An efficient synthesis of a potential (-)-reserpine intermediate from (-)-shikimic acid of the chiral pool

Article abstract of DOI:10.1002/hlca.200790138

A highly stereoselective route to the polysubstituted chiral octahydrobenzofuran 12, a potential synthon for the E-ring core in the (-)-reserpine synthesis, is described. The α-bromo acetal 11 was obtained from inexpensive (-)-shikimic acid (3) through a series of highly stereoselective chemical reactions (Scheme). Et₃B/Bu ₃SnH-Mediated intramolecular radical cyclization of 11 led to compound 12 with the required configuration.

Full text of DOI:10.1002/hlca.200790138

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Helvetica Chimica Acta – Vol. 90 (2007)
An Efficient Synthesis of a Potential (ꢀ)-Reserpine Intermediate from
(ꢀ)-Shikimic Acid of the Chiral Pool
by Jian Huang and Fen-Er Chen*
Department of Chemistry, Fudan University, Shanghai, 200433, P. R. China
(fax: þ 86-21-65643811; e-mail: rfchen@fudan.edu.cn)
A highly stereoselective route to the polysubstituted chiral octahydrobenzofuran 12, a potential
synthon for the E-ring core in the (ꢀ)-reserpine synthesis, is described. The a-bromo acetal 11 was
obtained from inexpensive (ꢀ)-shikimic acid (3) through a series of highly stereoselective chemical
reactions (Scheme). Et3B/Bu3SnH-Mediated intramolecular radical cyclization of 11 led to compound 12
with the required configuration.
Introduction. – (ꢀ)-Reserpine (1), a lipid-soluble pentacyclic indole alkaloid, has
attracted wide interest of synthetic organic chemists for almost half a century due to
both its remarkable bioactivity and structural complexity [1]1). Eleven elegant
strategies have provided successful access to this complex pentacyclic alkaloid since
its total synthesis was first accomplished by Woodward and co-workers in 1958 [2]. The
crucial issue in the reserpine synthesis is the construction of the configurationally
complex E-ring core with five contiguous stereogenic centers. In the reported
syntheses, the most attractive strategy lies in Hanessianꢀs approach [3] in which the
easily available (ꢀ)-quinic acid (¼1a,3R,4a,5R)-1,3,4,5-tetrahydroxycyclohexanecar-
boxylic acid) was used as a template from the chiral pool to construct the key E-ring
core, the chiral hexahydrobenzofuran 2.
We envisioned that the (2R,3aS,4S,6R,7R,7aS)-octahydrobenzofuran 12, an ana-
logue of Hanessianꢀs E-ring core 2, is a potential precursor for the E-ring segment in the
1
)
For a review on total syntheses of reserpine, see [1b].
ꢁ 2007 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 90 (2007)
1367
(ꢀ)-reserpine synthesis. Herein we report an efficient synthesis of 12 by employing
inexpensive (ꢀ)-shikimic acid (3) as starting material.
Results and Discussion. – For the synthesis of 12, the commercially available (ꢀ)-
shikimic acid (3) was esterificated in MeOH in the presence of acidic cation resin to
give the corresponding ester 4, whose OH groups at C(3) and C(5) were selectively
t
protected as BuMe2Si ether to provide compound 5 [4] (Scheme). Under usual
reaction conditions (MeI/KH or MeI/Ag2O), the methylation of the OH group at C(4)
of 5 led to the formation of a mixture of compounds which could not be separated by
column chromatography (silica gel). Interestingly, on BaO/Ba(OH)2-mediated meth-
ylation with Me2SO4 in DMSO/DMF 1:1, compound 5 furnished methyl ether 6 in 82%
yield [5]. Desilylation of 6 with dilute AcOH in THF at 408 for 36 h generated diol 7,
which was subjected to pyridinium dichromate (PDC) oxidation [6] to yield the a,b-
t
unsaturated ester 8 in 85% yield. A BuMe2Si group at OHꢀC(5) of 8 was smoothly
Scheme
a) MeOH, acidic cation resin, reflux, 15 h; 96%. b) tBuMe2SiCl, 1H-imidazole, N,N-dimethylpyridin-4-
amine (DMAP), DMF, 0 – 258, 12 h; 95%. c) Me2SO4, BaO, Ba(OH)2, DMSO, DMF, 0 – 258, 18 h; 82%.
