Kinetic resolution of diols and pyridyl alcohols by cu(II)(borabox)- catalyzed acylation

Article abstract of DOI:10.1021/ol060443t

Boron-bridged bisoxazoline (borabox) ligands have been used in the copper(II)-catalyzed benzoylation of pyridyl alcohols and 1,2-diols. Efficient kinetic resolution of 1,2-diols was achieved using both borabox and bisoxazoline (box) ligands. Borabox ligands induced high selectivities in the benzoylation of suitable pyridyl alcohols, where they outperformed bisoxazolines. In addition, highly enantioselective Cu(II)(borabox)-catalyzed benzoylation has been used for the synthesis of both enantiomers of a pyridyl alcohol.

Full text of DOI:10.1021/ol060443t

ORGANIC
LETTERS
2006
Vol. 8, No. 9
1879-1882
Kinetic Resolution of Diols and Pyridyl
Alcohols by Cu(II)(borabox)-Catalyzed
Acylation
Cle´ment Mazet, Stephen Roseblade, Valentin Ko1hler, and Andreas Pfaltz*
Department of Chemistry, UniVersity of Basel, St. Johanns-Ring 19,
CH-4056 Basel, Switzerland
andreas.pfaltz@unibas.ch
Received February 20, 2006
ABSTRACT
Boron-bridged bisoxazoline (borabox) ligands have been used in the copper(II)-catalyzed benzoylation of pyridyl alcohols and 1,2-diols. Efficient
kinetic resolution of 1,2-diols was achieved using both borabox and bisoxazoline (box) ligands. Borabox ligands induced high selectivities in
the benzoylation of suitable pyridyl alcohols, where they outperformed bisoxazolines. In addition, highly enantioselective Cu(II)(borabox)-
catalyzed benzoylation has been used for the synthesis of both enantiomers of a pyridyl alcohol.
The design of C2-symmetric nitrogen-based chiral ligands
for asymmetric catalysis has developed rapidly since the
semicorrin ligands 1 were introduced (Figure 1).1 The
(borabox) in which the central bridging carbon atom has been
replaced by a quaternary boron atom. These ligands were
found to induce high enantioselectivities in the copper-
catalyzed asymmetric cyclopropanation of olefins and in the
asymmetric desymmetrization of meso-1,2-diols, where they
outperformed the bisoxazolines 2.3
Kinetic resolution of alcohols by asymmetric acylation
with nonenzymatic reagents or catalysts has attracted atten-
tion recently.4 For instance, Matsumura and co-workers
reported that monobenzoylation of trans-1,2-diols using 5
mol % of CuCl2 and box ligand 2a was highly selective.5
Herein, we report kinetic resolution of 1,2-diols and
pyridyl alcohols by Cu(II)(borabox)-catalyzed acylation.
(1) Fritschi, H.; Leutenegger, U.; Pfaltz, A. Angew. Chem. 1986, 98,
1028-1029; Angew. Chem., Int. Ed. Engl. 1986, 25, 1005-1006. Pfaltz,
A. Acc. Chem. Res. 1993, 26, 339-345.
Figure 1. Semicorrin, bisoxazoline (box), and borabox ligands.
(2) (a) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron:
Asymmetry 1998, 9, 1. (b) Fache, F.; Schulz, E.; Tommasino, M. L.;
Lemaire, M. Chem. ReV. 2000, 100, 2159-2232. (c) McManus, H. A.;
Guiry, P. J. Chem. ReV. 2004, 104, 4151-4202. (d) Johnson, J. S.; Evans,
D. A. Acc. Chem. Res. 2000, 33, 325-335.
(3) Mazet, C.; Ko¨hler, V.; Pfaltz, A. Angew. Chem., Int. Ed. 2005, 44,
4888-4891; Angew. Chem. 2005, 117, 4966-4969.
bisoxazolines 2 have emerged as especially versatile ligands
for achieving high levels of stereocontrol in various metal-
catalyzed asymmetric reactions.2 In this context, we recently
introduced a new class of monoanionic bisoxazolines 3
10.1021/ol060443t CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/01/2006

