Organic Process Research & Development
Article
purification through column chromatography (toluene−
7.10 (d, J = 8.5 Hz, 2H), 7.07 (d, J = 8.5 Hz, 2H), 5.70 (t, J =
10.0 Hz, 1H), 5.58 (d, J = 10.0 Hz, 1H), 5.37 (dd, J = 10.5,
10.0 Hz, 1H), 5.21 (d, J = 12.5 Hz, 1H), 5.12 (d, J = 12.5 Hz,
1H), 4.37 (ddd, J = 10.5, 4.0, 2.0 Hz, 1H), 4.16 (dd, J = 12.5,
2.0 Hz, 1H), 4.10 (dd, J = 12.5, 4.0 Hz, 1H), 3.93 (s, 2H), 2.60
(q, J = 8.0 Hz, 2H), 1.203 (s, 9H), 1.200 (t, J = 8.0 Hz, 3H),
1.17 (s, 9H), 1.11 (s, 9H), 0.71 (s, 9H). 13C NMR (125 MHz,
CDCl3) δ 178.0, 177.0, 176.5, 176.4, 142.0, 141.5, 138.0,
137.9, 135.9, 130.9, 128.6 (C × 2), 127.9 (C × 2), 123.3,
120.6, 109.0, 73.0, 71.1, 70.9, 70.4, 67.9, 61.6, 41.4, 38.8, 38.72,
38.67, 38.5, 28.4, 27.2 (C × 3), 27.08 (C × 3), 27.06 (C × 3),
26.5 (C × 3), 15.6. HRMS (ESI+) calcd for C42H59O10 [M +
H]+, 723.4103; found, 723.4109.
(1S,3′R,4′S,5′S,6′R)-6-(4-Ethylbenzyl)-6′-(hydroxymethyl)-
3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-pyran]-
3′,4′,5′-triol (1). To a solution of 14a (5.19 g, 7.18 mmol) in
methanol (36 mL) was added lithium hydroxide monohydrate
(903.0 mg, 21.5 mmol) at room temperature, followed by
stirring at room temperature for 6.5 h. The solvent was
removed under reduced pressure. To the residue was added
saturated NaCl, and then the resulting mixture was extracted
with AcOEt. The organic layer was washed with saturated
NaCl and dried over Na2SO4. The solvent was removed under
reduced pressure. The crude product was recrystallized from
acetone−H2O to afford 1 (1.75 g, 60% as monohydrate).
Spectral data were identical to those described in the
literature.2b
AcOEt). 2b: colorless oil. [α]20 +62.4 (c 1.17, CH2Cl2).
D
FTIR (cm−1, neat) 2969, 1741, 1660, 1608, 1479, 1461, 1280,
1
1132, 1033. H NMR (500 MHz, CDCl3) δ 8.01 (brs, 1H),
7.94 (dd, J = 8.0, 1.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.45
(d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H), 5.67 (t, J = 9.5
Hz, 1H), 5.51 (d, J = 9.5 Hz, 1H), 5.33 (t, J = 9.5 Hz, 1H),
5.32 (d, J = 14.0 Hz, 1H), 5.03 (d, J = 14.0 Hz, 1H), 4.19−
4.02 (m, 3H), 2.75 (q, J = 7.5 Hz, 2H), 1.30 (t, J = 7.5 Hz,
3H), 1.14 (s, 9H), 1.12 (s, 9H), 1.07 (s, 9H), 0.88 (s, 9H). 13
C
NMR (125 MHz, CDCl3) δ 195.2, 178.0, 176.9, 176.5, 176.2,
149.9, 145.2, 137.4, 135.8, 134.5, 131.6, 130.5 (C × 2),
128.1(C × 2), 125.0, 121.7, 109.5, 72.1, 72.0, 71.4, 70.2, 68.0,
62.1, 38.7 (C × 2), 38.6, 38.5, 29.0, 27.13 (C × 3), 27.06 (C ×
3), 27.0 (C × 3), 26.9 (C × 3), 15.1. HRMS (ESI+) calcd for
C42H57O11 [M + H]+, 737.3895; found, 737.3903.
