RSC Advances
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pressure to produce 30 as a colourless oil (0.0286 g, 46% over diastereoisomers to be 67% and 66% ee respectively. Diaste-
the 2 steps). [a]D22 ¼ +50 (c 0.31, CHCl3); nmax (neat)/cmꢁ1: 3019, reomer 32a upon recrystallization from IPA gave 0.0511 g of
2978, 1779, 1742; 1H NMR (500 MHz, CDCl3) dH 7.22 (d, J ¼ material from the supernatant at 99% ee. Data for major, rst
8.7 Hz, 2H), 6.81 (d, J ¼ 8.7 Hz, 2H), 4.87 (d, J ¼ 15.1 Hz, 1H), eluting diastereoisomer 32a: [a]2D3 ¼ +6.2 (c 0.71, CHCl3) (99%
4.19 (d, J ¼ 15.1 Hz, 1H), 3.89 (d, J ¼ 9.8 Hz, 1H), 3.77 (s, 3H), ee) nmax (neat)/cmꢁ1: 3418, 2973, 2926, 1743, 1697; 1H NMR (500
3.75 (d, J ¼ 9.8 Hz, 1H), 3.31 (s, 3H), 1.34 (s, 3H), 1.28 (s, 3H), MHz, CDCl3) dH 7.24 (d, J ¼ 8.7 Hz, 2H), 6.81 (d, J ¼ 8.7 Hz, 2H),
1.05 (s, 9H); 13C NMR (126 MHz, CDCl3) dC 209.1, 177.3, 166.9, 4.71 (d, J ¼ 15.2 Hz, 1H), 4.46 (d, J ¼ 15.2 Hz, 1H), 3.99–3.87 (m,
159.3, 130.5, 128.2, 113.8, 75.8, 74.1, 58.9, 55.4, 52.8, 46.1, 43.3, 2H), 3.82 (d, J ¼ 9.7 Hz, 1H), 3.78 (s, 3H), 3.65 (s, 3H), 3.44 (d, J ¼
27.2, 22.2, 20.6; HRMS (NSI-FTMS) m/z [M + H]+ calcd for 9.7 Hz, 1H), 2.12 (s, 3H), 1.60 (s, 3H), 1.04 (s, 9H); 13C NMR (126
[C21H30NO6]+ 392.2068, found 392.2068. Determination of ee MHz, CDCl3) dC 173.0, 172.1, 158.9, 130.4, 129.6, 113.7, 77.9,
was carried out by HPLC using an Eurocel 01 Knauer column, 74.1, 70.7, 62.8, 55.4, 53.4, 52.5, 45.2, 27.2, 22.9, 12.3; HRMS
95 : 5 hexane/IPA, 230 nm, 0.8 mL minꢁ1, 25 C.
(NSI-FTMS) m/z [M + H]+ calcd for [C21H32NO6S]+ 426.1945,
found 426.1942. Data for the minor, second eluting diaste-
reomer 32b: [a]2D2 ¼ +5.26 (c 0.38, CHCl3) (66% ee) nmax (neat)/
cmꢁ1: 3385, 3016, 2975, 1743, 1686; 1H NMR (500 MHz, CDCl3)
d 7.18 (d, J ¼ 8.6 Hz, 2H), 6.81 (d, J ¼ 8.7 Hz, 2H), 4.77 (d, J ¼
15.5 Hz, 1H), 4.43 (d, J ¼ 15.5 Hz, 1H), 4.32 (s, 1H), 3.96 (d, J ¼
9.6 Hz, 1H), 3.77 (s, 3H), 3.75 (s, 1H), 3.67 (d, J ¼ 9.7 Hz, 1H),
3.64 (s, 3H), 2.19 (s, 3H), 1.53 (s, 3H), 1.02 (s, 9H); 13C NMR (126
MHz, CDCl3) d 173.8, 171.7, 158.8, 130.3, 128.9, 113.7, 78.0,
74.4, 71.6, 62.1, 55.7, 55.4, 52.7, 45.3, 27.1, 22.6, 12.7; HRMS
(NSI-FTMS) m/z [M + H]+ calcd for [C21H32NO6S]+ 426.1945,
found 426.1945. Determination of ee was carried out by HPLC
using an AD-H Chꢀiralpak column, 90 : 10 hexane/IPA, 230 nm,
0.8 mL minꢁ1, 25 C.
