4
R. D. Gaikwad et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
15 min. To this mixture was added dropwise a solution of NaBH4
(0.238 g, 6.1 mmol) in dry THF (10 mL). The reaction mixture was
allowed to stir for 4 h. The reaction was monitored by TLC, then
quenched with water, and extracted with EtOAc, washed with
brine and dried over anhydrous Na2SO4. The solvent was removed
in vacuum and residue was subjected to column chromatography
phenylpentanone 7b (1.5 g, 6.8 mmol) while maintaining the tem-
perature at 0 °C and the reaction was kept stirring for 4 h. The reac-
tion was quenched with NH4Cl solution. THF was removed in
vacuum. The residue was extracted with EtOAc and the aqueous
layer was separated and extracted with EtOAc. The combined
organic layer was washed with brine and dried over anhydrous
Na2SO4. Solvent was removed in vacuum and the residue was sub-
jected to column chromatography on silica gel to give hydroxyl
on silica gel to give 10a, Yield: 0.693 g (84.7%); [
0.54, CHCl3); IR
700 cmÀ1
a
]
20 = À20.2 (c
D
m
max: 3414, 2978, 1732, 1404, 1224, 1049, 758,
,
1H NMR (500 MHz, CDCl3): d 7.35–7.15 (m, 5H), 4.97
compound 8b, Yield: 1.20 g (79.50%); [
lit17 20 = +1 (c 1, CHCl3); chiral GC analysis: tR(minor)
= 32.53 min, tR(major) = 33.65 min; IR
1732, 1603, 1495, 1454, 1373, 1320, 1183 cmÀ1
a]
20 = +5.2 (c 0.24, CHCl3);
D
(dd, J = 3.0, 9.0 Hz, 1H), 4.30 (m, 1H), 3.62 (bs, 1H), 2.41 (m,
1H),1.96–1.72 (m, 2H), 1.46 (s, 9H); 13C NMR (125 MHz, CDCl3): d
172.4, 144.7, 128.5, 127.6, 125.8, 81.5, 74.4, 68.8, 44.2, 42.7, 28.3;
GCMS (m/z): 266 (M+), 251, 236, 221, 209, 193, 177, 165, 151,
134, 121, 107, 90, 77, 64, 51, 40; HRMS (m/z) calcd for C15H22O4;
266.3364; found: 266.3358.
[a]
D
m
max: 3429, 3027, 2931,
1H NMR
;
(500 MHz, CDCl3): d = 7.24 (m, 5H), 4.17 (q, J = 7.5 Hz, 2H), 4.05–
3.95 (m, 1H), 3.05 (bs, -OH), 2.50 (dd, J = 3.5, 16.5 Hz, 1H), 2.43
(dd, J = 8.5, 16.5 Hz, 1H), 2.86–2.79 (m, 1H), 2.73–2.67 (m, 1H),
1.89–1.70 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d = 173.0, 141.8, 128.5, 128.5, 125.9, 67.3, 60.7, 41.4, 38.2,
31.8, 28.0, 14.2; GCMS (m/z): 222 (M+), 204, 176, 159, 145, 130,
117, 104, 91, 77, 60, 43. HRMS (m/z) calcd for C13H18O3;
222.2834; 222.2842.
4.6. Synthesis of (4S,6R)-tetrahydro-4-hydroxy-6-phenylpyran-
(2H)-2-one 6a
A catalytic amount of p-toluenesulfonic acid (0.052 g) was
added to a stirred solution of 10a (0.5 g, 1.87 mmol) in dry CH2Cl2
(10 mL) under an N2 atmosphere and the reaction mixture was
stirred at rt for 3 h. After completion of the reaction, the reaction
mixture was quenched by the addition of solid NaHCO3 and the
solvent was removed under vacuum. The crude residue was sub-
jected to column chromatography to give lactone 6a, Yield:
4.9. Synthesis of t-butyl (R)-5-hydroxy-3-oxo-7-phenylheptanoate
9b
To a mixture of diisopropyl amine (2.26 g, 0.022 mol) and dry
THF (20 mL), cooled to 0 °C under an N2 atmosphere was added n-
BuLi (14.12 mL, 0.021 M) over 10 min, stirring was continued for
20 min. After 20 min, the solution was cooled to À78 °C and t-butyl
acetate (2.5 g, 5.4 mmol) was added over 5 min. The stirring was
continued for 20 min, and the resulting solution at À78 °C was
transferred via syringe over 5 min to a solution of compound 8b
(1.2 g, 5.4 mmol) and THF at 0 °C. The reaction flask was placed in
a rt water bath and stirred for 1.5 h. The reaction mixture was
quenched with saturated NH4Cl solution. THF was removed in vac-
uum and the residue was extracted in EtOAc. The aqueous layer was
washed with EtOAc. The solvent was removed in vacuum from the
combined extracts and the residue was subjected to column chro-
matography on silica gel to give 9b, Yield: 1.15 g (73.80%), liquid;
0.216 g (60.0%); [a]
20 = +5.6 (c 0.16, CHCl3); lit8 (4R,6S isomer,
D
[a
]
D
20 = À9.4 (c 1.3, CHCl3); Chiral GC analysis: tR(major)
= 34.76 min; IR mmax: 3430, 3015, 2927, 1728, 1495, 1455, 1348,
1257, 1044, 860, 768 cmÀ1 1H NMR (500 MHz, CDCl3): d 7.40–
;
7.35 (m, 5H), 5.76 (dd, J = 3.0, 11.50 Hz, 1H), 4.45 (q, J = 3.9, 1H),
2.86 (dd, 4.9, 17.5, H), 2.74 (ddd, J = 1.5, 3.5, 17.5 Hz, H), 2.25–
2.05 (m, 3H); 13C NMR (125 MHz, CDCl3): d 170.8, 139.4, 128.9,
128.8, 128.5, 125.8, 76.9, 62.6, 38.7, 38.4; GCMS (m/z): 192 (M+),
176, 160, 148, 134, 117, 104, 90, 77, 65, 52, 40; HRMS (m/z) calcd
for C11H12O3: 192.2140, found: 192.2132.
