Synthesis of tetrahydrofurans through a novel pseudo-meso-trick

Article abstract of DOI:10.1055/s-2005-869840

Diastereoselective synthesis of trisubstituted tetrahydrofuran (D-lyxo-4) from the equimolar diastereomeric mixture of D-erythro-/D-threo-1-pentenitols (1) is described. The synthesis exploits a sequence of two novel reactions: diastereospecific palladium

Full text of DOI:10.1055/s-2005-869840

LETTER
1609
Synthesis of Tetrahydrofurans through a Novel Pseudo-meso-trick
Synthesisof
T
etrahydr
a
ofurans tej Babjak, L’uboš Remeň, Ol’ga Karlubíková, Tibor Gracza*
Department of Organic Chemistry, Slovak University of Technology, Radlinského 9, 812 37 Bratislava, Slovak Republic
E-mail: tibor.gracza@stuba.sk
Received 30 March 2005
OH
O
O
Abstract: Diastereoselective synthesis of trisubstituted tetrahydro-
furan (D-lyxo-4) from the equimolar diastereomeric mixture of D-
erythro-/D-threo-1-pentenitols (1) is described. The synthesis ex-
ploits a sequence of two novel reactions: diastereospecific palladi-
um(II)-catalyzed bicyclization of pentenitols 1 with degeneration of
the allylic stereogenic center and subsequent regioselective ring-
opening of bicyclic skeleton 2.
[I+]
I
I
+
HO
HO
OBn
HO
OBn
OBn
D-xylo-4
(cis)
D-threo-1
D-lyxo-4
(trans)
11:1
Scheme 1
Key words: palladium, catalysis, stereoselective synthesis, cy-
clizations, diastereoselectivity
Our synthesis commences from the equimolar diastereo-
meric mixture of pentenetriols 1, readily available from D-
Methods for the preparation of substituted oxygen hetero- glyceraldehyde.6 The first step is the palladium(II)-cata-
cycles have attracted considerable attention since furan lyzed bicyclization of 1, see Scheme 2.
and pyran substructures have been found in polyether an-
tibiotics and other biologically active natural products.1
As a part of our ongoing project aimed at the application
of palladium(II)-catalyzed cyclizations in the natural
product synthesis,2 we required a versatile method for the
stereoselective construction of substituted tetrahydro-
furans with trans-relationship at C2–C3. Our previous
work showed that unsaturated polyols undergo Pd(II)-
catalyzed intramolecular oxycarbonylation with high
chemo-, regio- and stereoselectivity.3 The process is
characterized by excellent threo-selectivity concerning
the newly formed stereogenic center with respect to the
configuration at the allylic carbon. Thus, the tetrahydro-
furanyl lactones with cis-arrangement of C2–C3 substi-
tuents are served.
O
OH
5
2
5
PdCl2, CuCl2
2
3
3
4
1
4
HO
1
AcONa, AcOH
79%
OBn
OBn
O
2
D-erythro-1/D-threo-1
(1:1)
Scheme 2
The reaction was carried out using palladium(II) chloride
as catalyst (0.1 equiv), copper(II) chloride as reoxidant (3
equiv) and sodium acetate (3 equiv) in acetic acid as buff-
er at room temperature. This new type of Pd(II)-initiated
bicyclization of diastereomeric alkenols 1 furnished bicy-
clic anhydroalditol 2 as the sole product in 79% yield. The
structure of 1,4:2,5-dianhydro-3-O-benzyl-D-lyxitol (2)
was established by comparison of NMR data and specific
rotation value {[a]D20 +48.5} with the reported data for 24
{[a]D25 +50.5} and for its enantiomer7 {[a]D20 –48.1}, re-
spectively, which were prepared by alkaline treatment of
both D-lyxo-4 and 1,4-anhydro-2-O-tosyl-3-O-benzyl-L-
xylitol to confirm their absolute configurations.
Herein, we present the stereoselective two-step synthesis
of
3-O-benzyl-1-deoxy-1-iodo-2,5-anhydro-D-lyxitol
[(3R,4S,5S)-4-benzyloxy)-5-iodomethyltetrahydrofuran-
3-ol] (D-lyxo-4) from the equimolar diastereomeric mix-
ture of D-erythro-/D-threo-1-pentenitols (1).
To the best of our knowledge, there is only one paper4 in
the literature, which describes the formation of D-lyxo-4.
However, it has been reported as a minor product of the
iodocyclization of diastereomerically pure D-threo-1-pen-
tenitol (D-threo-1) along with the formation of major D-
xylo diastereomer (D-xylo-4) in a ratio of 11:1 (Scheme 1).
