C
A. Sharada et al.
Paper
Synthesis
ed Barbier allylation, Still–Gennari olefination, and aceton-
ide hydrolysis followed by lactonization. These are the key
steps involved in the current synthesis.
(1S,2R,3R)-2-(tert-Butyldimethylsiloxy)-1-chloro-1-phenylhex-5-
en-3-ol (10a) and (1S,2R,3S)-2-(tert-Butyldimethylsiloxy)-1-
chloro-1-phenylhex-5-en-3-ol (10b)
To a stirred solution of IBX (1.14 g, 4.08 mmol) in DMSO (5 mL) was
added alcohol 8 (0.817 g, 2.72 mmol) in CH2Cl2 (8 mL) and the mix-
ture was stirred at r.t. for 6 h. Then, it was diluted with CH2Cl2 (50
mL). The mixture was filtered through a pad of Celite and the filtrate
was washed with sat. Na2S2O3·5H2O solution (10 mL) and brine solu-
tion (10 mL), and dried (Na2SO4). It was then concentrated to afford
the residue which was purified by column chromatography (silica gel,
petroleum ether/EtOAc, 98:2) to furnish aldehyde 9 (0.747 g, 92%) as
a viscous liquid. To a stirred solution of aldehyde 9 (0.747 g, 2.50
mmol) in THF/H2O (1:1, 8 mL), indium powder (0.574 g, 5.0 mmol)
and allyl bromide (0.420 μL, 5.0 mmol) were added at 0 °C and the
mixture was stirred for 12 h at r.t. The mixture was diluted with wa-
ter and extracted with EtOAc; the combined extracts were dried
(Na2SO4). The obtained residue was purified by column chromatogra-
phy (silica gel) and yielded 10a and 10b (0.767 g, 90%).
All moisture sensitive reactions were carried out in anhydrous sol-
vents under N2 atmosphere. All anhydrous solvents were distilled pri-
or to use. THF from Na/benzophenone and CH2Cl2, DMSO and DMF
over CaH2. Commercial reagents were used without further purifica-
tion. Column chromatography was carried out with silica gel (Merck
60–120 mesh and 100–200 mesh), technical grade hexane and EtOAc
were distilled and used as the mobile phase. Specific optical rotations
[α]D were given in 10–1 deg cm2 g–1. Infrared spectra were recorded by
using KBr optics/neat (as mentioned). TOF analyzer technique was
used for the HRMS measurement. 1H and 13C NMR spectra were re-
corded with an internal deuterium lock on Bruker 300 MHz, Avance
400 MHz, and Inova 500 MHz spectrophotometers. Compounds 5 and
6 were prepared according to the reported methods.12,13
IR (CHCl3): 3476, 2954, 2856, 1640, 1459, 1253, 697 cm–1
.
(1S,2R)-2,3-[Bis(tert-butyldimethylsiloxy)]-1-chloro-1-phenylpro-
pane (7)
(1S,2R,3R)-2-(tert-Butyldimethylsiloxy)-1-chloro-1-phenylhex-5-
en-3-ol (10a)
1H NMR (400 MHz, CDCl3): δ = 7.46–7.39 (m, 2 H), 7.37–7.27 (m, 3 H),
5.90–5.80 (m, 1 H), 5.22–5.15 (m, 2 H), 4.92 (d, J = 6.7 Hz, 1 H), 4.16
(dd, J = 6.6, 4.2 Hz, 1 H), 3.89–3.82 (m, 1 H), 2.52–2.44 (m, 1 H), 2.30–
2.20 (m, 1 H), 0.79 (s, 9 H), 0.08 (s, 3 H), –0.21 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 139.0, 134.7, 128.8, 128.4, 128.1,
118.6, 79.2, 71.4, 62.5, 36.2, 25.9, 18.3, –4.2, –4.7.
HRMS (EI): m/z [M + Na]+ calcd for C18H29ClNaO2Si: 363.15230; found:
363.15216.
To a stirred solution of diol 5 (1.30 g, 6.97 mmol) in DMF (10 mL)
were added imidazole (1.90 g, 27.88 mmol), TBSCl (4.20 g, 27.9
mmol), and DMAP (0.425 g, 3.48 mmol) at 0 °C and the mixture was
stirred at r.t. for 24 h. The mixture was quenched by the addition of
cold water (20 mL) and extracted with EtOAc (3 × 30 mL). The com-
bined organic phases were dried (Na2SO4) and the solvent was re-
moved under vacuum. The residue was purified by column chroma-
tography (silica gel, petroleum ether) to afford bis-silyl ether 7 (2.60
g, 90%) as a colorless oil; [α]D25 +29 (c 0.5, CHCl3).
