Enantioselective haloetherification by asymmetric opening of meso -halonium ions

Article abstract of DOI:10.1021/ol1028805

A new approach to enantioselective haloetherification reactions via desymmetrization of in situ-generated meso-halonium ions is described. The combination of N-haloamides as a halogen source and sodium salts of chiral phosphoric acids as catalysts can be used for the cyclization of symmetrical ene-diol substrates, yielding the haloetherification products under practical conditions in enantioenriched form.(Figure Presented)

Full text of DOI:10.1021/ol1028805

ORGANIC
LETTERS
2011
Vol. 13, No. 5
860–863
Enantioselective Haloetherification by
Asymmetric Opening of meso-Halonium
Ions
€
€
Ulrich Hennecke,* Christian H. Muller, and Roland Frohlich
€
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat, Corrensstrasse 40,
€
48149 Mu€nster, Germany
ulrich.hennecke@uni-muenster.de
Received November 29, 2010
ABSTRACT
A new approach to enantioselective haloetherification reactions via desymmetrization of in situ-generated meso-halonium ions is described. The
combination of N-haloamides as a halogen source and sodium salts of chiral phosphoric acids as catalysts can be used for the cyclization of
symmetrical ene-diol substrates, yielding the haloetherification products under practical conditions in enantioenriched form.
Halocyclization reactions such as halolactonization or
haloetherification are powerful for the preparation of
heterocycles. The combination of a cyclization with the
stereoselective generation of two new stereocenters and the
introduction of a new functional group (halogen) for
further transformations have led to their frequent use in
natural product synthesis. However, there are only a few
reported reagent-controlled asymmetric variants of these
reactions.1 Early examples from the Taguchi group used
stoichiometric amounts of titanium taddolates to promote
iodocyclizations with enantioselectivities up to 65% ee.2
Various complexes of iodine-electrophiles with chiral ami-
nes have been used in iodocyclization reactions; however,
only moderate enantioselectivities were achieved (up to
45% ee).3 Excellent enantioselectivities (up to 99%) were
reported by the Ishihara group in an electrophilic iodine
induced polyene cyclization cascade using a stoichiometric
quantity of a phosphoramidite promoter.4 Efficient cata-
lytic asymmetric halocyclization reactions are evenscarcer,
and only in 2002 did Kang et al. develop the first catalytic
asymmetric iodoetherification reaction employing a cobalt
salen complex.5 Very recently asymmetricchloro-, bromo-,
and iodolactonizations of alkenenoic acids have been
reported by the groups of Borhan,6 Jacobsen,7 Yeung,8
(4) Sakakura, A.; Ukai, A.; Ishihara, K. Nature 2007, 445, 900.
(5) (a) Kang, S. H.; Sung, B. L.; Park, C. M. J. Am. Chem. Soc. 2003,
125, 15748. (b) Kwon, H. Y.; Park, C. M.; Sung, B. L.; Youn, J.-H.;
Kang, S. H. Chem.;Eur. J. 2008, 14, 1023. (c) Kang, S. H.; Park, C. M.;
Lee, S. B.; Kim, M. Synlett 2004, 1279. For a recent application of this
catalyst system to iodolactonizations, see: Ning, Z.; Jin, R.; Ding, J.;
Gao, L. Synlett 2009, 2291.
(1) (a) French, A. N.; Bissmire, S.; Wirth, T. Chem. Soc. Rev. 2004,
33, 354. (b) Chen, G.; Ma, S. Angew. Chem., Int. Ed. 2010, 49, 8306.
(2) Kitagawa, O; Hanano, T.; Tanabe, K.; Shiro, M.; Taguchi, T.
J. Chem. Soc., Chem. Commun. 1992, 1005.
(6) Whitehead, D. C.; Yousefi, R.; Jaganathan, A.; Borhan, B. J. Am.
Chem. Soc. 2010, 132, 3298.
(7) Veitch, G. E.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2010, 49,
7332.
(8) Zhou, L.; Tan, C. K.; Jiang, X.; Chen, F.; Yeung, Y.-Y. J. Am.
Chem. Soc. 2010, 132, 15474.
(3) (a) Grossmann, R. B.; Trupp, R. J. Can. J. Chem. 1998, 76, 1233.
(b) Haas, J.; Piguel, S.; Wirth, T. Org. Lett. 2002, 4, 297. (c) Hass, J.;
Bissmire, S.; Wirth, T. Chem.;Eur. J. 2005, 11, 5777. (d) Garnier, J. M.;
Robin, S.; Rousseau, G. Eur. J. Org. Chem. 2007, 3281. For a related
chiral pyridine/bromonium electrophile and its application, see: Cui,
X. L.; Brown, R. S. J. Org. Chem. 2000, 56, 5653.
r
10.1021/ol1028805
Published on Web 02/08/2011
2011 American Chemical Society

