Synthesis of enantiomerically pure 2,5-disubstituted 3-oxygenated tetrahydrofurans

Article abstract of DOI:10.1055/s-0030-1258263

The synthesis of enantiomerically pure 2,5-disubstituted 3-oxygenated tetrahydrofurans has been achieved from cheap and commercially available l-malic acid. This method was used to prepare an advanced intermediate toward CMI-977, a promising candidate for the treatment of chronic asthma. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1258263

PAPER
3883
Synthesis of Enantiomerically Pure 2,5-Disubstituted 3-Oxygenated
Tetrahydrofurans
2
, 5-Disubstituted
a
3-Oxygena
r
ted Tetr
l
ahydro
afurans Álvarez, Manuel Pérez, Andrea Zúñiga, Generosa Gómez,* Yagamare Fall*
Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, 36310 Vigo, Spain
Fax +34(98)6812262; E-mail: yagamare@uvigo.es; E-mail: ggomez@uvigo.es
Received 26 July 2010; revised 2 August 2010
We wish to report a new method for the synthesis of chiral
2,5-disubstituted 3-oxygenated tetrahydrofurans such as
of compounds 7 and 8 (Scheme 1). Compound 7 is inter-
esting because it can be considered as an advanced syn-
thetic intermediate of CMI-977 containing the trans-
juxtapositioned ring. Our synthesis is outlined retrosyn-
thetically in Scheme 1.
Abstract: The synthesis of enantiomerically pure 2,5-disubstituted
3-oxygenated tetrahydrofurans has been achieved from cheap and
commercially available L-malic acid. This method was used to pre-
pare an advanced intermediate toward CMI-977, a promising candi-
date for the treatment of chronic asthma.
Key words: furan, tetrahydrofuran, singlet oxygen, butenolide,
oxacycles, natural products
We anticipated that the relatively inexpensive and readily
available chiral pool material L-malic acid could lead to
chiral furan 9 containing the 4-fluorophenyl ether moiety,
setting the stage for the synthesis of compounds 7 and 8
The 2,5-disubstituted 3-oxygenated tetrahydrofuran moi-
ety is present in a plethora of natural products, some of
which are depicted in Figure 1. Dihydroxytetrahydro-
furans 11 and 22 are marine natural products that were iso-
lated from Notheia anomala, a brown algae found along
the southern Australian coast. Because of their antiparasit-
ic properties these compounds have attracted the attention
of many synthetic chemists.3 trans-Kumausyne (3)4 and
(–)-kumausallene (4)5 are halogenated secondary metabo-
lites isolated from the Japanese red algae, Laurencia nip-
ponica and several synthetic approaches toward these
molecules can be found in the literature.6 The significance
of (+)-muscarine (5) has led to a growing demand, which
at present cannot be covered from the current natural re-
sources, such as fungi of the genera Amanita,7 Clitocybe,8
and Inocybe9 alone. Therefore, methods for the enantiose-
lective synthesis of this alkaloid and its diastereomers
have received considerable attention from the scientific
community.10 CMI-977, renamed later as LDP-977 is a
promising candidate for chronic asthma.11 Its 2,5-disubsti-
tuted tetrahydrofuran ring might be obtained by removal
of the hydroxy group of the corresponding 2,5-disubstitut-
ed 3-oxygenated tetrahydrofuran.
OH
OH
7
O
O
7
H
H
H
H
OH
HO
1
2
AcO
O
H
H
H
H
O
Br
.
trans-kumausyne (3)
Et
H
O
H
H
HO
Br
O
Br
(–)-kumausallene (4)
+
NMe3
O
O
X–
O
(+)-muscarine (5)
N
OH
NH2
H
H
F
CMI-977 (LDP-977) (6)
Figure 1 2,5-Disubstituted tetrahydrofuran-containing natural pro-
ducts
OH
O
OTBDPS
O
H
H
O
OH
TBDPSO
O
F
7
HO
F
OH
OH
O
O
9
10
O
OTBDPS
O
H
H
F
8
Scheme 1 Retrosynthetic analysis of 2,5-disubstituted 3-oxygenated tetrahydrofurans 7 and 8
SYNTHESIS 2010, No. 22, pp 3883–3890
x
x.
x
x
.
2
0
1
0
Advanced online publication: 22.09.2010
DOI: 10.1055/s-0030-1258263; Art ID: Z18910SS
© Georg Thieme Verlag Stuttgart · New York

3884
C. Álvarez et al.
PAPER
OH
OTBDPS
O
O
OH
O
O
i
ii
iii
iv
MeO
MeO
O
HO
O
OTBS
OTBS
OH
OH
OTBS
O
O
O
O
O
12
10
11
13
14
OTBDPS
HO
vi
OTBS
OTBS
OTBDPS
15
viii
v
vii
+
F
O
18
OTBS
OTBDPS
F
OH
H
17
O
16
TBDPSO
O
TBDPSO
O
O
OTBDPS
ix
x
F
F
F
O
OEt
OEt
H
OH
O
9
19
20
21
Scheme 2 Reagents and conditions: (i) cyclohexanone, BF3·OEt2, Et2O, 0 °C (78%); (ii) a) BH3·SMe2, B(OMe)3, THF, 0 °C to r.t., b) TBSCl,
imidazole, DMAP, THF, r.t. (87%, 2 steps); (iii) NaOMe, MeOH, r.t. (97%); (iv) TBDPSCl, imidazole, DMAP, DMF, r.t. (95%); (v) DIBAL-H,
CH2Cl2, –78 °C (15, 73%; 16,17%); (vi) NaBH4, MeOH, 0 °C (99%); (vii) PPh3, DIAD, 17, THF, r.t. (68%); (viii) AcOH–THF–H2O (3:1:1),
r.t. (80%); (ix) (COCl)2, DMSO, Et3N, CH2Cl2, –78 °C to r.t. (87%); (x) a) 21, n-BuLi, THF, –78 to 0 °C (86%), b) H2, Lindlar catalyst, MeOH,
r.t. (70%).
using a methodology we developed in our laboratories and steps). Removal of the cyclohexylidene protecting group
for which we coined the furan approach to oxacyclic sys- with sodium methoxide afforded hydroxy ester 13 in 97%
tem.12
yield. The hydroxy group of 13 was protected as tert-bu-
tyldiphenylsilyl ether affording 14 in 95% yield. Reaction
of ester 14 with DIBAL-H gave the desired alcohol 15 in
73% yield, together with aldehyde 16 (17%), which could
be easily transformed into alcohol 15 by reduction with
sodium borohydride in methanol in quantitative yield.
Mitsunobu reaction15 of alcohol 15 with readily available
4-fluorophenol (17) gave ether 18 in 68% yield. Selective
Accordingly, compound 9 was prepared as shown in
Scheme 2. Reaction of L-malic acid (10) with cyclohex-
anone in the presence of a Lewis acid,13 gave the protected
acid 11 in 78% yield. Reduction of the latter with borane
dimethyl sulfide complex14 afforded a rather labile alco-
hol, which was protected as tert-butyldimethylsilyl ether
without further purification to give 12 in 87% yield (2
H
TBDPSO
O
TBDPSO
O
O
O
H
i
iii
ii
F
F
O
F
O
O
O
O
OMe
MeO
9
22
23
H
H
O
H
OH
OH
OTBDPS
OTBDPS
v
O
iv
O
O
O
O
F
F
F
OH
OH
O
24
25
26
O
OTBDPS
O
H
H
H
F
F
vi
7
OH
O
OTBDPS
O
H
8
Scheme 3 Reagents and conditions: (i) a) O2, hn, Rose Bengal, MeOH–CH2Cl2, b) Ac2O, pyridine, r.t. (82%, 2 steps); (ii) TBAF, THF, r.t.
(82%); (iii) BF3·OEt2, LiAlH4, Et2O, r.t. (96%); (iv) TBDPSCl, imidazole, DMAP, DMF, r.t. (52%); (v) TPAP, NMO, molecular sieves,
CH2Cl2, r.t. (80%); (vi) L-Selectride, THF, –78 °C (7, 56%; 8, 43%).