d) AcOH/H2O/THF 3 :1:1, 408, 36 h; 90%. e) PDC, DMF, 158, 2 h, 85%. f) tBuMe2SiCl, 1H-imidazole,
DMAP, DMF, 08, 12 h; 90%. g) NaBH4, CeCl3 · 7 H2O, MeOH, ꢀ 208, 0.5 h; 85%. h) BrCH2BrCHOEt,
PhNMe2, CH2Cl2, ꢀ 78 to 258, 24 h; 83%. i) Bu3SnH, Et3B/O2, toluene, 08, 5 h; 52%.

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t
introduced by reaction of 8 with BuMe2SiCl and 1H-imidazole in DMF at room
temperature (90% yield). Subsequent reduction of 9 under Lucheꢀs conditions
(NaBH4/CeCl3 · 7 H2O) [7] afforded the allylic alcohol 10 as a single product with the
required (3S) configuration.
With compound 10 in hand, our next concern was to introduce the a-bromoethyl
ether side chain at OHꢀC(3). Initially, when allylic alcohol 10 was treated with N-
bromosuccinimide and ethyl vinyl ether [8], no desirable a-bromo acetal 11 was
obtained. Later on, treatment of 10 with 1,2-dibromoethyl ethyl ether (generated in situ
from Br2 and ethyl vinyl ether) in the presence of N,N-dimethylaniline led to a-bromo
acetal 11 as an inseparable mixture of diastereoisomers (ratio 1.5 :1, as determined by
1H-NMR). In the final step, the remaining two stereogenic centers of the E-ring core of
reserpine had to be introduced. Gratifyingly, treatment of 11 with Et3B/Bu3SnH [9]2)
induced an intramolecular radical cyclization, delivering the 3a,7a-ꢂexoꢀ cyclized
product 12 with the required (3aS,4S) configuration.
The configuration of 12 was unambiguously ascertained by a sequence of 1D selective NOESY
experiments as shown in Fig. 1. Irradiation of the HꢀC(7a) resonance at d 3.99 resulted in NOE
enhancements for protons HꢀC(4) at d 2.73, HꢀC(3a) at d 2.93 and HꢀC(6) at d 3.36 (Fig. 1,b), while
irradiation of the HꢀC(3a) resonance at d 2.93 resulted in NOE enhancements for HꢀC(2) at d 5.11 and
HꢀC(7a) at d 3.99 (Fig. 1,c). Key NOE correlations of 12 are presented in Fig. 2. The NOE signals
between HꢀC(2), HꢀC(3a), HꢀC(4), HꢀC(6), and HꢀC(7a) indicated that they had the same
relative orientation (a).
Conclusions. – In conclusion, starting from the commercially available (ꢀ)-shikimic
acid (3), we succeeded in establishing an efficient synthetic method for the
construction of the (2R,3aS,4S,6R,7R,7aS)-octahydrobenzofuran framework, which is
a potential synthon for the E-ring segment of (ꢀ)-reserpine. Further efforts toward the
asymmetric total synthesis of (ꢀ)-reserpine are currently underway.
Experimental Part
General. THF was distilled from Na/benzophenone, CH2Cl2, toluene from calcium hydride, and
DMF and DMSO from calcium hydride under reduced pressure. BaO was ground to a fine powder in a
mortar. Other reagents were obtained from commercial sources and used as received. Flash column
chromatography (FC): silica gel. M.p.: uncorrected; WRS-1B digital melting-point apparatus. Optical
rotations: Jasco P1020 digital polarimeter. IR Spectra: Jasco FT/IR-4200 spectrometer; n˜max in cmꢀ1. 1H-
and 13C-NMR Spectra: Bruker Avance-400 spectrometer; at 400 (1H) and 100 (13C) MHz; in CDCl3 or
(D6)DMSO with CHCl3 (d(H) 7.24) or DMSO (d(H) 2.49) and CDCl3 (d(C) 77.0) or (D6)DMSO (d(C)
39.5) as internal standards; d in ppm, J in Hz. Mass spectra: Waters Quattro-Micromass instrument;
electrospray ionization (ESI) techniques; in m/z.
