The first solid-phase synthesis of bis(oxazolinyl)pyridine ligands

Article abstract of DOI:10.1021/jo050237j

Chiral Pybox (pyridine-2,6-bis(oxazoline)) ligands can be cleanly and efficiently prepared on polystyrene support via a five-step solid-phase synthetic sequence. Cu(I)-complexed polymer-bound Pybox was used as a catalyst in the first heterogeneously catal

Full text of DOI:10.1021/jo050237j

reported.4 Mayoral et al. reported preparation of an
immobilized Pybox ligand via copolymerization of styrene
and divinylbenzene with a soluble vinyl-bearing Pybox
monomer, which had to be prepared via a 12%-yielding
six-step sequence.4a Moberg et al. prepared the im-
mobilized ligand through grafting of a soluble Pybox
containing a remote carboxylate or hydroxyl onto a
suitably functionalized polymer.4b The preparation of the
precursor in solution in this case involved a 51%- and
59%-yielding five-step sequence. It is noteworthy that the
immobilization of related bis(oxazoline) (Box) ligands was
also always achieved via grafting or polymerization of
the ligand precursors pre-synthesized in solution.5 On the
other hand, we recently presented an alternative ap-
proach for the synthesis of bis(oxazolinyl) ligandss
stepwise solid-phase synthesis.6 This approach was ap-
plied for the synthesis of supported Box and Phebox
(phenyl-2,6-bis(oxazoline)) ligands and bears potential
advantages, such as technical simplicity and more easily
attainable diversity, over the two existing methods. The
synthetic methodology was recently extended to the
synthesis of Pybox ligands as we report herein.
The First Solid-Phase Synthesis of
Bis(oxazolinyl)pyridine Ligands
Avi Weissberg, Baruch Halak, and Moshe Portnoy*
School of Chemistry, Raymond and Beverly Sackler Faculty
of Exact Sciences, Tel-Aviv University,
Tel-Aviv 69978, Israel
portnoy@post.tau.ac.il
Received February 6, 2005
The synthetic procedure starts with the immobilization
of a long spacer, 11-bromoundecan-1-ol, on Wang trichlo-
roacetimidate resin (Scheme 1). Dimethyl ester of
chelidamic acid, which can easily be prepared from the
commercially available acid,7 is then efficiently anchored
to the spacer. The key step of the synthesis is the base-
induced aminolysis of the ester groups with â-amino
alcohols that we recently introduced.6a In the case of the
Pybox ligand precursors, this reaction proceeds cleanly
and efficiently for all substituents. The synthesis was
accomplished via chlorodehydroxylation and base-in-
duced cyclization steps. Both steps are highly efficient
and clean for amino alcohols with aliphatic substituents.
However, for phenylglycinol, the last step produces only
a small amount of a significantly contaminated ligand.
To overcome this problem, we applied an alternative
oxazoline-forming procedure, direct cyclization of the
hydroxyamide precursor 1g with Burgess reagent (Scheme
2). This method was previously applied in solution, and
we recently adapted the procedure for the solid-phase
synthesis of oxazolines derived from serine or threo-
nine.8,9
Chiral Pybox (pyridine-2,6-bis(oxazoline)) ligands can be
cleanly and efficiently prepared on polystyrene support via
a five-step solid-phase synthetic sequence. Cu(I)-complexed
polymer-bound Pybox was used as a catalyst in the first
heterogeneously catalyzed asymmetric addition of alkynes
t
to imines. Best enantioselectivity was observed with Bu-
substituted oxazolines.
In recent years, supported catalysts, based on well-
defined catalytic units tethered to an insoluble matrix,
have become the subject of intense research activity. Such
heterogeneous substitutes of homogeneous catalystic
systems demonstrated promising results in a number of
important transformations.1 Herein, we report the prepa-
ration of the polymer-supported tridentate Pybox ligands
and the enantioselective addition of alkynes to imines,
catalyzed by supported Pybox-copper complexes. Both the
synthesis and catalysis are first examples of their kind.
