Diastereoselective synthesis of 2,5-disubstituted tetrahydrofuran derivatives

Article abstract of DOI:10.1016/S0957-4166(00)00351-7

5-Substituted lactol 1 was converted to 2,5-disubstituted tetrahydrofuran derivatives by a Lewis acid-promoted reaction with allylsilanes. High trans selectivity (12:1) was obtained when hindered allylsilane 8 was employed. 5-Substituted lactol 16 was transformed into 2,5-cis-disubstituted tetrahydrofuran 17b (6:1 ratio) by a TiCl₄-promoted intramolecular allyl transfer process. Additionally, 2,5-cis-disubstituted tetrahydrofuran derivatives were obtained in good yields and diastereoselectivities after alkyllithium addition to lactone 6, followed by Et₃SiH/BF₃.OEt₂ reduction of the corresponding hemiketals. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00351-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3675–3686
Diastereoselective synthesis of 2,5-disubstituted
tetrahydrofuran derivatives
Ronaldo A. Pilli* and Vale´ria B. Riatto
Instituto de Qu´ımica, Unicamp, Cx. Postal 6154, 13083-970 Campinas, SP, Brazil
Received 30 May 2000; revised 23 August 2000; accepted 23 August 2000
Abstract
5-Substituted lactol 1 was converted to 2,5-disubstituted tetrahydrofuran derivatives by a Lewis
acid-promoted reaction with allylsilanes. High trans selectivity (12:1) was obtained when hindered
allylsilane 8 was employed. 5-Substituted lactol 16 was transformed into 2,5-cis-disubstituted tetra-
hydrofuran 17b (6:1 ratio) by a TiCl4-promoted intramolecular allyl transfer process. Additionally,
2,5-cis-disubstituted tetrahydrofuran derivatives were obtained in good yields and diastereoselectivities
after alkyllithium addition to lactone 6, followed by Et3SiH/BF3·OEt2 reduction of the corresponding
hemiketals. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
Functionalized tetrahydrofurans moieties are found in many biologically important natural
products including pheromones,1 polyether antibiotics2 and acetogenins.3,4 In particular, the
stereoselective synthesis of 2,5-disubstituted tetrahydrofurans has received much attention.
Although widely used in carbohydrate chemistry,5 the Lewis acid-promoted substitution at the
anomeric carbon of g-lactols via oxocarbenium ions was rarely applied to the diastereoselective
synthesis of 2,5-disubstituted tetrahydrofurans.6–9
Suzuki and co-workers reported that the replacement of the hydroxyl group of 5-substituted
g-lactols by the alkyl group of organometallic reagents such R2Zn and R3Al, via an oxocar-
benium ion intermediate, proceeded with trans selectivity.10 Meanwhile, Yoda and co-workers
reported that the direct conversion of 5-substituted g-lactones to 2,5-disubstituted tetra-
hydrofurans via Lewis acid-induced reduction of hemiketal intermediates with Et3SiH displayed
low cis selectivity11 (Scheme 1).
* Corresponding author. E-mail: pilli@iqm.unicamp.br
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00351-7

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R. A. Pilli, V. B. Riatto / Tetrahedron: Asymmetry 11 (2000) 3675–3686
Scheme 1.
In order to investigate the stereochemical outcome of the inter- and intramolecular addition
of allylsilanes to chiral cyclic oxocarbenium ions, we elected lactol 1 due to its strategic relevance
for the asymmetric synthesis of tetrahydrofuran-containing natural products.
2. Results and discussion
Lactol 1,12 readily available from (S)-glutamic acid via lactone 6,13–15 was prepared by
DIBAL-H reduction at low temperature as a 2:1 epimeric mixture (Scheme 2).
Scheme 2.
We initially investigated the influence of the Lewis acid in the nucleophilic addition of
commercially available allylsilane 7 to lactol 1. Good yields of 2,5-disubstituted tetra-
hydrofurans 11a/11b were obtained in the reactions promoted by BF3·OEt2, TiCl4 and TiF4, but
modest trans selectivity was observed (Table 1, entries 1–3). These results contrast with the large
trans preference reported by Suzuki and co-workers10 when lactol 1 reacted with organometallic
compounds in the presence of BF3·OEt2 ascribed to the rather remote orientation of the C-5
substituent in the intermediate oxocarbenium ion.7
The intermediate oxocarbenium ion derived from lactol 1 may adopt pseudo-chair conforma-
tions A and B, which differ in their reactivity to a small extent. Since the ꢀCH2OTBDPS group
is located at a remote position from the electrophilic center, low diastereoselection is expected
(Scheme 3).
