Efficient alcoholysis of 5,6-dihydro-1,10-phenanthroline-5,6-epoxide with ytterbium(III) triflate and subsequent enantioselective transesterification with lipases

Article abstract of DOI:10.1016/j.tetasy.2009.07.021

New 5,6-dihydro-1,10-phenanthroline derivatives were prepared in high yield via ytterbium(III) triflate-catalyzed alcoholysis of the corresponding epoxide. Enzymatic transesterifications of racemic alkoxy alcohols afforded enantioselective separations wit

Full text of DOI:10.1016/j.tetasy.2009.07.021

Tetrahedron: Asymmetry 20 (2009) 1897–1902
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Tetrahedron: Asymmetry
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Efficient alcoholysis of 5,6-dihydro-1,10-phenanthroline-5,6-epoxide with
ytterbium(III) triflate and subsequent enantioselective transesterification with
lipases
*
Elke Schoffers , Lars Kohler
Department of Chemistry, Western Michigan University, 3425 Wood Hall, Kalamazoo, MI 49008-5413, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
New 5,6-dihydro-1,10-phenanthroline derivatives were prepared in high yield via ytterbium(III) triflate-
catalyzed alcoholysis of the corresponding epoxide. Enzymatic transesterifications of racemic alkoxy
alcohols afforded enantioselective separations with up to 99% ee. The lipase derived from Burkholderia
cepacia (PSCI) was the most efficient, with E-values of up to 200. The steric effect of substituents in
the 6-position on reaction time and enantioselectivities was assessed.
Received 22 June 2009
Accepted 16 July 2009
Available online 19 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
due to the seminal contributions by Klibanov and co-workers.13–15
The preparation of enantiomerically pure compounds is possible
1,10-Phenanthroline derivatives are well known for their chela-
tion properties and have found numerous applications in analytical
chemistry.1 Regrettably, their development for asymmetric cataly-
sis remains slow because of limited access to optically active
material.2,3 Herein we report a new method toward optically active
B-ring-functionalized 1,10-phenanthroline derivatives. The first
step involves Lewis acid-catalyzed ring opening of epoxide 1 with
alcohols. The second step takes advantage of a lipase-mediated
enantiodifferentiation.
through enzymatic resolution of racemic mixtures or via asymmet-
rization of meso compounds. Enzymes may display a high degree
of substrate specificity and yet accept structurally related, ‘unnat-
ural’ compounds. Early examples of bulky aromatic and heterocy-
clic substrates include binaphthol A and quinoline B derivatives
by Kazlauskas16 and Hughes,17 respectively (Fig. 1). Imperiali
et al. reported the first successful biocatalysis to resolve a bipyri-
dine scaffold C.18 More recent publications describe the resolution
We previously found that while both magnesium perchlorate
and alumina catalyzed the ring opening of 1,10-phenanthroline-
5,6-epoxide with nitrogen nucleophiles, the former was more
effective.4 However, neither one of the reagents promoted reac-
tions with oxygen nucleophiles. Only two derivatives have been re-
ported thus far under different conditions.5,6
Lanthanide trifluorosulfonates (triflates) have been applied to a
range of reactions including aldol, Mannich, and Diels–Alder reac-
tions.7 Among them, ytterbium(III) triflate catalyzes epoxide con-
versions.8–11 In our studies it became the reagent of choice for
the formation of several chiral racemic alkoxy alcohol phenanthro-
line derivatives.
CO2CH3
S
CO2H
OH
OH
Cl
N
S
B
A
lipase PSL, 89% y, >98% ee
CE, 66% y, >99% ee
H2N
CO2CH3
N
N
OC(O)CH2CH2CH2CH3
OC(O)CH2CH2CH2CH3
D
C
N
N
Enzymes have long been employed in organic chemistry and are
instrumental in the preparation and separation of single stereoiso-
mers. Their use in organic solvents dates back as far as 1908.12
However, the prevalent use of aqueous solutions for biotransfor-
mations made the use of enzymes less appealing for synthetic
chemists in subsequent decades. Meanwhile, enzymatic reactions
in organic solvents, polar and non-polar, containing little to no
water, have become a mainstay in biotransformations in large part
CE, 46% y, >99% ee
subtilisin, quant., 98% ee
HO
OH
AcO
N
OAc
N
N
N
G
F
E
OH OH
O
O
Lipozyme®, 23% y, 97% ee
lipase AK, 38% y, 92% ee
CE, 48% y, >99% ee
* Corresponding author. Tel.: +1 269 387 2265; fax: +1 269 387 2909.
E-mail address: Elke.Schoffers@wmich.edu (E. Schoffers).
Figure 1. Selected resolution products for various enzymes, including cholesterol
esterase (CE).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.07.021

1898
E. Schoffers, L. Kohler / Tetrahedron: Asymmetry 20 (2009) 1897–1902
of 8,80-biquinoyl derivatives (‘azaBINOL’, D19 and hexamethylbi-
phenol E20 with cholesterol esterase (CE) as well as bipyridine
N,N-dioxide F21 and selected 1,10-phenanthroline congeners such
as G with lipases, respectively.6,22
Table 1
Yb(OTf)3-catalyzed reaction of ( )-1 with alcohols 2a–j
Entry
Nucleophile
Methoda
Product (R=)
Yield (%)
1
2
3
4
5
6
7
8
9
Methanol 2a
Ethanol 2b
A
A
A
A
A
B
B
A
A
B
B
–CH3, ( )-3a
–C2H5, ( )-3b
–C3H7, ( )-3c
–CH(CH3)2, ( )-3d
–C4H10, ( )-3e
98
99
91
99
95
98
92b
99
99
90
81
1-Propanol 2c
2-Propanol 2d
1-Butanol 2e
1-Butanol 2e
2-Butanol 2f
tert-Butanol 2g
Allyl alcohol 2h
Benzyl alcohol 2i
Cyclohexanol 2j
2. Results and discussion
2.1. Preparation of racemic trans-5,6-dihydro-1,10-phenanthroline
derivatives ( )-3a–j
–C4H10, ( )-3e
–CH(CH3)C2CH5, ( )-3f
–C(CH3)3, ( )-3g
–CH2–CH@CH2, ( )-3h
–CH2–C6H5, ( )-3i
–C6H11, ( )-3j
Epoxide ( )-15,23–25 was prepared using commercially available
bleach and served as a starting material for the practical prepara-
tion of trans-5,6-dihydro-1,10-phenanthroline derivatives ( )-3a–
j. Ytterbium(III) triflate was employed as a Lewis acid to activate
the epoxide toward alcohols 2a–j (Scheme 1).
10
11
a
Method A: Epoxide (0.510 mmol), alcohol (2.5 ml), Yb(OSO2CF3)3 (0.5 equiv),
60–80 °C, 12–24 h. Method B: Epoxide (0.510 mmol), nucleophile (1.5 equiv),
Yb(OSO2CF3)3 (0.5 equiv), CH3CN, 80 °C, 12–48 h.
b
No separation of diastereomers.