Initial studies of the Cu(II)-catalyzed benzoylation of 1,2-
diphenylethane-1,2-diol 4 using benzoyl chloride and
i-PrNEt2 with ligand 3d established that decreasing the
catalyst loading from 5 to 1 mol % did not cause a significant
decrease in the selectivity factor S or the conversion.6
Subsequent ligand screening using catalyst loadings of 1
mol % revealed that borabox ligands possessing benzyl
substituents at the stereogenic center of the oxazoline unit
gave higher selectivities than those bearing t-Bu substituents.
Ligand 3e, incorporating electron-poor perfluorinated aryl
groups at the boron atom, gave an S value of 225 under
optimized conditions. Bisoxazolines 2a and 2b were also
found to be highly selective, giving S values of around 200
(Table 1).7
16 to 21. For this substrate, borabox ligands 3d and 3e were
found to induce slightly higher selectivities than box ligand
2a (Table 2).
Table 2. Kinetic Resolution of 1,2-Cyclohexanediol
entry
ligand
ee 6 (%)a
ee 7 (%)a
conversion (%)b
Sb
1
2
3
2a
3d
3e
17
74
64
86
79
83
17
48
44
16
19
21
a HPLC assay. b Ref 7.
Table 1. Kinetic Resolution of 1,2-Diphenylethane-1,2-diol
The resolution of racemic 1,2-phenylethanediol 8 was also
investigated. Benzoylation occurs preferentially at the pri-
mary alcohol giving rise to monobenzoylated products 9 and
10, along with the enantioenriched starting diol 8 (Scheme
1).8
entry ligand ee 4 (%)a ee 5 (%)a conversion(%)b
Sb
1
2
3
4
5
6
7
2a
2b
3a
3b
3c
3d
3e
95
96
14
38
80
82
98
96
95
39
45
86
93
96
50
50
27
46
48
47
51
182
217
3
4
Scheme 1. Kinetic Resolution of 1,2-Phenylethanediol
32
71
225
a HPLC assay. b Ref 7.
By comparison, benzoylations of trans-1,2-cyclohex-
anediol 6 were less selective giving S values ranging from
The ee values of the enantioenriched diol 8 and the
monobenzoylated secondary alcohol 9 were moderate with
all ligands tested.9 Although the overall process is rather
inefficient, the higher ee value observed for the primary
alcohol 10 is consistent with the selectivities obtained in the
benzoylation of 1,2-diphenylethane-1,2-diol and 1,2-cyclo-
hexanediol. These results indicate that the presence of a large
substituent adjacent to the hydroxy group is required for high
selectivity.
Chiral pyridyl alcohols are valuable intermediates in the
synthesis of ligands for asymmetric catalysis, chiral nucleo-
philic catalysts, and biologically active compounds.10 Ap-
proaches to their asymmetric synthesis have focused on
enantioselective reduction of the corresponding ketones.11
Kinetic resolution of pyridyl alcohols is an attractive alterna-
tive, and an enzymatic approach has been reported.12 We
(4) (a) Fu, G. C. Acc. Chem. Res. 2000, 33, 412-420. (b) France, S.;
Duerrin, D. J.; Miller, S. J. Chem. ReV. 2003, 103, 2985-3012. (c) Vedejs,