(3R,4S,5R)-3,4,5-Trihydroxycyclohex-1-ene-1-carboxylic Acid Methyl Ester (4). A mixture of (ꢀ)-
shikimic acid (3; 20 g, 0.11 mol), acidic cation resin (32 g), and MeOH (600 ml) was heated under reflux
for 15 h. After being cooled to r.t., the mixture was filtrated. The filtrate was concentrated and the
residue recrystallized from AcOEt: 4 (20.7 g , 96%). White solid. M.p. 112 – 1138. [a]2D5 ¼ ꢀ139 (c ¼ 0.7,
MeOH). IR (KBr): 3321, 2901, 1718, 1656, 1433, 1242, 1094, 1069, 747, 609. 1H-NMR ((D6)DMSO): 6.61
(m, ¼CH); 4.78 (br. s, OH); 4.58 (br. s, OH); 4.22 (s, CH); 3.85 (dd, J ¼ 10.0, 4.4, CH); 3.66 (s, Me); 3.57
(dd, J ¼ 4.8, 4.8, CH); 3.28 (br. s, OH); 2.43 (dddd, J ¼ 18, 4.8, 2.4, 2.4, 1 H); 2.05 (ddd, J ¼ 18, 3.6, 1.6,
2
)
For a review on organoboranes as a source of radicals, see [9c].

Helvetica Chimica Acta – Vol. 90 (2007)
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Fig. 1. a) 1H-NMR Spectrum of 12 in CDCl3. b) and c) 1D Selective NOESY plots. Arrows indicate
irradiated peaks.
Fig. 2. Observed NOE correlations of 12. TBS ¼ tBuMe2Si.
1 H). 13C-NMR ((D6)DMSO): 166.7; 139.7; 127.3; 70.0; 66.7; 65.3; 51.5; 29.6. ESI-MS: 211.2 ([ M þ
Na]þ).
(3R,4S,5R)-3,5-Bis{[(tert-butyl)dimethylsilyl]oxy}-4-hydroxycyclohex-1-ene-1-carboxylic Acid
Methyl Ester (5). To a soln. of 4 (15 g, 80 mmol) in DMF (150 ml) at 08 were added sequentially 1H-
t
imidazole (14.3 g, 210 mmol) and DMAP (4.8 g, 39.2 mmol). After the soln. turned clear, BuMe2SiCl
(26.4 g, 175 mmol) was added in three parts at 08. The resultant soln. was stirred at 08 for 2 h and at 258

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for 10 h. Then the soln. was diluted with AcOEt (400 ml) and washed with sat. aq. NH4Cl soln. and brine,
dried (MgSO4), and concentrated. The residue was purified by FC (AcOEt/hexane 1:9): 5 (31.6 g, 95%)
as a viscous oil, which slowly crystallized upon standing. M.p. 40 – 438 ([4]: M.p. 39 – 43.58). [a]2D5 ¼ ꢀ65.5
(c ¼ 0.81, MeOH) ([4]: [a]2D1 ¼ ꢀ68.7 (c ¼ 0.53, MeOH)). IR (film): 3541, 2952, 2929, 2856, 1704, 1625,
1437, 1248, 1103, 1076, 893, 835, 777. 1H-NMR (CDCl3): 6.57 (m, ¼CH); 4.48 (s, CH); 4.13 (dd, J ¼ 9.2,
3.6, CH); 3.68 (s, Me); 3.64 (dd, J ¼ 4.4, 4.4, CH); 2.56 (dddd, J ¼ 18.4, 4.4, 2.4, 2.4, 1 H); 2.51 (s, OH);
2.17 (ddd, J ¼ 18.0, 1.2, 1.2, 1 H); 0.87 (s, 1 Me3CSi); 0.80 (s, 1 Me3CSi); 0.09 (s, 1 MeSi); 0.08 (s, 1 MeSi);
0.02 (s, 1 MeSi); 0.01 (s, 1 MeSi). 13C-NMR (CDCl3): 167.1; 137.3; 128.5; 70.7; 68.3; 67.6; 51.6; 29.6; 25.74;
25.63; 17.96; ꢀ 4.7; ꢀ 4.86; ꢀ 4.96; ꢀ 5.03. ESI-MS: 439.3 ([M þ Na]þ).
