Effective Modular Iminooxazoline (IMOX) Ligands for Asymmetric Catalysis: [Zn(IMOX)]-Promoted Enantioselective Reduction of Ketones by Catecholborane

Article abstract of DOI:10.1002/anie.200351754

Closing the door to nucleophilic attack on one face of the substrate by using a bulky substituent (see schematic formula) was the key to obtaining high enantiomeric excesses in the reduction of methyl ketones by catecholborane with promotion by zinc complexes of new chiral iminooxazoline (IMOX) ligands. The modular nature, simple design, and possibility to produce tailored IMOX ligands could be advantages in designing the next generation of these chiral ligands.

Full text of DOI:10.1002/anie.200351754

Communications
Enantioselective Alcohol Synthesis
oxazoline/imine ligands that simulate BOX-type N,N coordi-
nation. We first focused on the commercial availability of the
necessary chiral building blocks A–D containing the oxazo-
line framework (Figure 2). Aromatic, heterocyclic, and ferro-
Effective Modular Iminooxazoline (IMOX)
Ligands for Asymmetric Catalysis: [Zn(IMOX)]-
Promoted Enantioselective Reduction of Ketones
by Catecholborane**
Manuela Locatelli and Pier Giorgio Cozzi*
Chiral catalysts based on readily available chiral ligands are
widely used in academia and industry for the synthesis of
enantioenriched precursors of materials, sensors, and drugs.[1]
The C2-symmetric bisoxazoline (BOX) ligands (Figure 1)
Figure 2. Readily available oxazoline frameworks.
Figure 1. Bisoxazoline (BOX) ligands.
cenyl oxazolines are readily available and can be further
functionalized without difficulty. We reasoned that introduc-
tion of a bulky group near the imino moiety would be the key
to efficiently blocking one face of the chiral metal complexes
(Figure 3). In addition, free coordination sites on the complex
were introduced into asymmetric catalysis by Pfaltzet al. [2] in
their seminal work on semicorrins, and have since been
applied to a wide variety of asymmetric transformations.[3]
Indeed, Diels–Alder, aldol, ene, amination, Friedel–Crafts,
and other Lewis acid catalyzed reactions are all effectively
promoted by chiral metal BOX complexes.[4] The underlying
feature of the aforementioned reactions is substrate activa-
tion by two-point binding to the chiral metal BOX complex.
Chiral information seems to be poorly transmitted when the
two-point binding criterion is not met (i.e., one-point bind-
ing).[5] Hence, the development of a new family of chiral
N,N ligands capable of general substrate activation by one-
point binding would be a significant advance in the field of
Lewis acid/BOX-mediated reactions.
Earlier we showed that a new catalyst system capable of
reducing a-alkoxyketones with up to 82% ee is obtained by
combining BOX ligands and Zn(OTf)2 in the presence of
catecholborane.[6] Unfortunately, the reduction of nonchelat-
ing ketones led to racemic products, a typical symptom of
BOX-mediated processes with two-point binding. We tackled
this problem by designing a new family of novel modular[7]
Figure 3. Blocking one face of the chiral complex with a bulky group.
could be controlled by subtle conformational changes of the
bulky group. Hence, we employed a hindered amine bearing
aromatic rings, namely, tritylamine, as a bulky group in the
synthesis of a variety of iminooxazoline (IMOX) ligands.
Oxazolines 1–5 were prepared without difficulty by known
procedures.[8] The aldehyde moiety near the oxazoline ring
was introduced by reaction of the corresponding lithium
derivatives with DMF (Scheme 1). Facile metalation of
benzothienyl- and thienyloxazolines occured with nBuLi,
whereas ferrocenyloxazolines required nBuLi/TMEDA. Met-
alation was achieved by lithium/bromine exchange in the case
of the oxazoline obtained from 2-bromobenzonitrile. Alde-
hydes 6–10 were thus obtained in fair to good yields. To the
best of our knowledge, syntheses of 6–10 have not been
reported in the literature. This was quite surprising, given the
potential utility of aldehyde oxazolines for the preparation of
a variety of chiral ligands.[9] The IMOX ligands 11–15 were
obtained by adding tritylamine to a solution of aldehydes 6–
10 in CH2Cl2 in the presence of magnesium sulfate as a
[*] Prof. Dr. P. G. Cozzi, Dr. M. Locatelli
Dipartimento di Chimica “G. Ciamician”
Università di Bologna
Via Selmi 2, 40126 Bologna (Italy)
Fax: (+39)051-2099-456
E-mail: pgcozzi@ciam.unibo.it
[**] We thank CNR (Rome), MIUR (Rome) “Progetto Stereoselezione in
Chimica Organica – Metodologie ed Applicazioni”, and the
University of Bologna (funds for selected research topics) for
financial support of this research. P.G.C. thanks Dr. Nicole End
(Ciba Research Group, Basel) for the generous gift of benzo[b]-
thiophene oxazolines. Prof. Kenny Lipkowitz is acknowledged for
preliminary calculations on metal IMOX complexes.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
4928
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200351754
Angew. Chem. Int. Ed. 2003, 42, 4928 –4930

Angewandte
Chemie
Scheme 2. Asymmetric reduction of acetophenone with catecholborane
with promotion by chiral [Zn(IMOX)] complexes.
