Poly(ethylene glycol)-supported bisoxazolines as ligands for catalytic enantioselective synthesis

Article abstract of DOI:10.1021/jo010077l

Two chiral bisoxazolines (box) supported on a modified poly(ethylene glycol) (PEG) have been prepared by a reaction sequence that involved formation of the properly functionalized box and their attachment to the polymer matrix by means of a spacer and a linker. The solubility properties of PEG allowed use of the supported box as ligands in some catalytic asymmetric transformations carried out under homogeneous conditions and to recover the ligands as if bound to an insoluble support. When the supported box were employed in combination with Cu(II) salts in the Diels-Alder cycloaddition between cyclopentadiene and N-acryloyloxazolidinone, low levels of enantioselectivity were observed (up to 45% ee). Much better results were obtained in the cyclopropanation of styrenes carried out in the presence of CuOTf (up to 93% ee) and in the ene-reaction between α-methylstyrene or methylenecyclohexane and ethylglyoxalate (up to 95% ee). One of the ligands, readily recovered by precipitation and filtration, was recycled two times in the ene-reaction with marginal loss in the catalytic activity and very limited erosion of the enantioselectivity.

Full text of DOI:10.1021/jo010077l

3160
J . Org. Chem. 2001, 66, 3160-3166
P oly(eth ylen e glycol)-Su p p or ted Bisoxa zolin es a s Liga n d s for
Ca ta lytic En a n tioselective Syn th esis
Rita Annunziata, Maurizio Benaglia, Mauro Cinquini, Franco Cozzi,* and Manuela Pitillo
Centro CNR and Dipartimento di Chimica Organica e Industriale, Universita’ degli Studi di Milano,
Via Golgi 19-20133 Milano, Italy
franco.cozzi@unimi.it
Received J anuary 22, 2001
Two chiral bisoxazolines (box) supported on a modified poly(ethylene glycol) (PEG) have been
prepared by a reaction sequence that involved formation of the properly functionalized box and
their attachment to the polymer matrix by means of a spacer and a linker. The solubility properties
of PEG allowed use of the supported box as ligands in some catalytic asymmetric transformations
carried out under homogeneous conditions and to recover the ligands as if bound to an insoluble
support. When the supported box were employed in combination with Cu(II) salts in the Diels-
Alder cycloaddition between cyclopentadiene and N-acryloyloxazolidinone, low levels of enantiose-
lectivity were observed (up to 45% ee). Much better results were obtained in the cyclopropanation
of styrenes carried out in the presence of CuOTf (up to 93% ee) and in the ene-reaction between
R-methylstyrene or methylenecyclohexane and ethylglyoxalate (up to 95% ee). One of the ligands,
readily recovered by precipitation and filtration, was recycled two times in the ene-reaction with
marginal loss in the catalytic activity and very limited erosion of the enantioselectivity.
In tr od u ction
the use of these soluble polymer-supported ligands in
some enantioselective transformations.9
The immobilization of chiral ligands and catalysts on
polymer supports is a current subject of intense research
activity. This effort aims to improve the efficiency of
asymmetric catalysis1 by allowing simple ligand or
catalyst recovery and recycle.
While the use of insoluble polymeric supports has been
widespread,2 immobilization on soluble polymers has
received much less attention.3 This is surprising since
soluble polymers, allowing the reaction to be carried out
under homogeneous conditions, secure higher enantiose-
lectivity and more catalytic cycles than insoluble sup-
ports, as recently demonstrated by J anda and Reger.3e,4
Moreover, a judicious choice of the soluble polymer can
provide an ideal support, that combines the advantages
of running a reaction under homogeneous conditions with
those of recovering and recycling a heterogeneous cata-
lyst.
(2) For a review claiming literature coverage until J uly 1999, see:
(a) Shuttleworth, S. J .; Allin, S. M.; R. D. Wilson, D. Nasturica
Synthesis 2000, 1035-1074. For more recent works on the covalent
immobilization of chiral ligands and catalysts on insoluble polymers,
see the following references. For reactions with salen complexes: (b)
Peukert, S.; J acobsen, E. N. Org. Lett. 1999, 1, 1245-1248. (c) Amis,
D. A.; J acobsen, E. N. J . Am. Chem. Soc. 1999, 121, 4147-4154. (d)
Zhou, X.; Yu, X.; Huang, J .; Li, S.; Li, L.; Che, C. J . Chem. Soc., Chem.
Commun. 1999, 1789-1790. (e) Song, C. E.; Roh, E. J .; Yu, B. M.; Chi,
D. Y.; Kim, S. C.; Lee, K. J . Chem. Soc., Chem. Commun. 2000, 615-
616. (f) Canali, L.; Cowan, E.; Deleuze, H.; Gibson, C. L.; Sherrington,
D. C. J . Chem. Soc., Perkin Trans. 1 2000, 2055-2066. For diethylzinc
addition to aldehydes: (g) Abramson, S.; Lasperas, M.; Gelarneau, A.;
Desplentier-Giscard, D.; Brunel, D. J . Chem. Soc., Chem. Commun.
2000, 1773-1774. (h) Yang, X.; Sheng, Da, C.; Wang, H.; Su, W.; Wang,
R.; Chen, A. S. C. J . Org. Chem. 2000, 65, 295-296. (i) Bae, S. J .;
Kim, S. W.; Hyeon, T.; Kim, R. M. J . Chem. Soc., Chem. Commun.
2000, 31-32. (j) Hodge, P.; Sung, D. W. L.; Stratford, P. W. J . Chem.
Soc., Perkin Trans. 1 1999, 2335-2342. (k) ten Holte, P.; Wijgarganges,
J .; Thijs, L.; Zwanenburg, B. Org. Lett. 1999, 1, 1095-1097. (l) Brawer,
A. J .; van der Linden, H.; Liskamp, R. M. J . J . Org. Chem. 2000, 65,
1750-1757. (m) Dangel, B. D.; Polt, R. Org. Lett. 2000, 2, 3003-3006.
For cycloaddition reactions: (n) Heckel, A.; Seebach, D. Angew. Chem.,
Int. Ed. 2000, 39, 163-165. (o) Altava, B.; Burguete, M. I.; Fraile, J .
M.; Garcia, J . I.; Luis, S. V.; Mayoral, J . A.; Vincent, M. J . Angew.
Chem., Int. Ed. 2000, 39, 1503-1506. (p) Kobayashi, S.; Kusakabe,
K.; Ishitani, H. Org. Lett. 2000, 2, 1225-1227. (q) Burguete, M. I.;
Fraile, J . M.; Garcia, J . I.; Garcia-Verdugo, E.; Luis, S. V.; Mayoral, J .
A. Org. Lett. 2000, 2, 3905-3908; and references therein. For alkene
dihydroxylation: (r) Salvadori, P.; Pini, D.; Petri, A. Synlett 1999,
1181-1190. For miscellaneous reactions: (s) ter Halle, R.; Colasson,
B.; Schulz, E.; Spagnol, M.; Lemaire, M. Tetrahedron Lett. 2000, 41,
643-646. (t) Fujii, AA.; Sodeoka, M. Tetrahedron Lett. 1999, 40, 8011-
8014. (u) Itsuno, S.; Matsumoto, T.; Sato, D.; Inoue, T. J . Org. Chem.
2000, 65, 5879-5881.