(3R,4S,5R)-3,5-Bis{[(tert-butyl)dimethylsilyl]oxy}-4-methoxycyclohex-1-ene-1-carboxylic Acid
Methyl Ester (6). To a soln. of 5 (30 g, 72 mmol) in DMF/DMSO 1:1 (484 ml), barium oxide (96 g,
625 mmol) and barium hydroxide octahydrate (54 g, 170 mmol) were added at 08. Dimethyl sulfate
(143 ml, 1.51 mol) was then added dropwise at 08 under N2. After stirring for 18 h at 08, the mixture was
treated with conc. aq. ammonia soln. (60 ml), and subsequently neutralized (pH 7) at 08 with 4m HCl.
The resultant soln. was extracted twice with AcOEt, the org. layer washed with brine, dried (Na2SO4),
and concentrated, and the residue purified by FC (AcOEt/hexane 1:10): 6 (25.4 g, 82%). Viscous oil
which slowly crystallized upon standing. M.p. 59 – 608. [a]2D5 ¼ ꢀ32.3 (c ¼ 0.89, MeOH). IR (film): 2942,
1
2736, 2708, 1719, 1650, 1434, 1363, 1338, 1258, 1190, 1110, 952, 845, 780. H-NMR (CDCl3): 6.70 (m,
¼CH); 4.63 (s, CH); 4.15 (dd, J ¼ 8.8, 4.0, CH); 3.70 (s, 1 MeO); 3.47 (s, 1 MeO); 3.26 (dd, J ¼ 4.4, 4.0,
CH); 2.56 (dddd, J ¼ 18.4, 4.4, 2.4, 2.4, 1 H); 2.17 (ddd, J ¼ 18.4, 1.2, 1.2, 1 H); 0.91 (s, 1 Me3CSi); 0.84 (s,
1 Me3CSi); 0.10 (s, 1 MeSi); 0.09 (s, 1 MeSi); 0.06 (s, 1 MeSi); 0.04 (s, 1 MeSi). 13C-NMR (CDCl3): 167.1;
139.2; 127.9; 81.2; 67.8; 67.2; 59.7; 51.6; 30.3; 25.9; 25.7; 18.2; 17.9; ꢀ 4.4; ꢀ 4.73; ꢀ 4.75; ꢀ 4.85. ESI-HR-
MS: 453.7315 (C21H42NaO5Siþ2 ; calc. 453.7223).
(3R,4S,5R)-3,5-Dihydroxy-4-methoxycyclohex-1-ene-1-carboxylic Acid Methyl Ester (7). A mixture
of 6 (20 g, 46.4 mmol), AcOH (120 ml, 2.08 mol), tetrahydrofuran (40 ml, 0.488 mol), and H2O (40 ml,
2.22 mol) was stirred at 408 for 36 h. Then the mixture was concentrated and the residue purified by FC
(AcOEt): 7 (8.4 g, 90%). Viscous oil. [a]2D5 ¼ ꢀ104 (c ¼ 0.96, MeOH). IR (neat): 3420, 2952, 1707, 1653,
1439, 1263, 1100, 1042, 750, 666. 1H-NMR (CDCl3): 6.84 (ddd, J ¼ 4.0, 2.0, 2.0, ¼CH); 4.50 (dd, J ¼ 4.4,
4.4, CH); 4.09 (ddd, J ¼ 8.0, 8.0, 5.6, CH); 3.72 (s, 1 MeO); 3.49 (s, 1 MeO); 3.26 (dd, J ¼ 8.4, 4.4, CH);
2.82 (dd, J ¼ 18.0, 5.2, 1 H); 2.48 (br. s, 2 OH); 2.21 (dddd, J ¼ 18.4, 8.4, 2.0, 1.2, 1 H). 13C-NMR (CDCl3):
166.7; 136.1; 130.3; 82.0; 65.2; 63.5; 58.1; 52.0; 31.3. ESI-HR-MS: 225.1967 (C9H14NaOþ5 ; calc. 225.1961).