In order to evaluate the effect of the bulkiness of the nucleophile, we examined the addition
of allylsilanes 8 and 916 (entries 4–5). Allylsilane 9 produced 13a/13b in good yield but with low
trans-2,5 preference, while terminally disubstituted allylsilane 8 produced trans-2,5-tetra-
hydrofuran 12a in good yield and diastereoisomeric ratio (trans/cis=12:1). It is apparent that an
increase in the steric bulkiness near to the nucleophilic center brings about an overriding
interaction with the ꢀCH2OTBDPS group at the 5-position of the oxocarbenium ion. These

R. A. Pilli, V. B. Riatto / Tetrahedron: Asymmetry 11 (2000) 3675–3686
3677
Scheme 3.
Table 1
Nucleophilic addition of allylsilanes to lactol 1

3678
R. A. Pilli, V. B. Riatto / Tetrahedron: Asymmetry 11 (2000) 3675–3686
results are also consistent with a recent report by Worpel8 on a large increase in trans-1,2
selectivity when a more hindered nucleophile was employed.
The major diastereoisomer 11a was isolated by column chromatography on silica gel and its
trans stereochemistry was assigned by NOE experiments after comparison with the NOE data
obtained for cis-11b prepared from 17b (Scheme 5). The major isomer 12a was isolated by
column chromatography on silica gel and its trans stereochemistry was unambiguously charac-
terized by NOE experiments (Fig. 1). Irradiation of H-5 led to a 2.4% enhancement in the Ha
signal, while irradiation of H-2 led to a 2.1 and 2.9% enhancement in the aromatic hydrogens.
No increment in the H-2 signal was observed upon irradiation of H-5 and vice-versa. The
relative stereochemistry of the major isomer 13a was tentatively assigned as trans based on
1
comparison of the H and 13C NMR data for a mixture of trans-13a and cis-13b with those of
12a.
Figure 1.
Tetrahydrofuran derivatives 11a and 11b containing functional groups at C-2 and C-5
amenable to further functionalization are valuable synthetic intermediates, but their efficient
preparation through the intermolecular addition of allylsilanes to the oxocarbenium ion derived
from 1 seems to be limited to heavily substituted allylsilanes.
Reetz developed a different strategy for the allylation of b-hydroxyaldehydes, which relies on
the intramolecular allyl transfer by a silyloxy tether.17,18 The advantages of the intramolecular
reaction over the corresponding intermolecular version are well documented.19 The decrease in
the entropic demands often lead to higher reaction rates and milder reaction conditions.
Reduction in the degree of freedom of the unimolecular transition state often results in higher
levels of asymmetric induction by the resident stereogenic center.
In order to test such an approach, lactol 16 was prepared after O-allyldimethylsilylation of
lactone 14, followed by its DIBAL-H reduction (Scheme 4).
Scheme 4.

R. A. Pilli, V. B. Riatto / Tetrahedron: Asymmetry 11 (2000) 3675–3686
3679
Labile lactol 16 was immediately treated with Lewis acid to afford 2,5-disubstituted tetra-
hydrofurans 17a/17b in good yields and cis-2,5 preference (Table 2).
Table 2
Intramolecular allylation of lactol 16
Entry
Lewis acida
T (°C)
Dilution (M)
Yieldb (%)
17a/17bc
1
2
3
4
5
6
TiCl4
TiCl4
TiCl4
−78
−78
−78
−78
−78 to rt
−78
0.5
73
77
–
72
76
75
1:1.5
1:6
1:6
1:3
1:3
5×10−3
1×10−3
5×10−3
5×10−3
5×10−3
d
SnCl4
BF3·OEt2
e
TiF4
1.5:1
a 3 equiv. employed.
b Yields for two steps.
c Ratio determined by GC/MS analysis.
d Only 50% of conversion was observed by GC analysis.
e TiF4 in CH3CN solution was employed.
Compared with the intermolecular additions (Table 1), which displayed poor trans stereo-
selectivity (except when the more hindered allylsilane 8 was employed, entry 4), the intramolec-
ular allylation of lactol 16 provided a preparatively useful approach to cis-2,5-disubstituted
tetrahydrofuran 17b.
The diastereoselection proved to be dependent on the dilution condition employed: when the
reaction was carried out at a 0.5 M concentration (entry 1), almost no diastereoselection was
observed probably due to the intervention of intermolecular allyl transfer. However, when the
reaction was carried out at higher dilution, a significant increase in the cis-selectivity was
observed (entries 2, 4–5). Among the Lewis acid tested at 5×10−3 M dilution, TiCl4 performed
better (6:1, entry 2) than SnCl4 and BF3·OEt2 and a 6:1 mixture of 17b/17a was obtained in 77%
yield with TiCl4 as Lewis acid at 5×10−3 M dilution. At 1×10−3 M concentration the same
cis/trans ratio was observed but with lower conversion rate (entry 3). Surprisingly, the use of
TiF4 produced 2,5-trans-disubstituted tetrahydrofuran 17a as the major isomer probably due to
fluoride desilylation of lactol 16 and the occurrence of intermolecular addition reaction.
