S1
Supporting Information for
2-Ene-1,4-diols by Dimerization of Terminal Epoxides using Hindered Lithium Amides David M. Hodgson,*† Christopher D. Bray† and Nicholas D. Kindon‡ †
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, U.K. ‡
AstraZeneca R&D Charnwood Medicinal Chemistry, Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K.
Contents General Details
S2
Spectral Data (3S,4E,6S)-2,2,7,7-Tetramethyloct-4-ene-3,6-diol (S,S)-2a
S2
(1R,2Z,4R)-1,4-Dicyclohexylbut-2-ene-1,4-diol 3b
S2
(1R,2E,4R)-1,4-Dicyclohexylbut-2-ene-1,4-diol 3a
S2
(1S,4S)-1,4-Dicyclohexylbutane-1,4-diol 7
S3
(6R,7Z,9R)-Tetradec-7-ene-6,9-diol 4b
S3
(6R,7E,9R)-Tetradec-7-ene-6,9-diol 4a
S3
(2S,3E,5S)-1,6-Bis(trityloxy)hex-3-ene-2,5-diol 6
S4
1
13
H and C NMR Spectra
(3S,4E,6S)-2,2,7,7-Tetramethyloct-4-ene-3,6-diol (S,S)-2a
S5
(1R,2E,4R)-1,4-Dicyclohexylbut-2-ene-1,4-diol 3a
S6
(1R,2Z,4R)-1,4-Dicyclohexylbut-2-ene-1,4-diol 3b
S7
(1S,4S)-1,4-Dicyclohexylbutane-1,4-diol 7
S8
(6R,7E,9R)-Tetradec-7-ene-6,9-diol 4a
S9
(6R,7Z,9R)-Tetradec-7-ene-6,9-diol 4b
S10
(2S,3E,5S)-1,6-Bis(trityloxy)hex-3-ene-2,5-diol 6
S11
Synthetic D-mannitol
S12
Natural D-mannitol
S13
Synthetic D-iditol
S14
Natural L-iditol
S15
X-ray Data (3S,4E,6S)-2,2,7,7-Tetramethyloct-4-ene-3,6-diol (S,S)-2a
S16
(3R*,4Z,6R*)-2,2,7,7-Tetramethyloct-4-ene-3,6-diol 2b
S16
(1R,2E,4R)-1,4-Dicyclohexylbut-2-ene-1,4-diol 3a
S16
References
S17
S2
General Details All reactions required anhydrous conditions and were conducted in flame-dried apparatus under an atmosphere of argon. THF was filtered through activated alumina; TMP and tBuOMe were distilled from CaH2; all other reagents were used as received. Column chromatography was carried out on Kieselgel 60 (40-63 µm) silica gel unless otherwise stated. Light petrol refers to the fraction of petroleum boiling between 30 ºC and 40 ºC. IR spectra were recorded as thin films or KBr discs, using a 1750 FTIR spectrophotometer. 1H and 13C NMR spectra were recorded at 25 ºC, with DPX250, DPX400, AV400 or AMX500 spectrometers unless otherwise stated. Chemical shifts are reported relative to CHCl3 [1H δ 7.27]/CDCl3 [13C δ 77.0] or MeOH-d4 [1H δ 3.31, 13C δ 49.0]. Coupling constants (J) are given in Hz, multiplicities are given as multiplet (m), singlet (s) (and where applicable are described as broad (b)), doublet (d) or triplet (t). Mass spectra were obtained using a GCT spectrometer or by the EPSRC National Mass Spectrometry Service Centre at the University of Swansea using a high resolution double focusing mass spectrometer with tandem ion trap.
