First isolation of disubstituted cis-5,6-dihydro-1,10-phenanthrolines. Lipase-mediated resolution of cis- and trans-phenoxy alcohol isomers and assignment of absolute stereochemistry via CD and NMR spectroscopy

Article abstract of DOI:10.1002/chir.21989

5,6-Dihydro-1,10-phenanthrolines can display axial and central chirality. In conjunction with the ligating properties of the diimino moiety, this class of compounds is of great interest to applications in supramolecular chemistry. We report the first preparation of cis-5,6-dihydro-1,10-phenanthroline derivatives by reacting triphenyl borate with the corresponding epoxide precursor. We found that solvent and temperature choice determined the stereoselectivity of the epoxide opening giving rise to the cis (14:1 dr) or trans (99:1 dr) product. Racemates of each stereoisomeric mixture, cis- and trans-phenoxy alcohol, were separated via highly enantioselective transesterifications with lipase PSCI from Burkholderia cepacia (97% ee, E > 200). Stereochemical assignments were carried out using CD and X-ray analyses in conjunction with NMR studies of α-methoxy-α-(trifluoromethyl)phenylacetic acid and α-methoxyphenylacetic acid esters. Copyright

Full text of DOI:10.1002/chir.21989

CHIRALITY 24:245–251 (2012)
First Isolation of Disubstituted cis-5,6-Dihydro-1,10-
phenanthrolines. Lipase-Mediated Resolution of cis- and
trans-Phenoxy Alcohol Isomers and Assignment of Absolute
Stereochemistry via CD and NMR Spectroscopy
1
2
LARS KOHLER,1 ELKE SCHOFFERS,1 ERIN DRISCOLL, MATTHIAS ZELLER, AND CARLA SCHMIESING1
*
1Department of Chemistry, Western Michigan University, Kalamazoo, Michigan
2Department of Chemistry, Youngstown State University, Youngstown, Ohio
ABSTRACT
5,6-Dihydro-1,10-phenanthrolines can display axial and central chirality. In con-
junction with the ligating properties of the diimino moiety, this class of compounds is of great
interest to applications in supramolecular chemistry. We report the first preparation of cis-5,6-
dihydro-1,10-phenanthroline derivatives by reacting triphenyl borate with the corresponding
epoxide precursor. We found that solvent and temperature choice determined the stereoselec-
tivity of the epoxide opening giving rise to the cis (14:1 dr) or trans (99:1 dr) product. Race-
mates of each stereoisomeric mixture, cis- and trans-phenoxy alcohol, were separated via highly
enantioselective transesterifications with lipase PSCI from Burkholderia cepacia (97% ee, E >
200). Stereochemical assignments were carried out using CD and X-ray analyses in conjunction
with NMR studies of a-methoxy-a-(trifluoromethyl)phenylacetic acid and a-methoxyphenylace-
C
VV
tic acid esters. Chirality 24:245–251, 2012.
2012 Wiley Periodicals, Inc.
KEY WORDS: axial chirality; epoxide opening; triphenyl borate; solvent effect; enzymatic
resolution; transesterification; Mosher ester
INTRODUCTION
EXPERIMENTAL SECTION
Commercial chemicals and reagents in 981 purity were used without
further purification. Amano lipases were purchased from Aldrich. Sol-
vents were acquired as reagent grade for reactions and as high-perform-
ance liquid chromatography (HPLC) grade for analytical measurements.
1,10-Phenanthroline-5,6-epoxide was synthesized according to the litera-
ture.53–56 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 spec-
tra were obtained from Bruker Equinox 55 and Perkin–Elmer 1710 Fou-
rier Transform Infrared Spectrometers. Elemental analyses were carried
out by Numega Resonance Labs, San Diego, CA. HPLC data were col-
lected using a Shimadzu instrument consisting of a column (Chiralcel1
OD-H), solvent delivery system (LC-20AT), detector (SPD-20A), auto-
sampler (SIL-20A), and degasser (DGU-20A5). CD spectra were
recorded in spectroscopy grade methanol with a Jasco J-815 CD Spec-
trometer using a 0.1-cm path cell at 208C.