The major diastereoisomer 17b was isolated by column chromatography on silica gel and its
cis stereochemistry was planned to be assigned by NOE experiments, but no definitive evidence
emerged from these experiments. To circumvent this, 17b was converted to cis-11b and the cis
stereochemistry was confirmed by NOE experiments after comparison with the data obtained
for trans-11a (Scheme 5): irradiation of H-1%% in cis-11b led to a 0.6% enhancement in the signal
of the allylic hydrogens while no increment was observed in the H-2 signal. Irradiation of H-1%%

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R. A. Pilli, V. B. Riatto / Tetrahedron: Asymmetry 11 (2000) 3675–3686
Scheme 5.
in trans-11a led to a 0.4% enhancement in the H-2 signal while no increment was observed for
the allylic hydrogens.
The cis preference can be explained by taking into account that the intramolecular attack of
the allyl group to the si face of the oxocarbenium carbon is geometrically favored (Scheme 6).
The conversion of lactones to cyclic ethers via Lewis acid-induced reduction of the corre-
sponding lactols with Et3SiH has been extensively studied in the domain of the synthesis of
C-glycosides and it is of potential utility for the preparation of cis-2,5-disubstituted tetra-
hydrofurans with substituents at C-5 other than the allylated ones.
Scheme 6.
In order to evaluate the feasibility of this strategy for the preparation of cis-2,5-disubstituted
tetrahydrofurans, we examined the addition of some alkyllithium reagents to lactone 6 followed
by Lewis acid-promoted Et3SiH deoxygenation (Table 3).
As shown in Table 3, the addition of alkyllithium reagents to lactone 6 afforded hemiketals
18a–c, which were reduced with Et3SiH in the presence of BF3·OEt2 to afford 2,5-cis-disubsti-
tuted tetrahydrofurans 19b–21b in moderate yields. The cis preference increased with the steric
requirement of the R group (Table 3) and a single isomer was observed when R=Ph. The major
diastereoisomers were isolated by column chromatography on silica gel and the cis stereochem-
istry of 20b and 21b was assigned by NOE experiments (NOESY 1D). As shown in Fig. 2,
strong NOE correlations were observed between H-2/H-5 in the NOESY-1D spectra of 20b and
21b while for 19b weak NOE increments were observed in H-2 signal upon irradiation at H-5.
Tetrahydrofuran trans-19a was independently prepared according to the procedure reported
1
by Suzuki and co-workers.10 Comparison of the H and 13C NMR data for trans-19a with those
of 19b confirm the cis stereochemistry of the major isomer formed in the Et3SiH reduction of
lactol 18a.

R. A. Pilli, V. B. Riatto / Tetrahedron: Asymmetry 11 (2000) 3675–3686
3681
Table 3
Nucleophilic addition of alkyllithium reagents to lactone 6 followed by deoxygenation
Entry
RLi
Hemiketal
Major isomera,b
Yieldb (%)
cis/transc
1
2
3
MeLi
n-BuLi
PhLi
18a
18b
18c
19b
20b
21b
54
54
51
3:1
5:1
\95:5
a Yields for two steps.
b The major diastereoisomers were isolated and characterized.
1
c Ratio determined by H NMR analysis.
Figure 2.
3. Conclusions
In summary, we have demonstrated that the synthesis of 2,5-disubstituted tetrahydrofuran
derivatives can be achieved in good yields and divergent diastereoselectivity by intermolecular or
intramolecular replacement of the hydroxyl group of 5-substituted g-lactols by the allyl group.
Furthermore, Lewis acid-induced reduction of hemiketals derived from the lactone 6 is an
alternative method to synthesize 2,5-cis-disubstituted tetrahydrofurans. These strategies provide
a new synthetic opportunity for the synthesis of biologically active natural products.