O
O
HO
R
obtained in 99% ee after only 4 days (entry 4). The enantiopurity
of acetate 4a was improved from 70% to 82% ee by reducing the
conversion rate to 51% after 2 days (entry 5) but the enantiopurity
was lower than that with lipase AK (entry 2). We assigned the ste-
reochemistry by comparing our product with the literature report
for entry 1 in which the absolute configuration of methoxy alcohol
3a was determined to have the (S,S)-configuration based on CD and
NMR analyses.6 The configuration of the remaining derivatives was
identified assuming that the enzyme operates with the same ste-
reochemical preference.
Our specific rotations confirmed that lipases AK and PSCI prefer-
entially operate on the (R,R)-isomer. A notable improvement in
enantiodifferentiation with either enzyme was observed when the
substituent at the 6-position changed from the methyl to the ethyl
group (see entries 3/6 and 4/7). Entries 6 and 7 provide a direct com-
parison of the two lipases for the ethoxy substrate 3b. Again, resolu-
tion with lipase AK was much slower (15 days) than that with PSCI
(4 days) whereas E-values were over 200 for both resolutions. Based
on these encouraging results we predominantly focused on the use
of PSCI for the remaining substrates. It should be noted that sub-
strates derived from primary alcohols show high enantioselectivi-
ties with E-values close to, or over, 200 (entries 6–8, 10, 13, and
14). This includes allyl alcohol adduct 3h. Therefore, a slight increase
in bulkiness from ethyl to n-propyl to n-butyl had little influence.
Transformations with benzyl alcohol derivative 3i were somewhat
slower (6 days) with E = 152. Nonetheless, the corresponding prod-
ucts were isolated in very good yield and isomeric purity (entry 14;
alcohol 3i in 45% yield, 90% ee; acetate 4 in 48% yield, 96% ee). We ob-
served that more sterically hindered substrates derived from sec-
ondary alcohols (isopropoxy and cyclohexyloxy derivatives 3d and
3j) showed an additional drop in E-values and required longer con-
version times; 11 and 18 days, respectively (entries 9 and 15). Sub-
strate 3g which contains a very bulky tert-butoxy group showed
negligible conversion with either enzyme.
Yb(OTf)3
+
R
OH
N
N
N
N
2a-j
( )-1
( )-3a-j
Scheme 1. Epoxide opening of ( )-1 with alcohols 2a–j.
A complete conversion was already achieved with 0.1 equiv of
catalyst but resulted in significant amounts of side products. How-
ever, impurities were avoided with an increase of Yb(OTf)3 to
0.5 equiv, giving rise to clean products in very good yields (81–
99%). We developed two different procedures depending on the
nucleophile used. Method A utilized inexpensive alcohols with
low boiling points in large excess which served as nucleophile
and solvent (2a–e and 2g–h). Method B required 1.5 equiv of alco-
hol in small amounts of acetonitrile as a solvent (see 2i, j). The re-
sults are summarized in Table 1 and reveal the generality of this
reaction, including primary, secondary, tertiary, and unsaturated
alcohols. In contrast, the reaction with phenol was unsuccessful.
2.2. Lipase-catalyzed resolution
Our work focused on two readily available Amano lipases, Pseu-
domonas fluorescence (AK) and Burkholderia cepacia (PSCI—PS
immobilized on ceramic), to identify the best conditions for our
newly-prepared 1,10-phenanthroline alkoxy alcohol derivatives
( )-3 (Scheme 2).
O
HO
N
O
N
R
HO
N
O
N
R
O
O
N
R
lipase
+
vinyl acetate
(VA)
N
( )-3
(S,S)-3
(R,R)-4
3. Conclusion
Scheme 2. Enzymatic kinetic resolution of ( )-3.
A recent report has described the kinetic resolution of methoxy
alcohol 3a in a vinyl acetate (VA)/methanol mixture (Table 2, entry
1, E = 44). The corresponding acetate 4a was obtained with 89% ee
after 11 days, the remaining alcohol 3a in 82% ee. The enantiomeric
excess of the latter was improved to 97% via a second resolution in
35% yield. Our studies showed that a change in solvent from meth-
anol to acetonitrile (ACN) provided better selectivities affording
acetate (R,R)-4a in 96% ee (entry 2, E = 147). Prolonged conversion
to 50% afforded both, the alcohol and acetate, in 94% ee (entry 3,
E = 115). We also found that the same substrate could be resolved
much faster with a different lipase, Amano PSCI. Alcohol 3a was
In conclusion, we have developed a practical new method to
convert 1,10-phenanthroline epoxide 1 into several alkoxyalcohol
derivatives 3a–j by using ytterbium triflate as catalyst. The racemic
products 3 were subjected to lipase-mediated kinetic resolution.
Major findings include that the use of acetonitrile (instead of meth-
anol) in vinyl acetate significantly improves the enantiopurity of
(R,R)-4a from 89% to 96% ee when lipase AK is employed. More-
over, our results show that lipase PSCI provides faster conversion
rates with high enantioselectivities of up to 99% ee for most sub-
strates. A total of 16 new single isomer 1,10-phenanthroline deriv-
atives have been fully characterized.

E. Schoffers, L. Kohler / Tetrahedron: Asymmetry 20 (2009) 1897–1902
1899
Table 2
Enzymatic resolutiona of alkoxy alcohol ( )-3 with lipases AK and PSCI
Entry
Substrate (R)
Enzyme
Solvent
Time (days)
Temp (°C)
Conversionb (%)
% (S,S)-3 (% eeS)c
% (R,R)-4 (% eeP)c
Eb
16
2
3
4
5
6
7
8
9
10
11
12
13
14
15
–CH3, ( )-3a
–CH3, ( )-3a
–CH3, ( )-3a
–CH3, ( )-3a
AK
AK
AK
VA/8% MeOH
VA/20% ACN
VA/20% ACN
VA/20% ACN
VA/20% ACN
VA/10% ACN
VA/10% ACN
VA/10% ACN
VA/10% ACN
VA/10% ACN
VA/10% ACN
VA/10% ACN
VA/10% ACN
VA/20% ACN
VA/10% ACN
11
10
10
4
2
15
4
4
11
4
10
10
4
45
45
45
50
50
45
50
50
50
50
50
45
50
50
50
48.0
48.1
50.0
58.6
51.2
47.6
50.5
49.5
47.8
49.5
10.0d
2.0d
49.5
48.4
46.8
48 (82)
46 (89)
46 (94)
40 (99)
44 (86)
46 (89)
43 (99)
43 (96)
43 (86)
42 (96)
N/A
48 (89)
47 (96)
47 (94)
54 (70)
50 (82)
46 (98)
49 (97)
49 (98)
47 (94)
47 (98)
N/A
44
147
115
28
PSCI
PSCI
AK
PSCI
PSCI
PSCI
PSCI
PSCI
AK
–CH3, ( )-3a
28
–C2H5, ( )-3b
–C2H5, ( )-3b
–C3H7, ( )-3c
–CH(CH3)2, ( )-3d
–C4H10, ( )-3e
–C(CH3)3, ( )-3g
–C(CH3)3, ( )-3g
–CH2–CH@CH2 ( )-3h
–CH2–C6H5 ( )-3i
–C6H11, ( )-3j
>200
>200
>200
90
>200
N/A
N/A
>200
152
52
N/A
N/A
PSCI
PSCI
PSCI
44 (96)
45 (90)
45 (80)
47 (98)
48 (96)
46 (91)
6
18
a
Substrate ( )-3 (100 mg) was stirred with 500 mg lipase in 25 ml solvent.
b
c
Conversion rates and E-values were determined from the enantiomeric excess of the substrate (S,S)-3 and product (R,R)-4.26
Determined via HPLC of isolated products.
d
Determined via 1H NMR.
