ISSN 0012-5008, Doklady Chemistry, 2008, Vol. 419, Part 2, pp. 113115. Pleiades Publishing, Ltd., 2008.Original Russian Text A.V. Chemagin, N.V. Yashin, E.B. Averina, T.S. Kuznetsova, N.S. Zefirov, 2008, published in Doklady Akademii Nauk, 2008, Vol. 419, No. 6, pp. 772774.

113

At present, the development of methods for prepar-ing nonnatural polycyclic dibasic amino acids is animportant problem in the field of medicinal and organicchemistry [13]. Dibasic amino acids of the cyclopro-pane series, which are the most promising ligands ofmetabotropic glutamate receptors and play an impor-tant role in studying metabolic processes and the mech-anism of action of enzymes, are of special interest [4,5].

The development of approaches to the synthesis ofunique dibasic amino acids containing spiropentanefragment continues our studies in the field of triangu-lanes and amino acids of the polyspirocycloalkaneseries [610]. Only two compounds of this series areknown to date: 4-carboxyspiro[2.2]pentylglycine

1

,

prepared by us [6], and 1-aminospiro[2.2]pentane-1,4-dicarboxylic acid

2

,

described in [5].

It should be noted that the known method for thesynthesis of amino acid

2

is rather labor-consuming, itinvolves many stages, and the total yield of the targetamino acid is low [5]. In this work, we have developedan alternative simpler method for preparing spiropen-tane amino acid

2

starting from available methyl2-methylenecyclopropanecarboxylate (

3

) (Scheme 1).The key stage of the proposed synthesis of spiropen-

tane amino acid

2

is the reaction of [2+1]-cycloadditionof ethyl nitrodiazoacetate (ENDA) to methyl methyle-necyclopropanecarboxylate

3

to form 1-ethoxycarbo-nyl-4-methoxycarbonyl-1-nitrospiro[2.2]pentane

4

. Itsreduction followed by the hydrolysis of reduction prod-uct

5

results in target compound

2

(Scheme 1).

NH2

CO2HHO2C

NH2

CO2HHO2C

1 2

Scheme 1.

COOMe COOMe

NO2

COOEt

COOMe

NH2

COOEt

COOMe

NH2

COOH3 4, 52% 5, 74% 2, 86%

ENDA, Rh2(OAc)4 Zn, AcOH, isopropanol(1) NaOH, EtOH

(2) H3O+COOH

The [2 + 1] cycloaddition of ENDA to olefin

3

in thepresence of dirhodium tetraacetate proceeds in 52%yield. Adduct

4

was purified by preparative columnchromatography. The moderate yield of nitrocyclopro-panecarboxylate

4

seems to be caused by the partialdeactivation of the double bond of methylenecyclopro-pane

3

by the neighboring electron-withdrawing estergroup.

The reduction of 1-nitrocyclopropanecarboxylate

4

to amino ester

5

is an especially difficult stage in thesynthesis of target amino acid

2

. For this purpose, weused the ZnAcOH

i

-PrOH system [7, 12], which isefficient for the reduction of strained cyclopropane-containing nitrocarboxylates. The reaction takes placeunder mild conditions (ambient temperature, 6 h),which makes it possible to avoid undesirable openingof three-membered rings to form by-products.

The structure of amino ester

5

was confirmed byNMR data. As compared with starting nitrocarboxylate

4

, the NMR spectra of amino ester

5

show an upfieldshift of signals from the protons and carbon atoms of

New Method for the Synthesis of 1-Aminospiro[2.2]pentane-1,4-dicarboxylic Acid

A. V. Chemagin, N. V. Yashin, E. B. Averina, T. S. Kuznetsova, and

Academician

N. S. Zefirov

Received September 19, 2007

DOI:

10.1134/S0012500808040095

Moscow State University, Vorobevy gory, Moscow, 119992 Russia

CHEMISTRY

114

DOKLADY CHEMISTRY

Vol. 419

Part 2

2008

CHEMAGIN et al.

the three-membered ring containing the aminocarboxy-ethyl moiety (see Experimental).