4. Experimental
4.1. General
1H NMR and 13C NMR spectra were recorded in CDCl3 solution at 300 and 75 MHz,
respectively, using a Varian Gemini 2000 spectrometer and at 500 and 125 MHz, respectively,
using a Varian Inova 500 spectrometer. Chemical shifts are expressed in ppm relative to
tetramethylsilane followed by multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; quint,
quintet; m, multiplet), coupling constant (Hz) and number of protons. The values in parentheses
refer to the chemical shift of the minor isomer. Infrared spectra were recorded on a Nicolet

3682
R. A. Pilli, V. B. Riatto / Tetrahedron: Asymmetry 11 (2000) 3675–3686
Impact 410 spectrophotometer. High resolution mass spectra were obtained via electron impact
(70 eV) on a VG Autospec spectrometer. Optical rotations were measured at 24°C in a Polamat
A (Carl Zeiss). GC analyses were performed in a Hewlett-Packard 5890 series II chromatograph
equipped with flame ionization detector, nitrogen as the carrier gas and capillary columns (30
m×0.53 mm) with 1% phenylmethylsilicone (HP-1) or cross-linked polyethyleneglycol (Car-
bowax 20M) as stationary phases. GC–MS analyses were performed on a Hewlett-Packard 5890
series II gas chromatograph coupled to a MSD 5970 mass detector equipped with a capillary
column (Carbowax 20M, 25 m×0.20 mm×0.33 mm). Column chromatography was performed
using silica gel (70-230 mesh), except when stated otherwise, and reactions were monitored by
TLC (plates from Macherey–Nagel, Germany).
Tetrahydrofuran was treated with sodium/benzophenone and distilled immediately prior to
use. Dichloromethane and triethylamine were treated with calcium hydride and distilled immedi-
ately prior to use. BF3·OEt2, TiCl4 and SnCl4 were distilled prior to use. The remaining reagents
employed were purchased from commercial suppliers and used without further purification. The
reactions involving anhydrous solvents were carried out under argon atmosphere.
4.2. Preparation of k-lactol 1
4.2.1. (5S)-(tert-Butyldiphenylsilyloxymethyl)-tetrahydrofuran-2-ol 1
A CH2Cl2 solution (5.4 mL) of lactone 6 (0.959 g, 2.70 mmol) was cooled to −78°C, treated
with DIBAL-H (3.24 mL, 1.0 M in toluene, 3.24 mmol) and stirred at −78°C for 1 h. The
reaction was quenched by the addition of AcOEt (6.5 mL) and warmed to room temperature.
Then, saturated solution of sodium potassium tartarate (6.5 mL) were added and the mixture
was stirred for 2 h. The layers were separated and the aqueous layer was extracted with CH2Cl2
(3×2 mL). The combined organic layers were washed with brine (2 mL), dried over MgSO4,
filtered and concentrated to afford an anomeric mixture of 1 (0.953 g, 2.67 mmol, 99% yield, 2:1
ratio) as a clear oil, which was used in the next step without further purification (Rf 0.45 in 30%
1
AcOEt–hexanes). H NMR (CDCl3, 300 MHz) l 1.05 and 1.08 (s, 9H), 1.72–2.12 (m, 5H),
3.55–3.90 (m, 2H), 4.10–4.40 (m, 1H), 5.26–5.60 (m, 1H), 7.20–7.45 (m, 6H), 7.66–7.70 (m, 4H);
13C NMR (CDCl3, 75 MHz) l 19.0, 25.3 (23.6), 26.6, 31.8 (34.6), 66.0 (66.2), 78.6 (80.2), 100.8
(98.6), 127.8 (128.0), 129.8 (130.1), 135.8 (133.9), 135.9 (136.0); IR (film) 3415, 2929, 2856, 1471,
1427, 1112 cm−1; LRMS (EI) m/z 199 (100%), 299 (15%); HRMS (IE) m/z calcd for C17H19O3Si
[M−C4H9]+ 299.11035. Found: 299.11038.
4.3. General procedure for the allylation of k-lactol 1
To a 0.5 M CH2Cl2 solution of lactol 1 (1.0 equiv.) at −78°C was added Lewis acid (3.0
equiv.) followed by allylsilane (2.0 equiv.). The reaction mixture was stirred for 3 h at the
temperature indicated in Table 1. The reaction was quenched by the addition of saturated
aqueous NH4Cl, the layers were separated and the aqueous layer was extracted with CH2Cl2.
The combined organic layers were washed with brine, dried over MgSO4, filtered and concen-
trated. The crude mixture was purified by column chromatography as indicated below.
