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R. Badorrey, C. Cativiela, M. D. Dıaz-de-Villegas, R. Dıez, J. A. Galvez
FULL PAPER
the coupling constants (J) in Hertz. The following abbreviations
(2S,3R)-3-tert-Butoxycarbonylamino-1,2-hexanediol (syn-4): Homo-
are used: s, singlet; d, doublet; t, triplet; m, multiplet; br. s, broad allylamine syn-2b (415 mg, 1 mmol) was dissolved in methanol
1
singlet; bd, broad doublet; dd, doublet of doublets. The H NMR
and 13C NMR spectra of N-Boc-protected compounds were not
conclusive at room temperature, due to the presence of a dynamic
equilibrium between rotamers caused by the restricted rotation of
the nitrogen-carbon bond of the urethane group. In order to over-
come this problem, NMR spectra of these compounds were
(15 mL). Pd(OH)2/C (20%, 150 mg) and di-tert-butyl dicarbonate
(655 mg, 3 mmol) were then successively added to the solution. The
mixture was stirred under H2 at 50 atm for 5 days at room temper-
ature and then filtered, and the solvent was evaporated in vacuo.
The residue was purified by flash chromatography with diethyl
ether/hexane (1:1) to give 175 mg (75%) of N-Boc-aminodiol syn-4
as a white solid. M.p. 63 °C (ref.[20] for the enantiomer, m.p. 62Ϫ63
acquired at 60 °C. Optical rotations were measured on
a
PerkinϪElmer 241-C polarimeter at 20 °C with concentrations °C). [α]2D0 ϭ Ϫ12.0 (c ϭ 1 in CHCl3). 1H NMR (CDCl3, 300 MHz,
given in g/100 mL. High-resolution Mass Spectra (HRMS) were
recorded on a VG-autospec instrument. Elemental analyses were
performed with a PerkinϪElmer 200 C,H,N,S elemental analyser.
60 °C): δ ϭ 0.92 (t, J ϭ 7.5 Hz, 3 H), 1.45 (s, 9 H), 1.45Ϫ1.54 (m,
4 H), 2.31 (br. s, 2 H), 3.50Ϫ3.60 (m, 2 H), 3.65Ϫ3.72 (m, 2 H),
4.59 (bd, 1 H) ppm. 13C NMR (CDCl3, 75 MHz, 60 °C): δ ϭ 13.8,
19.4, 28.5, 34.4, 51.5, 64.1, 73.6, 79.9, 157.1 ppm.
{(R)-1-[(S)-1,2-Bis(benzyloxy)ethyl]but-3-enyl}[(S)-1-phenylethyl]-
amine (syn-2b): A solution of the chiral imine 1b (373 mg, 1 mmol)
in dry diethyl ether (5 mL) was added dropwise at Ϫ30 °C under
argon to a stirred solution of allylmagnesium bromide in diethyl
ether (1 , 2.1 mL, 2.1 mmol), further diluted with dry diethyl ether
(10 mL). After stirring for 12 h at room temperature, the reaction
mixture was poured into saturated aqueous NH4Cl (10 mL), the
organic phase was separated, and the water layer was extracted
with diethyl ether (2 ϫ 20 mL). The combined organic layers were
dried over anhydrous MgSO4, filtered and concentrated to give an
oily residue. Purification of the residue by flash chromatography
with diethyl ether/hexane (1:4) afforded 270 mg (65%) of com-
pound syn-2b as a colourless oil. [α]2D0 ϭ Ϫ29.5 (c ϭ 1 in CHCl3).