Target amino acid

2

was obtained by hydrolysis ofamino ester

5

with an NaOH solution in ethanol. Thereaction proceeds quantitatively at ambient temperatureover two days. Resultant amino acid

2

was isolated andpurified by ion exchange chromatography followed byrecrystallization from aqueous ethanol. The formationof the target amino acid was confirmed by the absenceof signals from the protons of methoxy and ethoxygroups in

1

and

13

C NMR spectra.Thus, we have developed a new method of synthesis

of dibasic spiropentane amino acid

2

starting fromavailable methylenecyclopropane

3

, more convenientthan that known from the literature [5]. This methodallows us to prepare the target amino acid in rather highyield, whereas the use of chiral rhodium catalysts [13,14] at the cyclopropanation stage enables asymmetricsynthesis, which opens a way for the use of the methodin synthetic practice.

EXPERIMENTAL

1

and

13

C NMR spectra of the compounds obtainedwere recorded on a Bruker Avance 400 spectrometer(operating at 400 and 100 MHz, respectively). The sig-nal of chloroform (

7.27,

77.10

ppm) was used asan internal reference. MALDI mass spectra of positiveions were obtained on a Bruker Daltonics Ultraflexmass spectrometer with the use of 1,8,9-trihydroxyan-thracene as a matrix.

The reaction course and purity of chemicals wasmonitored by TLC (Silufol UV-254). Preparative col-umn chromatography was carried out using silica gelwith particle size 0.040.06 mm (Maderey-Nagel). Ionexchange chromatography was performed usingDowex 50WX8-100 ion exchange resin (Sigma-Ald-rich).

Ethyl nitrodiazoacetate (ENDA) [15], methyl2-methylenecyclopropanecarboxylate

3

[11], and1-ethoxycarbonyl-4-methoxycarbonyl-1-nitrospiro[2,2]pen-tane

4

were obtained by known procedures.

1-Ethoxycarbonyl-4-methoxycarbonyl-1-amino-spiro[2.2]pentane 5.

Zinc powder (900 mg, 14 mmol)was added in small portions over 30 min to a solutionof 170 mg (0.7 mmol) of nitrocarboxylate

4

and 420 mg(7 mmol) of glacial acetic acid in 15 mL of isopropanolat ambient temperature. The mixture was stirred for 6 hand treated with saturated sodium hydrocarbonate solu-tion to pH 8. The precipitate was filtered off and washedwith 10 mL of ethyl acetate, the organic layer was sep-arated, and the aqueous layer was extracted withCH

2

Cl

2

(4

5 mL). The combined organic fractionswere washed with water (4

5 mL) and dried overMgSO

4

, the solvent was evaporated, and the resultingamino ester was used without additional purification.

The yield was 110 mg (74%); the diastereomer ratiowas 1 : 1.

1

H

NMR (

CDCl

3

,

, ppm,

J

, Hz) for the mixture oftwo diastereomers: 1.22 (t, 3H,

3

J

= 7.1, OCH

2

CH

3

),1.23

(t, 3H,

3

J

= 7.1, OCH

2

CH

3

), AB system 1:

1.37

(1, = 4.8, CH

a

H

b

)

, 1.401.43 (m, 1H, CH,cyclopropyl), AB system 2:

1.48 (1, = 4.8,

CH

a

H

b

)

, 1.601.66 (m, 2H,

CH

2

, cyclopropyl), AB sys-tem 1:

1.80 (1, = 4.8, CH

a

H

b

)

, AB system 2:

1.92 (1, = 4.8,

b

)

, 2.002.03 (m, 1H,CH, cyclopropyl), 2.09 (br. s, 2H, NH

2

), 2.102.13 (m,2H,

CH

2

, cyclopropyl), 3.67 (s, 3H, OCH

3

), 3.68 (s, 3H,OCH

3

), 4.09 (q, 2H,

3

J

= 7.1,

OCH

2

CH

3

), 4.16

(q, 2H,

3

J

= 7.1, OCH

2

CH

3

).