4.3.1. (2S,5S)-2-Allyl-5-(tert-butyldiphenylsilyloxymethyl)-tetrahydrofuran 11a
Chromatography on silica gel (5% AcOEt in hexanes, v/v) afforded a diastereoisomeric
mixture of 11a/11b in 94% yield and 2:1 trans/cis ratio. An analytically pure sample of 11a was

R. A. Pilli, V. B. Riatto / Tetrahedron: Asymmetry 11 (2000) 3675–3686
3683
1
obtained as a colorless oil (Rf 0.50 in 10% AcOEt–hexanes). [h]2D4 +15.2 (c 0.3, CH2Cl2); H
NMR (500 MHz, CDCl3) l 1.05 (s, 9H), 1.50–1.58 (m, 1H), 1.80–1.88 (m, 1H), 1.97–2.05 (m,
2H), 2.20–2.26 (m, 1H), 2.32–2.37 (m, 1H), 3.62 (dd, J=5.1, 10.5 Hz, 1H), 3.66 (dd, J=4.5, 10.5
Hz, 1H), 3.99–4.04 (m, 1H), 4.13–4.18 (m, 1H), 5.02–506 (m, 1H), 5.10 (dq, J=17.0, 1.7 Hz,
1H), 5.82 (ddt, J=17.0, 10.0, 7.1 Hz, 1H), 7.37–7.42 (m, 6H), 7.67–7.70 (m, 4H); 13C NMR (125
MHz, CDCl3) l 19.2, 26.8, 28.0, 31.3, 40.2, 66.5, 78.8, 79.1, 116.6, 127.6, 129.5, 133.7, 135.2,
135.6; IR (film) 3070, 2956, 2929, 2852, 1641, 1115 cm−1; LRMS (EI) m/z 199 (100%), 323
(36%); HRMS (IE) m/z calcd for C20H23O2Si [M−C4H9]+ 323.14673. Found: 323.14674.
4.3.2. (2S,5S)-2-(1,1-Dimethyl-2-propenyl)-5-(tert-butyldiphenylsilyloxymethyl)-tetrahydrofuran
12a
Chromatography on silica gel (1% AcOEt in hexanes, v/v) afforded a diastereoisomeric
mixture of 12a/12b in 74% yield and 12:1 trans/cis ratio. An analytically pure sample of 12a was
obtained as a colorless oil (Rf 0.38 in 5% AcOEt–hexanes). [h]2D4 −4.8 (c 4.2, CH2Cl2); H NMR
1
(300 MHz, CDCl3) l 1.00 (s, 3H), 1.05 (s, 3H), 1.06 (s, 9H), 1.56–1.72 (m, 1H), 1.73–2.05 (m,
3H), 3.67 (m, 2H), 3.77 (dd, J=5.5, 8.8 Hz, 1H), 4.07–4.13 (m, 1H), 4.96–5.06 (m, 2H), 5.91 (dd,
J=10.3, 18.0 Hz, 1H), 7.32–7.48 (m, 6H), 7.64–7.78 (m, 4H); 13C NMR (75 MHz, CDCl3) l
19.0, 22.7, 23.7, 26.6, 27.1, 28.3, 40.3, 66.6, 79.8, 86.7, 112.0, 127.8, 129.7, 134.0, 135.9, 145.4;
IR (film) 3070, 2958, 2929, 2856, 1605, 1589, 1471, 1427, 1112 cm−1; LRMS (EI) m/z 199
(100%), 351 (20%); HRMS (EI) m/z calcd for C22H27O2Si [M−C4H9]+ 351.17803. Found:
351.17828.
4.3.3. (2S,5S)-2-(Phenyl-2-propenyl)-5-(tert-butyldiphenylsilyloxymethyl)-tetrahydrofuran 13a
Chromatography on silica gel (1% AcOEt in hexanes, v/v) afforded the product as a clear oil
(Rf 0.30 in 1% AcOEt–hexanes) in 73% yield (2:1 trans/cis selectivity). Major diastereoisomer
1
(13a): H NMR (300 MHz, CDCl3) l 0.91 (s, 9H), 1.34–1.52 (m, 2H), 1.62–1.78 (m, 2H), 2.41
(dd, J=14.2, 7.3 Hz, 1H), 2.78 (dd, J=14.2, 5.5 Hz, 1H), 3.41–3.54 (m, 2H), 3.78–3.91 (m, 2H),
4.97 (d, J=1.5 Hz, 1H), 5.17 (d, J=1.5 Hz, 1H), 7.02–7.30 (m, 11H), 7.49–7.58 (m, 4H); 13C
NMR (75 MHz, CDCl3) l 19.0, 26.7, 27.5, 30.6, 41.7, 66.4, 78.4, 79.5, 114.4, 126.4, 127.1, 127.8,
128.5, 129.8, 133.9, 135.9, 141.3, 145.8; IR (film) 3070, 2956, 2929, 2856, 1624, 1598, 1112 cm−1;
LRMS (EI) m/z 199 (100%), 399 (19%); HRMS (EI) m/z calcd for C26H27O2Si [M−C4H9]+
