PAPER
Enantiodivergent Syntheses of Pantolactone and Pantothenic Acid
1105
trated under reduced pressure. Crude material was found to be a sin-
gle diastereomer 4b [GC (temperature program: 50 °C, increasing
20 °C/min up to 310 °C): tR = 5.405 min] and was chromatographed
(silica gel, 100–200 mesh, 5% EtOAc–PE) to yield 4b as a colorless
oil; yield: 2.90 g (90%).
1H NMR (300 MHz, CDCl3): δ = 0.91 (s, 3 H), 0.98 (s, 3 H), 1.37
(s, 3 H), 1.47 (s, 3 H), 2.04–2.08 (br s, 1 H), 3.39 (s, 2 H), 3.67 (d,
J = 3.3 Hz, 1 H), 4.05 (dd, J = 6.9, 1.2 Hz, 2 H), 4.33 (td, J = 7.2,
3.6 Hz, 1 H), 4.64 (d, J = 11.1 Hz, 1 H), 4.87 (d, J = 11.1 Hz, 1 H),
7.28–7.36 (m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 21.2, 22.0, 24.9, 26.4, 39.1, 65.3,
70.6, 75.5, 76.5, 84.6, 108.0, 126.9, 127.7 (2 C), 128.4 (2 C), 138.2.
HRMS (FAB): m/z [M + H]+ calcd for C17H27O4: 295.1909; found:
295.1905.
Ethyl (S)-3-(Benzyloxy)-3-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-
2,2-dimethylpropanoate (6a); Typical Procedure
To a stirred soln of 4a (5 g, 20.32 mmol) in DMF (80 mL) at 0 °C
was added NaH (1.46 g, 50% oil dispersion, 30.48 mmol) in several
portions over 1 h. After stirring for a further 1 h at 0 °C, BnBr (4.17
g, 2.9 mL, 24.38 mmol) in DMF (20 mL) was added dropwise.
When the addition was complete, the mixture was stirred overnight
at r.t. The mixture was cooled to 0 °C and quenched with sat. NH4Cl
soln (100 mL). The aqueous layer was extracted with Et2O (3 × 100
mL) and the combined organic extracts were washed with brine (2
× 50 mL), dried (Na2SO4), and concentrated under reduced pres-
sure. The crude material was chromatographed (silica gel, 100–200
mesh, 5% EtOAc–PE) to yield 6a as a colorless oil; yield: 5.80 g
(85%).
(R)-3-(Benzyloxy)-3-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-
dimethylpropan-1-ol (7b)
Following the typical procedure for 7a using 6b (3.105 g, 9.23
mmol) and LiAlH4 (1.55 g, 40.84 mmol) in Et2O (30 mL) afforded
7b as pure colorless oil; yield: 2.61 g (96%).
[α]D27 +24.7 (c 0.53, CHCl3) {Lit.21 [α]D20 +25.8 (c 1.21, CHCl3)}.
IR (neat): 3443, 1460, 1375, 1218, 1063, 860 cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.95 (s, 3 H), 1.02 (s, 3 H), 1.39
(s, 3 H), 1.43 (s, 3 H), 2.97 (t, J = 6.3 Hz, 1 H), 3.22 (d, J = 3.9 Hz,
1 H), 3.47 (t, J = 6.0 Hz, 2 H), 3.78 (t, J = 7.8 Hz, 1 H), 4.06 (dd,
J = 7.8, 6.9 Hz, 1 H), 4.33–4.39 (m, 1 H), 4.65 (d, J = 11.1 Hz, 1 H),
4.78 (d, J = 11.1 Hz, 1 H), 7.29–7.37 (m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 21.5, 24.2, 25.8, 26.2, 40.1, 67.2,
69.0, 76.0, 76.2, 85.4, 109.0, 127.6, 127.7 (2 C), 128.3 (2 C), 138.3.
[α]D27 +2.5 (c 1.15, CHCl3).
IR (neat): 1729, 1462, 1377, 1258, 1067, 861 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.18 (s, 3 H), 1.22 (s, 3 H), 1.23
(t, J = 7.1 Hz, 3 H), 1.33 (s, 3 H), 1.41 (s, 3 H), 3.98–4.18 (m, 6 H),
4.63 (d, J = 11.3 Hz, 1 H), 4.83 (d, J = 11.3 Hz, 1 H), 7.29–7.33 (m,
5 H).
13C NMR (75 MHz, CDCl3): δ = 14.0, 20.6, 22.2, 24.8, 26.2, 46.4,
60.5, 65.6, 75.3, 76.5, 83.6, 108.0, 127.3 (2 C), 127.4, 128.2 (2 C),
138.5, 176.0.
HRMS (FAB): m/z [M + H]+ calcd for C17H27O4: 295.1909; found:
295.1902.
(S)-3-(Benzyloxy)-3-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-
dimethylpropyl Acetate (8a); Typical Procedure
HRMS (FAB): m/z [M + H]+ calcd for C19H29O5: 337.2015; found:
337.1994.