IMOX ligands gave high enantioselectivities with this non-
chelating substrate. The reaction conditions were further
optimized with the most readily available ligand 11, by
varying the number of equivalents of reducing agent, temper-
ature, and catalyst loading. A reaction temperature of À158C
with 1.4 equiv of catecholborane[11] and 4 mol% [Zn-
(IMOX)](OTf)2 catalyst were found to be optimal. The
generality of these optimal conditions is shown in Table 2 and
Table 2: Enantioselective reduction of methylketones catalyzed by
[Zn(IMOX)] complexes.
Entry[a]
Ligand
Ketone
Yield [%][b]
ee of 17 [%][c]
1
2
5
3
4
8
2
3
9
15
12
15
11
12
12
11
15
11
11
11
16a
16b
16b
16c
16d
16e
16 f
16 f
16g
16h
16i
76
80
57
84
83
81
62
70
85
54
92
92 (R)
89 (R)
93 (R)
88 (R)
87 (R)
86 (R)
87 (R)
91 (R)
86 (R)
92 (R)[d]
53 (R)[d]
Scheme 1. Preparation of the IMOX ligands: a) nBuLi, Et2O, À788C
30 min, 08C 30 min, then DMF, À788C; b) TritylNH2, MgSO4, CH2Cl2,
RT; c) nBuLi, TMEDA, À788C, DMF, À788C; d) nBuLi, À788C, THF,
then DMF, À788C; e) nBuLi, Et2O, À788C, then DMF, À788C.
TMEDA=N,N,N’N’-tetramethyethylenediamine.
10
11
dehydrating agent (Scheme 1).[10] The IMOX ligands were
isolated after purification by chromatography on triethyl-
amine-deactivated silica gel. However, even under these mild
isolation conditions, purification of 14 was complicated by
ligand decomposition. Our preliminary studies with the novel
IMOX ligands were carried out on the reduction of aceto-
phenone as model substrate with modification of the solvent
and the reaction temperature (Table 1, Scheme 2). The
[a] All reactions were performed at À158C in a freezer without stirring.
[b] Yield of isolated product after flash chromatography. [c] Determined
by chiral GC analysis (see Supporting Information for details). [d] Deter-
mined by chiral HPLC analysis (Chiralcel OD column).
Scheme 3. Various aromatic methylketones were reduced in
good-to-excellent yields and with excellent enantiomeric
excesses. Other aromatic alkyl ketones were also reduced in
good yield, although the results were inferior in terms of
enantioselectivity.[12] High ee values (86–93%) were obtained
with p-substituted aromatic acetyl ketones. Electron-with-
drawing groups accelerate the reactions considerably, while
Table 1: Enantioselective reduction of acetophenone promoted by
[Zn(IMOX)] complexes.[a]
Entry
IMOX
Yield [%][b]
T [8C]
ee [%][c]
1
2
3
4
5
6
7
8
11
12
11
12
14
13
11
11
86
88
77
75
0
0
84
84
89
90
86
20
56
77
À15
À15
À15
À15
0
[d]
–
–
[d]
60[e]
76[f]
0
[a] All the reactions were carried out in anhydrous CH2Cl2 at the indicated
temperature for 48 h. [b] Yield of isolated product after chromatographic
purification. [c] Determined by chiral GC analysis (see Supporting
Information for details). The absolute configurations of the products
were determined by comparison with analytical data reported in the
literature. [d] Not determined. [e] The reaction was performed in Et2O.
[f] The reaction was performed in toluene.
Scheme 3. Asymmetric reduction of methyl ketones promoted by
IMOX ligands 11, 12, and 15.