13

NMR (

CDCl

3

,

, ppm) for the mixture of twodiastereomers:

13.47 (

2

, cyclopropyl), 14.27 (CH3,OCH2CH3), 14.30 (CH3, OCH2CH3), 15.72 (CH2,cyclopropyl), 19.34 (CH, cyclopropyl), 21.26 (CH,cyclopropyl), 22.65 (CH2, cyclopropyl), 22.66 (CH2,cyclopropyl), 32.51 (Cspiro), 32.88 (Cspiro), 40.67(C(NH2)), 40.85 (C(NH2)), 51.68 (OCH3), 51.79(OCH3), 61.16 (CH2, OCH2CH3), 61.21 (CH2,OCH2CH3), 172.77 (COOCH2CH3), 173.06(COOCH2CH3), 174.28 (COOCH3), 174.45(COOCH3). MS MALDITOF (m/z): 213 [M]+.

1-Aminospiro[2.2]pentane-1,4-dicarboxylic acid2. A 1 M solution of sodium hydroxide in ethanol (1.2mL) was added to a solution of 130 mg (0.61 mmol) ofaminodicarboxylate 5 in 3 mL of absolute ethanol. Thereaction mixture was stirred at ambient temperature for48 h; then 0.2 M hydrochloric acid was added to pH 3,the solvent was evaporated under reduced pressure, andthe residue was dissolved in 3 mL of distilled water andchromatographed (Dowex 50, 0.9 M aqueous ammoniasolution as eluent). The solvent was evaporated, and theresidue was recrystallized from aqueous ethanol (1 : 1).The yield was 90 mg (86%); the diastereomer ratio was1 : 1.

1H NMR (CDCl3, , ppm, J, Hz) for the mixture oftwo diastereomers: 1.311.36 (m, 2H, H2, cyclopro-pyl), 1.381.44 (m, 2H, 2, cyclopropyl), AB system1: 1.53 (1H, = 6.3, CHaHb), AB system 2: 1.61 (1H, = 6.1, CHaHb), B 1.92 (1H, =

6.1, CHaHb), AB system 1: 1.85 (1H, = 6.1,CHaHb), 1.901.93 (m, 1H, CH, cyclopropyl), 2.012.05 (m, 1H, CH, cyclopropyl).

13C NMR (CDCl3, , ppm) for the mixture of twodiastereomers: 13.89 (CH2, cyclopropyl), 15.10 (CH2,cyclopropyl), 18.56 (2 CH, cyclopropyl), 23.78 (CH2,

J2HaHb

J2HaHb

J2HaHb

J2HaHb

J2HaHb

J2HaHb

J2HaHb

J2HaHb

DOKLADY CHEMISTRY Vol. 419 Part 2 2008

NEW METHOD FOR THE SYNTHESIS 115

cyclopropyl), 24.57 (CH2, cyclopropyl), 28.26 (2 Cspiro), 41.93 (C(NH2)), 42.05 (C(NH2)), 171.23(COOH), 171.31 (COOH), 175.93 (2COOH).

ACKNOWLEDGMENTSThis work was supported by the Russian Foundation

for Basic Research (project no. 050332906), theRussian Academy of Sciences (the program Biomo-lecular and Medicinal Chemistry), and the Ministry ofEducation and Science (project no. NSh2552.2006.3).

REFERENCES1. Cativiela, C., Diaz-De-Villegas M.D, Tetrahedron, 2000,

vol. 11, no. 3, pp. 645732.2. Komarov, I.V., Grigorenko, A.O., Turov, A.V., and Khi-

lya, V.P., Usp. Khim., 2004, vol. 73, no. 8, pp. 849876.3. Salan, J., Top. Curr. Chem., 2000, vol. 207, pp. 167.4. Baskin, I.I., Belenikin, M.S., Ekimova, E.V., Constan-

tino, G., Palyulin, V.A., Pellicciari, R., and Zefirov, N.S.,Dokl. Chem., 2000, vol. 374, nos. 13, pp. 191194[Dokl. Akad. Nauk, 2000, vol. 374, no. 3, pp. 347351].