399.17803. Found: 399.17809.
4.4. Preparation of 17b and 11b
4.4.1. (5S)-(Allyldimethylsilyloxymethyl)-tetrahydrofuran-2-one 15
A solution of lactone 14 (0.568 g, 4.89 mmol) in CH2Cl2 (10 mL) was treated with
triethylamine (0.818 mL, 5.87 mmol), a catalytic amount of N,N-dimethyl-4-aminopyridine
(0.0597 g, 0.489 mmol) and allyldimethysilyl chloride (0.857 mL, 5.87 mmol). The mixture was
stirred 1 h at room temperature and poured into water. The layers were separated and the
organic phase was washed with saturated NH4Cl solution (3 mL), brine (3 mL), dried over
MgSO4 and concentrated. Chromatography on silica gel (30% AcOEt in hexanes, v/v) of the
crude product afforded 15 (0.734 g, 3.42 mmol, 70% yield) as a colorless oil (Rf 0.42 in 30%
AcOEt–hexanes). [h]2D4 +27.5 (c 5.9, CH2Cl2); H NMR (300 MHz, CDCl3) l 0.08 (s, 6H), 1.57
1
(d, J=8.1 Hz, 2H), 1.98–2.27 (m, 2H), 2.40–2.60 (m, 2H), 3.63 (dd, J=3.3, 11.4 Hz, 1H), 3.78
(dd, J=3.0, 11.4 Hz, 1H), 4.49–4.55 (m, 1H), 4.81–4.88 (m, 2H), 5.65–5.79 (m, 1H); 13C NMR

3684
R. A. Pilli, V. B. Riatto / Tetrahedron: Asymmetry 11 (2000) 3675–3686
(75 MHz, CDCl3) l −2.9, −2.8, 23.4, 24.0, 28.4, 64.5, 79.9, 114.0, 133.6, 177.6; IR (film) 3076,
2958, 2871, 1778, 1630 cm−1; LRMS (EI) m/z 129 (100%), 173 (40%); HRMS (EI) m/z calcd for
C7H13O3Si [M−C3H5]+ 173.06340. Found: 173.06338.
4.4.2. General procedure for the preparation of (2R,5S)-2-allyl-5-(hydroxymethyl)-
tetrahydrofuran 17b
A CH2Cl2 solution (0.5 M) of lactone 15 was cooled to −78°C, treated with DIBAL-H (1.0 M
in toluene, 1.2 equiv.) and stirred at −78°C for 1 h. The reaction was quenched by the addition
of AcOEt, warmed to room temperature and saturated solution of sodium potassium tartarate
was added. After 2 h the layers were separated and the aqueous layer was extracted with
CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4, filtered and
concentrated. To a 0.5 M solution of lactol 16 (1.0 equiv.) in dry CH2Cl2 at −78°C were added
3.0 equiv. of Lewis acid (Table 2) and the mixture was stirred for 3 h at temperature indicated
in Table 2. The reaction was quenched by the addition of saturated aqueous NH4Cl, the layers
were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers
were washed with brine, dried over MgSO4, filtered and concentrated. The crude mixture was
purified by silica gel chromatography (50% AcOEt in hexanes, v/v) to afford 17a/17b as a clear
oil (see Table 2, for yields and cis/trans ratios). An analytically pure sample of the major
diastereoisomer 17b was isolated and characterized (Rf 0.21 in 40% AcOEt–hexanes). [h]2D4 −31.3
1
(c 0.3, CH2Cl2); H NMR (CDCl3, 300 MHz) l 1.52–2.06 (m, 5H), 2.19–2.42 (m, 2H), 3.49 (dd,
J=5.5, 11.7 Hz, 1H), 3.71 (dd, J=3.3, 11.7 Hz, 1H), 3.94–4.06 (m, 2H), 5.05–5.14 (m, 2H), 5.82
(ddt, J=17.2, 10.2, 7.0 Hz, 1H); 13C NMR (CDCl3, 75 MHz) l 26.8, 30.7, 40.0, 65.1, 79.1, 79.4,
117.2, 134.8; IR (film) 3423, 3076, 2931, 2871, 1641 cm−1; LRMS (EI) m/z 57 (100%), 142 (05%);
HRMS (EI) m/z calcd for C8H14O2 [M]+ 142.09937. Found: 142.09959.