To a stirred soln of 7a (5.53 g, 18.84 mmol) in anhyd CH2Cl2 (150
mL) at 0 °C were added Et3N (13.14 mL, 94.2 mmol) and DMAP
(460 mg, 3.77 mmol). After 15 min, Ac2O (4.45 mL, 47.1 mmol)
was added dropwise and the mixture was stirred for 12 h at r.t. The
reaction was quenched with H2O (50 mL) and the CH2Cl2 layer was
separated. The aqueous layer was extracted with CH2Cl2 (2 × 50
mL). The combined organic layers were washed with H2O (1 × 50
mL) and brine (2 × 50 mL), dried (Na2SO4), and concentrated under
reduced pressure to yield a crude material which was chromato-
graphed (silica gel, 100–200 mesh, 5% EtOAc–PE) to yield 8a as a
colorless oil; yield: 5.82 g (92%).
Ethyl (R)-3-Benzyloxy-3-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-
2,2-dimethylpropanoate (6b)
Following the typical procedure for 6a using 4b (2.83 g, 11.5
mmol), NaH (0.83 g, 50% oil dispersion, 17.29 mmol), BnBr (2.36
g, 1.64 mL, 13.79 mmol) in DMF (60 mL) with column chromatog-
raphy (silica gel, 100–200 mesh, 3% EtOAc–PE) afforded 6b as a
colorless oil; yield: 3.20 g (83%).
[α]D27 +26.8 (c 0.72, CHCl3).
IR (neat): 1729, 1461, 1375, 1256, 1067, 862 cm–1.
[α]D27 –7.9 (c 1.15, CHCl3).
IR (neat): 1740, 1465, 1375, 1241, 1056, 861 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.16 (s, 3 H), 1.24 (t, J = 7.2 Hz,
3 H), 1.28 (s, 3 H), 1.36 (s, 3 H), 1.43 (s, 3 H), 3.62 (t, J = 8.1 Hz, 1
H), 3.78 (d, J = 6.9 Hz, 1 H), 3.74 (dd, J = 8.1, 6.3 Hz, 1 H), 4.09
(q, J = 6.9 Hz, 2 H), 4.24 (q, J = 7.2 Hz, 1 H), 4.58 (d, J = 11.1 Hz,
1 H), 4.92 (d, J = 11.3 Hz, 1 H), 7.27–7.34 (m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 14.1, 20.6, 22.2, 25.7, 26.5, 46.8,
60.7, 66.6, 75.3, 77.4, 84.2, 108.5, 127.3, 127.5 (2 C), 128.2 (2 C),
138.8, 176.4.
1H NMR (300 MHz, CDCl3): δ = 0.89 (s, 3 H), 0.99 (s, 3 H), 1.37
(s, 3 H), 1.45 (s, 3 H), 2.04 (s, 3 H), 3.73 (d, J = 2.4 Hz, 1 H), 3.85
(d, J = 10.5 Hz, 1 H), 3.96–4.00 (m, 2 H), 4.06 (t, J = 7.7 Hz, 1 H),
4.34 (td, J = 7.5, 2.4 Hz, 1 H), 4.56 (d, J = 11.1 Hz, 1 H), 4.90 (d,
J = 11.1 Hz, 1 H), 7.26–7.34 (m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 20.6, 20.8, 22.2, 24.9, 26.4, 38.0,
64.9, 70.3, 75.3, 76.7, 81.6, 107.6, 127.4, 127.5 (2 C), 128.2 (2 C),
138.5, 170.8.
HRMS (FAB): m/z [M + H]+ calcd for C19H29O5: 337.2015; found:
337.2004.
HRMS (FAB): m/z [M + H]+ calcd for C19H29O5: 337.2015; found:
(S)-3-(Benzyloxy)-3-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-
dimethylpropan-1-ol (7a); Typical Procedure
337.2003.
Compound 6a (6.5 g, 19.34 mmol) in Et2O (40 mL) at 0 °C was add-
ed dropwise to a stirred suspension of LiAlH4 (3.25 g, 85.63 mmol)
in Et2O (30 mL) and the mixture was stirred for 4 h at 0 °C. The re-
action was quenched with sat. Na2SO4 soln (50 mL). Excess H2O
was absorbed with solid Na2SO4, which was then filtered through a
Büchner funnel and the filtercake was washed with CHCl3 (3 × 120
mL). The solvent was evaporated under reduced pressure to yield
sufficiently pure 7a as a colorless; yield: 5.63 g (99%).
(R)-3-(Benzyloxy)-3-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-
dimethylpropyl Acetate (8b)
Following the typical procedure for 8a using 7b (2.4 g, 8.18 mmol),
Et3N (5.70 mL, 40.86 mmol), Ac2O (1.93 mL, 20.43 mmol), and
DMAP (200 mg, 1.64 mmol) in CH2Cl2 (65 mL) with column chro-
matography (silica gel, 100–200 mesh, 5% EtOAc–PE) furnished
8b as a colorless oil; yield: 2.47 g (90%).
[α]D27 +26.6 (c 2.10, CHCl3).
IR (neat): 1738, 1461, 1375, 1243, 1058, 861 cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.95 (s, 3 H), 0.99 (s, 3 H), 1.38
(s, 3 H), 1.45 (s, 3 H), 2.04 (s, 3 H), 3.30 (d, J = 6.3 Hz, 1 H), 3.69
[α]D27 +10.3 (c 1.33, CHCl3) {Lit.21 [α]D20 +12.2 (c 2.8, CHCl3)}.
IR (neat): 3467, 1460, 1375, 1214, 1057, 859 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1102–1108