4.7. Synthesis of ethyl 3-oxo-5-phenylpentanone 7b
[
a
]
20 = À12.8 (c 0.45, CHCl3); lit.11a ethyl ester [
a
]
20 = À12.5 (c 1,
D
D
To a solution of diisopropyl amine (3.84 g, 27.0 mmol) in dry
THF (20 mL), cooled to À50 °C under an N2 atmosphere was added
n-BuLi (20 mL, 30.6 mmol) over 10 min, after which stirring was
continued for 20 min, while the reaction mixture was maintained
at À50 °C. Next, ethyl acetoacetate (2 g, 15.4 mmol) was added
dropwise within period of 15 min, and stirring was continued for
30 min. A solution of benzyl bromide (2.63 g, 15.4 mmol) and dry
THF (6 mL) was added dropwise within 20 min and the reaction
was maintained at À50 °C for 3 h. After completion of the reaction,
it was quenched with saturated NH4Cl (1 mL). THF was removed in
vacuum. The residue was extracted in EtOAc and washed with
water (10 mL), and dried over anhydrous Na2SO4. The solvent
was removed in vacuum and residue was subjected to column
chromatography to give compound 7b 2.31 g (63.0%), liquid; IR
CHCl3); Chiral GC analysis: tR(minor) = 26.4 min, tR(major)
= 27.5 min; IR
m
max: 3428, 2932, 1730, 1714, 1603, 1495, 1454,
1370, 1258, 1154, 1030, 843, 754 cmÀ1
;
1H NMR (500 MHz,
CDCl3): d 7.33–7.18 (m, 5H), 4.16 (t, J = 4.45 Hz, 2H), 4.06–3.99
(m, 1H), 2.86–2.67 (m, 2H), 2.50 (dd, J = 3.45, 16.45 Hz, 1H), 2.46
(dd, J = 8.7, 16.4 Hz, 1H),3.16 (bs, 1H),1.90–1.70 (m 2H), 1.48 (s,
9H); 13C NMR (125 MHz, CDCl3): d 192.2, 173.2, 141.8, 128.9,
128.4, 126.6, 126.4, 67.3, 64.7, 49.4, 38.3, 31.9, 30.7, 28.2, 19.2,
14.1. HRMS (m/z) calcd for C17H24O4; 292.3742; found: 292.3736.
4.10. Synthesis of t-Butyl (3R,5R)-3,5-dihydroxy-7-phenylhe-
ptanoate 10b
To a stirred solution of compound 9b (0.668 g, 2.28 mmol) in
dry THF (15 mL), cooled at À10 °C under an N2 atmosphere was
added triethylborane (0.278 mL, 2.7 mmol). The reaction was stir-
red for 15 min. To this mixture was added dropwise a solution of
NaBH4 (0.180 g, 4.6 mmol) in dry THF (5 mL). The reaction mixture
was allowed to stir for 4 h. The reaction was monitored on TLC. It
was then quenched with water and extracted with EtOAc, washed
with brine and dried over anhydrous Na2SO4. The solvent was
removed in vacuum and the residue was subjected to column chro-
matography on silica gel to give 10b, Yield: 0.577 g (85.80%), vis-
m
max: 3028, 2984, 1743, 1714, 1497, 1454, 1368, 1317, 1031,
757 cmÀ1 1H NMR (60 MHz, CDCl3): d 7.27 (m, 5H), 4.10 (q,
;
J = 7.0 Hz, 3H), 3.40 (s, 2H), 2.90 (m, 4H), 1.22 (t, J = 7.0 Hz, 2H);
GCMS (m/z): 220 (M+), 202, 177, 159, 147, 131, 119, 104, 91, 78,
65, 41; HRMS (m/z) calcd for C13H16O3; 220.2676; found: 220.2668.
4.8. Synthesis of ethyl (R)-3-hydroxy-5-phenylpentanoate 8b
To a stirred solution of NaBH4 (0.740 g, 14.2 mmol) in dry THF
(15 mL), cooled at 0 °C under an N2 atmosphere was added (S)-
(À)-1,1-diphenyl-prolinol (0.290 g, 1.2 mmol). The mixture was
stirred for 5 min. To this solution was added trimethylborate
(0.2–0.3 mL) followed by the dropwise addition of ethyl 3-oxo-5-
cous liquid;
[
a
]
20 = À5.5 (c 0.51, CHCl3); lit.11a ethyl ester
D
[a]
20 = À4.8 (c 1, CHCl3); Chiral GC analysis: tR(minor) = 29.8 min,
D
tR(major) = 30.4 min; IR
mmax: 3435, 3018, 2981, 1713, 1495,
1454, 1394, 1369, 1216, 1152, 1085, 740; 1H NMR (500 MHz,