Epoxides are important building blocks because they read-
ily react with numerous nucleophiles. Most reactions pro-
ceed with anti-selectivity while only few reports describe syn-
selective openings. Examples include the direct reaction of
epoxides with nitric oxide,1,2 the hydrofluorination of aryl
epoxides using BF3ꢀOEt2,3 the epoxide opening with aryl
borates,4,5 the aluminum-, boron-, or zinc-mediated opening
of glycal and 2,3-dihydrofuran epoxides,6–9 and the tin-medi-
ated palladium catalyzed etherification of vinyl epoxides.10
syn-Adducts are isolated indirectly by inverting the alcohol of
the anti product. Methods include the Mitsunobu reaction11–19
and the substitution of sulfonates.20–24 The preparation of
cis-1-amino-2-indanol is a notable industrial example and was
carried out independently by researchers at Merck and
Sepracor. Each synthesis entailed the conversion of indene
oxide to its cis amino alcohol but involved either a Ritter
reaction or a benzoxazole intermediate to control the stereo-
chemistry.25–27
Determination of Enantiomeric Excess and E-Values
The enantiomerically enriched alcohols and acetates were chromato-
graphically separated (SiO2; CHCl3/1% MeOH) and analyzed by chiral
1,10-Phenanthroline derivatives have found use in or-
ganic, inorganic, medicinal, and biochemistry28–30 including
their application in chiral catalysis,31–33 bioaffinity assays,34
medicine35–40 and as sensors.41–44 B-ring-modified 5,6-dihy-
dro-1,10-phenanthrolines have unique structural properties
and can display axial chirality and/or central chirality; the
latter typically referring to the presence of one or more
stereogenic centers in the absence of an axis or plane.45–47
A few derivatives were recently prepared via epoxide-open-
ing with oxygen- and nitrogen nucleophiles,48–51 and via
intramolecular Ullmann coupling of two ethyl-bridged pyri-
dine rings.52 Until now no optically active cis-5,6-dihydro
derivatives that contain axial and central chirality have
been reported.
Additional Supporting Information may be found in the online version of this
article.
Contract grant sponsor: National Institutes of Health; Contract grant number:
1R15GM67670-1
Contract grant sponsor: US Army; Contract grant number: WS911QY-07-1-
0003
Contract grant sponsor: National Science Foundation; Contract grant num-
ber: DBI-0552517
Contract grant sponsor: Dissertation Completion Fellowship, Gwen Frostic
Doctoral Fellowship
*Correspondence to: Prof. Elke Schoffers, Western Michigan University,
Department of Chemistry, 3425 Wood Hall, Kalamazoo, MI 49008-5413, USA.
E-mail: elke.schoffers@wmich.edu
Received for publication 21 June 2011; Accepted 2 November 2011
DOI: 10.1002/chir.21989
Published online 18 January 2012 in Wiley Online Library
(wileyonlinelibrary.com).
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VV
2012 Wiley Periodicals, Inc.

246
KOHLER ET AL.
HPLC using a 70:30 mixture of isopropanol and hexane as eluent at a 0.5
ml/min flow rate and UV–vis detection at 266 nm. Enantiomeric excess
was obtained by comparing the area percentage of each enantiomer. E-
values were calculated from the enantiomeric excess of the substrate
(eeS) and the product (eeP).57
508C. After 50% substrate conversion (monitored by 1H-NMR) the reac-
tion mixture was filtered through Celite, the solvent removed in vacuo
and the residue purified by column chromatography (SiO2; chloroform/
1% methanol).
Characterization of Enantiomerically
Enriched Phenoxy Alcohols
Preparation of (6)-trans-5,6-Dihydro-6-phenoxy-1,10-
phenanthrolin-5-ol ((6)-trans-5,6-Dihydro-5-hydroxy-6-
phenoxy-1,10-phenanthroline) [(6)-trans-Alcohol 2]
(S,S)-trans-5,6-Dihydro-6-phenoxy-1,10-phenanthrolin-5-ol ((S,S)-
trans-5,6-dihydro-5-hydroxy-6-phenoxy-1,10-phenanthroline) [(1)-
(S,S)-trans-alcohol 2]. Forty-six milligrams (46%) yield; ee 5 97%;
[a]2D5 5 174.58 (c 1, methanol); chiral HPLC analysis: tR 5 13.0 min
((S,S)-enantiomer) and tR 5 10.8 min ((R,R)-enantiomer); CD: (c 5 3.44
3ꢀ1024 mol/l).
