Ethyl (1S,2S)-2-(tert-butoxycarbonylamino)cyclohex-3-
enecarboxylate [(-)-13]
General procedure for fluorination of keto-amino ester 15 or 16
Deoxofluor (50% in toluene) and 1 drop of EtOH were added at
A white solid, mp 58–61 ◦C (n-hexane). Yield: 21%. [a]2D5 = +65.2
(c 0.5, EtOH).
0 C to a solution of amino ester 15 or 16 (1 mmol) in CH2Cl2
◦
(10 mL), and the mixture was stirred at this temperature for 8 h.
Then the mixture was diluted with CH2Cl2 (20 mL) and washed
with an aqueous solution of NaHCO3. The organic layer was next
dried over Na2SO4 and concentrated, and the crude product was
purified by flash chromatography on silica gel (n-hexane–EtOAc
4 : 1).
Ethyl (1R,2S,5R)-2-(tert-butoxycarbonylamino)-5-
fluorocyclohexanecarboxylate [(-)-7]
◦
A white solid, mp 94–96 C (n-hexane). Yield: 15% (two steps).
ee > 98%, [a]2D5 = -10.8 (c 0.59, EtOH).
Ethyl (1R*,2R*)-2-(tert-butoxycarbonylamino)-3,3-
difluorocyclohexanecarboxylate (17)
Ethyl (1R,2S,5S)-2-(tert-butoxycarbonylamino)-5-
fluorocyclohexanecarboxylate [(-)-8]
◦
A white solid, mp 83–85 C (n-hexane). Yield: 32% (Rf 0.65, n-
◦
A white solid, mp 62–63 C; (n-hexane); Yield: 15% (two steps).
1
hexane–EtOAc 4 : 1). H NMR (400 MHz, CDCl3): d = 1.23 (t,
ee > 98%, [a]2D5 = -27.5 (c 0.455, EtOH).
3H, CH3, J = 7.15 Hz), 1.41 (s, 9H, tBu), 1.58–1.70 (m, 1H, CH2),
2.04–2.20 (m, 3H, CH2), 2.41–2.59 (m, 3H, CH2 and H-1), 4.07–
4.20 (m, 2H, OCH2), 4.44–4.53 (m, 1H, H-2), 5.09 (brs, 1H, N–H).
Anal. Calcd. for C14H23F2NO4: C, 54.71; H, 7.54; N, 4.56. Found:
C, 54.43; H, 7.29; N, 4.27.
Ethyl (1S,2S,5S)-2-(tert-butoxycarbonylamino)-5-fluorocyclohex-
3-enecarboxylate [(-)-10]
A white solid, mp 120-123 ◦C (n-hexane). Yield: 52%. ee > 98%,
[a]2D5 = +39.1 (c 0.405, EtOH).
Ethyl (1S*,2R*)-2-(tert-butoxycarbonylamino)-3,3-
difluorocyclohexanecarboxylate (18)
Ethyl (1S,2R,3R)-2-(tert-butoxycarbonylamino)-3-
fluorocyclohexanecarboxylate [(-)-12]
A white solid, mp 88-90 ◦C (n-hexane). Yield: 39% (Rf 0.60, n-
1
A white solid, mp 95–97 ◦C (n-hexane). Yield: 41%. ee > 98%,
[a]2D5 = -7.1 (c 0.35, EtOH).
hexane–EtOAc 4 : 1). H NMR (400 MHz, CDCl3): d = 1.22 (t,
3H, CH3, J = 7.15 Hz), d = 1.40 (s, 9H, tBu), 1.46–1.73 (m, 3H,
CH2), 1.78–1.84 (m, 1H, CH2), 1.93–2.00 (m, 1H, CH2), 2.17–2.23
(m, 1H, CH2), 2.41–2.50 (m, 1H, H-1), 4.09–4.21 (m, 3H, OCH2
and H-2), 4.71 (brs, 1H, N–H). Anal. Calcd. for C14H23F2NO4: C,
54.71; H, 7.54; N, 4.56. Found: C, 54.46; H, 7.20; N, 4.23.
General procedure for oxidation of 9 and 11
Sulfur trioxide-pyridine complex (3 equiv) and DMSO (2 mL) and
Et3N (4 equiv), were added at 0 ◦C to a solution of amino ester 9
or 11 (2 mmol) in CH2Cl2 (20 mL) and the mixture was stirred for
Acknowledgements
◦
10 h at 20 C. It was then diluted with CH2Cl2 (20 mL), washed
with H2O (3 ¥ 20 mL), dried over Na2SO4 and concentrated. The
crude product was purified by flash chromatography on silica gel
(n-hexane–EtOAc 3 : 1).
We are grateful to the Hungarian Research Foundation (OTKA
No. T81371) for financial support, and acknowledge the receipt of
Bolyai Ja´nos Fellowships for Lora´nd Kiss and Eniko˝ Forro´. We
would also like to thank MICINN (CTQ2010-19774) of Spain and
Generalitat Valenciana (PROMETEO/2010/061) for financial
support. We acknowledge the support from COST-CM0803
(European Cost action: Functional peptidomimetic foldamers:
from unnatural amino acids to self-assembling nanomaterials).
Ethyl (1R*,2R*)-2-(tert-butoxycarbonylamino)-3-
oxocyclohexanecarboxylate (15)
◦
A white solid, mp 60–63 C; (n-hexane); Yield: 70%; (Rf 0.6, n-
hexane–EtOAc 2 : 1). 1H NMR (400 MHz, CDCl3): d = 1.22 (t, 3H,
CH3, J = 7.20 Hz), 1.43 (s, 9H, tBu), 1.78–1.88 (m, 1H, CH2), 1.97–
2.22 (m, 3H, CH2), 2.33–2.40 (1H, CH2), 2.58–2.63 (m, 1H, CH2),
3.78–3.82 (m, 1H, H-1), 4.13–4.18 (m, 2H, OCH2), 4.30–4.36 (m,
1H, H-2), 5.62 (brs, 1H, N–H). Anal. Calcd. for C14H23NO5: C,
58.93; H, 8.12; N, 4.91. Found: C, 58.61; H, 7.84; N, 4.62.
References
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Ethyl (1S*,2R*)-2-(tert-butoxycarbonylamino)-3-
oxocyclohexanecarboxylate (16)
A white solid, mp 90–92 ◦C; (n-hexane); Yield: 74%; (Rf 0.55, n-
1
hexane–EtOAc 2 : 1). H NMR (400 MHz, CDCl3): d = 1.23 (t,
3H, CH3, J = 7.20 Hz), 1.41 (s, 9H, tBu), 1.59–1.72 (m, 1H, CH2),
2.07–2.20 (m, 3H, CH2), 2.39–2.58 (m, 3H, CH2 and H-1), 4.09–
4.20 (m, 2H, OCH2), 4.46–4.52 (m, 1H, H-2), 5.08 (brs, 1H, N–H).
13C NMR (400 MHz, CDCl3): d = 14.5, 25.9, 28.4, 28.6, 41.1, 52.5,
60.6, 61.6, 80.2, 155.7, 172.2, 206.1. Anal. Calcd. for C14H23NO5:
C, 58.93; H, 8.12; N, 4.91. Found: C, 58.66; H, 7.88; N, 4.65.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 6528–6534 | 6533
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