Spectral Data (3S,4E,6S)-2,2,7,7-Tetramethyloct-4-ene-3,6-diol (S,S)-2a1 According to the general procedure (R)-tert-butyloxirane (244 μL, 2.00
OH
mmol) gave enediol (S,S)-2a as a white solid (172 mg, 86%); Rf 0.41 OH
(90% Et2O in petrol); mp 119-120 ºC (lit.1 120-121 ºC); [α]D24 –52.7 (c =
1.0, MeOH) (lit.1 −55.4 (c = 2.17, MeOH)); IR vmax/cm-1 (KBr) 3419, 2964, 1473, 1363, 1313, 1265, 1085, 1051, 1003; 1H NMR (400 MHz, MeOH-d4) δ 5.72-5.63 (m, 2H, 2 × =CH), 4.91 (bs, 2H, 2 × OH), 3.73-3.65 (m, 2H, 2 × OCH), 0.91 (s, 18H, 2 × CMe3);
13
C
NMR (100 MHz, MeOH-d4) δ 133.3 (2 × =CH), 81.6 (2 × OCH), 35.9 (2 × CMe3), 26.4 (2 × CMe3); Anal. calcd for C12H24O2: C, 71.95; H, 12.08. Found C, 71.87; H, 11.98.
(1R,2Z,4R)-1,4-Dicyclohexylbut-2-ene-1,4-diol 3b and (1R,2E,4R)-1,4-dicyclohexylbut-2ene-1,4-diol 3a1 OH O
HO OH
+ OH
According to the general procedure (R)-cyclohexyloxirane (271 μL, 2.00 mmol) first of all gave (Z)-enediol 3b as a white solid (66 mg, 26%); Rf 0.70 (Et2O); mp 110-111 °C; [α]D24 −2.4 (c = 0.25, CHCl3); IR vmax/cm-1 (KBr) 3383, 2922, 2851, 1449, 1083, 1010; 1H NMR (400 MHz, MeOH-d4) δ 5.47-5.41 (m, 2H, 2 × =CH), 4.90 (bs, 2H, 2 × OH), 4.09-4.01 (m,
S3
2H, 2 × OCH), 2.02-0.80 (m, 22H, 2 × Cy);
13
C NMR (100 MHz MeOH-d4) δ 133.8 (2 ×
=CH), 73.1 (2 × OCH), 45.6 (2 × CH), 29.9 (2 × CH2), 29.9 (2 × CH2), 27.8 (2 × CH2), 27.4 (2 × CH2), 27.3 (2 × CH2); HRMS m/z (M + NH4+) Found: 270.2430. C16H32O2N requires 270.2428. Second to elute was (E)-enedio1 3a as a white solid (129 mg, 51%); Rf 0.30 (Et2O); mp 114-116 °C (lit.1 117-120 °C); [α]D24 −30.3 (c = 1.0, CHCl3) (lit.1 +39.0 (c = 1.5, CHCl3) for (ent)-3a (82% ee); IR vmax/cm-1 (KBr) 3411, 2919, 2838, 2441, 1618, 1448, 1011; 1
H NMR (400 MHz, MeOH-d4) δ 5.60-5.57 (m, 2H, 2 × =CH), 4.91 (bs, 2H, 2 × OH), 3.80-
3.72 (m, 2H, 2 × OCH), 2.00-0.80 (m, 22H, 2 × Cy); 13C NMR (MeOH-d4, 100 MHz) δ 134.1 (2 × =CH), 78.0 (2 × OCH), 45.2 (2 × CH), 30.1 (4 × CH2), 27.8 (2 × CH2), 27.4 (2 × CH2), 27.3 (2 × CH2). (1S,4S)-1,4-Dicyclohexylbutane-1,4-diol 71 O
OH
OH
OH
OH
(R)-Cyclohexyloxirane (271 μL, 2.00 mmol) was dimerized according to the general procedure, following addition of MeOH (3 cm3), the reaction was separated between EtOAc (10 cm3) and 0.05 M H3PO4 (10 cm3). The aqueous phase was extracted with EtOAc (10cm3) and the combined organic phases were washed with brine (20 cm3) then dried with MgSO4. Removal of the solvent in vacuo gave a colorless oil that was dissolved in EtOH (40cm3). 5% Pt/C (20 mg) was added and the suspension was stirred under 50 atm of hydrogen for 2 h. Afterwards, the mixture was filtered through a pad of Celite, the solvent was removed in vacuo and the residue was purified by flash chromatography to give diol 7 as a white solid (193 mg, 76%); Rf 0.31 (40% EtOAc in petrol); mp 154-155 ºC (lit.1 116-118 ºC (82% ee)); [α]D24 −18.4 (c = 1.0, CHCl3) (lit.1 −12.5 (c = 0.6, CHCl3)(82% ee)); IR vmax/cm-1 (KBr) 3398, 2922, 2852; 1H NMR (400 MHz, CDCl3) δ 3.46-3.28 (m, 2H, OCH), 2.11 (bs, 2H, OH), 1.90-0.95 (m, 26H, 12 × CH2 and 2 × CH); 13C NMR (100 MHz, CHCl3) δ 43.9 (2 × CH), 30.9 (2 × CH2), 29.1 (2 × CH2), 27.9 (2 × CH2), 26.5 (2 × CH2), 26.3 (2 × CH2), 26.1 (2 × CH2). (6R,7Z,9R)-Tetradec-7-ene-6,9-diol 4b2 and (6R,7E,9R)-Tetradec-7-ene-6,9-diol 4a3 O C5H11
