Enantioselective Addition of Diethylzinc to Aldehydes Catalyzed by Chiral O,N,O-tridentate Phenol Ligands Derived from Camphor

Article abstract of DOI:10.1002/chir.22543

Chiral O,N,O-tridentate phenol ligands bearing a camphor backbone were found to be effective chiral catalysts for the enantioselective addition of diethylzinc to aromatic aldehydes, resulting in high enantioselectivities (80-95% ee) at room temperature.

Full text of DOI:10.1002/chir.22543

CHIRALITY 28:65–71 (2016)
Enantioselective Addition of Diethylzinc to Aldehydes Catalyzed by
Chiral O,N,O-tridentate Phenol Ligands Derived From Camphor
*
DONG-SHENG LEE, SHU-MING CHANG, CHUN-YING HO, AND TA-JUNG LU
Department of Chemistry, National Chung-Hsing University, Taichung, Taiwan R.O.C.
ABSTRACT
Chiral O,N,O-tridentate phenol ligands bearing a camphor backbone were found
to be effective chiral catalysts for the enantioselective addition of diethylzinc to aromatic
aldehydes, resulting in high enantioselectivities (80–95% ee) at room temperature. Chirality
28:65–71, 2016. © 2015 Wiley Periodicals, Inc.
KEY WORDS: tridentate chiral ligand; enantioselective addition; asymmetric catalysis
determined by high-performance liquid chromatography (HPLC) analysis
on chiral columns using isopropanol and n-hexane as the mobile phase.
Optically pure secondary alcohols serve as important
intermediates in the synthesis of pharmaceuticals. For exam-
ple, PNU-142721,1 (S)-duloxetine,2 Singulair,3 neobenodine,4
fluoxetine,5 and tomoxetin6 (Fig. 1) are all physiologically
active compounds based on optically pure secondary alco-
hols. Therefore, the development of efficient methods for
the preparation of optically pure secondary alcohols has re-
ceived much attention, and the asymmetric addition of
diethylzinc to aldehydes is one of the most effective ap-
proaches for preparing them.7,8
Although many bidentate chiral ligands have been prepared
and tested in the catalytic asymmetric addition of diethylzinc
to aldehydes,9–23 the development of efficient tridentate
ligands have not been studied extensively. Tridentate ligands
should confer more rigidity to the reactive zinc chelate catalyst
structures, thereby allowing better discrimination between the
two enantiotopic faces of an aldehyde in the transition state
complex. Recently, some tridentate and polydentate chiral
ligands have been synthesized and applied to the
enantioselective addition of diethylzinc to aldehydes.24–41 In
this line, Hayashi et al. have developed O,N,O-ligands based
on Schiff bases derived from tert-leucinol and salicylaldehyde,
which were effective for the asymmetric addition of
diethylzinc to aldehydes (up to 96% enantiomeric excess
[ee] for benzaldehyde). Although most of these ligands
provide good results, some of them are difficult to purify or
prepare efficiently. Since camphor skeleton has proven to
be highly effective as a chiral template in asymmetric synthe-
sis,42–48 and on the basis of the above, we became interested
in developing new tridentate aminodiols ligands based on
2-aminoisoborneol and phenol, and derived from Schiff bases
obtained from camphor.
(1R,4S)-(À)-1,7,7-Trimethyl-2,3-dione-bicyclo[2.2.1]heptane (2).
To a solution of camphor (2.00 g, 13.0 mmol) in acetic anhydride
(3.30 mL) was added selenium dioxide (3.31 g, 30.0 mmol) and heated
to reflux for 19 h. The solution was cooled to room temperature and
filtered to remove the black selenium precipitate. The residue was
washed with acetic anhydride (10.0 mL). The liquid was added to cold
water (50 mL) to separate camphorquinone 2 from acetic anhydride,
then filtered by Buchner funnel. The filtrate was neutralized with
saturated NaOH(aq) and extracted with EtOAc (20 mL × 3). The
combined organic layers were dried over MgSO4, filtered, and concentrated
to afford the crude product, which was subjected to the next reaction with-
out any purification. The crude product was a yellow solid (2.14 g, 99%).
[α]D25 = À96.8° (c = 1.00, CHCl3) [Lit.49 [α] D25 = À108.3° (c = 1.86, CHCl3)];
1H NMR (CDCl3, 400 MHz, δ): 2.63 (d, J = 5.2 Hz, 1H), 2.18–2.12 (m, 1H),
1.94–1.86 (m, 1H), 1.67–1.59 (m, 2H), 1.10 (s, 3H), 1.06 (s, 3H), 0.93
(s, 3H); 13C NMR (CDCl3, 100 MHz, δ): 204.8, 202.8, 58.6, 57.9, 42.5, 29.9,
22.2, 21.1, 17.4, 8.8. The data match those of the literature report.49
(1R,4S)-(+)-3-(Hydroxyimino)-2-oxo-1,7,7-trimethylbicyclo[2.2.1]heptane
(3). To a solution of camphorquinone 2 (2.00 g, 12.0 mmol) in ethanol (9.00
mL) was added the solution of hydroxylamine hydrochloride (1.00 g,
14.4 mmol) and sodium acetate (1.78 g, 21.6 mmol) in water (5.00
mL) at room temperature. The resulting solution was stirred for 1 h at
room temperature. Ethanol was removed by rotary evaporator, and the
residual mixture was extracted with EtOAc (20 mL × 3). The combined
organic layers were dried with MgSO4, filtered, and concentrated to give
oxime 3 as a yellow solid (2.15 g, 99%). The crude compound was recrystallized
from ether to afford the desired product as off-white solids (1.74 g, 80%, E:Z =
2.95:1, the ratio was determined by crude NMR spectrum). [α]2D5 = +198.8 (c
25
= 1.00, CHCl3) [Lit.50 [α] = +199° (c = 1.41, CHCl3)]; 1H NMR (CDCl3,
D
400 MHz, δ): 8.88 (br, 1H, C=NOH), 3.25 (d, J = 4.4 Hz, 1H), 2.04–2.00 (m,
1H), 1.82–1.74 (m, 1H), 1.59–1.52 (m, 2H), 1.02 (s, 3H), 1.00 (s, 3H), 0.88
(s, 3H); 13C NMR (CDCl3, 100 MHz, δ): 204.4, 159.8, 58.5, 46.6, 44.9, 30.6,
23.7, 20.7, 17.6, 8.9. The data match those of the literature report.50
Herein we report novel O,N,O-tridentate chiral ligands for
the enantioselective addition of diethylzinc to aldehydes.