To a solution of 1,10-phenanthrolin-5,6-epoxide (1.00 g, 5.10 mmol) in
acetonitrile (1 ml) was added a solution of triphenyl borate (2.96 g, 10.19
mmol) in acetonitrile (1 ml) under an argon atmosphere. The reaction
mixture was stirred at room temperature for 3 days after which aqueous
NaOH (10%, 10 ml) and chloroform (100 ml) were added, the organic
layer was separated and the aqueous layer extracted twice with chloro-
form (50 ml). The combined organic layer was washed twice with aque-
ous NaOH (10%, 10 ml), dried with Na2SO4, filtered, and concentrated.
The product was isolated after column chromatography (SiO2; chloro-
form/1% methanol) in 58–74% yield (0.86–1.10 g) (trans:cis ratio 5
>99:1). M.p. 2158C; 1H-NMR (400 MHz, CDCl3) d: 8.76–8.73 (2H, m),
8.09 (1H, app d, J 5 7.7 Hz), 7.75 (1H, app d, J 5 7.7 Hz), 7.37 (1H, dd, J
5 4.8 Hz, J 5 7.7 Hz), 7.34–7.24 (3H, m), 7.06–7.01 (3H, m), 5.53 (1H, d,
J 5 10.6 Hz), 5.26 (1H, d, J 5 10.3 Hz), 3.29 (1H, br s); 1H-NMR (400
MHz, CD3OD) d: 8.69–8.67 (2H, m), 8.07 (1H, app d, J 5 7.7 Hz), 7.87
(1H, app d, J 5 7.3 Hz), 7.49 (1H, dd, J 5 4.8 Hz, J 5 7.7 Hz), 7.41 (1H,
dd, J 5 4.9 Hz, J 5 7.9 Hz), 7.31–7.26 (2H, m), 7.08 (2H, app d, J 5 7.7
Hz), 6.99 (1H, app t, J 5 7.3 Hz), 5.56 (1H, d, J 5 8.0 Hz), 5.11 (1H, d, J
5 8.1 Hz); 13C-NMR (100 MHz, CDCl3) d: 159.0, 150.4, 150.4, 150.2,
149.7, 134.0, 133.8, 132.9, 131.5, 130.1, 124.4, 124.0, 122.4, 115.6, 80.0,
71.3; FTIR (KBr, pellet) m/cm21: 3131, 3063, 2889, 1595, 1584, 1565,
1492, 1433, 1420, 1232, 1172, 1123, 1057, 1036, 1008, 854, 795, 751, 714,
691; analysis calculated for C18H14N2O2: C, 74.47; H, 4.86; N, 9.65 Found:
C, 74.52; H, 4.51; N, 9.45.
(5S,6R)-cis-5,6-Dihydro-6-phenoxy-1,10-phenanthrolin-5-ol((5S,
6R)-cis-5,6-dihydro-5-hydroxy-6-phenoxy-1, 10-phenanthroline) [(2)-
(5S,6R)-cis-alcohol 3]. Forty-eight milligrams (48%) yield; ee 5 97%;
[a]2D5 5 282.28 (c 1, methanol); chiral HPLC analysis: tR 5 19.1 min
((5S,6R)-enantiomer) and tR 5 16.2 min ((5R,6S)-enantiomer); CD: (c 5
6.89ꢀ3 1024 mol/l).
Hydrolysis of (2)-(5R,6S)-cis-acetate 5 using NH4OH/MeOH afforded
(1)-(5R,6S)-cis-alcohol 3 in quantitative yield. ee 5 97%, [a]2D5 5 184.38
(c 1, methanol).
