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

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

References and Notes

• 1 Mann J. In Secondary Metabolism   Oxford University Press; Oxford: 1991.  Chap. 3. p.417 
• 2 For a review on the application of isotopic labeling in protein-structure determination, see: Lian L.-Y. Middleton DA. Prog. Nucl. Magn. Reson. Spectrosc.  2001,  39:  171 
• For example, see:
• 3a Baldwin JE. Adlington RM. Marquess DG. Pitt AR. Porter MJ. Russell AT. Tetrahedron  1996,  52:  2515 
• 3b Church NJ. Young DW. J. Chem. Soc., Perkin Trans. 1  1998,  52:  1475 
• 3c Pirrung MC. Acc. Chem. Res.  1999,  32:  711 
• 4a Namy J.-L. Girard P. Kagan HB. New J. Chem.  1977,  1:  5 
• 4b Girard P. Namy J.-L. Kagan HB. J. Am. Chem. Soc.  1980,  102:  2693 
• 5a Molander GA. Harris CR. Chem. Rev.  1996,  96:  307 
• 5b Molander GA. Harris CR. Tetrahedron  1998,  54:  3321 
• 5c Krief A. Laval AM. Chem. Rev.  1999,  99:  745 
• 5d Steel PG. J. Chem. Soc., Perkin Trans. 1  2001,  2727 
• 5e Kagan HB. Tetrahedron  2003,  59:  10351 
• 5f Concellón JM. Rodríguez-Solla H. Chem. Soc. Rev.  2004,  33:  599 
• 6a Molander GA. In Organic Reactions   Vol. 46:  Paquette LA. John Wiley; New York: 1994.  p.211 
• 6b Dahlén A. Hilmersson G. Eur. J. Inorg. Chem.  2004,  3393 
• 6c Concellón JM. Rodríguez-Solla H. Eur. J. Org. Chem.  2006,  1613 
• 7 Concellón JM. Rodríguez-Solla H. Chem. Eur. J.  2001,  7:  4266 
• 8 Concellón JM. Rodríguez-Solla H. Chem. Eur. J.  2002,  8:  4493 
• 9 Concellón JM. Bernad PL. Rodríguez-Solla H. Angew. Chem. Int. Ed.  2001,  40:  3897 
• 10 Concellón JM. Bardales E. Gómez C. Tetrahedron Lett.  2003,  44:  5323 
• 11 Concellón JM. Rodríguez-Solla H. Concellón C. Tetrahedron Lett.  2004,  45:  2129 
• 12a Evans DA. Michael FE. Tedrow JS. Campos KR. J. Am. Chem. Soc.  2003,  125:  3534 
• 12b Daumas M. Vo-Quang L. Le Goffic F. Synth. Commun.  1990,  20:  3395 
• 12c Schmidt U. Lieberknecht A. Wild J. Synthesis  1984,  20:  53 
• 13 The solution of SmI₂ in THF was rapidly obtained by reaction of diiodomethane with samarium powder in the presence of sonic waves: Concellón JM. Rodríguez-Solla H. Bardales E. Huerta M. Eur. J. Org. Chem.  2003,  1775 
• b-Amino alkanols are important building blocks and have been used to prepare a large number of biologically active natural and synthetic compounds, including unnatural amino acids:
• 17a Corey EJ. Zhang F. Angew. Chem. Int. Ed.  1999,  38:  1931 
• 17b O’Brien P. Angew. Chem. Int. Ed.  1999,  38:  326 
• 17c Johannes CW. Visser MS. Weatherhead GS. Hoveyda AH. J. Am. Chem. Soc.  1998,  120:  8340 
• 17d Chang BL. Ganesan A. Bioorg. Med. Chem. Lett.  1997,  7:  1511 
• 17e Li G. Chang HT. Sharpless KB. Angew. Chem. Int. Ed.  1996,  35:  451 
• 17f Rogers GA. Parsons SM. Anderson DS. Nilson LM. Bahr BA. Kornreich WD. Kaufman R. Jacobs RS. Kirtman B. J. Med. Chem.  1989,  32:  1217 

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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.

15

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%.

16

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

18

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.