Development of methods for the enantioselective prepa-
ration of chiral compounds, particularly the introduction
of chiral catalysts, is currently one of the core subjects
of organic synthesis. Pybox ligands, which demonstrate
great versatility in complexation of the transition metals,
have attracted increased attention in recent years.2 The
interest in Pybox ligands was inspired by a number of
remarkable, highly enantioselective catalytic processes,
such as hydrosilylation, the reductive aldol reaction, and
the ring opening of meso epoxides, performed by their
complexes.3 Only two examples of immobilization of a bis-
(oxazoline)pyridine (Pybox) ligand have thus far been
1
The acidolytic cleavage of ligands 3, followed by H
NMR, reveals high overall yields (66%-90%) and purity
(80%-95%). Although the oxazolines are hydrolyzed
under cleavage conditions, formation of the characteristic
protonated bis(aminoester) hydrolysis product clearly
demonstrates the existence of oxazolines prior to the
cleavage.10 Formation of the expected Pybox products is
(4) (a) Cornejo, A.; Fraile, J. M.; Garcia, J. I.; Garcia-Verdugo, E.;
Gil, M. J.; Lagaretta, G.; Luis, S. V.; Martinez-Merino; Mayoral, J. A.
Org. Lett. 2002, 4, 3927. (b) Lundgren, S.; Lutsenko, S.; Jo¨nsson, C.;
Moberg, C. Org. Lett. 2003, 5, 3663.
(5) Rechavi, D.; Lemaire, M. Chem. Rev. 2002, 102, 3467.
(6) (a) Weissberg, A.; Portnoy, M. Synlett 2002, 2, 247. (b) Weissberg,
A.; Portnoy, M. Chem. Commun. 2003, 1538.
(1) (a) McNamara, A. C.; Dixon, M. J.; Bradley, M. Chem. Rev. 2002,
102, 3217. (b) Leadbeater, N. E.; Marco, M. Chem. Rev. 2002, 102, 3217.
(c) Song, C. E.; Lee, S.-G. Chem. Rev. 2002, 102, 3495.
(2) Desimoni, G.; Faita, G.; Quadrelli, P. Chem. Rev. 2003, 103, 3119.
(3) (a) Nishiyama, H.; Sakaguchi, H.; Nakamura, T.; Horihata, M.;
Kondo, M.; Itoh, K. Organometallics 1989, 8, 846. (b) Nishiyama, H.;
Yamaguchi, S.; Kondo, M.; Itoh, H. J. Org. Chem. 1992, 57, 4306. (c)
Zhao, C.-X.; Duffey, M. O.; Taylor, S. J.; Morken, J. P. Org. Lett. 2001,
3, 1829. (d) Schaus, S. E.; Jacobsen, E. N. Org. Lett. 2000, 2, 1001.
(7) Nakatsuji, Y.; Bradshaw, J. S.; Tse, P.-K.; Arena, G.; Wilson, B.
E.; Dalley, N. K.; Izatt, R. M. Chem. Commun. 1985, 749.
(8) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 907.
(9) Halak, B.; Portnoy, M. Unpublished results.
(10) Wipf, P.; Miller, C. P. J. Am. Chem. Soc. 1992, 114, 10975.
10.1021/jo050237j CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/03/2005
4556
J. Org. Chem. 2005, 70, 4556-4559

SCHEME 1. Synthesis of Polymer-Bound Pybox Ligandsa
a Reagents and conditions: (a) 11-bromoundecan-1-ol, BF3‚OEt2, cyclohexane/CH2Cl2, rt; (b) dimethyl ester of chelidamic acid, LiH,
DMF, 60 °C; (c) â-amino alcohol, LDA, DMF, 50 °C; (d) PPh3, C2Cl6, THF, rt; (e) DBU, THF, 60 °C.