Characterization of Enantiomerically
Enriched Phenoxy Acetates
(R,R)-trans-5,6-Dihydro-6-phenoxy-1,10-phenanthrolin-5-yl acetate
((R,R)-trans-5,6-dihydro-5-acetoxy-6-phenoxy-1,10-phenanthroline)
[(2)-(R,R)-trans-alcohol 4]. Fifty-five milligrams (48%) yield, ee 5
97%; [a]2D5 5 2232.98 (c 1, methanol); m.p. 1248C; 1H-NMR (400 MHz,
CDCl3) d: 8.85–8.83 (2H, m), 7.79 (1H, app d, J 5 7.7 Hz), 7.69 (1H, app
d, J 5 7.7 Hz), 7.36–7.29 (4H, m), 7.06–6.99 (3H, m), 6.46 (1H, d, J 5 7.7
Preparation of (6)-cis-5,6-Dihydro-6-phenoxy-1,10-
phenanthrolin-5-ol ((6)-cis-5,6-Dihydro-5-hydroxy-6-
phenoxy-1,10-phenanthroline) [(6)-cis-Alcohol 3]
1
Hz), 5.61 (1H, d, J 5 7.7 Hz), 2.01 (3H, s); H-NMR (400 MHz, CD3OD)
d: 8.75–8.73 (2H, m), 7.92 (1H, app d, J 5 7.7 Hz), 7.87 (1H, app d, J 5
7.7 Hz), 7.49–7.44 (2H, m), 7.32–7.27 (2H, m), 7.06–6.99 (3H, m), 6.37
(1H, d, J 5 6.2 Hz), 5.80 (1H, d, J 5 6.6 Hz), 1.96 (3H, s); 13C-NMR (100
MHz, CDCl3) d: 170.4, 158.1, 151.1, 151.0, 150.7, 150.4, 135.8, 135.7,
130.2, 129.9, 129.4, 124.3, 124.2, 122.5, 116.4, 76.6, 71.2, 20.9; FTIR (KBr,
pellet) m/cm21 3054, 3001, 2962, 2924, 2852, 1726, 1583, 1488, 1455,
1428, 1372, 1344, 1292, 1242, 1172, 1127, 1079, 1019, 967, 890, 753, 715,
697; analysis calculated for C20H16N2O3ꢀ1/4CHCl3: C, 67.15; H, 4.52; N,
7.73 Found: C, 66.78; H, 4.81; N, 7.59; chiral HPLC analysis: tR 5 14.1
min ((S,S)-enantiomer) and tR 5 41.3 min ((R,R)-enantiomer). CD: (c 5
3.01ꢀ3 1024 mol/l).
To a solution of 1,10-phenanthrolin-5,6-epoxide (1.00 g, 5.10 mmol) in
dimethylformamide (DMF) (5 ml) was added a solution of triphenyl borate
(1.77 g, 6.12 mmol) in DMF (5 ml) under argon atmosphere. The reaction
mixture was stirred at 808C for 3 days after which the solvent was evapo-
rated and aqueous NaOH (10%, 10 ml) and chloroform (150 ml) were
added. After stirring the mixture for 1 h at room temperature the organic
layer was separated and the aqueous layer extracted twice with chloroform
(50 ml). The combined organic layer was washed with aqueous NaOH
(10%, 10 ml), dried with Na2SO4, filtered, and concentrated. The product
was isolated via column chromatography (SiO2; chloroform/1% methanol)
in 35% yield (520 mg) (cis:trans ratio 5 14:1). M.p. 2228C; 1H-NMR (400
MHz, CDCl3) d: 8.85–8.80 (2H, m), 7.99 (1H, app d, J 5 7.7 Hz), 7.64 (1H,
app d, J 5 7.7 Hz), 7.40 (1H, dd, J 5 4.8 Hz, J 5 7.7 Hz), 7.32–7.23 (3H, m),
7.05 (1H, app t, J 5 7.3 Hz), 6.95 (2H, app d, J 5 7.7 Hz), 5.46 (1H, d, J 5
4.0 Hz), 5.15 (1H, d, 3.3 Hz), 2.74 (1H, br s); 1H-NMR (400 MHz, CD3OD)
d: 8.71–8.66 (2H, m), 8.05 (1H, app d, J 5 7.7 Hz), 7.87 (1H, app d, J 5 7.7
Hz), 7.50 (1H, dd, J 5 4.8 Hz, J 5 7.7 Hz), 7.38 (1H, dd, J 5 4.8 Hz, J 5 7.7
Hz), 7.29–7.24 (2H, m), 7.03 (2H, app d, J 5 7.7 Hz), 6.98 (1H, app t, J 5
7.3 Hz), 5.62 (1H, d, J 5 3.7 Hz), 5.14 (1H, d, J 5 3.3 Hz); 13C-NMR (100
MHz, CDCl3) d: 157.2, 151.0, 150.4, 150.3, 149.8, 136.5, 136.1, 132.9, 130.0,
129.7, 124.6, 123.9, 123.3, 118.2, 78.3, 69.0; FTIR (KBr, pellet) m/cm21
3145, 2911, 2848, 1590, 1563, 1487, 1423, 1341, 1212, 1160, 1132, 1104,
1089, 1069, 1035, 970, 948, 873, 822, 773, 756, 727, 697; analysis calculated
for C18H14N2O2: C, 74.47; H, 4.86; N, 9.65 Found: C, 74.39; H, 5.20; N, 9.63.
