Single and Double Stereoselective Fluorination of (E)-Allylsilanes
Marcin Sawicki, Angela Kwok, Matthew Tredwell, Véronique Gouverneur*
University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, UK,
OX1 3TA.
Additional Material
General Information
1
H NMR spectra were recorded in deuterated solvents by using Bruker AV400 or
AV500 spectrometers, calibrated using residual protonated solvent as an internal
reference. 13C NMR spectra were recorded in deutrated solvent by using Bruker AV400
or AV500 spectrometers.
19
F NMR spectra were recorded on a Bruker AV400
spectrometer. Chemical shifts () are reported in parts per million (ppm) and coupling
constants (J) are measured in hertz (Hz). The following abbreviations are used to
describe multiplicities s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m =
multiplet. NMR were processed in either MestRe-C or ACD/SpecManager. IR spectra
were recorded on a Bruker Tensor 27 FTIR spectrometer. Absorption bands are
measured in wavenumbers (cm-1) and only peaks on interest are reported. Mass spectra
(m/z) and HRMS were recorded on a Micromass LCT in ElectronSpray Ionisation
(ESI), Field Ionization (FI) mode or on a Micromass AutoSpec (CI+). All reactions
requiring anhydrous conditions were conducted in dried apparatus under an inert
atmosphere of argon or nitrogen. Solvents were dried and purified before use,
according to standard procedures. Thin layer chromatography (TLC) was performed
using Merck Kieselgel 60F254 and visualized with a UV lamp or by staining with
S1
KMnO4. Column chromatography was carried out over Merck silica gel C60 (40-60
µm) and eluents as indicated.
Compounds 1a, 1e and 1h were synthesized according to reported procedures.1
(E)-3-(Trimethylsilyl)hex-4-en-1-ol (1b).
OH
SiMe3
A solution of (E)-3-(trimethylsilyl)hex-4-enoate (897mg, 4.2mmol) in Et2O (21ml)
was added dropwise to a slurry of LiAlH4 (800mg, 21mmol) in Et2O (21ml) and
allowed to stir at room temperature for 4hrs. The reaction was quenched by the
addition of a saturated solution of NH4Cl at 0°C. The aqueous phase was extracted
with Et2O. The combined organic phases were dried over MgSO4 and the solvent
removed in vacuo. Purification by silica gel chromatography (pentane: Et2O, 80:20;
Rf = 0.19) afforded (E)-3-(trimethylsilyl)hex-4-en-1-ol (1b) (791mg, 84% yield). 1H
NMR (400 MHz, C6D6): δ -0.46 (s, 9H), 0.77 (br, 1H), 1.31-1.41 (m, 1H), 1.44-1.52
(m, 1H), 1.52-1.58 (m, 1H), 1.56 (d, J=5.7 Hz, 3H), 3.43 (ddd, J=10.4 Hz, 7.6 Hz, 6.4
Hz, 1H), 3.53 (ddd, J=10.4 Hz, 7.1 Hz, 4.6 Hz, 1H), 5.28 (dd, J=15.1 Hz, 7.4 Hz, 1H),
5.30 (dq, J=15.1 Hz, 5.7 Hz 1H); 13C NMR (100 MHz, C6D6) δ -3.2 (3 x CH3), 18.2
(CH3), 29.7 (CH2), 32.2 (CH), 62.5 (CH2), 123.2 (CH), 132.3 (CH); IR (neat): 3333,
2956, 1248, 1034, 968, 837; MS: HRMS: calculated for C9H20NaOSi: m/z 195.1181,
found: m/z 195.1186.
(E)-2,2-Dimethyl-3-(trimethylsilyl)hex-4-enoate (1c).
O
Me3 Si
O
To a solution of diisopropylamine (1.57ml, 11.8mmol, 1.3 eq) in THF (9ml) at 0°C
was added n-BuLi (2.5M, 4.4ml, 11.0mmol, 1.2eq) and allowed to stir for 30 min.
S2
The solution was cooled to -78°C and a solution of ethyl-(E)-2-methyl-3trimethylsilylhex-4-enoate (2.052g, 9.0mmol) in THF (4.5ml) was added via a
syringe. The temperature was gradually raised to -40°C over a period of 2hrs. After
which time iodomethane (0.735ml, 11.8mmol, 1.3 eq) was added and the reaction
mixture was allowed to warm to room temperature overnight. The reaction was
quenched with saturated NH4Cl at 0°C. The aqueous phase was extracted with Et2O,
the combined organic extracts were washed with saturated brine and dried over
MgSO4, filtered and the solvent removed in vacuo to afford crude ethyl (E)-2-methyl3-(trimethylsilyl)hex-4-enoate (1c) as a yellow oil. Purification by silica gel
chromatography (40°-60° petroleum ether: Et2O, 9:1, Rf = 0.40) afforded (1c) 1.560g,
71% yield. 1H NMR (400 MHz, CDCl3): δ -0.23 (s, 9H), 1.13 (s, 3H), 1.19 (s, 3H),
1.24 (t, J=7.1 Hz, 3H), 1.67 (d, J=4.9 Hz, 3H), 1.94 (d, J=10.2 Hz, 1H), 4.04 (dq,
J=10.5 Hz, 7.1 Hz, 1H), 4.10 (dq, J=10.5 Hz, 7.1 Hz, 1H), 5.28 (dd, J=14.9 Hz, J=9.8
Hz, 1H), 5.30 (dq, J=14.9 Hz, 4.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ -0.9 (3 x
CH3), 14.2 (CH3), 18.1 (CH3), 23.8 (CH3), 26.4 (CH3), 42.3 (CH), 44.2 (C), 60.2
(CH2), 126.1 (CH), 128.3 (CH), 178.3 (C); IR (neat): 2966, 1729, 1248, 1147, 971,
839; HRMS: calculated for C13H26O2Si: m/z 242.1702, found: m/z 242.1709.
(E)-2,2-Dimethyl-3-(trimethylsilyl)hex-4-en-1-ol (1d).
OH
SiMe 3
A solution of ethyl-(E)-2,2-dimethyl-3-(trimethylsilyl)hex-4-enoate (1c) (1.150g,
4.5mmol) in Et2O (22.5ml) was added to a slurry of LiAlH4 (860mg, 22.5mmol) in
Et2O (22.5ml) dropwise, the reaction was allowed to stir at room temperature for 4hrs.
The reaction was quenched by the addition of a saturated solution of NH4Cl at 0°C.
The aqueous phase was extracted with Et2O, the combined organic extracts were
S3
washed with saturated brine and dried over MgSO4, filtered and the solvent removed
in vacuo. Purification by silica gel chromatography (hexane: Et2O, 80:20; Rf = 0.35)
afforded (1d) 772mg, 80% yield. 1H NMR (400 MHz, C6D6): δ 0.06 (s, 9H), 0.86 (s,
3H), 0.96 (s, 3H), 1.20 (br, 1H), 1.56 (d, J=11.8 Hz, 1H), 1.57 (dd, J=6.2 Hz, 1.4 Hz,
3H), 3.12 (d, J=10.6 Hz, 1H), 3.26 (d, J=10.6 Hz, 1H), 5.15 (dq, J=14.9 Hz, 6.2 Hz,
1H), 5.45 (ddq, J=14.9 Hz, 11.8 Hz, 1.4 Hz, 1H; H4); 13C NMR (100 MHz, C6D6): δ
0.4 (3 x CH3), 18.1 (CH3), 23.7 (CH3), 25.7 (CH3), 38.2 (C), 41.9 (CH), 72.2 (CH2),
125.0 (CH), 130.4 (CH); IR (neat): 3385, 1248, 1038, 973, 836. HRMS: calculated
for C11H24OSi: m/z 223.1489, found: m/z 223.1493.
anti-(E)-Ethyl-2-methyl-3-(trimethylsilyl)hex-4-enoate (1f).
O
Me3 Si
O
To a solution of diisopropylamine (1.10ml, 7.8mmol, 1.3 eq) in THF (5.0ml) at 0°C
was added n-BuLi (2.5M, 2.9ml, 7.2mmol, 1.2eq.), the reaction was allowed to stir for
30 min. The solution was cooled to -78°C and a solution of ethyl-(E)-3trimethylsilylhex-4-enoate (1.28g, 6.0mmol) in THF (5ml) was added via a syringe.
