
(13) Charette, A. B.; Wurz, R. P.; Ollevier, T. J. Org. Chem.
2000, 65, 9252.
Synthesis 2006, No. 2, 279–284 © Thieme Stuttgart · New York