(5R,6S)-cis-5,6-Dihydro-6-phenoxy-1,10-phenanthrolin-5-yl ace-
tate ((5R,6S)-cis-5,6-dihydro-5-acetoxy-6-phenoxy-1,10-phenan-
throline) [(2)-(5R,6S)-cis-acetate 5]. Fiftysix milligrams (49%)
yield, ee 5 97%; [a]2D5 5 2103.88 (c 1, methanol); 1H-NMR (400 MHz,
CDCl3) d: 8.89–8.84 (2H, m), 7.95–7.91 (2H, m), 7.41–7.30 (4H, m), 7.06
(1H, app t, J 5 7.3 Hz), 7.00 (2H, app d, J 5 7.7 Hz), 6.23 (1H, d, J 5 3.7
1
Hz), 5.67 (1H, d, J 5 3.6 Hz), 1.99 (3H, s); H-NMR (400 MHz, CD3OD)
d: 8.76–8.70 (2H, m), 8.02–7.96 (2H, m), 7.50–7.45 (2H, m), 7.33–7.28
(2H, m), 7.06 (2H, app d, J 5 7.7 Hz); 7.01 (1H, app t, J 5 7.3 Hz), 6.31
(1H, d, J 5 3.6 Hz), 5.90 (1H, d, J 5 3.6 Hz), 1.96 (3H, s); 13C-NMR (100
MHz, CDCl3) d: 170.7, 157.7, 151.6, 151.2, 150.5, 150.1, 137.5, 134.7,
130.7, 130.0, 128.8, 124.3, 124.2, 122.9, 117.1, 75.3, 69.5, 21.0; FTIR (KBr,
pellet) m/cm21 3062, 2961, 2926, 2854, 1748, 1587, 1568, 1491, 1422,
1372, 1234, 1039, 796, 753, 694; analysis calculated for C20H16N2O3ꢀ1/
5CHCl3: C, 68.11; H, 4.58; N, 7.86 Found: C, 67.81; H, 4.72; N, 7.57; chi-
ral HPLC analysis: tR 5 17.6 min ((5S,6R)-enantiomer) and tR 5 30.6
min ((5R,6S)-enantiomer); CD: (c 5 4.42ꢀ3 1024 mol/l).
General Procedure for Lipase Catalyzed Kinetic
Resolution of Racemic Phenoxy Alcohols
A solution of racemic phenoxy alcohol (100 mg) in acetonitrile (5 ml)
and vinyl acetate (20 ml) was placed in a 50-ml round bottomed flask.
Amano lipase PSCI (500 mg) was added and the flask was closed with a
glass stopper and sealed with Parafilm1. The suspension was stirred at
Acetylation of (2)-(5S,6R)-cis-alcohol 3 using Mg(ClO4)2 (0.1 eq.) and
acetic anhydride (1.2 eq.) afforded (1)-(5S,6R)-cis-acetate 5 in quantita-
tive yield. ee 5 97%, [a]2D5 5 1101.38 (c 1, methanol).
Chirality DOI 10.1002/chir

DISUBSTITUTED cis-5,6-DIHYDRO-1,10-PHENANTHROLINES
247
Scheme 1. Opening of epoxide 1 with triphenyl borate.
fluorescens (AK) and Burkholderia cepacia (PSCI).49–51 Our
previous studies showed that PSCI provides 4–5 times faster
conversion rates with similar enantioselectivities in compari-
son to lipase AK.51 Therefore, lipase PSCI was our first
choice for the kinetic resolution of trans- and cis-phenoxy
alcohols 2 and 3 (Schemes 2 and 3).
