A general method for the highly regioselective introduction of substituents into the 3-position of 5-unsubstituted 4-O-alkyl tetronates

Article abstract of DOI:10.1055/s-2005-918915

A new, general method for the highly regioselective introduction of substituents into the 3-position of 5-unsubstituted 4-O-alkyl tetronates has been developed. 3-Lithiated 4-alkoxy-2-triisopropylsilyloxyfurans generated from the corresponding 3-iodoprecursors via halogen-metal exchange serve as key intermediates. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918915

LETTER
2735
A General Method for the Highly Regioselective Introduction of Substituents
into the 3-Position of 5-Unsubstituted 4-O-Alkyl Tetronates
Tetronates ranz F. Paintner,* Lars Allmendinger, Gerd Bauschke
Department Pharmazie – Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, Haus C,
81377 München, Germany
Fax +49(89)218077247; E-mail: franz.paintner@cup.uni-muenchen.de
Received 22 August 2005
Dedicated to Prof. Dr. Klaus Görlitzer on the occasion of his 65th birthday.
Abstract: A new, general method for the highly regioselective in-
troduction of substituents into the 3-position of 5-unsubstituted 4-
O-alkyl tetronates has been developed. 3-Lithiated 4-alkoxy-2-tri-
isopropylsilyloxyfurans generated from the corresponding 3-iodo-
precursors via halogen–metal exchange serve as key intermediates.
Key words: tetronates, iodination, lithiation, regioselectivity,
furans
5-Unsubstituted 4-O-alkyl tetronates (4-alkoxy-5H-furan-
2-ones) 1 bearing an alkyl or acyl group at C-3 serve as
versatile building blocks in natural product synthesis as
Scheme 1
well as for the construction of complex heterocyclic scaf-
folds in general.1 Probably, the most direct approach to
compounds 1 is the regioselective alkylation or acylation
deuterated methanol followed by phosphate buffer pH 5.5
of an appropriate 5-unsubstituted 4-O-alkyl tetronate
led to C-3 mono-deuterated tetronate (2H)-6a in high
building block (Scheme 1).2 To date, however, little work
yields containing >95% deuterium (Scheme 2).8 Neither
has been directed toward this goal. Ley et al. reported the
deuterium incorporation at C-5 of (2H)-6a nor formation
direct palladium-catalyzed acylation of 3-tributylstannyl
4-O-methyl tetronate (3) with a variety of acid chlorides
to afford the corresponding 3-acyl tetronates in reasonable
of C-5 deuterated 3-iodo tetronate 7a, indicating a com-
peting deprotonation of 8a at C-5,9 was observed.
to good yields.3 Preliminary attempts, conducted in the
same laboratory, to regioselectively acylate the 3-lithiated
dianion 2 failed and were not pursued further.4–6 More re-
cently, we have introduced the chelation-controlled C-3
selective hydroxyalkylation of boron 4-methoxy-2-fura-
nolates 4 with aldehydes leading to 3-acyl tetronates after
oxidation of the intermediate alcohols.7 This method,
however, although highly regioselective and good yield-
ing, is essentially restricted to aliphatic aldehydes and
thus limited in scope.
As depicted in Scheme 2, the 3-iodo-substituted precur-
sors 8a and 8b could be obtained in two steps from the
readily available 4-O-alkyl tetronates 6a10 and 6b,11 re-
spectively. First, C-3-selective iodination of the tetronates
6 has to be achieved. To the best of our knowledge, to date
there is only one report in the literature concerning the io-
dination of 4-O-alkyl tetronates: Campos et al. described
We now report a new, general and highly efficient method
for the regioselective introduction of a wide variety of
substituents into the C-3 position of 5-unsubstituted 4-O-
alkyl tetronates involving 3-lithiated 2-triisopropylsilyl-
oxyfurans 5 as key intermediates. These intermediates
were envisioned to arise from 4-alkoxy-3-iodo-2-triiso-
propylsilyloxyfurans 8 via a halogen–metal exchange. In-
deed, treatment of compound 8a with either 1.1
equivalents of n-BuLi or 2.0 equivalents of t-BuLi in THF
at –78 °C for 15 minutes and subsequent quenching with
Scheme 2 Reagents and conditions: (a) I2 (4.0 equiv), pyridine (1.0
equiv), DMF, r.t. (7a: 86%; 7b: 80%); (b) TIPSOTf, Et3N, CH2Cl2,
0 °C (8a: 95%; 8b: 91%); (c) n-BuLi (1.1 equiv) or t-BuLi (2.0
equiv), THF, –78 °C; (d) i) CD3OD, –78 °C; ii) phosphate buffer pH
5.5 (quant.; >95% 2H).
