Catalytic cyclopropanation of methylenecyclobutanes using ethyl nitrodiazoacetate. Synthesis of spirohexane amino acids

Article abstract of DOI:10.1016/j.tetlet.2003.09.083

The reaction of ethyl nitrodiazoacetate with a series of methylenecyclobutanes was studied and both [1+2]- and [2+3]-cycloaddition pathways were observed depending on olefin structure. Amino acids of a spirohexane type were synthesized from methylenecyclobutanes by a three-step synthesis.

Full text of DOI:10.1016/j.tetlet.2003.09.083

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8241–8244
Catalytic cyclopropanation of methylenecyclobutanes using ethyl
nitrodiazoacetate. Synthesis of spirohexane amino acids
Nikolai V. Yashin, Elena B. Averina, Sergei M. Gerdov, Tamara S. Kuznetsova* and
Nikolai S. Zefirov
Department of Chemistry, Moscow State University, 119899 Moscow, Russia
Received 15 July 2003; revised 2 September 2003; accepted 11 September 2003
Abstract—The reaction of ethyl nitrodiazoacetate with a series of methylenecyclobutanes was studied and both [1+2]- and
[2+3]-cycloaddition pathways were observed depending on olefin structure. Amino acids of a spirohexane type were synthesized
from methylenecyclobutanes by a three-step synthesis.
© 2003 Elsevier Ltd. All rights reserved.
As a part of our continuing studies devoted to the
triangulanes and their derivatives1 as well as to the
ligands of glutamate receptors2 we have now carried
out research on the synthesis of novel polycyclic amino
acids, containing a cyclopropane framework. In fact,
cyclopropane analogues of physiologically active com-
pounds can be considered as conformationally
restricted analogues, with potentially interesting biolog-
ical activities (examples for ligands of glutamate recep-
tors, see2a,3).
Transition metal-catalyzed cyclopropanation of alkenes
with nitro diazoesters4 (Path A) seemed to be a direct
approach for preparation of 1-nitrocyclopropanecar-
boxylates of type 2. Starting ethyl nitrodiazoacetic ester
(1, ENDA) is readily available and can be easily pre-
pared by a diazotransfer reaction of ethyl diazoacetate
with triflyl azide.5 In general, 1-nitrocylopropanecar-
boxylates (Path A) can be considered an amino acid
equivalent after reduction of the nitro group.
However, there is one obvious possible complication:
analysis of the resonance structures of transient nitro-
carboethoxycarbene 4 indicates that it can be consid-
ered as a 1,3-dipole 4b and, hence, could participate in
[2+3]-cycloaddition (Path B) to give an isoxazoline
structure. To the best of our knowledge, this pathway
has not been observed in cycloaddition reactions of 1;
however, the thermal rearrangement of nitrocyclo-
propanes 2 into isoxazolines 3 is known.4 In fact, this
type of [1,3]-sigmatropic rearangement6 of cyclo-
propane systems connected to a double bond, is well
documented.7
The development of an efficient and expedient method
for the synthesis of cyclopropane amino acids via
reduction of a nitro group is of particular interest.
In the present study, we have examined (i) this synthetic
approach for the preparation of some unnatural amino
acids containing a spirohexane moiety and (ii) the
structural dependence of Path A versus Path B for some
cyclopropane/cyclobutane containing olefins.
Keywords: ethyl nitrodiazoacetate; spirohexane amino acids; [1+2]-
cycloaddition; [2+3]-cycloaddition; 1-ethoxycarbonyl-nitropolyspiro-
cycloalkanes.
* Corresponding author. Fax: (+) 7-095-9390290; e-mail: kuzn@
org.chem.msu.ru
First, we studied the cycloaddition reactions of ENDA
1, with olefins 5a–c of the methylenecyclobutane series
(Table 1).
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.083

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N. V. Yashin et al. / Tetrahedron Letters 44 (2003) 8241–8244
Table 1.
The reaction of ENDA with methylenecyclobutanes 5
in the presence of catalytic amounts of dirhodium
tetraacetate afforded ethyl nitrospiro[2.3]hexanecar-
boxylates 6 in good yields (Table 1) in accordance with
Path A ([1+2]-cycloaddition).8 We note first, that bicy-
clobutylidene 5b gives the corresponding tricyclic
adduct 6b as a single product (Table 1) and, hence, even
the tetrasubstituted C=C double bond in 5b possesses
sufficient reactivity for addition of the transient nitro-
carbethoxycarbenoid. Second, the presence of the elec-
tron-withdrawing ester group at C-3 of the cyclobutane
ring of alkene 5c does not significantly influence the
product yield, nitroester 6c being obtained in high yield
(Table 1) as a mixture of two diastereomers in a ratio of
1.6:1 (according to NMR data).