Synthesis 2010, No. 22, 3883–3890 © Thieme Stuttgart · New York

PAPER
2,5-Disubstituted 3-Oxygenated Tetrahydrofurans
3885
was carried out with a Hewlett-Packard 5988A spectrometer. Flash
chromatography (FC) was performed on silica gel (Merck 60, 230–
400 mesh); analytical TLC was performed on plates precoated with
silica gel (Merck 60 F254, 0.25 mm).
removal of the TBS protecting group of 18 afforded alco-
hol 19 (80%), which underwent Swern oxidation to give
aldehyde 20 in 87% yield. Aldehyde 20 was easily trans-
formed into furan 9 in two steps (60% yield) using our
previously described method.16
(S)-2-(3-Oxo-1,4-dioxaspiro[4.5]decan-2-yl)acetic Acid (11)
To a solution of 10 (10.2 g, 76 mmol) in Et2O (100 mL) cooled to 0
°C was added first BF3·OEt2 (14 mL, 110.2 mmol) and then distilled
cyclohexanone (8.7 mL, 83.6 mmol). The mixture was stirred at 0
°C for 1 h and then at r.t. for 19 h. The reaction mixture was
quenched with aq 10% NaOAc (150 mL), the solution was stirred
for 20 min, and then extracted with EtOAc (4 × 100 mL). The com-
bined organic phases were dried (Na2SO4), filtered and the solvent
evaporated under reduced pressure. The residue was chromato-
graphed on silica gel using 20% EtOAc–hexane, then 50% EtOAc–
hexane affording 11 as a white crystalline solid; yield: 12.6 g (78%);
mp 108.4 °C; Rf = 0.78 (EtOAc); [a]D23 +24.8 (c = 0.43, CHCl3).
With furan 9 in hand, the stage was set for the crucial ox-
idation step using singlet oxygen (Scheme 3).
Furan 9 was subjected to singlet oxygen oxidation, fol-
lowed by treatment with acetic anhydride in pyridine to
afford butenolide 22 in 82% overall yield. Treatment of 22
with TBAF led to the bycyclic compound 23 through an
intramolecular Michael addition (82% yield). On reaction
with LiAlH4 in the presence of BF3·OEt2, 23 afforded a
96% yield of unseparable diastereoisomeric alcohols 24.
Selective protection of the primary hydroxy group of 24,
followed by TPAP oxidation afforded diastereoisomeric
ketones 26, which could not be separated by column chro-
matography. Stereoselective reduction of ketones 26 by
L-Selectride afforded easily separable trisubstituted tet-
rahydrofurans 7 and 8 in 56% and 43% yield, respective-
ly. The stereochemistry of 7 and 8 was established from
the NOE correlations of the corresponding acetates 27 and
28 (Figure 2).
IR (NaCl, neat): 3035, 2943, 2866, 1793, 1724 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.71 (dd, J = 3.9, 6.5 Hz, 1 H, H-
2), 2.98 (dd, J = 3.9, 17.2 Hz, 1 H, H-1¢), 2.83 (dd, J = 6.5, 17.2 Hz,
1 H, H-1¢), 1.83 (m, 2 H, CHeq-6, CHeq-10), 1.6–1.77 (m, 6 H, CHax-
6, CHax-10, CH2-7, CH2-9), 1.44 (m 2 H, CH2-8).
13C NMR (100 MHz, CDCl3): d = 174.46 (C-2¢), 171.92 (C-3),
112.21 (C-5), 70.01 (CH-2), 36.19 (CH2-1¢), 36.15, 35.33 (CH2-6,
CH2-10), 24.40 (CH2-8), 22.93 (CH2-7, CH2-9).
MS (ESI+): m/z (%) = 237.07 ([M + Na]+, 100), 215.09 ([M]+, 12),
201.04 (13), 179.01 (21), 157.01 (27).
HRMS (ESI+): m/z calcd for C10H14O5 + Na: 237.0739; found:
8.8%
237.0733.
H
OTBDPS
O
(S)-3-[2-(tert-Butyldimethylsilyloxy)ethyl]-1,4-dioxa-
spiro[4.5]decan-2-one (12)
H
O
F
OAc
To a solution of 11 (5.8 g, 27.2 mmol) in anhyd THF (40 mL)
cooled to 0 °C was added BH3·SMe2 (3.9 mL, 40.8 mmol), followed
by B(OMe)3 (4.6 mL, 40.8 mmol). The mixture was stirred for 19 h,
before adding MeOH (30 mL) at 0 °C. The mixture was stirred for
an additional 1 h, the solvent was evaporated, and the residue was
dissolved again in MeOH (30 mL) at 0 °C and the mixture stirred
for 1 h. Solvent evaporation afforded the expected alcohol that was
used in the next reaction without further purification. It was dis-
solved in THF (55 mL), imidazole (3.7 g, 54 mmol), catalytic
amount of DMAP, and TBSCl (4.1 g, 29.7 mmol) were added and
the mixture was stirred at r.t. for 20 h. The solvent was evaporated
and H2O (40 mL) was added and the product extracted with CH2Cl2
(4 × 40 mL). The combined organic layers were dried (Na2SO4), fil-
tered and the solvent was evaporated. The residue was chromato-
graphed on silica gel using 5% EtOAc–hexane affording 12 as a
colorless oil; yield: 7.36 g (87%); Rf = 0.79 (30% EtOAc–hexane);
[a]D23 +26.5 (c = 0.78, CHCl3).
H
27
10%
8.8%
2%
O
H
OTBDPS
3%
O
H
F
OAc
H
28
5.2%
Figure 2 NOE correlation for 27 and 28
In conclusion, we have demonstrated that the synthesis of
enantiomerically pure 2,5-disubstituted 3-oxygenated tet-
rahydrofurans could be achieved from cheap and com-
IR (NaCl, neat): 2943, 2862, 1799 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.51 (m, 1 H, H-3), 3.81 (m, 1 H,
mercially available L-malic acid and using the furan H-2¢), 3.73 (m, 1 H, H-2¢), 2.07 (m, 1 H, H-1¢), 1.83 (m, 3 H, CH2eq
-
6, CH2eq-10, H-1¢), 1.6–1.77 (m, 6 H, CHax-6, CHax-10, CH2-7, CH2-
9), 1.44 (m 2 H, CH2-8), 0.87 (s, 9 H, t-C4H9), 0.03 [s, 6 H,
Si(CH3)2].
13C NMR (100 MHz, CDCl3): d = 173.66 (C-2), 111.18 (C-5),
70.29 (CH-3), 58.24 (CH2-2¢), 36.67 (CH2-1¢), 35.36, 34.85 (CH2-6,
CH2-10), 25.80 [SiC(CH3)3], 24.40 (CH2-8), 22.99, 22.94 (CH2-7,
CH2-9), 18.21 [SiC(CH3)3], –5.48 [Si(CH3)2].
approach. The application of this method for the synthesis
of CMI-977 as well as some of the biologiacally active
compounds depicted in Figure 1 is currently under way in
our laboratories.
Solvents were purified and dried by standard procedures before use.
1
Melting points are uncorrected. H NMR and 13C NMR spectra
MS (ESI+): m/z (%) = 337.18 ([M + Na]+, 76), 315.2 ([M]+, 100).
HRMS (ESI+): m/z calcd for C16H31O4Si: 315.1992; found:
were recorded with a Bruker ARX-400 spectrometer (400 MHz for
1H NMR, 100.61 MHz for 13C NMR) using TMS as internal
standard (chemical shifts in d values, J in Hz). Mass spectrometry
315.1975.
Synthesis 2010, No. 22, 3883–3890 © Thieme Stuttgart · New York

3886
C. Álvarez et al.
PAPER
(S)-Methyl 4-(tert-Butyldimethylsilyloxy)-2-hydroxybutanoate
(13)
15
Yield: 3.29 g (73%); colorless oil; Rf = 0.28 (10% EtOAc–hexane);
To a solution of 12 (7.3 g, 23.0 mmol) in MeOH (100 mL) cooled
at 0 °C was added a solution of NaOMe in MeOH (25%) and the
mixture was stirred for 15 min under the same conditions. MeOH
(100 mL) was added, followed by Amberlist till pH 6. The resin was
filtered and the solvent was evaporated. The residue was chromato-
graphed on silica gel using 20% EtOAc–hexane affording 13 as a
colorless oil; yield: 5.53 g (97%); Rf = 0.63 (30% EtOAc–hexane);
[a]D23 –37.5 (c = 0.5, CHCl3).
[a]D23 +8.28 (c = 1.13, CHCl3).
IR (NaCl, neat): 3425, 3066, 2939, 2889, 2862 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.79 (m, 4 H, CHo-Ph), 7.46 (m, 6
H, CHp,m-Ph), 4.06 (m, 1 H, H-2), 3.82 (m, 1 H, H-4), 3.60 (m, 3 H,
H-4, H-1), 2.95 (s, 1 H, OH), 1.85 (m, 2 H, H-3), 1.15 (s, 9 H, t-
C4H9-TBDPS), 0.95 (s, 9 H, t-C4H9-TBS), 0.03 [s, 6 H, Si(CH3)2].