The light yellow solution was stirred for 30 min, followed by the dropwise addition of
a solution of benzyl bromide (0.890ml, 7.5mmol, 1.2 eq) in THF (1 mL). The reaction
mixture was allowed to stir and warm to room temperature overnight. The reaction
was quenched by the addition of a saturated solution of NH4Cl at 0°C. The aqueous
phase was extracted with Et2O. The combined organic phases were washed with
saturated brine, dried over MgSO4, filtered and the solvent removed in vacuo.
Purification by silica gel chromatography (hexane: Et2O, 9:1; Rf = 0.50) afforded (1f)
as a colourless oil 1.480g, 81% yield, d.r >20:1. 1H NMR (400 MHz, acetone-d6) δ -
S4
0.03 (s, 9H), 1.01 (t, J=7.1 Hz, 3H), 1.72 (d, J=4.8 Hz, 3H), 1.89-1.95 (m, 1H), 2.70
(t, J=11.6 Hz, 1H), 2.76 (ddd, J=11.6 Hz, 8.8 Hz, 3.0 Hz, 1H), 2.99 (dd, J=12.4 Hz,
J=2.3 Hz, 1H), 3.90 (qd, J=7.1 Hz, 1.8 Hz, 1H), 5.36-5.48 (m, 3H), 7.14-7.19 (m,
2H), 7.22-7.28 (m, 2H);
13C
NMR (100 MHz, acetone-d6) δ -2.5 (3 x CH3), 13.9
(CH3), 17.8 (CH3), 37.0 (CH), 38.9 (CH2), 48.9 (CH), 59.8 (CH2), 125.4 (CH),126.4
(CH), 128.5 (2 x CH), 129.3 (2 x CH), 130.0 (CH), 140.5 (C), 174.6 (C); IR (neat):
2957, 1732, 1453, 1249, 1153, 839, 699; HRMS: calculated for C18H29O2Si: m/z
305.1931, found: m/z 305.1921.
(E)-2-Methyl-3-(trimethylsilyl)hex-4-en-1-ol (1g).
OH
SiMe3
A
solution
of
anti-ethyl-(E)-2-methyl-3-(trimethylsilyl)hex-4-enoate
(1.030g,
4.5mmol) in Et2O (22.5ml) was added dropwise to a slurry of LiAlH4 (860mg,
22.5mmol) in Et2O (22.5ml) and allowed to stir at room temperature for 4hrs. The
reaction was quenched by the addition of a saturated solution of NH4Cl at 0°C. The
aqueous phase was extracted with Et2O. The combined organic phases were dried
over MgSO4, filtered and the solvent removed in vacuo. Purification by silica gel
chromatography (hexane: EtOAc, 80:20; Rf = 0.34) gave (1g) 757mg, 90% yield, dr
>20:1. 1H NMR (400 MHz, CDCl3): δ –0.35 (s, 9H), 0.89 (d, J=7.0 Hz, 3H) 1.50 (br,
1H), 1.64 (d, J=4.8 Hz, 3H), 1.69 (dd, J=9.9 Hz, 3.4 Hz, 1H), 1.84 (qtd, J=7.0 Hz,
7.0 Hz, 3.4 Hz, 1H), 3.37 (dd, J=10.6 Hz, 7.0 Hz, 1H), 3.41 (dd, J=10.6 Hz, 7.0 Hz,
1H), 5.22-5.38 (m, 2H); 13C NMR (100 MHz, CDCl3): δ -2.1 (3 x CH3), 13.9 (CH3),
18.2 (CH3), 35.0 (CH), 35.5 (CH), 68.3 (CH2), 125.0 (CH), 127.9 (CH); IR (neat):
3334, 2958, 1248, 1033, 971, 836. HRMS: calculated for C10H22NaOSi: m/z
209.1332, found: m/z 209.1338.
S5
(E)-2-Methyl-3-(trimethylsilyl)hex-4-en-1-ol (1i).
OH
SiMe3
A solution of syn-ethyl-(E)-2-methyl-3-(trimethylsilyl)hex-4-enoate (41 mg, 0.2
mmol) in Et2O (1.0 ml) was added dropwise to a slurry of LiAlH4 (35 mg, 1.0 mmol)
in Et2O (1.0 ml) and allowed to stir at room temperature for 4hrs. The reaction was
quenched by the addition of a saturated solution of NH4Cl at 0°C. The aqueous phase
was extracted with Et2O. The combined organic phases were dried over MgSO4,
filtered and the solvent removed in vacuo. Purification by silica gel chromatography
(hexane: Et2O, 1:1; Rf = 0.4) afforded (1i) 31 mg, 84% yield, d.r = 9:1. 1H NMR (400
MHz, acetone-d6): δ 0.02 (s, 9H), 0.98 (d, J=6.6 Hz, 3H), 1.48 (dd, J=9.9 Hz, 6.6 Hz,
1H), 1.65 (d, J= 4.8 Hz, 3H), 1.77-1.87 (m, 1H), 3.26 (ddd, J=10.4 Hz, 7.8 Hz,5.6
Hz, 1H), 3.42 (t, J=5.3 Hz, 1H), 3.61 (dt, 10.4 Hz, 4.8 Hz, 1H), 5.26 (dq, J=15.2 Hz,
5.6 Hz, 1H), 5.33 (dd, J=15.2 Hz, 5.6 Hz, 1H); 13C NMR (100 MHz, acetone-d6): δ 2.1 (3 x CH3), 13.9 (CH3), 18.2 (CH3), 35.0 (CH), 35.5 (CH), 68.3 (CH2), 125.0 (CH),
127.9 (CH); IR (neat): 3333, 2957, 1453, 1248, 1030, 97, 835. HRMS: calculated for
C10H22NaOSi: m/z 209.1332, found: m/z 209.1336.
General Procedure A for the electrophilic fluorodesilylation of esters.
To a solution of substrate in acetonitrile (0.1 M) was added Selectfluor™ (1.5 eq.)
and NaHCO3 (1eq.). The reaction mixture was allowed to stir at room temperature for
12hrs. The reaction was diluted with Et2O, filtered and the organic phase was washed
with water. The organic phase was dried over MgSO4, filtered and the solvent
removed in vacuo. (Caution: The corresponding allylic fluoride products are volatile,
unstable on silica, alumina (basic and neutral) and decompose upon heating).
S6
Ethyl 5-fluorohex-3-enoate (2a).
O
F
O
General procedure A. 515mg, 81 % yield, E/Z = 1.3:1. The trans isomer: 1H NMR
(400 MHz, C6D6): δ 0.92 (t, J=7.1Hz, 3H), 1.11 (ddd, J=23.1 Hz, 6.4 Hz, 2.2 Hz,
3H), 2.76 (m,1H), 3.88 (q, J=7.1 Hz, 2H), 4.74 (dqd, J=48.2 Hz, J=6.4 Hz, J=6.4 Hz,
1H), 5.32-5.42 (m, 1H), 5.75 (dtd, J=15.6 Hz, 7.2 Hz, 4.1Hz, 1H);
13C
NMR (100
MHz, C6D6): δ 14.1 (CH3), 21.1 (d, J=24.4 Hz; CH3), 30.1 (CH2), 60.5 (CH2), 89.2 (d,
J=163.8 Hz; CH), 125.2 (d , J=11.7 Hz; CH), 133.6 (d , J=19.6Hz; CH), 170.4 (C);
19F
NMR (376.5 MHz, C6D6) δ -166.6 (dqdd, J=48.2 Hz, 23.1Hz, 11.8Hz, 4.1Hz),
HRMS: calculated for C8H13FNaO2 m/z 183,0792 found: m/z 183.0793. The cis
isomer: 1H NMR (400 MHz, C6D6): δ 0.93 (t, J=7.1 Hz, 3H), 1.13 (ddd, J=23.2 Hz,
6.4 Hz, 2.5 Hz 3H), 2.84 (m,1H), 3.89 (q, J=7.1 Hz, 2H), 5.05 (dm, J=48.7 Hz, 1H),
5.42-5.52 (m, 1H), 5.60-5.70 (m, 1H);
13C
NMR (100 MHz, C6D6): δ 14.1 (CH3),
21.4 (d, J=24.9 Hz; CH3), 33.1 (CH2), 60.5 (CH2), 85.4 (d, J=161.4 Hz; CH), 125.0
(d, J=9.9 Hz, CH), 132.6 (d, J=20.3 Hz; CH), 170.5 (C);
19F
NMR (376.5 MHz,
C6D6) δ -166.9 (dqdd, J=48.7 Hz, 23.2 Hz, 11.8 Hz, 2.5 Hz).