(1S,3′R,4′S,5′R,6′R)-6-(4-Ethylbenzoyl)-6′-((pivaloyloxy)-
methyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-
pyran]-3′,4′,5′-triyl Tris(2,2-dimethylpropanoate) (2a). The
mixture of 2a and 2b, which was obtained by the above-
described procedure (17.6 g out of 35.2 g), was dissolved in
toluene (420 mL) at room temperature. To this solution was
added boron trifluoride etherate (3.0 mL, 23.9 mmol) at 0 °C,
followed by stirring at room temperature for 2 h. After addition
of saturated NaHCO3 at 0 °C, the resulting mixture was
extracted with AcOEt. The organic layer was washed with
saturated NaCl and dried over Na2SO4. The solvent was
removed under reduced pressure. The crude product was
recrystallized from methanol to afford 2a as a white powder
Synthesis of the Anomer of 1 (15). (1R,3′R,4′S,5′R,6′R)-
6-(4-Ethylbenzyl)-6′-((pivaloyloxy)methyl)-3′,4′,5′,6′-tetra-
hydro-3H-spiro[isobenzofuran-1,2′-pyran]-3′,4′,5′-triyl Tris-
(2,2-dimethylpropanoate) (14b). Hydrogenolysis of 2b (2.98
g, 4.04 mmol), which was isolated from the mixture of 2a and
2b by silica gel column chromatography (toluene−AcOEt),
was carried out in DME (18 mL)−isopropanol (12 mL)−
AcOH (60 μL) over 20% Pd(OH)2 on carbon (50% wet, 596
mg) under H2 at room temperature for 7 h. After filtration, the
solvent was removed under reduced pressure. To the residue
was added saturated NaHCO3, and then the resulting mixture
was extracted with AcOEt. The organic layer was washed with
saturated NH4Cl and aqueous NaCl, successively, and dried
over Na2SO4. The solvent was removed under reduced
pressure, and the crude product was purified by column
chromatography (AcOEt−heptane) to give 14b as a colorless
oil (1.60 g, 55%). [α]20D +38.3 (c 1.07, CH2Cl2). FTIR (cm−1,
(8.2 g, 52% from 5). Mp 172.6 °C. [α]20 +34.5 (c 1.00,
D
CH2Cl2). FTIR (cm−1, neat) 2966, 1743, 1726, 1656, 1606,
1
1479, 1280, 1160, 1139, 1087, 1014. H NMR (500 MHz,
CDCl3) δ 7.92 (dd, J = 8.0, 1.5 Hz, 1H), 7.74 (d, J = 8.5 Hz,
2H), 7.73 (d, J = 1.5 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.35
(d, J = 8.5 Hz, 2H), 5.73 (t, J = 10.0 Hz, 1H), 5.60 (d, J = 10.0
Hz, 1H), 5.34 (t, J = 10.0, Hz, 1H), 5.31 (d, J = 13.5 Hz, 1H),
5.25 (d, J = 13.5 Hz, 1H), 4.39 (ddd, J = 10.0, 4.0, 2.0 Hz,
1H), 4.15 (dd, J = 12.5, 2.0 Hz, 1H), 4.09 (dd, J = 12.5, 4.0
Hz, 1H), 2.76 (q, J = 7.5 Hz, 2H), 1.31 (t, J = 7.5 Hz, 3H),
1.18 (s, 9H), 1.17 (s, 9H), 1.12 (s, 9H), 0.82 (s, 9H). 13C
NMR (125 MHz, CDCl3) δ 195.1, 178.0, 177.0, 176.5, 176.4,
149.7, 144.2, 138.1, 135.6, 134.5, 131.9, 130.5 (C × 2), 127.9
(C × 2), 124.9, 121.0, 108.9, 72.9, 70.85, 70.78, 70.5, 67.8,
61.6, 38.8, 38.71, 38.66, 38.5, 28.9, 27.2 (C × 3), 27.05 (C ×
3), 27.03 (C × 3), 26.6 (C × 3), 15.1. HRMS (ESI+) calcd for
C42H57O11 [M + H]+, 737.3895; found, 737.3901.