OH
HO OH
C5H11
C5H11 + C H 5 11
C5H11 OH
According to the general procedure (R)-1,2-epoxyheptane (271μL, 2.00 mmol) first of all gave (Z)-enediol 4b as a colorless oil (43 mg, 19%); Rf 0.24 (25% EtOAc in petrol); [α]D24 0
S4
(c = 0.1, CHCl3); IR vmax/cm-1 (film) 3383, 2930, 2859, 1727, 1466, 1369, 1255, 1175, 1126, 1005; 1H NMR (400 MHz, CDCl3) 5.55-5.45 (m, 2H, 2 × =CH), 4.49-4.37 (m, 2H, 2 × OCH), 1.79-1.23 (m, 18H, 8 × CH2 and 2 × OH), 0.90 (t, 6H, J = 7, 2 × Me); 13C NMR (100 MHz) 134.3 (2 × =CH), 68.3 (2 × OCH), 37.6 (2 × CH2), 31.7 (2 × CH2), 25.1 (2 × CH2), 22.6 (2 × CH2), 14.0 (2 × Me). Second to elute was (E)-enediol 4a as a colorless oil (99 mg, 43%); Rf 0.15 (25% EtOAc in petrol); [α]D24 −6.6 (c = 1.0, CHCl3) (lit.3 +6.3 (c = 2.3, CHCl3) (ent)-4a); IR vmax/cm-1 (film) 3346, 2930, 2859, 1466, 1131, 1024; 1H NMR (400 MHz, CDCl3) δ 5.69-5.60 (m, 2H, 2 × =CH), 4.08-4.00 (m, 2H, 2 × OCH), 2.10 (d, 2H, J = 4, OH), 1.60-1.20 (m, 16H, 8 × CH2), 0.88 (t, 6H, J = 7, 2 × Me);
13
C NMR δ (100 MHz, CDCl3)
133.9 (2 × =CH), 72.5 (2 × OCH), 37.2 (2 × CH2), 31.7 (2 × CH2), 25.1 (2 × CH2), 22.6 (2 × CH2), 14.0 (2 × CH2).
(2S,3E,5S)-1,6-Bis-(trityloxy)-hex-3-ene-2,5-diol 6 To a solution of di-tert-amylamine (1.02 cm3, 5.04 mmol) and
OH TrO
OTr OH
TMEDA (0.76 cm3, 5.04 mmol) in THF (1 cm3) at 0 °C was added n-BuLi (1.6 mol dm-3; 3.15 cm3, 5.04 mmol) dropwise.
The solution was warmed to 25 °C and stirred for 30 min. before being cooled to −72 °C. A solution of (S)-tritylglycidyl ether (800 mg, 2.52 mmol) in THF (1 cm3) was added dropwise over 10 min and the solution was then stirred at this temperature for 40 h. The reaction was quenched with MeOH (2.5 cm3). The reaction mixture was separated between EtOAc (10 cm3) and sat. aq. NH4Cl (10 cm3). The aqueous layer was washed with EtOAc (10 cm3) and the combined organic phases were then dried (MgSO4), filtered and the solvent removed in vacuo. Purification of the residue by column chromatography (Florisil, 30% EtOAc in petrol) gave enediol 6 as a white solid (409 mg, 51%), Rf 0.53 (40% EtOAc in petrol); mp 6061 °C; [α]D24 +2.2 (c = 1.0, CHCl3), IR vmax/cm-1 (KBr) 3424, 3057, 2921, 2869, 1596, 1490, 1448, 1319, 1219, 1155, 1075, 1032; 1H NMR (400 MHz, CDCl3) δ 7.50-7.23 (m, 30H, 2 × CPh3), 5.73-5.71 (2H, m, 2 × =CH), 4.31-4.28 (2H, m, 2 × OCH), 3.18 (4H, ddd, J = 17, 9 and 3, 2 × CH2O), 2.42 (2H, d, J = 3, 2 × OH); 13C NMR (100 MHz) δ 143.7 (6 × ArCquat) 130.7 (2 × =CH), 128.6 (12 × ArCH), 127.9 (12 × ArCH), 127.1 (6 × p-ArCH), 86.8 (2 × OCPh3), 71.1 (2 × OCH), 67.4 (2 × CH2); HRMS m/z (M + NH4+) Found: 650.3267 C44H44O4N requires 650.3265.