Ethyl-(E)-5-fluoro-2,2-dimethylhex-3-enoate (2c).
O
F
O
General procedure A. 95% yield, E/Z > 20:1. The trans isomer (major): 1H NMR
(400 MHz, C6D6): δ 0.89 (t, J=7.1 Hz, 3H), 1.13 (dd, J=23.0 Hz, 6.3 Hz, 3H), 1.23 (s,
6H), 3.89 (q, J=7.1 Hz, 2H), 4.79 (dqd, J=48.3 Hz, 6.3 Hz, 6.3 Hz, 1H), 5.54 (ddd,
J=15.9 Hz, 11.8 Hz, 6.3 Hz, 1H); 5.97 (dd., J=15.9 Hz, 3.8 Hz, 1H); 13C NMR (100
MHz, C6D6): δ 14.0 (CH3), 21.6 (CH3), 21.9 (CH3), 25.2 (d, J=21.7 Hz; CH3), 44.2
S7
(C), 60.9 (CH2), 89.8 (d, J=164.1 Hz; CH), 128.9 (d, J=19.7 Hz; CH), 137.6 (d ,
J=11.1 Hz; CH), 175.5 (C). 19F NMR (376.5 MHz, C6D6): δ -166.4 (dqdd J=48.3 Hz,
23.0Hz, 11.8 Hz, 3.8 Hz); IR (neat): 2983, 1732,1471, 1386, 1250, 1145, 1050, 972,
860HRMS: calculated for C10H17FNaO2 m/z 211.1105, found: m/z 211.1105
syn-Ethyl 5-fluoro-2-methyl-hex-3-enoate (2e).
O
F
O
General procedure A. 310mg, 95% yield, syn/anti = 19:1, E/Z (syn) 15:1, E/Z (anti)
>20:1. The trans-syn: 1H NMR (400 MHz, C6D6): δ 0.90 (t, J=7.1 Hz, 3H), 1.09 (dd,
J=23.3 Hz, 6.3 Hz, 3H), 1.12 (d, J=6.8 Hz, 3H), 2.93 (dq, J=7.2 Hz, 6.8 Hz, 1H), 3.89
(q, J=7.1 Hz, 2H), 4.73 (dqd, J=47.8 Hz, 6.3 Hz, 6.3Hz, 1H), 5.46 (ddd., J=15.6 Hz,
11.7 Hz, 6.3 Hz, 1H); 5.80 (ddd, J=15.6 Hz, 7.2 Hz, 3.9 Hz 1H);
13C
NMR (100
MHz, C6D6): δ 14.1 (CH3), 17,1 (CH3), 21.4 (d, J=24.4 Hz; CH3), 42.6 (CH), 60.5
(CH2), 89.3 (d, J=164.8 Hz; CH), 131.6 (d , J=19.7 Hz; CH), 132.0 (d , J=11.3 Hz;
CH), 173.5 (C). 19F NMR (376.5 MHz, C6D6): δ -166.6 (dqddd, J=47.8 Hz, 23.3Hz,
11.7 Hz, 3.9 Hz, 2.4 Hz); IR (neat): 2983, 1737,1457, 1376, 1325, 1260, 1046, 971,
805HRMS: calculated for C9H15FNaO2 m/z 197.0948, found: m/z 197.0946.
syn-(E)-Ethyl-2-benzyl-5-fluorohex-3-enoate (2f).
O
F
O
General procedure A. 112.0mg, 90% yield, syn/anti >20:1, E/Z (syn) 11:1, E/Z (anti)
>20:1. The trans-syn isomer: 1H NMR (400 MHz, C6D6): δ 0.93 (t, J=7.1 Hz, 3H),
1.15 (dd, J=23.2 Hz, 6.6 Hz, 3H), 2.83 (dd, J=13.4 Hz, 6.6 Hz, 1H), 3.16 (dd, J=13.4
Hz, 6.6 Hz, 1H), 3.37 (dd, J=8.1 Hz, 6.6 Hz, 1H), 3.96 (q, J=7.1 Hz, 2H), 4.80 (dqd,
S8
J=48.3 Hz, 6.3 Hz, 6.3 Hz, 1H), 5.53 (ddd., J=15.7 Hz, 12.6 Hz, 6.8 Hz, 1H); 5.80
(ddd, J=15.7 Hz, 8.6 Hz, 3.5 Hz 1H); 13C NMR (100 MHz, C6D6): δ 14.0 (CH3), 21.2
(d, J=24.0 Hz; CH3), 39.0 (CH2), 50.9 (CH), 60.5 (CH2), 88.5 (d, J=166.2 Hz; CH),
126.7 (CH), 128.5 (2 x CH), 129.4 (2 x CH), 129.8 (d , J=11.2 Hz; CH), 132.0 (d ,
J=19.2 Hz; CH), 172.6 (C). 19F NMR (376.5 MHz, C6D6): δ -166.6 (dqdd, J=48.3 Hz,
23.2 Hz, 12.6 Hz, 3.5 Hz); IR (neat): 2982, 1733, 1454, 1260, 1158, 1033, 799,
700HRMS: calculated for C15H19FNaO2 m/z 273.1261, found: m/z 273.1262.
anti-(E)-Ethyl 5-fluoro-2-methyl-hex-3-enoate (2h).
O
F
O
General procedure A. 33mg, 96% yield, syn/anti 1:6, E/Z (syn) >20:1, E/Z (anti) 11:1.
The trans-anti isomer: 1H NMR (400 MHz, C6D6): δ 1.02 (t, J=7.3 Hz, 3H), 1.20
(dd, J=23.2 Hz, 6.3 Hz, 3H), 1.23 (d, J=7.1 Hz, 3H), 3.06 (qd, J=7.1 Hz, 2.8 Hz, 1H),
4.01 (q, J=7.1 Hz, 2H), 4.85 (dqd, J=48.3 Hz, 6.3 Hz, 6.3Hz, 1H), 5.58 (dddd, J=15.6
Hz, 11.2 Hz, 6.1, 1.0 Hz, 1H); 5.93 (dddd, J=15.7 Hz, 7.6 Hz, 3.8 Hz, 1.0 Hz, 1H);
13C
NMR (100 MHz, C6D6): δ 14.1 (CH3), 17,0 (CH3), 21.3 (d, J=24.8 Hz; CH3),
42.5 (CH), 60.5 (CH2), 89.2 (d, J=164.6 Hz; CH), 131.5 (d , J=20.0 Hz; CH), 131.8 (d
, J=11.2 Hz; CH), 173.5 (C). 19F NMR (376.5 MHz, C6D6): δ -166.6 (dqddd, J=48.1
Hz, 23.1 Hz, 12.0 Hz, 3.8 Hz, 2.7 Hz); IR (neat): 2982, 2360, 1736, 1456, 1376,
1259, 1181, 1046, 970, 853, 738HRMS: calculated for C9H15FNaO2 m/z 197.0948,
found: m/z 197.0954.
General Procedure B for electrophilic fluorodesilylation of alcohols.
To a solution of substrate in acetonitrile (0.1 M) was added Selectfluor™ (1.5 eq.)
and NaHCO3 (1eq.). The reaction was allowed to stir for 4hrs at room temperature.
The reaction was diluted with Et2O, filtered and the organic phase was washed with
S9
water. The organic phase was dried over MgSO4, filtered and the solvent removed in
vacuo. The crude products were purified by rapid silica gel chromatography.
(Caution: The corresponding allylic fluoride products are volatile, unstable on silica,
alumina (basic and neutral) on prolonged exposure and decompose upon heating).
(E)-5-Fluorohex-3-en-1-ol (2b).