(10 ml), dried with Na2SO4, filtered, and concentrated. The product
was isolated by column chromatography (SiO2; chloroform/1–3%
methanol).
4. Experimental
Commercial chemicals and reagents were obtained in >98% pur-
ity and used without further purification unless otherwise noted.
Lipases were purchased from Aldrich or Amano Pharmaceuticals,
Inc. Solvents were purchased as reagent grade for synthetic proce-
dures and as HPLC grade for ee determination. The preparation of
1,10-phenanthroline-5,6-epoxide has been described in the litera-
ture.5,23–25 Melting points were determined in open capillaries
using a Thomas–Hoover Unimelt instrument. NMR spectra were
recorded using a 400 MHz Jeol Eclipse nuclear magnetic resonance
instrument. IR spectra were obtained from Bruker Equinox 55 and
Perkin Elmer 1710 Fourier Transform Infrared Spectrometers. Ele-
mental analyses were carried out by Numega Resonance Labs,
Inc. in San Diego, CA. For HPLC analysis we used a Shimadzu instru-
ment outfitted with a column (ChiralcelÒ OD-H), solvent delivery
system (LC-20AT), detector (SPD-20A), autosampler (SIL-20A),
and degasser (DGU-20A5). We used a Waters Micromass GCT
instrument for HRMS measurements.
4.2.2. Method B
1,10-Phenanthroline-5,6-epoxide (100 mg, 0.510 mmol), ytter-
bium(III) triflate (158 mg, 0.255 mmol) and the appropriate alcohol
(0.765 mmol of 2e–f or 2i–j, see Table 1) were dissolved in dry
CH3CN (0.5 ml). After stirring the reaction mixture at 80 °C for
12–24 h chloroform (40 ml) and aqueous NaOH (10%, 3 ml) were
added. The organic layer was separated and the aqueous layer ex-
tracted twice with CHCl3 (10 ml). The combined organic layers
were washed with brine (10 ml), dried with Na2SO4, filtered, and
concentrated. The product was isolated by column chromatogra-
phy (SiO2; chloroform/1–3% methanol).
4.3. Characterization of racemic alcohols ( )-3a–j
4.3.1. ( )-trans-5,6-Dihydro-6-methoxy-1,10-phenanthrolin-5-ol, ( )-
3a [( )-trans-5,6-dihydro-5-hydroxy-6-methoxy-1,10-phenanthroline]
Prepared according to Method A using methanol 2a; 114 mg
(98%); mp 196 °C; 1H NMR (400 MHz, CDCl3): d 8.73–8.70 (2H,
m), 7.99 (1H, app d, J = 7.7 Hz), 7.83 (1H, app d, J = 7.7 Hz), 7.34–
7.30 (2H, m), 4.97 (1H, d, J = 9.5 Hz), 4.49 (1H, d, J = 9.5 Hz), 3.67
(3H, s), 3.15 (1H, br s); 13C NMR (100 MHz, CDCl3): d 150.4,
150.2, 150.0, 149.7, 134.3, 134.2, 133.5, 131.9, 124.3, 124.0, 82.3,
4.1. Determination of the enantiomeric excess and conversion
Enantiomerically enriched alcohols and acetates were separated
using flash column chromatography (SiO2; CHCl3/MeOH = 99:1)
and analyzed by chiral HPLC using a 70:30 mixture of isopropanol
and hexane as eluent, 0.5 ml/min flow rate, and UV–vis detection
at 266 nm. The enantiomeric excess was obtained by comparing
the percentage areas of the (S,S)-enantiomer and the (R,R)-enantio-
mer. Substrate conversion was calculated using the enantiomeric
excess of the substrate (eeS) and the product (eeP), c = (eeS)/
(eeP + eeS).26
71.4, 60.0; FT-IR (NaCl)
m
/cmꢀ1 3242, 3065, 2991, 2934, 2828,
1583, 1566, 1467, 1429, 1419, 1355, 1217, 1186, 1130, 1086,
1041, 1032, 963, 880, 842, 806, 757, 746, 712, 626. This compound
was previously prepared by Shen and Sullivan5 in 60% yield by
reacting epoxide 1 with sodium methoxide in methanol.
4.2. General procedure for the preparation of racemic alcohols
( )-3a–j
4.3.2. ( )-trans-5,6-Dihydro-6-ethoxy-1,10-phenanthrolin-5-ol, ( )-
3b [( )-trans-5,6-dihydro-6-ethoxy-5-hydroxy-1,10-phenanthroline]
Prepared via Method A using ethanol 2b; 122 mg (99%); mp
172 °C; 1H NMR (400 MHz, CDCl3): d 8.74 (2H, m), 8.02 (1H, app
d, J = 7.7 Hz), 7.84 (1H, app d, J = 7.7 Hz), 7.36–7.32 (2H, m), 4.95
(1H, d, J = 10.2 Hz), 4.57 (1H, d, J = 10.3 Hz), 3.93–3.87 (2H, m),
2.97 (1H, br s), 1.37 (3H, t, J = 7.0 Hz); 13C NMR (100 MHz, CDCl3):
d 150.4, 150.0, 149.9, 149.8, 133.9, 133.7, 133.6, 132.7, 124.3,
4.2.1. Method A
1,10-Phenanthroline-5,6-epoxide (100 mg, 0.510 mmol) and
ytterbium(III) triflate (158 mg, 0.255 mmol) were dissolved in the
appropriate alcohol (2.5 ml of 2a–e or 2g–h, see Table 1). After stir-
ring the reaction mixture at 60–80 °C for 12–24 h the remaining
alcohol was evaporated and the residue dissolved in chloroform
(40 ml). Aqueous NaOH (10%, 3 ml) was added, the organic layer
separated, and the aqueous layer extracted twice with CHCl3
(10 ml). The combined organic layers were washed with brine
124.0, 80.8, 71.6, 68.1, 15.6; FT-IR (KBr pellet)
3056, 2960, 2880, 1582, 1564, 1421, 1294, 1181, 1125, 1083,
m
/cmꢀ1 3374,

1900
E. Schoffers, L. Kohler / Tetrahedron: Asymmetry 20 (2009) 1897–1902
1061, 1041, 796, 744. Anal. Calcd for C14H14N2O2: C, 69.41; H, 5.82;
N, 11.56. Found: C, 69.45; H, 5.44; N, 11.76; HRMS (EI, m/z) calcd
for C14H14N2O2 242.1055, found 242.1058.