E.; Jure, M. Angew. Chem., Int. Ed. 2005, 44, 3974. (d) Dalko, P. I.; Moisan,
L. Angew. Chem., Int. Ed. 2004, 43, 5138. (e) Birman, V. B.; Uffman, E.
W.; Jiang, H.; Li, X.; Kilbane, C. J. J. Am. Chem. Soc. 2004, 126, 12226-
12227. (f) Spivey, A. C.; Leese, D. P.; Zhu, F.; Davey, S. G.; Jarvest, R.
L. Tetrahedron 2004, 60, 4513-4525 and references therein.
(5) (a) Matsumura, Y.; Maki, T.; Murakami, S.; Onomura, O. J. Am.
Chem. Soc. 2003, 125, 2052-2053. For the use of a chiral tin catalyst, see:
(b) Iwasaki, F.; Maki, T.; Nakashima, W.; Onomura, O.; Matsumura, Y.
Org. Lett. 1999, 1, 969-972. (c) Iwasaki, F.; Maki, T.; Onomura, O.;
Nakashima, W.; Matsumura, Y. J. Org. Chem. 2000, 65, 996-1002. (d)
Matsumura, Y.; Maki, T.; Tsurumaki, K.; Onomura, O. Tetrahedron Lett.
2004, 45, 9131-9134. (e) For the use of aza-bisoxazoline ligands, see:
Gissibl, A.; Finn, M. G.; Reiser, O. Org. Lett. 2005, 7, 2325-2328.
(6) See Supporting Information for details. Benzoyl chloride was found
to be the best choice of acylating agent when compared to alkyl acid
t
chlorides such as AcCl and BuCOCl.
(7) Conversions and enantioselectivities were determined using ee values
obtained from chiral HPLC of the products (pr) and starting materials (sm);
conversion (C) ) eesm/(eesm + eepr). S ) ln[1 - C(1 + eepr)]/ln[1 - C(1
- eepr)] ) ln[(1 - C)(1 - eesm)]/ln[(1 - C)(1 + eesm)]. See: (a) Kagan,
H. B.; Fiaud, J.-C. Top. Stereochem. 1988, 18, 249-330. (b) Sih, C. J.;
Wu, S. H. Top. Stereochem. 1989, 19, 63. (c) Kagan, H. Tetrahedron 2001,
57, 2449-2468. (d) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. AdV. Synth.
Catal. 2001, 343, 5-26. The selectivity factors reported here differ from
those reported previously by Matsumura and co-workers. In that study,
selectivity factors were determined from the enantiomeric excess of the
monobenzoylated products and their isolated yields. It has been noticed in
kinetic resolution using chemical or biochemical methods that this approach
gives variable accuracy, leaving the major error on conversion C.
(8) (a) Guette´, J.-P.; Horeau, A. Bull. Soc. Chim. Fr. 1967, 1747-1752.
(b) Kagan, H. B. Croat. Chem. Acta 1996, 69, 669-680.
(9) See Supporting Information for details.
(10) (a) Drury, W. J., III; Zimmerman, N.; Keenan, M.; Hayashi, M.;
Kaiser, S.; Goddard, R.; Pfaltz, A. Angew. Chem., Int. Ed. 2004, 43, 70-
74. (b) Kaiser, S. Ph.D. Dissertation, University of Basel, 2005. (c) Kang,
J.; Kim, H. Y.; Kim, J. P. Tetrahedron: Asymmetry 1999, 10, 2523-2533.
(d) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1996, 118, 1809-1810. (e)
Roszkowski, A. P.; Govier, W. M. Pharmacologist 1959, 1, 60. (f) Barouh,
V.; Dall, H.; Patel, D.; Hite, G. J. Med. Chem. 1971, 14, 834.
1880
Org. Lett., Vol. 8, No. 9, 2006