OH
F
General procedure B. 86mg, 64% yield, E/Z = 3:1. The trans isomer: 1H NMR (400
MHz, C6D6): δ 1.27 (dd, J=23.0 Hz, 6.3 Hz, 3H), 2.03 (br, 1H), 2.14 (td, J=6.5 Hz,
6.0Hz, 2H), 3.46 (t, J=6.5 Hz, 2H), 4.90 (dqd, J=48.6 Hz, 6.3 Hz, 6.3 Hz, 1H), 5.525.70 (m, 2H);
13C
NMR (100 MHz, C6D6): δ 21.4 (d, J=24.7 Hz, CH3), 35.8 (CH2),
61.3 (CH2), 89.7 (d, J=163.2 Hz; CH), 130.0 (d , J=11.2 Hz; CH), 132.6 (d , J=19.2
Hz; CH);
19F
NMR (376.5 MHz, C6D6): δ -164.6 (m). HRMS: calculated for
C6H11FNaO m/z 141.0686, found: m/z 141.0684. The cis isomer: 1H NMR (400
MHz, C6D6): δ 1.29 (dd, J=23.0 Hz, 6.2 Hz, 3H), 2.03 (br, 1H), 2.14 (td, J=6.5 Hz,
6.0 Hz, 2H), 3.41 (t, J=6.5 Hz, 2H), 5.32 (dqd, J=48.8 Hz, 6.5 Hz, 6.5 Hz, 1H), 5.425.52 (m, 1H); 5.52-5.70 (m, 1H); 13C NMR (100 MHz, C6D6): δ 21.7 (d, J=25.2 Hz;
CH3), 31.4 (CH2), 65.9 (CH2), 85.4 (d, J=159.9 Hz; CH), 130.1 (d , J=10.4 Hz; CH),
132.1 (d , J=20.4 Hz; CH): 19F NMR (376.5 MHz, C6D6): δ -166.5 (m).
(E)-5-Fluoro-2,2-dimethylhex-3-enoate (2d).
OH
F
General procedure B. Purification by silica gel chromatography (20-50%
Et2O/hexane) 46mg, 70% yield, E/Z > 20:1. The trans- isomer: 1H NMR (400 MHz,
C6D6): δ 0.87 (s, 3H), 0.88 (s, 3H), 1.18 (dd, J=23.0 Hz, 6.3 Hz, 3H), 1.94 (br, 1H),
S10
3.13 (s, 2H), 4.83 (dqdd, J=48.4 Hz, 6.3 Hz, 6.3 Hz, 0.7 Hz, 1H), 5.47 (ddd, J=15.9
Hz, 10.6 Hz, 6.3 Hz, 1H), 5.61 (ddd, J=15.9 Hz, 3.9 Hz, 0.7 Hz, 1H); 13C NMR (100
MHz, C6D6): δ 21.3 (d, J=24.8 Hz; CH3), 23.3 (CH3), 23.4 (CH3), 37.8 (C), 71.0 (d,
J=2.3 Hz, CH2), 90.3 (d, J=163.6 Hz; CH), 128.2 (d , J=19.4 Hz, CH), 140.0 (d ,
J=10.7 Hz, CH); 19F NMR (376.5 MHz, C6D6): δ -164.7 (dqdd, J=48.4 Hz, 23.0 Hz,
10.6 Hz, 3.9 Hz); IR (neat): 3386, 2963, 1379, 1048, 975, 856; HRMS: calculated for
C8H15FNaO m/z 169.0999, found: m/z 169.1001.
syn-(E)-5-Fluoro-2-methylhex-3-en-1-ol (2g).
OH
F
General procedure B. Purification by silica gel chromatography (20-50%
Et2O/hexane) 87mg, 66% yield, syn/anti >20:1, E/Z (syn) 15:1, E/Z (anti) >20:1. The
trans-syn isomer: 1H NMR (400 MHz, C6D6): δ 0.86 (d, J=6.8 Hz, 3H), 1.18 (dd,
J=23.0 Hz, 6.3 Hz, 3H), 1.96 (br, 1H), 2.08-2.18 (m, 1H), 3.23 (t, J=6.5 Hz, 2H), 4.81
(dqd, J=47.6 Hz, 6.3 Hz, 5.9 Hz, 1H), 5.43-5.56 (m, 2H);
13C
NMR (100 MHz,
C6D6): δ 16.6 (CH3), 22.0 (d, J=24.7 Hz, CH3), 39.6 (CH), 67.5 (CH2), 90.2 (d,
J=163.5 Hz, CH), 131.0 (d , J=19.3 Hz, CH), 136.2 (d , J=10.8 Hz; CH);
19F
NMR
(376.5 MHz, C6D6): δ -164.7 (dqdd, J=47.6 Hz, 23.0 Hz, 8.2 Hz, 4.3 Hz); IR (neat):
3374, 2930, 1377, 1041, 972, 844HRMS: calculated for C7H13FNaO m/z 155.0843,
found: m/z 155.0842.
anti-(E)-5-Fluoro-2-methylhex-3-en-1-ol (2i).
OH
F
General procedure B. 11.5mg, 86% yield, syn/anti 1:8, E/Z (syn) 14:1, E/Z (anti) 10:1.
The trans-anti isomer: 1H NMR (400 MHz, C6D6): δ 0.92 (d, J=6.8 Hz, 3H), 1.27
S11
(dd, J=23.0 Hz, 6.3 Hz, 3H), 2.16-2.22 (m, 1H), 3.29 (d, J=6.6 Hz, 2H), 4.89 (dm,
J=48.3 Hz, 1H), 5.43-5.56 (m, 2H); 13C NMR (100 MHz, C6D6): δ 16.2 (CH3), 21.5
(d, J=24.8 Hz, CH3), 39.2 (CH), 67.0 (CH2), 89.7 (d, J=163.8 Hz, CH), 130.7 (d ,
J=19.2 Hz, CH), 135.8 (d , J=10.4 Hz; CH); 19F NMR (376.5 MHz, C6D6): δ -164.7
(dqdd, J=51.7 Hz, 23.0 Hz, 7.1 Hz, 2.8 Hz); IR (neat): 3385, 2962, 2927, 2281, 1455,
1377, 1037, 802HRMS: calculated for C7H13FNaO m/z 155.0843, found: m/z
155.0844.
(E)-Ethyl 6-(benzyloxy)-3-(trimethylsilyl)hex-4-enoate (4).
Me3Si
BnO
O
O
A mixture of (E)-1-(benzyloxy)-4-(trimethylsilyl)but-3-en-2-ol (735mg, 2.95mmol,
1eq.), triethylacetate (1.08ml, 5.9mmol, 2eq.) and catalytic propionic acid in toluene
was allowed to reflux for 3 days. After that time the mixture was cooled to room
temperature. The crude reaction mixture was diluted with hexane (15ml) and purified
directly by silica gel chromatography (100% hexane to hexane:Et2O 2:1) to afford (4)
700 mg, 74% yield. 1H NMR (400 MHz, acetone-d6): δ 0.05 (s, 9H), 1.20 (t, J=7.1
Hz, 3H), 2.10 (td, J=9.4 Hz, 4.8 Hz, 3H), 2.38 (dd, J=15.2 Hz, 10.4 Hz, 1H), 2.46 (dd,
J=15.2 Hz, 4.8 Hz, 1H), 3.97 (d, J=6.1 Hz, 2H), 4.07 (q, J=7.1 Hz, 2H), 4.46 (s, 2H),
5.45 (dt, J=15.4 Hz, 6.3 Hz, 1H), 5.69 (dd, J=15.4 Hz, 8.8 Hz, 1H), 7.24-7.30 (m,
1H), 7.33-7.35 (m, 4H);
13C
NMR (100 MHz, acetone-d6): δ -3.6 (3 x CH3), 14.2
(CH3), 29.7 (CH), 34.1 (CH2), 60.1 (CH2), 70.9 (CH2), 71.1 (CH2), 125.0 (CH), 127.6
(CH), 127.8 (2 x CH), 128.5 (2 x CH), 134.7 (CH), 139.6 (C), 172.9 (C); IR (neat):
2955, 1736, 1249, 1097, 841, 737; HRMS: calculated for C18H28NaO3Si m/z
343.1700, found: m/z 343.1701.