5. Pellicciari, R., Marinozzi, M., Camaioni, E., Nunez, M.,Constantino, G., Gasparini, F., Giorgi, G., Mac-chiarulo, A., and Submanian, N., J. Org. Chem., 2002,vol. 67, no. 16, pp. C. 54975507.

6. Averina, E.B., Yashin, N.V., Grishin, Yu.K., Kuzne-tsova, T.S., and Zefirov, N.S., Synthesis, 2006, no. 5,pp. 880884.

7. Yashin, N.V., Averina, E.B., Grishin, Yu.K., Kuznets-ova, T.S., and Zefirov, N.S., Synthesis, 2006, no. 2,pp. 279284.

8. Averina, E.B., Yashin, N.V., Shvorina, E.B.,Grishin, Yu.K., and Kuznetsova, T.S., Vestn. Mosk. Univ.,Ser. 2: Khim., 2002, vol. 43, no. 4, pp. 246247.

9. Yashin, N.V., Averina, E.B., Gerdov, S.M., Kuzne-tsova, T.S., and Zefirov, N.S., Tetrahedron Lett., 2003,vol. 44, no. 45, pp. 82418244.

10. Averina, E.B., Yashin, N.V., Kuznetsova, T.S., andZefirov, N.S., Vestn. Mosk. Univ., Ser. 2: Khim., 2002,vol. 43, no. 4, pp. 246247.

11. Akhachinskaya, T.V., Donskaya, N.A., Kalyakina, I.V.,Oprunenko, Yu.F., and Shabarov, Yu.S., Zh. Org. Khim.,1989, vol. 25, no. 8, pp. 16451651.

12. Wurz, R.P. and Charette, A.B., J. Org. Chem., 2004,vol. 69, no. 4, pp. 12621269.

13. Davies, H.M., Huby, N.J.S., Cantrell, W.R.,Cantrell, W.R., and Olive, J.L., J. Am. Chem. Soc., 1993,vol. 115, no. 21, pp. 94689479.

14. Moye-Sherman, D., Welch, M.B., Reibenspies, J., andBurgess, K., J. Chem. Soc., Chem. Commun., 1998,no. 21, pp. 23772378.

15. Charette, A.B., Wurz, R.P., and Ollivier, T., J. Org.Chem., 2000, vol. 65, no. 26, pp. 92529254.

/ColorImageDict > /JPEG2000ColorACSImageDict > /JPEG2000ColorImageDict > /AntiAliasGrayImages false /DownsampleGrayImages true /GrayImageDownsampleType /Bicubic /GrayImageResolution 150 /GrayImageDepth -1 /GrayImageDownsampleThreshold 1.50000 /EncodeGrayImages true /GrayImageFilter /DCTEncode /AutoFilterGrayImages true /GrayImageAutoFilterStrategy /JPEG /GrayACSImageDict > /GrayImageDict > /JPEG2000GrayACSImageDict > /JPEG2000GrayImageDict > /AntiAliasMonoImages false /DownsampleMonoImages true /MonoImageDownsampleType /Bicubic /MonoImageResolution 600 /MonoImageDepth -1 /MonoImageDownsampleThreshold 1.50000 /EncodeMonoImages true /MonoImageFilter /CCITTFaxEncode /MonoImageDict > /AllowPSXObjects false /PDFX1aCheck false /PDFX3Check false /PDFXCompliantPDFOnly false /PDFXNoTrimBoxError true /PDFXTrimBoxToMediaBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXSetBleedBoxToMediaBox true /PDFXBleedBoxToTrimBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXOutputIntentProfile (None) /PDFXOutputCondition () /PDFXRegistryName (http://www.color.org?) /PDFXTrapped /False

/Description >>> setdistillerparams> setpagedevice