2-Ene-1,4-diols by dimerization of terminal epoxides using hindered lithium amides

Article abstract of DOI:10.1021/ol050402h

(Chemical Equation Presented) Reaction of hindered lithium amides with readily available (enantiopure) terminal epoxides gives 2-ene-1,4-diols via carbenoid dimerization of the corresponding α-lithiated epoxides. D-Mannitol and D-iditol were synthesized u

Full text of DOI:10.1021/ol050402h

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
(1R,2Z,4R)-1,4-Dicyclohexylbut-2-ene-1,4-diol 3b
(1R,2E,4R)-1,4-Dicyclohexylbut-2-ene-1,4-diol 3a
(1S,4S)-1,4-Dicyclohexylbutane-1,4-diol 7
(6R,7Z,9R)-Tetradec-7-ene-6,9-diol 4b
(6R,7E,9R)-Tetradec-7-ene-6,9-diol 4a
(2S,3E,5S)-1,6-Bis(trityloxy)hex-3-ene-2,5-diol 6
1H and 13C NMR Spectra
S2
S2
S2
S3
S3
S3
S4
(3S,4E,6S)-2,2,7,7-Tetramethyloct-4-ene-3,6-diol (S,S)-2a
(1R,2E,4R)-1,4-Dicyclohexylbut-2-ene-1,4-diol 3a
(1R,2Z,4R)-1,4-Dicyclohexylbut-2-ene-1,4-diol 3b
(1S,4S)-1,4-Dicyclohexylbutane-1,4-diol 7
(6R,7E,9R)-Tetradec-7-ene-6,9-diol 4a
(6R,7Z,9R)-Tetradec-7-ene-6,9-diol 4b
(2S,3E,5S)-1,6-Bis(trityloxy)hex-3-ene-2,5-diol 6
Synthetic D-mannitol
S5
S6
S7
S8
S9
S10
S11
S12
S13
S14
S15
Natural D-mannitol
Synthetic D-iditol
Natural L-iditol
X-ray Data
(3S,4E,6S)-2,2,7,7-Tetramethyloct-4-ene-3,6-diol (S,S)-2a
(3R*,4Z,6R*)-2,2,7,7-Tetramethyloct-4-ene-3,6-diol 2b
(1R,2E,4R)-1,4-Dicyclohexylbut-2-ene-1,4-diol 3a
References
S16
S16
S16
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 t-
BuOMe 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
1
spectra were recorded as thin films or KBr discs, using a 1750 FTIR spectrophotometer. H
13
and C 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
13
7.27]/CDCl3 [13C δ 77.0] or MeOH-d4 [1H δ 3.31, C 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
(90% Et2O in petrol); mp 119-120 ºC (lit.1 120-121 ºC); [α]D24 –52.7 (c =
OH
1.0, MeOH) (lit.1 −55.4 (c = 2.17, MeOH)); IR vmax/cm-1 (KBr) 3419, 2964, 1473, 1363,
1
1313, 1265, 1085, 1051, 1003; H NMR (400 MHz, MeOH-d4) δ 5.72-5.63 (m, 2H, 2 ×
13
=CH), 4.91 (bs, 2H, 2 × OH), 3.73-3.65 (m, 2H, 2 × OCH), 0.91 (s, 18H, 2 × CMe3); 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-2-
ene-1,4-diol 3a1
OH
HO OH
O
+
OH
According to the general procedure (R)-cyclohexyloxirane (271 μL, 2.00 mmol) first of all
24
gave (Z)-enediol 3b as a white solid (66 mg, 26%); Rf 0.70 (Et2O); mp 110-111 °C; [α]D
1
−2.4 (c = 0.25, CHCl3); IR vmax/cm-1 (KBr) 3383, 2922, 2851, 1449, 1083, 1010; H 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
13
2H, 2 × OCH), 2.02-0.80 (m, 22H, 2 × Cy); 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;
1H 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]D −18.4 (c = 1.0, CHCl3) (lit.1 −12.5 (c = 0.6, CHCl3)(82% ee)); IR vmax/cm-1 (KBr)
24
3398, 2922, 2852; 1H NMR (400 MHz, CDCl3) δ 3.46-3.28 (m, 2H, OCH), 2.11 (bs, 2H,
13
OH), 1.90-0.95 (m, 26H, 12 × CH2 and 2 × CH); C 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
OH
O
HO OH
C5H11
OH
C5H11
C5H11
+
C5H11
C5H11
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,
1
1005; H 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)
1
(ent)-4a); IR vmax/cm-1 (film) 3346, 2930, 2859, 1466, 1131, 1024; H 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),
13
1.60-1.20 (m, 16H, 8 × CH2), 0.88 (t, 6H, J = 7, 2 × Me); 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
TMEDA (0.76 cm3, 5.04 mmol) in THF (1 cm3) at 0 °C was
TrO
OTr
added n-BuLi (1.6 mol dm-3; 3.15 cm3, 5.04 mmol) dropwise.
OH
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 60-
61 °C; [α]D24 +2.2 (c = 1.0, CHCl3), IR vmax/cm-1 (KBr) 3424, 3057, 2921, 2869, 1596, 1490,
1
1448, 1319, 1219, 1155, 1075, 1032; H 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
13
and 3, 2 × CH2O), 2.42 (2H, d, J = 3, 2 × OH); C 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
1H and 13C NMR Spectra
OH
OH
(S,S)-2a
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
ppm (f1)
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0

S6
OH
OH
3a
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
ppm (f1)
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
ppm (f1)

S7
HO OH
3b
10.0
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
ppm (f1)
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0

S8
OH
OH
7
10.0
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
ppm (f1)
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
ppm (f1)

S9
OH
C5H11
OH
C5H11
4a
10.0
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
ppm (f1)
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
ppm (f1)

S10
HO
OH
C5H11
C5H11
4b
10.0
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
ppm (t1)
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
ppm (f1)

S11
OH
TrO
OTr
OH
6
10.0
ppm (f1)
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
ppm (f1)

S12
Synthetic D-mannitol
3.900
ppm (f1)
3.850
3.800
3.750
3.700
3.650
3.600
3.550
3.500
3.450
7.00
6.50
6.00
5.50
5.00
4.50
4.00
3.50
3.00
2.50
2.00
1.50
1.00
0.50
0.00
ppm (f1)
130
ppm (f1)
120
110
100
90
80
70
60
50
40
30
20

S13
Natural D-mannitol
3.900
3.850
3.800
3.750
3.700
3.650
3.600
3.550
3.500
3.450
ppm (f1)
7.00
6.50
6.00
5.50
5.00
4.50
4.00
3.50
3.00
2.50
2.00
1.50
1.00
0.50
0.00
ppm (f1)
Na
130
120
110
100
90
80
70
60
50
40
30
20
10
0
ppm (f1)

S14
Synthetic D-Iditol
3.850
ppm (f1)
3.800
3.750
3.700
3.650
3.600
3.550
3.500
3.450
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
ppm (f1)
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
ppm (f1)

S15
Natural L-Iditol
3.800
ppm (f1)
3.750
3.700
3.650
3.600
3.550
3.500
3.450
3.400
7.00
6.50
6.00
5.50
5.00
4.50
4.00
3.50
3.00
2.50
2.00
1.50
1.00
0.50
0.00
ppm (f1)
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
ppm (f1)

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.