Diastereoselective synthesis of tetrahydrofurans via reaction of γ,δ-epoxycarbanions with aldehydes

Article abstract of DOI:10.1021/ol0509080

(Chemical Equation Presented) Hydroxymethyl-substituted tetrahydrofurans were prepared with high diastereoselectivity by reaction of the carbanion derived from 3,4-epoxybutyl phenyl sulfone with aldehydes in the presence of a mixture of lithium and potass

Full text of DOI:10.1021/ol0509080

ORGANIC
LETTERS
2005
Vol. 7, No. 14
2945-2948
Diastereoselective Synthesis of
Tetrahydrofurans via Reaction of
γ,δ
-Epoxycarbanions with Aldehydes†
Mieczysław Ma¸kosza,* Michał Barbasiewicz, and Dariusz Krajewski
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52,
01-224 Warsaw, Poland
icho-s@icho.edu.pl
Received April 25, 2005
ABSTRACT
Hydroxymethyl-substituted tetrahydrofurans were prepared with high diastereoselectivity by reaction of the carbanion derived from 3,4-epoxybutyl
phenyl sulfone with aldehydes in the presence of a mixture of lithium and potassium tert-butoxides. Initial formation of aldol-type adducts is
a nondiastereoselective but reversible process; thus, subsequent formation of one main diastereoisomer is controlled by the relative rates of
cyclization. The configuration of the carbon stereocenter at the oxirane ring is inverted in the course of the SN2 process, and two new centers
are created diastereoselectively.
Many natural and synthetic biologically active compounds
contain tetrahydrofuran rings; thus, methods of synthesis of
substituted tetrahydrofurans are of great interest.1 One of the
valuable synthetic methods for the constructing tetrahydro-
furans is cyclization of epoxyalcohols.2 Both γ,δ-3 and δ,ꢀ-
epoxyalcohols can be exploited in this reaction depending
on the preferred mode of the cyclization. For example, δ,ꢀ-
epoxyalcohols cyclize predominantly in a 5-exo mode,
leading to tetrahydrofurans,4 but intensive effort has suc-
cessfully forced an 6-endo process, yielding tetrahydropyrane
derivatives.5-7
Recently, we reported reaction of simple γ-halocarbanion
precursors with aldehydes leading to formation of 2,3-
disubstituted tetrahydrofurans in a one-pot addition-
alkylation process.8 Despite the fast cyclization of γ-
halocarbanions, deprotonation of γ-chlorobutyronitrile, γ-
chloropropyl phenyl sulfone in the presence of the aldehydes
allows trapping of these carbanions to produce aldol-type
anions. Subsequent intramolecular 1,5-substitution of the
halogen in these O-anions results in the formation of
substituted tetrahydrofurans. The major obstacle for wide use
of this valuable reaction is a high rate of the intramolecular
reaction of γ-halocarbanions, which limits the intermolecular
process to active electrophiles such as aromatic aldehydes.
An attractive extension of this concept therefore would
be use of carbanions containing less active leaving groups
in the γ-position such as γ,δ-epoxycarbanions, where the
intramolecular oxirane ring opening is anticipated be a rather
† Part of this work is the subject of the M.S. Thesis of D. Krajewski at
Faculty of Chemistry, Warsaw University of Technology.
(1) See for example: Faul, M. M.; Huff, B. E. Chem. ReV. 2000, 100,
2407.
(2) Heffron, T. P.; Jamison, T. F. Org. Lett. 2003, 5, 2339.
(3) Karikomi, M.; Watanabe, S.; Kimura, Y.; Uyehara, T. Tetrahedron
Lett. 2002, 43, 1495.
(4) Coxon, J. M.; Hartshorn, M. P.; Swallow, W. H. Aust. J. Chem. 1973,
26, 2521.
(5) Nicolaou, K. C.; Duggan, M. E.; Kwang, C.-K.; Somers, P. K. J.
Chem. Soc., Chem. Commun. 1985, 1359.
(6) Wu, M. H.; Hansen, K. B.; Jacobsen, E. N. Angew. Chem., Int. Ed.
1999, 38, 2012.
(8) (a) Ma¸kosza, M.; Judka, M. Chem. Eur. J. 2002, 8, 4234. (b)
Ma¸kosza, M.; Przyborowski, J.; Klain, R.; Kwast, A. Synlett 2000, 1773.
(c) Fleming, F. F.; Gudipati, V.; Steward, O. W. J. Org. Chem. 2003, 68,
3943. For an analogous process with Michael acceptors, see: Ma¸kosza,
M.; Judka, M. Synlett 2004, 717.
(7) Janda, K. D.; Shevlin, C. G.; Lerner, R. A. Science 1993, 259, 490.
10.1021/ol0509080 CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/04/2005

