Modular synthesis of chiral homo- and heterotrisoxazolines. Improving the enantioselectivity in the asymmetric Michael addition of indole to benzylidene malonate

Article abstract of DOI:10.1021/jo050595m

A simple approach to a diverse set of chiral trisoxazolines is described. Deprotonation of bisoxazolines 2, followed by treatment of 2- chloromethyloxazolines 3, affords chiral trisoxazolines, including chiral homo- and hetero-trisoxazolines in good to hi

Full text of DOI:10.1021/jo050595m

SCHEME 1. Previous Synthesis of Trisoxazolinesa
Modular Synthesis of Chiral Homo- and
Heterotrisoxazolines.† Improving the
Enantioselectivity in the Asymmetric
Michael Addition of Indole to Benzylidene
Malonate
Meng-Chun Ye, Bin Li, Jian Zhou, Xiu-Li Sun, and
Yong Tang*
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry,
354 Fenglin Lu, Shanghai 200032, China
tangy@mail.sioc.ac.cn
Received March 23, 2005
a Reagents and conditions: (a) Na, MeOH, then BrCH2CO2Me,
0 °C to reflux, 46%; (b) Na, MeOH then CH3I, 0-40 °C, 80%; (c)
amino alcohol, 70 °C, solvent free; (d) PPh3, CCl4, Et3N, CH3CN,
25 °C.
able yields, the liberated methanol must be removed in
a vacuum after the reaction mixture is to room temper-
ature every 10 h. Thus, this method is very tedious and
also limited to the preparation of homo-trisoxazolines.
In this paper, we wish to report a conveniently modular
approach for the synthesis of a diverse set of chiral
trisoxazolines.
In the literature, there are two strategies for the
synthesis of trisoxazolines. One directly constructs the
three oxazolines from the corresponding carboxylic acids
or derivatives thereof. The advantage of this method is
to enable the synthesis of such ligands in relatively few
steps, and thus, this strategy is mostly adopted.2e-i
However, the direct synthesis suffered from poor yields
in the key step sometimes, and most of all, this method
is limited to the preparation of chiral homo-trisoxazolines
with identical oxazoline subunits, as in the case of the
A simple approach to a diverse set of chiral trisoxazolines
is described. Deprotonation of bisoxazolines 2, followed by
treatment of 2-chloromethyloxazolines 3, affords chiral
trisoxazolines, including chiral homo- and hetero-trisoxazo-
lines in good to high yields. These trisoxazolines are suc-
cessfully applied in the asymmetric reaction of indole with
benzylidene malonate, and ee’s up to 93% were obtained.
C2-symmetrical bisoxazolines (BOX) have proven to be
very powerful chiral ligands for a wide range of metal-
catalyzed reactions.1 Recently, several trisoxazolines have
been developed and applied successfully in some asym-
metric catalytic reactions2 and molecular recognition.3 In
a previous study on asymmetric catalysis, we designed
the pseudo-C3-symmetric4 trisoxazoline 1a by a sidearm
approach and found it very useful in the asymmetric
Michael-type indole alkylation,5 the Diels-Alder reaction,6a
the 1,3-diploar cycloaddition reaction,6b and the Kinugasa
reaction.6c The originally reported protocol for the syn-
thesis of chiral trisoxazoline 1 started from triester 4
(Scheme 1).5a In this protocol, the condensation of triester
4 with amino alcohols is performed under a nitrogen
atmosphere at 80 °C for 7-10 days. To achieve reason-
(2) For chiral trisoxazolines, see: (a) Kim, S.-G.; Seong, H. R.; Kim,
J.; Ahn, K. H. Tetrahedron Lett. 2004, 45, 6835. (b) Rocchetti, M. T.;
Fino, V.; Capriati, V.; Florio, S.; Luisi, R. J. Org. Chem. 2003, 68, 1394.
(c) Bellemin-Laponnaz, S.; Gade, L. H. Angew. Chem., Int. Ed. 2002,
41, 3473. (d) Kim, S.-G.; Ahn, K. H. Tetrahedron Lett. 2001, 42, 4175.
(e) Kohmura, Y.; Katsuki, T. Tetrahedron Lett. 2000, 41, 3941. (f)
Chuang, T.-H.; Fang, J.-M. Bolm, C. Synth. Commun. 2000, 30, 1627.