Modified poly(ethylene glycol)s (PEGs) of Mw > 2000
Da recently emerged as readily functionalized, inexpen-
sive polymers that, conveniently, are soluble in some
solvents and insoluble in a few other solvents.5 Recently,
the monomethyl ether of PEG
(MeOPEG) has suc-
5000
cessfully being used for supporting chiral ligands to be
transformed in catalysts for the asymmetric dihydroxy-
lation 3a,b and epoxidation reactions.3e MeOPEG has also
been employed by us for the immobilization of achiral6
and chiral7 catalysts. In both cases the obtained species
showed catalytic activity and stereocontrol ability very
similar to (and in some instances even superior than)
those displayed by the nonsupported catalysts.
(3) (a) Han, H.; J anda, K. D. Tetrahedron Lett. 1997, 38, 1527-1530,
and references therein. (b) Bolm, C.; Gerlach, A. Eur. J . Org. Chem.
1956, 21, 1-27, and references therein. (c) Bolm, C.; Dinter, C. L.;
Seger, A.; Ho¨cker, H.; Brozo, J . J . Org. Chem. 1999, 64, 5730-5731.
(d) Fan, Q.; Ren, C.; Yeung, C.; Hu, W.; Chan, A. S. C. J . Am. Chem.
Soc. 1999, 121, 7407-7408. (e) Reger, T. S.; J anda, K. D. J . Am. Chem.
Soc. 2000, 122, 6929-6934. (f) Glos, M.; Reiser, O. Org. Lett. 2000, 2,
2045-2048. For leading references to the immobilization of achiral
catalysts, see: (g) Bergbreiter, D. E.; Osborn, P. L.; Liu, Y. J . Am.
Chem. Soc. 1999, 121, 9531-9538, and references therein. (h) Neu-
mann, R.; Cohen, M. Angew. Chem., Int. Ed. Engl. 1997, 36, 1738-
1740.
As a part of these studies, here we report the im-
mobilization on MeOPEG of two chiral ligands belonging
to the extremely useful bisoxazoline (box) family,8 and
(1) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley:
New York, 1994.
10.1021/jo010077l CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/06/2001

Ligands for Catalytic Enantioselective Synthesis
J . Org. Chem., Vol. 66, No. 9, 2001 3161
Sch em e 1. Differ en t Ap p r oa ch es to th e Syn th esis
of MeOP EG-Su p p or ted Bisoxa zolin es
Sch em e 2. Syn th esis of Box 8a a n d 8b
Resu lts a n d Discu ssion
Two different strategies can in principle be followed
to prepare MeOPEG-supported box: reaction of a pre-
formed, metalated box with a MeOPEG activated toward
nucleophilic substitution (Scheme 1, path a); or construc-
tion of the box moiety on a MeOPEG carrying a malonate-
type substitution (Scheme 1, path b). Path b had the
advantages of a polymer-supported stepwise synthesis
(easy product isolation and purification) and in principle
seemed more appealing. However, preliminary experi-
ments showed MeOPEG malonic acid derivatives to be
poorly reactive. Therefore, path a was pursued.
The synthesis of the box ligands was designed, taking
into account (i) the necessity of introducing a spacer to
separate the MeOPEG core from the ligand; (ii) a mild
and efficient reaction to attach the box/spacer array to
the polymer; and (iii) the need for disubstitution at the
box bridging atom, a feature known to enhance the
stereoselectivity of box-promoted reactions.8 On the basis
of our previous experience in the field of PEG-supported
synthesis of small organic molecules,6,10 the reaction
sequence outlined in Scheme 2 was performed.
O-Benzyl and -allyl protected 4-alkoxybenzyl bromides
1 and 2 were easily obtained from the commercially
available 4-hydroxymethylphenol by phenoxide ion alky-
lation and reaction with PBr3 (80 and 82% overall yield
for 1 and 2, respectively). These bromides were used to
alkylate the lithium enolate of dimethyl methylmalonate
to afford esters 3 (R ) benzyl, 86%) and 4 (R ) allyl,
94% yield). These were then transformed by standard
procedures into the corresponding dichlorides that were
obtained as crude products in g 95% yield.
Conversion to box was accomplished by a stepwise
procedure11 involving amide formation with commercially
available (S)-amino alcohols 5a (R ) Ph) and 5b (R )
t-Bu), followed by alcohol activation as tosylate (R ) Ph)
or mesylate (R ) t-Bu), and oxazoline ring closure
promoted by DMAP. The overall yields from esters 3 and
4 were 47% for 6a , 45% for 6b, 40% for 7a , and 72% for
7b.
Finally, deprotection of the phenol oxygen was studied.
After some attempts, it was found out that microwave-
promoted transfer hydrogenation12 gave 8a and 8b in 66
and 32% yield, respectively. These products were ob-
tained in higher yield (67 and 82%, respectively) by
deallylation of 7a ,b, that was best accomplished by a
modification of a literature procedure13 involving the use
of Pd(OAc)2 and PPh3 in EtOH in the presence of SiO2.
(4) For recent studies on the effect of polymer matrixes on the
reactivity of supported organic molecules, see: (a) Li, W.; Yan, B. J .
Org. Chem. 1998, 63, 4092-4097. (b) Gerritz, S. W.; Trump, R. P.;
Zuercher, W. J . J . Am. Chem. Soc. 2000, 122, 6357-6363.
(5) Review: Gravert, D. J .; J anda, K. D. Chem. Rev. 1997, 97, 489-
509.
(6) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Tocco, G.
Org. Lett. 2000, 2, 1737-1739.
(7) Benaglia, M.; Celentano, G.; Cozzi, F. Adv. Synth. Catal. 2001,
343, 171-173.
(8) Review: (a) Ghosh, A. K.; Mathivanan, P.; Cappiello, J . Tetra-
hedron: Asymmetry 1998, 9, 1-45.
(9) During the completion of this work, two syntheses of polymer-
supported bisoxazolines have been reported. In the first case (ref 3f)
the new ligands aza-bisoxazolines were synthesized, attached to
MeOPEG, and tested in the asymmetric cyclopropanation of styrene.
In the second case (ref 2q) different insoluble polymers containing
bisoxazoline units have been prepared and used in the same reaction.
The results obtained with these supported ligands are discussed in
the text.
(11) (a) Denmark, S. E.; Nakajima, N.; Nicaise, O. J . C.; Faucher,
A.-M.; Edward, J . P. J . Org. Chem. 1995, 60, 4884-4892. (b) Evans,
D. A.; Peterson, G. S.; J ohnson, J . S.; Barnes, D. M.; Campos, K. R.;
Woerpel, K. A. J . Org. Chem. 1998, 63, 4541-4544.
(12) Banik, B. K.; Barakat, K. J .; Wagle, D. R.; Manhas, M. S.; Bose,
A. K. J . Org. Chem. 1999, 64, 5746-5753.
(10) (a) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Ressel,
S. J . Org. Chem. 1998, 63, 8628-8629. (b) Benaglia, M.; Cinquini, M.;
Cozzi, F. Tetrahedron Lett. 1999, 40, 2019-2020. (c) Annunziata, R.;
Benaglia, M.; Cinquini, M.; Cozzi, F. Chem. Eur. J . 2000, 6, 133-138.
(13) Guibe’, F. Tetrahedron 1998, 54, 2967-3042, and references
therein.

3162 J . Org. Chem., Vol. 66, No. 9, 2001
Annunziata et al.