IR (CHCl3): 2953, 2929, 2886, 1466, 1360, 753 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.44–7.40 (m, 2 H), 7.33–7.24 (m, 3 H),
5.05 (d, J = 5.0 Hz, 1 H), 4.06 (dt, J = 6.4, 4.8 Hz, 1 H), 3.64 (dd, J = 10.2,
4.5 Hz, 1 H), 3.3 (dd, J = 10.2, 6.5 Hz, 1 H), 0.92 (s, 9 H), 0.81 (s, 9 H),
0.05 (s, 3 H), 0.03 (s, 6 H), –0.05 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 138.0, 129.0, 128.0, 127.7, 76.9, 64.5,
62.7, 25.9, 25.7, 18.2, 18.0, –4.5, –5.0, –5.4, –5.4.
(1S,2R,3S)-2-(tert-Butyldimethylsiloxy)-1-chloro-1-phenylhex-5-
en-3-ol (10b)
1H NMR (400 MHz, CDCl3): δ = 7.46–7.39 (m, 2 H), 7.37–7.27 (m, 3 H),
5.90–5.80 (m, 1 H), 5.15–5.10 (m, 2 H), 4.93 (d, J = 7.7 Hz, 1 H), 4.00
(dd, J = 7.8, 2.0 Hz, 1 H), 3.89–3.82 (m, 1 H), 2.52–2.44 (m, 1 H), 2.30–
2.20 (m, 1 H), 0.82 (s, 9 H), 0.04 (s, 3 H), –0.56 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 139.1, 134.7, 128.8, 128.5, 128.3,
117.3, 77.7, 70.9, 62.9, 39.0, 26.0, 18.3, –4.2, –5.2.
HRMS (ESI): m/z [M + H]+ calcd for C21H40ClO2Si2: 415.22499; found:
415.22453.
MS (EI): m/z = 363 [M + Na]+.
(2R,3S)-2-(tert-Butyldimethylsiloxy)-3-chloro-3-phenylpropan-1-
ol (8)
(1S,2R,3R)-1-Chloro-1-phenylhex-5-ene-2,3-diol (11a)
CSA (72 mg, 0.31 mmol) was added to a stirred solution of the dipro-
tected TBS ether 7 (1.30 g, 3.13 mmol) in MeOH (10 mL) at 0 °C and
stirring was maintained for 2 h. The reaction was quenched with sol-
id NaHCO3 (0.052 g, 0.62 mmol), filtered, and extracted with CH2Cl2 (3
× 20 mL), and the combined extracts were dried (Na2SO4). Concentra-
tion under vacuum and purification of the residue by flash column
chromatography (petroleum ether/EtOAc, 98:2) yielded alcohol 8
(0.80 g, 85%) as a colorless oil; [α]D25 +36 (c 0.25, CHCl3).
To a stirred solution of homoallylic alcohols 10a and 10b (0.832 g,
2.44 mmol) in MeOH (10 mL) at 0 °C was added PTSA (48 mg, 0.25
mmol) and the mixture was stirred at r.t. for 2 h. The reaction was
quenched with sat. NaHCO3 (5 mL) at 0 °C, MeOH was removed under
reduced pressure, and extracted with EtOAc (3 × 50 mL). The com-
bined organic extracts were dried (Na2SO4) and concentrated under
reduced pressure. The residue was purified by column chromatogra-
phy (silica gel, petroleum ether/EtOAc, 8:2) to give diol 11a (0.390 g,
70%) as a colorless oil; [α]D25 +46 (c 0.25, CHCl3).
IR (CHCl3): 3448, 2953, 2929, 2887, 1493, 1254, 1044, 753 cm–1
.
IR (CHCl3): 3420, 2922, 2853, 1640, 1454, 1196, 700 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.41–7.37 (m, 2 H), 7.35–7.27 (m, 3 H),
4.93 (d, J = 7.9 Hz, 1 H), 4.05–3.99 (m, 2 H), 3.69 (dd, J = 12.2, 4.0 Hz, 1
H), 0.74 (s, 9 H), –0.04 (s, 3 H), –0.41 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 139.0, 128.5, 128.3, 128.2, 76.6, 63.7,
61.6, 25.5, 17.8, –4.8, –5.6.
1H NMR (500 MHz, CDCl3): δ = 7.52–7.48 (m, 2 H), 7.40–7.31 (m, 3 H),
5.86–5.75 (m, 1 H), 5.22–5.19 (m, 1 H), 5.18–5.14 (m, 2 H), 4.02 (t, J =
6.1 Hz, 1 H), 3.54–3.46 (m, 1 H), 2.60–2.52 (m, 1 H), 2.41 (br s, 1 H),
2.29–2.20 (m, 1 H), 1.91 (br s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 137.1, 134.0, 128.6, 128.6, 128.4,
119.2, 77.4, 70.1, 63.4, 37.0.
HRMS (EI): m/z [M + Na]+ calcd for C15H25ClO2SiNa: 323.12100; found:
323.11989.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E