ꢀ
(R)-Methyl 2-(hydroxymethyl)-1-(4-methoxybenzyl)-4,4-
dimethyl-3,5-dioxopyrrolidine-2-carboxylate 31
Lactam 30 (0.0109 g, 0.027 mmol) was dissolved in dry DCM (0.1
mL), and TFA (0.1 mL) added. The solution was stirred under
nitrogen for 1.5 h until TLC showed complete consumption of
starting material. The solution was diluted to 50 mL with DCM
and washed with water (50 mL). The organic layer was washed
with a saturated NaHCO3 solution (50 mL), dried (sodium
sulfate), ltered, and the solvents removed under reduced
pressure to give a colourless solid, which was puried by
column chromatography using petroleum ether (40–60 ꢀC)/ethyl
acetate (2 : 1) as eluent to yield the deprotected alcohol 31 as
a gum (0.0062 g, 67%). [a]2D4 ¼ ꢁ7.74 (c 0.62, CHCl3) (86% ee)
nmax (neat)/cmꢁ1: 3396, 2919, 1778, 1742, 1678; H NMR (500
1
(2R,3R,4R)-Methyl 3-hydroxy-2-(hydroxymethyl)-1-(4-methoxybenzyl)-4-
methyl-4-(methylthio)-5-oxopyrrolidine-2-carboxylate 13 (ref. 18)
MHz, CDCl3) dH 7.30 (d, J ¼ 8.7 Hz, 2H), 6.86 (d, J ¼ 8.7 Hz, 2H),
4.89 (d, J ¼ 15.1 Hz, 1H), 4.31 (d, J ¼ 15.1 Hz, 1H), 4.14 (dd, J ¼
12.3, 8.6 Hz, 1H), 3.85 (dd, J ¼ 12.3, 4.4 Hz, 1H), 3.79 (s, 3H),
3.55 (s, 3H), 1.35 (s, 3H), 1.28 (s, 3H), 1.17 (dd, J ¼ 8.6, 4.5 Hz,
1H); 13C NMR (126 MHz, CDCl3) dC 208.3, 177.3, 166.4, 159.6,
130.1, 128.7, 114.5, 77.3, 60.8, 55.4, 53.2, 46.1, 43.7, 22.0, 20.5;
HRMS (NSI-FTMS) m/z [M + H]+ calcd for [C17H22NO6]+
336.1442, found 336.1443. Determination of ee (86% ee) was
carried out by HPLC using an AD-H Chꢀiralpak column, 80 : 20
hexane/IPA, 230 nm, 0.8 mL minꢁ1, 25 C.
Alcohol 32a (0.0427 g, 0.1 mmol) was dissolved in anhydrous
DCM (0.21 mL) in a ame-dried ask. TFA (0.21 mL) was added,
and the mixture stirred under an atmosphere of nitrogen until
TLC showed complete consumption of starting material (about
1.5 h). The mixture was diluted with DCM (20 mL) and washed
with water (20 mL). The aqueous layer was extracted with DCM
(20 mL), and the combined organic layers were washed with
saturated aqueous NaHCO3 (20 mL) and brine (20 mL), dried
(sodium sulfate), ltered, and the solvents removed under
reduced pressure. The residue was puried by column chro-
matography using petroleum ether (40–60 ꢀC)/ethyl acetate 1 : 1
as eluent to yield 13 as a colourless solid (0.0279 g, 75%). Mp
128–130 ꢀC (lit18 129 ꢀC); [a]D23 ¼ ꢁ33.84 (c 0.13, CHCl3) (lit18
[a]D23 ¼ ꢁ41.8 (c 0.1, CHCl3)) nmax (neat)/cmꢁ1: 3416, 2925, 2852,
(2R,3R,4R)-Methyl 2-(tert-butoxymethyl)-3-hydroxy-1-(4-
methoxybenzyl)-4-methyl-4-(methylthio)-5-oxopyrrolidine-
2-carboxylate 32a and (2R,3S,4S)-methyl 2-(tert-butoxymethyl)-3-
hydroxy-1-(4-methoxybenzyl)-4-methyl-4-(methylthio)-5-oxopyrrolidine-
2-carboxylate 32b
1
1737, 1675; H NMR (500 MHz, CDCl3) dH 7.29 (d, J ¼ 8.5 Hz,
2H), 6.85 (d, J ¼ 8.7 Hz, 2H), 5.11 (d, J ¼ 15.3 Hz, 1H), 4.13 (d, J ¼
7.7 Hz, 1H), 4.05 (d, J ¼ 15.3 Hz, 1H), 3.85–3.77 (m, 5H), 3.76 (s,
3H), 3.67 (d, J ¼ 8.1 Hz, 1H), 2.14 (s, 3H), 1.61 (s, 3H); 13C NMR
(126 MHz, CDCl3) dC 173.5, 171.6, 159.5, 129.8, 129.6, 114.6,
76.8, 72.4, 62.5, 55.4, 53.4, 52.9, 44.8, 22.9, 12.4; HRMS (NSI-
FTMS) m/z [M + H]+ calcd for [C17H24NO6S]+ 370.1319, found
370.1320. Determination of ee was carried out by HPLC using an
AD-H Chiralpak column, 80 : 20 hexane/IPA, 230 nm, 0.8
The mixture of diastereoisomers 28a/b (0.1407 g, 0.33 mmol)
was dissolved in ethanol (9 mL) and the solution cooled with an
ice bath. Sodium borohydride (0.0073 g, 0.19 mmol, 0.6 equiv.)
was added, and the mixture stirred for 20 min. Water (40 mL)
was added, and the resulting solution extracted with ethyl
acetate (3 ꢂ 40 mL). The combined organic extracts were
washed with brine (120 mL), dried (sodium sulfate), ltered,
and the solvents removed under reduced pressure. The residue
was puried using column chromatography using petroleum
ether (40–60 ꢀC)/ethyl acetate (8 : 2–2 : 1) as eluent to provide
two separable diastereoisomers as gums, 32a, the rst eluting
diastereoisomer (0.0764 g, 54%) and 32b, the second (0.0181 g,
mL minꢁ1, 25 C.
ꢀ
Conflicts of interest
13%). Analysis by chiral HPLC showed the ees of the There are no conicts to declare.
30030 | RSC Adv., 2019, 9, 30019–30032
This journal is © The Royal Society of Chemistry 2019