Here we present a conceptually different approach to
enantioselective halocyclizations trying to avoid the pro-
blems caused by alkene-to-alkene transfer. Up to now, all
catalysis attempts have focused on the enantioselective
formation of the intermediate halonium ion as the stereo-
chemistry-determining step (Scheme 1, a).
Scheme 1. Stereochemistry-Determining Steps of Halocycliza-
tions
Our approach is instead based on the selective opening
of halonium ions in the presence of a suitable chiral
counteranion (Scheme 1, b).16 By catalyzing this second
step we should avoid all problems connected to the
potentially insufficient stereochemical integrity of halo-
nium ions.
To demonstrate our concept we chose (Z)-oct-4-en-1,
8-diol 1a as our model substrate. Upon treatment with an
electrophilic iodine source, a meso-iodonium ion should
form that further reacts in a 5-exo cyclization to the
tetrahydrofuran product2a. Initial experiments withchiral
phosphoric acids to activate the iodine source and as chiral
counterion in the iodonium opening gave encouraging
results. Reactions were performed using 20 mol % of the
catalyst in toluene with N-iodosuccinimide (NIS) as iodine
source at low temperature. Molecular sieves were added to
ensure reproducibility.17 Yields were generally high, but
whereas phosphoric acids based on 3,30-diarylBINOL18 4
or VAPOL19 5 led to no detectable enantioselectivity, the
and Fujioka,9 respectively, using organocatalysts. A re-
lated enantioselective bromolactonization of conjugated
enynes catalyzed by chinchonidine ureas was reported by
Tang et al.10 With these methods, highly enantioselective
halolactonizations of a range of alkenoic acids are now
possible. However, asymmetric halocyclization reactions
are still regarded as difficult reactions and in many cases
only low selectivities were obtained.11 This is often attrib-
uted to the rapid loss of enantiomeric purity of the
halonium ion intermediate by rapid alkene-to-alkene
transfer as shown by Brown12 and Denmark.13 On the
other hand, it has been demonstrated by Braddock14 and
Denmark13,15 that enantiopure halonium ions can be
prepared and stereospecifically trapped.
combination of NIS and BINOL-derived acid 3 H20
3
yielded the product with 22% ee (Table 1, entries 1-4).
Attempts to improve the selectivity using other iodine
sources (iodine, 1,3-diiodo-5,5-dimethylhydantoin, bis-
(collidine)iodonium hexafluorophosphate, and benzyltri-
methylammonium dichloroiodate21) were not rewarding
(data not shown). The combination of silver carbonate and
iodine led to a slight improvement (entry 5, 30% ee) but
rendered isolation of the product difficult due to the
lability of the alkyl iodide 2a in presence of the silver
salt. A first significant improvement was achieved when
N-iodopyrrolidinone 6 (NIPyr), a iodine source similar to
NIS, was tested.22 Application of NIPyr 6 gave an im-
proved enantioselectivity (entry 6, 34% ee). A second key
improvement came with the use of the sodium salt of
(9) Murai, K.; Matsushita, T.; Nakamura, A.; Fukushima, S.;
Shimura, M.; Fujioka, H. Angew Chem. Int. Ed. 2010, 49, 9174.
(10) Zhang, W.; Zheng, S.; Liu, N.; Werness, J. B.; Guzei, I. A.; Tang,
W. J. Am. Chem. Soc. 2010, 132, 3664.
(11) (a) Ahmad, S. M.; Braddock, D. C.; Cansell, G.; Hermitage,
S. A.; Redmond, J. M.; White, A. J. P. Tetrahedron Lett. 2007, 48, 5948.
(b) Wang, M.; Gao, L. X.; Mai, W. P.; Xia, A. X.; Wang, F.; Zhang, S. B.
J. Org. Chem. 2004, 69, 2874. For an extensive study of achiral Lewis
base catalysis in halocyclization reactions, see: Denmark, S. E.; Burk,
M. T. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20655.
(12) Neverov, A. A.; Brown, R. S. J. Org. Chem. 1996, 61, 962.
(13) Denmark, S. E.; Burk, M. T.; Hoover, A. J. J. Am. Chem. Soc.
2010, 132, 1232. For related work on thiiranium and seleniranium ions,
see: Denmark, S. E.; Collins, W. R.; Cullen, M. D. J. Am. Chem. Soc.
2009, 131, 3490.
(14) Braddock, D. C.; Hermitage, S. A.; Kwok, L.; Pouwer, R.;
Redmond, J. M.; White, A. J. P. Chem. Commun. 2009, 1082.
(15) For a related study on thiiranium and seleniranium ions, see:
Denmark, S. E.; Vogler, T. Chem.;Eur. J. 2009, 15, 11737.
(16) For related desymmetrization reactions of aziridines and thiir-
anium ions, see: (a) Rowland, E. B.; Rowland, G. B.; Rivera-Otero, E.;
Antilla, J. C. J. Am. Chem. Soc. 2007, 129, 12084. (b) Hamilton, G. L.;
Kanai, T.; Toste, F. D. J. Am. Chem. Soc. 2008, 130, 14984–14986.
(c) Larson, S. E.; Baso, J. C.; Li, G.; Antilla, J. C. Org. Lett. 2009, 11,
5186. For chiral counter anion catalysis in general, see:(a) Lacour, J.;
Hebbe-Viton, V. Chem. Soc. Rev. 2003, 32, 373. (b) Mayer, S.; List, B.
Angew. Chem., Int. Ed. 2006, 45, 4193–4195. (c) Hamilton, G. L.; Kang,
E. J.; Mba, M.; Toste, F. D. Science 2007, 317, 496. (d) Raheem, I. T.;
Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N. J. Am. Chem. Soc. 2007,
129, 13404. (e) Rueping, M.; Antonchick, A. P.; Brinkmann, C. Angew.
Chem., Int. Ed. 2007, 46, 6903. (f) Lacour, J.; Moraleda, D. Chem.
Commun. 2009, 7073.
phosphoric acid 3 H. The identity of this salt, prepared
3
by simply treating the acid with NaOH followed by
recrystallization, was proven by X-ray crystallography
(see Supporting Information for details). Using 3 Na the
3
enantioselectivity increased to 44% ee (entry 7). Optimiza-
tion of the solvent (with chlorinated solvents being slightly
superior to other solvents, entries 8-11) and reaction
temperature led to a further improvement to 62% ee.
Experiments with the lithium and the potassium salts of
(17) Trace amounts of water led to lower enantioselectivities.
(18) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew.
Chem., Int Ed. 2004, 43, 1566. (b) Uraguchi, D.; Terada, M. J. Am.
Chem. Soc. 2004, 126, 5356.
(19) Rowland, G. B.; Zhang, H.; Rowland, E. B.; Chennamadhavuni,
S.; Wang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2005, 127, 15696.
(20) Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2006, 128, 84.
(21) Kajigaeshi, S.; Kakinami, T.; Yamasaki, H.; Fujisaki, S.;
Okamoto, T. Bull. Chem. Soc. Jpn. 1988, 61, 600.
(22) For details on the preparation see Supporting Information.
Org. Lett., Vol. 13, No. 5, 2011
861