Ta ble 1. En a n tioselective Rea ction s Ca ta lyzed by
Liga n d s 10a ,b
Sch em e 3. Syn th esis of MeOP EG-Su p p or ted Box
Liga n d s 10a a n d 10b
isolated
yield %
diast.
ratioa
eq
catalyst (mol %)
product
ee %b
1
1
1
1
2
2
3
4
5
4
4
10b/Cu(OTf)2 (15)
10b/Cu(SbF6)2 (15)
10b/Cu(OTf)2 (15)c
10b/Cu(OTf)2 (15)d
10b/CuOTf (10)
10b/CuOTf (10)
10b/CuOTf (10)
10a /Cu(OTf)2 (10)
10a /Cu(OTf)2 (10)
10a /Cu(OTf)2 (10)e
10a /Cu(OTf)2 (10)f
11
11
11
11
12
12
13
14
15
14
14
91
98
70
83
45
63
45
96
91
91
93
>98:2
>98:2
>98:2
>98:2
70:30
77:23
-
0
5
30
45
87
91
93
95
87
90
88
-
-
-
-
a
For product 11: endo:exo ratio; for product 12: trans:cis ratio.
These ratios were determined by 1H NMR on the crude reaction
Sch em e 4. En a n tioselective Rea ction s Ca ta lyzed
by Meta l Com p lexes of Box Liga n d s 10a a n d 10b
products. As determined by 1H NMR/chiral shift reagent tech-
b
nique (for 11), by optical rotation measurement (on pure samples
of 12 and 13 obtained by flash chromatography), or by the Mosher
ester method (for 14 and 15); in the case of compound 12 the ee
determined by optical rotation was confirmed by chiral HPLC.
c With a sample of ligand prepared by reaction of the Cs salt of
d
8b with 9 and thoroughly washed with water. With a sample of
e
ligand prepared by reaction of the Bu4N+ salt of 8b with 9. With
a sample of ligand employed in eq 4 and recovered and recycled
for the 2nd run. f With a sample of ligand employed for two runs
in eq 4 and recovered and recycled for the 3rd run.
as that of other Lewis acids (Mg(OTf)2,15 MgI2/I2 16) in
combination with ligand 10a .
Many factors can be responsible for the observed poor
enantioselectivity. For instance, the supported ligands
10a ,b lack the C2 symmetry common to the most effective
box ligands for the Diels Alder reaction.8 However, we
could show that the complex formed by nonsupported box
7b and Cu(OTf)2 catalyzed the reaction of eq 1 leading
to 11 in 88% yield, complete endo selectivity, and 95%
enantiomeric excess (ee).17
PEG itself was also considered as a potential disturbing
factor for a metal-promoted reaction such as that of eq
1, on the basis of the possible interference exerted by the
PEG oxygens with the box/copper (II) coordination pro-
cess. However, this phenomenon was also ruled out when
the synthesis of 11 performed in the presence of the
commercially available gem-dimethyl-substituted box
derived from (S)-tert-leucinol (8b with two methyls at the
bridging carbon atom), Cu(OTf)2, and the bismethyl ether
of PEG2000 gave the product in 90% yield and 96% ee.
Another explanation for the poor enantiocontrol ex-
erted by ligand 10b in eq 1 was envisaged in the possible
contamination by (1H NMR undetectable) minor amounts
of Cs2CO3 that could coprecipitate during ligand isolation.
Cs2CO3 could provide a carbonate counterion for copper-
(II) other than the triflate and/or Cs ions that can possibly
act as catalysts per se. In both cases a poorly enantiose-
lective catalyst can be at work.18 Partial support to this
hypothesis was found when the Diels-Alder cycloaddi-
Mesylate 9 (easily prepared in >98% yield from
MeOPEG)10c was selected for immobilization of box 8a ,b
(Scheme 3). The reaction was performed in DMF using
different bases to generate the phenoxide ion. Supported
box 10a and 10b were obtained in 90 and 92% yield using
Cs2CO3, 60 and 57% yield using NaH, and 83 and 87%
yield using Bu4N+HO- (see the Experimental Section for
isolation, purification, and yield and purity determination
of PEG-supported compounds).
The supported ligands 10a ,b were then tested in
the representative enantioselective transformations re-
ported in Scheme 4 (eqs 1-5). The results were collected
in Table 1.
(14) Evans, D. A.; Miller, S. J .; Lectka, T.; von Matt, P. J . Am. Chem.
Soc. 1999, 121, 7559-7573.
(15) Carbone, P.; Desimoni, G.; Faita, G.; Filippone, S.; Righetti, P.
Tetrahedron 1998, 54, 6099-6110.
The Diels Alder cycloaddition between cyclopentadiene
(10 mol equiv) and N-acryloyloxazolidinone (1.0 mol
equiv) was carried out in CH2Cl2 in the presence of 15
mol % each of ligand 10b and Cu(OTf)2 (-78 °C for 3 h
and then from -78 °C to RT, total reaction time 15 h).14
The reaction occurred to afford adduct 11 in good yield,
excellent endo stereoselectivity, but with no enantiose-
(16) Corey, E. J .; Ishihara, K. Tetrahedron Lett. 1992, 33, 6807-
6810.
(17) For a recent discussion on the influence of the substitution
pattern at the box bridging carbon on the steric course of a box-
mediated asymmetric synthesis, see Denmark, S. E.; Stiff, C. M. J .
Org. Chem. 2000, 65, 5875-5878, and references therein.
(18) For a discussion on the importance of Cu(II) counterions in
determining the stereoselectivity of the box/Cu(II)-catalyzed Diels Alder
reaction, see ref 14.
14
lectivity. Also the use of Cu(SbF6)2 was unsuccessful,

Ligands for Catalytic Enantioselective Synthesis
J . Org. Chem., Vol. 66, No. 9, 2001 3163
tion was run with a sample of 10b prepared by reaction
of the Cs salt of 8b with 9, that was thoroughly washed
with water and reprecipitated. In this case the adduct
11 was obtained in 70% yield and 30% ee. Further
improvement of the enantioselectivity was observed using
a sample of ligand obtained by reacting PEG 9 with the
phenoxide ion of box 8b prepared with Bu4N+HO- as
base. This reaction releases Bu4N+MsO-, a species that
being soluble in diethyl ether can readily be eliminated
during the purification of 10b, affording a “counterion
free” ligand. The use of this ligand in eq 1 led to the
formation of adduct 11 in 83% yield and 45% ee.19
The low degree of enantioselectivity observed in the
Diels Alder cycloadditions remained unexplained and was
even more surprising in the light of the much better
results obtained in other asymmetric catalytic transfor-
mations promoted by the supported box ligands.
addition of R-methylstyrene and methylenecyclohexane
(1 mol equiv) to ethyl glyoxylate (50% solution in toluene,
10 mol equiv) carried out from 0 °C to RT for 18 h in
CH2Cl2 in the presence of 10 mol % each of ligand 10a
and Cu(OTf)2 afforded adducts 14 and 15 in 96 and 91%
yield, and 95 and 87% ee, respectively (ee determined
by the Mosher ester method).22 Using the unsupported
catalytic system at identical concentration, Evans23
isolated adducts 14 and 15 in higher yields (99% for both
compounds) and in 89 and 87% ee, respectively.