S5
0.91
3.73 3.70 3.69 3.69 3.68 3.65
4.91 5.67 5.63
H and 13C NMR Spectra 5.72 5.68 5.68 5.67
1
OH
OH
(S,S)-2a
6.0
5.0
9.64
7.0
1.00
8.0
0.86
0.96
9.0
4.0
3.0
2.0
1.0
0.0
150
140
130
120
110
100
90
80
70
60
50
40
26.4
35.9
81.6
133.3
ppm (f1)
30
20
10
0
3.79 3.77 3.76
4.91
5.59 5.59 5.58
S6 OH
OH
3a
6.0
5.0
12.00
7.0
0.96
8.0
1.00
0.96
9.0
4.0
3.0
2.0
1.0
0.0
150 ppm (f1)
140
130
120
110
100
90
80
70
60
50
30.1 27.8 27.4 27.3
45.2
78.0
134.1
ppm (f1)
40
30
20
10
0
150
140
130
120
110 6.0
100
90 5.0
80 4.0
70
60 3.0
50
40
30
27.8 27.4 27.3
7.0
29.9 29.9
8.0
45.6
73.1
9.0 12.73
10.0 ppm (f1) 1.02
1.00
133.8
4.09 4.07 4.06 4.05 4.05 4.03 4.03 4.01
5.42
5.48
5.46 5.45 5.44 5.44
S7
HO OH
3b
2.0 1.0
20
0.0
10
0
2.11
3.39 3.37 3.35
S8
OH
OH
7
4.0
3.0
2.0
160 150 ppm (f1)
140
130
120
110
100
90
80
70
60
50
40
1.0
30
0.0
26.5 26.3 26.1
5.0
27.9
6.0
30.9 29.1
7.0
43.9
8.0
13.37
9.0
1.09
1.00
10.0 ppm (f1)
20
10
0
0.87
0.90
0.89
2.10 2.10
3.91
4.09 4.08 4.26
5.60
5.65 5.65 5.64 5.64
5.69
S9
OH C5H11
C5H11
OH
4a
160 150 ppm (f1)
140
130
120
110
100
90
80
70
60
50
40
30
20
0.0
14.0
22.6
1.0
25.1
2.0
31.7
3.0
72.5
4.0
37.2
5.0
133.9
6.0
3.00
7.0
8.20
8.0
0.92
9.0
0.88
0.85
10.0 ppm (f1)
10
0
HO OH
0.90
5.55 5.51 5.51 5.49 5.48 5.45 4.49 4.48 4.46 4.44 4.42 4.41 4.53 4.37
S10
C5H11
C5H11
4b
160 ppm (f1)
150
140
3.0
2.0
68.3
4.0
130
120
110
100
90
80
70
60
50
40
30
1.0
20
0.0
14.0
5.0
22.6
6.0
25.1
7.0
31.7
8.0
37.6
9.0
134.3
10.0 ppm (t1)
10
0
140
130
120
110 6.0
100 5.0
90
80
70 67.4
7.0
71.1
86.8
8.0 4.0
60 0.88
9.0 1.92
160 150 ppm (f1)
3.26 3.25 3.23 3.21 3.16 3.13 3.09 2.42 2.41
4.31 4.30 4.33 4.28
7.47 7.46 7.44 7.43 7.36 7.34 7.34 7.30 7.29 7.28 7.27 5.72 5.72 5.71 5.71
OH
1.00
10.0 ppm (f1)
130.7 128.6 127.9 127.1
TrO
0.89
18.37
143.7
S11
OTr
6 OH
3.0
50
2.0
40 1.0
30
20
0.0
10
0
3.900 ppm (f1)
6.00
5.50
5.00
4.50
4.00
3.50
3.00
130 ppm (f1)
120
110
100
90
80
70
3.800
2.50
3.700
2.00
3.650
3.600
1.50
3.550
1.00
3.53
3.55
3.57
3.59
3.62 3.61
3.65 3.64
3.68
3.71
3.750