These tridentate ligands 1 (Fig. 2) have the following charac-
teristics: 1) they have two different types of oxygen atoms,
binding to zinc in distinct ways, and 2) the substituents on
the aromatic ring induce electronic and steric effects.
(1R,2S,3R,4S)-3-Amino-2-hydroxy-1,7,7-trimethylbicyclo[2.2.1] heptane
(4).To a solution of LAH (2.00 g, 52.7 mmol) in dry THF (15.0 mL) was added
the solution of camphorquinone oxime 3 (3.19 g, 17.6 mmol) in THF (15.0 mL)
at 0°C over a period of 30 min. The solution was allowed to warm to
ambient temperature and heated to reflux for 1 h. After cooling to room
Contract grant sponsor: National Science Council of the Republic of China
Contract grant number: 102WFA0500216
*Correspondence to: D.-S. Lee, Department of Chemistry, National Chung-
Hsing University, 250, Kuo Kuang Rd., Taichung 402, Taiwan R.O.C. E-mail:
dslee@mail.nchu.edu.tw
Received for publication 16 April 2015; Accepted 22 July 2015
DOI: 10.1002/chir.22543
Published online 21 October 2015 in Wiley Online Library
(wileyonlinelibrary.com).
MATERIALS AND METHODS
General Methods
1H and 13C NMR (nuclear magnetic resonance) spectra were recorded
on a 400 MHz spectrometer. Chloroform (δ = 7.26) or dimethyl sulfoxide
(DMSO) (δ = 2.49) was used as internal standard in 1H NMR spectra. The
central peak of CDCl3 (δ = 77.0) or DMSO-d6 (δ = 39.5) was used as inter-
nal standard in 13C NMR spectra. The ee value of secondary alcohols were
© 2015 Wiley Periodicals, Inc.

66
LEE ET AL.
Fig. 1. Some examples of pharmaceutical products.
product 1b (1.11 g, 72%) as a white solid. Mp = 91–94°C ; [α]2D5 = +28.1
(c = 1.00, CHCl3); 1H NMR (CDCl3, 400 MHz, δ): 7.16 (t, J = 8.0 Hz, 1H),
7.00 (d, J = 7.2 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.77 (t, J = 7.6 Hz, 1H),
4.02 (d, J = 13.4 Hz, 1H), 3.94 (d, J = 13.4 Hz, 1H), 3.77 (d, J = 7.6 Hz,
1H), 2.79 (d, J = 7.6 Hz, 1H), 1.78 (d, J = 4.4 Hz, 1H), 1.72–1.65 (m, 1H),
1.51–1.45 (m, 1H), 1.72–1.65 (m, 1H), 1.14 (s, 3H), 1.03–0.95 (m, 2H),
0.93 (s, 3H), 0.81 (s, 3H); 13C NMR (CDCl3, 100 MHz, δ): 158.0, 128.7,
128.3, 123.3, 118.9, 116.3, 80.0, 66.1, 53.0, 50.1, 49.1, 46.7, 33.1, 26.7,
21.7, 21.0, 11.3; HRMS (EI, m/z): M+ calcd for C17H25NO2, 275.1885;
found, 275.1877; Anal. Calcd. for C17H25NO2: C 74.14, H 9.15, N 5.09,
O 11.62; found: C 73.59, H 9.35, N 4.86, O 11.50.
Fig. 2. The stucture of O,N,O-tridentate ligands 1.
temperature, the mixture was quenched by water (1 mL) and filtered
by Buchner funnel. The precipitate was washed by EtOAc (20 mL × 3).
