7408
L. Tan et al. / Tetrahedron 58 (2002) 7403–7410
The organic layer was washed with 1N HCl and brine and
concentrated to ,35 mL. Hexane (200 mL) was added and
the solid was collected by filtration to 18.4 g (91%) of 3 as a
white solid: mp 35–378C. [a ]2D5¼þ0.98 (c¼0.56, CH3OH).
IR (neat): 1750 cm21. 1H NMR (400 MHz, CDCl3): d 9.54
(bs, 1H), 4.54 (qq, J¼6 and 6 Hz, 1H), 1.85 (m, 2H), 1.50 (s,
3H), 1.25 (d, J¼6 Hz, 3H), 1.24 (d, J¼6 Hz, 3H), and 0.84
(dd, J¼7.5 and 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3): d
171.6, 165.4, 118.5, 82.4, 73.8, 29.5, 23.3, 22.0(3), 22.0(0),
and 7.3. HRMS Calcd for C10H17O4 (MþHþ): 201.1127.
Found: 201.1127.
25.2, 23.2, and 7.9. HRMS Calcd for C9H18NO2 (MþHþ):
172.1338. Found: 172.1338.
4.1.6. (S )-2-Hydroxy-2-methyl-1-(4-methylthiophenyl)-
butan-1-one 5. To a solvent mixture of THF (4.04 L) and
toluene (21.2 L) was added a solution of amide 11 in toluene
(3 L, 2.1 kg assayed 11, 12.3 mol) and triphenylmethane
(10.1 g, 41 mmol). The solution was degassed by
vacuum/N2 purge. The mixture was cooled to 235 to
2308C and n-BuLi (1.6 M in hexane, 7.66 L, 12.3 mol) was
added slowly over 2–4 h, keeping the temperature below
2308C. In another flask, 4-bromothioanisole (2.74 kg,
13.5 mol) was dissolved in a 6:1 (v/v) mixture of
toluene/THF (28.2 L) and cooled to 235 to 2308C. The
solution was also degassed thoroughly. n-BuLi (1.6 M in
hexane, 8.05 L, 12.9 mol) was added slowly to the cold
solution over 2 h to form a white slurry, keeping the
temperature below 2308C. The amide-alkoxide solution
was transferred into the aryllithium slurry over a 30 min
period via cannula. The resulting solution was warmed to
2158C over 1 h and then to 258C over 1 h period. The
mixture was aged at 258C until the reaction was complete
as determined by HPLC assay. The reaction was quenched
by cannulation into ice-cold aqueous 2N hydrochloric acid
(25.4 L) with vigorous stirring. The layers were separated at
room temperature and the organic layer was washed
saturated sodium bicarbonate (9 L) and concentrated to
11 L. This affords 2.50 kg (95%) of hydroxyketo sulfide 5 as
a toluene solution. An analytical sample was obtained by
concentration and chromatography separation (hexane/ethyl
acetate, 5:1) over silica gel. [a]2D5¼215.28 (c¼1.03,
4.1.4. (S )-5-Ethyl-5-methyl-3-methylethoxy-4-(4-
methylthiophenyl)oxolen-2-one 10. To a solution of 3
(4.0 g, 20 mmol) in CH2ClCH2Cl (40 mL) at 08C was added
pyridine (2.1 mL, 26 mmol) and then Tf2O (4.1 mL,
26 mmol). The mixture was aged for 2 h at 08C. Saturated
NH4Cl (20 mL) was added. The two layers were separated.
The organic layer was washed with brine (20 mL) and
concentrated to dryness. To the residue was added
4-(methylthio)phenyl boronic acid 2 (5.0 g, 30 mmol),
2 M aqueous Cs2CO3 (22 mL, 44 mmol), Pd(PPh3)4
(1.2 g, 1 mmol) in ethylene glycol dimethyl ether (DME,
91 mL) at room temperature. The mixture was degassed 3
times by vacuum/N2 purge and then refluxed at 808C for
18 h. The mixture was diluted with ethyl acetate (90 mL)
and the two layers were separated. The aqueous layer was
extracted with ethyl acetate (2£90 mL). The combined
organic solutions were washed with brine (90 mL) and
concentrated. Chromatography of the residue over silica gel
(hexane/ethyl acetate, 90:10) gave 4.9 g (80%) of 10 as an
oil. [a ]2D5¼222.58 (c¼0.47, CH3OH). IR (neat):
CH3OH). IR (neat): 1735 cm21 1H NMR (400 MHz,
.
1
1756 cm21. H NMR (CDCl3): 7.60 (d, J¼8.4 Hz, 2H),
CDCl3): d 7.95 (m, 2H), 7.27 (m, 2H), 4.30 (s, 1H), 2.52
(s, 3H), 2.00 (m, 2H), 1.59 (s, 3H), and 0.82 (dd, J¼7.4 and
7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3): d 203.4, 146.3,
130.0, 129.7, 124.8, 78.9, 34.3, 27.2, 14.6, and 7.9. Anal.