S12
(E)-ethyl 6-(benzyloxy)-2-fluoro-3-(trimethylsilyl)hex-4-enoate (6).
Me3Si
O
BnO
O
F
To a solution of diisopropylamine (430uL, 2.6mmol, 1.3eq.) in THF (2 ml) at 0°C
was added n-BuLi (2.5M, 1.2ml, 2.4mmol, 1.2eq.) dropwise. The mixture was
allowed to stir at this temperature for 30 min. The reaction was then cooled to –78°C
and (E)-ethyl-6-(benzyloxy)-3-(trimethylsilyl)hex-4-enoate (4) (640mg, 2.0mmol,
1eq.) in THF (2 mL) was added dropwise. The reaction was allowed to stir at –78°C
for 1hr. After this time N-fluorobenzenesulfonimide (NFSI) (950mg, 3.0mmol,
1.5eq.) in THF (2 mL) was added dropwise and the mixture allowed to warm room
temperature overnight. The reaction was then cooled to 0°C and quenched by the
addition of a saturated solution of NH4Cl. The organic phase was separated and
aqueous phase extracted with Et2O. The combined organic extracts were dried over
MgSO4, filtered and the solvent removed in vacuo.
Purification by silica gel
chromatography gave (6) 380mg 56% yield, d.r >20:1. 1H NMR (400 MHz, acetoned6): δ 0.14 (s, 9H), 1.23 (t, J=7.1 Hz, 3H), 2.28 (ddd, J=45.0 Hz, 10.4 Hz, 3.0 Hz,
1H), 3.97 (dd, J=12.4 Hz, 6.1 Hz, 1H), 4.01 (dd, J=11.9 Hz, 5.3 Hz, 1H), 4.15 (dq,
J=10.9 Hz, 7.1 Hz, 1H), 4.21 (dq, J=10.9 Hz, 7.1 Hz, 1H), 4.48 (s, 2H), 5.21 (dd,
J=47.0 Hz, 3.0 Hz, 1H), 5.29 (dd, J=15.4 Hz, 6.0 Hz, 1H), 7.24-7.31 (m, 1H), 7.337.37 (m, 4H); 13C NMR (100 MHz, acetone-d6): δ -2.8 (3 x CH3), 14.3 (CH3), 37.8 (d,
J=25.6 Hz, CH), 61.1 (CH2), 70.6 (CH2), 71.3 (CH2), 90.2 (d, J=182.2 Hz, CH), 127.7
(CH), 127.8 (2 x CH), 128.4 (CH), 128.6 (2 x CH), 128.8 (CH), 139.4 (C), 169.4 (d,
J=27.2 Hz, C);
19F
NMR (376.5 MHz, acetone-d6): δ –196.1 (dtd, J=47.3 Hz, 26.9
Hz, 9.9 Hz, 1F), -191.3 (pt, J=46.1 Hz, 1F), IR (neat): 2957, 1760, 1250, 1205, 1097,
S13
843, 738; HRMS: calculated for C18H27F1NaO3Si1 m/z 361.1606, found: m/z
361.1605.
(E)-Ethyl 6-(benzyloxy)-2,5-difluorohex-3-enoate (3).
F
O
BnO
O
F
To a solution of (E)-ethyl-6-(benzyloxy)-2-fluoro-3-(trimethylsilyl)hex-4-enoate (6)
(340mg, 1.0mmol, 1eq) in acetonitrile (10ml) was added Selectfluor™ (700mg,
2.5mmol, 2.5 eq.) and NaHCO3 (84mg, 1.0mmol, 1eq.) at 50°C. The reaction was
allowed to stir at this temperature for 12hrs. The reaction mixture was cooled to room
temperature, diluted with Et2O, filtered and the organic phase washed with water. The
organic phase was dried over MgSO4, filtered and the solvent removed in vacuo to
give (3) as colourless oil, 280mg 98% yield, syn/anti = 5:1, E/Z (syn) 6:1, E/Z (anti)
1:1. 1H NMR (400 MHz, acetone-d6): δ 1.26 (t, J=7.1 Hz, 3H), 3.66 (ddd, J=22.5 Hz,
11.4 Hz, 6.1 Hz, 1H), 3.71 (ddd, J=26.0 Hz, 11.4 Hz, 3.3Hz, 1H), 4.23 (q, J=7.1 Hz,
2H), 4.60 (s, 2H), 5.26 (dm, J=49.0 Hz, 1H), 5.53 (dm, J=47.8, 1H), 6.02-6.22, (m,
2H), 7.27-7.32 (m, 1H), 7.34-7.39 (m, 4H); 13C NMR (100 MHz, acetone-d6): δ 13.9
(CH3), 61.8 (CH2), 72.0 (dd, J=22.4 Hz, 1.6 Hz, CH2), 73.3 (CH2), 87.8 (d, J=182.1
Hz, CH), 91.3 (d, J=172.6 Hz, CH), 128.0 (CH), 128.1 (2 x CH), 128.7 (2 x CH),
131.0 (dd, J=19.2 Hz, 11.2Hz, CH), 138.8 (C), 167.9 (dd, J=24.8 Hz, 1.6 Hz, C); 19F
NMR (376.5 MHz, acetone-d6): δ –188.4 (ddm, J=47.4 Hz, 14.7 Hz, 1F), -186.3 (m,
1F), IR (neat): 2937, 1761, 1453, 1371, 1274, 1207, 1115, 1027, 970, 740. 700;
HRMS: calculated for C15H18FNaO3 m/z 307.1116, found: m/z 307.1110.
S14
Ethyl 6-(benzyloxy)-2,5-(syn)-difluoro-3,4-(anti)-dihydroxyhexanoate (8).
F
OH
BnO
O
O
OH
F
To a solution of N-methylmorpholine (246mg, 2.1mmol, 3eq), osmium tetraoxide
(9mg, 0.05eq) in water (38uL) and DCM (3.5 mL) was added (E)-ethyl-6(benzyloxy)-2,5-difluorohex-3-enoate (3) (200mg, 0.7mmol, 1eq) in DCM (3.5 mL).
The mixture was allowed to stir at room temperature for 3hrs. A saturated solution of
NaHSO3 was then added and stirred for a further 15 min. DCM was added and the
phases separated. The aqueous phase was extracted with EtOAc and the combined
organic phases were dried over Na2SO4, filtered and the solvent removed in vacuo
Purification by silica gel chromatography (EtOAc:hexane 2:1, Rf = 0.5) to yield (8)
126mg, 56% yield. NMR data of the major diastereoisomer: 1H NMR (400 MHz,
acetone-d6): δ 1.47 (t, J=7.1 Hz, 3H), 4.03 (ddd, J=30.1 Hz, 11.9 Hz, 5.1 Hz, 1H),
4.13 (ddd, J=25.0 Hz, 11.9 Hz, 2.0 Hz, 1H), 4.18-4.24 (m, 1H), 4.26-4.33 (m, 1H),
4.44 (q, J=7.1 Hz, 2H), 4.65 (d, J=7.8, 1H), 4.72, (d, J=8.1 Hz, 1H), 4.79 9s, 2H),
4.92 (dm, J=47.5 Hz, 1H), 5.14 (dd, J=48.5 Hz, 8.1 Hz, 1H), 7.46-7.50 (m, 1H), 7.537.58 (m, 4H);
13C
NMR (100 MHz, acetone-d6): δ 14.1 (CH3), 61.7 (CH2), 67.5 (d,
J=24.8 Hz, CH2), 69.4 (dd, J=24.8 Hz, 3.2 Hz, CH), 70.1 (d, J=19.2 Hz, CH), 73.5
(CH2), 88.7 (d, J=182.2 Hz, CH), 91.5 (d, J=175.0 Hz, CH), 128.0 (CH), 128.1 (2 x
CH), 128.8 (2 x CH), 139.2 (C), 168.9 (d, J=22.4 Hz, C);
19F
NMR (376.5 MHz,
acetone-d6): δ –194.1 (ddddd, J=47.6 Hz, 29.6 Hz, 27.1 Hz, 5.1 Hz, 2.5 Hz, 1F), 196.1 (ddd, J=48.5 Hz, 9.7 Hz, 2.3 Hz 1F), HRMS: calculated for C15H20F2NaO5 m/z
341.1171, found: m/z 341.1170.