slow process.9 Trapping the γ,δ-epoxycarbanion with an
aldehyde10 should produce an intermediate epoxyalkoxide
that will subsequently cyclize to tetrahydrofuran in a
preferred 5-exo mode.
Table 1. Synthesis of Tetrahydrofurans under Optimized
Conditions
Probing this potential strategy, we employed 3,4-epoxy-
butyl phenyl sulfone 1. In our first experiments, we observed
that cyclization of 1- via intramolecular oxirane ring opening
does not proceed without Lewis acids and that addition of
this carbanion to benzaldehyde is a fast but nonstereoselective
process. Thus, 1 in the presence of t-BuOK in THF at -75
°C gave a mixture of four diastereoisomers of the epoxy-
alcohols in high yield upon protonation at low temperature.11
When the mixture was kept at room temperature for 18 h,
the expected hydroxymethyl tetrahydrofuran was formed in
a moderate yield (34%) as a mixture of two diastereoisomers
(Scheme 1).
Scheme 1. Reactions of Epoxycarbanions with Aldehydes
of the complexing oxygen atom affecting the transition state
geometry (entry 6). Reactions of aliphatic aldehydes (entries
7, 8) were unselective, and low yields were obtained with
isobutyraldehyde (entry 8) and acetaldehyde (entry 9) prob-
ably because of aldol condensation.
Reactions of 1 with other electrophilic partners such as
ketones, imines, and Michael acceptors carried out under the
optimized conditions failed to give the expected products,
whereas 1 was partially recovered.
Since efficient cyclization of epoxyalkoxides requires
activation of the oxirane ring by Lewis acids, we tested of
a number of additives (LiBr, LiCl, LiClO4, CeCl3, BF3‚OEt2,
Ti(i-OPr)4, ZnCl2, CuOTf, Cu(OTf)2, Sc(OTf)3) and observed
lithium cations to be the most effective. Lithium bromide,
used in excess, promoted the cyclization but with poor
diastereoselectivity. After some variations, we found that a
mixture of lithium and potassium tert-butoxides provided
good yield and diastereoselectivity of the products.
We assume that under these conditions, aldol-type addition
of carbanion of 1 to aldehydes is a reVersible process since
the diastereoselectivity of tetrahydrofurans does not cor-
respond to the ratio of initially formed aldol adducts obtained
after protonation of the mixture at low temperature (Scheme
1
2). H NMR analysis of 2 showed that addition is not
Under the optimized conditions,12 a series of reactions of
aldehydes with 1 were performed, giving substituted hy-
droxymethyl tetrahydrofurans (Table 1). Aromatic aldehydes
reacted with 1 in good yields and diastereoselectivity (Table
1, entries 1-5). Only in the case of furfural were the yield
and diastereoselectivity reduced, probably due to the presence
selective, as pairs of erythro and threo diastereoisomers were
equimolar mixtures of products differing by the configuration
at the oxirane ring. Since the configuration of the stereogenic
center at the benzylic position in intermediate adducts can
change only by the dissociation-addition mechanism, cy-
clization of this mixture should lead to an equimolar mixture
of 3, as opening of the oxirane ring proceeds stereospecifi-
cally with inversion of configuration.13
(9) Conversion of 1 into 1-phenylsulfonyl-2-hydroxymethyl-cyclopropane
requires activation with Lewis acids such as Li+: Corbel, B.; Decesare, J.
M.; Durst, T. Can. J. Chem. 1978, 56, 505.
(10) For other reactions of epoxycarbanions, see: (a) Reference 9.
(b) Najera, C.; Yus, M. J. Org. Chem. 1989, 54, 1491. (c) Cere, V.; et al.
J. Org. Chem. 1991, 56, 4513.
(11) Mixture of four diastereoisomers was separated chromatographically
into two pairs, namely, erythro and threo, having different configurations
of stereogenic centers of the oxirane ring within the pair. Providing that
this center is inverted in a SN2-type cyclization process, they should cyclize
to mixtures of 2,3-trans (3a, 3b) and 2,3-cis (3c, 3d) tetrahydrofurans,
respectively (Scheme 2).
(12) General Procedure (Table 1). To a solution of 1 (212 mg, 1 mmol)
and aldehyde (1.25 mmol) in THF (4 mL) at -75 °C under argon were
added consecutively solutions of t-BuOK (1 mL, 1 M in THF) and t-BuOLi
(1 mL, 1 M in THF, Aldrich) . The flask was left at between -20 and -15
°C for 10 h; then, aqueous NH4Cl was added, and the mixture was extracted
with ethyl acetate, washed with brine, and dried with MgSO4. Chromato-
graphic separation with hexane/ethyl acetate (3:1) mixture gave 2-substituted
3-phenylsulfonyl-5-hydroxymethyltetrahydrofuran as a mixture of diastereo-
isomers. See Supporting Information for details.
2946
Org. Lett., Vol. 7, No. 14, 2005

