Beilstein J. Org. Chem. 2012, 8, 1485–1498.
We would like to stress here that studies on systems of this size was added dropwise over 7 h. The solvent was evaporated and
are influenced quite strongly by dispersion contributions [60- flash chromatography on silica gel (first with ethyl acetate to
66] and that standard DFT calculations should be supplemented elute impurities, then with ethyl acetate/ethanol 8:1) gave 3
by at least single-point MP2 energy corrections with an (1.731 g, 6.24 mmol, 56%) as a colourless solid. [α]D25 −85 (c
extensive, large basis set. The DFT-D method agrees very well 1.0, chloroform); 1H NMR (300 MHz, DMSO-d6) δ 0.90–1.30
with the MP2 results.
(m, 4H), 1.39 (d, J = 7.0 Hz, 3H), 1.49–1.67 (m, 2H), 1.72–1.84
(m, 1H), 1.88–2.02 (m, 1H), 2.40–2.46 (m, 1H), 5.34–5.52 (m,
1H), 7.14–7.42 (m, 5H) ppm; 13C NMR (75 MHz, DMSO-d6) δ
Experimental
General: Reagents obtained from commercial sources were 22.81, 24.71, 24.84, 31.82, 34.69, 52.63, 54.53, 59.73, 126.42,
used without further purification. Dichloromethane was dried 126.95, 128.59, 144.85, 182.03 ppm; MS–FAB (m/z): 181, 262,
by heating under reflux over P2O5 and by distillation. Diethyl- 278 [M + H]+, 289, 391.
ether was dried by heating under reflux over sodium/benzo-
phenone and by distillation prior to use. Solvents for chroma- Compound 5: A solution of 3 (0.100 g, 0.36 mmol, 1.0 equiv),
tography were distilled prior to use. TLC chromatography was 1,3-bis(tert-butoxycarbonyl)-2-(trifluoromethylsulfonyl)-guani-
performed on precoated aluminium silica gel ALUGRAM SIL dine (0.141 g, 0.36 mmol, 1.0 equiv) and triethylamine
G/UV254 plates (Macherey-Nagel GmbH & Co.). Flash chro- (0.036 g, 0.049 mL, 0.36 mmol, 1.0 equiv) in dichloromethane
matography was performed on silica gel 60 Å (Acros particle (5 mL) was stirred for 24 h at ambient temperature and evapor-
size: 0.035–0.070 mm). NMR spectra were recorded on a ated. The residue was purified by flash chromatography over
Bruker Avance 300. FAB mass spectra were measured with a silica gel (petrol ether/ethyl acetate 6:1) to obtain 5 (0.182 g,
Micromass: ZabSpec. The enantiomeric excess of products was 0.35 mmol, 98%) as a colourless solid. 1H NMR (300 MHz,
determined by chiral HPLC analysis in comparison with DMSO-d6) δ 1.17–1.36 (m, 4H) 1.41 (s, 3H), 1.45 (s, 9H), 1.47
authentic racemic material. HPLC measurements were (s, 9H), 1.51–1.60 (m, 2H), 1.63–1.79 (m, 1H), 1.89–2.07 (m,
performed using Agilent 1200 Series equipment: vacuum 1H), 2.60–2.68 (m, 1H), 3.83–3.98 (m, 1H), 4.15–4.32 (m, 1H),
degasser G1322-90010, quaternary pump G1311-90010, ther- 7.16–7.39 (m, 5H), 7.77 (m, 1H), 8.33 (d, J = 7.7 Hz, 1H), 9.02
mostated column compartment G1316-90010, diode array and (m, 1H), 11.56 (m, 1H) ppm; MS–FAB (m/z): 193, 199, 205,
multiple-wavelength detector SL G1315-90012, standard and 225, 260, 287, 320 [M − 2Boc + H]+, 420 [M – Boc + H]+, 521
preparative autosampler G1329-90020, and Agilent Chemsta- [M + H]+.
tion for LC software.
Compound 6: A solution of 5 (0.160 g, 0.31 mmol, 1.0 equiv)
(R)-(−)-α-Methylbenzyl isothiocyanate (2): To a solution of in dichloromethane (3 mL) was treated with trifluoroacetic acid
(R)-1-phenylethylamine (3.000 g, 3.151 mL, 24.76 mmol, (1.535 g, 1.0 mL, 13.46 mmol, 43.4 equiv) at ambient tempera-
1.0 equiv) in anhydrous diethyl ether (20 mL), cooled to 0 °C ture for 7 h. The solvents were evaporated and the residue was
and under a nitrogen atmosphere, carbon disulfide (12.065 g, purified by column chromatography over silica gel (dichloro-
158.46 mmol, 9.6 mL, 6.4 equiv) and N,N′-dicyclohexylcarbo- methane/methanol 95:5) to yield 6 (0.112 g, 0.26 mmol, 85%)
diimide (5.109 g, 24.76 mmol, 1.0 equiv) were added. The reac- as a colourless, hygroscopic solid. [α]D25 −13.62 (c 0.1,
tion mixture was stirred overnight and allowed to warm to ethanol); 1H NMR (300 MHz, DMSO-d6) δ 1.05–1.35 (m, 4H),
ambient temperature during this time. The precipitated N,N″- 1.41 (d, J = 6.2 Hz, 3H), 1.51–1.74 (m, 2H), 1.79–1.93 (m, 1H),
dicyclohexylthiourea was filtered off, washed three times with 1.93–2.19 (m, 1H), 2.56–2.68 (m, 1H), 3.37–3.47 (m, 1H), 4.11
diethyl ether and discarded. After evaporation of the filtrate, the (d, J = 6.2 Hz, 1H), 6.65–6.97 (m, 2H), 7.12–7.58 (m, 9H),
residue was subjected to flash chromatography over silica gel 7.91–8.06 (m, 1H) ppm; 13C NMR (75 MHz, DMSO-d6) δ
(petrol ether/ethyl acetate 8:1) to yield 2 (3.909 g, 23.94 mmol, 14.15, 20.72, 22.39, 23.54, 30.92, 31.45, 53.55, 59.72, 115.64,
97%) as a colourless oil. [α]D25 −4.3 (c 1.0, acetone); 1H NMR 118.76, 125.52, 126.03, 126.23, 128.33, 144.46, 156.41, 158.44,
(300 MHz, CDCl3) δ 1.68 (d, J = 6.7 Hz, 3H), 4.92 (q, J = 170.34 ppm. MS–FAB (m/z): 107, 120, 124, 136, 154, 199, 286,
6.7 Hz, 1H), 7.27–7.50 (m, 5H) ppm; 13C NMR (75 MHz, 289, 307, 320 [M − CF3COO−]+, 376, 391; Anal. calcd: C,
CDCl3) δ 24.96, 57.00, 125.39, 128.18, 128.88, 140.11 ppm. 49.87; H, 6.05; N, 16.16; S, 7.40; found: C, 47.41; H, 5.37; N,
13.98; S, 7.26.
Primary amine-thiourea 3: To a solution of (S,S)-1,2-
diaminocyclohexane (1) (1.273 g, 11.15 mmol, 1.0 equiv) in an- Guanidine-thiourea 7: Compound 6 (0.115 g, 0.27 mmol,
hydrous dichloromethane (100 mL), at ambient temperature and 1.0 equiv) was treated with Amberlyst A26 (OH− form) (1.885
under a nitrogen atmosphere, a solution of 2 (1.820 g, g) in methanol (20 mL) for 15 min. The ion exchanger was
11.15 mmol, 1.0 equiv) in anhydrous dichloromethane (60 mL) filtered off over Celite and the filtrate was evaporated to yield 7
1495