Angew. Chem. Int. Ed. 2003, 42, 4928 –4930
www.angewandte.org
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4929

Communications
Evans, T. Rovis, M. C. Kozlowski, J. S. Tedrow, J. Am. Chem.
Soc. 1999, 121, 1994 – 1995.
electron-donating groups decrease the reaction rates. It is
noteworthy that IMOX ligands 11 and 12 give virtually
identical enantiomeric excesses in the reduction of acetophe-
none. Hence, these ligands were used interchangeably
throughout our work. Benzo[b]thiophene-derived ligand 15
appeared to give slightly better results, but its synthesis is
more laborious than those of 11 and 12. Unsaturated ketones
are chemoselectively and enantioselectively reduced by this
system (Table 2, entry 10). We believe that the new IMOX
ligands create a suitable chiral pocket in which the methyl-
ketones are coordinated such that nonbonding interactions
are minimized (Figure 3, R3 = aryl). The trityl group serves to
control the size of the pocket and hinder the approach of the
reducing agent to one face of the substrate.[13] Our work
suggests that hindered aromatic amines can be effectively
used as elements of stereocontrol in the design of effective,
novel catalysts.
In summary we have synthesized, in a modular fashion, a
novel class of chiral iminooxazoline (IMOX) ligands capable
of effectively promoting enantioselective reductions of aro-
matic methyl ketones with good enantioselectivity (86–
93% ee). This facile synthetic approach to IMOX ligands
may lend itself to the creation of large libraries of these
compounds. The application of IMOX ligands to other
asymmetric transformations is currently under investigation
in our laboratories.
[5] Copper–PyBOX complexes promote enantioselective Diels–
Alder reactions of monodentate dienophiles.[4m]
[6] M. Bandini, P. G. Cozzi, M. DeAngelis, A. Umani-Ronchi,
Tetrahedron Lett. 2000, 41, 1601 – 1605.
[7] For efficient modular ligands, see a) H. Deng, M. P. Isler, M. L.
Snapper, A. H. Hoveyda, Angew. Chem. 2002, 114, 1051 – 1054;
Angew. Chem. Int. Ed. 2002, 41, 1009 – 1012; b) C. A. Luchaco-
Cullis, H. Mizutani, K. E. Murphy, A. H. Hoveyda, Angew.
Chem. 2001, 113, 1504 – 1508; Angew. Chem. Int. Ed. 2001, 40,
1456 – 1460; c) K. D. Shimizu, B. M. Cole, C. A. Krueger, K. W.
Kuntz, M. L. Snapper, A. H. Hoveyda, Angew. Chem. 1996, 108,
1776 – 1779; Angew. Chem. Int. Ed. Engl. 1996, 35, 1668 – 1674;
d) I. Chataigner, C. Gennari, U. Piarulli, S. Ceccarelli, Angew.
Chem. 2000, 112, 953 – 956; Angew. Chem. Int. Ed. 2000, 39, 916 –
918; e) J. Blankenstein, A. Pfaltz, Angew. Chem. 2001, 113,
4577 – 4579; Angew. Chem. Int. Ed. 2001, 40, 4445 – 4447.
[8] Oxazoline 3: M. Peer, J. C. de Jong, M. Kiefer, T. Langer, H.
Rieck, H. Schell, P. Sennhenn, J. Sprinz, H. Steinhagen, B. Wiese,
G. Helmchen, Tetrahedron 1996, 52, 7547 – 7583. Oxazoline 4:
C. J. Richards, A. W. Mulvaney, Tetrahedron: Asymmetry 1996,
7, 1419 – 1430. Oxazolines 1, 2, and 5: a) P. G. Cozzi, F. Menges,
S. Kaiser, Synlett 2003, 833 – 836; b) L. F. Tietze, J. K. Lohmann,
Synlett 2002, 2083 – 2085.
[9] Modular ligands described by Hoveyda, Snapper, et al. were
prepared by condensation between aldehydes bearing a coordi-
nating group and chiral amines.[7] See also a) N. S. Josephsohn,
M. L. Snapper, A. H. Hoveyda, J. Am. Chem. Soc. 2003, 125,
4018 – 4019; b) K. E. Murphy, A. H. Hoveyda, J. Am. Chem. Soc.
2003, 125, 4690 – 4691.
Received: April 28, 2003
Revised: July 16, 2003 [Z51754]
[10] We have obtained a preliminary crystal structure for IMOX
ligand 13. The absolute planar chiral configuration was assigned
on the basis of the crystal structure (P. G. Cozzi, M. Monari, S.