The compound 8 can also be considered as a vinyl
cyclopropane, and following literature precedents,6,7 it
is possible to speculate that exactly this fragment is
responsible for the observed result.
To test this hypothesis we exposed 1,1-dicyclopropyl-
ethylene 10 to this reaction. Indeed, in accordance with
expectation, the reaction of 10 with ENDA gave the
isoxazoline N-oxide.8 Of course, more information is
needed to prove this hypothesis, but it certainly may be
considered as a guideline for future studies.
In the second part of this work, we have developed a
protocol for the synthesis of some cyclopropane amino
acids 7 from the nitrocyclopropanecarboxylates 6
obtained. The method involves two steps, namely
reduction followed by hydrolysis.
However, the reaction of methylenespirohexane 8 with
ENDA gave a completely different result. Instead of
the expected [1+2]-cycloadduct of type 2, we obtained
the tricyclic isoxazoline-N-oxide 9 in a moderate yield
under the same reaction conditions8 and, hence, the
reaction proceeds via Path B ([2+3]-cycloaddition).
The crucial factor in the reduction of the cyclopropane
nitro esters 6 is the choice of an effective reducing agent
and a catalyst. We have tested some known catalytic
systems, namely NaBH4–Pd/C,9 Raney Ni–N2H4×

N. V. Yashin et al. / Tetrahedron Letters 44 (2003) 8241–8244
8243
HCO2H10 and HCO2NH4–Pd/C11. The most suitable
proved to be ammonium formate in the presence of
catalytic amounts of palladium on charcoal.11 Reduc-
tion with this system took place quantitatively forming
the corresponding amino esters with no by-products.12,13
Hydrolysis then smoothly led to the corresponding
amino acids 7, but the separation of the product from
inorganic compounds reduced yields to 50–60%.
gel and the product (a colorless oil) was isolated by flash
column chromatography (ether-light petroleum ether as
the eluent, 0–30%).
1-Nitro-spiro[2.3]hexane-1-carboxylic acid ethyl ester 6a:
Rf 0.45 (SiO2, hexane–ether 3:1) 1H NMR (300 MHz,
3
CDCl3) l 4.24 (m, J=7.2 Hz, 2H, OCH2), 2.60–2.40 (m,
2H, cy-Bu), 2.35–2.20 (m, 2H, cy-Bu), 2.15–1.90 (m, 2H,
cy-Bu), 2.14 (AB-system, 2J=6.8 Hz, 1H, CH2, cy-Pr),
1.83 (AB-system, 2J=6.8 Hz, 1H, CH2, cy-Pr), 1.27 (t,
3J=7.2 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3) l
The amino acids 7 obtained with this method are shown
in Table 1. It should be noted that amino acid 7c
containing a second carboxyl group is a conformation-
ally restricted analogue of glutamic acid and this com-
pound should be considered as a potential ligand of
methabotropic glutamate receptors.
164.25 (C6
OOEt), 72.07 (C), 62.28 (1JC,H=151 Hz, OCH2),
38.18 (Cspiro), 28.19 (1JC,H=138 Hz, CH2, cy-Bu), 27.66
(1JC,H=139 Hz, CH2, cy-Bu), 24.87 (1JC,H=168 Hz, CH2,
cy-Pr), 15.37 (1JC,H=139 Hz, CH2, cy-Bu), 13.90 (1JC,H
=
127 Hz, CH3). Anal. calcd for C9H13NO4: C, 54.26; H,
6.58; N, 7.03. Found: C, 54.34; H, 6.67; N, 7.11.
9-Nitro-dispiro[3.0.3.1]nonane-9-carboxylic acid ethyl ester
References
1
6b: Rf 0.65 (SiO2, hexane–ether 3:1) H NMR (300 MHz,
3
CDCl3) l 4.23 (m, J=7.2 Hz, 2H, OCH2), 2.40–2.25 (m,
1. (a) Zefirov, N. S.; Kozhushkov, S. I.; Kuznetsova, T. S.;
Kokoreva, O. V.; Lukin, K. A. J. Am. Chem. Soc. 1990,
112, 7702–7707; (b) Zefirov, N. S.; Kuznetsova, T. S.;
Eremenko, O. V.; Kokoreva, O. V.; Zatonsky, B. I.;
Ugrak, B. I. J. Org. Chem. 1994, 59, 4087–4089; (c)
Ivanova, O. A.; Yashin, N. V.; Averina, E. B.; Grishin,
Yu. K.; Kuznetsova, T. S.; Zefirov, N. S. Russ. Chem.