However, there is also the possibility of cyclization of the
threo adducts to 2,3-cis products (3c, 3d)14 and subsequent
epimerization at the carbon bearing a PhSO2 group to the
2,3-trans configuration, but this pathway is probably not
realized. 1H NMR studies based on 3J(H,H) coupling
constants revealed that the preferred conformations of the
intermediate epoxyalkoxides favor the anti orientation of
sterically demanding phenyl and phenylsulfonyl groups.15
While in erythro adducts reacting centers are synclinal, the
antiperiplanar orientation in threo adducts precludes cycliza-
tion to a five-membered ring (Scheme 4, see Supporting
Information for details).16
Scheme 2. Cyclization of Diastereoisomers of Adducts
According to a SN2 Pathway
Scheme 4. Preferred Conformations of Intermediate
Epoxyalkoxides 2 and Their Reactivity
To prove that under the reaction conditions there is
equilibration between diastereoisomeric adducts via a dis-
sociation-addition process, an exchange experiment was
carried out. The mixture of diastereoisomers of the aldol
products from the reaction of 1 with benzaldehyde and
p-methoxybenzaldehyde was subjected to the standard condi-
tions. Isolated tetrahydrofurans contained phenyl and p-
methoxyphenyl substituents, confirming our hypothesis
(Scheme 3).
The stereoselectivity is effectively controlled by the
epoxide stereochemistry. Formation of one predominant
diastereoisomer in high yield without racemization of the
stereogenic center at the oxirane ring could result in the
formation of valuable 2,3,5-trisubstituted tetrahydrofurans in
optically pure form in a one-pot procedure. Hydrolysis of
racemic 1 with Jacobsen catalyst under kinetic resolution
conditions provided (R)-1 with an enantiomeric excess as
high as 91% (HPLC).17 Under the standard conditions,
reaction of this oxirane with benzaldehyde gave two dia-
stereomeric tetrahydrofurans with enantiomeric purities equal
to purity of the starting oxirane (Scheme 5).
Scheme 3. Reaction of Aldol Adducts of Benzaldehyde with
1 and p-Methoxybenzaldehyde under Optimized Reaction
Conditions
Scheme 5. Synthesis of Optically Enriched 1 and Its Reaction
with Benzaldehyde under Optimized Conditions
Thus, the preferred formation of one tetrahydrofuran
diastereoisomer indicated that the final composition of the
product is controlled by rates of cyclization of the isomeric
adducts being in equilibrium, according to the Curtin-
Hammett postulate (1 / 2 f 3).
Additionally, we can assume that only erythro adducts
cyclize directly to 2,3-trans-tetrahydrofurans 3a and 3b.
The absolute configuration of the products was established
by X-ray analyses of the (-)-ω-camphanic acid18 ester
derivatives and confirms the SN2 inversion of configuration
in the course of the ring-opening process (Figure 1).
(13) Ratio of diastereoisomers of 3 obtained after cyclization mixture
of 2 according to SN2 mechanism should be 35:35:15:15. Subsequent
isomerization of tetrahydrofurans could lead to a (35 + 15):(35 + 15) )
50:50 mixture.
Org. Lett., Vol. 7, No. 14, 2005
2947

In conclusion, we have developed a novel, high-yield,
chemo-, regio-, and diastereoselective method of synthesizing
2-substituted 3-phenylsulfonyl-5-hydroxymethyltetrahydro-
furans. The potential of these products and the simplicity of
the procedure will make this tandem addition-cyclization
strategy useful in natural product synthesis.
Acknowledgment. This work was supported by National
Scientific Council (KBN), Grant 4T09A 05 625. Authors
thank Dr. Zofia Lipkowska (Institute of Organic Chemistry
PAS, Warsaw) and the Crystallographic Unit of the Physical
Chemistry Laboratory at the Chemistry Department of the
University of Warsaw for solving of X-ray structures.
Additionally, chiral HPLC analysis by Dr. Jacek Młynarski
and Mr. Piotr Kwiatkowski is greatly acknowledged.
Figure 1. X-ray structure of the main diastereoisomer of tetrahy-
drofuran obtained from chiral epoxide precursor 1 and benzaldehyde
as an ester with (-)-ω-camphanic acid.
Supporting Information Available: Experimental pro-
cedures, characterization data for all new compounds with
reprints of some NMR spectra, and additional X-ray infor-
mation (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
The cyclization stereochemistry and the crossover experi-
ment leads to the following mechanistic conclusions. The
first step of the reaction, aldol-type addition of the sulfonyl
carbanion to the carbonyl group, is a relatively fast and
nondiastereoselective but reversible process. Subsequent
cyclization is faster for one diastereoisomer, and an equi-
librium process operates until conversion of all the substrates
in a favored manner is complete.
OL0509080
(15) Truce, W. E.; Klingler, T. C. J. Org. Chem. 1970, 35, 1834.
(16) For analogous literature precedence, see: Hassner, A.; Usak, D.;
Kumareswaran, R.; Friedman, O. Eur. J. Org. Chem. 2004, 2421.
(17) Jin, C.; Ramirez, R. D.; Gopalan, A. S. Tetrahedron Lett. 2001, 42,
4747.
(14) Diastereoisomers 3c and 3d were isolated only during the optimiza-
tion process. Under optimized conditions, no traces of 3c or 3d were detected
(see Supporting Information for details).
(18) Konował, A.; Jurczak, J.; Zamojski, A. Tetrahedron 1976, 32, 2957.
2948
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