The recovery and recycle of the supported ligands was
then studied in the case of eq 4. The high enantioselec-
tivity of this reaction was considered a probing test to
show erosion of the ligand efficiency upon recycle. When
a sample of catalyst employed in the synthesis of com-
pound 14 was recovered by precipitation and filtration,
1
the isolated material showed a poorly resolved H NMR
The cyclopropanation of styrene (5 mol equiv) carried
out with ethyl diazoacetate (1 mol equiv, addition time
1.5 h) in the presence of 10 mol % each of ligand 10b
and CuOTf in CH2Cl2 (20 h, RT; Scheme 4, eq 2) gave a
70:30 mixture of the trans:cis cyclopropane adducts in
45% yield.The major trans isomer 12 had an 87% ee. An
increase of the time of addition of ethyl diazoacetate from
1.5 to 5.0 h and the reaction time from 20 to 40 h led to
12 in 63% yield and 91% ee (trans:cis ) 77:23). When
the reaction was carried out on 1,1-diphenylethylene (eq
3) under the same conditions, adduct 13 was obtained in
45% yield and 93% ee.20
spectrum, possibly because it contained an undetermined
amount of Cu(II) ions.24 Decomplexation of the pale green
CH2Cl2 solution of this species with a 0.3 M aqueous
solution of KCN gave back ligand 10a in 85% isolated
yield.25 This recovered ligand was employed in the
reaction of eq 4, leading to compound 14 in slightly lower
yield (91 vs 96%) and ee (90 vs 95%). A second recycle
afforded 14 in 93% yield and 88% ee.
Con clu sion s
In conclusion, a modified poly(ethylene glycol) has been
used for the immobilization of ad hoc synthesized, enan-
tiomerically pure bis-oxazolines, that have been suitably
functionalized for anchoring to the polymer. The sup-
ported ligands were employed in combination with Cu-
(II) and Cu(I) salts in some representative homogeneous
catalytic asymmetric reactions. The results depended on
the reaction type. Poor enantioselectivity was observed
in the Diels-Alder cycloaddition between N-acryloylox-
azolidinone and cyclopentadiene (up to 45% ee). Better
stereocontrol was observed in the cyclopropanations of
styrene and 1,1-diphenylethylene with ethyl diazoacetate
(up to 93% ee), and in the ene-reactions between ethyl-
glyoxalate and R-methylstyrene or methylenecyclohexane
(up to 95% ee). In the last two reactions, ee comparable
to those observed with structurally related, nonsupported
ligands were observed. Experimentally simple recovery
and recycling of one of the ligand was shown to be
possible with marginal erosion of the catalytic activity
and very limited loss in the enantioselectivity. As a
These results were inferior to those observed by Evans
while studying the same reactions carried out with
21a
the gem-dimethyl-substituted box related to 10b (1 mol
% of catalyst). In this case, compound 12 was obtained
in 99% ee (77% yield for the trans:cis 73:27 mixture), and
compound 13 in 70% yield and 99% ee. Another relevant
comparison can be made between our results and those
obtained by Reiser with a similarly substituted, MeOPEG-
supported aza-bisoxazoline (2.2 mol % of catalyst).3f In
this case, cyclopropyl esters 12 and 13 were obtained in
69 and 78% yield, and 91 and 90% ee, respectively.
Finally, it is worth mentioning that our PEG-supported
ligand perfomed better than those obtained by Mayoral
with insoluble polymers containing various bisoxazoline
ligands (up to 79% ee for compound 12).2q
From these comparisons it can be concluded that the
catalytic activity of the 10b/CuOTf complex is inferior
to both that of Evans’s nonsupported catalyst and (at a
lesser extent) of Reiser’s supported aza-bisoxazoline/
CuOTf complex. In terms of enantioselectivity, however,
the two MeOPEG-supported catalysts behaved very
similarly, with a slight preference for our ligand. Once
again, however, immobilization of chiral ligands on
soluble polymeric supports led to an enantioselective
catalytic system more efficient than its heterogeneous
counterpart, as elsewhere shown by J anda.3c
(22) The ee of both alcohols 14 and 15 were determined by 1H NMR
analysis of the corresponding Mosher’s esters obtained by reaction with
the (R)-enantiomer of the Mosher’s acid chloride. The esters gave
signals identical to those reported by Evans (see the Supporting
Information of ref 23). For the esters of compound 14 the diagnostic
signals were those of the vinyl protons that resonated at δ 5.40 and
5.22 for the major (R,R)-isomer and at δ 5.23 and 5.02 for the minor
(S,R)-isomer. Since the peaks of the minor isomer were barely
detectable, their identity was unambiguously established by preparing
the enantiomer of the (S,R)-isomer reacting 14 with the (S) acid
chloride. The diagnostic peaks for the esters derived from alcohol 15
were the broad singlets of the vinyl proton at δ 5.52 for the major (R,R)-
isomer and at δ 5.22 for the minor (S,R)-isomer, and the singlets of
the methoxy protons at δ 3.56 for the major isomer and at δ 3.64 for
the minor isomer.
The good levels of stereocontrol observed in the cyclo-
propanation reactions were maintained by the ene-
reaction described in eqs 4 and 5 (Scheme 4). The
(19) It is worth mentioning that insertion of a longer spacer between
the box ligand and the PEG core (by two or three iterations of the -O-
Ph(CH2)3-O unit) did not lead to an improvement of the ee of adduct
11.
(23) Evans, D. A.; Tregay, S. W.; Burgey, C. S.; Paras, N. A.;
Vojkovsky J . Am. Chem. Soc. 2000, 122, 7936-7943.
(20) Remarkably, in the cyclopropanation reaction high ee were
obtained independently of the method of preparation of the ligand.
(21) (a) Evans, D. A.; Woerpel, K. A.; Hinman, M. N.; Faul, M. M.
J . Am. Chem. Soc. 1991, 113, 726-728. See also: (b) Lowenthal, R.
E.; Abiko, A.; Masamune, S. Tetrahedron Lett. 1990, 31, 6005-6009.
(24) Further support to this hypothesis was found when a sample
of the recovered material was shown to catalyze the reaction of eq 4,
leading to compound 14 in 45% isolated yield and 83% ee.
(25) An excess of KCN was used to ensure complete Cu(II) removal
from the ligand.

3164 J . Org. Chem., Vol. 66, No. 9, 2001
Annunziata et al.
(s, 3H). Anal. Calcd for C16H20O5: C, 65.74; H, 6.90. Found:
C, 65.62; H, 6.79.
whole, these results confirm that chiral ligands im-
mobilized on a soluble polymeric matrix can partecipate
in enantioselective, catalytic transformations at least as
efficiently as their counterparts supported on insoluble
polymers.
Ester Hyd r olysis. This was performed by treating a 0.1
M solution of the esters 3 and 4 (8.0 mmol) in a 3:1 EtOH:
water mixture (80 mL) with solid KOH (1.46 g, 25.6 mmol) at
reflux for 48 h. The crude acids were obtained in quantitative
yield by acidification with 1 N aqueous HCl, followed by
extraction with CH2Cl2, anidrification, and evaporation of the
solvent under vacuum. The benzyl-protected acid had mp 165
°C; the allyl protected acid had mp 126-128 °C.
Syn th esis of th e Acid Ch lor id es. This was performed by
treating a solution of the acids (3.34 mmol) in dry toluene (25
mL) with a 10-fold excess of freshly distilled thionyl chloride
(2.45 mL, 33.4 mmol) at reflux for 4 h. The solvent was then
evaporated under vacuum and the oily residue thoroughly
dried under high vacuum. The crude dark yellow products
were used as such.