Bull. 2001, 50, 2101–2105; (d) De Meijere, A.;
Kozhushkov, S. I. Chem. Rev. 2000, 100, 93–142.
2. (a) Zefirov, N. S.; Zefirova, O. N. Russ. J. Org. Chem.
2000, 36, 1231–1258; (b) Bachurin, S. O.; Bukatina, E. E.;
Lermontova, N. N.; Tkachenko, S. E.; Afanas’ev, A. Z.;
Grigor’ev, V. U.; Grigorieva, I. V.; Ivanov, Yu.; Sablin,
S.; Zefirov, N. S. Annals N. Y. Acad. Sci. 2001, 939,
325–335; (c) Tikhonova, I. G.; Baskin, I. I.; Palyulin, V.
A.; Zefirov, N. S.; Bachurin, S. O. J. Med. Chem. 2002,
45, 3836–3843.
3. (a) Pellicciari, R.; Marinozzi, M.; Camaioni, E.; Nunez,
M.; Costantino, G.; Fabrizio, G.; Giorgi, G.; Mac-
chiarulo, A.; Subramanian, N. J Org. Chem. 2002, 67,
5497–5507; (b) Salau¨n, J.; Baird, M. S. Curr. Med. Chem.
1995, 2, 511–542; (c) Brauer-Osborne, H.; Egebjerg, J.;
Nielson, E.; Madsen, U.; Krogsgaard-Larsen, P. J. Med.
Chem. 2000, 43 (14), 2609–2645.
4H, cy-Bu), 2.20–1.95 (m, 8H, cy-Bu), 1.27 (t, 3J=7.2 Hz,
3H, CH3). 13C NMR (75 MHz, CDCl3)
l
164.42
(C6 OOEt), 74.76 (C), 62.12 (OCH2), 42.72 (Cspiro), 24.65
(2×CH2, cy-Bu), 24.42 (2×CH2, cy-Bu), 15.62 (2×CH2,
cy-Bu), 14.26 (CH3). Anal. calcd for C12H17NO4: C, 60.24;
H, 7.16; N, 5.85. Found: C, 60.41; H, 7.19; N, 5.98.
1-Nitro-spiro[2.3]hexane-1,5-dicarboxylic acid 1-ethyl ester
5-methyl ester 6c: a mixture of two isomers (A/B=8:5); Rf
0.50 (SiO2, hexane–ether 3:1) 1H NMR (300 MHz,
CDCl3) for the mixture of two isomers: l 3.98 (m,
2H+2H, OCH2), 3.41 (s, 3H, CH3, for isomer A), 3.37 (s,
3H, CH3, for isomer B), 3.10–2.85 (m, 1H +1H, cy-Bu),
2.60–2.45 (m, 1H+1H, cy-Bu), 2.35–2.00 (m, 3H+3H,
cy–Bu), 1.91 (AB-system, 2J=6.8 Hz, 1H, CH2, cy-Pr, for
2
isomer B), 1.85 (AB-system, J=7.1 Hz, 1H, CH2, cy-Pr,
for isomer A), 1.65 (AB-system, 2J=6.8 Hz, 1H, CH2,
cy-Pr, for isomer B), 1.59 (AB-system, 2J=7.1 Hz, 1H,
CH2, cy-Pr, for isomer A), 0.99 (t, 3J=7.1, 3H+3H,
OCH3). 13C NMR (75 MHz, CDCl3) for isomer A: l
174.05 (C6 OOMe), 163.41 (C6 OOEt), 71.53 (C), 61.97
(OCH2), 51.22 (OCH3), 34.71 (Cspiro), 31.73 (CH), 30.57
(CH2, cy-Bu), 30.01 (CH2, cy-Bu), 26.97 (CH2, cy-Pr),
13.30 (CH3). 13C NMR (75 MHz, D2O) for isomer B: l
173.38 (COOMe), 163.31 (COOEt), 70.76 (C), 61.97
(OCH2), 51.16 (OCH3), 33.79 (Cspiro), 31.23 (CH), 30.87
(CH2, cy-Bu), 29.94 (CH2, cy-Bu), 27.05 (CH2, cy-Pr),
13.30 (CH3). Anal. calcd for C11H15NO6: C, 51.36; H,
5.88; N, 5.45. Found: C, 51.33; H, 5.90; N, 5.46.
4. O’Bannon, P. E.; Dailey, W. P. Tetrahedron 1990, 46,
7341–7373.