S15
Ethyl-6-(benzyloxy)-2,5-(syn)-difluoro-3-O-,4-O-(anti)-isopropylidene-hexanoate
(9).
BnO
F F
O
O
O
To
a
O
solution
of
ethyl-6-(benzyloxy)-2,5-(syn)-difluoro-3,4-(anti)-
dihydroxyhexanoate (8) (95mg, 0.3mmol, 1eq.) in acetone (1.5ml) was added
dimethoxypropane (1.5ml) and p-TSA (6mg). The mixture was allowed to stir at room
temperature overnight. The solvent was removed in vacuo and the crude product
purified by silica gel chromatography (1:1 Et2O:hexane, Rf = 0.6) to yield (9) 96mg,
90% yield as a pale yellow oil. NMR data of the major diastereoisomer: 1H NMR
(400 MHz, acetone-d6): δ 1.28 (t, J=7.3 Hz, 3H), 1.37 (s, 3H), 1.38 (s, 3H), 3.75 (ddd,
J=28.3 Hz, 11.9 Hz, 5.1 Hz, 1H), 3.85 (ddd, J=26.3 Hz, 11.9 Hz, 2.5 Hz, 1H), 4.23 (q,
J=7.1 Hz, 2H), 4.24 (q, J=7.1 Hz, 2H), 4.46 (dt, J=9.9 Hz, 6.8 Hz, 1H), 4.53-4.63 (m,
1H), 4.76 (dddd, J=47.5 Hz, 6.8 Hz, 5.3 Hz, 2.5 Hz, 1H), 5.24 (dd, J=48.0 Hz, 2.3 Hz,
1H), 7.28-7.32 (m, 1H), 7.35-7.40 (m, 4H); 13C NMR (100 MHz, acetone-d6): δ 13.9
(CH3), 26.6 (CH3), 26.9 (CH3), 61.7 (CH2), 69.7 (d, J=20.0 Hz, CH2), 73.4 (CH2),
74.4 (dd, J=27.2 Hz, 7.2 Hz, CH), 79.5 (dd, J=22.4 Hz, 3.2 Hz, CH), 88.6 (d, J=189.3
Hz, CH), 93.1 (d, J=175.0 Hz, CH), 111.3 (C), 127.9 (CH), 128.0 (2 x CH), 128.7 (2
x CH), 138.7 (C), 166.8 (d, J=24.0 Hz, C); 19F NMR (376.5 MHz, acetone-d6): δ –
196.1 (dtd, J=47.3 Hz, 26.9 Hz, 9.9 Hz, 1F), -198.4 (dd, J=48.0 Hz, 22.1 Hz, 1F),
HRMS: calculated for C18H24F2NaO5 m/z 381.1484, found: m/z 381.1484.
S16
Ethyl
6-(benzyloxy)-2,5-(syn)-difluoro-3-O-,4-O-anti-isopropylidene-1-hexanol
(10).
BnO
F F
OH
O
O
To suspension of LiAlH4 (38mg, 1mmol) in Et2O (2.5 mL) at 0°C was added ethyl-6(benzyloxy)-2,5-(syn)-difluoro-3-O-,4-O-(anti)-isopropylidene-hexonate (9) (90mg,
0.25mmol, 1eq) in Et2O (2.5 mL) dropwise. The reaction was then allowed to stir at
0°C for 3hrs. The reaction was quenched by the addition of a saturated solution of
NH4Cl, and the aqueous phase extracted with Et2O. The combined organic extracts
dried over Na2SO4, filtered and the solvent removed in vacuo. Purification by silica
gel chromatography (1:1 Et2O:hexane Rf = 0.3), to give (10) 67mg 85 % yield as a
mixture of stereoisomers. NMR data of the major diastereoisomer: 1H NMR (400
MHz, acetone-d6): δ 1.38 (s, 3H), 1.39 (s, 3H), 3.72-3.92 (m, 4H), 4.12 (t, J=6.0 Hz,
1H), 4.34 (dt, J=11.7 Hz, 6.0 Hz, 1H), 4.38 (dt, J=12.3 Hz, 6.0 Hz, 1H), 4.59 (dtd,
J=48.2 Hz, 5.7 Hz, 2.8 Hz, 1H), 4.61 (s, 2H), 4.80 (dtd, J=48.2 Hz, 5.7 Hz, 2.8 Hz),
7.29-7.32 (m, 1H), 7.35-7.40 (m, 4H); 13C NMR (100 MHz, acetone-d6): δ 27.5 (2 x
CH3), 60.9 (d, J=22.9 Hz, CH2), 69.9 (d, J=21.0 Hz, CH2), 73.8 (CH2), 77.1 (dd,
J=25.8 Hz, 4.8 Hz, CH), 77.6 (dd, J=24.8 Hz, 3.8 Hz, CH), 93.3 (d, J=176.4 Hz, CH),
95.0 (d, J=174.5 Hz, CH), 111.3 (C), 128.4 (CH), 128.5 (2 x CH), 129.2 (2 x CH),
139.3 (C); 19F NMR (376.5 MHz, acetone-d6): δ –194.7 (m, 1F), -197.4 (m, 1F); IR
(neat): 3442, 2938, 1455, 1373, 1217, 1069, 867; HRMS: calculated for
C16H22F2NaO4 m/z 339.1378, found: m/z 339.1384.
S17
4,5-Bis(2-(benzyloxy)-1-fluoroethyl)-2,2-dimethyl-1,3-dioxolane (11).
BnO
F F
OBn
O
O
To a suspension of NaH (23mg, 0.6mmol, 3eq) in DMF (1 ml) at 0°C was added
ethyl-6-(benzyloxy)-2,5-(syn)-difluoro-3-O-,4-O-(anti)-isopropylidene-1-hexanol (10)
(63mg, 0.2mmol, 1eq) DMF (1 mL). The mixture was allowed to stir at 0°C for 1hr
after which time benzyl bromide (75uL, 0.6mmol, 3eq) was added dropwise. The
reaction mixture was then heated at 40°C for 6hr. After cooling to 0°C the reaction
was quenched by the addition of water. The aqueous phase was extracted with DCM,
the combined organic extracts were dried over Na2SO4, filtered and the solvent
removed in vacuo. Purification by silica gel chromatography (1:1 DCM:hexane) to
yield (11) 63mg 78% yield as a mixture of stereoisomers. NMR data of the major
diastereoisomer: 1H NMR (400 MHz, acetone-d6): δ 1.38 (s, 6H), 3.75 (ddd, J=24.6
Hz, 11.7 Hz, 6.0 Hz, 2H), 3.83 (ddd, J=27.1 Hz, 11.7 Hz, 2.5 Hz, 2H), 4.12-4.40 (m,
2H), 4.61 (s, 4H), 4.80 (dm, J=48.2 Hz, 2H), 7.29-7.32 (m, 2H), 7.35-7.40 (m, 8H);
13C
NMR (100 MHz, acetone-d6): δ 27.5 (2 x CH3), 69.9 (d, J=22.9 Hz, 2 x CH2),
73.9 (2 x CH2), 77.4 (dd, J=25.8 Hz, 2.9 Hz, 2 x CH), 93.3 (d, J=175.5 Hz, 2 x CH),
111.5 (2 x C), 128.4 (2 x CH), 128.5 (4 x CH), 129.2 (4 x CH), 139.3 (2 x C); 19F
NMR (376.5 MHz, acetone-d6): δ –194.5 (dtd, J=47.7 Hz, 26.8 Hz, 2.6 Hz, 1F), IR
(neat): 2938, 1453, 1371, 1068, 736; HRMS: calculated for [M+NH4] C23H32F2N1O4
m/z 424.2292, found: m/z 424.2294.
S18
1,6-bis(benzyloxy)-2,5-difluorohexane-3,4-diol (7).