SYNLETT 2005, No. 18, pp 2735–2738
Advanced online publication: 10.10.2005
DOI: 10.1055/s-2005-918915; Art ID: D24505ST
© Georg Thieme Verlag Stuttgart · New York
0
3
.1
1
.2
0
0
5

2736
F. F. Paintner et al.
LETTER
the reaction of compound 6a with bis(pyridine)iodoni- propylsilyloxyfurans 8a and 8b were then generated in
um(I) tetrafluoroborate (IPy2BF4) in the presence of two high yields (95% and 91%, respectively) by treatment of
equivalents of triflic acid to give iodide 7a in a 54% the corresponding tetronates 7 with triisopropylsilyl tri-
yield.12 We found that simple treatment of 4-O-alkyl fluoromethanesulfonate (TIPSOTf) in the presence of
tetronates with excess iodine (4.0 equiv) and 1.0 equiva- triethylamine (CH2Cl2, 0 °C).14
lents of pyridine in DMF at room temperature is a much
cheaper and even more efficient alternative. In this way 3-
iodo tetronates 7a and 7b were obtained in 86% and 80%
Starting from the 3-iodofurans 8a and 8b, a number of 3-
substituted tetronates 1 were prepared. The lithiated inter-
mediates 5 were generated as described above and then re-
yield, respectively, from the corresponding 3-unsubstitut-
acted with a variety of carbon-, sulfur- and silicon-
ed tetronates 6.13 Somewhat lower yields were observed in
centered electrophiles (1.1–2.0 equiv, –78 °C to r.t.).15
The results are summarized in Table 1. In the case of
the absence of pyridine. The 3-iodo-substituted 2-triiso-
Table 1 Reaction of 3-Lithiated 4-Alkoxy-2-Triisopropylsilyloxyfuranes 5 with Various Electrophiles
Entry
Iodide
8a
Electrophile
Product
1a17
1b
R
E
Yield (%)a
1
2
3
4
5
6
MeI (2.0 equiv)
Me
Bn
Bn
Me
Me
Bn
Me
92
91
82
85
88
57
8b
MeI (2.0 equiv)
Me
8b
n-C12H25I (2.0 equiv)
CH2=CHCH2Br (2.0 equiv)
BnBr (2.0 equiv)
1c
n-C12H25
CH2=CHCH2
Bn
8a
1d
8a
1e17
1f
8b
(2.0 equiv)
(1.1 equiv)
7
8a
8b
1g7
1h
Me
Bn
84
70
8b
(1.1 equiv)
(1.1 equiv)
(1.25 equiv)
9c
10c
11
8a
8a
8a
1i3,7
Me
Me
Me
62
44
70
1j
1k
PhS
(1.1 equiv)
TMSCl (1.25 equiv)
12b
8a
1l
Me
TMS
91
a Yield of isolated, purified product base on 8.
b n-BuLi (1.1. equiv) was used for halogen–metal exchange.
c Reactions were run at –78 °C.
Synlett 2005, No. 18, 2735–2738 © Thieme Stuttgart · New York

LETTER
Tetronates
2737
(6) For the regioselective deprotonation of 5-monoalkyl-
primary alkyl iodides, allyl bromide and benzyl bromide
high yields of the corresponding 3-alkylation products
were obtained (entries 1–5). Even with an epoxide the
result was satisfactory (entry 6). Reactions with both ali-
phatic and aromatic aldehydes proceeded smoothly to af-
ford the corresponding 3-hydroxyalkylation products in
good yields (entries 7, 8). This is particularly remarkable,
since product 1g had hardly been accessible with our
previously reported boron furanolate-based 3-hydroxy-
alkylation method.7 3-(1-Hydroxyalkyl) tetronates, e.g.