The filtrate was dried over MgSO4, filtered, and concentrated to afford
(1R,2S,3R,4S)-3-[ (2-Methoxybenzyl)-amino] -2-hydroxy-1,7,7-
trimethylbicyclo[2.2.1]heptane (1c). 2-Methoxybenzaldehyde
(0.57 mL, 5.61 mmol), amino alcohol 4 (1.00 g, 5.91 mmol), MeOH
(25.0 mL), and NaBH4 (0.420 g, 11.2 mmol) were used to afford desired
product 1c (0.75 g, 46%) as a yellow solid. Mp = 81–82°C ; [α]2D5 = 21.9
(c = 1.00, CHCl3); 1H NMR (CDCl3, 400 MHz, δ): 7.26 (td, J = 15.6, 1.6 Hz, 1H),
7.21 (dd, J = 7.6, 1.6 Hz, 1H), 6.93–6.87 (m, 2H), 3.86 (s, 3H), 3.80 (d, J = 13.2 Hz,
1H), 3.71 (d, J = 13.2 Hz, 1H), 3.45 (d, J = 7.6 Hz, 1H), 2.78 (d, J = 7.6 Hz,
1H), 1.67–1.60 (m, 1H), 1.46 (d, J = 4.4 Hz, 1H), 1.42–1.35 (m, 1H), 1.03
(s, 3H), 1.00–0.96 (m, 2H), 0.94 (s, 3H), 0.75 (s, 3H); 13C NMR (CDCl3,
100 MHz, δ): 157.7, 129.8, 128.5, 128.1, 120.4, 110.2, 78.7, 65.4, 55.2,
51.9, 50.6, 48.7, 46.5, 32.9, 27.1, 21.9, 21.3, 11.4; HRMS (EI, m/z): M+ calcd
for C18H27NO2, 289.2042; found, 289.2038; Anal. Calcd. for C18H27NO2:
C 74.70, H 9.40, N 4.84, O 11.06; found: C 74.09, H 8.90, N 4.90, O 10.90.
crude product 4 as a white solid (2.86 g, 96%). [α]2D5 = À3.6° (c = 1.00,
25
MeOH) [Lit.50 [α]
= À6.2 (c = 1.08, MeOH)]; 1H NMR (CDCl3,
D
400 MHz, δ): 3.38 (d, J = 7.2 Hz, 1H), 3.06 (d, J = 7.2 Hz, 1H), 1.74–1.67
(m, 1H), 1.56 (d, J = 4.8 Hz, 1H), 1.43–1.39 (m, 1H), 1.06 (s, 3H),
1.05–0.96 (m, 1H), 0.95 (s, 3 H), 0.90–0.87 (m, 1H), 0.79 (s, 3 H); 13C
NMR (CDCl3, 100 MHz, δ): 79.0, 57.3, 53.3, 48.7, 46.6, 33.1, 26.9, 21.9,
21.2, 11.4. The data match those of the literature report.50
General Procedure for Ligand 1
Aldehyde or its derivative (5.61 mmol) in MeOH (10.0 mL) was added
to a solution of amino alcohol 4 (5.61 mmol) in MeOH (15.0 mL) at room
temperature and the reaction was stirred for 2 h. Then NaBH4 (0.420 g,
11.2 mmol) was added. After 2 h, methanol was removed and the residue
was extracted with EtOAc (10 mL × 3). The combined organic phases were
dried with Na2SO4, filtered, and concentrated to afford the crude product,
which was purified by chromatography (EtOAc/hexane = 1/20–1/5) to give
ligand 1.
(1R,2S,3R,4S)-3-[(2-Hydroxy-5-methylbenzyl)-amino]-2-hydroxy-1,7,7-
trimethylbicyclo[2.2.1]heptane (1d). 2-Hydroxy-5-methylbenzaldehyde
(0.760 g, 5.61 mmol), amino alcohol 4 (1.00 g, 5.91 mmol), MeOH (25.0 mL),
and NaBH4 (0.420 g, 11.2 mmol) were used to afford desired product 1d
(1.44 g, 89%) as a white solid. Mp = 132–134°C ; [α]2D5 = 25.3 (c = 1.00, CHCl3);
1H NMR (CDCl3, 400 MHz, δ): 6.96 (dd, J = 8.0, 2.0 Hz, 1H), 6.81 (d, J = 2.0 Hz,
1H), 6.73 (d, J = 8.0 Hz, 1H), 3.96 (d, J = 13.6 Hz, 1H), 3.90 (d, J = 13.6 Hz, 1H),
3.75 (d, J = 7.6 Hz, 1H), 2.87 (d, J = 7.6 Hz, 1H), 2.24 (s, 3H), 1.76 (d, J = 4.4 Hz,
1H), 1.71–1.64 (m, 1H), 1.51–1.43 (m, 1H), 1.14 (s, 3H), 1.03–0.96 (m, 2H), 0.93
(s, 3H), 0.81 (s, 3H); 13C NMR (CDCl3, 100 MHz, δ): 155.7, 129.0, 128.9, 127.9,
123.0, 116.0, 80.0, 66.1, 53.0, 50.0, 49.0, 46.7, 33.1, 26.7, 21.7, 21.0, 20.4, 11.3;
HRMS (EI, m/z): M+ calcd for C18H27NO2, 289.2042; found, 289.2039; Anal.
Calcd. for C18H27NO2: C 74.70, H 9.40, N 4.84, O 11.06; found: C 74.29, H
9.20, N 4.74, O 11.37.