F
OH
BnO
OBn
OH
F
A solution of 4,5-bis(2-(benzyloxy)-1-fluoroethyl)-2,2-dimethyl-1,3-dioxolane (11)
(41mg, 0.1mmol) in AcOH:H2O 7:3 (1 mL) and was heated at 100°C for 24hrs. The
reaction was allowed to cool and toluene was added. The solvents were removed in
vacuo. Purification by silica gel chromatography (1:1 EtOAc:hexane) to give (7) 30
mg, 82% yield as a mixture of stereoisomers. NMR data of the major
diastereoisomer: 1H NMR (400 MHz, CDCl3): δ 2.77 (d, J=7.3, 2H), 3.81 (ddd,
J=27.4 Hz, 11.4 Hz, 4.4 Hz, 2H), 3.88 (ddd, J=27.1 Hz, 11.4 Hz, 3.5 Hz, 2H), 4.08
(dd, J=7.9 Hz, 7.3 Hz, 2H), 4.59 (d, J=11.9 Hz, 2H), 4.64 (d, J=11.9 Hz, 2H),4.67
(dm, J=46.5 Hz, 2H), 7.30-7.38 (m, 10H); 13C NMR (100 MHz, CDCl3): δ 68.6 (dd,
J=24.8 Hz, 3.8 Hz, 2 x CH), 69.5 (d, J=21.9 Hz, 2 x CH2), 74.1 (2 x CH2), 90.7 (d,
J=174.5 Hz, 2 x CH), 128.1 (4 x CH), 128.3 (2 x CH), 128.8 (4 x CH), 137.7 (2 x C);
19F
NMR (376.5 MHz, CDCl3): δ –194.8 (dddd, J=47.7 Hz, 28.3 Hz, 21.4 Hz, 7.9,
2F), The major stereoisomer was identical in all aspects with sample prepared by
previously published method.2
References:
1. a) G. Procter, A. T. Russel, P. J. Murphy, T. S. Tan, A. N. Mather, Tetrahedron,
1988, 44, 3953; b) M. A. Sparks, J. S. Panek, J. Org. Chem. 1991, 56, 3431; c) J. S.
Panek, R. Beresis, F. Xu, M. Yang, J. Org. Chem. 1991, 56, 7341; d) J. S. Panek, M.
Yang, J. S. Solomon, J. Org. Chem. 1993, 58, 1003; e) C. E. Masse, B. S. Knight, P.
Stavropoulos, J. S. Panek, J. Am. Chem. Soc. 1997, 119, 6040.
2. L. Hunter, D. O’Hagan, A. M. Z. Slawin, J. Am. Chem. Soc. 2006, 128, 16422.
S19
OH
SiMe3
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
9.00
1.13
1.16
3.74
2.01
1.80
1b
0.5
0
S20
200
180
160
140
120
100
80
60
40
18.18
32.20
29.66
62.47
123.16
132.33
-3.21
OH
SiMe3
1b
20
0
S21
128.26
128.02
127.78
O
Me 3Si
O
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
9.46
6.12
3.06
1.00
2.00
2.00
1c
1.0
0.5
0
S22
178.31
180
160
140
120
100
80
60
42.34
40
18.13
14.19
Me 3Si
26.46
23.82
44.21
60.20
128.28
126.11
O
O
1c
20
0
S23
-0.85
77.34
77.03
76.71
OH
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
9.23
6.45
1.07
4.06
1.04
1.00
0.96
0.93
SiMe3
1d
0.5
0
S24
200
180
160
140
120
100
80
60
40
25.70
23.73
18.09
41.94
38.16
72.20
125.04
130.40
0.40
OH
SiMe3
1d
20
0
S25
128.26
128.02
127.78
Bn
O
Me 3Si
O
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
9.71
3.03
3.05
1.01
2.22
1.09
1.97
2.00
4.83
1f-anti/ syn >20:1
0.5
0
S26
200
180
140.50
174.63
160
140
120
48.85
100
80
60
40
17.79
13.87
28.81
128.50
129.26
Me 3Si
38.88
36.97
29.96
59.83
130.00
126.41
125.43
Bn
O
O
1f-anti/ syn >20:1
20
0
S27
-2.48
29.77
29.57
29.38
29.19
29.00
205.63
OH
SiMe3
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
9.28
3.19
4.09
1.30
0.99
2.00
1.89
1g-anti/ syn >20:1
0.5
0
S28
200
180
160
140
120
100
80
60
40
18.16
13.92
77.31
77.00
76.68
1g-anti/ syn >20:1
35.48
35.01
68.34
127.85
124.98
OH
SiMe3
20
0
S29
-2.05
OH
SiMe3
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
9.00
3.21
1.07
2.97
0.87
1.02
0.90
1.83
1i - anti/ sy n = 1:9
0.5
0
S30
200
180
160
140
120
100
80
60
40
17.93
17.75
37.93
37.27
66.35
123.98
130.97
29.77
29.00
SiMe3
1i - anti/ sy n = 1:9
-1.61
29.20
OH
20
0
S31
29.58
205.68
29.39
O
F
O
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
3.00
3.10
2.02
1.91
0.53
0.43
0.94
0.91
2a - E/ Z = 1.3:1
1.0
0.5
0
S32
200
180
160
140
133.75
120
100
80
60
40
21.57
21.30
21.05
37.45
14.11
60.52
60.43
F
33.17
89.95
88.32
86.17
84.56
125.22
125.10
125.02
124.92
133.56
170.40
O
O
2a - E/ Z = 1.3:1
20
0
S33
128.24
128.00
127.76
-166.71
O
F
O
-166.97
2a - E/ Z = 1.3:1
-166.0
-166.5
-167.0
-167.5
S34
OH
F
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
3.31
2.16
1.07
2.00
0.73
0.26
1.97
2b - E/ Z = 3:1
1.5
1.0
0.5
0
S35
200
180
160
140
120
100
80
60
40
21.64
31.38
35.72
61.64
21.55
21.31
90.53
88.91
86.18
84.59
132.65
132.46
OH
F
2b - E/ Z = 3:1
20
0
S36
128.24
128.00
127.76
-164.61
OH
F
-164.53
2b - E/ Z = 3:1
-163.5
-164.0
-164.5
-165.0
-165.5
-166.0
-166.5
S37
O
F
O
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
2.91
9.30
1.91
0.94
0.89
0.85
2c
1.0
0.5
0
S38
200
180
160
140
120
100
80
60
25.04
24.84
21.57
21.33
14.04
60.60
F
43.96
90.38
88.74
128.72
137.40
175.25
O
O
2c
40
20
0
S39
128.23
127.99
127.75
-166.41
O
F
O
2c
-165.0
-165.5
-166.0
-166.5
-167.0
-167.5
S40
OH
F
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
6.00
2.97
1.00
1.82
0.85
1.69
2d
1.0
0.5
0
S41
200
180
160
140
120
100
80
60
40
70.97
23.38
23.29
21.46
21.21
37.82
90.66
89.03
128.28
128.08
140.06
139.95
OH
F
2d
20
0
S42
127.91
127.67
127.43
-166.40
OH
F
2d
-164.5
-165.0
-165.5
-166.0
-166.5
-167.0
-167.5
-168.0
S43
O
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
3.00
6.29
0.87
1.95
0.90
0.98
0.84
F
O
2e - sy n/ anti = 19:1, E/ Z
(syn) = 15:1, E/ Z (anti)
>20:1
1.0
0.5
0
S44
128.24
128.00
127.75
O
173.48
200
180
160
140
120
100
80
60
40
21.41
21.17
17.10
42.57
90.08
88.44
131.98
131.87
60.45
14.10
F
O
2e - sy n/ anti = 19:1, E/ Z
(syn) = 15:1, E/ Z (anti)
>20:1
20
0
S45
-166.63
O
-165.31
-166.86
F
O
2e - sy n/ anti = 19:1, E/ Z
(syn) = 15:1, E/ Z (anti)
>20:1
-165.5
-166.0
-166.5
-167.0
S46
Bn
O
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
2.91
3.07
1.03
1.14
0.87
0.09
1.91
0.85
0.14
0.97
0.83
5.62
F
O
2f - syn/ ant i >20:1, E/ Z
(sy n) = 11:1, E/ Z (sy n)
>20:1
1.0
0.5
0
S47
200
180
160
140
120
100
80
60
40
21.35
21.11
60.49
126.70
14.04
50.90
39.03
