Kinetic resolution of pyridyl alcohols by Cu(II)(borabox)-catalyzed acylation

Article abstract of DOI:10.1055/s-2007-983850

Kinetic resolution of pyridyl alcohols has been achieved using copper(II)(borabox)-catalyzed benzoylation. Selectivity factors (k _rel) of up to 125 have been observed and application to the synthesis of chiral pyridyl phosphine ligands is descr

Full text of DOI:10.1055/s-2007-983850

PRACTICAL SYNTHETIC PROCEDURES
3751
Kinetic Resolution of Pyridyl Alcohols by Cu(II)(Borabox)-Catalyzed
Acylation
K
inetic Resolu
t
tion of
e
Pyridyl Al
p
cohols hen J. Roseblade, Andreas Pfaltz*
Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland
Fax +41(61)2671103; E-mail: andreas.pfaltz@unibas.ch
PSP
Received 24 April 2007
No103
Abstract: Kinetic resolution of pyridyl alcohols has been achieved using copper(II)(borabox)-catalyzed benzoylation. Selectivity factors
(krel) of up to 125 have been observed and application to the synthesis of chiral pyridyl phosphine ligands is described.
Key words: kinetic resolution, asymmetric catalysis, copper, bisoxazoline ligands, pyridines
CuCl2 (1 mol%),
L* (1 mol%)
+
Ph
N
Ph
N
Ph
N
PhCOCl (0.51 equiv)
DIPEA (1.0 equiv)
CH2Cl2, 0 °C, 16 h
OH
OBz
OH
91% ee
94% ee
4
5
NaOH (2 equiv)
EtOH, r.t., then
recrystallization
recrystallization
B
–
+
O
O
L* =
N
N
H
Bn
Bn
Ph
N
2
Ph
N
S
R
OH
OH
39% yield
95% ee
42% yield
97% ee
Scheme 1 Preparative scale pyridyl alcohol resolution
BArF–
R
R
Chiral pyridyl alcohols are valuable intermediates in the
synthesis of ligands for asymmetric catalysis,1 chiral nu-
cleophilic catalysts,2 and biologically active compounds.3
Our interest in the asymmetric synthesis of pyridyl alco-
hols arose because cationic iridium complexes 1 contain-
ing chiral P,N-ligands which are derived from pyridyl
alcohols are highly selective catalysts for asymmetric hy-
drogenation of unfunctionalized olefins (Figure 1).1 Liter-
ature approaches to their asymmetric synthesis have
focused on enantioselective reduction of the correspond-
ing ketones,4 although enzymatic resolution has also been
reported.5 We have recently found that chiral boron-
bridged bisoxazolines (borabox) are efficient ligands for
the kinetic resolution of 1,2-diols and pyridyl alcohols
through Cu-catalyzed acylation.6 Herein, we describe the
use of this method for the synthesis of enantiomerically
enriched pyridyl alcohols, with very high selectivities be-
ing achieved in some cases.
B
O
O
n
–
R
N
N
N
O
Ir
PR2
Bn
borabox Bn
2 R = Et
1
3 R = 3,5-(CF3)2C6H3
Figure 1 Pyridyl alcohol derived iridium complexes for catalytic
asymmetric hydrogenation and borabox ligands for alcohol resolution
(BArF = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate)
For example, kinetic resolution of pyridyl alcohol 4 was
carried out efficiently using the readily available borabox
ligand 2 (Scheme 1).7 Benzoylation under optimized con-
ditions (1 M, CH2Cl2, 1 mol%, 0 °C, 16 h) was followed
by column chromatography on silica gel to separate the al-
cohol and benzoate. The alcohol was recovered with an ee
of 91% S and subsequent recrystallization from hexane–
EtOAc provided S-alcohol in 39% yield and 95% ee. The
benzoate 5 was isolated with 94% ee R. This corresponds
to an S value of 100.8 Reducing the amount of CuCl2 and
ligand 2 to 0.5 mol% resulted in a decrease in selectivity
(S = 25). Benzoylation of 4 using 1 mol% catalyst at
SYNTHESIS 2007, No. 23, pp 3751–3753
x
x.
x
x
.