Syn th esis of th e Am id es. To a stirred solution of amino
alcohols 5a ,b (8.35 mmol) and triethylamine (1.86 mL, 13.4
mmol) in dry CH2Cl2 (20 mL) stirred under nitrogen was added
a solution of the acid chloride (3.34 mmol) in CH2Cl2 (10 mL)
dropwise. The mixture was stirred at RT for 15 h, and the
reaction was quenched by addition of a saturated aqueous
solution of ammonium chloride. The aqueous phase was
extracted three times with CH2Cl2, and the combined organic
phases were dried and concentrated under vacuum to give the
crude products. These were purified by flash chromatography
with a 9:1 CH2Cl2:MeOH mixture as eluant.
Exp er im en ta l Section
1
Gen er a l. H NMR spectra were recorded at 300 MHz and
were referenced to tetramethylsilane (TMS) at 0.00 ppm. 13C
NMR spectra were recorded at 75 MHz and were referenced
to 77.0 ppm in chloroform-d (CDCl3). Optical rotations were
measured at the Na-D line in a 1 dm cell at 22 °C. IR spectra
were recorded on thin film or as solution in CH2Cl2.
All the PEG samples were melted at 80 °C in a vacuum for
30 min before use to remove traces of moisture. After reaction,
PEG-supported product purification involved evaporation of
the reaction solvent in vacuum and addition of the residue
dissolved in a few milliliters of CH2Cl2 to diethyl ether (50 mL
g-1 of polymer), which was stirred and cooled at 0 °C. After
20-30 min stirring at 0 °C, the obtained suspension was
filtered through a sintered glass filter and the solid repeatedly
washed on the filter with diethyl ether (up to 100 mL g-1 of
polymer, overall).
Yield a n d P u r ity Deter tm in a tion of P EG-Su p p or ted
Com p ou n d s. The yield of the PEG-supported compounds
were determined by weight with the assumption that Mw is
5000 Da for the PEG fragment. The Mw actually ranged from
4500 to 5500. The indicated yields were for pure compounds.
The purity of these compounds was determined by 1H NMR
analysis in CDCl3 at 300 MHz with presaturation of the
methylene signals of the polymer at δ ) 3.63. In recording
the NMR spectra, a relaxation time of 6 s and an acquisition
time of 4 s were used to ensure complete relaxation and
accuracy of the integration. The relaxation delay was selected
after T1 measurements. The integration of the signals of the
PEG CH2OCH3 fragment at δ ) 3.30 and 3.36 were used as
internal standard. The estimated integration error was ( 5%.
(S,S)-Bis-N-1-(1-p h en yl-2-h yd r oxyeth yl) 2-m eth yl-2-(4-
ph en ylm eth oxy)-ph en yl m eth yl 1,3-pr opan diam ide (fr om
5a ). Yield 82%. Thick yellow oil. [R]22D +32.1 (c 1.1 in CHCl3).
1
IR: 3349, 1672, 1510, 1265 cm-1. H NMR: δ 7.33-7.04 (m,
15H), 6.88 (B part of an AB system, J ) 8.5 Hz, 2H), 6.69 (A
part of an AB system, J ) 8.5 Hz, 2H), 6.00 (bs, 2H), 5.02 (m,
2H), 4.92 (s, 2H), 4.10 (bs, 2H), 3.80 (B part of an AB system,
J ) 12.0, 4.1 Hz, 2H), 3.73 (A part of an AB system, J ) 6.8,
4.1 Hz, 2H), 3.18 (B part of an AB system, J ) 13.5 Hz, 1H),
3.02 (A part of an AB system, J ) 13.5 Hz, 1 H), 1.32 (s, 3H).
13C NMR: δ 174.0, 157.8, 143.0, 138.6, 131.1, 129.8, 128.8,
128.3, 127.9, 127.8, 127.4, 126.6, 114.5, 69.9, 66.2, 56.0, 55.0,
43.9, 18.7. Anal. Calcd for C34H36N2O5: C,73.89; H, 6.56; N,
5.07. Found: C, 73.72; H, 6.69; N, 4.93.
Syn th esis of Box 8a ,b. These compounds were prepared
by a multistep synthesis starting from the known benzyl
bromides 126 and 2.27
(S,S)-Bis-N-2-(1-h yd r oxy-3,3-d im eth ylbu tyl) 2-m eth yl-
2-(4-p h en ylm eth oxy)-p h en ylm eth yl 1,3-p r op a n d ia m id e
Syn th esis of th e Bis-Alk yla ted Ma lon a tes 3 a n d 4. To
a stirred solution of LDA (10.7 mmol) in dry THF (30 mL)
cooled at 0 °C under nitrogen was added dimethyl methyl
malonate (1.3 mL, 9.75 mmol) in THF, 10 mL) dropwise. After
1 h stirring at 0 °C, the benzyl bromide (9.75 mmol) in THF
(10 mL) was added dropwise, and the reaction mixture was
stirred for 1 h at 0 °C and then 15 h at RT. The rection was
quenched by the addition of a saturated aqueous solution of
NaCl (20 mL), and the resulting mixture was extracted three
times with 20 mL of Et2O. The combined organic phases were
dried over Na2SO4 and concentrated under vacuum. The
residue was purified by flash chromatography with a 9:1
hexanes:EtOAc mixture as eluant.
(fr om 5b). Yield 90%. Thick yellow oil. [R]22 -5.9 (c 0.2 in
D
1
CHCl3). IR: 3358, 1672, 1510, 1266 cm-1. H NMR: δ 7.46-
7.33 (m, 5H), 7.13 (B part of an AB system, J ) 8.2 Hz, 2H),
6.93 (d, J ) 9.0 Hz, 1H), 6.87 (A part of an AB system, J ) 8.2
Hz, 2H), 6.67 (d, J ) 9.0 Hz, 1H), 5.04 (s, 2H), 3.93-3.73 (m,
4H), 3.50-3.37 (m, 2H), 3.05 (bs, 1H), 2.95 (A part of an AB
system, J ) 13.4 Hz, 1H), 2.65 (bs, 1H), 1.35 (s, 3H), 0.95 (s,
9H), 0.87 (s, 9H). 13C NMR: δ 174.0, 173.0, 157.5, 137.0, 131.2,
128.9, 128.5, 127.9, 127.4, 114.6, 70.0, 63.0, 62.4, 60.1, 59.6,
55.0, 43.6, 33.5, 33.1, 26.8, 18.2. Anal. Calcd for C30H44N2O5:
C, 70.28; H, 8.65; N, 5.46. Found: C, 70.51; H, 8.77; N, 5.39.
(S,S)-Bis-N-1-(1-p h en yl-2-h yd r oxyeth yl) 2-m eth yl-2-[4-
(1-p r op en yl-3-oxy) p h en ylm et h yl] 1,3-p r op a n d ia m id e
Dim eth yl 2-Meth yl-2-(4-ph en ylm eth oxy)ph en ylm eth yl-
(fr om 5a ). Yield 70%. Pale yellow solid, mp 58-60 °C. [R]22
1,3-p r op a n d ioa te 3. Yield 86%. White solid, mp 70-71 °C.
D
IR: 1735, 1510, 1245 cm-1 1H NMR: δ 7.50-7.35 (m, 5H),
.