4.4.3. (2R,5S)-2-Allyl-5-(tert-butyldiphenylsilyloxymethyl)-tetrahydrofuran 11b
A solution of 17b (0.200 g, 1.41 mmol) in CH2Cl2 (3.0 mL) was treated with triethylamine
(0.24 mL, 1.7 mmol), a catalytic amount of N,N-dimethyl-4-aminopyridine (0.0172 g, 0.141
mmol) and tert-butyldiphenylsilyl chloride (0.44 mL, 1.7 mmol). The mixture was stirred 1 h at
room temperature and poured into water. The layers were separated and the organic phase was
washed with saturated NH4Cl solution (1 mL), brine (1 mL), dried over MgSO4 and concen-
trated. Chromatography on silica gel (10% AcOEt in hexanes, v/v) of the crude product afforded
11b (0.531 g, 1.40 mmol, 99% yield) as a colorless oil (Rf 0.50 in 10% AcOEt–hexanes). [h]2D4+7.8
1
(c 1.3, CH2Cl2); H NMR (500 MHz, CDCl3) l 1.06 (s, 9H), 1.50–1.62 (m, 1H), 1.86–1.98 (m,
3H), 2.21–2.28 (m, 1H), 2.34–2.41 (m, 1H), 3.63 (dd, J=5.2, 10.5 Hz, 1H), 3.67 (dd, J=4.4, 10.5
Hz, 1H), 3.92–3.96 (m, 1H), 4.03–4.05 (m, 1H), 5.01–5.05 (m, 1H), 5.05–5.11 (m, 1H), 5.83 (ddt,
J=17.3, 10.0, 7.0 Hz, 1H), 7.36–7.45 (m, 6H), 7.60–7.73 (m, 4H); 13C NMR (75 MHz, CDCl3)
l 19.3, 26.8, 27.7, 30.6, 40.3, 66.4, 79.3, 79.5, 116.6, 127.6, 129.6, 133.7, 135.2, 135.6; IR (film)
3070, 2956, 2929, 2852, 1641, 1115 cm−1; LRMS (EI) m/z 199 (100%), 323 (35%); HRMS (IE)
m/z calcd for C20H23O2Si [M−C4H9]+ 323.14673. Found: 323.14674.
4.5. General procedure for tandem alkyllithium addition to lactone 6/Et3SiH reduction
A 0.5 M THF solution of lactone 6 was cooled to −78°C, treated with alkyllithium reagent
(1.2 equiv.) and stirred at −78°C for 3 h. The reaction was quenched by the addition of saturated
aqueous NH4Cl, the layers were separated and the aqueous layer was extracted with Et2O. The

R. A. Pilli, V. B. Riatto / Tetrahedron: Asymmetry 11 (2000) 3675–3686
3685
combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated.
A solution of crude hemiketal in dry CH2Cl2 (0.5 M) was cooled to −78°C, treated with
BF3·OEt2 (3.0 equiv.) and Et3SiH (2.0 equiv.). The mixture was stirred 3 h at −78°C and the
reaction was quenched by the addition of saturated aqueous NH4Cl, the layers were separated
and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed
with brine, dried over MgSO4, filtered and concentrated. The crude mixture was purified as
indicated below.
4.5.1. (2S,5S)-2-Methyl-5-(tert-butyldiphenylsilyloxymethyl)-tetrahydrofuran 19b
Chromatography on silica gel (1% AcOEt in hexanes, v/v) afforded the product as a clear oil
in 54% yield (3:1 cis/trans). An analytically pure sample of the major diastereoisomer 19b was
isolated and characterized (Rf 0.35 in 5% AcOEt–hexanes). [h]2D4 −12.3 (c 0.81, CH2Cl2); H
1
NMR (500 MHz, C6D6) l 1.13 (d, J=5.9 Hz, 3H), 1.17 (s, 9H), 1.52–1.61 (m, 4H), 3.64 (dd,
J=4.9, 10.7 Hz, 1H), 3.68 (dd, J=4.4, 10.7 Hz, 1H), 3.82–3.86 (m, 1H), 3.95–4.00 (m, 1H),
1
7.21–7.25 (m, 6H), 7.79–7.83 (m, 4H); H NMR (500 MHz, CDCl3) l 1.06 (s, 9H), 1.23 (d,
J=5.9 Hz, 3H), 1.44–1.48 (m, 1H), 1.87–1.97 (m, 3H), 3.60 (dd, J=5.6, 10.5 Hz, 1H), 3.68 (dd,
J=4.4, 10.5 Hz, 1H), 3.98–4.05 (m, 2H), 7.35–7.42 (m, 6H), 7.68–7.71 (m, 4H); 13C NMR (125
MHz, CCl4) l 22.4, 24.1, 29.8, 30.9, 35.9, 69.3, 78.2, 82.0, 130.3, 132.2, 136.9, 138.4; IR (film)
2962, 2929, 2856, 1113 cm−1; LRMS (EI) m/z 199 (100%), 297 (70%); HRMS (EI) m/z calcd for
C18H21O2Si [M−tBu]+ 297.13108. Found: 297.13101.