5. Charette, A. B.; Wurz, R. P.; Ollevier, T. J. Org. Chem.
2000, 65, 9252–9254.
6. (a) Zefirov, N. S.; Tratch, S. S. Anal. Chim. Acta 1990,
235, 115–134; (b) Tratch, S. S.; Zefirov, N. S. J. Chem.
Inf. Comput. Sci. 1998, 38, 331–348; (c) Tratch, S. S.;
Molchanova, M. S.; Zefirov, N. S. MATCH 2002, 46,
275–301.
7. (a) Danishevsky, S. J. Acc. Chem. Res. 1979, 12, 66–72;
(b) Zefirov, N. S.; Kozhushkov, S. I.; Kuznetsova, T. S.;
Ershov, B. A.; Selivanov, S. I. Tetrahedron 1986, 42,
709–713; (c) Zefirov, N. S.; Kozhushkov, S. I.;
Kuznetsova, T. S. Tetrahedron 1982, 38, 1693–1697.
8. General procedure for the preparation of compounds 6, 9,
11: Ethyl nitrodiazoacetate 1 (1 mmol) was added slowly
to a stirred mixture of alkene (5–10 mmol) and Rh2(OAc)4
(3% mol) at 0–5°C. Then the reaction mixture was stirred
at ꢀ20°C for 1 h. Excess alkene was removed under
reduced pressure, the catalyst was filtered through silica
6-Oxy-5-oxa-6-aza-dispiro[2.0.4.2]dec-6-ene-7-carboxylic
acid ethyl ester 9: Rf 0.35 (SiO2, hexane–ether 3:1) 1H
NMR (300 MHz, CDCl3) l 4.27 (q, 3J=7.2 Hz, 2H,
OCH2), 3.38 (s, 2H, CH2), 2.75–2.60 (m, 1H, cy-Bu),
2.40–2.28 (m, 1H, cy-Bu), 2.10–1.86 (m, 2H, cy-Bu), 1.30
(t, 3J=7.2 Hz, 3H, CH3), 1.11–1.02 (m, 1H, cy-Pr),
0.67–0.50 (m, 3H, cy-Pr). 13C NMR (75 MHz, CDCl3) l
159.21 (C6 =
OOEt), 109.04 (C), 84.17 (C-O), 61.79 (1JC,H
147 Hz, OCH2), 39.83 (1JC,H=139 Hz, C
6 H2C=), 34.27
(1JC,H=137 Hz, CH2, cy-Bu), 29.82 (Cspiro), 22.55
(1JC,H=140 Hz, CH2, cy-Bu), 14.10 (1JC,H=127 Hz,
CH3), 10.43 (1JC,H=163 Hz, CH2, cy-Pr), 8.95 (1JC,H
=
161 Hz, CH2, cy-Pr). Anal. calcd for C11H15NO4: C,
58.86; H, 6.70; N, 6.31. Found: C, 58.66; H, 6.71; N, 6.22.

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2
5,5 - Dicyclopropyl - 2 - oxy - 4,5 - dihydro-isoxazole - 3 - car-
cy-Bu), 2.50–2.10 (m, 4H, cy-Bu), 1.92 (AB-system, J=
7.0 Hz, 1H, CH2, cy-Pr), 1.71 (AB-system, 2J=7.0 Hz,
1H, CH2, cy-Pr). 13C NMR (75 MHz, D2O) l 171.95
(COOH), 40.28 (C), 33.50 (Cspiro), 27.08 (1JC,H=136 Hz,
CH2, cy-Bu), 25.70 (1JC,H=138 Hz, CH2, cy-Bu), 24.87
(1JC,H=164 Hz, CH2, cy-Pr), 15.49 (1JC,H=141 Hz, CH2,
cy-Bu). MS (EI, 70 eV): m/z (%)=113 [M−C2H4]+ (16),
96 [M−CO2H]+ (100), 95 (20), 68 [M−CO2H–C2H4]+ (21),
67 (37), 41 (26), 39 (20).
boxylic acid ethyl ester 11: Rf 0.30 (SiO2, hexane–ether
1
3
3:1) H NMR (300 MHz, CDCl3) l 4.01 (q, J=7.1 Hz,
3
2H, OCH2), 3.06 (s, 2H, CH2), 1.24 (t, J=7.1 Hz, 3H,
CH3), 1.10–1.01 (m, 2H, cy-Pr), 0.50–0.38 (m, 6H, cy-Pr).