13C NMR (100 MHz, CDCl3): d = 135.79 (CHo-Ph), 133.91 (C-Ph),
129.88 (CHm-Ph), 127.72 (CHp-Ph), 71.92 (CH-2), 66.09 (CH2-1),
59.43 (CH2-4), 37.13 (CH2-3), 26.71 [C(CH3)3-TBS], 25.98
[C(CH3)3-TBDPS], 19.43 [C(CH3)3-TBDPS], 18.26 [C(CH3)3-
TBS], –5.28 [Si(CH3)2].
MS (ESI+): m/z (%) = 481.26 ([M + Na]+, 96), 459.27 ([M + 1]+,
100), 381.23 (19), 203.12 (13), 171.09 (19).
HRMS (ESI+): m/z calcd for C26H43O3Si2: 459.2751; found:
459.2745.
IR (NaCl, neat): 3487, 2951, 2862, 1740 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.33 (m, 1 H, H-2), 3.78 (m, 2 H,
H-4), 3.73 (s, 3 H, CH3O), 2.00 (m, 1 H, H-3), 1.85 (m, 3 H, H-3),
0.85 (9 H, s, t-C4H9), 0.03 [6 H, s, Si(CH3)2].
13C NMR (100 MHz, CDCl3): d = 175.24 (C-1), 68.79 (CH-2),
59.74 (CH2-4), 52.23 (CH3O), 36.16 (CH2-3), 25.80 [SiC(CH3)3],
18.21 [SiC(CH3)3], –5.58 [Si(CH3)2].
MS (ESI+): m/z (%) = 271.14 ([M + Na]+, 100), 249.15 ([M + 1]+,
34).
16
HRMS (ESI+): m/z calcd for C11H24O4Si + Na: 271.1336; found:
Yield: 1.71 g (17%); colorless oil; Rf = 0.56 (10% EtOAc–hexane);
271.1336.
[a]D23 +10.5 (c = 0.84, CHCl3)].
1H NMR (400 MHz, CDCl3): d = 9.64 (s, 1 H, H-1), 7.69 (m, 4 H,
CHo-Ph), 7.41 (m, 6 H, CHp,m-Ph), 4.22 (m, 1 H, H-2), 3.94 (m, 1 H,
H-4), 3.68 (m, 1 H, H-4), 2.01 (m, 1 H, H-3), 1.81 (m, 1 H, H-3),
1.18 (s, 9 H, t-C4H9-TBDPS), 0.92 (s, 9 H, t-C4H9-TBS), 0.08 [s, 6
H, Si(CH3)2].
13C NMR (100 MHz, CDCl3): d = 203.41 (C=O), 135.83 (CHo-Ph),
133.26 (C-Ph), 130.03 (CHm-Ph), 127.83 (CHp-Ph), 75.82 (CH-2),
57.75 (CH2-4), 37.01 (CH2-3), 26.71 [C(CH3)3-TBS], 25.98
[C(CH3)3-TBDPS], 19.43 [C(CH3)3-TBDPS], 18.26 [C(CH3)3-
TBS], –5.28 [Si(CH3)2].
(S)-Methyl 4-(tert-Butyldimethylsilyloxy)-2-(tert-butyldiphe-
nylsilyloxy)butanoate (14)
To a solution of 13 (5.0 g, 20.3 mmol) in DMF (20 mL) was added
imidazole (3.32 g, 48.8 mmol), a catalytic amount of DMAP, and
TBDPSCl (6.8 mL, 26.4 mmol), and the mixture was stirred at r.t.
for 6 d. EtOAc (50 mL) was added and the solution was washed
with H2O (4 × 30 mL). The organic phase was dried (Na2SO4), fil-
tered and the solvent was evaporated. The residue was chromato-
graphed on silica gel using 5% EtOAc–hexane affording 14 as a
colorless oil; yield: 9.36 g (95%); Rf = 0.81 (30% EtOAc–hexane);
[a]D23 –28.2 (c = 0.6, CHCl3).
Reduction of Aldehyde 16 to Alcohol 15: To aldehyde 16 (5.7 g, 12.5
mmol) in MeOH (30 mL) at 0 °C was added NaBH4 (709 mg, 18.75
mmol) and the mixture stirred for 15 min, then quenched with H2O
(30 mL). Extraction with EtOAc (4 × 30 mL) and evaporation of the
solvent gave a residue that was identical to alcohol 15.
IR (NaCl, neat): 2951, 2889, 2858, 1751 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.68 (m, 4 H, CHo-Ph), 7.39 (m, 6
H, CHp,m-Ph), 4.37 (t, J = 5.8 Hz, 1 H, H-2), 3.73 (t, J = 6.5 Hz, 2
H, H-4), 3.42 (s, 3 H, CH3O), 1.94 (m, 2 H, H-3), 1.09 (s, 9 H, t-
C4H9-TBDPS), 0.85 (s, 9 H, t-C4H9-TBS), 0.03 [s, 6 H, Si(CH3)2].
13C NMR (100 MHz, CDCl3): d = 173.47 (C-1), 135.79 (CHo-Ph),
133.29 (C-Ph), 129.73, (CHm-Ph), 127.58 (CHp-Ph), 69.89 (CH-2),
58.76 (CH2-4), 51.30 (CH3O), 38.09 (CH2-3), 26.89 [C(CH3)3-
TBS], 25.92 [C(CH3)3-TBDPS], 19.43 [C(CH3)3-TBDPS], 18.27
[C(CH3)3-TBS], –5.28 [Si(CH3)2].
MS (ESI+): m/z (%) = 509.25 ([M + Na]+, 100), 487.27 ([M + 1]+,
36), 201.04 (32), 169.08 (22).
HRMS (ESI+): m/z calcd for C27H43O4Si2: 487.2700; found:
487.2694.
(S)-5-[(4-Fluorophenoxy)methyl]-2,2,9,9,10,10-hexamethyl-3,3-
diphenyl-4,8-dioxa-3,9-disilaundecane (18)
To a solution of 15 (3.70 g, 8 mmol) in THF (40 mL) was added
PPh3 (3.14 g, 12 mmol), 4-fluorophenol (17; 1.34 g, 12 mmol), and
DIAD (2.4 mL, 12 mmol). The mixture was stirred for 19 h at r.t.
and with sonication. The solvent was evaporated and the residue
chromatographed on silica gel using 5% EtOAc–hexane affording
18 as a colorless oil; yield: 3.03 g (68%); Rf = 0.79 (10% EtOAc–
hexane); [a]D23 –16.9 (c = 1.05, CHCl3).
IR (NaCl, neat): 2935, 2862, 2357, 1508, 1466 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.65 (m, 4 H, CHo-Ph), 7.43 (m, 6
H, CHp,m-Ph), 6.88 (m, 2 H, H-3¢), 6.57 (m, 2 H, H-2¢), 4.29 (m, 1
H, H-2), 3.82 (m, 4 H, H-1, H-4), 1.90 (m, 2 H, H-3), 1.15(s, 9 H, t-
C4H9-TBDPS), 0.95 (s, 9 H, t-C4H9-TBS), 0.03 [s, 6 H, Si(CH3)2].
(S)-4-(tert-Butyldimethylsilyloxy)-2-(tert-butyldiphenylsilyl-
oxy)butan-1-ol (15) and (S)-4-(tert-Butyldimethylsilyloxy)-2-
(tert-butyldiphenylsilyloxy)butanal (16)
To a solution of 14 (4.80 g, 9.87 mmol) in CH2Cl2 (35 mL) cooled
to –78 °C, was added a solution of DIBAL-H in hexane (1 M, 14.8
mL, 14.8 mmol) and the mixture was stirred for 90 min at –78 °C.
Then, t-BuOMe (17 mL) and H2O (1 mL) were added and the mix-
ture was stirred for 15 min whence a translucent gel was obtained.
Aq 4 M NaOH (1 mL) and H2O (1 mL) were then added. The mix-
ture was stirred till a white precipitate was formed and Na2SO4 (0.5
g) was added. The solid was filtered and the solution was evaporat-
ed and the residue was chromatographed on silica gel using 3%
EtOAc–hexane, then 5% EtOAc–hexane affording 15 and 16.