1568, 1430, 1377, 1353, 1283, 1219, 1175, 1131, 1089, 1061,
1032, 905, 879, 845, 821, 762, 710. Anal. Calcd for C16H18N2O2: C,
71.09; H, 6.71; N, 10.36. Found: C, 70.95; H, 7.11; N, 10.51; HRMS
(EI, m/z) calcd for C16H18N2O2 270.1368, found 270.1373.
4.3.3. ( )-trans-5,6-Dihydro-6-propoxy-1,10-phenanthrolin-5-
ol, ( )-3c ( )-trans-5,6-dihydro-5-hydroxy-6-propoxy-1,10-
phenanthroline
4.3.7. ( )-trans-5,6-Dihydro-6-tert-butoxy-1,10-phenanthrolin-
5-ol, ( )-3g [( )-trans-5,6-dihydro-6-tert-butoxy-5-hydroxy-
1,10-phenanthroline]
Prepared according to Method A using 1-propanol 2c; 119 mg
(91%); mp 61 °C; 1H NMR (400 MHz, CDCl3): d 8.72–8.69 (2H, m),
8.01 (1H, app d, J = 7.7 Hz), 7.84 (1H, app d, J = 7.7 Hz), 7.34–7.29
(2H, m), 4.96 (1H, d, J = 10.3 Hz), 4.55 (1H, d, J = 10.3 Hz), 3.78
(2H, t, J = 6.8 Hz), 3.25 (1H, br s), 1.74 (2H, app sextet, J = 7.1 Hz),
0.99 (3H, t, J = 7.5 Hz); 13C NMR (100 MHz, CDCl3): d 150.4, 150.0,
149.9, 149.8, 133.8, 133.7, 133.6, 132.8, 124.2, 124.0, 81.0, 74.5,
Prepared according to Method
A using tert-butanol (2g);
137 mg (99%); mp 219 °C; 1H NMR (400 MHz, CDCl3): d 8.77–
8.71 (2H, m), 8.04 (1H, app d, J = 7.7 Hz), 7.93 (1H, app d,
J = 7.7 Hz), 7.36 (1H, dd, J = 4.8, 7.7 Hz), 7.32 (1H, dd, J = 4.8,
7.7 Hz), 4.80 (1H, d, J = 11.0 Hz), 4.73 (1H, d, J = 11.0 Hz), 2.75
(1H, br s), 1.37 (9H, s); 13C NMR (100 MHz, CDCl3): d 150.8,
150.0, 149.9, 149.6, 134.8, 133.9, 133.8, 133.3, 124.2, 123.6, 76.2,
71.7, 23.5, 10.7; FT-IR (KBr pellet)
m
/cmꢀ1 3298, 3065, 2962,
2935, 2875, 1582, 1565, 1464, 1421, 1349, 1281, 1250, 1212,
1180, 1130, 1084, 1037, 965, 800, 746, 711, 624; HRMS (EI, m/z)
calcd for C15H16N2O2 256.1212, found 256.1222.
73.9, 71.4, 28.9; FT-IR (KBr, pellet) m
/cmꢀ1 3207, 3072, 2972,
2929, 2851, 1584, 1564, 1469, 1417, 1392, 1369, 1349, 1287,
1232, 1190, 1126, 1075, 1045, 1022, 987, 906, 869, 807, 748; HRMS
(EI, m/z) calcd for C16H18N2O2 270.1368, found 270.1377.
4.3.4. ( )-trans-5,6-Dihydro-6-isopropoxy-1,10-phenanthrolin-
5-ol, ( )-3d [( )-trans-5,6-dihydro-5-hydroxy-6-isopropoxy-
1,10-phenanthroline]
4.3.8. ( )-trans-5,6-Dihydro-6-allyloxy-1,10-phenanthrolin-5-
ol, ( )-3h [( )-trans-5,6-dihydro-6-allyloxy-5-hydroxy-1,10-
phenanthroline]
Prepared according to Method A using 2-propanol 2d; 129 mg
(99%); mp 211 °C; 1H NMR (400 MHz, CDCl3): d 8.75–8.71 (2H,
m), 8.04 (1H, app d, J = 7.7 Hz), 7.85 (1H, app d, J = 7.7 Hz), 7.36–
7.31 (2H, m), 4.90 (1H, dd, J = 2.9, 10.6 Hz), 4.62 (1H, d,
J = 11.0 Hz), 3.99 (2H, septet, J= 6.1 Hz), 2.98 (1H, d, J = 2.9 Hz),
1.35 (6H, d, J = 6.2 Hz); 13C NMR (100 MHz, CDCl3): d 150.5,
149.9, 149.9, 149.8, 133.6, 133.5, 133.4, 124.2, 124.0, 78.7, 73.8,
Prepared according to Method A using allyl alcohol (2h);
128 mg (99%); mp 133 °C; 1H NMR (400 MHz, CDCl3): d 8.70–
8.67 (2H, m), 8.01 (1H, app d, J = 7.7 Hz), 7.84 (1H, app d,
J = 7.7 Hz), 7.33–7.28 (2H, m), 6.05–5.95 (1H, m), 5.37–5.32 (1H,
m), 5.26–5.23 (1H, m), 5.00 (1H, d, J = 9.9 Hz), 4.65 (1H, d,
J = 9.9 Hz), 4.36–4.33 (2H, m), 3.31 (1H, br s); 13C NMR (100 MHz,
CDCl3): d 150.4, 150.0, 149.9, 149.8, 134.2, 134.1, 134.0, 133.7,
71.7, 22.8, 22.7; FT-IR (KBr pellet)
m
/cmꢀ1 3288, 3065, 2970,
132.5, 124.3, 124.0, 118.3, 80.2, 73.2, 71.6; FT-IR (KBr, pellet) m/
cmꢀ1 3160, 2871, 1581, 1563, 1465, 1419, 1354, 1216, 1180,
1134, 1084, 1038, 996, 934, 793, 757, 744, 624; HRMS (EI, m/z)
calcd for C15H14N2O2 254.1055, found 254.1070.
2931, 2871, 1582, 1564, 1465, 1420, 1380, 1332 1212, 1177,
1124, 1080, 1069, 1038, 850, 800; HRMS (EI, m/z) calcd for
C15H16N2O2 256.1212, found 256.1219.