Table 1. Optimization of Reaction Conditions
Table 2. Substrate Scope of the Iodoetherification Using NIPyr 6
iodine
catalyst
source
ee
(%)d
entry
(20 mol %)
(1.2 equiv)
solvent
temp (°C)
1
3 H
NIS
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
DCE
-78 to rt
-78 to rt
-78 to rt
-78 to rt
-78
-78 to rt
0
22
0
3
2
4a
4b
5
NIS
3
NIS
0
4
NIS
0
5
3 H
I2, Ag2CO3
NIPyr
NIPyr
NIPyr
NIPyr
NIPyr
NIPyr
NIPyr
NIPyr
NIPyr
NIPyr
30
34
44
62
60
46
58
56
46
62
50
3
6
3 H
3
7
3 Na
3
8
3 Na
0
3
9
3 Na
0
3
10
11
12
13
14
15
3 Na
PhCF3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
3
3 Na
-78 to rt
3
3 Lia
0
0
0
0
3
3 K
3
3 Hb
3
3 Nac
3
a Prepared in situ from 3 H and LiOH. b 0.5 equiv of sodium
3
carbonate was added to generate 3 Na in situ. c 5 mol % catalyst 3 Na
3
3
was used. d Determined by HPLC on a chiral stationary phase.
a 1 equiv of Na2CO3 was added to the reaction. b Determined by
HPLC on a chiral stationary phase.
3 H (3 Li, 3 K; entries 12, 13) gaveslightly inferior results.
Instead of 3 Na a combination of 3 H and sodium
3
3
3
3
3
by dehalogenation of 2a and comparison with an authentic
standard prepared from enantiopure tetrahydrofurfuryl
alcohol.23 This established S,S-2a as the major enantiomer
carbonate can be used to generate 3 Na in situ leading
to the same enantioselectivity then using 3 Na directly
3
3
(entry 14). If the amount of catalyst 3 Na is decreased to
3
derived from catalyst (S)-3 Na.
The use of catalyst 3 Na in combination with electro-
3
5 mol %, the enantioselctivity is reduced from 62% to
50% (entry 15).
3
philic reagents derived from other elements gave mixed
results. The cyclization of 1a withN-(phenylseleno)-phtha-
limide, N-(phenylthio)phthalimide, and N-chloro-succini-
mide gave almost no conversion, even at room tempera-
ture. With N-bromosuccinimide, however, full conversion
to the bromoetherification product 7a was achieved at 0
°C. Again, oct-4-en-1,8-diol substrates with or without
substituents at the 2,7-position could be cyclized using
NBS (Table 3). The enantioselctivities observed for these
cyclizations are generally lower than those for the iodocy-
clization but can reach up to 67% ee.
To test the substrate scope of this reaction, the optimized
reaction conditions were applied to a range of oct-4-en-1,
8-diol substrates (Table 2). Substitution at the 2,7-positions
(Me, Ph) was well tolerated and led to even better en-
antioselectivities if 1 equiv of sodium carbonate was added
(entries 2, 3). Methyl-substitution at the 1,8-positions, on
the other hand, had a detrimental effect, leading to an
almost racemic product. Application of the optimized con-
ditions to the cyclization of dec-5-en-1,10-diol 1e (6-exo)
yielded the pyran product with moderate 18% ee. The ab-
solute configuration of the excess enantiomer was determined
Iodolactonization using catalyst 3 Na was also at-
tempted using diacide 8 as a model substrate, but only
3
(23) See Supporting Information for details.
862
Org. Lett., Vol. 13, No. 5, 2011