13C NMR (100 MHz, CDCl3): d = 158.25, 155.89 (d, J = 236.9 Hz,
C-Ph-4¢), 154.76, 154.74 (d, J = 3.2 Hz, C-Ph-1¢), 135.71 (CHo-Ph-
TBDPS), 133.86 (C-Ph-TBDPS), 129.69 (CHm-Ph), 127.75 (CHp-
Ph-TBDPS), 115.65, 115.49 (d, J = 23.3 Hz, CH-Ph-H3¢), 115.23,
115.16 (d, J = 8.3 Hz, CH-Ph-H2¢), 72.12 (CH2-1), 69.45 (CH-2),
59.46 (CH2-4), 37.51 (CH2-3), 26.81 [C(CH3)3-TBS], 25.96
[C(CH3)3-TBDPS], 19.49 [C(CH3)3-TBDPS], –5.28 [Si (CH3)2].
MS (ESI+): m/z (%) = 575.28 ([M + Na]+, 44), 553.3 ([M + 1]+, 100),
475.25 ([M – Ph]+, 13), 341.23 (23), 319.25 (67), 203.13 (19).
HRMS (ESI+): m/z calcd for C32H46FO3Si2: 553.2970; found:
553.2964.
Synthesis 2010, No. 22, 3883–3890 © Thieme Stuttgart · New York

PAPER
2,5-Disubstituted 3-Oxygenated Tetrahydrofurans
3887
(S)-3-(tert-Butyldiphenylsilyloxy)-4-(4-fluorophenoxy)butan-1-
ol (19)
BuLi (2.5 M in hexane, 2.15 mL, 5.37 mmol). The mixture was
stirred at 0 °C for 2 h. Then a solution of 20 (1.95 g, 4.47 mmol) in
THF (5 mL) was added at –78 °C via cannula and the mixture was
stirred at r.t. for 3 h. The reaction was quenched with H2O (40 mL)
and the mixture extracted with CH2Cl2 (3 × 30 mL). The combined
organic layers were dried (Na2SO4), filtered, and the solvent was re-
moved by rotary evaporation. The residue was chromatographed on
silica gel using 10% EtOAc–hexane, 20% EtOAc–hexane, then
50% EtOAc–hexane to afford the expected propargylic alcohol
(2.17 g, 86%). The latter (1.38 g, 2.39 mmol) was dissolved in
MeOH (50 mL) and Lindlar catalyst (200 mg) was added. The mix-
ture was stirred in H2 atmosphere at r.t. for 5 days, and fresh catalyst
(200 mg) was added every 24 h. After filtration, the filtrate was
evaporated and the residue dissolved in CH2Cl2 (30 mL), and
washed with aq 1 M HCl (3 × 10 mL). Drying (Na2SO4), filtering,
and solvent evaporation afforded a residue, which was chromato-
graphed on silica gel using 3% EtOAc–hexane, 5% EtOAc–hexane,
then 10% EtOAc–hexane affording 9 as a yellow oil; yield: 721 mg
(70%); Rf = 0.56 (20% EtOAc–hexane); [a]D24 –22 (c = 1.07,
CHCl3)].
A solution of 18 (3.7 g, 6.7 mmol) in a mixture of AcOH–THF–H2O
(3:1:1, 116 mL) was stirred for 16 h. Afterwards, sat. aq NaHCO3
(150 mL) was added. Then, solid NaHCO3 was added till pH 7. The
aqueous layer was extracted with EtOAc (5 × 40 mL). The com-
bined organic layers were dried (Na2SO4), filtered, and the solvent
was removed by rotary evaporation. The residue was chromato-
graphed on silica gel using 10% EtOAc–hexane, then 50% EtOAc–
hexane affording 19 as a colorless oil; yield: 2.34 g (80%); Rf = 0.44
(30% EtOAc–hexane); [a]D21 –33.5 (c = 0.5, CHCl3).
IR (NaCl, neat): 3386, 2935, 2889, 2862 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.70 (m, 4 H, CHo-Ph), 7.41 (m, 6
H, CHp,m-Ph), 6.86 (m, 2 H, H-3¢), 6.52 (m, 2 H, H-2¢), 4.24 (m, 1
H, H-3), 3.80 (m, 4 H, H-1, H-4), 1.89 (m, 2 H, H-2), 1.07 (s, 9 H,
t-C4H9-TBDPS).
13C NMR (100 MHz, CDCl3): d = 158.23, 155.87 (d, J = 238.0 Hz,
C-Ph-4¢), 154.29, 154.27 (d, J = 2.8 Hz, C-Ph-1¢), 135.71 (CHo-Ph-
TBDPS), 133.86 (C-Ph-TBDPS), 129.69 (CHm-Ph), 127.75 (CHp-
Ph-TBDPS), 115.69, 115.46 (d, J = 22.9 Hz, CH-Ph-3¢), 115.13,
115.05 (d, J = 8.1 Hz, CH-Ph-2¢), 71.16 (CH2-4), 69.65 (CH-3),
59.40 (CH2-1), 36.32 (CH2-2), 25.76 [C(CH3)3-TBDPS], 19.49
[C(CH3)3-TBDPS].
IR (NaCl, neat): 2931, 2858, 2357 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.68 (m, 4 H, CHo-Ph), 7.40 (m, 6
H, CHp,m-Ph), 7.32 (m, 1 H, H-5), 6.90 (m, 2 H, H-3¢¢), 6.61 (m, 2
H, H-2¢¢), 6.31 (m, 1 H, H-4), 6.03 (m, 1 H, H-3), 4.36 (dd, J = 5.5,
10.9 Hz, 1 H, H-2¢), 3.82 (d, J = 5.0 Hz, 2 H, H-3¢), 2.99 (t, J = 6.7
Hz, 2 H, H-1¢), 1.07 (s, 9 H, t-C4H9-TBDPS).
13C NMR (100 MHz, CDCl3): d = 158.32, 155.95 (d, J = 238 Hz, C-
Ph-4¢), 154.71, 154.69 (d, J = 2.11 Hz, C-Ph-1¢¢), 141.17 (CH-5),
135.86 (CHo-Ph-TBDPS), 133.99 (C-Ph-TBDPS), 129.70 (CHm-
Ph-TBDPS), 127.50 (CHp-Ph-TBDPS), 115.68, 115.45 (d, J = 23.3
Hz, CH-Ph-H3¢) 115.36, 115.28 (d, J = 7.7 Hz, CH-Ph-H2¢),
110.27 (CH, C-4), 71.21 (CH2-3¢), 70.59 (CH-2¢), 33.10 (CH2-1¢),
37.51 (CH2-3), 110.27 (CH-4), 107.34 (CH-3), 71.19 (CH2-3¢),
70.59 (CH-2¢), 33.09 (CH2-1¢), 26.85 [C(CH3)3-TBDPS], 19.27
[C(CH3)3-TBDPS].
MS (ESI+): m/z (%) = 461.19 ([M + Na]+, 61), 439.21 ([M + 1]+, 40),
361.17 (([M – Ph]+, 100), 315.17 (16), 301.13 (13), 283.12 (56).
HRMS (ESI+): m/z calcd for C26H32FO3Si: 439.2105; found:
439.2095.
(S)-3-(tert-Butyldiphenylsilyloxy)-4-(4-fluorophenoxy)butanal
(20)
To a solution of (COCl)2 (2 M in CH2Cl2, 5.25 mL, 10.5 mmol) in
CH2Cl2 (5 mL) cooled to –78 °C was added a solution of DMSO
(1.48 mL, 20.9 mmol) in CH2Cl2 (10 mL). The mixture was stirred
at –78 °C for 1 h. A solution of 19 (2.3 g, 5.25 mmol) in CH2Cl2 (15
mL) was added and stirred for 4 h. Et3N (4.5 mL) was added and the
stirring was continued for 15 min at –78 °C and 30 min at 0 °C. The
reaction mixture was quenched with H2O (50 mL) and stirred for 20
min at r.t. The organic layer was washed with aq 2% HCl (3 × 30
mL), H2O (30 mL), sat. aq NaHCO3 (2 × 30 mL), H2O (30 mL), and
finally with brine (30 mL). Drying (Na2SO4), filtering, and solvent
evaporation afforded aldehyde 20 as a brown oil; yield: 2 g (87%);
Rf = 0.70 (30% EtOAc–hexane); [a]D21 –20.4 (c = 0.43, CHCl3).
MS (ESI+): m/z (%) = 497.19 ([M + Na]+, 31), 475.21 ([M + 1]+, 11),
397.16 ([M – Ph]+, 43), 391.28 (100), 355.13 (21), 337.13 (25),
291.19 (20).
HRMS (ESI+): m/z calcd for C29H31FO3Si + Na: 497.1924; found:
497.1919.
(S)-5-[2-(tert-Butyldiphenylsilyloxy)-3-(4-fluorophenoxy)pro-
pyl]-5-methoxyfuran-2(5H)-one (22)
IR (NaCl, neat): 2931, 2858, 2357, 1723, 1504 cm–1.