89.81
88.16
138.87
133.12
132.93
129.82
172.56
129.44
128.54
Bn
O
F
O
2f - syn/ anti >20:1, E/ Z
(sy n) = 11:1, E/ Z (syn)
>20:1
20
0
S48
128.25
128.01
127.76
-167.81
Bn
O
-165.5
-166.0
-167.39
-165.66
-166.35
F
O
2f - syn/ anti >20:1, E/ Z
(sy n) = 11:1, E/ Z (syn)
>20:1
-166.5
-167.0
-167.5
-168.0
S49
OH
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
3.20
3.18
1.04
0.96
2.08
0.96
1.90
F
2g - syn/ anti > 20:1, E/ Z
(syn) = 15:1, E/ Z (anti)
>20:1
1.0
0.5
S50
128.25
128.00
127.76
OH
200
180
160
140
120
100
80
60
40
21.68
21.44
16.14
39.20
90.60
88.98
67.06
135.75
130.79
F
2g - syn/ anti > 20:1, E/ Z
(syn) = 15:1, E/ Z (anti)
>20:1
20
0
S51
-164.77
OH
-163.95
-164.36
F
2g - syn/ anti > 20:1, E/ Z
(syn) = 15:1, E/ Z (anti)
>20:1
-163.5
-164.0
-164.5
-165.0
S52
O
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
3.34
8.02
0.86
1.22
2.00
0.88
0.09
1.10
0.84
F
O
2h - sy n/ anti = 1:6, E/ Z
(syn) >20:1, E/ Z (anti) =
11:1
1.0
0.5
0
S53
128.25
128.00
127.76
O
180
160
140
120
100
80
60
40
16.97
21.38
42.46
65.87
90.00
88.36
131.86
173.47
200
60.49
14.10
F
O
2h - sy n/ anti = 1:6, E/ Z
(syn) >20:1, E/ Z (anti) =
11:1
20
0
S54
-166.86
O
-165.29
-167.08
-166.62
F
O
2h - sy n/ anti = 1:6, E/ Z
(syn) >20:1, E/ Z (anti) =
11:1
-165.5
-166.0
-166.5
-167.0
S55
OH
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
3.52
6.31
1.06
4.00
0.92
0.18
1.86
F
2i - syn/ ant i = 1:8, E/ Z
(syn) = 14:1, E/ Z (anti) =
10:1
2.0
1.5
1.0
0.5
0
S56
128.25
128.01
127.76
OH
200
180
160
140
120
100
80
60
40
21.67
21.42
16.18
39.24
67.04
90.54
88.91
130.64
135.80
F
2i - syn/ anti = 1:8, E/ Z
(sy n) = 14:1, E/ Z (ant i) =
10:1
20
0
S57
-164.68
OH
-163.02
-164.94
F
2i - syn/ anti = 1:8, E/ Z
(sy n) = 14:1, E/ Z (ant i) =
10:1
-162.5
-163.0
-163.5
-164.0
-164.5
-165.0
-165.5
S58
O
BnO
Me 3Si
O
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
10.00
3.00
0.92
2.20
3.95
1.85
0.99
0.93
4.89
4
2.0
1.5
1.0
0.5
0
S59
200
180
160
140
120
100
80
60
40
14.72
-3.09
30.22
29.61
206.11
29.91
29.76
30.07
O
29.46
34.65
129.05
128.36
Me3 Si
60.61
71.58
71.43
128.10
125.55
140.08
135.22
173.35
BnO
O
4
20
0
S60
F
O
BnO
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
9.21
3.00
0.90
2.05
1.97
1.97
1.01
0.94
0.96
4.47
Me 3Si
O
6 - major anti/ sy n >20:1
1.0
0.5
0
S61
200
180
160
140
120
100
37.89
37.63
91.13
89.32
139.44
30.03
28.88
169.52
169.25
127.84
80
60
29.65
O
40
14.25
Me3 Si
O
6 - major anti/ sy n >20:1
29.27
BnO
29.84
29.07
61.06
71.26
70.58
128.82
127.66
128.59
205.61
-2.76
29.46
F
20
0
S62
-191.25
F
O
BnO
-182.59
Me3 Si
O
6 - major anti/ sy n >20:1
-181
-182
-183
-184
-185
-186
-187
-188
-189
-190
-191
-192
-193
S63
F
O
BnO
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.61
2.00
2.14
2.01
0.84
0.96
0.27
1.80
4.05
F
O
3 - syn/ anti = 5:1, E/ Z (syn)
= 6:1, E/ Z (ant i) = 1:1
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
S64
200
180
160
140
120
61.98
138.79
100
80
30.05
28.90
72.09
71.88
92.19
90.48
88.74
86.93
126.63
126.44
126.32
131.18
131.07
168.00
167.74
61.82
F
O
3 - sy n/ anti = 5:1, E/ Z (syn)
= 6:1, E/ Z (anti) = 1:1
60
29.67
BnO
205.86
127.95
29.28
O
40
13.94
29.86
29.09
73.27
128.68
29.47
F
20
0
S65
-188.39
-186.27
F
O
BnO
-181
-182
-183
-184
-185
-186
-191.23
-189.22
-186.40
-183.36
-183.38
-180.12
-180.14
-180
-188.62
F
O
3 - sy n/ anti = 5:1, E/ Z (syn)
= 6:1, E/ Z (anti) = 1:1
-187
-188
-189
-190
-191
S66
OH
F
O
BnO
F
OH
O
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.00
1.88
2.07
1.75
3.40
1.06
1.02
0.28
4.11
8 - Major stereoisomer
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
S67
200
180
160
140
120
100
80
60
14.09
O
206.03
29.98 29.79
29.60
29.22
29.41
F
40
29.02
30.18
BnO
61.70
73.54
128.01
128.82
128.05
F
70.21
70.02
92.31
90.57
89.64
87.83
139.22
169.02
168.80
OH
OH O
8 - Major stereoisomer
20
0
S68
OH
F
O
BnO
F
OH O
8 - Major stereoisomer
-180
-182
-184
-186
-188
-190
-192
-194
-196
-198
-200
-202
-204
-206
-208
-210
-212
-214
-216
-218
-220
S69
F F
BnO
O
O
O
O
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.00
2.10
1.85
0.95
2.95
0.89
0.22
0.93
4.15
9 - major stereoisomer
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
S70
200
180
160
140
120
100
80
60
29.77
29.00
O
40
20
13.91
F F
26.88 28.80
26.63
29.96
73.39
128.67
127.96
O
69.66
69.46
61.71
94.00
92.27
89.52
87.64
79.56
79.37
111.31
127.86
138.69
166.91
166.67
BnO
O
O
9 - major stereoisomer
0
S71
29.57
29.38
29.19
205.67
BnO
O
F F
O
O
O
9 - major stereoisomer
-160
-170
-180
-190
-200
-210
-220
-230
S72
F F
BnO
OH
O
O
7.0
6.5
6.0
5.5
5.0
4.5
4.0
6.19
3.97
0.82
1.94
1.07
2.94
4.89
10 - major stereoisomer
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
S73
200
180
160
140
120
100
80
70.01
69.84
62.02
61.84
27.49
73.83
129.16
128.44
10 - major stereoisomer
30.35
O
77.21
77.00
95.66
94.28
94.03
92.62
111.31
139.33
O
29.42
206.19
BnO
30.19
30.04
29.88
29.72
29.57
F F
OH
60
40
20
0
S74
F F
BnO
OH
O
O
10 - major stereoisomer
-180
-182
-184
-186
-188
-190
-192
-194
-196
-198
-200
-202
-204
-206
-208
-210
S75
BnO
F F
OBn
O
O
7.0
6.5
6.0
5.5
5.0
4.5
4.0
5.79
4.00
3.80
1.89
2.04
9.27
11 - major stereoisomer
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
S76
200
180
160
140
120
100
80
27.48 29.43
69.82
30.35
73.85
129.17
128.45
O
77.56
77.33
94.02
92.62
111.45
139.30
BnO
F F
OBn
O
11 - major stereoisomer
60
40
20
0
S77
30.20
30.05
29.89
29.74
29.59
206.17
BnO
F F
OBn
O
O
11 - major stereoisomer
-160
-170
-180
-190
-200
-210
-220
S78