1H NMR (CDCl3, 300 MHz, 25 °C): δ ϭ 1.28 (d, J ϭ 6.6 Hz, 3
H), 1.51 (br. s, 1 H), 2.27Ϫ2.32 (m, 2 H), 2.49Ϫ2.55 (m, 1 H),
3.52Ϫ3.58 (m, 1 H), 3.58 (dd, J ϭ 9.6, J ϭ 4.5 Hz, 1 H), 3.70 (dd,
J ϭ 9.6, J ϭ 6 Hz, 1 H), 3.88 (q, J ϭ 6.6 Hz, 1 H), 4.40 (s, 2 H),
4.49 (d, J ϭ 11.7 Hz, 1 H), 4.73 (d, J ϭ 11.7 Hz, 1 H), 4.92Ϫ4.99
(m, 2 H), 5.61Ϫ5.73 (m, 1 H), 7.22Ϫ7.35 (m, 15 H) ppm. 13C NMR
(CDCl3, 75 MHz, 25 °C): δ ϭ 25.2, 35.0, 55.2, 55.7, 71.9, 73.0,
73.3, 79.3, 116.7, 126.8, 127.0, 127.4, 127.6, 127.8, 128.2, 136.1,
138.4, 138.9, 145.9 ppm. HRMS (FAB) for C28H34NO2 [M ϩ Hϩ]:
calcd. 416.2589; found 416.2593.
(2S,3S)-3-tert-Butoxycarbonylamino-1,2-hexanediol (anti-4): Homo-
allylamine anti-2c (415 mg, 1 mmol) was dissolved in methanol
(15 mL). Pd(OH)2/C (20%, 150 mg) and di-tert-butyl dicarbonate
(655 mg, 3 mmol) were then successively added to the solution. The
mixture was shaken under H2 at 1 atm at room temperature for 5
days and filtered, and the solvent was evaporated in vacuo. The
residue was purified by flash chromatography with diethyl ether/
hexane (1:1) to give 130 mg (55%) of N-Boc-aminodiol anti-4 as a
white solid. M.p. 90 °C (ref.,[20] m.p. 90Ϫ91 °C). [α]2D0 ϭ ϩ9.3 ( c ϭ
1 in CHCl3). 1H NMR (CDCl3, 300 MHz, 60 °C): δ ϭ 0.92 (t, J ϭ
7.2 Hz, 3 H), 1.43 (s, 9 H), 1.35Ϫ1.44 (m, 2 H), 1.49Ϫ1.57 (m, 2
H), 2.35 (br. s, 1 H), 2.78 (br. s, 1 H), 3.47Ϫ3.55 (m, 2 H),
3.58Ϫ3.68 (m, 2 H), 4.61 (bd, 1 H) ppm. 13C NMR (CDCl3,
75 MHz, 60 °C): δ ϭ 13.8, 19.4, 28.4, 34.4, 51.5, 64.1, 73.6, 79.9,
157.1 ppm.
Typical Procedure for Norvaline Synthesis: Small portions of NaIO4
(850 mg, 4 mmol) were added to a stirred solution of the corres-
ponding syn or anti N-Boc-aminodiol 4 (233 mg, 1 mmol) in ace-
tonitrile/carbon tetrachloride/water (2:2:3, 20 mL). The mixture
was vigorously stirred for 5 min after completion of the addition
and was then treated with RuCl3·H2O (9.2 mg, 0.04 mmol). Stirring
was continued for an additional 2 h. Dichloromethane (25 mL) was
added and the mixture was extracted with aqueous NaHCO3 (1 ).
The aqueous solution was washed with diethyl ether, cooled to 0
°C, carefully acidified with saturated aqueous KHSO4 and ex-
tracted with diethyl ether (3 ϫ 30 mL). The combined organic
layers were dried over anhydrous MgSO4, filtered and concentrated
in vacuo. The residue was dissolved in THF (5 mL) and hydrolysed
by heating under reflux in hydrochloric acid (3 ) for 12 h. The
reaction mixture was diluted with THF (5 mL), washed with diethyl
ether (3 ϫ 30 mL) and evaporated to give the (R)- or (S)-norvaline
hydrochloride, from which the free amino acid was isolated by ion-
exchange chromatography (Dowex 50 W ϫ 8, Hϩ) as a white solid.
{(S)-1-[(S)-1,2-Bis(benzyloxy)ethyl]but-3-enyl}[(R)-1-phenylethyl]-
amine (anti-2c): A solution of allyl-9-BBN (2.1 mmol) was prepared
from a solution of 9-BBN in THF (0.5 , 4.2 mL, 2.1 mmol), meth-
anol (67.2 mg, 2.1 mmol) and a solution of allyl bromide in diethyl
ether (1 , 2.1 mL, 2.1 mmol). The solution of allyl-9-BBN was
slowly added at Ϫ78 °C under Ar to a solution of the imine 1c
(373 mg, 1 mmol) in dry diethyl ether (10 mL). After stirring for
5 h the reaction mixture was quenched at Ϫ78 °C with HCl (10 ,
5 mL) and stirred for an additional 5 days at room temperature.