+32.1 (c 0.6 in CHCl3). IR: 3332, 1642, 1511 cm-1. H NMR:
1
7.08 (B part of an AB system, J ) 8.5 Hz, 2H), 6.90 (A part of
an AB system, J ) 8.5 Hz, 2H), 5.00 (s, 2H), 3.75 (s, 6H), 3.15
(s, 2H), 1.33 (s, 3H). Anal. Calcd for C20H22O5: C, 70.16; H,
6.48. Found: C, 70.02; H, 6.61.
δ 7.33-7.25 (m, 8H), 7.17 (m, 2H), 6.97 (B part of an AB
system, J ) 8.5 Hz, 2H), 6.72 (A part of an AB system, J )
8.5 Hz, 2H), 6.00 (m, 1H), 5.43 (dq, J ) 17.2, 1.8 Hz, 1H), 5.30
(dq, J ) 10.2, 1.4 Hz, 1H), 5.12 (m, 2H), 4.49 (d, J ) 5.0 Hz,
2H), 3.93-3.77 (m, 4H), 3.28 (B part of an AB system, J )
13.5 Hz, 1H), 3.13 (part A of an AB system, J ) 13.5 Hz, 1 H),
1.39 (s, 3H). 13C NMR: δ 173.5, 172.8, 157.6, 138.6, 138.5,
133.3, 131.1, 128.8, 128.7, 128.3, 127.8, 127.7, 126.7, 126.6,
117.6, 114.4, 68.7, 66.1, 66.0, 55.9, 55.8, 43.8, 18.6. Anal. Calcd
for C30H34N2O5: C, 71.69; H, 6.82; N, 5.57. Found: C, 71.53;
H, 6.66; N, 5.48.
Dim eth yl 2-Meth yl-2-[4-(1-pr open yl-3-oxy)ph en ylm eth -
yl]-1,3-p r op a n d ioa te 4. Yield 94%. Colorless liquid. IR: 1735,
1
1510, 1245 cm-1. H NMR: δ 7.03 (B part of an AB system, J
) 8.6 Hz, 2H), 6.83 (A part of an AB system, J ) 8.6 Hz, 2H),
6.00 (m, 1H), 5.41 (dq, J ) 17.2, 1.5 Hz, 1H), 5.28 (dq, J )
10.2, 1.4 Hz, 1H), 4.51 (m, 2H), 3.73 (s, 6H), 3.18 (s, 2H), 1.36
(S,S)-Bis-N-2-(1-h yd r oxy-3,3-d im eth ylbu tyl) 2-m eth -
yl-2-[4-(1-p r op en yl-3-oxy) p h en ylm eth yl] 1,3-p r op a n d i-
(26) Cho, H. F.. Mak, C. C. J . Org. Chem. 1997, 62, 5116-5127. In
this paper compound 1 was synthesized en route to an achiral dendritic
box ligand.
(27) Nakayama, T.; Nomura, M.; Haga, K.; Ueda, M. Bull. Chem.
Soc. J pn. 1998, 71, 2979-2984.
a m id e (fr om 5b). Yield 90%. White solid, mp 46-48 °C. [R]22
D
-5.1 (c 0.5 in CHCl3). IR: 3358, 1662, 1510, 1265 cm-1 1H
.
NMR: δ 7.11 (B part of an AB system, J ) 8.5 Hz, 2H), 7.00

Ligands for Catalytic Enantioselective Synthesis
J . Org. Chem., Vol. 66, No. 9, 2001 3165
(d, J ) 7.0 Hz, 1H), 6.80 (A part of an AB system, J ) 8.5 Hz,
2H), 6.61 (d, J ) 7.0 Hz, 1H), 6.05-5.95 (m, 1H), 5.43 (dq, J
) 17.2, 1.5 Hz, 1H), 5.30 (dq, J ) 10.2, 1.4 Hz, 1H), 4.49 (dt,
J ) 5.2, 1.5 Hz, 2H), 3.93-3.77 (m, 4H), 3.48 (B part of an AB
system, J ) 13.5 Hz, 1H), 3.48-3.40 (m, 2H), 2.95 (part A of
an AB system, J ) 13.5 Hz, 1 H), 1.33 (s, 3H), 0.95 (s, 9H),
0.86 (s, 9H). 13C NMR: δ 174.4, 173.4, 157.55, 133.2, 131.2,
128.7, 117.5, 114.4, 68.7, 62.5, 62.2, 59.9, 59.6, 55.3, 43.5, 33.4,
33.1, 26.8, 26.7, 18.1. Anal. Calcd for C26H42N2O5: C, 67.50;
H, 9.15; N, 6.06. Found: C, 67.73; H, 9.34; N, 6.22.
21.1. Anal. Calcd for C30H40N2O3: C, 75.60; H, 8.46; N, 5.88.
Found: C, 75.51; H, 8.67; N, 5.77.
Box 7b. Yield 80%. Thick yellow oil. [R]22 -75.5 (c 1.3 in
D
CHCl3). IR: 1656, 1513, 1217 cm-1. H NMR: δ 7.10 (B part
1
of an AB system, J ) 8.5 Hz, 2H), 6.80 (A part of an AB system,
J ) 8.5 Hz, 2H), 6.10-6.02 (m, 1H), 5.39 (dq, J ) 17.2, 1.5
Hz, 1H), 5.28 (dq, J ) 10.2, 1.4 Hz, 1H), 4.50 (dt, J ) 5.2, 1.5
Hz, 2H), 4.20 (B part of an AB system, J ) 10.0, 4.0 Hz, 1H),
4.16 (B part of an AB system, J ) 9.0, 4.0 Hz, 1H), 4.12 (dd,
J ) 7.0, 8.0 Hz, 1H), 4.05 (t, J ) 8.0 Hz, 1H), 3.88 (A part of
an AB system, J ) 10.0, 8.0 Hz, 1H), 3.81 (A part of an AB
system, J ) 10.0, 7.0 Hz, 1H), 3.33 (B part of an AB system,
J ) 13.6 Hz, 1H), 3.16 (A part of an AB system, J ) 13.6 Hz,
1 H), 1.43 (s, 3H), 0.88 (s, 9H), 0.85 (s, 9H). 13C NMR: δ 167.7,
167.3, 157.4, 133.5, 131.5, 129.1, 117.5, 114.2, 75.6, 75.4, 68.8,
68.7, 43.5, 41.2, 33.9, 33.8, 25.8, 25.7, 21.1. Anal. Calcd for
Syn th esis of Box 6a a n d 7a . To a stirred solution of bis-
amide (1 mmol), triethylamine (0.61 mL, 4.4 mmol), and
DMAP (12 mg, 0.1 mmol) in CH2Cl2 (15 mL) kept under
nitrogen was added tosyl chloride (380 mg, 2 mmol) dissolved
in CH2Cl2 (5 mL) dropwise. The mixture was stirred at RT for
24 h. A saturated aqueous solution of ammonium chloride was
then added, and the aqueous phase was extracted three times
with CH2Cl2 (15 mL). The combined organic phases were
washed with a saturated aqueous solution of sodium bicarbon-
ate, dried, and concentrated under vacuum to give the crude
product that was purified by flash chromatography with a 8:2
CH2Cl2:AcOEt mixture as eluant.
C
26H38N2O3: C, 73.20; H, 8.98; N, 6.57. Found: C, 73.41; H,
8.77; N, 6.84.
Dep r otection of Box 6a ,b a n d 7a ,b to Box 8a ,b. De-
ben zyla tion . This was accomplished following the described
procedure.12 In a typical experiment to a solution of O-benzyl-
protected box 6a and 6b (0.15 mmol) in ethylene glycol (10
mL) were added 10% Pd/C (50 mg) and ammonium formate
(63 mg, 1 mmol) in this order. The resulting mixture was
heated at 150 °C in a microwave oven for 6 min. After cooling,
the mixture was filtered through a Celite cake, and the filtrate
was diluted with water (10 mL) and extracted three times with
CH2Cl2 (15 mL). The combined organic phases were dried and
concentrated under vacuum. The residue was purified by flash
chromatography with a 7:3 CH2Cl2:AcOEt mixture as eluant
to give the product.
