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V.S. Wills et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
a 95:5 mixture of Z and E olefin isomers. Both the 1H and 13C NMR
of bishomoprenyl bromide (13a, 202 mg, 1.14 mmol) in DMF
(5.5 mL). A parallel work-up using Et2O provided the desired azide
15a (48%). The azide intermediate then was dissolved in a solution
of t-BuOH and H2O (4:1, 3.4 mL), followed by addition of acetylene
14 (136 mg, 0.42 mmol), saturated CuSO4 (0.01 mL), and sodium
ascorbate (25 mg, 0.13 mmol) in sequence. Standard work-up
and purification afforded the desired triazole 16a (118 mg, 61%)
as a yellow oil: 1H NMR (300 MHz, CDCl3) d 7.47 (s, 1H), 5.10–
5.04 (m, 1H), 4.27 (t, J = 7.3 Hz, 2H), 4.20–4.06 (m, 8H), 3.32 (td,
JHP = 16.2 Hz, J = 6.7 Hz, 2H), 2.95 (tt, JHP = 23.4 Hz, J = 6.7 Hz, 1H),
2.06–1.97 (m, 2H), 1.96–1.87 (m, 2H), 1.69 (s, 3H), 1.57 (s, 3H),
1.32–1.24 (m, 12H); 13C NMR (75 MHz, CDCl3) d 145.1, 133.6,
122.5, 122.4, 63.0 (d, JCP = 6.5 Hz, 2C), 62.7 (d, JCP = 6.8 Hz, 2C),
49.8, 36.8 (t, JCP = 133.0 Hz), 30.6, 25.9, 25.0, 22.3 (br), 18.0, 16.6
(d, JCP = 3.6 Hz, 2C), 16.5 (d, JCP = 3.4 Hz, 2C); 31P NMR d 22.5; HRMS
(ES+) m/z calcd for C19H38N3O6P2 (M+H)+ 466.2236, found
466.2234.
data were consistent with literature data.21
5.14. Representative preparation of bishomoallylic bromides:
Bishomogeranyl bromide (13b)
According to the published protocol,36 a stirred solution of alco-
hol 12b (1.18 g, 6.46 mmol) in CH2Cl2 (60 mL) at 0 °C, was treated
with NEt3 (1.4 mL, 9.96 mmol), followed by methanesulfonyl chlo-
ride (0.65 mL, 8.40 mmol). The reaction mixture was allowed to
stir at 0 °C for 1 h and then was quenched by addition of H2O.
The organic extract was washed with 1 N HCl (2Â), brine, and sat-
urated NaHCO3 (2Â), dried (Na2SO4), and filtered, and the filtrate
was concentrated in vacuo. The resulting mesylate then was added
to a stirred solution of LiBr (1.69 g, 19.5 mmol) in anhydrous ace-
tone (23 mL) and was heated at reflux. After 1 h, the heat was
turned off, and the reaction was allowed to stir overnight while
it cooled to room temperature. After the solvent was removed in
vacuo, the resulting residue was dissolved in H2O and extracted
with Et2O (4Â). The combined organic extracts were dried (Na2-
SO4), and filtered, and the filtrate was concentrated in vacuo. Final
purification by flash column chromatography (100% hexanes)
afforded the desired bromide 13b (966 mg, 61%) as a clear oil.
The 1H NMR data was consistent with literature data.37 13C NMR
(75 MHz, CDCl3) d 137.0, 131.7, 124.4, 122.6, 39.9, 33.7, 33.0,
26.8, 26.5, 25.9, 17.9, 16.3.
5.18. Tetraethyl (4E)-(2-(1-(5,9-dimethyldeca-4,8-dienyl)-1H-1,2,3-
triazol-4-yl)ethane-1,1-diyl)bis(phosphonate) (16b)
According to the general procedure for preparation of tria-
zoles,11 solid NaN3 (128 mg, 1.97 mmol) was added to a solution
of bishomogeranyl bromide (13b, 315 mg, 1.29 mmol) in DMF
(6.2 mL). Standard work-up using Et2O provided the desired azide
15b (73%). The azide intermediate then was dissolved in a solution
of t-BuOH and H2O (4:1, 5.09 mL), followed by addition of acety-
lene 14 (235 mg, 0.72 mmol), saturated CuSO4 (0.01 mL), and
sodium ascorbate (43 mg, 0.22 mmol) in sequence. Standard
work-up and purification afforded the desired triazole 16b
(202 mg, 53%) as a yellow oil: 1H NMR (300 MHz, CDCl3) d 7.47
(s, 1H), 5.14–5.05 (m, 2H), 4.29 (t, J = 7.2 Hz, 2H), 4.24–4.06 (m,
8H), 3.33 (td, JHP = 16.1 Hz, J = 6.3 Hz, 2H), 2.97 (tt, JHP = 23.4 Hz,
J = 6.0 Hz, 1H), 2.13–1.88 (m, 8H), 1.68 (s, 3H), 1.60 (s, 3H), 1.58
(s, 3H), 1.30 (t, J = 6.9 Hz, 6H), 1.28 (t, J = 6.9 Hz, 6H); 13C NMR
(125 MHz, CDCl3) d 145.1, 137.3, 131.7, 124.3, 122.4 (2C), 63.0 (d,
JCP = 6.5 Hz, 2C), 62.7 (d, JCP = 6.6 Hz, 2C), 49.8, 39.9, 36.9 (t,
JCP = 132.1 Hz), 30.6, 26.8, 25.9, 24.9, 22.3 (t, JCP = 5.0 Hz), 17.9,
16.5 (d, JCP = 6.3 Hz, 2C), 16.5 (d, JCP = 6.1 Hz, 2C), 16.3; 31P NMR d
22.5; HRMS (ES+) m/z calcd for C24H45N3O6P2Na (M+Na)+
556.2681, found 556.2690.
