Cu(II)-aza(bisoxazoline)-catalyzed asymmetric benzoylations

Article abstract of DOI:10.1021/ol0505252

(Chemical Equation Presented) Racemic 1,2-diols and α-hydroxy carbonyl compounds can be asymmetrically benzoylated in a kinetic resolution in the presence of various Cu(II)-aza(bisoxazoline) catalysts. A novel bisbenzyl-substituted aza(bisoxazoline) ligand proved to be especially effective when immobilized on MeOPEG₅₀₀₀, giving from 91 to ≥99% ee in 37-49% yield for each of five sequential reactions.

Full text of DOI:10.1021/ol0505252

ORGANIC
LETTERS
2005
Vol. 7, No. 12
2325-2328
Cu(II)−Aza(bisoxazoline)-Catalyzed
Asymmetric Benzoylations
Anja Gissibl, M. G. Finn,† and Oliver Reiser*
Institut fu¨r Organische Chemie der UniVersita¨t Regensburg, UniVersita¨tsstrasse 31,
D-93053 Regensburg, Germany
oliVer.reiser@chemie.uni-regensburg.de
Received March 10, 2005
ABSTRACT
Racemic 1,2-diols and
Cu(II) aza(bisoxazoline) catalysts. A novel bisbenzyl-substituted aza(bisoxazoline) ligand proved to be especially effective when immobilized
on MeOPEG5000, giving from 91 to 99% ee in 37 49% yield for each of five sequential reactions.
r-hydroxy carbonyl compounds can be asymmetrically benzoylated in a kinetic resolution in the presence of various
−
g
−
Enzyme-catalyzed asymmetric acylation reactions are power-
ful tools for the kinetic resolution or desymmetrization of
alcohols.1 Likewise, a number of efficient metal- and
organocatalysts have been developed to effect this and related
transformations.2 We were especially intrigued by a report
of Matsumura and co-workers3 who recently reported the
asymmetric benzoylation of 1,2-diols ((-1) with the Cu-
(II)-bis(oxazoline) 2 in high yields and excellent selectivities
(Scheme 1).
Scheme 1. Cu(II)-Catalyzed Asymmetric Benzoylation by
Matsumura and Co-workers
We recently introduced aza(bisoxazolines) 6a-c and 7a-c
(Scheme 2) as chiral ligands for asymmetric catalysis,4 which
are readily synthesized by condensation of 4 and 5, being
both conveniently available5 from the chiral pool in either
enantiomeric form. An attractive feature of these ligands is
their facile attachment to organic and inorganic supports
through alkylation of the central nitrogen, thus, arriving at
recyclable catalysts. Moreover, since aza(bisoxazolines) are
considerably more electron rich than the corresponding bis-
(oxazolines), metal complexes of the former but not of the
latter can also be immobilized in ionic liquids6 and on Nafion
or clays by ion exchange and employed as catalysts.7 On
the other hand, metal-aza(bisoxazoline) complexes display
a reduced Lewis acidity compared to their bis(oxazoline)
† Department of Chemistry and The Skaggs Institute for Chemical
Biology, The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, CA 92037, USA.
(1) Enzyme Catalysis in Organic Synthesis: A ComprehensiVe Handbook;
Drauz, K., Waldmann, H., Eds.; Wiley-VCH Verlag GmbH: Weinheim,
Germany, 2002; Vols. I-III.
(2) (a) Brunner, H.; Obermann, U.; Wimmer, P. Organometallics 1989,
8, 821. (b) Vedejs, E.; Daugulis, O.; Tuttle, N. J. Org. Chem. 2004, 69,
1389. (c) Mizuta, S.; Sadamori, M.; Fujimoto, T.; Yamamoto, I. Angew.
Chem., Int. Ed. 2003, 42, 3383. (d) Fu, G. C. Acc. Chem. Res. 2004, 37,
542. (e) Miller, S. J. Acc. Chem. Res. 2004, 37, 601.
(3) (a) Matsumura, Y.; Maki, T.; Murakami, S.; Onomura, O. J. Am.
Chem. Soc. 2003, 125, 2052. (b) Matsumura, Y.; Maki, T.; Tsurumaki, K.;
Onomura, O. Tetrahedron Lett. 2004, 45, 9131.
(4) (a) Glos, M.; Reiser, O. Org. Lett. 2000, 2, 2045. (b) Werner, H.;
Vicha, R.; Gissibl, A.; Reiser, O. J. Org. Chem. 2003, 68, 10166.
10.1021/ol0505252 CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/10/2005

