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Synlett 2008(3): 402-404  
DOI: 10.1055/s-2008-1032063
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis and Synthetic Applications of α,β-Dideuterio-α-amino Esters Promoted by Samarium Diiodide

José M. Concellón*, Humberto Rodríguez-Solla*, Carmen Concellón, Paula Tuya
Departamento Química Orgánica e Inorgánica, Universidad de Oviedo, C/ Julián Clavería 8, 33006 Oviedo, Spain
e-Mail: jmcg@uniovi.es;
Further Information

Publication History

Received 11 October 2007
Publication Date:
23 January 2008 (online)

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Abstract

A new, easy, and high-yielded route to isotopically labeled amino acid derivatives is reported. This process takes place through a SmI2-promoted 1,4-reduction of a variety of dehydro­amino esters in the presence of D2O. The dideuterio amino esters were transformed into other dideuterated compounds such as a-amino acids and 1,2-amino alcohols. A mechanism to explain the 1,4-reduction process is also proposed.

Key words

amino acids - deuteration - reductions - samarium

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General Procedure for Compound 6a
Under nitrogen, a solution of SmI2 (1.2 mmol) in THF (15 mL) was added dropwise to a stirred solution of the starting material 5a in D2O (2 mL) and THF (2 mL) at r.t. The reaction mixture was stirred for 30 min and then treated with 0.1 M aq HCl (5 mL). Standard workup afforded the crude 2,3-dideuterio-2-amino ester 6a, which was purified by flash column chromatography on SiO2 (hexane-EtOAc, 5:1):
Methyl 2-Acetylamino-2,3-dideuteriodecanoate (6a)
R f = 0.26 (hexane-EtOAc, 1:1). 1H NMR (300 MHz, CDCl3): d = 6.16 (br s, 1 H), 3.70 (s, 3 H), 1.99 (s, 3 H), 1.65-1.51 (m, 1 H), 1.33-1.10 (m, 12 H), 0.84 (t, J = 6.7 Hz, 3 H). 13C NMR (75 MHz, CDCl3): d = 173.2 (C), 169.8 (C), 52.1 (CH3), 51.7 (t, J = 21.8 Hz, CD), 31.8 (t, J = 19.6 Hz, CHD), 31.6 (CH2), 29.2 (CH2), 29.0 (2 ¥ CH2), 24.9 (CH2), 22.9 (CH3), 22.5 (CH2), 13.9 (CH3). MS (70 eV): m/z (%) = 245 (5) [M+], 186 (55), 144 (100). HRMS: m/z calcd for C13H23D2NO3: 245.1960; found: 245.1944. IR (neat): 3263, 3063, 2922, 1742, 1652, 1374 cm-1.

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In the mass spectra (MS and HRMS) of deuterated compounds 6a,c,e,g, the [M]+ peaks of the corresponding nondeuterated compounds are either absent or very weak, indicating that these species are present to an extent of <2%.

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However, the deuteration of 8 to give 9 produced by D2O could not be rejected.

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General Procedure for the Synthesis of Compound 11e 2-Acetylamino-3-cyclohexyl-2,3-dideuteriopropanoic acid methyl ester (6e, 100 mg, 0.43 mmol) was refluxed in concd HCl for 12 h. Then, aq HCl was evaporated at low pressure and 2-amino-3-cyclohexyl-2,3-dideuteriopropanoic acid hydrochloride was recovered as a colorless solid; quant. yield. 1H NMR (300 MHz, D2O): d = 1.68 (d, J = 7.9 Hz, 1 H), 1.63-1.40 (m, 5 H), 1.35-1.21 (m, 1 H), 1.10-1.01 (m, 3 H), 0.98-0.72 (m, 2 H). 13C NMR (75 MHz, D2O): d = 175.3 (C), 52.8 (CD, J = 20.5 Hz), 39.3 (CHD, J = 19.0 Hz), 35.2 (CH), 34.9 (CH2), 34.1 (CH2), 28.1 (CH2), 27.8 (CH2), 27.7 (CH2). IR (neat): = 3425, 2926, 1652, 1265 cm-1 .
General Procedure for the Synthesis of Compound 12e To a solution of 2-acetylamino-3-cyclohexyl-2,3-dideuteriopropanoic acid methyl ester (6e, 57 mg, 0.25 mmol) in THF (5 mL), a 1.0 M in THF solution of LiAlH4 (0.28 mL, 0.28 mmol) was added dropwise at 0 °C under nitrogen. The resulting solution was stirred at r.t. for 12 h, then quenched with ice water and filtered through a pad of Celite®. The aqueous layer was extracted with Et2O, dried over Na2SO4 and finally the solvents were removed under vacuum, to afford 2-acetylamino-3-cyclohexyl-2,3-dideuteriopropan-1-ol as a white solid; 83% yield. 1H NMR (300 MHz, CDCl3): d = 5.63 (br s, 1 H), 3.66 (d, J = 11.1 Hz, 1 H), 3.50 (d, J = 11.1 Hz, 1 H), 2.01 (s, 3 H), 1.79-0.84 (m, 12 H). 13C NMR (75 MHz, CDCl3): d = 171.1 (C), 66.3 (CH2), 49.1 (t, J = 20.0 Hz, CD), 38.2 (t, J = 19.5 Hz, CHD), 34.1 (CH), 33.6 (CH2), 32.8 (CH2), 26.3 (CH2), 26.1 (CH2), 26.0 (CH2), 23.4 (CH3). IR (neat): 1653, 1636, 1558, 1540 cm-1.