became interested in this transformation in connection with
our work on asymmetric hydrogenation, as cationic iridium
complexes containing chiral P,N-ligands, which are derived
from pyridyl alcohols, are highly selective catalysts for
asymmetric hydrogenation of unfunctionalized olefins
(Figure 2).13
benzoylation of pyridyl alcohol 12, the borabox ligands 3d
and 3e both impart levels of enantioselectivity which are
useful synthetically, with an S value of 51 for ligand 3e.
Substrate 13 is benzoylated with an S value of 19 using
ligand 3e, indicating that when a six-membered ring is fused
to the pyridine ring the enantioselectivity can be higher than
that with a five-membered ring analogue. During benzoy-
lation of substrate 14, containing a phenyl group R to the
pyridine N atom and a six-membered ring, borabox ligands
3d and 3e were highly enantioselective, giving S values of
around 100. Substrate 15, containing an R-chloro substituent,
exhibited selectivities similar to those for the unsubstituted
analogue 13.
Figure 2. Pyridyl alcohol resolution during ligand synthesis.
Kinetic resolution of 1 g of pyridyl alcohol 14 was then
carried out using the readily available borabox ligand 3d
(Scheme 2).
Like the diol substrates, pyridyl alcohols should be able
to chelate copper(II), which is thought to be an essential
requirement for achieving high enantioselectivities.5a To test
their suitability in this process, several pyridyl alcohols were
synthesized and examined in the Cu-catalyzed benzoylation.
Initially, reactions were carried out using 0.5 mmol of
substrate and 1 mol % of copper complex in dichloromethane
at 0 °C.
Scheme 2. Preparative Scale Pyridyl Alcohol Resolution
We found that while the copper box complex 2b exhibited
poor selectivities with all substrates examined the selectivities
obtained with the borabox ligands were generally higher,
although highly dependent on the structure of the substrate
(Table 3). A comparison of pyridyl alcohols 11 and 12 shows
that substitution at the R-CH of the pyridine ring with a
phenyl group greatly enhances the selectivity. During
Table 3. Kinetic Resolution of Pyridyl Alcohols
Following benzoylation under optimized conditions (1 M,
CH2Cl2, 1 mol %, 0 °C), the alcohol and benzoate were
separated by column chromatography. The alcohol was
recovered with an ee of 91% (S), and subsequent recrystal-
lization from hexane/EtOAc provided (S)-alcohol in 39%
yield and 95% ee. The benzoate was isolated with 94% ee
(R); subsequent hydrolysis was accomplished without race-
mization to yield the (R)-alcohol in 42% yield and 97% ee
after recrystallization from hexane/EtOAc. A straightforward
synthesis of both enantiomers of the ligand precursor 14 has
thus been accomplished, with the borabox ligand inducing
very high enantioselectivity.
alcohol
ee (%)a
benzoate
ee (%)a
conversionb
(%)
substrate
ligand
Sb
11
11
11
12
12
12
13
13
13
14
14
14
15
15
15
2b
3d
3e
2b
3d
3e
2b
3d
3e
2b
3d
3e
2b
3d
3e
1
16
5
1
33
5
26
84
91
8
60
76
17
96
97
6
50
33
46
24
36
45
27
62
52
15
39
42
53
44
47
1
2
1
8
2
50
76
3
>99
83
3
61
70
6
62
58
18
51
1
9
19
2
92
125
1
17
8
In conclusion, we have developed a catalytic system for
the kinetic resolution of 1,2-diols and pyridyl alcohols which
(11) (a) Ohkuma, T.; Koizumi, M.; Makato, Y.; Noyori, R. Org. Lett.
2000, 2, 1749-1751. (b) Okano, K.; Murata, K.; Ikariya, T. Tetrahedron
Lett. 2000, 41, 9277-9280. (c) Bolm, C.; Zehnder, M.; Bur, D. Angew.
Chem., Int. Ed. 1990, 29, 205. (d) Corey, E. J.; Helal, C. J. Tetrahedron
Lett. 1996, 37, 5675-5678.
(12) (a) Uenishi, J.; Hiraoka, T.; Hata, S.; Nishiwaki, K.; Yonemitsu,
O. J. Org. Chem. 1998, 63, 2481-2487. (b) Uenishi, J.; Hamada, M.
Tetrahedron: Asymmetry 2001, 12, 2999-3006. (c) Uenishi, J.; Hamada,
M. Synthesis 2002, 5, 625-630.
(13) Bell, S.; Wu¨stenberg, B.; Kaiser, S.; Menges, F.; Netscher, T.; Pfaltz,
A. Science 2006, 311, 642-644.
80
65
a HPLC assay. b Ref 7.
Org. Lett., Vol. 8, No. 9, 2006
1881

operates efficiently at 1 mol % catalyst loading. Enantio-
selectivities in the benzoylation of 1,2-diols are higher
when a large substituent is adjacent to the hydroxy group,
and excellent enantioselectivities were achieved using bo-
rabox and box ligands. We found that borabox ligands induce
high selectivities during benzoylation of suitable pyridyl
alcohols, where they outperformed an analogous bisoxazo-
line.
Acknowledgment. Financial support from the Swiss
National Science Foundation is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and analytical data for all new compounds, including
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL060443T
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Org. Lett., Vol. 8, No. 9, 2006