4.3.9. ( )-trans-5,6-Dihydro-6-benzyloxy-1,10-phenanthrolin-
5-ol, ( )-3i [( )-trans-5,6-dihydro-6-benzyloxy-5-hydroxy-1,10-
phenanthroline]
4.3.5. ( )-trans-5,6-Dihydro-6-butoxy-1,10-phenanthrolin-5-ol, ( )-
3e [( )-trans-5,6-dihydro-6-butoxy-5-hydroxy-1,10-phenanthroline]
The use of 1-butanol 2e afforded 131 mg (95%) in Method A and
135 mg (98%) via Method B; mp 71 °C; 1H NMR (400 MHz, CDCl3):
d 8.75–8.72 (2H, m), 8.02 (1H, app dt, J = 1.3, 7.3 Hz), 7.84 (1H, app
dt, J = 1.3, 7.7 Hz), 7.36–7.31 (2H, m), 4.96 (1H, d, J = 10.6 Hz), 4.56
(1H, d, J = 10.3 Hz), 3.88–3.79 (2H, m), 2.84 (1H, br s), 1.72 (2H, app
quintet, J = 7.2 Hz), 1.46 (2H, app sextet, J = 7.3 Hz), 0.96 (3H, t,
J = 7.4 Hz); 13C NMR (100 MHz, CDCl3): d 150.4, 150.1, 150.0,
149.8, 133.8, 133.6, 132.7, 124.3, 124.0, 81.0, 72.8, 71.7, 32.3.
Prepared according to Method B using benzyl alcohol 2i;
140 mg (90%); mp 110 °C; 1H NMR (400 MHz, CDCl3): d 8.75–
8.73 (2H, m), 7.99 (1H, app d, J = 7.7 Hz), 7.86 (1H, app d,
J = 7.7 Hz), 7.47–7.29 (7H, m), 5.02 (1H, d, J = 9.9 Hz), 4.92 (1H,
ABq, J = 11.7 Hz), 4.84 (1H, ABq, J = 11.7 Hz), 4.75 (1H, d,
J = 9.5 Hz), 2.92 (1H, br s); 13C NMR (100 MHz, CDCl3): d 150.5,
150.2, 150.1, 149.8, 137.6, 134.1, 133.4, 132.2, 128.9, 128.4,
128.0, 124.3, 124.0, 80.5, 74.4, 71.7; FT-IR (KBr, pellet)
m
/cmꢀ1
19.5, 14.0; FT-IR (KBr pellet)
m
/cmꢀ1 3289, 3169, 3074, 2952,
3416, 3054, 3027, 2912, 2857, 2820, 2713, 1581, 1564, 1453,
1421, 1400, 1350, 1293, 1212, 1185, 1125, 1085, 1069, 1039,
1009, 796, 758, 745, 701; HRMS (EI, m/z) calcd for C19H16N2O2
304.1212, found 304.1214.
2929, 2903, 2869, 1690, 1582, 1565, 1421, 1404, 1377, 1338,
1306, 1129, 1090, 1055, 1037, 791, 741; HRMS (EI, m/z) calcd for
C16H18N2O2 270.1368, found 270.1374.
4.3.6. ( )-trans-5,6-Dihydro-6-(2-butoxy)-1,10-phenanthrolin-
5-ol, ( )-3f [( )-trans-5,6-dihydro-6-(2-butoxy)-5-hydroxy-1,10-
phenanthroline]
4.3.10. ( )-trans-5,6-Dihydro-6-cyclohexyloxy-1,10-phenanthrolin-
5-ol, ( )-3j [( )-trans-5,6-dihydro-6-cyclohexyloxy-5-hydroxy-1,10-
phenanthroline]
Prepared according to Method B using 2-butanol 2f afforded
127 mg (92%) of a diastereomeric mixture; mp 178 °C; 1H NMR
Prepared according to the general procedure B using cyclohex-
anol 2j; 122 mg (81%); mp 213 °C; 1H NMR (400 MHz, CDCl3): d
8.76–8.71 (2H, m), 8.04 (1H, app d, J = 7.7 Hz), 7.87 (1H, app d,
J = 7.7 Hz), 7.38–7.31 (2H, m), 4.91 (1H, br d, J = 10.3 Hz), 4.68
(1H, d, J = 11.0 Hz), 3.64–3.56 (1H, m), 2.96 (1H, br s), 2.19–1.20
(10H, m); 13C NMR (100 MHz, CDCl3): d 150.4, 149.9, 149.8,
133.6, 133.5, 133.4, 124.2, 124.0, 80.0, 78.7, 71.7, 33.3, 33.2, 25.7,
(400 MHz, CDCl3):
d 8.75–8.72 (4H, m), 8.02 (2H, app d,
J = 7.7 Hz), 7.87 (2H, app d, J = 7.7 Hz), 7.39–7.30 (4H, m), 4.94
(1H, d, J = 10.6 Hz), 4.90 (1H, d, J = 10.3 Hz), 4.66 (1H, d,
J = 10.6 Hz), 4.63 (1H, d, J = 10.6 Hz), 3.82–3.71 (2H, m), 2.88 (2H,
br s), 1.87–1.73 (2H, m), 1.67–1.54 (2H, m), 1.31 (3H, d,
J = 6.2 Hz), 1.28 (3H, d, J = 6.2 Hz), 1.01 (3H, t, J = 7.5 Hz), 0.96
(3H, t, J = 7.5 Hz); 13C NMR (100 MHz, CDCl3): d 150.5, 150.4,
149.9, 149.9, 149.8, 133.6, 133.5, 133.4, 133.4, 124.2, 124.0,
123.9, 79.2, 78.8, 78.4, 78.3, 72.2, 71.7, 30.0, 29.7, 20.0, 19.8, 10.2,
24.6, 24.5; FT-IR (KBr, pellet)
m
/cmꢀ1 3327, 3069, 2926, 2854,
1581, 1564, 1451, 1417, 1382, 1355, 1342, 1285, 1253, 1130,
1084, 1072, 1035, 800, 745; HRMS (EI, m/z) calcd for C18H20N2O2
296.1525, found 296.1529.
10.2; FT-IR (KBr, pellet)
m
/cmꢀ1 3227, 3061, 2969, 2928, 1584,

E. Schoffers, L. Kohler / Tetrahedron: Asymmetry 20 (2009) 1897–1902
1901
4.4. General procedure for lipase-catalyzed kinetic resolution
of racemic alcohols ( )-3
4.5.8. (S,S)-5,6-Dihydro-6-cyclohexyloxy-1,10-phenanthrolin-5-
ol, (S,S)-3j [(S,S)-5,6-dihydro-6-cyclohexyloxy-5-hydroxy-1,10-
phenanthroline]
A solution of racemic alcohol ( )-3 (100 mg) in the appropriate
solvent (see Table 2) was placed in a 50 ml round-bottomed
flask. Lipase (500 mg) was added and the flask was closed with a
glass stopper and sealed with ParafilmÒ. The suspension was stir-
red at 45 °C for lipase AK ‘Amano’ and at 50 °C for lipase PSCI
‘Amano’. After approximately 50% substrate conversion (monitored
by 1H NMR) the reaction mixture was filtered through Celite, the
solvent removed in vacuo, and the residue purified by column
chromatography.
45 mg (45%); ee = 80%; ½a D25
¼ þ43:9 (c 1, methanol); chiral
ꢁ
HPLC analysis: tR = 12.2 min [(S,S)-enantiomer] and tR = 8.9 min
[(R,R)-enantiomer].
