M. Trajkovic et al. / Tetrahedron: Asymmetry 23 (2012) 602–604
603
same procedure was repeated twice. The residue was diluted with
ethyl acetate (30 mL), washed with water, dried over anhyd
MgSO4, and concentrated under reduced pressure, to give the
crude title compound 2c, as a pale yellow viscous oil, which was
used in the next step without further purification.
1. Boc2O
2. Me2C(OMe)2, H+
O
NBoc
COSEt
O
NBoc
CHO
Et3SiH
Pd/C
1
3. i BuOC(O)Cl
EtSH, Et3N
88%
53%
4
5
3.1.3. (S)-tert-Butyl 4-(ethylthiocarbonyl)-2,2-dimethyl-
oxazolidine-3-carboxylate 5
>95% ee
Isobutyl chloroformate (2.51 g; 2.40 mL; 18.36 mmol) and tri-
ethylamine (2.25 g; 3.10 mL; 22.24 mmol) were added to a cold
(0 °C) solution of aminoacetal 2c from the previous step
(ꢁ3.35 g; 14.27 mmol) in dichloromethane (11 mL) under an argon
atmosphere. The reaction mixture was vigorously stirred for
30 min at 0 °C, then ethanethiol (2.01 g; 2.40 mL; 32.41 mmol)
and triethylamine (2.25 g; 3.10 mL; 22.24 mmol) were added.
The resulting solution was stirred for 30 min at 0 °C and 45 min
at rt. The reaction mixture was diluted with dichloromethane
(25 mL), washed with water (40 mL) and brine (30 mL), dried over
anhydrous MgSO4, concentrated under reduced pressure and puri-
fied by distillation under reduced pressure (bp 110 °C/0.3 mmHg)
to give 2.19 g (53% over three steps) of thioester 5, as white crys-
Scheme 2. Synthesis of the Garner aldehyde.
target aldehyde 4, which was isolated in the analytically pure form
in 88% yield. The product had all physical data identical with those
described in the literature. The enantiomeric purity of the product
was confirmed by its specific rotation (96–98% ee), as well as by its
conversion to the Mosher ester of the corresponding alcohol 3,6a
where the content of the other enantiomer, according to 1H NMR
spectrum, was below the level of detection. The procedure was re-
peated 10 times and always proceeded in a reproductive fashion,
without event. In addition to its experimental simplicity, the other
advantage of this method is its rapidity, with the Garner aldehyde
being obtained in high chemical purity and enantiomeric excess in
gram quantities within 24 h.
tals. Physical data for 5: mp 43 °C; ½a D20
¼ ꢀ103:4 (c 0.84, CHCl3);
ꢃ
1H NMR (500 MHz, 65 °C, C6D6) d: 4.60–4.20 (m, 1H), 3.88 (d,
J = 8.1 Hz, 1H), 3.78–3.69 (m, 1H), 2.80–2.54 (m, 2H), 1.90 (s, 3H),
1.47 (s, 3H), 1.42 (s, 9H), 1.01 (t, J = 7.4 Hz, 3H). 13C NMR
(126 MHz, C6D6) d: 200.1, 152.1, 96.2, 80.8, 67.4, 67.0, 28.8, 26.2,
23.6, 23.6, 15.0. IR (film): 2978, 2935, 2880, 1708, 1370, 1264,
1207, 1169, 1094. HRMS (ESI) calcd for C13H23NO4S [MNa]+:
312.1242, found: 312.1240. Anal. Calcd for C13H23NO4S: C, 53.95;
H, 8.01; N, 4.84; S, 11.08. Found: C, 53.99; H, 7.82; N, 4.70; S, 10.78.
The residue after extraction can also be purified by dry-flash
chromatography (SiO2; eluent: petroleum-ether/EtOAc = 9:1).
3. Experimental
3.1. General experimental
All chromatographic separations were performed on Silica, 10–
18, 60A, ICN Biomedicals. Standard techniques were used for the
purification of reagents and solvents. NMR spectra were recorded
on Bruker Avance III 500 (1H NMR at 500 MHz, 13C NMR at
125 MHz). Chemical shifts are expressed in ppm (d) using tetra-
methylsilane as the internal standard. IR spectra were recorded
on a Nicolet 6700 FT instrument, and are expressed in cmꢀ1. Mass
spectra were obtained on Agilent technologies 6210 TOF LC/MS
instrument (LC: series 1200). Microanalyses were performed at
the Vario EL III instrument CHNOS Elementar Analyzer, Elementar
Analysensysteme GmbH, Hanau-Germany. Melting points were
determined on a Kofler hot-stage apparatus and are uncorrected.