for 3a). Methylation of the central nitrogen in 6 further
improved the selectivity of this process from 87 to 93% ee
(Table 1, entries 3 vs 5 (ligands 6c vs 7c)). The apparent
beneficial effect of aryl substituents on the ligand prompted
us to subsequently prepare the new bis(benzylated) aza-
(bisoxazoline) ligands 6d and 7d following our general
strategy outlined in Scheme 2.12 We were pleased to find
that both of these ligands again considerably improved the
selectivity for the formation of 3a using the standard 5 mol
% catalyst (Table 1, entries 4 and 6) and that especially 7d
was found to be highly efficient even at a catalyst concentra-
tion of 0.5 mol % (Table 1, entry 7).
Scheme 2. Synthesis of Aza(bisoxazoline) Ligandsa
Racemic cyclohexene and cycloheptene diols 1b and 1c,
respectively, were also benzoylated in good yields but with
generally lower selectivities (Table 2). Moreover, the non-
a Reagents and conditions: For synthesis of 6a-c and 7a-c, see
ref 4b. For synthesis of 6d/7d: (b) 4d (1.2 equiv), 5d (1 equiv),
p-TSA, toluene, reflux, 24 h, 35%; (c) (i) n-BuLi, THF, -78 °C;
(ii) MeI, -78 °C to rt, 98%.
counterparts, as reflected, for example, in the inability of
Cu(II)-aza(bisoxazoline) complexes to catalyze [4 + 2]-cy-
cloadditions in sharp contrast8 to their bis(oxazoline) ana-
logues. Nevertheless, we report here that Cu(II)-aza-
(bisoxazoline) complexes are not only good catalysts for the
asymmetric benzoylation but, moreover, can be repeatedly
used for this transformation and subsequently recovered after
being immobilized on a poly(ethyleneglycol) support.9
Following the protocol developed by Matsumura and co-
workers,3a we tested ligands 6 and 7 for the asymmetric
benzoylation of (()-1a. Initial optimization studies with the
previously reported4 6a-c, performed with the complete
consumption of benzoyl chloride, assuming an identical
degree of completion,11 revealed that phenyl substitution (6c)
gave the best results with respect to selectivity and yield for
the benzoylated product 3a (Table 1, entries 1-3). Mat-
sumura and co-workers also found phenyl substitution, i.e.,
bis(oxazoline) 2, to be most effective (>99% ee (s > 645)
Table 2. Cu(II)-Catalyzed Benzoylation of Aliphatic Cyclic
Diols in the Presence of Various Aza(bisoxazoline) Ligands
monobenzoylated product 3
entry
ligand
6a
6b
(ent)-6c 1b
6d 1b
(ent)-7c 1b
7d
6a
6b
(ent)-6c 1c
6d 1c
(ent)-7c 1c
7d 1c
diol yield (%) ee (%)e configuration
sf
1
2b
3c
4
5d
6
7
8
9
1b
1b
44
43
46
41
47
45
46
43
44
38
50
41
67
27
83
70
52
73
82
32
79
80
76
80
R,R
R,R
S,S
R,R
S,S
R,R
R,R
R,R
S,S
R,R
S,S
R,R
8.4
2.1
22
9.1
4.9
1b
1c
1c
11
21
2.4
16
15
17
16
Table 1. Cu(II)-Catalyzed Benzoylation of (()-1a in the
Presence of Various Aza(bisoxazoline) Ligands
10
11c
12
a Reagents and conditions: 5 mol % CuCl2, 5 mol % ligand, 0.5 equiv
of PhCOCl, 3 h, CH2Cl2, 0 °C. b Reaction time ) 5 h. c Reaction time )
2 h. d Reaction time ) 2.5 h. e Determined by chiral GC (3b) or chiral HPLC
(3c). f Determined according to ref 10.
monobenzoylated product 3a
entry ligand yield (%) ee (%)g configuration selectivity (s)h
alkylated aza(bisoxazoline) 6c proved to be best for 1b (Table
2, entry 3), while for 1c the nonalkylated aza(bisoxazoline)
6a was most selective (Table 2, entry 7).
1b
2
6a
6b
(ent)-6c
6d
(ent)-7c
7d
38
49
48
45e
46
45f
49
68
33
87
97
93
99
99
R,R
R,R
S,S
R,R
S,S
R,R
R,R
7.8
2.6
35
160
66
501
751
3
4c
5
(5) (a) Wittekind, R. R.; Rosenau, J. D.; Poos, G. I. J. Org. Chem. 1961,
26, 444. (b) Rein, K.; Goicochea-Pappas, M.; Anklekar, T. V.; Hart, G. C.;
Smith, A. L.; Gawley, R. E. J. Am. Chem. Soc. 1989, 111, 2211.
(6) Fraile, J. M.; Garcia, J. I.; Herrerias, C. I.; Mayoral, J. A.; Reiser,
O.; Vaultier, M. Tetrahedron Lett. 2004, 45, 6765.
(7) (a) Fraile, J. M.; Garcia, J. I.; Harmer, M. A.; Herrerias, C. I.;
Mayoral, J. A.; Reiser, O.; Werner, H. J. Mater. Chem. 2002, 12, 3290. (b)
Fraile, J. M.; Garc´ıa, J. I.; Herrer´ıas, C. I.; Mayoral, A.; Reiser, O.;
Socue´llamos, A.; Werner, H. Chem. Eur. J. 2004, 10, 2997.
(8) Evans, D. A.; Miller, S. J.; Lectka, T.; von Matt, P. J. Am. Chem.
Soc. 1999, 121, 7559.
6c
7c,d 7d
a Reagents and conditions: 5 mol % CuCl2, 5 mol % ligand, 0.5 equiv
of PhCOCl, CH2Cl2, 3 h, 0 °C. b Reaction time ) 2.5 h. c Reaction time )
2 h. d Performed with 0.5 mol % CuCl2, 0.5 mol % ligand. e (S,S)-1a was
isolated in 42% yield and 83% ee. f (S,S)-1a was isolated in 54% yield and
87% ee. g Determined by chiral GC. h Determined according to ref 10.
2326
Org. Lett., Vol. 7, No. 12, 2005