1g, are known to be readily oxidized with various reagents
such as IBX7 or MnO216 to give the corresponding 3-acyl
tetronates. However, 3-acyl tetronates are also directly
accessible from intermediates 5 by reaction with acid
chlorides at –78 °C (entry 9). Analogously, the benzyl-
oxycarbonyl derivative 1j was obtained by reaction with
benzyl cyanoformate albeit in only a moderate yield
(entry 10). Finally, intermediate 5a was trapped with
heteroatom-centered electrophiles. In this way the 3-phe-
nylthio derivative 1k was prepared by reaction with N-
phenylthiophthalimide (entry 11), while the 3-silylated
tetronate 1l could be readily obtained by treatment with
trimethylsilyl chloride (entry 12).
substituted 4-O-methyl tetronates at C-3 under kinetically
controlled conditions and subsequent trapping of the 3-
lithiated intermediates with electrophiles, see: Miyata, O.;
Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1982, 21, 637.
(7) Paintner, F. F.; Allmendinger, L.; Bauschke, G. Synthesis
2001, 2113.
(8) Quenching the reaction with deuterated MeOH followed by
phosphate buffer (pH 7.5) led to a mixture of (2H)-6a and 3-
deuterated 4-methoxy-2-triisopropylsilyloxyfuran. Our
attempts to isolate the 2-triisopropylsilyloxyfuran by
chromatography failed due to rapid hydrolysis to the
corresponding tetronate (2H)-6a. This is in accordance with
previous findings showing 4-O-alkyl 2-trialkylsilyloxy-
furans to be very prone to hydrolysis (ref. 5).
(9) The facile deprotonation of 2-alkoxy- or 2-trialkylsilyloxy
furans in 5-position with t-BuLi at low temperature has
previously been reported, see for example: (a) Kraus, G. A.;
Sugimoto, H. J. Chem. Soc., Chem. Commun. 1978, 30.
(b) Jefford, C. W.; Rossier, J.-C.; Boukouvalas, J.; Huang, P.
Helv. Chim. Acta 1994, 77, 661.
(10) 4-O-Methyl tetronate (6a) is commercially available, e.g.
from Acros Organics BVBA, Janssen Pharmaceuticalaan 3a,
B-2440 Geel, Belgium
(11) Paintner, F. F.; Allmendinger, L.; Bauschke, G. Synlett
2003, 83.
(12) Campos, P. J.; Tan, C.-Q.; Rodríguez, M. A. Tetrahedron
Lett. 1995, 36, 5257.
In conclusion, we have developed a new, general and
efficient method for the regioselective introduction of a
wide variety of substituents into the 3-position of 5-un-
substituted 4-O-alkyl tetronates.
(13) Typical Procedure.
A solution of iodine (10.15 g, 40 mmol) in DMF (20 mL)
was added to an ice-cold solution of 6a (1.14 g, 10 mmol)
and pyridine (807 mL, 10 mmol) in DMF (20 mL). The
mixture was allowed to warm to r.t. and stirred under the
exclusion of light for 22 h, at which time it was poured into
sat. aq NaHCO3 (100 mL). The mixture was extracted with
CH2Cl2. The combined organic extracts were washed with
aq Na2S2O3 and H2O, dried (MgSO4) and evaporated under
reduced pressure. The resulting residue was recrystallized
from EtOAc to give 7a (2.06 g, 86%) as pale yellow crystals;
mp 158–160 °C. IR (KBr): 3001, 2950, 1732, 1643, 1621
cm–1. 1H NMR (500 MHz, CDCl3): d = 4.14 (s, 3 H), 4.81 (s,
2 H). 13C NMR (100 MHz, CDCl3): d = 50.5, 58.4, 68.4,
170.7, 178.5. Anal. Calcd for C5H5IO3: C, 25.02; H, 2.10; I,
52.88. Found: C, 25.01; H, 2.05; I, 52.84.
Acknowledgment
We are greatly indebted to Prof. Dr. Klaus T. Wanner for his
generous support.
References
(1) For some recent examples, see: (a) Padwa, A.; Kissell, W.
S.; Eidell, C. K. Can. J. Chem. 2001, 79, 1681. (b) Kende,
A. S.; Martin Hernando, J. I.; Milbank, J. B. J. Tetrahedron
2002, 58, 61. (c) Velázquez, F.; Olivo, H. F. Org. Lett. 2002,
4, 3175. (d) Paintner, F. F.; Allmendinger, L.; Bauschke, G.;
Polborn, K. Synlett 2002, 1308. (e) Brueggemann, M.;
McDonald, A. I.; Overman, L. E.; Rosen, M. D.; Schwink,
L.; Scott, J. P. J. Am. Chem. Soc. 2003, 125, 15284.