Selva, unpublished results).
[11] Other reducing agents (silanes, BH3, poly(methylhydroxysilox-
ane) (PMSH)) were also studied. However, racemic products or
low enantiomeric excesses were obtained in the reduction of
acetophenone. For enantioselective reduction of ketones by
metal complexes and catecholborane, see a) W.-S. Huang, Q.-S.
Hu, L. Pu, J. Org. Chem. 1999, 64, 7940 – 7956; b) A. J. Blake, A.
Cunningham, A. Ford, A. J. Teat, S. Woodward, Chem. Eur. J.
2000, 6, 3586 – 3594; c) I. Sarvary, F. Almqvist, T. Frejd, Chem.
Eur. J. 2001, 7, 2158 – 2166.
[12] The following aromatic ketones were reduced under the
optimized reaction conditions: phenyl isopropyl ketone (60%
yield, 49% ee), isovalerophenone (82% yield, 78% ee), a-
bromoacetophenone (76% yield, 76% ee), and butyrophenone
(84% yield, 85% ee).
[13] To stress the importance of the hindered trityl group next to the
imino moiety, IMOX ligands prepared from different aromatic
and aliphatic amines were studied in the enantioselective
reduction of acetophenone under the optimized reaction con-
ditions. However, only racemic products or low enantiomeric
excesses were obtained (see Supporting Information).
Keywords: alcohols · asymmetric catalysis · enantioselectivity ·
.
ligand design · reduction
[1] H.-U. Blaser, Chem. Commun. 2003, 293 – 296.
[2] A. Pfaltz, Synlett 1999, 835 – 843.
[3] T. P. Yoon, E. N. Jacobsen, Science 2003, 299, 1691 – 1693.
[4] For recent examples of C2 bisoxazoline–Lewis acid complexes as
catalysts, see a) J. S. Johnson, D. A. Evans, Acc. Chem. Res. 2000,
33, 325 – 335; b) N. Gathergood, W. Zhuang, K. A. Jørgensen, J.
Am. Chem. Soc. 2000, 122, 12517 – 12522; c) K. B. Jensen, J.
Thorhauge, R. G. Hazell, K. A. Jørgensen, Angew. Chem. 2001,
113, 164 – 167; Angew. Chem. Int. Ed. 2001, 40, 160 – 163; d) H.
Audrain, K. A. Jørgensen, J. Am. Chem. Soc. 2000, 122, 11543 –
11544; e) K. Juhl, N. Gathergood, K. A. Jørgensen, Angew.
Chem. 2001, 113, 3083 – 3085; Angew. Chem. Int. Ed. 2001, 40,
2995 – 2997; f) K. R. Knudsen, T. Risgaard, N. Nishiwaki, K. V.
Gothelf, K. A. Jørgensen, J. Am. Chem. Soc. 2001, 123, 5843 –
5844; g) N. Nishiwaki, K. R. Knudsen, K. V. Gothelf, K. A.
Jørgensen, Angew. Chem. 2001, 113, 3080 – 3083; Angew. Chem.
Int. Ed. 2001, 40, 2992 – 2995; h) K. Juhl, K. A. Jørgensen, J. Am.
Chem. Soc. 2002, 124, 2420 – 2421; i) J. Thorhauge, M. Roberson,
R. G. Hazell, K. A. Jørgensen, Chem. Eur. J. 2002, 8, 1888 – 1898;
j) D. A. Evans, M. C. Kozlowski, J. A. Murry, C. S. Burgey, K. R.
Campos, B. T. Connell, R. J. Staples, J. Am. Chem. Soc. 1999,
121, 669 – 685; k) D. A. Evans, C. S. Burgey, M. C. Kozlowski,
S. W. Tregay, J. Am. Chem. Soc. 1999, 121, 686 – 699; l) D. A.
Evans, K. A. Scheidt, J. N. Johnston, M. C. Willis, J. Am. Chem.
Soc. 2001, 123, 4480 – 4491; m) D. A. Evans, D. M. Barnes, J. S.
Johnson, T. Lectka, P. von Matt, S. J. Miller, J. A. Murry, R. D.
Norcross, E. A. Shaughnessy, K. R. Campos, J. Am. Chem. Soc.
1999, 121, 7582 – 7594; n) D. A. Evans, S. J. Miller, T. Lectka, P.
von Matt, J. Am. Chem. Soc. 1999, 121, 7559 – 7573; o) D. A.
4930
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 4928 –4930