(4S,5R)-5-Hydroxy-4-methoxy-3-oxocyclohex-1-ene-1-carboxylic Acid Methyl Ester (8). To a soln. of
7 (8 g, 39.6 mmol) in DMF (133 ml), PDC (17.9 g, 47.7 mmol) was added slowly at 108. After being stirred
at 158 for 2 h, the soln. was diluted with AcOEt (250 ml). The resultant mixture was washed with sat. aq.
NH4Cl soln. and brine, dried (Na2SO4), and concentrated. The residue was purified by FC (AcOEt/
hexane 1:1): 8 (6.73 g, 85%). Light yellow oil. [a]2D5 ¼ ꢀ101.7 (c ¼ 0.55, MeOH) ([3]: [a]D ¼ ꢀ142.0 (c ¼
1.12, CHCl3)). IR (neat): 3438, 2955, 2838, 1724, 1694, 1438, 1258, 1195, 1130, 738, 665. 1H-NMR
(CDCl3): 6.73 (d, J ¼ 2.8, ¼CH); 4.02 (ddd, J ¼ 20.0, 10.0, 5.2, CH); 3.82 (s, 1 MeO); 3.66 (d, J ¼ 10.4,
CH); 3.65 (s, 1 MeO); 3.16 (dd, J ¼ 18.8, 5.2, 1 H); 2.82 (br. s, OH); 2.57 (ddd, J ¼ 18.8, 9.6, 3.2, 1 H).
13C-NMR (CDCl3): 198.0; 165.9; 144.8; 132.3; 87.3; 69.7; 60.3; 52.9; 32.4. ESI-MS: 223.1 ([ M þ Na]þ).
(4S,5R)-5-{[(tert-Butyl)dimethylsilyl]oxy}-4-methoxy-3-oxocyclohex-1-ene-1-carboxylic Acid Meth-
yl Ester (9). To a soln. of 8 (6.5 g, 32.5 mmol) in DMF (100 ml) at 08, 1H-imidazole (3.5 g, 51.4 mmol),
DMAP (1.1 g, 9 mmol), and tBuMe2SiCl (5.9 g, 39.4 mmol) were added sequentially. After being stirred
for 12 h at 08, the soln. was diluted with AcOEt (200 ml) and washed with sat. aq. NH4Cl soln. and brine,
dried (Na2SO4), and concentrated. The residue was purified by FC (AcOEt/hexane 1:10): 9 (9.19 g,
90%). Light yellow oil. [a]2D5 ¼ ꢀ77.4 (c ¼ 0.80, MeOH) ([3]: [a]D ¼ ꢀ78.7 (c ¼ 1.21, CHCl3)). IR (neat):
2954, 2930, 2857, 1727, 1697, 1250, 1135, 1117, 836, 779, 666. 1H-NMR (CDCl3): 6.72 (m, ¼CH); 4.12 (ddd,
J ¼ 8.4, 7.2, 4.8, CH); 3.82 (s, 1 MeO); 3.54 (s, CH); 3.51 (s, 1 MeO); 2.93 (ddd, J ¼ 18.4, 4.8, 0.8, 1 H); 2.58
(ddd, J ¼ 18.8, 7.2, 2.4, 1 H); 0.86 (s, Me3CSi); 0.07 (s, 1 MeSi); 0.06 (s, 1 MeSi). 13C-NMR (CDCl3): 198.1;
166.4; 144.5; 131.7; 86.0; 70.6; 59.8; 52.7; 33.2; 25.7; 18.0; ꢀ 4.7; ꢀ 5.0. ESI-MS: 337.2 ([M þ Na]þ).