(g) Chan, T. H. Zheng, G. Z. Can. J. Chem. 1997, 75, 629. (h) Kawasaki,
K.; Katsuki, T. Tetrahedron 1997, 53, 6337. (i) Kawasaki, K.; Tsumura,
S.; Katsuki, T. Synlett 1995, 1245. For achiral trisoxazolines, see: (j)
Capriati, V.; Florio, S.; Luisi, R.; Rocchetti, M. T. J. Org. Chem. 2002,
67, 759. (k) Bellemin-Laponnaz, S.; Gade, L. H. Chem. Commun. 2002,
1286. (l) Sorrell, T. N.; Pigge, F. C.; White, P. S. Inorg. Chim. Acta
1993, 210, 87.
(3) (a) Kim, S.-G.; Kim, K.-H.; Kim, Y. K.; Shin, S. K.; Ahn, K. H. J.
Am. Chem. Soc. 2003, 125, 13819. (b) Ahn, K. H.; Ku, H.-y.; Kim, Y.;
Kim, S.-G.; Kim, Y. K.; Son, H. S.; Ku, J. K. Org. Lett. 2003, 5, 1419.
(c) Kim, S.-G.; Kim, K.-H.; Jung, J.; Shin, S. K.; Ahn, K. H. J. Am.
Chem. Soc. 2002, 124, 591. (d) Kim, S.-G.; Ahn, K. H. Chem. Eur. J.
2000, 6, 3399. (e) Ahn, K. H.; Kim, S.-G.; Jung, J.; Kim, K.-H.; Kim,
J.; Chin, J.; Kim, K. Chem. Lett. 2000, 170.
(4) For a review on C3-symmetric chiral ligands in asymmetric
catalysis, see: Moberg, C. Angew. Chem., Int. Ed. 1998, 37, 248.
(5) (a) Zhou, J.; Tang, Y. J. Am. Chem. Soc. 2002, 124, 9030. (b).
Zhou, J.; Ye, M.-C.; Huang, Z.-Z. Tang, Y. J. Org. Chem. 2004, 69,
1309. (c) Zhou, J.; Ye, M.-C.; Tang, Y. J. Comb. Chem. 2004, 6, 301.
(d) Zhou, J.; Tang, Y. Chem. Commn. 2004, 432.
(6) (a) Zhou, J.; Tang, Y. Org. Biomol. Chem. 2004, 2, 429. (b) Huang,
Z.-Z.; Kang, Y.-B.; Zhou, J.; Ye, M.-C.; Tang, Y. Org. Lett. 2004, 6, 1677.
(c) Ye, M.-C.; Zhou, J.; Huang, Z.-Z. Tang, Y. Chem. Commun. 2003,
2554.
† Chiral homo-trisoxazolines refer to trisoxazolines with three
identical oxazoline subunits, while in chiral hetero-trisoxazolines, the
oxazoline subunits are different from each other (or at least one
oxazoline subunit is different from the other two).
(1) Reviews: (a) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000,
33, 325. (b) Jørgensen, K. A.; Johannsen, M.; Yao, S.; Audrain, H.;
Thorhauge, J. Acc. Chem. Res. 1999, 32, 605. (c) Pfaltz, A. J. Heterocycl.
Chem. 1999, 36, 1437. (d) Ghosh, A. K.; Mathivanan, P.; Cappiello, J.
Tetrahedron: Asymmetry 1998, 9, 1. (e) Meyers, A. I. J. Heterocycl.
Chem. 1998, 35, 991. (f) Reiser, O. Nachr. Chem. Technol. Lab. 1996,
44, 744. (g) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297. (h)
Pfaltz, A. Acc. Chem. Res. 1993, 26, 339. (i) Bolm, C. Angew. Chem.
1991, 103, 556.
10.1021/jo050595m CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/22/2005
6108
J. Org. Chem. 2005, 70, 6108-6110

TABLE 1. Modular Synthesis of Trisoxazolinesa
a All reactions were performed in THF at -78 °C to room temperature under nitrogen. Scale: 1.1 equiv of tert-butyllithium, 1.0 equiv
of bisoxazoline, and 1.4 equiv of 2-chloromethyloxazoline. b Isolated yield. c On a 4.16 mmol scale.
synthesis of pseudo-C3-symmetric trisoxazoline 1a.5a
SCHEME 2
Another way is by modular synthesis, developed by Florio
and Gade. Florio et al. developed a novel tris(oxazolinyl)-
cyclopropane via “trimerization” of metalated 2-chloro-
alkyl-2-oxazolines.2b,i Almost at the same time, Gade and
co-workers reported the preparation of C3-symmetric
trisoxazolines from bisoxazoline by addition-elimination
reaction.2c,k Very recently, to synthesize a chiral benzene-
based hetero-trisoxazoline, Ahn et al. described an ox-
azoline exchange reaction with amino alcohols.2a The
reacted with different halides to give bisoxazoline deriva-
most promising character of these modular methods is
tives.7 Very recently, we found that i-Pr-bisoxazoline,
after deprotonation by LDA/TMEDA, could couple readily
to enable the synthesis of trisoxazolines with different
oxazoline subunits, so that both chiral homo- and hetero-
with functionalized bromide to give bisoxazoline with a
trisoxazolines can be synthesized at will. For this reason,
pendant functional group.5c However, we failed to extend
we tried the strategy shown in Scheme 2, by alkylation
this methodology to synthesis of chiral trisoxazoline 1.