SCHEME 2. Synthesis of 3ga
TABLE 1. Reaction of Phenyl Acetylene and
Benzilideneaniline in the Presence of 4a
entry
catalyst
solvent
yieldb (%)
ee (%)
1
2
4a
4b
4d
4e
4f
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
90
8
20
44
52
83
82
<5
54
55
60
<5
85
3
77
4
87
5
63
6c
7
4f
20
a Reagents and conditions: Burgess reagent, dioxane, 100 °C.
4g
4f
traces
8
80
also confirmed by gel-phase 13C NMR. Thus, character-
istic changes are observed upon comparison of the spectra
of â-chloroamides with those of oxazolines (the last
synthetic step). For instance, the signals of two carbons,
R and â to the nitrogen, are shifted from 45 and 56 ppm
in the chloroamide 2f to 69 and 76 ppm, respectively, in
the corresponding Pybox ligand 3f.
9d
10e
11
4f
THF
77
4f
THF
THF
56
4f
80, 78, 78f
a Reaction conditions: 1 equiv of N-benzilideneaniline, 1.5 equiv
of phenylacetylene, 10% of 4, 40 °C, 24 h. b NMR-determined yield.
c Catalyst recovered from entry 5. d Catalyst recovered from entry
8. e Catalyst recovered from entry 9. f Three consecutive runs in
the presence of ascorbic acid.
The prepared Pybox ligands were tested in an enan-
tioselective alkynylation of imines. Chiral propargy-
lamines are important building blocks that are used in
the synthesis of drug candidates and natural products.11
Although a number of stoichiometric routes to enan-
tiopure propargylamines are known, catalytic routes to
this type of compounds are scarce.12 Only recently was a
successful reaction, based on homogeneous catalysis with
copper complexes of Pybox, reported.13 Accordingly, we
decided to test the supported Pybox ligands for the first
heterogeneously catalyzed chiral addition of alkynes to
imines leading to propargylamines.
1, ee ) 8%) could be increased in parallel with the
increase in steric size of the substituent, reaching 83%
t
for 4f (R ) Bu, entry 5). Surprisingly, the complex 4g,
derived from the Ph-substituted ligand, the analogue of
which demonstrated high enantioselectivity in solution,13
exhibited disappointing reactivity and formed a practi-
cally racemic product (entry 7). The catalyst recovered
after one catalytic cycle exhibited diminished reactivity,
while the enantioselectivity was unaffected (entry 6). The
reason for the reduced reactivity is, most probably, the
strong propensity of the catalytic complex to undergo
oxidation and, possibly, some leaching of the metal. A
separate experiment demonstrated that CuII complexes
of 3 are not catalytically active in the model reaction. The
remaining Pybox-CuI complex is responsible for the
residual activity as well as preservation of the enantio-
selectivity.
Thus, the resin-bound Pybox were incubated with a
dichloromethane solution of CuOTf, filtered, and washed,
yielding a light brown polymer (eq 1). The polymer-bound
catalysts were tested in a model alkyne addition reaction
between phenylacetylene and benzylideneaniline (eq 2,
Table 1). Our experiments revealed the steric bulk of the
oxazoline substituent strongly influences the enantio-
selectivity. The low ee obtained with 4a (R ) Me) (entry
(11) (a) Kauffman, G. S.; Harris, G. D.; Dorow, R. L.; Stone, B. P.
R.; Parsons, R. L., Jr.; Pesti, J. A.; Magnus, N. A.; Fortunak, J. M.;
Confalone, P. N.; Nugent, W. A. Org. Lett. 2000, 2, 3119. (b) Huffman,
M. A.; Yasuda, N.; Decamp, A. E.; Grabowski, E. J. J. J. Org. Chem.
1995, 60, 1590.
(12) Rae, A.; Ker, J.; Tabor, A. B. Tetrahedron Lett. 1998, 39, 6561.
J. Org. Chem, Vol. 70, No. 11, 2005 4557

to substantial simplification of the spectra upon conversion of
the hydroxyamides to chloroamides.