13C NMR (75 MHz, CDCl3) l 158.85 (C
6
OOEt), 109.07
H2C=), 18.17
(C), 82.30 (C-O), 61.48 (OCH2), 39.35 (C
6
(2×CH, cy-Pr), 14.10 (CH3), 1.11 (2×CH2, cy-Pr), 0.15
(2×CH2, cy-Pr). Anal. calcd for C12H17NO4: C, 60.24; H,
7.16; N, 5.85. Found: C, 60.18; H, 7.03; N, 5.57.
9-Amino-dispiro[3.0.3.1]nonane-9-carboxylic acid 7b: mp
274–277°C 1H NMR (300 MHz, D2O) l 2.05–2.4 (m,
12H, cy-Bu). 13C NMR (75 MHz, D2O) l 170.48
(COOH), 43.58 (C), 38.80 (Cspiro), 23.83 (2×CH2, cy-Bu),
22.24 (2×CH2, cy-Bu), 14.94 (2×CH2, cy-Bu). MS (EI, 70
eV): m/z (%)=153 [M−C2H4]+ (37), 136 [M−CO2H]+ (60),
120 [M−NH2–CO2H]+ (8), 108 [M−CO2H–C2H4]+ (100),
107 (58), 91 (19), 79 (33), 67 (16), 53 (21), 39 (21).
1-Amino-spiro[2.3]hexane-1,5-dicarboxylic acid 7c: (a mix-
ture of two isomers (A/B=7:5); mp 222–224°C H NMR
(300 MHz, D2O) for the mixture of two isomers: l
3.78–3.41 (m, 1H+1H, cy-Bu), 2.95–2.62 (m, 4H+4H,
cy-Bu), 2.09 (AB-system, J=7.3 Hz, 1H, CH2, cy-Pr, for
isomer B), 2.03 (AB-system, J=7.4 Hz, 1H, CH2, cy-Pr,
9. Petrini, M.; Ballini, R.; Rosini, G. Synthesis 1987, 713–
714.
10. Godwa, S.; Godwa, D. C. Tetrahedron 2002, 58, 2211–
2213.
11. Fu, Y.; Hammartstrom, G. J.; Miller, T. J.; Fronczek, F.
R.; McLaughlin, M. L.; Hammer, R. P. J. Org. Chem.
2001, 66, 7118–7124.
12. The completeness of the reduction was confirmed by
NMR spectroscopy and the amino esters were used for
the next stage without isolation.
1
13. General procedure for the preparation of amino acids 7:
Ammonium formate (10 mmol) was added to a stirred
2
mixture of ethyl 1-nitrocylopropanecarboxylate
6 (1
2
mmol), 10% Pd/C (10% mol) in anhydrous ethanol (10
ml). The reaction mixture was stirred for 40 h at rt, then
the catalyst was removed by filtering. The solvent was
evaporated under reduced pressure and the residue was
stirred with 1N NaOH solution in ethanol (2 ml) for 48 h.
The reaction mixture was acidified with 2N HCl to pH 3,
the solvent was evaporated under reduced pressure, the
residue was dissolved in the distilled water (2 ml), put on
a Dowex 50 ion-exchange column and eluted with 0.9 N
NH3 solution, the solvent was evaporated and crystalline
residue was recrystallized from ethanol–water (1:1).
1-Amino-spiro[2.3]hexane-1-carboxylic acid 7a: mp 281–
282°C 1H NMR (300 MHz, D2O) l 2.75–2.50 (m, 2H,
for isomer A), 1.93 (AB-system, 2J=7.3 Hz, 1H, CH2,
cy-Pr, for isomer B), 1.87 (AB-system, 2J=7.4 Hz, 1H,
CH2, cy-Pr, for isomer A). 13C NMR (75 MHz, D2O) for
isomer A: l 178.97 (COOH), 171.44 (COOH), 40.26 (C),
32.73 (CH), 30.52 (Cspiro), 30.23 (CH2, cy-Bu), 28.66
(CH2, cy-Bu), 24.47 (CH2, cy-Pr). 13C NMR (75 MHz,
D2O) for isomer B: l 179.33 (COOH), 171.44 (COOH),
40.03 (C), 32.27 (CH), 30.95 (Cspiro), 30.04 (CH2, cy-Bu),
29.14 (CH2, cy-Bu), 24.61 (CH2, cy-Pr). MS (EI, 70 eV):
m/z (%)=140 [M−CO2H]+ (48), 139 (18), 113 [M−CO2H–
CH2–CH]+ (100), 95 [M−CO2H–CO2H]+ (15), 94 (98), 93
(43), 68 (41), 67 [M−CO2H–CO2H–C2H4]+ (100), 55 (31).