3.500
0.50
3.450
0.00
63.6
6.50
71.1 69.6
7.00 ppm (f1)
3.850
3.74 3.73
3.79 3.78
Synthetic D-mannitol
3.79 3.78 3.74 3.73 3.71 3.68 3.65 3.64 3.62 3.61 3.59 3.57 3.55 3.53
4.71
S12
60
50
40
30
20
S13
3.900 ppm (f1)
7.00 ppm (f1)
6.50
6.00
5.50
5.00
4.50
4.00
3.50
3.850
3.800
3.00
3.750
3.700
2.50
2.00
3.650
1.50
3.600
3.550
3.52
3.55
3.57
3.59
3.61
3.65 3.64
3.67
3.71
3.74 3.73
3.79 3.78
3.79 3.78 3.74 3.73 3.71 3.67 3.65 3.64 3.61 3.59 3.57 3.55 3.52
4.71
Natural D-mannitol
3.500
1.00
0.50
20
10
3.450
0.00
130 ppm (f1)
120
110
100
90
80
70
63.6
71.1 69.6
Na
60
50
40
30
0
S14
3.850 ppm (f1)
5.0
4.0
140 ppm (f1)
130
120
110
100
90
3.0
80
70
3.700
3.650
3.600
2.0
3.550
3.50
3.53
3.55
3.57
3.59
3.60
3.63
3.65
3.72
3.75 3.74 3.73 3.750
3.500
1.0
3.450
0.0
63.1
6.0
72.0 71.5
7.0 ppm (f1)
3.800
3.76
3.78
3.78 3.63 3.60 3.59 3.57 3.55 3.75 3.74 3.73 3.72 3.76 3.53 3.50
4.68
Synthetic D-Iditol
60
50
40
30
20
10
0
3.800 ppm (f1)
6.00
5.50
5.00
4.50
4.00
3.50
3.00
150 140 ppm (f1)
130
120
110
100
90
80
70
3.650
2.50
3.600
2.00
3.550
1.50
3.47
3.50
3.52
3.54
3.56
3.57
3.59
3.60
3.62
3.69
3.70 3.700
3.500
1.00
3.450
0.50
3.400
0.00
63.1
6.50
72.0 71.5
7.00 ppm (f1)
3.750
3.71
3.73
Natural L-Iditol
3.60 3.59 3.57 3.56 3.54 3.52 3.73 3.71 3.70 3.69 3.62 3.50 3.47
4.68
S15
60
50
40
30
20
10
0
S16
X-ray Data (orteps shown at 40% probability) (3S,4E, 6S)-2,2,7,7-Tetramethyloct-4-ene-3,6-diol (S,S)-2a4
(3R*, 4Z, 6R*)-2,2,7,7-Tetramethyloct-4-ene-3,6-diol 2b5
(1R,2E, 4R)-1,4-Dicyclohexylbut-2-ene-1,4-diol 3a6
S17
References 1. Bach, J.; Berenguer, R.; Garcia, J.; López, M.; Manzanal, J.; Vilarrasa, J. Tetrahedron 1998, 54, 14947−14962. 2. Amador, M.; Ariza, X.; Garcia, J.; Sevilla, S. Org.Lett. 2002, 4, 4511−4514. 3. Ariza, X.; Fernández, N.; Garcia, J., López, M.; Montserrat, L.; Ortiz, J. Synthesis 2004, 128−134. 4. CCDC 264354 available at http://www.ccdc.cam.ac.uk. 5. CCDC 264355 available at http://www.ccdc.cam.ac.uk. 6. CCDC 264353 available at http://www.ccdc.cam.ac.uk.