A solution of 9 (301 mg, 0.63 mmol) and Rose Bengal (13 mg) in
MeOH (5 mL) in CH2Cl2 (7 mL) was cooled to –78 °C in O2 atmo-
sphere and stirred for 30 min while irradiating with a 200 W lamp.
The solution was allowed to reach r.t. and the solvent evaporated.
The resulting residue was chromatographed on silica gel using 80%
EtOAc–hexane to remove the Rose Bengal. Solvent evaporation af-
forded a residue (379 mg), which was dissolved in pyridine (938
mL). Ac2O (330 mL) was added dropwise at 0 °C followed by a cat-
alytic amount of DMAP. The mixture was stirred at r.t. for 14 h.
MeOH (3 mL) was added and the stirring continued for 1 h. The sol-
vent was removed by rotary evaporation and the residue dissolved
in t-BuOMe (50 mL). The organic layer was washed with CuSO4
(3 × 30 mL), dried (Na2SO4), and filtered, affording 22 as an orange
oil; yield: 269 mg (82%); Rf = 0.13 (20% EtOAc–hexane).
1H NMR (400 MHz, CDCl3): d = 9.77 (t, J = 2.2 Hz, 1 H, H-1), 7.67
(m, 4 H, CHo-Ph), 7.39 (m, 6 H, CHp,m-Ph), 6.87 (m, 2 H, H-3¢), 6.56
(m, 2 H, H-2¢), 4.50 (m, 1 H, H-3), 3.84 (m, 2 H, H-4), 2.69 (dd,
J = 2.2, 6.1 Hz, 2 H, H-2), 1.04 (s, 9 H, t-C4H9-TBDPS).
13C NMR (100 MHz, CDCl3): d = 200.67 (CH-1), 158.48, 156.11
(d, J = 234.5 Hz, C-Ph-4¢), 154.24, 154.22 (d, J = 2.11 Hz, C-Ph-
1¢), 135.77 (CHo-Ph-TBDPS), 133.39 (C-Ph-TBDPS), 129.89
(CHm-Ph), 127.70 (CHp-Ph-TBDPS), 115.79, 115.56 (d, J = 23.3
Hz, CH-Ph-3¢), 115.33, 115.25 (d, J = 7.7 Hz, CH-Ph-2¢), 71.26
(CH2-4), 67.46 (CH-3), 48.36 (CH2-2), 26.87 [C(CH3)3-TBDPS],
19.28 [C(CH3)3-TBDPS].
MS (ESI+): m/z (%) = 459.17 ([M + Na]+, 19), 359.15 (18), 259.09
(100).
HRMS (ESI+): m/z calcd for C26H29FO3Si + Na: 459.1768; found:
459.1762.
IR (NaCl, neat): 3062, 2939, 2858, 2357, 1774 cm–1.
1H NMR (400 MHz, CDCl3): d (diastereoisomeric mixture) = 7.59
(m, 8 H, CHo-Ph), 7.28 (m, 12 H, CHp,m-Ph), 6.94 (d, J = 5.5 Hz, 1
H, H-4), 6.90 (d, J = 5.5 Hz, 1 H, H-4), 6.77 (m, 4 H, H-3¢¢), 6.46
(m, 4 H, H-2¢¢), 5.99 (d, J = 5.5 Hz, 1 H, H-3), 5.94 (d, J = 5.5 Hz,
1 H, H-3), 3.80 (m, 4 H, H-3¢), 3.66 (m, 2 H, H-2¢), 3.02 (s, 3 H,
CH3O), 3.01 (s, 3 H, CH3O), 2.11 (m, 4 H, H-1¢), 0.97 (s, 18 H, t-
C4H9-TBDPS).
(S)-tert-Butyl[1-(4-fluorophenoxy)-3-(furan-2-yl)propan-2-
yloxy]diphenylsilane (9)
To a solution of 3,3-diethoxyprop-1-yne (21; 770 mL, 5.37 mmol)
in THF (5 mL) cooled to –78 °C was slowly added a solution of n-
Synthesis 2010, No. 22, 3883–3890 © Thieme Stuttgart · New York

3888
C. Álvarez et al.
PAPER
13C NMR (100 MHz, CDCl3): d (diastereoisomeric mixture) =
169.45 (C-2), 169.41 (C-2), 158.32, 155.95 (d, J = 238.7 Hz, C-Ph-
4¢¢), 154.71, 154.69 (d, J = 2.11 Hz, C-Ph-1¢¢), 153.77 (CH-4),
153.75 (CH-4), 135.89 (CHo-Ph-TBDPS), 133.72 (C-Ph-TBDPS),
129.70 (CHm-Ph-TBDPS), 127.71 (CHp-Ph-TBDPS), 124.06 (CH-
3), 115.68, 115.45 (d, J = 23 Hz, CH-Ph-3¢¢), 115.66, 115.43 (d,
J = 23.1 Hz, CH-Ph-3¢¢), 115.33, 115.25, (d, J = 7.9 Hz, CH-Ph-
3¢¢), 115.28, 115.20 (d, J = 7.7 Hz, CH-Ph-3¢¢), 109.64 (C-5),
109.51 (C-5), 71.92 (CH2-3¢), 71.76 (CH2-3¢), 68.28 (CH-2¢), 68.27
(CH-2¢), 50.95 (CH3O), 50.86 (CH3O), 42.45 (CH2-1¢), 41.86 (CH2-
1¢), 26.83 [C(CH3)3-TBDPS], 19.30 [C(CH3)3-TBDPS].
13C NMR (100 MHz, CDCl3): d (diastereoisomeric mixture) =
158.76, 156.73 (d, J = 203.5 Hz, C-Ph-4¢¢), 154.53, 154.51 (d,
J = 2.4 Hz, C-Ph-1¢¢), 115.90, 115.83 (d, J = 23.3 Hz, CH-Ph-3¢¢),
115.75, 115.68, (d, J = 8.0 Hz, CH-Ph-2¢¢), 85.57 (CH-2), 75.73
(CH-1), 72.93 (CH-4), 71.27 (CH2OPh), 60.71 (CH2-2¢), 37.08
(CH2), 35.94 (CH2).
MS (ESI+): m/z (%) = 279.10 ([M + Na]+, 92), 257.12 ([M + 1]+, 66),
233.07 (14), 201.05 (100).
HRMS (ESI+): m/z calcd for C13H18FO4: 257.1189; found:
257.1184.
MS (ESI+): m/z (%) = 543.20 ([M + Na]+, 43), 505.22 ([M – CH3]+,
(5S)-2-[2-(tert-Butyldiphenylsilyloxy)ethyl]-5-[(4-fluorophen-
oxy)methyl]tetrahydrofuran-3-ol (25)
50), 443.17 ([M – Ph]+, 100), 429.15 (23), 321.25, (30).
HRMS (ESI+): m/z calcd for C30H33FO5Si + Na: 543.1979; found:
543.1973.
To a solution of 24 (130 mg, 0.51 mmol) in DMF (2 mL) was added
imidazole (138 mg, 2 mmol), a catalytic amount of DMAP, and
TBDPSCl (145 mL, 0.56 mmol) and the mixture was stirred at r.t.
for 5 days. The reaction was quenched with EtOAc (5 mL) and the
mixture was washed with H2O (3 × 10 mL). After the usual treat-
ment of the organic layer, the residue was chromatographed on sil-
ica gel using 3% EtOAc–hexane, then 10% EtOAc–hexane
affording 25 as a colorless oil; yield: 137 mg (52% for two steps);
Rf = 0.25 (30% EtOAc–hexane).
(5S)-5-[(4-Fluorophenoxy)methyl]-6a-methoxytetrahydro-
furo[3,2-b]furan-2(5H)-one (23)
To compound 22 (980 mg, 1.71 mmol) was added a 1 M solution of
TBAF in THF (1.71 mL, 1.71 mmol) and the mixture was stirred for
9.5 h at r.t. The mixture was quenched with aq NaHCO3 (20 mL)
and extracted with EtOAc (3 × 30 mL). The combined organic lay-
ers were washed with brine (2 × 30 mL), dried (Na2SO4), filtered.
The solvent was removed by rotary evaporation to give a residue,
which was chromatographed on silica gel using 2% EtOAc–hexane
then 5% EtOAc–hexane affording 23 as a diastereoisomeric mix-
ture; yield: 381 mg (82%), yellow oil; Rf = 0.26 (20% EtOAc–hex-
ane).
IR (NaCl, neat): 3494, 2953, 2862, 2360 cm–1.