In an attempt to improve the recyclability of the
catalyst, the reaction was carried out in solvents other
than dichloromethane. Indeed, in THF, the ability to
recycle the catalyst 4f was markedly improved (entries
8-10). Although the ee was lower than in dichlo-
romethane and the yields somewhat decreased during the
three consecutive cycles, the yield in the first run was
higher and the enantioselectivity through the cycles
improved. The trend of decrease in yields, while the
enantioselectivity is preserved, was also observed in the
two other supported Pybox catalytic systems reported.4
The addition of ascorbic acid, as a sacrificial reducing
agent, to the reaction mixture produced a fully recyclable
catalytic system (no change in yield in three consecutive
runs), but the enantioselectivity was lost (entry 11).
It is noteworthy that the tridentate coordination of CuI
seems essential for chiral induction. Both in solution
(according to the literature) and with a supported catalyst
(as observed by us), the use of bidentate oxazoline-
containing ligands leads to a racemic product.5,9
In conclusion, we developed a technically simple and
efficient methodology for the preparation of polymer-
supported Pybox ligands, demonstrating the advantages
of stepwise solid-phase ligand synthesis. We successfully
exploited the catalytic system derived from such ligands
for the first heterogeneously catalyzed chiral addition of
an alkyne to an imine. Investigation of additional asym-
metric transformations based on supported Pybox ligands
is underway.
Representative hydroxyamide characterization: 1e. Following
acidolytic cleavage: 1H NMR (200 MHz, CDCl3/TFA 1:1) δ 8.40
(d, J ) 9.2 Hz, 2H), 7.85 (s, 2H) 4.82 (m, 2H), 4.57 (m, 2H), 4.45
(t, J ) 6.4 Hz, 2H), 4.37 (m, 2H), 4.27 (t, J ) 6.4 Hz, 2H), 1.70-
2.09 (m, 6H), 134-1.36 (m, 14H), 1.09 (d, J ) 6.8 Hz, 6H) 1.05
(d, J ) 6.8 Hz, 6H); partial 13C NMR (100 MHz, CDCl3/TFA 1:1)
δ 171.0, 128.1, 112.7, 71.0, 69.3, 67.3, 56.1, 29.4, 29.0, 28.7, 28.1,
27.7, 25.1, 18.0.
Polymer-Bound Bis-chloro Amides (2a-f). Polymer-bound
bis-â-hydroxy amide (1a-f) resins were suspended in anhydrous
THF (20 mL/g resin) for 10 min. In a second flask, PPh3 (10
equiv) and C2Cl6 (10 equiv) were dissolved in dry THF. This
solution was cannulated to the resin suspension, and the
reaction mixture was stirred overnight at room temperature. The
resin was filtered, washed with THF and CH2Cl2, and then dried
under vacuum.
2b: partial gel-phase 13C NMR (100 MHz, C6H6) δ 150.0,
144.7, 71.9, 69.4, 68.0, 50.5, 47.2, 29.2, 25.9, 25.2, 24.7, 9.6.
Following acidolytic cleavage: 1H NMR (200 MHz, CDCl3/TFA
1:1) δ 8.17 (d, J ) 8.0 Hz, 2H), 7.92 (s, 2H), 4.34-4.40 (m, 6H),
3.68-3.79 (m, 4H), 1.67-1.88 (m, 4H), 1.29-1.32 (m, 14H), 1.00
(t, J ) 6.0 Hz, 6H).
2c. Following acidolytic cleavage: 1H NMR (200 MHz, CDCl3/
TFA 1:1) δ 8.24 (d, J ) 8.8 Hz, 2H), 7.95 (s, 2H), 4.53-4.59 (m,
2H), 4.42 (t, J ) 6.6 Hz, 2H), 4.35 (m, 2H), 3.65-3.84 (m, 4H),
1.60-1.89 (m, 8H), 1.34-1.36 (m, 14H), 0.97 (d, J ) 4.6 Hz, 12H).