Calcd for C12H16O2S: C, 64.25; H, 7.19. Found: C, 64.15;
H, 7.15.
7.24 (d, J¼8.4 Hz, 2H), 5.08 (qt, J¼6.1 Hz, 1H), 2.49 (s,
3H), 2.02 (q, J¼7.3 Hz, 2H), 1.92 (q, J¼7.3 Hz, 2H), 1.60
(s, 3H), 1.25 (d, J¼6.2 Hz, 3H), 1.23 (d, J¼6.2 Hz, 3H), and
0.77 (t, J¼7.3 Hz, 3H,). 13C NMR (CDCl3): 168.0, 142.2,
140.5, 139.3, 128.3, 126.7, 125.8, 85.9, 73.4, 31.6, 26.0,
22.6, 15.1, and 7.6. HRMS Calcd for C17H23SO3 (MþHþ):
307.1368. Found: 307.1368.
4.1.7. (S )-1-Ethyl-1-methyl-2-(4-methylthiophenyl)-2-
oxoethyl 2-(methylethoxy)acetate 12. Procedure A.
Under nitrogen, to a solution of hydroxyketone sulfide 5
4.1.5. (S)-2-Hydroxy-2-methyl-1-pyrrolidinyl butan-1-
one 11. To a solution of thionyl chloride (1.81 kg,
15.2 mol) in a mixture of THF (12 L) and toluene (12 L)
was added 6 (1.5 kg, 12.7 mol) portionwise at 215 to
2108C. Neat pyrrolidine (3.61 kg, 50.8 mol) was then
added dropwise over 2.5 h, keeping the temperature below
258C. The mixture was aged at 258C for 20 min and the
reaction was quenched by addition of saturated aqueous
sodium chloride (750 mL) followed by water (2.63 L). The
layers were separated and the aqueous was back extracted
with toluene (7.5 L). The combined organic solutions were
washed with a mixture of 3:1 (v/v) brine and 2N sodium
hydroxide (4.5 L), dried by azeotropic distillation, and used
as a toluene solution directly for the next step reaction.
Assay of the solution indicated 2.09 kg of amide 11 (96%).
An analytical sample was obtained by concentration and
chromatography separation (hexane/ethyl acetate, 4:1, v/v)
over silica gel: [a ]2D5¼þ0.68 (c¼1.02, CH3OH). IR (neat):
(67.3 g, 0.3 mol), isopropoxyacetic acid
4
(42.5 g,
0.36 mol), and DMAP (11.0 g, 90 mmol) in toluene
(540 mL) was added triethyl amine (104.5 mL, 0.75 mol)
at 108C followed by pivaloyl chloride (55.4 mL, 0.45 mol).
The reaction mixture was aged at room temperature for
3–4 h, quenched with water (350 mL), and stirred at
ambient temperature for 1 h. The two layers were separated
and the organic solution was used directly for the oxidation
reaction. This afforded 97.3 g (100%) ketoester sulfide 12 as
a toluene solution. An analytical sample was obtained by
concentration and chromatography separation (hexane/ethyl
acetate, 9:1) over silica gel. [a]2D5¼223.98 (c¼1.00,
1
CH3OH). H NMR (400 MHz, CDCl3): d 7.91 (m, 2H),
7.20 (m, 2H), 3.99 (d, J¼16 Hz, 1H), 3.98 (d, J¼16 Hz,
1H), 3.45 (hept, J¼6 Hz, 1H), 2.49 (s, 3H), 2.27 (dq, J¼15
and 5 Hz, 1H), 2.04 (dq, J¼15 and 5.0 Hz, 1H), 1.70 (s, 3H),
1.12 (d, J¼5.0 Hz, 6H), and 0.97 (dd, J¼7.5 and 7.6 Hz,
3H). 13C NMR (100 MHz, CDCl3): d 197.8, 169.8, 145.2,
130.9, 129.0, 124.8, 87.7, 72.5, 65.8, 30.8, 21.7, 21.6, 21.3,
14.7, and 7.6. Anal. Calcd for C17H24O4S: C, 62.94; H, 7.46.
Found: C, 63.02; H, 7.43.
1
1703, 1595, 1571 cm21. H NMR (400 MHz, CDCl3): d
3.55 (m, 4H), 1.96 (m, 2H), 1.85 (m, 2H), 1.75 (m, 2H), 1.41
(s, 3H), and 0.84 (dd, J¼7.5 Hz and 7.3 Hz). 13C NMR
(100 MHz, CDCl3): d 174.4, 74.3, 48.0, 47.5, 31.7, 27.0,