(1R,2S,3R,4S)-3-(Benzylamino)-2-hydroxy-1,7,7-trimethylbicyclo[2.2.1]
heptane (1a). Benzaldehyde (0.570 mL, 5.61 mmol), amino alcohol 4 (1.00 g,
5.91 mmol), MeOH (25.0 mL) and NaBH4 (0.420 g, 11.2 mmol) were used to
afford desired product 1a (0.90 g, 62%) as a white solid. Mp = 82–84°C ; [α]D25
=
+26.8 (c = 1.00, CHCl3); 1H NMR (CDCl3, 400 MHz, δ): 7.36–7.25 (m, 5H), 3.80
(s, 2H), 3.43 (d, J = 7.2 Hz, 1H), 2.82 (d, J = 7.2 Hz, 1H), 1.74–1.64 (m, 1H), 1.59
(d, J = 4.4 Hz, 1H), 1.47–1.39 (m, 1H), 1.05 (s, 3H), 1.03–0.97 (m, 2H), 0.95 (s,
3H), 0.78 (s, 3H); 13C NMR (CDCl3, 100 MHz, δ): 139.9, 128.5, 128.0, 127.2,
78.7, 65.6, 54.8, 51.8, 48.8, 46.6, 32.9, 27.2, 21.9, 21.3, 11.3; HRMS (EI, m/z): M+
calcd for C17H25NO, 259.1936; found, 259.1933; Anal. Calcd. for C17H25NO: C
78.72, H 9.71, N 5.40, O 6.17; found: C 78.44, H 9.35, N 5.16, O 6.51.
(1R,2S,3R,4S)-3-[ (2-Hydroxy-5-methoxybenzyl)-amino]-2-hy-
droxy-1,7,7-trimethylbicyclo[2.2.1]heptane (1e). 2-Hydroxy-5-
methoxybenzaldehyde (0.700 mL, 5.61 mmol), amino alcohol 4 (1.00 g, 5.91
mmol), MeOH (25.0 mL), and NaBH4 (0.420 g, 11.2 mmol) were used to af-
ford desired product 1e (1.39 g, 81%) as a yellow solid. Mp = 138–139°C ;
[α]2D5 = 23.9° (c = 1.00, CHCl3); 1H NMR (CDCl3, 400 MHz, δ): 6.76
(d, J = 8.8 Hz, 1H), 6.72 (dd, J = 8.8, 2.8 Hz, 1H), 6.59 (d, J = 2.8 Hz, 1H), 3.97
(1R,2S,3R,4S)-3-[ ( 2-Hydrooxybenzyl )-amino) ]-2-hydroxy-1,7,7-
trimethylbicyclo[2.2.1] heptane
(1b). 2-Hydroxybenzaldehyde
(0.600 mL, 5.61 mmol), amino alcohol 4 (1.00 g, 5.91 mmol), MeOH
(25.0 mL) and NaBH4 (0.420 g, 11.2 mmol) were used to afford desired
Chirality DOI 10.1002/chir

ENANTIOSELECTIVE ADDITION OF DIETHYLZINC TO ALDEHYDES
67
(d, J = 13.6 Hz, 1H), 3.89 (d, J = 13.6 Hz, 1H), 3.75 (d, J = 7.6 Hz, 1H), 3.74 (s, 3H),
2.77 (d, J = 7.6 Hz, 1H), 1.75 (d, J = 4.8 Hz, 1H), 1.71–1.64 (m, 1H), 1.50–1.44
(m, 1H), 1.13 (s, 3H), 1.02–0.94 (m, 2H), 0.92 (s, 3H), 0.80 (s, 3H); 13C NMR
(CDCl3, 100 MHz, δ): 152.4, 151.9, 124.0, 116.5, 114.4, 113.4 , 80.0, 66.1, 55.8,
53.1, 50.1, 49.1, 46.7, 33.1, 26.7, 21.7, 21.0, 11.3; HRMS (EI, m/z): M+ calcd
for C18H27NO3, 305.1991; found, 305.1984; Anal. Calcd. for C18H27NO3: C
70.79, H 8.91, N 4.59, O 15.72; found: C 70.69, H 9.13, N 4.31, O 15.40.
NMR (CDCl3, 400 MHz, δ): 7.26–7.08 (m, 4H), 4.56 (t, J = 6.4 Hz, 1H ),
2.36 (s, 3H), 1.86–1.71 (m, 2H), 0.92 (t, J = 7.6 Hz, 3H).
1-(2-Methylphenyl)propan-1-ol (7d) (example from Table 2, entry
4). The use of 2-tolualdehyde 6d (1.00 mmol) gave chiral adduct 7d
(0.126 g) in 84% yield. HPLC (Chiralcel OB, 10% IPA/n-hexane,
0.5 mL/min, 254 nm): tr(major): 8.42 min, tr(minor): 10.46 min, 92% ee; 1H
NMR (CDCl3, 400 MHz, δ): 7.47–7.12 (m, 4H), 4.85 (t, J = 6.4 Hz, 1H ),
2.34 (s, 3H), 1.80–1.73 (m, 2H), 0.96 (t, J = 7.6 Hz, 3H).