4.6. Characterization of enantiomerically enriched acetates
(R,R)-4a–e and (R,R)-4h–j
4.6.1. (R,R)-5,6-Dihydro-6-methoxy-1,10-phenanthrolin-5-yl
acetate, (R,R)-4a [(R,R)-5,6-dihydro-5-acetoxy-6-methoxy-1,10-
phenanthroline]
4.5. Characterization of enantiomerically enriched alcohols
(S,S)-3a–e and (S,S)-3h–j
56 mg (47%), ee = 96%; ½a D25
¼ ꢀ303:4 (c 0.4, methanol), litera-
ꢁ
ture:22 ee = 98%;
½
a 2D0
ꢁ
¼ ꢀ163:8 (c 0.4, methanol); 1H NMR
(400 MHz, CDCl3): d 8.84 (1H, dd, J = 1.5, 4.8 Hz), 8.80 (1H, dd,
J = 1.8, 4.8 Hz), 7.80 (1H, dd, J = 1.8, 7.7 Hz), 7.75 (1H, dd, J = 1.8,
7.7 Hz), 7.35 (1H, dd, J = 4.8, 7.3 Hz), 7.31 (1H, dd, J = 4.8, 7.6 Hz),
6.16 (1H, d, J = 4.8 Hz), 4.48 (1H, d, J = 4.8 Hz), 3.40 (3H, s), 2.00
(3H, s); 13C NMR (100 MHz, CDCl3): d 170.2, 151.1, 151.0, 150.9,
150.6, 137.7, 137.1, 129.8, 129.2, 124.1, 123.8, 78.0, 70.6, 57.7,
4.5.1. (S,S)-5,6-Dihydro-6-methoxy-1,10-phenanthrolin-5-ol,
(S,S)-3a [(S,S)-5,6-dihydro-5-hydroxy-6-methoxy-1,10-
phenanthroline]
40 mg (40%); ee = 99%; ½a D25
¼ þ108:4 (c 0.43, methanol), litera-
ꢁ
ture:22 ee = 97%; ½a 2D0
¼ þ93:2 (c 0.43, methanol); chiral HPLC
ꢁ
analysis: tR = 13.7 min [(S,S)-enantiomer] and tR = 9.9 min [(R,R)-
21.0; FT-IR (NaCl) m
/cmꢀ1 3065, 2995, 2939, 2831, 1740, 1585,
enantiomer].
1569, 1469, 1433, 1374, 1298, 1233, 1132, 1093, 1041, 1026,
930, 821, 761, 748, 716, 627; chiral HPLC analysis: tR = 11.6 min
[(S,S)-enantiomer] and tR = 24.2 min [(R,R)-enantiomer].
4.5.2. (S,S)-5,6-Dihydro-6-ethoxy-1,10-phenanthrolin-5-ol,
(S,S)-3b [(S,S)-5,6-dihydro-6-ethoxy-5-hydroxy-1,10-
phenanthroline]
4.6.2. (R,R)-5,6-Dihydro-6-ethoxy-1,10-phenanthrolin-5-yl
acetate, (R,R)-4b [(R,R)-5,6-dihydro-5-acetoxy-6-ethoxy-1,10-
phenanthroline]
43 mg (43%); ee = 99%; ½a D25
¼ þ75:2 (c 1, methanol); chiral
ꢁ
HPLC analysis: tR = 12.1 min [(S,S)-enantiomer] and tR = 9.0 min
[(R,R)-enantiomer].
54 mg (46%), ee = 98%; ½a D25
ꢁ
¼ ꢀ293:6 (c 1, methanol); 1H NMR
(400 MHz, CDCl3): d 8.82–8.78 (2H, m), 7.76 (2H, app d, J = 7.7 Hz),
7.36–7.30 (2H, m), 6.18 (1H, d, J = 5.5 Hz), 4.60 (1H, d, J = 5.1 Hz),
3.71–3.56 (2H, m), 2.04 (3H, s), 1.17 (3H, t, J = 7.0 Hz); 13C NMR
(100 MHz, CDCl3): d 170.3, 151.0, 150.9, 150.8, 137.1, 136.6,
130.7, 129.5, 124.1, 123.9, 76.7, 71.3, 66.0, 21.1, 15.4; FT-IR (NaCl)
4.5.3. (S,S)-5,6-Dihydro-6-propoxy-1,10-phenanthrolin-5-ol,
(S,S)-3c [(S,S)-5,6-dihydro-5-hydroxy-6-propoxy-1,10-
phenanthroline]
43 mg (43%); ee = 96%; ½a D25
¼ þ96:9 (c 1, methanol); chiral
ꢁ
HPLC analysis: tR = 12.9 min [(S,S)-enantiomer] and tR = 8.8 min
[(R,R)-enantiomer].
m
/cmꢀ1 3058, 2977, 2927, 2897, 1740, 1581, 1565, 1429, 1371,
1230, 1126, 1091, 1023, 975, 840, 759; chiral HPLC analysis:
tR = 10.0 min [(S,S)-enantiomer] and tR = 21.9 min [(R,R)-enantio-
mer]. HRMS (EI, m/z) calcd for C16H16N2O3 284.1161, found
284.1168.
4.5.4. (S,S)-5,6-Dihydro-6-isopropoxy-1,10-phenanthrolin-5-ol,
(S,S)-3d [(S,S)-5,6-dihydro-5-hydroxy-6-isopropoxy-1,10-
phenanthroline]
43 mg (43%); ee = 86%; ½a D25
¼ þ43:4 (c 1, methanol); chiral
ꢁ
HPLC analysis: tR = 11.3 min [(S,S)-enantiomer] and tR = 8.6 min
[(R,R)-enantiomer].
4.6.3. (R,R)-5,6-Dihydro-6-propoxy-1,10-phenanthrolin-5-yl
acetate, (R,R)-4c [(R,R)-5,6-dihydro-5-acetoxy-6-propoxy-1,10-
phenanthroline]
57 mg (49%), ee = 98%; ½a D25
ꢁ
¼ ꢀ292:1 (c 1, methanol); 1H NMR
4.5.5. (S,S)-5,6-Dihydro-6-butoxy-1,10-phenanthrolin-5-ol,
(S,S)-3e [(S,S)-5,6-dihydro-6-butoxy-5-hydroxy-1,10-
phenanthroline]
(400 MHz, CDCl3): d 8.81–8.78 (2H, m), 7.76–7.74 (2H, m), 7.35–
7.29 (2H, m), 6.18 (1H, d, J = 5.8 Hz), 4.59 (1H, d, J = 5.9 Hz),
3.59–3.47 (2H, m), 2.04 (3H, s), 1.61–1.49 (2H, m), 0.85 (3H, t,
J = 7.3 Hz); 13C NMR (100 MHz, CDCl3): d 170.3, 151.0, 150.8,
150.7, 137.0, 136.5, 130.8, 129.6, 124.0, 123.9, 76.9, 72.4, 71.3,
42 mg (42%); ee = 96%; ½a D25
¼ þ100:9 (c 1, methanol); chiral
ꢁ
HPLC analysis: tR = 12.7 min [(S,S)-enantiomer] and tR = 8.7 min
[(R,R)-enantiomer].