Box 6a . Yield 57%. Thick yellow oil. [R]22 -72.7 (c 0.8 in
D
CHCl3). IR: 1656, 1512, 1216 cm-1. 1H NMR: δ 7.38-7.19 (m,
13H), 7.09 (B part of an AB system, J ) 8.7 Hz, 2H), 7.02 (d,
J ) 7.5 Hz, 2H), 6.80 (A part of an AB system, J ) 8.7 Hz,
2H), 5.18 (t, J ) 8.2, 1H), 5.15 (dd, J ) 8.2, 7.7 Hz, 1H), 4.98
(s, 2H), 4.60 (dd, J ) 10.0, 8.2 Hz, 2H), 4.15-4.05 (m, 2H),
3.32 (s, 2H), 1.56 (s, 3H). 13C NMR: δ 169.7, 169.6, 158.3,
143.0, 142.5, 137.5, 132.0, 129.0, 128.9, 128.3, 127.9, 127.1,
114.9, 75.7, 70.4, 70.0, 66.2, 44.3, 22.0. Anal. Calcd for
C
34H32N2O3: C, 79.04; H, 6.24; N, 5.42. Found: C, 78.88; H,
Box 8a . Yield 66%. White solid, mp 89-91 °C. [R]22 -90.4
D
1
6.38; N, 5.28.
(c 0.56 in CHCl3). IR: 3583, 1652, 1515, 1266 cm-1. H NMR:
Box 7a . Yield 57%. Thick yellow oil. [R]22 -62.6 (c 0.4 in
δ 7.38-7.25 (m, 9H), 7.10 (t, J ) 7.5 Hz, 4H), 6.67 (d, J ) 7.5
Hz, 2H), 5.27 (dd, J ) 10.0, 8.0, 1H), 5.21 (dd, J ) 10.0, 7.5
Hz, 1H), 4.72 (m, 2H), 4.22 (t, J ) 8.2 Hz, 1H), 4.14 (t, J ) 8.0
Hz, 1H), 3.38 (s, 2H), 1.64 (s, 3H). 13C NMR: δ 169.0, 155.6,
142.0, 131.0, 131.55, 128.6, 127.5, 126.65, 115.1, 75.2, 69.4,
44.0, 41.3, 21.5. Anal. Calcd for C27H26N2O3: C, 76.03; H, 6.14;
N, 6.57. Found: C, 75.91; H, 6.06; N, 6.73.
D
CHCl3). IR: 1656, 1511, 1216 cm-1. 1H NMR: δ 7.35-7.25 (m,
8H), 7.15 (B part of an AB system, J ) 8.5 Hz, 2H), 7.08 (d, J
) 7.5 Hz, 2H), 6.85 (A part of an AB system, J ) 8.5 Hz, 2H),
6.11-6.04 (m, 1H), 5.43 (dq, J ) 17.2, 1.0 Hz, 1H), 5.30 (dq, J
) 10.2, 1.0 Hz, 1H), 5.28-5.18 (m, 2H), 4.71 (t, J ) 8.5 Hz,
2H), 4.54 (dd, J ) 5.0, 1.4 Hz, 2H), 4.20 (t, J ) 8.0 Hz, 1H),
4.13 (t, J ) 8.3 Hz, 1H), 3.40 (s, 2H), 1.63 (s, 3H). 13C NMR:
δ 169.3, 157.7, 142.3, 142.1, 131.5, 130.6, 128.7, 128.6, 128.5,
127.6, 127.5, 126.7, 117.6, 114.4, 75.3, 75.2, 69.5, 68.8, 43.8,
41.3, 21.6. Anal. Calcd for C30H30N2O3: C, 77.23; H, 6.48; N,
6.00. Found: C, 77.54; H, 6.61; N, 5.87.
Box 8b. Yield 32%. White solid, mp 171-173 °C. [R]22
D
-120.7 (c 0.17 in CHCl3). IR: 3583, 1653, 1516, 1266 cm-1
.
1H NMR: δ 6.97 (B part of an AB system, J ) 8.5 Hz, 2H),
6.62 (A part of an AB system, J ) 8.5 Hz, 2H), 6.33 (bs, 1H),
4.30-4.15 (m, 3H), 4.06 (t, J ) 8.5 Hz, 1H), 3.88 (dd, J ) 10.0,
8.5 Hz, 2H), 3.35 (B part of an AB system, J ) 14.0 Hz, 1H),
3.13 (A part of an AB system, J ) 14.0 Hz, 1H), 1.42 (s, 3H),
0.89 (s, 9H), 0.85 (s, 9H). 13C NMR: δ 168.5, 168.2, 155.3,
131.1, 127.3, 115.0, 75.45, 74.9, 68.9, 68.7, 43.8, 40.9, 34.1,
33.85, 25.7, 25.6, 20.7. Anal. Calcd for C23H34N2O3: C, 71.47;
H, 8.87; N, 7.25. Found: C, 71.20; H, 9.04; N, 7.45.
Syn th esis of Box 6b a n d 7b. To a stirred solution of bis-
amide (1 mmol) and triethylamine (0.61 mL, 4.4 mmol) in
CH2Cl2 (15 mL) kept under nitrogen at 0 °C was added mesyl
chloride (0.193 mL, 2.5 mmol) dissolved in CH2Cl2 (5 mL)
dropwise. The mixture was stirred at 0 °C for 20 min and at
RT for 2 h. A saturated aqueous solution of ammonium
chloride was then added, and the aqueous phase was extracted
three times with CH2Cl2 (15 mL). The combined organic phases
were washed with a saturated aqueous solution of sodium
chloride, dried, and concentrated under vacuum to give the
crude product. A solution of this crude mesylate, triethylamine
(0.61 mL, 4.4 mmol), and DMAP (12 mg, 0.1 mmol) in CH2Cl2
(20 mL) was stirred at 30 °C under nitrogen for 48 h. A
saturated aqueous solution of ammonium chloride was then
added, and the aqueous phase was extracted three times with
CH2Cl2 (15 mL). The combined organic phases were washed
with a saturated aqueous solution of sodium bicarbonate,
dried, and concentrated under vacuum to give the crude
product that was purified by flash chromatography with a 9:1
CH2Cl2:AcOEt mixture as eluant.
Dea llyla tion . This was accomplished by modification of a
described procedure.13 In a typical experiment a solution of
O-allyl protected box 7a and 7b (1 mmol) in ethanol (15 mL)
containing Pd(OAc)2 (22.4 mg, 0.1 mmol) and PPh3 (115 mg,
0.44 mmol) was refluxed for 90 min. The resulting mixture
was cooled at RT, and SiO2 (2 g) was added in one portion.
After 15 min stirring at RT, the mixture was filtered through
a Celite cake, the solvent was evaporated under vacuum, and
the residue was purified by flash chromatography with a 7:3
CH2Cl2: AcOEt mixture as eluant to give 8a in 67% yield and
8b in 82% yield.