Schemes 2 and 3 illustrate that PSCI promotes the resolu-
tion of both diastereomers with excellent enantioselectivities
(E > 200), giving rise to all compounds in 97% ee.
Single-Crystal Structure Analysis
Monocrystals of (6)-cis-alcohol 3 were obtained via recrystallization
from methanol. X-ray quality crystals of (6)-trans-acetate 4 were grown
in chloroform via slow solvent evaporation. Crystallographic data
(excluding structure factors) have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication numbers
CCDC 721749 [(6)-trans-acetate 4] and CCDC 796394 [(6)-cis-alcohol
3]. Copies of the data can be obtained, free of charge, upon request to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, [fax: 144-(0)1223-
336033 or e-mail: deposit@ccdc.cam.ac. Uk].
Conformational Analysis and Assignment
of Absolute Configuration
RESULTS AND DISCUSSION
Preparation of Racemic cis- and trans-5,6-Dihydro-6-
phenoxy-1,10-phenanthrolin-5-ol
The stereochemistry of all synthesized products was
assigned by a combination of X-ray crystallography, 1H-
NMR, and CD spectroscopy.
We previously found that magnesium perchlorate and alu-
mina catalyzed the ring-opening of epoxide 1 with nitrogen
nucleophiles, whereas oxygen nucleophiles required a stron-
ger Lewis acid, ytterbium(III) triflate.48,51 Reactions pro-
ceeded with a variety of alcohols in 81–99% yield but
attempts to use phenol were unsuccessful. We herewith
report the first isolation of phenoxy alcohol derivatives,
which was accomplished through the conversion of substrate
1 with triphenyl borate. Moreover, our findings revealed that
the stereoselectivity was highly temperature and solvent de-
pendent. Optimized conditions required the use of two equiv-
alents of triphenyl borate in acetonitrile at room temperature
to afford the trans-product in 58–74% yield and 99:1 dr. A
high cis-selectivity (14:1) was observed when 1.2 eq. of rea-
gent were employed in DMF at 808C (Scheme 1).
We observed that mainly two CD bands are important for
the stereochemical assignment of 5,6-dihydro-1,10-phenan-
throlines. The 230–280 nm region is associated with the hel-
icity of the cyclohexadiene moiety (B-ring, Fig. 1), whereas
the 210–235 nm region correlates with the helicity of the
biaryl chromophore (Fig. 2). A positive cotton effect (P) is
expected for a right-handed twist and a negative cotton effect
(M) for a left-handed twist (Fig. 2).
The coupling constants of the benzylic hydrogens,
J(5H,6H), of the (1)-trans-alcohol 2 and (2)-trans-acetate 4
were used to identify the preferred conformation as diequato-
rial (J(5H,6H) 5 8.1 Hz) and diaxial (J(5H,6H) 5 6.4 Hz),
respectively (Table 1). X-ray analysis of acetate 4 corro-
borated our NMR spectroscopy findings for the solid state
(Fig. 3).
Control experiments were carried out by heating a solu-
tion of (6)-trans-phenoxy alcohol 2 in DMF or acetonitrile at
808C for 2 days. No isomerization to (6)-cis-alcohol 3 was
observed leading to the conclusion that the products are
thermodynamically stable.
The CD spectrum of (2)-trans-acetate 4 is dominated by
the negative band at 217 nm, which correlates with the M-
helicity of the bipyridyl chromophore, and the 251 nm band
that is indicative of the M-helicity in the cis-diene moiety
(Fig. 3). These results clearly support a (5R,6R) configura-
tion.
Lipase-Catalyzed Resolution
Recent reports have focused on the enzymatic resolution
of a variety of trans-5,6-dihydro-1,10-phenanthroline deriva-
tives using two commercially available lipases, Pseudomonas
The absolute configuration of (1)-trans-alcohol 2 should
be exactly the opposite of (2)-trans-acetate 4. The (5S,6S)
assignment for compound 2 was confirmed by a negative
Scheme 2. Enzymatic kinetic resolution of (6)-trans-phenoxy alcohol 2.
Chirality DOI 10.1002/chir

248
KOHLER ET AL.
Scheme 3. Enzymatic kinetic resolution of (6)-cis-phenoxy alcohol 3.