We next investigated if the range of substrates can be
extended from 1,2-diols. While 1,3-diols proved to be
completely unreactive in the title transformation, R-hydroxy-
carbonyl compounds were amenable to this process. Thus,
benzoin (()-8 could be benzoylated using 6a with up to 79%
ee (Table 3, entry 1). It was most striking to note that the
Scheme 3. Attachment of Aza(bisoxazoline) Ligands to
MeOPEG5000
Table 3. Cu(II)-Catalyzed Benzoylation of R-Hydroxycarbonyl
Compounds in the Presence of Various Aza(bisoxazoline)
Ligands
benzoylated products 10 or 11
entry ligand substrate yield (%) ee (%)c configuration se
1
2
3
4
5
6
6a
6b
(ent)-6c
6d
(ent)-7c
7d
8
8
8
8
8
8
9
9
43
36
45
32
0
32
45
49
79d
10
39
R
R
S
16
1.3
3.1
11
77
R
27
75
53
R
R
R
2.0
13
5.3
7b 6a
8b 6d
a Reagents and conditions: 5 mol % CuCl2, 5 mol % ligand, 0.5 equiv
of PhCOCl, 4 h, CH2Cl2, 0 °C. b Reaction time ) 3 h. c Determined by
chiral HPLC. d (S)-8 was isolated in 38% yield and 81% ee. e Determined
according to ref 10.
The central nitrogen bridge in the aza(bisoxazoline) ligands
can be functionalized by alkylation and therefore offers a
convenient possibility for immobilization via attachment to
a polymeric support. Thus, by deprotonation with n-BuLi,
6d could be connected with the benzyl-modified poly-
(ethyleneglycol) MeOPEG5000 12 to give 13. However, only
20% ligand loading onto the polymer could be achieved even
when employing 5 equiv of 6d. We envisioned a more
effective immobilization strategy by using the copper-
catalyzed14 azide-alkyne cycloaddition15 (CuAAC) reaction,
which has proven to be very powerful for ligating functional
molecules to supporting scaffolds or to each other. Propar-
gylation of 6a was readily performed to yield 14 in nearly
quantitative yield, which was tested for coupling with benzyl
azide. Aza(bisoxazolines) are strongly coordinating ligands
for copper ions, thus greatly reducing their Lewis acidity to
the point that they are ineffective in the catalysis of Diels-
Alder reactions.16 Nevertheless, 17 could be obtained in 78%
yield in the presence of substoichiometric amounts of copper-
previously successful phenyl-substituted ligands 6c and 7c
performed very poorly with this substrate (Table 3, entries
3 and 5). Moreover, alkylation of the central nitrogen in the
aza(box) ligands was also not tolerated any longer (Table 3,
entries 5 and 6) in contrast to the previously discussed
reactions with 1,2-diols 1a-c. Although we have not yet
addressed these results in mechanistic studies, it is worth
noting that 6 and 7 differ in that the former can be an anionic
ligand while the latter cannot. The resulting Cu(II) complexes
of these ligands should therefore have significantly different
electronic properties. We have noted previously in the cobalt-
(II)-catalyzed conjugate reduction of R,â-unsaturated car-
bonyl compounds that there are profound differences in
catalytic activity upon switching from nonalkylated aza-
(bisoxazolines) 6 to the alkylated counterparts 7.13
(9) Reviews on (polymer-supported) bis(oxazoline) ligands: (a) Rechavi,
D.; Lemaire, M. Chem. ReV. 2002, 102, 3467. (b) McManus, H. A.; Guiry,
P. J. Chem. ReV. 2004, 104, 4151.
(10) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249.
(11) For selected examples (Table 1, entries 4 and 6; Table 3, entry 1),
also the starting materials were recovered and analyzed for their optical
purity, which corresponded well with the predicted values.
(12) Benzyl-substituted bis(oxazolines) were also successfully employed
in the benzoylation of meso-1,2,3-triols for the synthesis of phosphatidyli-
nositol-3,5-biphosphate: Hamaguchi A.; Nishikawa A.; Shirai, R. Book of
Abstracts, 19th International Congress of Heterocyclic Chemistry; Elsevier:
New York, 2003; p 96.
(13) Geiger, C.; Kreitmeier, P.; Reiser, O. AdV. Synth. Catal. 2005, 347,
249.
(14) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596. (b) Tornøe, C. W.; Christensen,
C.; Meldal, M. J. Org. Chem. 2002, 67, 3057. (c) Wang, Q.; Chan, T. R.;
Hilgraf, R.; Fokin, V. V.; Sharpless, K. B.; Finn, M. G. J. Am. Chem. Soc.
2003, 125, 3192. (d) Kolb, H. C.; Sharpless, K. B. Drug DiscoVery Today
2003, 8, 1128.
(15) Huisgen, R. Pure Appl. Chem. 1989, 61, 613.
Org. Lett., Vol. 7, No. 12, 2005
2327