2d: partial gel-phase 13C NMR (100 MHz, C6H6) δ 157.9, 149.9,
69.4, 68.1, 50.7, 46.2, 37.0, 29.1, 25.8, 25.2. Following acidolytic
cleavage: 1H NMR (200 MHz, CDCl3/TFA 1:1) δ 8.42 (d, J )
8.6 Hz, 2H), 7.82 (s, 2H), 7.27-7.38 (m, 10H), 4.68-4.71 (m, 2H),
4.42 (t, J ) 6.6 Hz, 2H), 4.26 (m, 2H), 3.71-3.90 (m, 4H), 3.09
(d, J ) 7.4 Hz, 4H), 1.74-1.94 (m, 4H), 1.34-1.37 (m, 14H).
2e: partial 13C NMR (200 MHz, CDCl3/TFA 1:1) δ 147.2, 128.1,
112.7, 71.1, 69.3, 67.3, 56.1, 29.4, 29.0, 28.7, 28.1, 27.7, 25.1,
18.0. Following acidolytic cleavage: 1H NMR (200 MHz, CDCl3/
TFA 1:1) δ 8.27 (d, J ) 9.2 Hz, 2H), 7.80 (s, 2H), 4.36-4.46 (m,
4H), 4.21 (m, 2H), 3.82 (m, 4H), 1.77-2.09 (m, 6H), 1.34-1.36
(m, 14H), 1.09 (d, J ) 6.6 Hz, 6H) 1.05 (d, J ) 6.6 Hz, 6H).
2f: partial gel-phase 13C NMR (100 MHz, C6H6) δ 158.7, 145.6,
71.9, 69.4, 68.0, 56.2, 45.1 34.6, 29.18.0, 26.1, 25.2. Following
acidolytic cleavage: 1H NMR (200 MHz, CDCl3/TFA 1:1): δ 8.13
(d, J ) 9.8 Hz, 2H), 8.00 (s, 2H), 4.30-4.47 (m, 6H), 3.93-4.00
(m, 2H), 3.66-3.71 (m, 2H), 1.78-1.99 (m, 4H), 1.36-1.37 (m,
14H), 1.11 (m, 18H).
Experimental Section
Polymer-Bound 11-Bromoundecan-1-ol. The solution of
11-bromoundecan-1-ol (2 equiv) in CH2Cl2 (20 mL/g resin) was
added dropwise to a suspension of Imidate Wang resin in
cyclohexane (20 mL/g resin). The mixture was stirred at room
temprature for 5 min. Then, a catalytic amount of boron
trifluoride etherate (0.1 equiv) was added, and the suspension
was stirred at room temprature for another 10 min. The resin
was filtered, washed with CH2Cl2, THF, and CH2Cl2, and then
dried under vacuum. Following acidolytic cleavage: 1H NMR
(200 MHz, CDCl3/TFA 1:1) δ 4.41 (t, J ) 6.8 Hz, 2H), 3.42 (t, J
) 6.8 Hz, 2H), 1.70-1.90 (m, 4H), 1.32-1.35 (m, 14H).
Polymer-Bound Dimethyl Ester of Chelidamic Acid.
Polymer-bound 11-bromoundecan-1-ol was suspended in anhy-
drous DMF (20 mL/g resin). In another flask, LiH (8 equiv) was
added to a solution containing the dimethyl ester of chelidamic
acid (5 equiv) in a minimal amount of dry DMF. After 5 min of
stirring, the solution was cannulated to the resin suspension, a
catalytic amount of tetrabutylammonium iodide was added, and
the reaction mixture was stirred for 36 h at 60 °C. The resin
was filtered, washed with DMF, DMF/H2O, H2O, THF, and CH2-
Cl2, and then dried under vacuum. Following acidolytic cleav-
age: 1H NMR (200 MHz, CDCl3/TFA 1:1) δ 8.12 (s, 2H), 4.54 (t,
J ) 6.4 Hz, 2H), 4.43 (t, J ) 6.6 Hz, 2H), 4.21 (s, 6H), 1.77-
2.05 (m, 4H), 1.36-1.39 (m, 14H).