1
neat) 2968, 1739, 1479, 1460, 1278, 1133, 1031. H NMR
(500 MHz, CDCl3) δ 7.47 (brs, 1H), 7.24−7.23 (m, 1H),
7.20−7.19 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.5 Hz, 2H), 7.11
(d, J = 8.5 Hz, 2H), 5.78 (t, J = 9.5 Hz, 1H), 5.48 (d, J = 9.5
Hz, 1H), 5.30 (t, J = 9.5 Hz, 1H), 5.21 (d, J = 12.5 Hz, 1H),
4.88 d, J = 12.5 Hz, 1H), 4.10 (dd, J = 12.0, 1.5 Hz, 1H), 4.08
(s, 2H), 4.03 (dd, J = 12.0, 5.5 Hz, 1H), 3.97 (ddd, J = 9.5, 5.5,
1.5 Hz, 1H), 2.61 (q, J = 7.5 Hz, 2H), 1.22 (t, J = 7.5 Hz, 3H),
1.19 (s, 9H), 1.14 (s, 9H), 1.06 (s, 9H), 0.83 (s, 9H). 13C
NMR (125 MHz, CDCl3) δ 178.0, 177.2, 176.6, 176.2, 142.1,
140.8, 139.0, 137.9, 136.0, 130.4, 128.6 (C × 2), 128.1 (C ×
2), 123.7, 121.6, 109.8, 72.1, 72.0, 71.5, 69.8, 68.3, 62.0, 41.3,
38.8, 38.72, 38.67, 38.5, 28.4, 27.11 (C × 3), 27.07 (C × 3),
26.9 (C × 3), 26.6 (C × 3), 15.6. HRMS (ESI+) calcd for
C42H59O10 [M + H]+, 723.4103; found, 723.4109.
(1S,3′R,4′S,5′R,6′R)-6-(4-Ethylbenzyl)-6′-((pivaloyloxy)-
methyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-
pyran]-3′,4′,5′-triyl Tris(2,2-dimethylpropanoate) (14a). A
solution of 2a (8.02 g, 10.9 mmol) in DME (48 mL)−
isopropanol (32 mL)−AcOH (160 μL) was hydrogenated over
20% Pd(OH)2 on carbon (50% wet, 1.6 g) under H2 at room
temperature for 7 h. After filtration, the solvent was removed
under reduced pressure. To the residue was added saturated
NaHCO3, and then the resulting mixture was extracted with
AcOEt. The organic layer was washed with saturated NH4Cl
and saturated NaCl, successively, and dried over Na2SO4. The
solvent was removed under reduced pressure. The crude
product was crystallized from isopropanol−H2O to afford 14a
as a white powder (5.4 g, 68%). Mp 82.4 °C. [α]20 +33.0 (c
(1R,3′R,4′S,5′S,6′R)-6-(4-Ethylbenzyl)-6′-(hydroxymethyl)-
3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-pyran]-
3′,4′,5′-triol (15). To a solution of 14b (1.47 g, 2.03 mmol) in
methanol (10 mL) was added lithium hydroxide monohydrate
D
1.00, CH2Cl2). FTIR (cm−1, neat) 2967, 1739, 1479, 1459,
1
1280, 1133, 1018. H NMR (500 MHz, CDCl3) δ 7.26 (brs,
1H), 7.17 (dd, J = 8.5, 1.5 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H),
H
Org. Process Res. Dev. XXXX, XXX, XXX−XXX