(3S,4R,5R)-5-{[(tert-Butyl)dimethylsilyl]oxy}-3-hydroxy-4-methoxycyclohex-1-ene-1-carboxylic
Acid Methyl Ester (10). A soln. of 9 (9.0 g, 28.6 mmol) and CeCl3 · 7 H2O (10.6 g, 28.6 mmol) in MeOH
(220 ml) was stirred for 0.5 h at 258 and then cooled to ꢀ 208. NaBH4 (1.1 g, 28.6 mmol) was added. After

Helvetica Chimica Acta – Vol. 90 (2007)
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being stirred at ꢀ 208 for 0.5 h, the mixture was concentrated, and H2O (40 ml) was added to the residue.
The resultant mixture was extracted with Et2O, the org. layer washed with brine, dried (Na2SO4) and
concentrated, and the residue purified by FC (AcOEt/hexane 1:4): 10 (7.62 g, 85%). Colorless oil.
[a]2D5 ¼ ꢀ20.5 (c ¼ 1.3, MeOH). IR (neat): 3429, 2953, 2930, 2857, 1721, 1655, 1437, 1252, 1110, 997, 837,
778, 666. 1H-NMR (CDCl3): 6.84 (dd, J ¼ 2.0, 2.0, ¼CH); 4.12 (s, CH); 4.10 (dd, J ¼ 6.4, 5.2, CH); 3.71 (s,
1 MeO); 3.48 (s, 1 MeO); 3.34 (dd, J ¼ 6.4, 4.4, CH); 2.84 (br. s, OH); 2.54 (ddd, J ¼ 18.0, 2.4, 2.4, 1 H);
2.37 (dddd, J ¼ 20.0, 3.2, 3.2, 1.6, 1 H); 0.86 (s, Me3CSi); 0.10 (s, 1 MeSi); 0.07 (s, 1 MeSi). 13C-NMR
(CDCl3): 167.1; 136.9; 127.6; 82.3; 68.6; 67.9; 59.3; 51.8; 30.9; 25.7; 17.9; ꢀ 4.9; ꢀ 5.0. ESI-HR-MS:
339.4578 (C15H28NaO5Siþ; calc. 339.4596).
(3S,4R,5R)-3-[(1RS)-2-bromo-1-ethoxyethoxy]-5-{[(tert-butyl)dimethylsilyl]oxy}-4-methoxycyclo-
hex-1-ene-1-carboxylic Acid Methyl Ester (11). To a soln. of ethyl vinyl ether (¼ethoxyethene; 3.4 ml,
35 mmol) in CH2Cl2 (30 ml) at ꢀ 788 was added dropwise a soln. of Br2 (1.7 ml, 33.2 mmol) in CH2Cl2
(30 ml). After the addition, the mixture was allowed to warm to 258 and stirred for 10 min, then recooled
to ꢀ 788. A soln. of N,N-dimethylaniline (¼ N,N-dimethylbenzenamine; 5.6 ml, 43.8 mmol) and 10 ( 7 g,
22.1 mmol) in CH2Cl2 (30 ml) was added dropwise while the temp. was kept at ꢀ 788. The mixture was
stirred at ꢀ 788 for 30 min, then allowed to warm to 258, and stirred for 24 h. The resultant mixture was
diluted with CH2Cl2 (200 ml), the soln. washed with 1m HCl, sat. aq. NaHCO3 soln., and brine, dried
(MgSO4), and concentrated, and the residue purified by FC (AcOEt/hexane 1:10): inseparable