(1R,2S,3R,4S)-3-[(2-Hydroxy-5-nitrobenzyl)-amino]-2-hydroxy-1,7,7-
trimethylbicyclo[2.2.1]heptane (1f). 2-Hydroxy-5-nitrobenzaldehyde (0.490 g,
.2.95 mmol), amino alcohol 4(0.500 g, 2.95 mmol), 2,2,2-trifluoroethanol (20.0 mL),
and NaBH4 (0.21 g, 5.90 mmol) were used to afford desired product 1f
(0.43g, 45 %) as a yellow solid. Mp = 216–218°C;[α]2D5 = 28.6(c = 1.00, CHCl3);
1H NMR (CDCl3, 400 MHz, δ): 7.94 (d, J = 3.2 Hz, 1H), 7.89 (dd, J = 9.2, 3.2 Hz,
1H), 6.36 (d, J = 9.2 Hz, 1H), 4.04 (d, J = 13.6 Hz, 1H), 3.91 (d, J = 13.6 Hz, 1H),
3.64(d,J=7.6Hz,1H),2.89(d,J=7.6Hz,1H),1.84(d,J=4.0Hz,1H),1.62–1.59
(m, 1H), 1.40–1.35 (m, 1H), 1.05 (s, 3H), 1.00–0.89 (m, 2H), 0.83 (s, 3H), 0.74
(s,3H);13CNMR(CDCl3,100MHz,δ):174.0,132.6,126.3,126.1,121.4,117.6,
77.1, 64.3, 50.9, 48.7, 48.1, 46.3, 32.1, 26.2, 21.4, 20.8, 11.4; HRMS (EI, m/z):
M+ calcd for C17H24N2O4, 320.1736; found, 320.1728.
1-(4-Methoxyphenyl)propan-1-ol (7e) (example from Table 2, entry
5). The use of 4-anisaldehyde 6e (1.00 mmol) gave chiral adduct 7e
(0.160 g) in 96% yield. HPLC (Chiralcel OD, 2% IPA/n-hexane,
1.0 mL/min, 254 nm): tr(major): 23.96 min, tr(minor): 21.77 min, 91% ee; 1H
NMR (CDCl3, 400 MHz, δ): 7.28–6.87 (m, 4H), 4.54 (t, J = 6.8 Hz, 1H ),
3.80 (s, 3H), 1.86–1.65 (m, 2 H), 0.90 (t, J = 7.6 Hz, 3H).
1-(3-Methoxyphenyl)propan-1-ol (7f) (example from Table 2, entry
6). The use of 3-anisaldehyde 6f (1.00 mmol) gave chiral adduct 7f
(0.153 g) in 92% yield. HPLC (Chiralcel OB, 2% IPA/n-hexane,
1.0 mL/min, 254 nm): tr(major): 16.15 min, tr(minor): 19.45 min, 88% ee; 1H
NMR (CDCl3, 400 MHz, δ): 7.28–6.80 (m, 4H), 4.57 (t, J = 6.4 Hz, 1H ),
3.81 (s, 3H), 1.87–1.71 (m, 2H), 0.92 (t, J = 7.6 Hz, 3H).
(1R,2S,3R,4S)-3-[(3-tert-Butyl-2-hydroxybenzyl)-amino] -2-hydroxy-
1,7,7-trimethylbicyclo[2.2.1]heptane (1g). 3-tert-Butyl-2-hydroxyben-
zaldehyde (2.45 mL, 13.6 mmol), amino alcohol 4 (3.00 g, 17.7 mmol),
MeOH (30.0 mL), and NaBH4 (1.03 g, 27.3 mmol) were used to afford
desired product 1g (3.84 g, 85%) as a white solid. Mp = 118–119°C ; [α]D25
1-(2-Methoxyphenyl)propan-1-ol (7g) (example from Table 2, entry
7). The use of 2-anisaldehyde 6g (1.00 mmol) gave chiral adduct 7g
(0.150 g) in 90% yield. HPLC (Chiralcel OB, 2% IPA/n-hexane,
1.0 mL/min, 254 nm): tr(major): 9.77 min, tr(minor): 14.52 min, 83% ee; 1H
NMR (CDCl3, 400 MHz, δ): 7.30–6.87 (m, 4 H), 4.76 (t, J = 6.4 Hz, 1H ),
3.85 (s, 3H), 1.84–1.78 (m, 2H), 0.93 (t, J = 7.6 Hz, 3H).
1
= 28.5 (c = 1.00, CHCl3); H NMR (CDCl3, 400 MHz, δ): 7.19 (dd, J = 7.6,
1.2 Hz, 1H), 6.88 (d, J = 6.4 Hz, 1H), 6.71 (t, J = 8.0, 7.6 Hz, 1H), 4.04
(d, J = 13.6 Hz, 1H), 3.90 (d, J = 13.6 Hz, 1H), 3.76 (d, J = 7.6 Hz, 1H),
2.77 (d, J = 7.6 Hz, 1H), 1.75 (d, J = 4.4 Hz, 1H), 1.69–1.61 (m, 1H),
1.50–1.44 (m, 1H), 1.42 (s, 9H), 1.15 (s, 3H), 1.02–0.96 (m, 2H), 0.93 (s, 3H),
0.80 (s, 3H); 13C NMR (CDCl3, 100 MHz, δ): 157.2, 136.7, 126.4, 125.8,
123.6, 118.1, 80.2, 66.2, 53.6, 49.9, 49.0, 46.7, 34.6, 33.2, 29.5, 26.6, 21.7,
21.0, 11.3; HRMS (EI, m/z): M+ calcd for C21H33NO2, 331.2511; found,
331.2504; Anal. Calcd. for C21H33NO2: C 76.09, H 10.03, N 4.23, O 9.65;
Found: C 76.10, H 9.83, N 4.03, O 9.75.