Polymer-Bound Bis-â-hydroxy Chelidamic Amides (1a-
g). The polymer-bound dimethyl ester of chelidamic acid was
suspended in anhydrous DMF (20 mL/g resin). In another flask,
LDA (20 equiv) was added dropwise to the solution of â-amino
alcohol (22 equiv) in a minimal amount of dry DMF at 10 °C.
This solution was mixed for 5 min, cannulated into the suspen-
sion in the first flask and stirred overnight at 60 °C. The resin
was filtered, washed with DMF, DMF/H2O, H2O, THF, and CH2-
Cl2, and then dried under vacuum. The resin-bound species were
usually characterized after the chlorodehydroxylation step, due
Polymer-Bound Pybox Ligands (3a-f). Polymer-bound
bis-chloro amide (2a-f) resins were suspended in anhydrous
THF (20 mL/g resin) to which DBU (100 equiv) was added. The
reaction mixture was stirred for 48 h at 60 °C. The resin was
filtered, washed with DMF, DMF/H2O (1:1), H2O, THF, and CH2-
Cl2, and then dried under vacuum.
3a: partial gel-phase 13C NMR (100 MHz, C6H6) δ 161.8, 148.3,
114.0, 111.4, 73.3, 72.0, 69.5, 67.5, 61.7, 29.2, 25.7, 25.3, 20.7.
Following acidolytic cleavage: 1H NMR (200 MHz, CDCl3/TFA
1:1) δ 7.88 (s, 2H), 5.43 (m, 2H) 4.98 (m, 4H), 4.39 (t, J ) 6.6
Hz, 2H), 4.25 (t, J ) 6.2 Hz, 2H), 1.79 (m, 4H), 1.71 (d, J ) 5.8
Hz, 6H), 1.33 (m, 14H).
3b: partial gel-phase 13C NMR (100 MHz, C6H6) δ 162.0, 148.3,
114.2, 111.6, 71.9, 69.4, 67.6, 29.2, 28.2, 26.0, 25.3, 9.6. Following
acidolytic cleavage: 1H NMR (200 MHz, CDCl3/TFA 1:1) δ 7.92
(s, 2H), 5.48 (t, J ) 9.8 Hz, 2H), 4.93 (t, J ) 9.2 Hz, 2H), 4.83
(m, 2H), 4.38 (t, J ) 6.6 Hz, 2H), 4.22 (t, J ) 6.4 Hz, 2H), 1.90
(m, 8H), 1.31 (m, 14H), 1.05 (t, J ) 7.2 Hz, 6H).
3c: partial gel-phase 13C NMR (100 MHz, C6H6) δ 166.9, 152.8,
114.3, 111.8, 72.9, 69.7, 67.7, 64.7, 44.9, 29.2, 28.2, 26.0, 24.8,
22.4, 21.8. Following acidolytic cleavage: 1H NMR (200 MHz,
CDCl3/TFA 1:1) δ 7.91 (s, 2H), 5.51 (t, J ) 9.6 Hz, 2H), 5.05 (t,
J ) 9.0 Hz, 2H), 4.88 (m, 2H), 4.42 (t, J ) 6.6 Hz, 2H), 4.26 (t,
J ) 6.4 Hz, 2H), 1.74-1.97 (m, 10H), 1.35 (m, 14H), 1.02 (m,
12H).
3d: partial gel-phase 13C NMR (100 MHz, C6H6) δ 162.4, 148.5,
137.5, 114.1, 111.7, 71.6, 69.4, 67.5, 40.9, 40.2, 29.2, 25.3, 22.9.
(13) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2002, 5638.
4558 J. Org. Chem., Vol. 70, No. 11, 2005

Following acidolytic cleavage: 1H NMR (200 MHz, CDCl3/TFA
1:1) 7.87(s, 2H), 7.20-7.37 (m, 10H), 5.15-5.36 (m, 6H), 4.42 (t,
J ) 6.6 Hz, 2H), 4.22 (t, J ) 6.2 Hz, 2H), 3.22 (m, 4H), 1.80 (m,
4H), 1.34 (m, 14H).
dissolved in a minimum amount of CH2Cl2. In another flask,
the resin-bound Pybox ligand (1 equiv) was suspended in CH2-
Cl2. The solution of the first flask was cannulated to the resin
suspension, and the mixture was stirred for 24 h at room
temprature. The resin was filtered, washed with THF and CH2-
Cl2, and dried under vacuum.