5.15. Bishomoprenyl bromide (13a)
According to the procedure used for formation of bromide 13b,
alcohol 12a (487 mg, 4.27 mmol) in CH2Cl2 (25 mL) was treated
with NEt3 (0.90 mL, 6.4 mmol) and methanesulfonyl chloride
(0.43 mL, 5.6 mmol) in succession, and the resulting mixture was
allowed to stir for 40 min. A parallel work-up provided the desired
mesylate. To a stirred solution of flame dried LiBr (947 mg) in
anhydrous acetone (10 mL), the mesylate (574 mg, 2.98 mmol) in
anhydrous acetone (7 mL) was added. The resulting mixture was
heated at reflux for 40 min. A parallel work-up provided the
desired bromide 13a (203 mg, 27%) as a yellow oil that was used
without further purification. The 1H NMR data was consistent with
literature data.23
5.16. Bishomoneryl bromide (13c)
5.19. Tetraethyl (4Z)-(2-(1-(5,9-dimethyldeca-4,8-dienyl)-1H-1,2,3-
triazol-4-yl)ethane-1,1-diyl)bis(phosphonate) (16c)
According to the procedure used for formation of bromide 13b,
alcohol 12c (502 mg, 2.76 mmol) in CH2Cl2 (26 mL) was treated
with NEt3 (0.60 mL, 4.1 mmol) and methanesulfonyl chloride
(0.28 mL, 3.6 mmol) in succession, and the resulting mixture was
allowed to stir for 2 days. A parallel work-up provided the desired
mesylate. To a stirred solution of flame dried LiBr (612 mg) in
anhydrous acetone (8 mL), the mesylate (284 mg, 1.09 mmol) in
anhydrous acetone (3 mL) was added. The resulting mixture was
heated at reflux for 2.5 h. A parallel work-up provided the desired
bromide 13c (281 mg, 42%) as an orange oil that was used without
further purification: 1H NMR (300 MHz, CDCl3) d 5.13–5.09 (m,
2H), 3.43–3.39 (t, J = 6.5 Hz, 2H), 2.19–2.11 (m, 2H), 2.07–2.06
(m, 4H), 1.94–1.85 (m, 2H), 1.70 (m, 6H), 1.62 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 137.0, 131.9, 124.3, 123.4, 33.8, 33.3, 32.1,
26.8, 26.5, 25.9, 23.6, 17.8.
According to the general procedure for preparation of tria-
zoles,11 solid NaN3 (116 mg, 1.78 mmol) was added to a solution
of bishomoneryl bromide (13c, 281 mg, 1.15 mmol) in DMF
(5.5 mL). Standard work-up using Et2O provided the desired azide
15c (75%). This azide intermediate then was dissolved in a solution
of t-BuOH and H2O (4:1, 5.25 mL), followed by addition of acety-
lene 14 (216 mg, 0.66 mmol), saturated CuSO4 (0.01 mL), and
sodium ascorbate (202 mg, 1.02 mmol) in sequence. Standard
work-up and purification afforded the desired triazole 16c
(169 mg, 48%) as a yellow oil: 1H NMR (300 MHz, CDCl3) d 7.48
(s, 1H), 5.14–5.05 (m, 2H), 4.29 (t, J = 7.5 Hz, 2H), 4.23–4.07 (m,
8H), 3.33 (td, JHP = 16.2 Hz, J = 7.0 Hz, 2H), 2.97 (tt, JHP = 23.4 Hz,
J = 6.4, 1H), 2.06–1.99 (m, 6H), 1.96–1.89 (m, 2H), 1.69–1.67 (m,
3H), 1.68 (s, 3H), 1.61 (s, 3H), 1.33–1.26 (m, 12H); 13C NMR
(125 MHz, CDCl3) d 145.2, 137.3, 132.0, 124.2, 123.2, 122.3, 63.0
(d, JCP = 6.7 Hz, 2C), 62.7 (d, JCP = 6.7 Hz, 2C), 49.9, 36.9 (t,
JCP = 133.0 Hz), 32.1, 30.9, 26.7, 25.9, 24.9, 23.6, 22.3 (t, JCP = 4.5
Hz), 17.8, 16.5 (d, JCP = 6.0 Hz, 2C), 16.5 (d, JCP = 6.3 Hz, 2C); 31P
NMR d 22.5; HRMS (ES+) m/z calcd for C24H46N3O6P2 (M+H)++
534.2862, found 534.2874.
5.17. Tetraethyl (2-(1-(5-methylhexa-4-enyl)-1H-1,2,3-triazol-4-yl)
ethane-1,1-diyl)bis(phosphonate) (16a)
According to the procedures described for preparation of tria-
zoles,11 solid NaN3 (120 mg, 1.85 mmol) was added to a solution