Most intriguing features of this transformation are: (i) dia-
stereospecific generation of a new stereocentre at C2 with
cis-arrangement according to hydroxyl group at C4 and
(ii) because of C2-symmetry of skeleton 2 degeneration of
the existing allylic stereogenic center of triols 1 at position
C3 occurred (Figure 1).
Generally, halogen-induced cycloetherifications of alken-
ols with allylic-O functionality prefer 5-exo cyclization to
form a tetrahydrofuran skeleton with cis-arrangement of
C2–C3 substituents5 due to the stereoelectronic effects.
C2
3
BnO
2
exo
1
O
endo
Nu
Nu
4
O
5
SYNLETT 2005, No. 10, pp 1609–1611
Advanced online publication: 12.05.2005
1
7
.0
6
.2
0
0
5
2
DOI: 10.1055/s-2005-869840; Art ID: G11005ST
© Georg Thieme Verlag Stuttgart · New York
Figure 1

1610
M. Babjak et al.
LETTER
Table 1 Ring-Opening of 1,4:2,5-Dianhydro-3-O-benzyl-D-lyxitol (2)
Entry
1
Reaction conditions
Yield (product, %)
D-lyxo:D-arabinoa
Sat. HBr, AcOH, Ac2O, 0 °C, 30 min
42 (D-lyxo-3)
1:1
47 (D-arabino-3)
2
3
4
5
BF3·OEt2 (1 equiv), TBAI (1 equiv), CHCl3, r.t., 3 d
Concd HCl, TBAI (1 equiv), CH2Cl2, r.t., 7 d
–
–
6:1
24 (D-lyxo-4)
59 (D-lyxo-4)
74 (D-lyxo-4)
TMSCl (1 equiv), NaI (1.5 equiv), MeCN, 0 °C, 90 min
TMSCl (1.1 equiv), TBAI (2.1 equiv), concd HCl, CH2Cl2, r.t., 28 h
8:1
10:1
a Determined by HPLC analysis of crude reaction mixture.
Thus, the enantiomerically pure bicyclic compound 2 is clization of triols 1 to furnish enantiomerically pure 2. The
formed by stereoconvergent reaction of diastereomeric configuration at C4 of 1 introduces a new stereocenter in
mixture (1:1) of triols 1.
2 in threo fashion along with concomitant degeneration of
allylic stereogenic center of an alkene. Regioselective
ring-opening of bicycle 2 provides a diastereomer D-lyxo-
4, a useful chiron.
Subsequent regioselective ring-opening of bicycle 2
should lead to one of both diastereomeric tetrahydro-
furans. Firstly, the addition of sat. HBr in acetic acid8 at
different reaction temperatures was examined. In all cases
both diastereomeric bromides D-lyxo-3 and D-arabino-3
as products of ring-opening were obtained in good yields
(68–89%), albeit with no regioselectivity (Scheme 3,
Table 1, entry 1). While the use of tetrabutylammonium
iodide with BF3·OEt2 failed (entry 2), the presence of con-
centrated HCl furnished both furan derivatives D-lyxo-4
and D-arabino-4 in a ratio 6:1, however, in a poor yield
1,4:2,5-Dianhydro-3-O-benzyl-D-lyxitol [(1R,4R)-7-benzyloxy-
2,5-dioxabicyclo[2.2.1]heptane] (2)
A 25 mL flask was charged with triols 1 (166 mg, 0.8 mmol), PdCl2
(10 mg, 0.06 mmol), AcONa (196 mg, 2.4 mmol), CuCl2 (320 mg,
2.4 mmol) and glacial acetic acid (8 mL) under argon atmosphere.
The green mixture was stirred at r.t. for 12 h, then diluted with Et2O
(20 mL), filtered through Celite® 2 × 1 cm pad and washed several
(24%, entry 3). Comparable selectivity but better yield of times with EtOAc (15 mL). Collected filtrates were concentrated in
4 (59%, entry 4) was obtained by treatment of 2 with tri-
vacuo and the residue was partitioned between EtOAc (30 mL) and
10% aq NaHCO3. After phase separation, the water layer was ex-
methylsilyl chloride/NaI in acetonitrile at 0 °C. The best
tracted with EtOAc, combined extracts were dried over anhyd
result in terms of yield and diastereoselectivity was
K2CO3 and concentrated. Pale green crude oil was purified by
Kugelrohr distillation under reduced pressure (180 °C, 0.05 Torr).
achieved using TMSCl/TBAI/HCl in CH2Cl2 at r.t. (74%,
82% de, entry 5). In all cases (except entry 1), D-lyxo-4
was formed as a major product via exo-attack of the nu-
cleophile to 2 due to the steric hindrance between the
bulky reagent and the benzyloxy group. The NMR data as
well as specific rotation value {[a]D20 +6.4} were in good
Title compound was isolated as exclusive product of reaction as a
colorless oil (130 mg, 79%).