23.1, 21.1, 10.6; FT-IR (NaCl)
m
/cmꢀ1 3056, 2965, 2936, 2877,
1741, 1580, 1565, 1465, 1429, 1371, 1335, 1230, 1129, 1084,
1038, 966, 812, 759, 712; chiral HPLC analysis: tR = 9.7 min [(S,S)-
enantiomer] and tR = 21.0 min [(R,R)-enantiomer]. HRMS (EI, m/z)
calcd for C17H18N2O3 298.1317, found 298.1334.
4.5.6. (S,S)-5,6-Dihydro-6-allyloxy-1,10-phenanthrolin-5-ol, (S,S)-
3h ((S,S)-5,6-dihydro-6-allyloxy-5-hydroxy-1,10-phenanthroline)
44 mg (44%); ee = 96%; ½a D25
¼ þ103:3 (c 1, methanol); chiral
ꢁ
HPLC analysis: tR = 12.1 min [(S,S)-enantiomer] and tR = 9.2 min
[(R,R)-enantiomer].
4.6.4. (R,R)-5,6-Dihydro-6-isopropoxy-1,10-phenanthrolin-5-yl
acetate, (R,R)-4d [(R,R)-5,6-dihydro-5-acetoxy-6-isopropoxy-
1,10-phenanthroline]
4.5.7. (S,S)-5,6-Dihydro-6-benzyloxy-1,10-phenanthrolin-5-ol,
(S,S)-3i ((S,S)-5,6-dihydro-6-benzyloxy-5-hydroxy-1,10-
phenanthroline)
55 mg (47%), ee = 94%; ½a D25
ꢁ
¼ ꢀ185:8 (c 1, methanol); 1H NMR
(400 MHz, CDCl3): d 8.80–8.76 (2H, m), 7.80 (1H, app d, J = 7.7 Hz),
7.69 (1H, app d, J = 7.7 Hz), 7.35–7.28 (2H, m), 6.16 (1H, d,
J = 7.3 Hz), 4.71 (1H, d, J = 7.3 Hz), 3.86 (1H, app septet,
J = 6.1 Hz), 2.11 (3H, s), 1.22 (1H, d, J = 6.2 Hz), 1.16 (1H, d,
45 mg (45%); ee = 90%; ½a D25
¼ þ95:9 (c 1, methanol); chiral
ꢁ
HPLC analysis: tR = 14.8 min ((S,S)-enantiomer) and tR = 11.9 min
((R,R)-enantiomer).

1902
E. Schoffers, L. Kohler / Tetrahedron: Asymmetry 20 (2009) 1897–1902
J = 5.9 Hz); 13C NMR (100 MHz, CDCl3): d 170.3, 150.8, 150.6, 150.5,
4.6.8. (R,R)-5,6-Dihydro-6-cyclohexyloxy-1,10-phenanthrolin-5-
yl acetate, (R,R)-4j [(R,R)-5,6-dihydro-5-acetoxy-6-cyclohexyloxy-
1,10-phenanthroline]
135.9, 135.7, 131.9, 129.9, 124.1, 124.0, 74.8, 72.3, 72.1, 22.6, 22.5,
21.1; FT-IR (NaCl)
m
/cmꢀ1 3054, 2933, 2857, 1744, 1579, 1563,
1449, 1428, 1371, 1342, 1229, 1183, 1132, 1074, 1038, 960, 799,
746, 733, 621; chiral HPLC analysis: tR = 9.7 min [(S,S)-enantiomer]
and tR = 22.3 min [(R,R)-enantiomer]. HRMS (EI, m/z) calcd for
C17H18N2O3 298.1317, found 298.1324.
52 mg (46%), ee = 91%; ½a D25
ꢁ
¼ ꢀ156:5 (c 1, methanol); 1H NMR
(400 MHz, CDCl3): d 8.78 (2H, app d, J = 4.4 Hz), 7.81 (1H, app d,
J = 7.7 Hz), 7.69 (1H, app d, J = 7.7 Hz), 7.35–7.28 (2H, m), 6.17
(1H, d, J = 7.4 Hz), 4.77 (1H, d, J = 7.3 Hz), 3.56–3.48 (1H, m), 2.11
(3H, s), 1.98–1.11 (10H, m); 13C NMR (100 MHz, CDCl3): d 170.3,
150.8, 150.7, 150.5, 150.4, 136.0, 135.8, 132.0, 129.9, 124.1,
4.6.5. (R,R)-5,6-Dihydro-6-butoxy-1,10-phenanthrolin-5-yl
acetate, (R,R)-4e [(R,R)-5,6-dihydro-5-acetoxy-6-butoxy-1,10-
phenanthroline]
124.0, 78.4, 74.6, 72.1, 32.8, 25.6, 24.3, 24.2, 21.1; FT-IR (NaCl) m/
cmꢀ1 3057, 2972, 2929, 1742, 1579, 1563, 1465, 1428, 1372,
1329, 1304, 1230, 1179, 1126, 1069, 1039, 976, 939, 802, 758,
747, 621; chiral HPLC analysis: tR = 9.7 min ((S,S)-enantiomer)
and tR = 21.7 min ((R,R)-enantiomer). HRMS (EI, m/z) calcd for
C20H22N2O3 338.1630, found 338.1621.
54 mg (47%), ee = 98%; ½a D25
ꢁ
¼ ꢀ240:5 (c 1, methanol); 1H NMR
(400 MHz, CDCl3): d 8.84–8.76 (2H, m), 7.79–7.72 (2H, m), 7.36–
7.29 (2H, m), 6.17 (1H, d, J = 5.8 Hz), 4.59 (1H, d, J = 5.9 Hz),
3.64–3.51 (2H, m), 2.04 (3H, s), 1.55–1.46 (2H, m), 1.29 (2H, app
sextet, J = 7.5 Hz), 0.85 (3H, t, J = 7.3 Hz); 13C NMR (100 MHz,
CDCl3): d 170.3, 151.0, 150.8, 150.7, 137.0, 136.5, 130.8, 129.6,
124.0, 123.9, 76.9, 71.3, 70.5, 31.9, 21.1, 19.3, 13.9; FT-IR (NaCl)
Acknowledgments
m
/cmꢀ1 3059, 2959, 2933, 2872, 1742, 1580, 1564, 1465, 1428,
The authors acknowledge support from Western Michigan Uni-
versity (WMU) and thank the National Institutes of Health
(1R15GM67670-1) and the US Army (WS911QY-07-1-0003) for
external funding. The authors also thank Dr. Andre R. Venter
(WMU) and Kalexsyn, Inc. for help with HRMS measurements.
1371, 1230, 1127, 1090, 1024, 968, 759, 711; chiral HPLC analysis:
tR = 9.6 min [(S,S)-enantiomer] and tR = 19.6 min [(R,R)-enantio-
mer]. HRMS (EI, m/z) calcd for C18H20N2O3 312.1474, found
312.1481.