of bisoxazoline7 with 2-chloromethyl oxazoline,8 to arrive
i
It was found that reaction of Pr-bisoxazoline, deproto-
at a modified synthesis of chiral trisoxazolines 1a. In
nated by LDA/TMEDA, with 2-chloromethyl-2-oxazoline
previous studies, Denmark reported that bisoxazoline
gave unexpected products. The reason, we proposed, is
could be easily deprotonated by LDA/TMEDA and then
probably the “trimerization” of the chloride by2b and the
replacement of diisopropylamine with the 2-chlorometh-
(7) Denmark, S. E.; Stiff, C. M. J. Org. Chem. 2000, 65, 5875.
yloxazoline. Thus, we tried to use t-BuLi instead of LDA,
and it was found that the coupling reaction worked well
under these conditions (Table 1, entries 1-11). iPr-BOX
2A, deprotonated by t-BuLi, could react with 2-chloro-
(8) (a) Musser, J. H.; Kubrak, D. M.; Chang, J.; Dizio, S. M.; Hite,
M.; Hand, J. M.; Lewis, A. J. J. Med. Chem. 1987, 30, 400. (b) Breton,
P.; Andre´-Barre´s, C.; Langlois, Y. Synth. Commun. 1992, 22, 2543. (c)
Sudo, A.; Hashimoto, Y.; Kimoto, H.; Hayashi, K.; Saigo, K. Tetra-
hadron: Asymmetry 1994, 5, 1333.
J. Org. Chem, Vol. 70, No. 15, 2005 6109

TABLE 2. Substituent Effects of Trisoxazolinesa
i
line backbone. Unlike Pr-BOX 2A, the installation of a
pendant oxazoline on tBu-BOX 2D resulted in decreasing
the enantiomeric excess and the reaction rate (entries 2
and 13), probably due to the steric effects of tert-butyl
group.
In summary, we have developed an efficient method
for the synthesis of various chiral trisoxazolines. Com-
pared with the previous report, this method provides an
easy and simplified access to a diverse set of homo- and
especially hetero-trisoxazolines in gram scale. By this
strategy, we found that the enantioselectivity of the
Cu(II)-catalyzed Michael addition of indole to benzylidene
malonate could be improved up to 93% ee under mild
conditions. The application of these newly developed
ligands in other reactions is now in progress in our
laboratory.
entry
ligand
yieldb (%)
eec (%)
1
2
iPr-BOX
tBu-BOX
1a
85
63d
90
83
75
85
80
89
90
92
79
65
50f
79
48
3
93 (90)e
90
4
1Ab
5
1Ac
89
6
1Ad
85
7
1Ae
86
8
1Af
90
Experimental Section
9
1Ag
85
General Procedure for the Synthesis of Chiral Homo-
and Hetero-trisoxazolines. To a solution of bisoxazoline (2A-
D) (2 mmol) in dried THF (30 mL) was added dropwise t-BuLi
(1.3 mL, 1.7 M in hexanes, 2.2 mmol) within 15-20 min at -78
°C. The resulting yellow solution was stirred for an additional
1 h at this temperature. Then a solution of 2-chloromethyl
oxazoline (2.8 mmol) in THF (10 mL) was added dropwise at
-78 °C over 10 min. The solution was slowly warmed to room
temperature and was stirred for a further 10 h. The mixture
was diluted with CH2Cl2 (20 mL) and was washed with H2O (5
mL). The aqueous layer was extracted with CH2Cl2 (5 mL), and
the combined organic phases were dried over Na2SO4, filtered,
and concentrated. The residue was purified by flash chroma-
tography (petroleum ether/acetone ) 1/10).