2
0
0
7
Advanced online publication: 08.08.2007
DOI: 10.1055/s-2007-983850; Art ID: Z10407SS
© Georg Thieme Verlag Stuttgart · New York

3752
S. J. Roseblade, A. Pfaltz
PRACTICAL SYNTHETIC PROCEDURES
Table 1 Enantioselective Benzoylation of Various Pyridyl Alcohols
CuCl2 (1 mol%)
Ligand (1 mol%)
+
n
n
n
PhCOCl (0.51 equiv)
DIPEA (1.0 equiv)
CH2Cl2, 0 °C, 2 h
R
N
R
N
R
N
OH
OBz
OH
6 R = H n = 1
7 R = Ph n = 1
8 R = H n = 2
4 R = Ph n = 2
9 R = Cl n = 2
Substrate
Ligand
Alcohol ee (%)a
Benzoate ee (%)a
Conversion (%)b
S (krel)b
6
6
7
7
8
8
4
4
9
9
2
3
2
3
2
3
2
3
2
3
16
5
33
5
33
46
36
45
62
52
39
42
44
47
2
1
50
76
99
83
61
70
62
58
84
91
60
76
96
97
80
65
18
51
9
19
92
125
17
8
a HPLC assay.
b Reference 8.
–24 °C and 22 °C also resulted in reduced selectivities dimethylmethylene-bridged bisoxazoline (box) complex
(S = 18 and 46, respectively).
did not result in efficient resolution for any of the sub-
strates.
Hydrolysis of the benzoate 5 was accomplished without
racemization (NaOH, EtOH, r.t.) to yield the R-alcohol in In conclusion, we have developed an efficient and conve-
42% yield and 97% ee after recrystallization from hex- nient method for the kinetic resolution of pyridyl alcohols
ane–EtOAc. A straightforward synthesis of both enantio- using Cu(II)(borabox)-catalyzed benzoylation, which al-
mers of the ligand precursor 4 has thus been lows straightforward access to pyridyl alcohols in high
accomplished, with the borabox ligand 2 inducing very enantiomeric excess.
high enantioselectivity.
The scope of this method was determined by benzoylation
of various pyridyl alcohols (Table 1). The selectivities ob-
tained were highly dependent on the structure of the sub-
strate. A comparison of pyridyl alcohols 6 and 7 shows
that substitution at the a-CH of the pyridine ring with a
phenyl group greatly enhances the selectivity. During
benzoylation of pyridyl alcohol 7 both borabox ligands
NMR spectra were recorded on 400 MHz and 500 MHz Bruker
Avance spectrometers. Mass spectra were recorded using Finnigan
MAT spectrometers. Elemental analyses were obtained from the
Micro-Analytical Laboratory of the Department of Chemistry at the
University of Basel. Optical rotations were measured on a Perkin-
Elmer polarimeter 341 equipped with a Na-lamp. Melting points
were recorded on a Büchi 535 apparatus and are uncorrected. An-
hyd CH2Cl2 was obtained by distillation from CaH2 under N2 or di-
tested impart levels of enantioselectivity, which are useful rectly from Fluka. All other reagents were purchased from Fluka
and used as received. Chromatography was carried out using Merck
synthetically, with an S value of 51 for ligand 3. Substrate
8 is benzoylated with an S value of 19 using ligand 3, in-
dicating that when a six-membered ring is fused to the py-
silica gel 60 (230–400 mesh ASTM). TLC was carried out using
Macherey-Nagel silica gel plates. Pyridyl alcohols 4,9 6,10 7,11 8,5c
9,12 and borabox ligands6a were prepared according to literature pro-
ridine ring the enantioselectivity can be higher than that of
cedures.
a five-membered ring analogue. As described above, ben-
zoylation of substrate 4, containing a phenyl group a to
the pyridine N atom and a six-membered ring, was highly
enantioselective with both borabox ligands, giving S val-
ues of around 100. Substrate 9, containing an a-chloro
substituent, exhibited similar selectivities to the unsubsti-
tuted analogue 8. It is also of note that use of an analogous
Gram-Scale Synthesis of Both Enantiomers of 8-Hydroxy-2-
phenyl-5,6,7,8-tetrahydroquinoline
Anhyd CuCl2 (6.0 mg, 1 mol%) and ligand 2 (17.3, mg, 1 mol%)
were dissolved in anhyd CH2Cl2 (5 mL) and stirred for 90 min at r.t.