3.1.4. (S)-tert-Butyl 4-formyl-2,2-dimethyloxazolidine-3-
carboxylate (Garner aldehyde) 4
Triethylsilane (1.27 g; 1.75 mL; 10.96 mmol) was added over
15 min to a suspension of thioester 5 (1.58 g; 5.45 mmol) and
10% palladium on charcoal (191.2 mg; 0.180 mmol) in acetone
(45 mL), at rt, under an argon atmosphere. Upon the completion
of the addition, the reaction mixture was stirred for an additional
15 min, then filtered and concentrated under reduced pressure.
The residue was purified by dry-flash chromatography (SiO2; elu-
ent: petroleum-ether/EtOAc = 85:15) to give 1.10 g (88%) of the
3.1.1. (S)-2-(tert-Butoxycarbonylamino)-3-hydroxypropanoic
acid (N-t-Boc-serine)
A solution of di-tert-butyl dicarbonate (3.15 g; 14.43 mmol) in
1,4-dioxane (5 mL) was added to a cold (0 °C) solution of L-serine
Garner aldehyde 4, as
a colorless oil. Physical data for 4:
½
a 2D0
ꢃ
¼ ꢀ92:2 (c 1.07, CHCl3). 1H NMR (500 MHz, 65 °C, C6D6) d:
9.35 (s, 1H), 3.76–3.91 (m, 1H), 3.67 (d, J = 7.1 Hz, 1H), 3.55 (t,
J = 8.2 Hz, 1H), 1.59 (br s, 3H), 1.44 (br s, 3H), 1.35 (s, 9H). 13C
NMR (126 MHz, 25 °C, C6D6) d: 198.8, 198.5, 152.8, 151.8, 95.5,
94.5, 80.9, 80.7, 65.5, 65.4, 64.0, 63.6, 28.5, 27.2, 26.3, 25.2, 24.3.
IR (ATR): 2979, 2936, 2882, 1739, 1698, 1391, 1372, 1256, 1169,
1095, 1061. HRMS (ESI) calcd for C11H19NO4: [MNa]+ 252.1206,
found: 252.1209. Anal. Calcd for C11H19NO4: C, 57.62; H, 8.35; N,
6.11. Found: C, 57.28; H, 8.59; N, 5.88.
(1.50 g; 14.27 mmol) in 1 M NaOH (1.2 g NaOH in 30 mL water).
The resulting solution was stirred for 30 min at 0 °C and 16 h at
rt (overnight). At the beginning the resulting solution had a white
suspension, but over time became clear. Next, the solution was
concentrated under reduced pressure and the residue dissolved
with an aqueous solution of KHSO4 (4 g in 30 mL water) and set
up pH ꢁ 2–3. The resulting mixture was extracted with ethyl-ace-
tate (3 ꢂ 40 mL), the organic extract was washed with brine,
dried over anhyd MgSO4 and concentrated under reduced pres-
sure to give the crude title compound (2.80 g) as a colorless
viscous oil, which was used in the next step without further
purification.
Acknowledgments
This work was supported by the Serbian Ministry of Education
and Science (Project No. 172027).
3.1.2. (S)-3-(tert-Butoxycarbonyl)-2,2-dimethyloxazolidine-4-
carboxylic acid 2c
References
1. (a) Garner, P. Tetrahedron Lett. 1984, 25, 5855–5858; (b) Garner, P.; Park, J. M. J.
Org. Chem. 1987, 52, 2361–2364.
2. For a review article on the Garner aldehyde, see: Liang, X.; Andersch, J.; Bols, M.
J. Chem. Soc., Perkin Trans. 1 2001, 2136–2157.
3. Garner, P.; Park, J. M. Org. Synth. Coll. 1998, Vol. 9, 300–305. Org. Synth. 1992, 70,
18–28.
At first, 2,2-dimethoxypropane (8.47 g; 10.0 mL; 79.4 mmol)
was added to a solution of N-t-Boc-serine (from the previous step:
2.80 g; 13.60 mmol) and p-toluenesulfonic acid (227.2 mg;
1.19 mmol) in dichloromethane (10 mL) and the solution was con-
centrated under reduced pressure, which caused it to turn red. The