25
Compound 2: Rf = 0.55 (50% EtOAc in hexanes); [a]D +48.5 (c
0.16, CH2Cl2) {lit.5 [a]D25 +50.5 (1.35, CHCl3); for enantiomer of 2
20
lit.7 [a]D –48.1 (c 1.43, CHCl3)}. IR (neat): n = 3005 (m), 2947
25
agreement with the reported data4 for D-lyxo-4 {[a]D
(m), 2882 (m), 1726 (m), 1497 (m), 1454 (m), 1363 (m), 1334 (m),
1292 (m), 1275 (m), 1235 (m), 1211 (m), 1176 (m), 1128 (s), 1068
(s), 1030 (s), 1003 (m), 951 (m), 885 (m), 856 (s), 700 (m) cm–1.
Anal. Calcd for C12H14O3 (206.2): C, 69.88; H, 6.84. Found: C,
69.96; H, 6.94. NMR data of isolated 2 were in full accordance with
lit.5,7
+7.8}. No debenzylation was observed under this reaction
conditions, although in situ generated TMSI is known as
an efficient benzylether cleaving agent.9
X
X
O
O
[X–]
4-O-Acetyl-3-O-benzyl-1-deoxy-1-bromo-2,5-anhydro-D-lyxi-
tol [(3R,4S,5S)-4-Benzyloxy-5-bromomethyltetrahydrofuran-3-
yl Acetate] (D-lyxo-3) and 4-O-Acetyl-3-O-benzyl-1-deoxy-1-
bromo-2,5-anhydro-D-arabitol [(3R,4R,5S)-4-Benzyloxy-5-bro-
momethyltetrahydrofuran-3-yl Acetate] (D-arabino-3)
The bicyclic derivative 2 (60 mg, 0.29 mmol) and Ac2O (0.1 mL, 1
mmol) were cooled to 0 °C and sat. HBr in HOAc (1 mL) was add-
ed. The mixture was stirred for 30 min at 0 °C under TLC control,
H2O (5 mL) was added after full conversion of substrate and the so-
+
2
OBn
OBn
RO
RO
D-lyxo-3 (R = Ac, X = Br)
D-lyxo-4 (R = H, X = I)
D-arabino-3 (R = Ac, X = Br)
D-arabino-4 (R = H, X = I)
Scheme 3
In conclusion, we have worked out a new two-step synthe- lution was extracted with CH2Cl2 (3 × 10 mL). Combined organic
extracts were dried over MgSO4 and concentrated. The crude oil
sis of 2,3,4-trisubstituted tetrahydrofurans with trans-re-
was purified by flash chromatography (9% EtOAc in hexanes). The
lationship of C2–C3 substituents from the equimolar
fractions with Rf = 0.69 (33% EtOAc in hexanes) contained D-lyxo-
diastereomeric mixture of D-erythro-/D-threo-1-penteni-
3 isomer, fractions with Rf = 0.60 (33% EtOAc in hexanes) con-
tols (1) through a novel pseudo-meso-trick. The goal of
tained D-arabino-3, and both isomers were isolated as colorless oils
the synthesis is a diastereospecific Pd(II)-catalyzed bicy-
(D-lyxo-3: 40 mg, 42%; D-arabino-3: 45 mg, 47%).
Synlett 2005, No. 10, 1609–1611 © Thieme Stuttgart · New York

LETTER
Synthesis of Tetrahydrofurans
1611
25
D-lyxo-3: [a]D +17.6 (c 0.29, CHCl3). 1H NMR (300 MHz,
CDCl3): d = 2.09 (s, 3 H, Ac), 3.42 (dd, 1 H, J1A,2 = 6.8 Hz,
J1A,1B = 10.5 Hz, H-1A), 3.46 (dd, 1 H, J1B,2 = 5.8 Hz, J1A,1B = 10.5
Hz, H-1B), 3.97 (ddd, 1 H, J2,3 = 3.4 Hz, J3,4 = 1.1 Hz, J3,5A = 0.9
Hz, H-3), 4.02 (br d, 1 H, J5A,5B = 10.5 Hz, H-5A), 4.11 (dd, 1 H,
J4,5B = 4.0 Hz, J5A,5B = 10.5 Hz, H-5A), 4.11 (m, 1 H, J1A,2 = 6.8 Hz,
H-2), 4.63, 4.73 (2 × d, 2 H, JA,B = 11.7 Hz, Bn), 5.21 (ddd, 1 H,
J4,5B = 4.0 Hz, J4,5A = 1.3 Hz, J3,4 = 1.1 Hz, H-4), 7.29–7.38 (m, 5 H,
Bn). 13C NMR (75 MHz, CDCl3): d = 21.0 (Ac), 31.8 (C-1), 72.1
(Bn), 72.3 (C-5), 77.9 (C-4), 3.5 (C-2), 85.4 (C-3), 127.9, 128.0,
128.5 (Bn), 137.3 (Bn), 170.2 (Ac). Anal. Calcd for C14H17BrO4
(329.2): C, 51.08; H, 5.21. Found: C, 50.96; H, 5.14.