1-(4-Chlorophenyl)propan-1-ol (7h) (example from Table 2, entry
8). The use of 4-chlorobenzaldehyde 6h (1.00 mmol) gave chiral adduct
7h (0.154 g) in 90% yield. HPLC (Chiralcel OD, 2.5% IPA/n-hexane,
1.0 mL/min, 254 nm): tr(major): 11.53 min, tr(minor): 12.74 min, 88% ee; 1H
NMR (CDCl3, 400 MHz, δ): 7.32–7.25 (m, 4H), 4.57 (t, J = 6.4 Hz, 1H ),
1.82–1.67 (m, 2H), 0.89 (t, J = 7.6 Hz, 3H).
1-(3-Chlorophenyl)propan-1-ol (7i) (example from Table 2, entry
9). The use of 3-chlorobenzaldehyde 6i (1.00 mmol) gave chiral adduct
7i (0.154 g) in 90% yield. HPLC (Chiralcel OB, 2% IPA/n-hexane,
1.0 mL/min, 254 nm): tr(major): 8.47 min, tr(minor): 10.23 min, 84% ee; 1H
NMR (CDCl3, 400 MHz, δ): 7.34–7.18 (m, 4H), 4.56 (t, J = 6.4 Hz, 1H ),
1.82–1.70 (m, 2H), 0.91 (t, J = 7.6 Hz, 3H).
General Procedures for the Asymmetric Addition of
Diethylzinc to Aldehydes
To a 10-mL round-bottomed flask containing ligand (57.0 mg, 20 mol%)
in toluene (1.80 mL) was added diethylzinc solution (2.50 mmol, 1.5 M in
toluene) at ambient temperature. After stirring for
1 h at room
temperature, to the mixture was added aldehyde (1.00 mmol) at room
temperature. After stirring for 2.5 h, the reaction was quenched with
1.0 M HCl(aq) (2.50 mL). The aqueous layer was extracted with EtOAc
(10 mL × 3). The combined organic layers were dried over Na2SO4,
filtered, and concentrated to give the crude product, which was purified
by flash chromatography (Hexane:EtOAc = 20:1). The ee value was
determined by HPLC on a chiral stationary phase.
1-(2-Chlorophenyl)propan-1-ol (7j) (example from Table 2, entry
10). The use of 2-chlorobenzaldehyde 6j (1.00 mmol) gave chiral ad-
duct 7j (0.145 g) in 85% yield. HPLC (Chiralcel OB, 5% IPA/n-hexane,
0.5 mL/min, 254 nm): tr(major): 9.11 min, tr(minor): 11.22 min, 80% ee; 1H
NMR (CDCl3, 400 MHz, δ): 7.56–7.17 (m, 4H), 5.07 (t, J = 3.6 Hz, 1H ),
1.85–1.70 (m, 2H), 0.99 (t, J = 7.6 Hz, 3H).
1-Phenylpropan-1-ol (7a) (example from Table 2, entry 1). The use of
benzaldehyde 6a (1.00 mmol) gave chiral adduct 7a (0.124 g) in 91% yield.
1-(4-Bromophenyl)propan-1-ol (7k) (example from Table 2, entry
11). The use of 4-bromobenzaldehyde 6k (1.00 mmol) gave chiral ad-
duct 7k (0.191 g) in 89% yield. HPLC (Chiralcel OB, 5% IPA/n-hexane,
0.5 mL/min, 254 nm): tr(major): 13.10 min, tr(minor): 14.29 min, 90% ee; H
NMR (CDCl3, 400 MHz, δ): 7.48–7.20 (m, 4H), 4.57 (t, J = 6.8 Hz, 1H ),
1.82–1.66 (m, 2H), 0.90 (t, J = 7.6 Hz, 3H).
HPLC (Chiralcel OD, 2% IPA/n-hexane, 1.5 mL/min, 254 nm): tr(major)
:
10.95 min, tr(minor): 8.63 min, 90% ee; 1H NMR (CDCl3, 400 MHz, δ):
7.36–7.26 (m, 5H), 4.59 (t, J = 6.4 Hz, 1H ), 1.90–1.72 (m, 2H), 0.92 (t, J
= 7.6 Hz, 3H).
1
1-(4-Methylphenyl)propan-1-ol (7b) (example from Table 2, entry
2). The use of 4-tolualdehyde 6b (1.00 mmol) gave chiral adduct 7b
(0.143 g) in 95% yield. HPLC (Chiralcel OB, 2% IPA/n-hexane, 0.5
mL/min, 254 nm): tr(major): 20.10 min, tr(minor): 23.49 min, 91% ee; 1H
NMR (CDCl3, 400 MHz, δ): 7.26–7.15 (m, 4H), 4.56 (t, J = 6.4 Hz, 1H ),
2.35 (s, 3H), 1.86–1.68 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).
1-(2-Fluorophenyl)propan-1-ol (7l) (example from Table 2, entry
12). The use of 2-fluorobenzaldehyde 6l (1.00 mmol) gave chiral
adduct 7l (0.136 g) in 88% yield. HPLC (Chiralcel OD, 2% IPA/n-hexane,
0.5 mL/min, 254 nm): tr(major): 14.02 min, tr(minor): 19.51 min, 85% ee; H
NMR (CDCl3, 400 MHz, δ): 7.47–6.99 (m, 4H), 4.94 (dd, J = 10.8, 6.4 Hz,
1H), 1.82–1.67 (m, 2H), 0.89 (t, J = 7.6 Hz, 3H).