Table 3. Substrate Scope of the Bromoetherification Using NBS
Scheme 2. Iodolactonization with Catalyst 3 Na
3
in the catalytic reactions suggest that 3 Na is not primar-
3
ily acting as a Lewis acid in these reactions.24 Instead of
acting as a (Lewis) acid the phosphate anion might
initially act as Lewis base toward the halogenating agent
forming a phosphate NIPyr complex25 and thereby acti-
vating the NIPyr via Lewis base activation.26 Iodination
of the double bond to the iodonium ion is then quickly
followed by an asymmetric opening controlled by the
chiral counteranion. This would mean that the mode of
activation of the NIPyr by the phosphate is distincly
different from other reactions catalyzed by BINOL phos-
phoric acids.
In summary, we present a new desymmetrizing ap-
proach to asymmetric haloetherification reactions. Using
the sodium phosphate 3 Na good yields and enantio-
selectivities can be achieved under practical reaction
conditions.
a 1 equiv of Na2CO3 was added to the reaction. b Determined by
HPLC on a chiral stationary phase.
3
the racemic cyclization product9 was obtained (Scheme 2).
This is an interesting observation highlighting the differ-
ences between the described catalytic system and most of
the recently reported systems for asymmetric halolactoni-
Acknowledgment. Financial support by the “Fonds
€
der chemischen Industrie” and the WWU Munster is
gratefully acknowledged. We thank Prof. A. Studer
zations.6-9 Whereas catalyst 3 Na can be used for asym-
€
(WWU Munster) for generous support and helpful discus-
sions and Prof. M. Oestreich (WWU Munster) for com-
3
€
metric haloetherifications but not for lactonizations, all
other newly described organocatalysts are potent in halo-
lactonizations, and no applications to etherifications have
been described.
ments on the manuscript.
Supporting Information Available. Experimental de-
tails and characterization data for the products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The higher catalytic activity of the sodium salt 3 Na as
compared to the acid 3 H suggests an interesting role for
3
3
BINOL phosphate in these halogenation reactions.
Althoughthe roleofthe sodium cation iscurrently unclear,
the similar selectivities of the sodium and the lithium salts
(25) Mixing 3 Na and NIPyr (ratio 1:1) in CD2Cl2 leads to upfield
3
shifts of the 1H NMR signals of NIPyr 6 (0.11 ppm for the 5-CH2, see
Supporting Information for details). For complexes of halide anions
with NIS, see: (a) Eberson, L.; Finkelstein, M.; Folkesson, B.; Hutchins,
(24) For BINOL-phosphates salts as Lewis acids, see: (a) Inanaga, J.;
Sugimoto, Y.; Hanamoto, T. New J. Chem. 1995, 19, 707. (b) Furuno,
H.; Hanamoto, T.; Sugimoto, Y.; Inanaga, J. Org. Lett. 2000, 2, 49.
(c) Rueping, M.; Koenigs, R. M.; Atodiresei, I. Chem.;Eur. J. 2010, 16,
9350. For an application of a chiral sodium phosphate, see: Shen, K.;
Liu, X.; Cai, Y.; Lin, L.; Feng, X. Chem.;Eur. J. 2009, 15, 6008.
€
G. A.; Jonsson, L.; Larsson, R.; Moore, W. M.; Ross, S. D. J. Org.
Chem. 1986, 51, 4400. (b) Ghassemzadeh, M.; Dehnicke, K.; Goesmann,
H.; Fenske, D. Z. Naturforsch. 1994, 49b, 602.
(26) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 49,
1560.
Org. Lett., Vol. 13, No. 5, 2011
863