under argon. The resulting dark yellow solution was filtered
through a syringe filter (CHROMAFIL O-20/15 MS 0.2 mM, Mach-
erey-Nagel) into a dry Schlenk tube containing racemic 8-hydroxy-
Synthesis 2007, No. 23, 3751–3753 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Kinetic Resolution of Pyridyl Alcohols
3753
2-phenyl-5,6,7,8-tetrahydroquinoline (4; 1.0 g, 4.44 mmol) under
argon. The resulting green solution was cooled to 0 °C in an ice
bath. DIPEA (773 mL, 1.0 equiv) was added dropwise, to give a
blue/green solution, followed by benzoyl chloride (284 mL, 0.55
equiv). The mixture was stirred overnight, during which time it was
allowed to warm slowly to r.t. H2O (5 mL) was added to the mixture
and the organic layer was separated. The aqueous layer was extract-
ed with CH2Cl2 (5 mL) and the combined organic layers were dried
(MgSO4), filtered, and concentrated. The benzoate and alcohol were
separated by column chromatography (15 cm × 2.5 cm, 10:1 pen-
tane–EtOAc) to give the R-benzoate (694 mg, 47%, 94% ee) as a
pale green oil and the S-alcohol (426 mg, 43%, 91% ee) as a pale
green crystalline solid. The alcohol was purified further by recrys-
tallization from hot 1:1 hexane–EtOAc to give 387 mg (39%) of
S-alcohol in 95% ee as colorless prisms; mp 88–90 °C.
[iridium (COD)]BArF complexes 1 which were analyzed by X-ray
diffraction.13
Acknowledgment
We thank Dr. Clément Mazet for recording NMR spectra and the
Swiss National Science Foundation for financial support.
References
(1) (a) Bell, S.; Wüstenberg, B.; Kaiser, S.; Menges, F.;
Netscher, T.; Pfaltz, A. Science 2006, 311, 642. (b) Kaiser,
S.; Smidt, S. P.; Pfaltz, A. Angew. Chem. Int. Ed. 2006, 45,
5194. (c) Drury, W. J. III.; Zimmerman, N.; Keenan, M.;
Hayashi, M.; Kaiser, S.; Goddard, R.; Pfaltz, A. Angew.
Chem. Int. Ed. 2004, 43, 70. (d) Liu, Q.-B.; Yu, C.-B.;
Zhou, Y.-G. Tetrahedron Lett. 2006, 47, 4733. (e) Kang, J.;
Kim, H. Y.; Kim, J. P. Tetrahedron: Asymmetry 1999, 10,
2523.
S-Alcohol 4
Rf = 0.13 (9:1 pentane–EtOAc); [a]D20 +143.0 (c = 1.0 in CH2Cl2).
HPLC (Chiralcel OD-H, 0.46 cm × 25 cm): Heptane–i-PrOH
(96:4), 0.5 mL/min, 20 °C); tR (min) = 23.5 (R), 21.0 (S).
(2) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1996, 118, 1809.
(3) (a) Roszkowski, A. P.; Govier, W. M. Pharmacologist 1959,
1, 60. (b) Barouh, V.; Dall, H.; Patel, D.; Hite, G. J. Med.
Chem. 1971, 14, 834.
(4) (a) Ohkuma, T.; Koizumi, M.; Makato, Y.; Noyori, R. Org.
Lett. 2000, 2, 1749. (b) Okano, K.; Murata, K.; Ikariya, T.
Tetrahedron Lett. 2000, 41, 9277. (c) Bolm, C.; Zehnder,
M.; Bur, D. Angew. Chem., Int. Ed. Engl. 1990, 29, 205.
(d) Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37,
5675.
(5) (a) Uenishi, J.; Hiraoka, T.; Hata, S.; Nishiwaki, K.;
Yonemitsu, O. J. Org. Chem. 1998, 63, 2481. (b) Uenishi,
J.; Hamada, M. Tetrahedron: Asymmetry 2001, 12, 2999.
(c) Uenishi, J.; Hamada, M. Synthesis 2002, 625. For
kinetic resolution of benzylic alcohols, see: (d) Birman, V.
B.; Uffman, E. W.; Jiang, H.; Li, X.; Kilbane, C. J. J. Am.
Chem. Soc. 2004, 126, 12226. (e) Spivey, A. C.; Leese, D.
P.; Zhu, F.; Davey, S. G.; Jarvest, R. L. Tetrahedron 2004,
60, 4513; and references cited therein.
(6) (a) Mazet, C.; Köhler, V.; Pfaltz, A. Angew. Chem. Int. Ed.
2005, 44, 4888. (b) Mazet, C.; Roseblade, S.; Köhler, V.;
Pfaltz, A. Org. Lett. 2006, 8, 1879. (c) Matsumura, Y.;
Maki, T.; Murakami, S.; Onomura, O. J. Am. Chem. Soc.
2003, 125, 2052. (d) Mitsuda, M.; Tanaka, T.; Tanaka, T.;
Demizu, Y.; Onomura, O.; Matsumura, Y. Tetrahedron Lett.
2006, 47, 8073; and references cited therein.