The organic phase was separated and the water layer was extracted
with diethyl ether. The water layer was adjusted to pH ϭ 11 with
10% NaOH and further extracted with diethyl ether (2 ϫ 20 mL).
The combined organic layers were dried over dry MgSO4, filtered
and concentrated to give an oily residue. Purification of the residue
by flash chromatography with diethyl ether/hexane (1:4) afforded
291 mg (70%) of compound anti-2c as a colourless oil. [α]2D0 ϭ ϩ5.2
(R)-Norvaline (R)-5: (82 mg, 70% yield), m.p. Ͼ300 °C, [α]2D0
ϭ
Ϫ22.2 (c ϭ 10 in 5 HCl); {ref.[13] [α]2D0 ϭ Ϫ24.0 (c ϭ 10 in 5
HCl)}. 1H NMR (D2O, 300 MHz, 25 °C): δ ϭ 0.85 (t, J ϭ 7.5 Hz,
3 H), 1.27Ϫ1.34 (m, 2 H), 1.69Ϫ1.78 (m, 2 H), 3.63 (t, J ϭ 7.5 Hz,
1 H) ppm. 13C NMR (D2O, 75 MHz, 25 °C): δ ϭ 12.7, 17.6, 32.6,
54.4, 175.1 ppm.
1
(c ϭ 1 in CHCl3). H NMR (CDCl3, 300 MHz, 25 °C): δ ϭ 1.28
(d, J ϭ 6.6 Hz, 3 H), 1.62 (br. s, 1 H), 2.21Ϫ2.42 (m, 2 H),
2.67Ϫ2.72 (m, 1 H), 3.46Ϫ3.52 (m, 1 H), 3.56 (dd, J ϭ 10.3, J ϭ
5.9 Hz, 1 H), 3.72 (dd, J ϭ 10.3, J ϭ 3.3 Hz, 1 H), 3.85 (q, J ϭ
6.6 Hz, 1 H), 4.44 (d, J ϭ 12.2 Hz, 1 H), 4.44 (d, J ϭ 11.7 Hz, 1
H), 4.51 (d, J ϭ 12.2 Hz, 1 H), 4.61 (d, J ϭ 11.7 Hz, 1 H),
5.01Ϫ5.07 (m, 2 H), 5.69Ϫ5.81 (m, 1 H), 7.19Ϫ7.36 (m, 15 H)
ppm. 13C NMR (CDCl3, 75 MHz, 25 °C): δ ϭ 24.6, 34.1, 55.1,
55.2, 70.9, 72.3, 73.2, 79.8, 117.3, 126.8, 126.9, 127.4, 127.5, 127.6,
(S)-Norvaline (S)-5: (76 mg, 65% yield), m.p. Ͼ300 °C, [α]2D0
ϭ
ϩ23.0 (c ϭ 10 in 5 HCl) {ref.,[13] [α]2D0 ϭ ϩ24.0 (c ϭ 10 in 5
HCl)}. 1H NMR (D2O, 300 MHz, 25 °C): δ ϭ 0.81 (t, J ϭ 7.5 Hz,
3 H), 1.19Ϫ1.29 (m, 2 H), 1.65Ϫ1.74 (m, 2 H), 3.60 (t, J ϭ 7.5 Hz,
1 H) ppm. 13C NMR (D2O, 75 MHz, 25 °C): δ ϭ 12.9, 17.8, 32.5,
54.6, 175.1 ppm.
127.7, 128.2, 128.3, 135.5, 138.4, 138.8, 145.9 ppm. HRMS (FAB) Typical Procedure for the Preparation of Norvaline Methyl Ester
for C28H34NO2 [M ϩ Hϩ]: calcd. 416.2589; found 416.2596.
(S)-MTPA Amides: Thionyl chloride (47.6 mg, 0.4 mmol) was ad-
3766
Eur. J. Org. Chem. 2002, 3763Ϫ3767