diastereoisomer mixture 11 (8.57 g, 83%; 1.5 :1 by 1H-NMR). Pale yellow oil. IR (neat): 2976, 1718, 1652,
1255, 1107, 1054, 1011, 836, 666. 1H-NMR (CDCl3): 6.67 (dd, J ¼ 5.6, 2.8, ¼CH); 4.92 (t, J ¼ 5.2, 0.6 H);
4.87 (t, J ¼ 5.2, 0.4 H); 4.22 (ddd, J ¼ 4.0, 2.0, 2.0, 0.4 H); 4.16 (ddd, J ¼ 4.0, 2.0, 2.0, 0.6 H); 3.77 – 3.59 (m,
overlapped, 3 H); 3.73 (s, 1.2 H); 3.72 (s, 1.8 H); 3.58 (s, 1.8 H); 3.56 (s, 1.2 H); 3.38 (ddd, J ¼ 14.8, 10.4,
4.8, CH2Br); 3.18 (dd, J ¼ 17.2, 9.6, CH); 2.66 (dd, J ¼ 17.6, 5.6, 1 H); 2.23 (dddd, J ¼ 17.6, 9.6, 3.2, 3.2,
1 H); 1.24 (t, J ¼ 7.2, Me); 0.89 (s, Me3CSi); 0.09 (s, 1 MeSi); 0.07 (s, 1 MeSi). 13C-NMR (CDCl3;
diastereoisomer mixture): 166.51; 166.47; 137.4; 136.4; 128.9; 103.3; 101.2; 86.1; 85.3; 78.0; 76.0; 71.11;
70.98; 62.4; 62.3; 61.3; 61.2; 51.99; 51.96; 33.99; 33.86; 32.14; 31.76; 25.81; 18.0; 15.19; 15.04; ꢀ 4.66;
ꢀ 4.77. ESI-HR-MS: 490.4638 (C19H35BrNaO6Siþ; calc. 490.4626).
(2R,3aS,4S,6R,7R,7aS)-6-{[(tert-Butyl)dimethylsilyl]oxy}-2-ethoxy-7-methoxyoctahydrobenzofur-
an-4-carboxylic Acid Methyl Ester (12). To a soln. of 11 (2 g, 4.27 mmol) and Bu3SnH (3.46 ml,
12.8 mmol) in toluene (400 ml) under N2 at 08, 1m Et3B in hexane (21.3 ml, 21.3 mmol) and air (20 ml)
were added simultaneously via syringe within 3 h. After the addition, the mixture was stirred at 08 for
another 2 h and then concentrated. The residue was purified by FC (AcOEt/hexane 1:10): 12 (0.86 g,
52%). Colorless oil. IR (neat): 2954, 2929, 2856, 1737, 1461, 1255, 1108, 1019, 837, 778, 666. 1H-NMR
(CDCl3): 5.11 (d, J ¼ 5.2, CH); 3.99 (dd, J ¼ 7.6, 7.6, CH); 3.71 (q, J ¼ 7.2, 1 H); 3.64 (s, 1 MeO); 3.52 (s,
1 MeO); 3.44 – 3.33 (m, 2 H); 2.93 (ddd, J ¼ 6.4, 12.8, 12.8, CH); 2.79 (dd, J ¼ 9.2, 7.6, CH); 2.73 (ddd, J ¼
13.6, 5.2, 4.4, CH); 1.86 – 1.78 (m, 2 H); 1.71 – 1.67 (m, 2 H); 1.14 (t, J ¼ 7.2, Me); 0.846 (s, Me3CSi); 0.04
(s, 1 MeSi); 0.02 (s, 1 MeSi). 13C-NMR (CDCl3): 173.4; 102.9; 87.4; 83.3; 72.1; 62.7; 60.7; 53.3; 51.8; 38.4;
37.7; 33.3; 30.7; 29.6; 25.8; 18.0; 15.1; ꢀ 4.59; ꢀ 4.65. ESI-HR-MS: 411.5675 (C19H36NaO6Siþ; calc.
411.5665).
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Received March 19, 2007