1H NMR (400 MHz, CDCl3): d = 8.00 (2 H, m), 7.58 (1 H, d, J = 8.0
Hz), 7.35–7.50 (4 H, m), 4.75 (1 H, dd, J = 9.1, 5.8 Hz, CHO), 4.38
(1 H, br s, OH), 2.80–2.93 (2 H, m), 2.33–2.43 (1 H, m), 1.96–2.10
(1 H, m), 1.75–1.92 (2 H, m).
13C NMR (100 MHz, CDCl3): d = 158.0, 154.6, 139.1, 138.3, 130.4,
129.3, 129.1, 127.1, 119.7, 69.5, 31.0, 28.4, 20.1.
MS (EI): m/z (%) = 225 (M+, 15), 196 (30), 169 (100).
Anal. Calcd for C15H15NO: C, 79.97; H, 6.71; N, 6.22. Found: C,
79.57; H, 6.76; N, 6.08.
R-Benzoate 5
Rf = 0.26 (9:1 pentane–EtOAc); [a]D20 –147.8 (c = 1.0 in CH2Cl2).
HPLC (Chiralcel OD-H, 0.46 cm × 25 cm): Heptane–i-PrOH
(96:4), 0.5 mL/min, 20 °C); tR (min) = 17.0 (R), 33.8 (S).
1H NMR (400 MHz, CDCl3): d = 8.08 (2 H, m), 7.94–7.97 (2 H, m),
7.63 (1 H, d, J = 8.1 Hz), 7.52–7.56 (2 H, m), 7.31–7.44 (5 H, m),
6.33 (1 H, t, J = 5.1 Hz, CHO), 2.95 (1 H, dt, J = 16.9, 5.6 Hz, Ar-
CHaHb), 2.84 (1 H, dd, J = 16.9, 8.8, 5.8 Hz, ArCHaHb), 2.29–2.34
(1 H, m), 2.17–2.25 (1 H, m), 2.05–2.11 (1 H, m), 1.89–1.97 (1 H,
m).
13C NMR (100 MHz, CDCl3): d = 166.6 (C=O), 155.4, 153.6, 139.4,
138.2, 133.1, 132.2, 131.4, 130.2, 129.1, 129.0, 128.7, 127.1, 120.0,
72.2 (CHO), 29.6, 28.6, 19.2.
MS (FAB): m/z (%) = 330 (M + H+, 85).
(7) Benzoyl chloride has been identified as the optimal acylating
reagent for kinetic resolution of 1,2-diols. See reference 6b.
(8) 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. (b) Kagan, H. B.
Tetrahedron 2001, 57, 2449. (c) Keith, J. M.; Larrow, J. F.;
Jacobsen, E. N. Adv. Synth. Cat. 2001, 343, 5.
Anal. Calcd for C22H19NO2: C, 80.22; H, 5.81; N, 4.25. Found: C,
80.32; H, 5.63; N, 4.27.
Hydrolysis of R-Benzoate 5
R-Benzoate 5 (330 mg, 1 mmol, 94% ee) was dissolved in EtOH (20
mL) and 2 N aq NaOH (1 mL, 2 mmol, 2 equiv) was added at r.t.
After stirring for 3 h, the mixture was diluted with H2O (20 mL) and
extracted with CH2Cl2 (3 × 20 mL). The combined organic layers
were dried (MgSO4), filtered, and concentrated to give the crude
R-alcohol 4 as a crystalline solid (93% ee). Recrystallization from
hot 1:1 hexane–EtOAc gave 200 mg (89%) of the R-alcohol 4 with
97% ee; mp 85–94 °C.
(9) Hahn, W. E.; Epsztajn, J. Rocz. Chem. 1963, 37, 403; Chem.
Abstr. 1963, 59, 62096.
(10) Robison, M. M. J. Am. Chem. Soc. 1958, 80, 6254.
(11) Kang, J.; Kim, H. Y.; Kim, J. H. Tetrahedron: Asymmetry
1999, 10, 2523; and references cited therein.
The absolute configuration of pyridyl alcohols 7 and 8 was assigned
by comparison of the [a]D values with those previously reported in
the literature.1e,5c The absolute configurations of the pyridyl alco-
hols 4 and 6 were determined by conversion to the corresponding
(12) Zimmerman, S. C.; Zeng, Z.; Wu, W.; Reichert, D. E. J. Am.
Chem. Soc. 1991, 113, 183.
(13) Kaiser, S. PhD Dissertation; University of Basel:
Switzerland, 2005.
Synthesis 2007, No. 23, 3751–3753 © Thieme Stuttgart · New York