4.5.2. (2S,5S)-2-n-Butyl-5-(tert-butyldiphenylsilyloxymethyl)-tetrahydrofuran 20b
Chromatography on silica gel (5% AcOEt in hexanes, v/v) afforded the product as a clear oil
in 54% yield (5:1 cis/trans). An analytically pure sample of the major diastereoisomer 20b was
1
isolated and characterized (Rf 0.39 in 5% AcOEt–hexanes). [h]2D4 +8.3 (c 0.3, CH2Cl2); H NMR
(500 MHz, CDCl3) l 0.89 (t, J=7.0 Hz, 3H), 1.05 (s, 9H), 1.28–1.64 (m, 7H), 1.85–1.95 (m, 3H),
3.60 (dd, J=5.4, 10.5 Hz, 1H), 3.67 (dd, J=4.4, 10.5 Hz, 1H), 3.82–3.86 (m, 1H), 4.00–4.03 (m,
1H), 7.35–7.43 (m, 6H), 7.68–7.71 (m, 4H); 13C NMR (125 MHz, CDCl3) l 14.1, 19.3, 22.8,
26.8, 27.9, 28.5, 31.1, 35.7, 66.5, 79.2, 80.1, 127.6, 129.5, 133.7, 135.6; IR (film) 2956, 2929, 2858,
1113 cm−1; LRMS (IE) m/z 199 (100%), 339 (75%); HRMS (EI) m/z calcd for C21H27O2Si
[M−tBu]+ 339.17803. Found: 339.17810.
4.5.3. (2R,5S)-2-Phenyl-5-(tert-butyldiphenylsilyloxymethyl)-tetrahydrofuran 21b
Chromatography on silica gel (4% AcOEt in hexanes, v/v) afforded the product as a clear oil
1
(Rf 0.28 in 5% AcOEt–hexanes) and 51% yield (single isomer detected by H NMR). [h]2D4 +34.9
1
(c 0.86, CH2Cl2); H NMR (300 MHz, CDCl3) l 1.07 (s, 9H), 1.76–1.89 (m, 1H), 1.96–2.13 (m,
2H), 2.22–2.33 (m, 1H), 3.80 (d, J=4.4 Hz, 2H), 4.18–4.25 (m, 1H), 4.91 (dd, J=6.2, 8.1 Hz,
1H), 7.23–7.43 (m, 11H), 7.69–7.74 (m, 4H); 13C NMR (75 MHz, CDCl3) l 19.2, 26.8, 28.0,
34.4, 66.2, 79.9, 81.4, 125.9, 127.2, 127.7, 128.2, 129.7, 133.7, 135.7, 143.2; IR (film) 2958, 2929,
2856, 1113 cm−1; LRMS (EI) m/z 199 (100%), 359 (20%); HRMS (EI) m/z calcd for C23H23O2Si
[M−tBu]+ 359.14673. Found: 359.14679.
4.6. (2R,5S)-2-Methyl-5-(tert-butyldiphenylsilyloxymethyl)-tetrahydrofuran 19a
To a solution of lactol 1 (0.180 g, 0.505 mmol) in dry CH2Cl2 (2.0 mL) at −78°C was added
BF3·OEt2 (0.186 mL, 1.51 mmol) and Me3Al (0.090 mL, 1.0 mmol). The mixture was stirred for

3686
R. A. Pilli, V. B. Riatto / Tetrahedron: Asymmetry 11 (2000) 3675–3686
3 h at −78°C and the reaction was quenched by the addition of saturated aqueous NH4Cl (2
mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×1 mL). The
combined organic layers were washed with brine (2 mL), dried over MgSO4, filtered and
concentrated. Chromatography on silica gel (5% AcOEt in hexanes, v/v) afforded 19a/19b (0.148
g, 0.417 mmol, 83% yield) as a clear oil (8:1 trans/cis). An analytically pure sample of the major
diastereoisomer 19a was isolated and characterized (Rf 0.37 in 5% AcOEt–hexanes). [h]2D4 −8.2 (c
1
1.22, CH2Cl2); H NMR (500 MHz, CDCl3) l 1.05 (s, 9H), 1.21 (d, J=6.1 Hz, 3H), 1.41–1.47
(m, 1H), 1.81–1.86 (m, 1H), 1.99–2.05 (m, 2H), 3.61 (dd, J=5.4, 10.5 Hz, 1H), 3.66 (dd, J=4.6,
10.5 Hz, 1H), 4.05–4.09 (m, 1H), 4.13–4.18 (m, 1H), 7.35–7.43 (m, 6H), 7.67–7.71 (m, 4H); 13C
NMR (125 MHz, CDCl3) l 19.3, 21.1, 26.9, 28.4, 33.7, 66.7, 75.3, 79.0, 127.6, 129.5, 133.8,
135.6; IR (film) 2962, 2929, 2856, 1113 cm−1; LRMS (EI) m/z 199 (100%), 297 (70%); HRMS
(EI) m/z calcd for C18H21O2Si [M−tBu]+ 297.13108. Found: 297.13122.
Acknowledgements
FAPESP for financial support and fellowship (VBR) and CNPq for fellowship (RAP).
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