1
1-(3-Methylphenyl)propan-1-ol (7c) (example from Table 2, entry
3). The use of 3-tolualdehyde 6c (1.00 mmol) gave chiral adduct 7c
(0.132 g) in 88% yield. HPLC (Chiralcel OD, 2% IPA/n-hexane, 0.5
mL/min, 254 nm): tr(major): 31.83 min, tr(minor): 22.34 min, 88% ee; 1H
1-(Naphthalen-1-yl)propan-1-ol (7m) (example from Table 2, entry
13). The use of 1-naphthaldehyde 6m (1.00 mmol) gave chiral adduct
7m (0.168 g) in 90% yield. HPLC (Chiralcel OD, 2% IPA/n-hexane,
1
1.0 mL/min, 254 nm): tr(major): 26.10 min, tr(minor): 51.55 min, 95% ee; H
Chirality DOI 10.1002/chir

68
LEE ET AL.
NMR (CDCl3, 400 MHz, δ): 8.14–7.47 (m, 7H), 5.4 (t, J = 7.6 Hz, 1H ),
2.05–1.90 (m, 2H), 1.04 (t, J = 7.6 Hz, 3H).
Amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (4) was ob-
tained in three steps from camphor in 60% overall yield. The
condensation of various aromatic aldehydes with 4 produced
imines, which were subsequently reduced with sodium boro-
hydride to afford chiral O,N,O-tridentate ligands 1 in good
yields (45–89%).
With O,N,O-tridentate ligands 1 in hand, a model reac-
tion (the addition of diethylzinc to benzaldehyde (6a))
was first tested to study the catalytic activity of the li-
gands. The reaction was carried out in the presence of
20 mol% of ligands 1 to afford the corresponding second-
ary alcohol 7a; the results are listed in Table 1. To reveal
the functionality of tridentate ligands for this
enantioselective organozinc addition, we prepared analo-
gous bidentate ligands 1a and 1c. Our results demon-
strate that tridentate chiral ligand 1b (entry 2, 87% yield,
60% ee) is superior to bidentate chiral ligand 1a (entry 1,
72% yield, 34% ee) for the asymmetric addition. The substitu-
tion of the hydroxyl group for a methyoxy group (1c)
1-(Naphthalen-2-yl)propan-1-ol (7n) (example from Table 2, entry
14). The use of 2-naphthaldehyde 6n (1.00 mmol) gave chiral adduct
7n (0.169 g) in 91% yield. HPLC (Chiralcel OD, 2% IPA/n-hexane,
1.0 mL/min, 254 nm): tr(major): 31.93 min, tr(minor): 38.11 min, 88% ee; 1H
NMR (CDCl3, 400 MHz, δ): 7.85–7.47 (m, 7H), 4.77 (t, J = 6.8 Hz, 1H ),
1.95–1.84 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H).
(E)-1-Phenylpent-1-en-3-ol (7o) (example from Table 2, entry
15). The use of (E)-cinnamaldehyde 6o (1.00 mmol) gave chiral adduct
7o (0.141 g) in 87% yield. HPLC (Chiralcel OD, 10% IPA/n-hexane,
1
0.5 mL/min, 254 nm): tr(major): 24.44 min, tr(minor): 16.21 min, 60% ee; H
NMR (CDCl3, 400 MHz, δ): 7.40–7.22 (m, 5H), 6.56 (d, J = 15.2 Hz, 1H),
6.19 (dd, J = 16.0, 6.8 Hz, 1H ), 4.24–4.19 (m, 1H), 1.72–1.62 (m, 2H),
0.95 (t, J = 7.2 Hz, 3H).
RESULTS AND DISCUSSION
A series of O,N,O-tridentate ligands 1 was readily synthe-
sized starting from camphor (Scheme 1). (1S,2S,4S)-3-
Scheme 1. The synthesis of new O,N,O-tridentate ligands 1a-g.
TABLE 1. Asymmetric addition of ZnEt2 to benzaldehyde using chiral ligands 1
Entry
Ligand 1
Et2Zn (eq)
Solvent
Temp.(°C)
Time (h)
Yield 7 (%)a
ee 7 (%)b
1
2
3
4
5
6
7
8
1a
1b
1b
1b
1b
1b
1b
1c
1d
1e
1f
2.5
2.5
2.0
1.2
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
C6H14/C7H8
C6H14/C7H8
C6H14/C7H8
C6H14/C7H8
THF/C6H14
C6H14
C7H8
C7H8
C7H8
C7H8
C7H8
C7H8
C7H8
C7H8
25
25
25
25
25
25
25
25
25
25
25
25
0
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
6.0
24
72
87
85
60
60
90
83
48
89
81
46
91
90
93
34 (S)
60 (S)
58 (S)
57 (S)
50 (S)
55 (S)
64 (S)
16 (R)
75 (S)
63 (S)
4 (S)
9
10
11
12
13
14
1g
1g
1g
90 (S)
82 (S)
80 (S)
À20
aAll yields were obtained by isolating of the products after purification.
bThe ee value was analyzed by HPLC with a Chiralcel OD column.