(f) Kemmler, M.; Herdtweck, E.; Bach, T. Eur. J. Org.
Chem. 2004, 4582. (g) Schobert, R.; Urbina-González, J. M.
Tetrahedron Lett. 2005, 46, 3657.
(2) For reviews on the synthesis and chemistry of tetronic acids,
see: (a) Pattenden, G. Fortschr. Chem. Org. Naturst. 1978,
35, 133. (b) Tejedor, D.; García-Tellado, F. Org. Prep.
Proced. Int. 2004, 36, 35.
(3) (a) Ley, S. V.; Wadsworth, D. J. Tetrahedron Lett. 1989, 30,
1001. (b) Ley, S. V.; Trudell, M. L.; Wadsworth, D. J.
Tetrahedron 1991, 47, 8285.
(14) Typical Procedure.
TIPSOTf (867 mL, 3.15 mmol) was slowly added to an ice-
cold solution of 7a (720 mg, 3.0 mmol) and Et3N (481 mL,
3.45 mmol) in CH2Cl2 (3 mL). After stirring for 1 h at 0 °C
the mixture was poured into ice-cold half-sat. aq NaHCO3
and extracted with Et2O. The combined organic extracts
were washed with ice-cold half-sat. aq NaHCO3 and brine,
dried (MgSO4) and evaporated under reduced pressure to
afford a mixture of 7a and 8a. To separate the product from
starting material the residue was dissolved in n-hexane,
filtered and evaporated under reduced pressure to leave 8a
(1.13 g, 95%, ≥ 97% pure as determined by 1H NMR
spectroscopy) as a pale yellow oil. 1H NMR (500 MHz,
CD2Cl2): d = 1.09 (d, J = 7.3 Hz, 18 H), 1.27 (sept, J = 7.3
Hz, 3 H), 3.68 (s, 3 H), 6.56 (s, 1 H).
(4) Wadsworth, D. J. PhD Thesis; Imperial College, University
of London: London, 1989.
(15) Typical Procedure.
A solution of t-BuLi (1.5 M in hexane, 666 mL, 1.0 mmol)
was added dropwise to a solution of 8a (198 mg, 0.5 mmol)
in THF (5 mL) at –78 °C. After stirring for 15 min at –78 °C,
benzyl bromide (121 mL, 1.0 mmol) was added. The reaction
mixture was stirred at –78 °C for 1 h and then was allowed
to warm to r.t. during 2 h. Phosphate buffer (pH 5.5, 5 mL)
was added and the resulting mixture was stirred for another
(5) Lithium 4-alkoxy 2-furanolates generated by deprotonation
of 5-unsubstituted 4-O-alkyl tetronates, e.g. 6a, have been
reported to react with electrophiles exclusively at C-5, see:
Pelter, A.; Al-Bayati, R. I. H.; Ayoub, M. T.; Lewis, W.;
Pardasani, P.; Hänsel, R. J. Chem. Soc., Perkin Trans. 1
1987, 717.
Synlett 2005, No. 18, 2735–2738 © Thieme Stuttgart · New York

2738
F. F. Paintner et al.
LETTER
HRMS: m/z calcd for C12H12O3 [M+]: 204.0787. Found:
30 min at r.t. before it was extracted with Et2O. The
combined organic extracts were dried (MgSO4) and
evaporated under reduced pressure. The resulting residue
was purified by flash chromatography (n-hexane–CH2Cl2–
Et2O, 20:20:60) to give 1e17 (90 mg, 88%) as a colorless oil.
1H NMR (500 MHz, CDCl3): d = 3.60 (s, 2 H), 3.93 (s, 3 H),
4.69 (s, 2 H). 13C NMR (100 MHz, CDCl3): d = 27.8, 57.7,
65.4, 102.7, 126.4, 128.3, 128.5, 139.1, 173.0, 174.6.
204.0774.
(16) Clemo, N. G.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1
1985, 2407.
(17) (a) Calam, C. T.; Todd, A. R.; Waring, W. S. Biochem. J.
1949, 45, 520. (b) Wengel, A. S.; Reffstrup, T.; Boll, P. M.
Tetrahedron 1979, 35, 2181.
Synlett 2005, No. 18, 2735–2738 © Thieme Stuttgart · New York