1,2,2-Tris[2-[(4S)-4-isopropyl-1,3-oxazolinyl]]propane 1a:
6a colorless oil (74%); [R]20D -47.2 (c 3.79, CHCl3); 1H NMR (300
MHz, CDCl3) δ 4.22-4.07 (m, 3H), 4.00-3.77 (m, 6H), 3.05 (ABd,
J ) 14.7 Hz, 1H), 2.91 (ABd, J ) 14.4 Hz, 1H), 1.79-1.61 (m,
3H), 1.56 (s, 3H), 0.90 (d, J ) 6.6 Hz, 6H), 0.86 (d, J ) 6.9 Hz,
3H), 0.82 (d, J ) 7.2 Hz, 6H), 0.81 (d, J ) 7.2 Hz, 3H).
10
11
12
13
1Ah
91
1Ba
73
1Ca
-61
1Dc
26
a Reactions are performed on a 0.25 mmol scale in BuOH (5
mL). b Isolated yield after 3 h. c Determined by HPLC analysis
i
(Chiracel OD-H, 10% PrOH/hexane, 0.9 mL/min, 254 nm). d Iso-
i
lated yield after 24 h. e Number in parentheses is the ee using
iPr-TOX prepared by the previous procedure. f Isolated yield after
96 h.
methyl-2-oxazoline with different substituents such as
isopropyl, phenyl, sec-butyl, benzyl, tert-butyl, indenyl,
etc. and afforded the chiral homo- or hetero-trisoxazolines
in moderate to good yields (Table 1, entries 1-8).9 In
addition, the lithiated 2A could also couple with both
enantiomers 3d and 3e smoothly to give desired diaster-
eomeric products. Not only iPr-BOX 2A but also phenyl-
and tBu-BOX are good substrates for this reaction.
Noticeably, tBu-BOX 2D allowed the incorporation of tert-
butyl-2-methyleneoxazoline to construct the bulky tert-
butyltrisoxazolines 1Dc, which could not be obtained by
the previously used direct synthesis, demonstrating the
superiority of the modular synthesis. This reaction was
General Procedures for Trisoxazoline/Cu(OTf)2-Cata-
lyzed Asymmetric Michael Addition Reaction. To a Schlenk
tube was added Cu(OTf)2 (0.10 equiv) followed trisoxazoline 1
(0.12 equiv) under air atomosphere. Then iBuOH (2.5 mL) was
added, and the resulting blue-green solution was stirred at room
temperature (10-25 °C) for 1 h before alkylidene malonate (1.0
i
equiv in BuOH, 2.5 mL) was added. The mixture was allowed
to stir at room temperature for 15 min, and then the indole (1.2
equiv) was added. After the reaction was complete (by TLC), the
mixture was concentrated under reduced pressure at room
temperature, and the residue was purified by flash column
chromatography on silica gel [eluted with CH2Cl2/petroleum
ether (1/1, v/v) then pure CH2Cl2] to afford the desired product.
Ethyl (3S)-2-ethoxycarbonyl-3-(3-indolyl)-3-phenylpro-
panoate 8:5b 1H NMR (300 MHz, CDCl3) δ 8.06 (brs, 1H), 7.55
(d, J ) 7.8 Hz, 1H), 7.36 (d, J ) 6.9 Hz, 2H), 7.10-7.30 (m, 6H),
7.03-7.06 (m, 1H), 5.08 (d, J ) 11.7 Hz, 1H), 4.29 (d, J ) 11.4
Hz, 1H), 3.99 (m, 4H), 1.00 (m, 6H).
i
performed on a gram scale in good yield for Pr-trisox-
azoline 1a (Table 1, entry 12).
With these trisoxazolines at hand, we examined the
effects of the pendant oxazolines on the enantioselectivity
of the indole alkylation with benzylidene malonates.5 The
results are summarized in Table 2. Trisoxazolines 1a-
i
1Ah, derived from Pr-BOX 2A, gave higher enantio-
selectivities (85%-93%) than the parent iPr-BOX under
the same conditions (entries 1, 3-10). Using the currently
i
prepared Pr-TOX 1a instead of the previous one, inter-
Acknowledgment. We are grateful for the financial
support from the Natural Sciences Foundation of China
and The Science and Technology Commission of Shang-
hai Municipality.
estingly, the enantiomeric excess was slightly improved,
and up to 93% ee was obtained at 15 °C. Compared with
the iPr-BOX-derived trisoxazolines, Ph-BOX-derived
trisoxzaolines gave lower ee’s (entries 11 and 12). Op-
posite enantioselectivities were observed using 1Ca and
1Ba, indicating that the stereochemical course of this
reaction depends on the stereochemistry of the bisoxazo-
Supporting Information Available: Characterization
data for all compounds and experimental procedures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(9) No desired product was isolated when 2-chloromethyl-2-oxazoline
without substitute was used.
JO050595M
6110 J. Org. Chem., Vol. 70, No. 15, 2005