However, the reaction rate with 17 was considerably slower
than with 15, requiring longer reaction times and resulting
in lower yields (entries 1-3) of 3a. Nevertheless, almost
quantitative recovery (g95% by mass) and subsequent reuse
of Cu(II)‚17 was possible (entries 2 and 3). In contrast,
excellent results in the benzoylation of 1a were achieved
with 13, allowing multiple runs at only 0.7 mol % catalyst
concentration (entries 5-9) with very comparable results
with respect to the nonimmobilized Cu(II)‚7d (entry 4).
In conclusion, we were able to demonstrate that aza-
(bisoxazolines) are capable ligands for the copper(II)-
catalyzed asymmetric benzoylation of 1,2-diols and R-hy-
droxycarbonyl compounds. However, success with these
substrates greatly depends on the type of aza(bisoxazolines)
being employed, i.e., being alkylated or nonalkylated at the
central nitrogen bridge. Finally, it was demonstrated that
immobilized catalysts can be employed for the title reaction,
allowing facile catalyst recovery and multiple reusability.
Table 4. Cu(II)-Catalyzed Benzoylation of (()-1a in the
Presence of Various PEG-Bound Aza(bisoxazoline) Ligands
3a
entry ligand (mol %) cycle time (h) yield (%) ee (%)b
sc
7.2
5.6
4.2
1
2
3
4
5
6
7
8
9
15 (5)
n/a
1
2
n/a
1
2
3
4
5
3
6
6
2
2
2
2
2
2
38
28
25
49
41
38
37
49
41
66
63
56
99
>99
98.5
97
91
98
17 (1.3)
17 (1.3)
7d (0.5)
13 (0.7)
13 (0.7)
13 (0.7)
13 (0.7)
13 (0.7)
751
>411
245
117
61
203
Acknowledgment. This work was supported by the
Bavarian California Technology Center (BACATEC), the
Fonds der Chemischen Industrie, and EU-COST D29/005
Sustainable/Green Chemistry and Chemical Technology and
through generous chemical gifts by Degussa Eva Zocher is
acknowledged for carrying out initial studies toward the
synthesis of 15.
a Reagents and conditions: CuCl2, ligand, 0.5 equiv of PhCOCl, CH2Cl2,
0 °C. b Determined by chiral GC. c Determined according to ref 10.
(II)chloride (0.5 equiv) and ascorbic acid (0.6 equiv),
followed by removal of copper from the product by several
extraction cycles with aqueous EDTA solution. Likewise,
ligation to MeOPEG-N3 16 could be achieved17 in a much
improved manner: employing only 1.5 equiv of 14, 67%
ligand loading onto MeOPEG was achieved. Both MeOPEG-
bound ligands 13 and 17 were employed in the copper-
catalyzed benzoylation of (()-1, being almost as enantiose-
lective as their nonimmobilized counterparts (Table 4).
Note Added after ASAP Publication. The substituents on
the oxazolines in structures 14, 15, and 17 were incorrectly
shown as Bn instead of iPr in Scheme 3 in the version
published ASAP on May 10, 2005. The corrected version
was published ASAP on May 13, 2005.
Supporting Information Available: Experimental and
analytical data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(16) Comparative measurements of reaction rates showed that 14 and
other aza(bisoxazoline) ligands are not strong accelerators of the azide-
alkyne cycloaddition reaction.
(17) Thermal azide cycloadditions with 16 have been reported: Garanti,
L.; Molteni, G. Tetrahedron Lett. 2003, 44, 1133.
OL0505252
2328
Org. Lett., Vol. 7, No. 12, 2005