3e: partial gel-phase 13C NMR (100 MHz, C6H6) δ 161.9, 148.5,
111.6, 72.4, 70.3, 67.7, 32.5, 29.3, 26.1, 25.2, 18.2. Following
acidolytic cleavage: 1H NMR (200 MHz, CDCl3/TFA 1:1) δ 7.94
(s, 2H), 5.38 (t, J ) 10.2 Hz, 2H), 5.19 (dd, J ) 10.2, 7.4 Hz,
2H), 4.70 (m, 2H), 4.43 (t, J ) 6.6 Hz, 2H), 4.28 (t, J ) 6.4 Hz,
2H), 2.22 (m, 2H), 1.87 (m, 4H), 1.35 (m, 14H), 1.10 (d, J ) 6.8
Hz, 6H), 1.06 (d, J ) 6.8 Hz, 6H).
General Procedure for the Catalysis. N-Benzilidene-
aniline (1 equiv) and phenylacetylene (1.5 equiv) were added to
the suspension of the catalyst (0.1 equiv). The mixture was
heated to 50 °C for 24 h. Then the resin was filtered and washed
twice with CH2Cl2. The crude obtained after evaporation of the
solvent from the combined solution was separated on a silica
gel column (Et2O/hexanes 1:10) to obtain the pure product.
Enantioselectivity was determined by HPLC using a Chiralcel
OD column (hexanes/2-propanol 95:5, flow rate 0.5 mL/min,
detection wavelength 254 nm); tR ) 14.4 min, tR ) 17.7 min.
3f: partial gel-phase 13C NMR (100 MHz, C6H6) δ 162.1, 148.4,
114.2, 111.7, 75.8, 71.9, 69.4, 68.5, 67.6, 33.1, 29.2, 28.3, 26.0,
25.2. Following acidolytic cleavage: 1H NMR (200 MHz, CDCl3/
TFA 1:1) δ 7.95 (s, 2H), 5.30 (m, 4H), 4.62 (dd, J ) 10.4, 7.0 Hz,
2H), 4.43 (t, J ) 6.6 Hz, 2H), 4.28 (t, J ) 6.4 Hz, 2H), 1.84 (m,
4H), 1.35 (m, 14H), 1.08 (m, 18H).
Procedure for the Transformation of 1g to 3g. Compound
1g was suspended in sodium-dried dioxane. Burgess reagent (4
equiv) was then added, and the reaction was refluxed for 4 h.
The resin was filtered and washed with THF, MeOH, THF, and
CH2Cl2 and then dried under vacuum.
Acknowledgment. This work was supported by the
Tel Aviv University Research Fund and the Israel
Science Foundation.
3g: partial gel-phase 13C NMR (100 MHz, C6H6): δ 163.1,
150.5, 114.1, 74.5, 71.9, 69.5, 68.0, 29.1, 25.9, 25.2. Following
acidolytic cleavage: 1H NMR (200 MHz, CDCl3/TFA): δ 7.95 (s,
2H), 7.30-7.50 (m, 10H), 5.83 (m, 4H), 5.35 (m, 2H), 4.44 (t, J
) 6.6 Hz, 2H), 4.28 (t, J ) 6.4 Hz, 2H), 2.01 (m, 2H), 1.84 (m,
2H), 1.31 (m, 14H).
Supporting Information Available: General experimen-
1
tal methods, H NMR of cleavage solutions of resins 2 and 3,
and gel-phase 13C NMR of ligands (3a-f). This material is
available free of charge via the Internet at http://pubs.acs.org.
General Procedure for Complexation of Polymer-
Bound Pybox Ligands. Copper(I) triflate (1.2 equiv) was
JO050237J
J. Org. Chem, Vol. 70, No. 11, 2005 4559