1H NMR (400 MHz, CDCl3): d (diastereoisomeric mixture) = 7.68
(m, 8 H, CHo-Ph), 7.40 (m, 12 H, CHp,m-Ph), 6.95 (m, 4 H, H-3¢¢),
6.88 (m, 4 H, H-2¢¢), 4.45 (s, 2 H, H-4), 3.93–3.70 (m, 8 H, H-1, H-
2, CH2OPh), 3.54–3.46 (m, 4 H, CH2OPh, H-2¢), 2.15–2.05 (m, 4 H,
H-5), 2.00–1.73 (m, 4 H, H-1¢), 1.06 (s, 9 H, t-C4H9-TBDPS).
IR (NaCl, neat): 2943, 2357, 1790 cm–1.
13C NMR (100 MHz CDCl3): d (diastereoisomeric mixture) =
158.47, 156.10 (d, J = 239.5 Hz, C-Ph-4¢¢), 154.97, 154.95 (d,
J = 2.11 Hz, C-Ph-1¢¢), 135.52 (CHo-Ph-TBDPS), 133.02 (C-Ph-
TBDPS), 129.83 (CHm-Ph-TBDPS), 127.75 (CHp-Ph-TBDPS),
115.78, 115.64 (d, J = 14.8 Hz, CH-Ph-H-3¢¢) 115.56 (CH-Ph-H-
2¢¢), 85.07 (CH-2), 82.72 (CH-2), 75.84 (CH-1), 75.59 (CH-1),
72.80 (CH-4), 71.67 (CH2OPh), 71.05 (CH2OPh), 61.60 (CH2-2¢),
61.15 (CH2-2¢), 36.48 (CH2-5), 36.34 (CH2-5), 31.79 (CH2-1¢),
31.68 (CH2-1¢), 26.77 [C(CH3)3-TBDPS], 19.24 [C(CH3)3-
TBDPS].
1H NMR (400 MHz, CDCl3): d (diastereoisomeric mixture) = 7.01
(m, 4 H, H-3¢¢), 6.88 (m, 4 H, H-2¢¢), 4.58 (m, 4 H, H-7, H-5), 3.97
(m, 4 H, H-1¢), 3.53 (s, 3 H, CH3O), 3.50 (s, 3 H, CH3O), 2.87 (m,
2 H, H-8), 2.67–2.57 (m, 4 H, H-4, H-8), 2.38 (m, 1 H, H-4).
13C NMR (100 MHz, CDCl3): d (diastereoisomeric mixture) =
174.67, 174.45 (C=O), 158.71, 156.33 (d, J = 238.5 Hz, C-Ph-4¢¢),
158.67, 156.30 (d, J = 238.5 Hz, C-Ph-4¢¢), 154.62, 154.60 (d,
J = 2.4 Hz, C-Ph-1¢¢), 154.53, 154.51 (d, J = 2.4 Hz, C-Ph-1¢¢),
116.01, 115.78 (d, J = 23.3 Hz, CH-Ph-3¢¢), 115.98, 115.75 (d,
J = 23.3 Hz, CH-Ph-3¢¢), 115.63, 115.55, (d, J = 8.0 Hz, CH-Ph-
2¢¢), 81.07 (CH-5), 80.23 (CH-5), 77.73 (CH-7), 77.66 (CH-7),
70.01 (CH2-1¢), 69.94 (CH2-1¢), 53.42 (CH3O), 52.98 (CH3O),
36.31 (CH2-8), 36.24 (CH2-8), 35.83 (CH2-4), 35.72 (CH2-4).
MS (ESI+): m/z (%) = 517.22 ([M + Na]+, 100), 495.24 ([M + 1]+,
35), 417.19 ([M – Ph]+, 21), 349.29 (3), 321.26 (10).
HRMS (ESI+): m/z calcd for C29H36FO4Si: 495.2367; found:
495.2361.
MS (ESI+): m/z (%) = 305.08 ([M + Na]+, 28), 283.50 ([M + 1]+, 41),
233.07 (13), 201.05 (100).
HRMS (ESI+): m/z calcd for C14H16FO5: 283.0982; found:
(5S)-2-[2-(tert-Butyldiphenylsilyloxy)ethyl]-5-[(4-fluorophen-
oxy)methyl]dihydrofuran-3(2H)-one (26)
283.0976.
To a solution of 25 (125 mg, 0.25 mmol) in CH2Cl2 (3 mL) were
added 4 Å molecular sieves (153 mg), NMO (59 mg, 0.51 mmol),
and a catalytic amount of TPAP and the mixture stirred at r.t. for 5
days. After solvent evaporation, the residue was chromatographed
on silica gel using 3% EtOAc–hexane, then 30% EtOAc–hexane af-
fording 26 as a colorless oil; yield: 100 mg (80%); Rf = 0.46 (30%
EtOAc–hexane).
(5S)-5-[(4-Fluorophenoxy)methyl]-2-(2-hydroxyethyl)tetrahy-
drofuran-3-ol (24)
To a solution of 23 (154 mg, 0.53 mmol) in Et2O (20 mL) was added
BF3·OEt2 (170 mL, 1.33 mmol). The mixture was stirred at r.t. for 40
min, cooled to 0 °C before adding slowly LiAlH4 (101 mg, 2.7
mmol). The stirring was continued at r.t. for 45 min. The mixture
was cooled again to 0 °C before adding some drops of H2O and
Na2SO4 (0.5 g). The mixture was filtered and the filtrate was evap-
orated affording 24 as a colorless oil; yield: 135 mg (96%);
Rf = 0.09 (20% EtOAc–hexane).
IR (NaCl, neat): 3070, 2931, 2858, 1759, 1506 cm–1.
1H NMR (400 MHz, CDCl3): d (diastereoisomeric mixture) = 7.68
(m, 8 H, CHo-Ph), 7.40 (m, 12 H, CHp,m-Ph), 6.97 (m, 4 H, H-3¢¢),
6.84 (m, 4 H, H-2¢¢), 4.70 (m, 1 H, H-4), 4.55 (m, 1 H, H-4), 4.35
(dd, 1 H, J = 4.8, 7.1 Hz, H-2), 4.10 (m, 5 H, CH2OPh, H-2), 3.91
(m, 2 H, H-2¢), 3.79 (m, 2 H, H-2¢), 2.60 (m, 4 H, H-5), 2.05 (m, 2
H, H-1¢), 1.92 (m, 2 H, H-1¢), 1.05 (s, 18 H, t-C4H9-TBDPS).
13C NMR (100 MHz, CDCl3): d (diastereoisomeric mixture) =
215.31 (C=O), 214.67 (C=O), 158.70, 156.32 (d, J = 239.5 Hz, C-
Ph-4¢¢), 158.67, 156.30 (d, J = 238.7 Hz, C-Ph-4¢¢), 154.67, 154.65
(d, J = 2.11 Hz, C-Ph-1¢¢), 154.52, 154.50 (d, J = 2.11 Hz, C-Ph-
IR (NaCl, neat): 3737, 3390, 2931, 2360 cm–1.
1H NMR (400 MHz, CDCl3): d (diastereoisomeric mixture) = 6.95
(m, 4 H, H-3¢¢), 6.88 (m, 4 H, H-2¢¢), 4.51 (s, 1 H, H-4), 4.35 (s, 1 H,
H-4), 4.13–3.68 (m, 12 H, H-1, H-2, H-2¢, CH2OPh), 2.10–1.53 (m,
8 H, H-1¢, H-5).
Synthesis 2010, No. 22, 3883–3890 © Thieme Stuttgart · New York

PAPER
2,5-Disubstituted 3-Oxygenated Tetrahydrofurans
3889
1¢¢), 135.59 (CHo-Ph-TBDPS), 133.54 (C-Ph-TBDPS), 129.88
(CHm-Ph-TBDPS), 127.65 (CHp-Ph-TBDPS), 115.97, 115.75 (d,
J = 21.9 Hz, CH-Ph-H3¢), 115.93, 115.70 (d, J = 23.3 Hz, CH-Ph-
H3¢), 115.62, 115.54 (d, J = 7.7 Hz, CH-Ph-H2¢), 115.62, 115.54
(d, J = 7.7 Hz, CH-Ph-H2¢), 78.27 (CH-2), 76.85 (CH-2), 74.04
(CH-4), 73.61 (CH-4), 71.50 (CH2OPh), 70.26 (CH2OPh), 59.59
(CH2-2¢), 59.57 (CH2-2¢), 39.08 (CH2-5), 38.29 (CH2-5), 34.28
(CH2-1¢), 34.00 (CH2-1¢), 26.79 [C(CH3)3-TBDPS], 19.16
[C(CH3)3-TBDPS].
