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J. M. Concellón et al.
LETTER
(6) (a) Molander, G. A. In Organic Reactions, Vol. 46; Paquette,
L. A., Ed.; John Wiley: New York, 1994, 211. (b) Dahlén,
A.; Hilmersson, G. Eur. J. Inorg. Chem. 2004, 3393.
(c) Concellón, J. M.; Rodríguez-Solla, H. Eur. J. Org. Chem.
2006, 1613.
(7) Concellón, J. M.; Rodríguez-Solla, H. Chem. Eur. J. 2001,
7, 4266.
(8) Concellón, J. M.; Rodríguez-Solla, H. Chem. Eur. J. 2002,
8, 4493.
(9) Concellón, J. M.; Bernad, P. L.; Rodríguez-Solla, H. Angew.
Chem. Int. Ed. 2001, 40, 3897.
(10) Concellón, J. M.; Bardales, E.; Gómez, C. Tetrahedron Lett.
2003, 44, 5323.
(11) Concellón, J. M.; Rodríguez-Solla, H.; Concellón, C.
Tetrahedron Lett. 2004, 45, 2129.
(16) However, the deuteration of 8 to give 9 produced by D2O
could not be rejected.
(17) β-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: (a) Corey, E. J.; Zhang, F. Angew. Chem. Int. Ed.
1999, 38, 1931. (b) O’Brien, P. Angew. Chem. Int. Ed. 1999,
38, 326. (c) Johannes, C. W.; Visser, M. S.; Weatherhead, G.
S.; Hoveyda, A. H. J. Am. Chem. Soc. 1998, 120, 8340.
(d) Chang, B. L.; Ganesan, A. Bioorg. Med. Chem. Lett.
1997, 7, 1511. (e) Li, G.; Chang, H. T.; Sharpless, K. B.
Angew. Chem. Int. Ed. 1996, 35, 451. (f) Rogers, G. A.;
Parsons, S. M.; Anderson, D. S.; Nilson, L. M.; Bahr, B. A.;
Kornreich, W. D.; Kaufman, R.; Jacobs, R. S.; Kirtman, B.
J. Med. Chem. 1989, 32, 1217.
(12) (a) Evans, D. A.; Michael, F. E.; Tedrow, J. S.; Campos, K.
R. J. Am. Chem. Soc. 2003, 125, 3534. (b) Daumas, M.; Vo-
Quang, L.; Le Goffic, F. Synth. Commun. 1990, 20, 3395.
(c) 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, J. M.; Rodríguez-Solla,
H.; Bardales, E.; Huerta, M. Eur. J. Org. Chem. 2003, 1775.
(14) General Procedure for Compound 6a
(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): δ = 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): δ = 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
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)
Rf = 0.26 (hexane–EtOAc, 1:1). 1H NMR (300 MHz,
CDCl3): δ = 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): δ = 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.
(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): δ = 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): δ = 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.
(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%.
Synlett 2008, No. 3, 402–404 © Thieme Stuttgart · New York