Acknowledgment
We are grateful to Dr. Szolcsányi for the help with the manuscript
preparation. This work was supported by Slovak Grant Agencies
(VEGA, Slovak Academy of Sciences and Ministry of Education,
Bratislava, project No. 1/7314/20, and APVT, Bratislava, project
No. APVT-20-010702).
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1
D-arabino-3: H NMR (300 MHz, CDCl3): d = 2.08 (s, 3 H, Ac),
3.50 (dd, 1 H, J1A,2 = 7.3 Hz, J1A,1B = 10.3 Hz, H-1A), 3.61 (dd, 1 H,
J1B,2 = 4.7 Hz, J1A,1B = 10.3 Hz, H-1B), 3.97 (br d, 1 H, J4,5A = 4.3
Hz, J5A,5B = 10.0 Hz, H-5A), 4.05 (dd, 1 H, J4,5B = 5.6 Hz,
J5A,5B = 10.0 Hz, H-5B), 4.25 (m, 2 H, J1B,2 = 4.7 Hz, J1A,2 = 7.3 Hz,
H-2, H-3), 4.56, 4.67 (2 × d, 2 H, JA,B = 11.3 Hz, Bn), 5.36 (dd, 1 H,
J4,5A = 4.3 Hz, J4,5B = 5.6 Hz, H-4), 7.30–7.41 (m, 5 H, Bn). 13C
NMR (75 MHz, CDCl3): d = 20.9 (Ac), 31.0 (C-1), 69.6 (Bn), 72.3
(C-2), 74.0 (C-5), 78.1 (C-4), 79.8 (C-3), 127.8, 128.0, 128.5 (Bn),
137.4 (Bn), 170.4 (Ac). Anal. Calcd for C14H17BrO4 (329.2): C,
51.08; H, 5.21. Found: C, 51.18; H, 5.17.
3-O-Benzyl-1-deoxy-1-iodo-2,5-anhydro-D-lyxitol [(3R,4S,5S)-
4-Benzyloxy-5-iodomethyltetrahydrofuran-3-ol] (D-lyxo-4)
Bicyclic derivative 2 (100 mg, 0.49 mmol), TMSCl (58 mg, 0.53
mmol), tetrabutylamonium iodide (337 mg, 1.03 mmol) and aq
concd HCl (150 mL) were stirred in CH2Cl2 (1.5 mL) at r.t. for 28 h.
The mixture was diluted with CH2Cl2 (10 mL), washed with H2O (3
mL), then with aq solution of Na2S2O3 (10%, 5 mL). Organic phase
was dried over MgSO4 and concentrated. Crude oil was purified by
flash chromatography (17% EtOAc in hexanes). Pure D-lyxo-4 was
isolated as colorless oil (121 mg, 74%), along with inseparable mix-
ture of 2 and D-arabino-4 (10 mg). HPLC analysis of crude product
mixture determined ratio D-lyxo-4/D-arabino-4 10:1 (Separon SGX
Si 100 column, 1 mL/min, 50% EtOAc in n-hexane).
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F. Vieweg & Sohn Verlagsgesellschaft: Braunschweig,
Wiesbaden, 1997, 321. (b) Gracza, T.; Hasenöhrl, T.; Stahl,
U.; Jäger, V. Synthesis 1991, 1108.
25
D-lyxo-4: Rf = 0.58 (50% EtOAc in hexanes); [a]D +6.4 (c 0.39,
CHCl3), {lit.4 [a]D +7.8 (c 1.46, CHCl3)}. Anal. Calcd for
25
C12H15IO3 (334.2): C, 43.13; H, 4.52. Found: C, 43.26; H, 4.56.
NMR data of isolated D-lyxo-4 as well as of minor D-arabino-4
were in full accordance with lit.4
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Synlett 2005, No. 10, 1609–1611 © Thieme Stuttgart · New York