36.94 (CH2-5), 31.81 (CH2-1¢), 26.97 [C(CH3)3-TBDPS], 19.28
[C(CH3)3-TBDPS].
MS (ESI+): m/z (%) = 517.22 ([M + Na]+, 100), 495.24 ([M + 1]+,
35), 417.19 ([M – Ph]+, 21), 349.29 (3), 321.26 (10).
HRMS (ESI+): m/z calcd for C29H36FO4Si: 495.2367; found:
495.2361.
(2R,3R,5S)-2-[2-(tert-Butyldiphenylsilyloxy)ethyl]-5-[(4-fluo-
rophenoxy)methyl]tetrahydrofuran-3-yl Acetate (27) and
(2S,3S,5S)-2-[2-(tert-Butyldiphenylsilyloxy)ethyl]-5-[(4-fluo-
rophenoxy)methyl]tetrahydrofuran-3-yl Acetate (28)
To a solution of 7 or 8 (0.043 mmol) in pyridine (80 mL) was added
Ac2O (0.43 mmol) and the mixture was stirred overnight at r.t.
MeOH (2 mL) was added and the stirring continued for 20 min. The
solvent was evaporated and Et2O (6 mL) was added. The organic
layer was washed with aq CuSO4 (4 × 8 mL), dried (Na2SO4), and
the solvent was removed by rotary evaporation affording 27 or 28.
MS (ESI+): m/z (%) = 515.22 ([M + Na]+, 74), 493.22 ([M + 1]+,
100), 415.17 ([M – Ph]+, 51), 209.63 (11).
HRMS (ESI+): m/z calcd for C29H34FO4Si: 493.2210; found:
493.2205.
(2S,3S,5S)-2-[2-(tert-Butyldiphenylsilyloxy)ethyl]-5-[(4-fluo-
rophenoxy)methyl]tetrahydrofuran-3-ol (8)
To a solution of 26 (43 mg, 0.09 mmol) in THF (2 mL) cooled to
–78 °C was a added a 1 M solution of L-Selectride in THF (874 mL,
0.9 mmol) and the mixture was stirred for 2 h under the same con-
ditions. Aq NH4Cl (10 mL) was added and the stirring continued for
30 min at r.t. The aqueous layer was extracted with EtOAc (4 × 15
mL). After the usual treatment of the organic layer, the residue was
chromatographed on silica gel using 3% EtOAc–hexane, then 15%
EtOAc–hexane affording 7 and 8 as colorless oils.
27
21
Yield: 99%; yellow oil; Rf = 0.48 (30% EtOAc–hexane); [a]D
–1.52 (c = 1.28, CHCl3).
IR (NaCl, neat): 3050, 2956, 2929, 2854, 1740 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.64 (m, 4 H, CHo-Ph), 7.36 (m, 6
H, CHp,m-Ph), 6.92 (m, 2 H, H-3¢¢), 6.82 (m, 2 H, H-2¢¢), 5.32 (m, 1
H, H-3), 4.48 (m, 1 H, H-5), 4.30 (m, 1 H, H-2), 3.95 (m, 2 H,
CH2OPh), 3.76 (m, 2 H, H-2¢), 2.18 (m, 2 H, H-4), 2.04 (s, 3 H,
CH3O), 1.83 (m, 2 H, H-1¢), 1.03 (s, 9 H, t-C4H9-TBDPS).
8
Yield: 18.5 mg (43%); Rf = 0.42 (30% EtOAc–hexane); [a]D22 +5.1
(c = 0.83, CHCl3).
13C NMR (100 MHz, CDCl3): d = 170.38 (C=O), 158.56, 156.19 (d,
J = 238.7 Hz, C-Ph-4¢¢), 154.94, 154.92 (d, J = 2.11 Hz, C-Ph-1¢¢),
135.56 (CHo-Ph-TBDPS), 133.80 (C-Ph-TBDPS), 129.59 (CHm-
Ph-TBDPS), 127.64 (CHp-Ph-TBDPS), 115.88, 115.66 (d, J = 21.8
Hz, CH-Ph-H3¢), 115.65, 115.58 (d, J = 7.7 Hz, CH-Ph-H2¢), 78.24
(CH-2), 75.76 (CH-3), 75.32 (CH-5), 70.89 (CH2OPh), 60.92 (CH2-
2¢), 35.66 (CH2-1¢), 32.25 (CH2-4), 26.83 [C(CH3)3-TBDPS], 21.04
(CH3O), 19.06 [C(CH3)3-TBDPS).
IR (NaCl, neat): 3435, 2933, 2858 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.66 (m, 4 H, CHo-Ph), 7.40 (m, 6
H, CHp,m-Ph), 6.95 (m, 2 H, H-3¢¢), 6.86 (m, 2 H, H-2¢¢), 4.30 (m, 2
H, H-1, H-4), 4.02 (m, 2 H, CH2OPh), 3.89 (m, 1 H, H-2), 3.81 (m,
1 H, H-2¢), 3.74 (m, 1 H, H-2¢), 2.44 (m, 1 H, H-5), 2.10 (m, 1 H, H-
1¢), 1.95 (m, 2 H, H-1¢, H-5), 1.05 (s, 9 H, t-C4H9-TBDPS).
13C NMR (100 MHz, CDCl3): d = 158.66, 156.28 (d, J = 237.3 Hz,
C-Ph-4¢¢), 154.70, 154.68 (d, J = 2.11 Hz, C-Ph-1¢¢), 135.56 (CHo-
Ph-TBDPS), 133.06 (C-Ph-TBDPS), 129.81 (CHm-Ph-TBDPS),
127.78 (CHp-Ph-TBDPS), 115.90, 115.79 (d, J = 10.6 Hz, CH-Ph-
H3¢), 115.71, 115.67 (d, J = 4.2 Hz, CH-Ph-H2¢), 82.72 (CH-2),
75.64 (CH-1), 72.02 (CH-4), 71.50 (CH2OPh), 61.35 (CH2-2¢),
37.16 (CH2-5), 31.73 (CH2-1¢), 26.80 [C(CH3)3-TBDPS), 19.06
[C(CH3)3-TBDPS].
MS (ESI+): m/z (%) = 559.22 ([M + Na]+, 100), 537.25 ([M + 1]+,
27), 459.20 ([M – Ph]+, 6), 321.25 (37).
HRMS (ESI+): m/z calcd for C31H38FO5Si: 537.2473; found:
537.2467.
28
Yield: 99%; yellow oil; Rf = 0.55 (30% EtOAc–hexane);
MS (ESI+): m/z (%) = 517.22 ([M + Na]+, 100), 495.24 ([M + 1]+,
[a]D20 +7.25 (c = 1.01, CHCl3).
35), 417.19 ([M – Ph]+, 21), 349.29 (3), 321.26 (10).
IR (NaCl, neat): 3070, 3050, 2956, 2931, 2857, 1740 cm–1.
HRMS (ESI+): m/z calcd for C29H36FO4Si: 495.2367; found:
495.2361.
1H NMR (400 MHz, CDCl3): d = 7.66 (m, 4 H, CHo-Ph), 7.39 (m, 6
H, CHp,m-Ph), 6.95 (m, 2 H, H-3¢¢), 6.84 (m, 2 H, H-2¢¢), 5.24 (m, 1
H, H-3), 4.24 (m, 1 H, H-5), 4.05 (m, 2 H, H-2, CH2OPh), 3.89 (m,
1 H, CH2OPh), 3.79 (m, 2 H, H-2¢), 2.50 (m, 1 H, H-1¢), 2.01 (s, 3
H, CH3O), 1.88 (m, 3 H, H-4 H-1¢), 1.04 (s, 9 H, t-C4H9-TBDPS).
7
Yield: 25 mg (56%); colorless oil; Rf = 0.74 (30% EtOAc–hexane);
[a]D22 –39.9 (c = 0.95, CHCl3).
13C NMR (100 MHz, CDCl3): d = 170.38 (C=O), 158.52, 156.15 (d,
J = 237.4 Hz, C-Ph-4¢¢), 154.89, 154.86 (d, J = 2.11 Hz, C-Ph-1¢¢),
135.55 (CHo-Ph-TBDPS), 133.79 (C-Ph-TBDPS), 129.59 (CHm-
Ph-TBDPS), 127.63 (CHp-Ph-TBDPS), 115.84, 115.63 (d, J = 21.2
Hz, CH-Ph-H3¢), 115.61, 115.56 (d, J = 5.6 Hz, CH-Ph-H2¢), 78.89
(CH-2), 75.41 (CH-3), 74.62 (CH-5), 71.11 (CH2OPh), 60.92 (CH2-
2¢), 36.25 (CH2-1¢), 32.03 (CH2-4), 26.84 [C(CH3)3-TBDPS), 21.03
(CH3O), 19.19 [C(CH3)3-TBDPS).