Syn th esis of P EG-Su p p or ted Box 10a ,b. To a solution
of mesylate 910c (2.34 g, 0.45 mmol) and box 8a or 8b (0.50
mmol) in DMF (10 mL) stirred under nitrogen was added
tetrabutylammonium hydroxide (0.4 mL of a 40 wt % solution
in water, 0.607 mmol). The mixture was warmed to 60 °C and
stirred at that temperature for 48 h. The solvent was then
evaporated under vacuum, and the residue was taken up into
CH2Cl2 (20 mL). This solution was washed with water, dried
over sodium sulfate, filtered, concentrated under vacuum, and
precipitated with diethyl ether (see above). The product was
isolated by filtration.
Box 6b. Yield 50%. Thick yellow oil. [R]22 -47.4 (c 0.54 in
D
CHCl3). IR: 1661, 1512, 1240 cm-1. 1H NMR: δ 7.46-7.33 (m,
5H), 7.12 (B part of an AB system, J ) 8.0 Hz, 2H), 6.87 (A
part of an AB system, J ) 8.0 Hz, 2H), 5.04 (s, 2H), 4.23-4.11
(m, 3H), 4.05 (t, J ) 7.5 Hz, 1H), 3.89 (dd, J ) 9.0, 7.1 Hz,
1H), 3.83 (dd, J ) 7.0, 10.0 Hz, 1H), 3.33 (B part of an AB
system, J ) 13.5 Hz, 1H), 3.17 (A part of an AB system, J )
13.5 Hz, 1H), 1.44 (s, 3H), 0.89 (s, 9H), 0.86 (s, 9H). 13C NMR:
δ 167.7, 167.2, 157.6, 137.2, 131.5, 129.2, 128.5, 127.9, 127.5,
114.3, 75.6, 75.4, 70.0, 68.7, 43.5, 41.2, 34.0, 33.8, 25.8, 25.7,
1
P EG-Su p p or ted Box 10a . Yield 83%. H NMR: δ 7.20-
7.00 (m, 14H), 6.88-6.82 (m, 4H), 5.31-5.17 (m, 2H), 4.71 (t,

3166 J . Org. Chem., Vol. 66, No. 9, 2001
Annunziata et al.
J ) 9.0 Hz, 1H), 4.20 (t, J ) 9.0 Hz, 1H), 4.12 (t, J ) 6.5 Hz,
2H), 3.94 (t, J ) 6.5 Hz, 1H), 3.92-3.81 (m, 3H), 3.41 (t, J )
7.0 Hz, 2 H), 3.38 (s, 3H), 2.75 (t, J ) 7.0 Hz, 2H), 2.12-2.04
(m, 2H), 1.63 (s, 3H).
concentrated under vacuum, and the residue, dissolved in
CH2Cl2 (2 mL), was slowly added to diethyl ether. The
precipitate was removed by filtration, and the filtrate was
concentrated under vacuum to give the crude product that was
purified by flash chromatography with a 97:3 hexanes:diethyl
ether mixture as eluant. Yields and ee of adduct 12 were
reported in Table 1. Compound 13 was similarly obtained from
1,1-diphenylethylene.
1
P EG-Su p p or ted Box 10b. Yield 87%. H NMR: δ 7.11 (B
part of an AB system, J ) 8.8 Hz, 2H), 7.08 (B part of an AB
system, J ) 8.8 Hz, 2H), 6.85 (A part of an AB system, J )
8.8 Hz, 2H), 6.75 (A part of an AB system, J ) 8.8 Hz, 2H),
4.20-4.12 (m, 3H), 4.05 (t, J ) 7.5 Hz, 1H), 3.99-3.93 (m, 4
H), 3.41 (t, J ) 7.0 Hz, 2 H), 3.38 (s, 3H), 3.33 (B part of an
AB system, J ) 13.5 Hz, 1H), 3.15 (A part of an AB system, J
) 13.5 Hz, 1H), 2.74 (t, J ) 7.0 Hz, 2H), 2.03 (m, 2H), 1.42 (s,
3H), 0.88 (s, 9H), 0.85 (s, 9H).
En e-Rea ction . A solution was prepared by dissolving under
nitrogen 10a (250 mg, 0.045 mmol) and Cu(OTf)2 (15.9 mg,
0.044 mmol) in dry CH2Cl2 (4 mL). The resulting dark green
solution was stirred at RT for 4 h and then cooled to 0 °C,
whereupon R-methylstyrene (0.029 mL, 0.225 mmol) and ethyl
glyoxylate (0.446 mL of a 50% solution in toluene, 2.25 mmol)
were added in this order. The resulting mixture was stirred
overnight while the temperature was allowed to slowly in-
crease from 0 °C to RT. The mixture was then concentrated
under vacuum, and the residue, dissolved in CH2Cl2 (2 mL),
was slowly added to diethyl ether. The precipitate was removed
by filtration, and the filtrate was concentrated under vacuum
to give the crude product that was purified by flash chroma-
tography with a 7:3 hexanes:diethyl ether mixture as eluant.
Yields and ee of adduct 14 were reported in Table 1. Compound
15 was similarly obtained from methylenecyclohexane.
Liga n d Recover y. The precipitated PEG-supported cata-
lyst was dissolved in CH2Cl2 (3 mL g-1 of polymer) and trteated
dropwise with a 0.3 M solution of KCN in water until the
organic phase turned permanently from pale green to colorless.
The mixture, diluted with CH2Cl2, was dried, filtered, and
concentrated under vacuum to give a solid residue that was
used as such. Purification of this material was possible by the
usual procedure to afford a ligand identical by NMR to a
sample freshly prepared.
Ster eoselective Syn th eses P r om oted by P EG-Su p -
p or ted Liga n d s 10a ,b
Diels-Ald er Cycloa d d ition . A solution was prepared by
dissolving under nitrogen 10b (200 mg, 0.036 mmol) and Cu-
(OTf)2 (11.6 mg, 0.032 mmol) in dry CH2Cl2 (2 mL). To the
resulting bright green solution, finely grounded 3 Å molecular
sieves (200 mg) were added. The mixture was stirred under
nitrogen for 4 h at RT and then was cooled at -78 °C,
whereupon N-acryloyl oxazolidinone (51 mg, 0.36 mmol) and
cyclopentadiene (0.3 mL, 3.6 mmol) were added in this
sequence. The reaction mixture was then allowed to warm to
RT, stirred for 15 h, and then filtered through a Celite cake.
The filtrate was concentrated under vacuum and the residue
dissolved in CH2Cl2 (2 mL) was slowly added to diethyl ether.
The precipitate was removed by filtration, and the filtrate was
concentrated under vacuum to give the crude product that was
purified by flash chromatography with a 1:1 CH2Cl2:AcOEt
mixture as eluant. Yields and ee of adduct 11 were reported
in Table 1.
Cyclop r op a n a tion . A solution was prepared by stirring,
at RT for 1 h under nitrogen, 10b (200 mg, 0.036 mmol) and
commercially available CuOTf‚0.5 PhH (8 mg, 0.032 mmol) in
dry CH2Cl2 (2 mL). To the resulting bright green solution was
added freshly distilled styrene (0.200 mL, 1.8 mmol). Ethyl
diazoacetate (0.038 mL, 0.36 mmol) dissolved in CH2Cl2 (1 mL)
was added over a period of 5 h by a syringe pump, and the
reaction was stirred for 40 h at RT. The mixture was then
Ack n ow led gm en t. This work was supported by
MURST (Progetto Nazionale Stereoselezione in Sintesi
Organica. Metodologie ed Applicazioni) and CNR. We
thank Dr. Marco Bellini for technical assistance.
J O010077L