4.6.6. (R,R)-5,6-Dihydro-6-allyloxy-1,10-phenanthrolin-5-yl
acetate, (R,R)-4h [(R,R)-5,6-dihydro-5-acetoxy-6-allyloxy-1,10-
phenanthroline]
References
55 mg (47%), ee = 98%; ½a D25
ꢁ
¼ ꢀ290:8 (c 1, methanol); 1H NMR
1. Thummel, R. P.; Chamchoumis, C. M. In Advances in Nitrogen Heterocycles;
Moody, C. J., Ed.; JAI Press: Stamford, CT, 2000; pp 107–158.
2. Schoffers, E. Eur. J. Org. Chem. 2003, 1145–1152.
3. Kwong, H.-L.; Yeung, H.-L.; Yeung, C.-T.; Lee, W.-S.; Lee, C.-S.; Wong, W.-L.
Coord. Chem. Rev. 2007, 251, 2188–2222.
4. Schoffers, E.; Tran, S. D.; Mace, K. Heterocycles 2003, 60, 769–772.
5. Shen, Y.; Sullivan, B. P. Inorg. Chem. 1995, 34, 6235–6236.
6. Sanfilippo, C.; Nicolosi, G. Tetrahedron: Asymmetry 2008, 19, 2171–2176.
7. Kobayashi, S. In Handbook on the Physics and Chemistry of Rare Earths;
Gschneider, K. A. J., Eyring, L., Eds.; Elsevier Science B. V., 2000; pp 315–375.
8. Likhar, P. R.; Kumar, M. P.; Bandyopadhyay, A. K. Synlett 2001, 836-838.
9. Monasson, O.; Ginisty, M.; Bertho, G.; Gravier-Pelletier, C.; Le Merrer, Y.
Tetrahedron Lett. 2007, 48, 8149–8152.
(400 MHz, CDCl3): d 8.84–8.78 (2H, m), 7.80–7.72 (2H, m), 7.37–
7.29 (2H, m), 6.17 (1H, d, J = 5.5 Hz), 5.91–5.80 (1H, m), 5.25 (1H,
dd, J = 1.5, 17.2 Hz), 5.21 (1H, app d, J = 10.6 Hz), 4.67 (1H, d,
J = 5.1 Hz), 4.10 (2H, d, J = 5.5 Hz), 2.02 (3H, s); 13C NMR
(100 MHz, CDCl3): d 170.3, 151.1, 151.0, 150.9, 137.4, 136.8,
134.0, 130.3, 129.4, 124.1, 123.9, 118.2, 75.6, 71.1, 71.0, 21.1; FT-
IR (NaCl)
m
/cmꢀ1 3061, 2992, 2922, 2866, 1740, 1580, 1565,
1429, 1371, 1335, 1230, 1129, 1074, 1025, 991, 969, 929, 811,
759, 747; chiral HPLC analysis: tR = 11.4 min [(S,S)-enantiomer]
and tR = 28.0 min [(R,R)-enantiomer]. HRMS (EI, m/z) calcd for
C17H16N2O3 296.1161, found 296.1155.
10. Serrano, P.; Llebaria, A.; Delgado, A. J. Org. Chem. 2002, 67, 7165–7167.
11. Tsuchiya, S.; Sunazuka, T.; Shirahata, T.; Hirose, T.; Kaji, E.; Omura, S.
Heterocycles 2007, 72, 91–94.
12. Jones, B. J.; Desantis, G. Acc. Chem. Res. 1999, 32, 99–107.
13. Kirchner, G.; Scollar, M. P.; Klibanov, A. M. J. Am. Chem. Soc. 1985, 107, 7072–
7076.
4.6.7. (R,R)-5,6-Dihydro-6-benzyloxy-1,10-phenanthrolin-5-yl
acetate, (R,R)-4i [(R,R)-5,6-dihydro-5-acetoxy-6-benzyloxy-1,10-
phenanthroline]
14. Klibanov, A. M. Acc. Chem. Res. 1990, 23, 114–120.
15. Fitzpatrick, P.; Klibanov, A. M. J. Am. Chem. Soc. 1991, 113, 3166–3171.
16. Kazlauskas, R. J. J. Am. Chem. Soc. 1989, 111, 4953–4959.
17. Hughes, D. L.; Bergan, J. J.; Amato, J. S.; Bhupathy, M.; Leazer, J. L.; McNamara, J.
M.; Sidler, D. R.; Reider, P. J.; Grabowski, E. J. J. J. Org. Chem. 1990, 55, 6252–
6259.
18. Imperiali, B.; Prins, T. J.; Fisher, S. L. J. Org. Chem. 1993, 58, 1613–1616.
19. Blakemore, P. R.; Milicevic, S. D.; Zakharov, L. N. J. Org. Chem. 2007, 72, 9368–
9371.
20. Takemura, T.; Emoto, G.; Satoh, J.; Kobayashi, Y.; Yaginuma, C.; Takahashi, Y.;
Utsukihara, T.; Horiuchi, C. A. J. Mol. Catal. B: Enzym. 2008, 55, 104–109.
21. Sanfilippo, C.; D’Antona, N.; Nicolosi, G. Tetrahedron: Asymmetry 2006, 17, 12–
14.
22. Sanfilippo, C.; Nicolosi, G. Tetrahedron: Asymmetry 2007, 18, 1828–1832.
23. Antkowiak, R.; Antkowiak, W. Z. Heterocycles 1998, 47, 893–909.
24. Krishnan, S.; Kuhn, D. J.; Hamilton, G. A. J. Am. Chem. Soc. 1977, 99, 8121–
8123.
55 mg (48%), ee = 96%; ½a D25
¼ ꢀ280:8 (c 1, methanol); mp
ꢁ
148 °C; 1H NMR (400 MHz, CDCl3): d 8.84–8.79 (2H, m), 7.77
(1H, app dd, J = 1.5, 7.7 Hz), 7.64 (1H, app dd, J = 1.5, 7.7 Hz),
7.38–7.24 (7H, m), 6.21 (1H, d, J = 5.1 Hz), 4.70 (1H, d,
J = 5.5 Hz), 4.65 (1H, ABq, J = 12.1 Hz), 4.61 (1H, ABq,
J = 12.1 Hz), 1.97 (3H, s); 13C NMR (100 MHz, CDCl3): d 170.2,
151.1, 151.0, 150.9, 137.6, 137.4, 137.1, 130.1, 129.3, 128.7,
128.2, 127.9, 124.1, 123.9, 75.5, 71.9, 70.9, 21.1; FT-IR (NaCl)
m
/cmꢀ1 3060, 3032, 2925, 2869, 1740, 1580, 1565, 1454, 1429,
1371, 1229, 1129, 1071, 1027, 968, 810, 758, 745, 700; chiral
HPLC analysis: tR = 15.0 min [(S,S)-enantiomer] and tR = 34.0 min
[(R,R)-enantiomer]. HRMS (EI, m/z) calcd for C21H18N2O3
346.1317, found 346.1307.
25. Moody, C. J.; Rees, C. W.; Thomas, R. Tetrahedron 1992, 48, 3589–3602.
26. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104,
7294–7299.