IR (NaCl, neat): 3435, 2933, 2858 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.65 (m, 4 H, CHo-Ph), 7.41 (m, 6
H, CHp,m-Ph), 6.94 (m, 2 H, H-3¢¢), 6.85 (m, 2 H, H-2¢¢), 4.61 (m, 1
H, H-1), 4.48 (m, 1 H, H-4), 4.06 (m, 1 H, H-2), 3.99 (m, 1 H,
CH2OPh), 3.93 (m, 1 H, CH2OPh), 3.80 (m, 1 H, H-2¢), 3.65 (m, 1
H, H-2¢), 2.20 (m, 1 H, H-5), 2.12 (m, 2 H, H-1¢, H-5), 1.96 (m, 1 H,
H-1¢), 1.06 (s, 9 H, t-C4H9-TBDPS).
13C NMR (100 MHz, CDCl3): d = 158.50, 156.13 (d, J = 238.8 Hz,
C-Ph-4¢¢), 155.05, 155.03 (d, J = 2.8 Hz, C-Ph-1¢¢), 135.55 (CHo-
Ph-TBDPS), 132.57 (C-Ph-TBDPS), 129.97 (CHm-Ph-TBDPS),
127.80 (CHp-Ph-TBDPS), 115.81, 115.68 (d, J = 12.7 Hz, CH-Ph-
H3¢) 115.60, 115.58 (d, J = 2.11 Hz, CH-Ph-H2¢), 82.88 (CH-2),
75.55 (CH-1), 72.84 (CH-4), 71.09 (CH2OPh), 61.18 (CH2-2¢),
MS (ESI+): m/z (%) = 559.23 ([M + Na]+, 100), 537.24 ([M + 1]+,
74), 459.20 ([M – Ph]+, 56), 321.25 (16).
HRMS (ESI+): m/z calcd for C31H38FO5Si: 537.2473; found:
537.2467.
Synthesis 2010, No. 22, 3883–3890 © Thieme Stuttgart · New York

3890
C. Álvarez et al.
PAPER
(8) Nitta, K.; Stadelmann, R. J.; Eugster, C. H. Helv. Chim. Acta
1977, 60, 1747.
(9) (a) Eugster, C. H.; Müller, G. Helv. Chim. Acta 1959, 42,
1189. (b) List, H. P.; Müller, H. Arch. Pharm. 1959, 292,
777. (c) Catalformo, P.; Eugster, C. H. Helv. Chim. Acta
1970, 53, 848. (d) Bollinger, H.; Eugster, C. H. Helv. Chim.
Acta 1971, 54, 1332.
(10) (a) Popsavin, V.; Popsavin, M.; Radic, L.; Beric, O.; Cirin-
Novta, V. Tetrahedron Lett. 1999, 40, 9305. (b) Kang, K.
H.; Cha, M. Y.; Pae, A. N.; Choi, K. L.; Cho, Y. S.; Koh, H.
Y.; Chung, B. Y. Tetrahedron Lett. 2000, 41, 8137.
(c) Hartung, J.; Kneuer, R. Tetrahedron: Asymmetry 2003,
14, 3019.
(11) (a) Gurjar, M. K.; Murugaiah, A. M. S.; Radhakrishna, P.;
Ramana, C. V.; Chorghade, M. S. Tetrahedron: Asymmetry
2003, 14, 1363. (b) Sharma, G. V. M.; Punna, S.;
Rajendra Prasad, T.; Krishna, P. R.; Chorgade, M. S.; Ley,
S. V. Tetrahedron: Asymmetry 2005, 16, 1113. (c) Sharma,
G. V. M.; Punna, S.; Krishna, P. R.; Chorghade, M. S.; Ley,
S. V. Tetrahedron: Asymmetry 2005, 16, 1125.
(12) (a) Fall, Y.; Vidal, B.; Alonso, D.; Gómez, G. Tetrahedron
Lett. 2003, 44, 4467. (b) Pérez, M.; Canoa, P.; Gómez, G.;
Terán, C.; Fall, Y. Tetrahedron Lett. 2004, 45, 5207.
(c) Alonso, D.; Pérez, M.; Gómez, G.; Covelo, B.; Fall, Y.
Tetrahedron 2005, 61, 2021. (d) Teijeira, M.; Suárez, P. L.;
Gómez, G.; Terán, C.; Fall, Y. Tetrahedron Lett. 2005, 46,
5889. (e) García, I.; Gómez, G.; Teijeira, M.; Terán, C.; Fall,
Y. Tetrahedron Lett. 2006, 47, 1333. (f) Canoa, P.; Pérez,
M.; Covelo, B.; Gómez, G.; Fall, Y. Tetrahedron Lett. 2007,
48, 3441.
Acknowledgment
This work was financially supported by the Spanish Ministry of
Education and Science (CTQ2007-61788) and the Xunta de Galicia
(INCITE08PXIB314253PR,
INCITE08PXIB314255PR). The NMR and MS services of the Uni-
versity of Vigo (CACTI) are also gratefully acknowledged. Manuel
Pérez thanks the Xunta de Galicia for an Angeles Alvariño contract.
INCITE08ENA314019ES
and
References
(1) Capon, R. J.; Barrow, R. A.; Rochfort, S.; Jobling, M.;
Skene, C.; Lacey, E.; Gill, J. H.; Friedl, T.; Wadsworth, D.
Tetrahedron 1998, 54, 2227.
(2) Warren, R. G.; Wells, R. J.; Blount, J. F. Aust. J. Chem.
1980, 33, 891.
(3) (a) Gadikota, R. R.; Callam, C. S.; Lowary, T. L. J. Org.
Chem. 2001, 66, 9046. (b) Nesbitt, C. L.; McErlean, C. S. P.
Tetrahedron Lett. 2009, 50, 6318; and references cited
therein.
(4) Suzuki, T.; Koizumi, K.; Suzuki, M.; Kurosawa, E. Chem.
Lett. 1983, 1643.
(5) Suzuki, T.; Koizumi, K.; Suzuki, M.; Kurosawa, E. Chem.
Lett. 1983, 1639.
(6) (a) Brown, M. J.; Harrison, T.; Overman, L. E. J. Am. Chem.
Soc. 1991, 113, 5378. (b) Grese, T. A.; Hutchinson, K. D.;
Overman, L. E. J. Org. Chem. 1993, 58, 2468. (c) Osumi,
K.; Sugimura, H. Tetrahedron Lett. 1995, 36, 5789.
(d) Lee, E.; Yoo, S.-K.; Cho, Y.-S.; Cheon, H.-S.; Chong, Y.
H. Tetrahedron Lett. 1997, 38, 7757. (e) Boukouvalas, J.;
Fortier, G.; Radu, I.-I. J. Org. Chem. 1998, 63, 916.
(f) Evans, P. A.; Murthy, V. S.; Roseman, J. D.; Rheingold,
A. L. Angew. Chem. Int. Ed. 1999, 38, 3175. (g) Braddock,
D. C.; Bhuva, R.; Millan, D. S.; Pérez-Fuentes, Y.; Roberts,
C. A.; Sheppard, R. N.; Solanki, S.; Stokes, E. S. E.; White,
A. J. P. Org. Lett. 2007, 9, 445.
(7) (a) Eugster, C. H. Helv. Chim. Acta 1956, 39, 1002.
(b) Kögl, F.; Salemink, C. A.; Schouten, H.; Jellinek, F.
Recl. Trav. Chim. Pays Bas 1957, 76, 109. (c) Eugster, C.
H. Naturwissenschaften 1968, 55, 305. (d) Bollinger, H.;
Eugster, C. H. Helv. Chim. Acta 1971, 54, 2704.
(13) Hanessian, S.; Tehim, A.; Chen, P. J. Org. Chem. 1993, 58,
7768.
(14) Hanessian, S.; Ugolini, A.; Dubé, D.; Glamyan, A. Can. J.
Chem. 1984, 62, 2146.
(15) Kumara Swamy, K. C.; Bhuvan Kumar, N. N.; Balaraman,
E.; Pavan Kumar, K. V. P. Chem. Rev. 2009, 109, 2551.
(16) Canoa, P.; Vega, N.; Pérez, M.; Gómez, G. Tetrahedron
Lett. 2008, 49, 1149.
Synthesis 2010, No. 22, 3883–3890 © Thieme Stuttgart · New York