Chirality DOI 10.1002/chir

ENANTIOSELECTIVE ADDITION OF DIETHYLZINC TO ALDEHYDES
69
resulted in a dramatic decrease of the ee (entry 8, 48%
yield, 16% ee). These results suggest the structural impor-
tance of the presence of the aromatic hydroxyl group in
the ligand, which allows for the O,N,O-tridentate coordina-
tion to the Zn metal center. A decrease in the amount of
diethylzinc results in a lower rate of reaction (entries 2–
4), and entry 7 shows that toluene is the best solvent
for this reaction. Ligand screening (entries 7–12) revealed
that ligand 1g provides the best enantioselectivity at room
temperature. With regard to the effect of substituents on
the aromatic ring, we found that the introduction of
electron-donating groups in the 4-position of the aromatic
ring leads to dramatic increases in both the yield and
the enantioselectivity (entries 9–11). For example, the
use of ligand 1f, bearing a nitro group in 4-position, re-
sults in poor catalytic activity (entry 11). On the other
hand, ligand 1d, bearing a methyl group in the 4-position,
effects the formation of 7a in 89% yield, with 75% ee (entry
9). In addition, we found that the steric effect of substitu-
ents on the aromatic rings of ligands is more important
than the electronic effect (entries 9 vs. 12). The ee de-
creases slightly upon a decrease in the temperature of
the reaction (entries 12–14).
Next, the scope of aromatic aldehydes 6 that can be
used for the asymmetric addition at room temperature
was examined, using 1g as a catalyst. The experimental
results are summarized in Table 2. The reaction of alde-
hydes bearing electron-donating groups (6b–6g) afforded
the corresponding chiral secondary alcohols 7b–7g with
high enantioselectivities (83–92% ee, entries 2–7), regard-
less of the position of the substituent. On the other hand,
in the reactions using o-, m-, and p-chlorobenzaldehyde
(6h–6j), the enantioselectivity depends on the position of
the substituent (entries 8–10). Concerning the electronic
effect of the substrate, the reaction of p-substituted alde-
hydes 6b, 6e, 6h, and 6k uniformly furnished the corre-
sponding chiral secondary alcohols
7
with high
TABLE 2. Asymmetric addition of ZnEt2 to various aromatic
aldehydes using chiral ligand 1ga
enantioselectivities, regardless of the property of the sub-
stituent on the aromatic ring (entries 2, 5, 8, and 11).
Both 1- and 2-naphthaldehyde (6m and 6n; entries 13
and 14) can be applied; the best ee was obtained in the
reaction of 1-naphthaldehyde with diethylzinc (entry 13).
The reaction of the α,β-unsaturated carbonyl compound
cinnamaldehyde (6o) affords 1,2-adduct 7o without any
1,4-addition product, albeit with lower enantioselectivity
(entry 15).
Entry
Aldehyde
Yield 7 (%)b
7 (ee %)c
1
2
3
4
5
6
7
8
Benzaldehyde
4-Tolualdehyde
3-Tolualdehyde
2-Tolualdehyde
4-Anisaldehyde
3-Anisaldehyde
2-Anisaldehyde
4-Chlorobenzaldehyde
3-Chlorobenzaldehyde
2-Chlorobenzaldehyde
4-Bromobenzaldehyde
2-Fluorobenzaldehyde
1-Naphthaldehyde
2-Naphthaldehyde
(E)-Cinnamaldehyde
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
91
95
88
84
96
92
90
90
90
85
89
88
90
91
87
90 (S)
91d (S)
88 (S)
92d (S)
91 (S)
88d (S)
83d (S)
88 (S)
84d (S)
80d (S)
90d (S)
85 (S)
95 (S)
88 (S)
60 (S)
With these observations in mind, the speculation on the
possible transition state of the alkyl transfer step is illus-
trated in Figure 3.26 The proposed complex 8 was formed
in situ when diethylzinc reacted with ligand 1g because of
the greater basicity of alkoxide than that of phenoxide. Af-
ter coordination to aldehyde, two possible transition states,
9 and 10, might be formed. We assumed that the more
favored transition states should be 10 because of the ste-
ric repulsion between the bulky tert-butyl group and the
aldehyde in 9. The predominant formation of the S enan-
tiomer in the addition should involve ethyl transfer from
the reagent to si face of the aldehyde.
9
10
11
12
13
14
15
aReaction was completed 2.5 h at room temperature.
bIsolated yield was reported.
cThe ee value was analyzed by HPLC with a Chiralcel OD column.
dThe ee value was analyzed by HPLC with a Chiralcel OB column.
O
H
N
Et
H
OH
Ph
O
Zn
O
Zn
Et
Et
(R)
Ph
H
9
O
H
N
O
Zn
Zn
Et
Et
8
O
H
Et
N
OH
H
O
Zn
Et
Zn
O
Ph
(S)
Et
H
Ph
10
Fig. 3. Proposed two transition states and their corresponding products.
Chirality DOI 10.1002/chir

70
LEE ET AL.
17. Gök Y, Kekeç L. Enantioselective addition of diethylzinc to aromatic
CONCLUSION
aldehydes catalyzed by C2-symmetric chiral diols. Tetrahedron Lett
In conclusion, chiral O,N,O-tridentate ligands 1 derived
from (+)-camphor were prepared in five steps in good overall
yield, and they are highly air-stable. These ligands have two
different types of oxygen atom and bind to zinc in distinct
ways. Good yields and enantioselectivities were obtained in
the addition reaction of Et2Zn to aromatic aldehydes using
tridentate ligand 1g. The reactions reached completion
within 2.5 h at ambient temperature. Therefore, the present
method is practical and economical.
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SUPPORTING INFORMATION
Additional supporting information may be found in the
online version of this article at the publisher’s web-site.
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Chirality DOI 10.1002/chir