Fig. 1. Helical chirality of the cyclohexadiene moiety.
band in the 210–230 nm region after taking into account a
preferential diequatorial conformation of both B-ring sub-
stituents. Furthermore, the positive band at 247 nm showed
the opposite sign of the 251 nm band of (2)-trans-acetate 4
(Fig. 3). It is known that the low energy CD band of com-
pounds with two axial hydrogens can have opposite sign
CD bands and disagree with the helicity of the diene moi-
ety.60,61 Our findings are supported by studies on related
idyl moiety. This can be explained by the interconversion of
the phenoxy and acetyl group between the pseudo-axial and
the pseudo-equatorial positions, which have similar A-values
(Fig. 4).
Assignment of Absolute Configuration Using NMR
Spectroscopy of MTPA and MPA Esters
In order to confirm the absolute configuration of (1)-trans-
alcohol 2 and (2)-cis-alcohol 3 after enzymatic resolution,
we prepared the a-methoxy-a-(trifluoromethyl)phenylacetic
acid (MTPA) and a-methoxyphenylacetic acid (MPA)
´
trans-9,10-dihydrophenanthrenes by Gawronski et al. who
utilized CD analyses to deduce both the absolute configura-
tion and the conformation of molecules. The authors found
that trans-9,10-dihydrophenanthrenes displayed a positive
band in the 230–280 nm region and assigned the (S,S)-con-
figuration.59
1
esters,63 assigned the proton signals by a combination of H,
NOE, and COSY NMR experiments and applied the Mosher
correlation model that was recently reviewed by Riguera and
coworkers.64 For both the cis- and trans-phenoxy-esters, we
found that the positive and negative Dd(1H) values are regu-
larly dispersed on the left and the right side of the MTPA
and MPA plane, respectively (see Supporting Information).
Negative Dd values were calculated for the protons in C2,
C3, and C4 position whereas positive values were determined
for the C6, C7, C8, and C9 position in addition to the phe-
noxy group. Only the C9 proton of the cis-phenoxy MTPA
esters has with 20.01 a slightly negative DdSR(1H) value.
Since this value is so close to zero and this proton is far away
from the chiral center and the shielding effect of the MTPA
1H-NMR spectroscopy failed to reveal the conformational
preferences of (2)-cis-alcohol 3 and (2)-cis-acetate 5 (Table
1), but the crystal structure of the former showed that the
smaller hydroxyl group assumes the pseudo-equatorial posi-
tion while the bigger phenoxy group occupies the pseudo-
axial position to avoid allylic strain with H7 (Fig. 4). The CD
spectrum of (2)-cis-alcohol 3 showed two negative bands
(M) in the 210–230 nm and 230–280 nm region, which is in
excellent agreement with the (5S,6R)-configuration. Our
results correlate well with CD studies of the structurally
related (1)-(R)-5-methyl-5,6-dihydro-1,10-phenathroline.62
The CD spectrum of (2)-cis-acetate 5 also exhibited a neg-
ative band at 210–230 nm indicating M-helicity of the bipyr-
TABLE 1. Summary of stereochemical assignmenta
Compound
(1)-trans-2 (2)-trans-4 (2)-cis-3 (2)-cis-5
CD Band (230–280 nm)
CD Band (210–230 nm)
J(5H,6H)/Hz in CD3OD
M
P
8.1
M
M
6.4
M
M
3.5
N/A
M
3.6
Absolute configuration/ (5S,6S)
(5R,6R) (5S,6R) (5R,6S)
conformation diequatorial diaxial
aJ(5H,6H) ꢁ 7 Hz for an equal population of the diaxal and diequatorial con-
formations; J(5H,6H) < 7 for a preference for the diaxial conformation;
J(5H,6H) > 7 for dominant diequatorial conformation.58,59
Fig. 2. Helicity of (R,R)-trans-5,6-dihydro-6-phenoxy-1,10-phenanthrolin-5-
yl acetate.
Chirality DOI 10.1002/chir

DISUBSTITUTED cis-5,6-DIHYDRO-1,10-PHENANTHROLINES
249
Fig. 3. CD spectra of (1)-trans-alcohol 2 (blue) and (2)-trans-acetate 4 (red). Two stereoviews of the solid-state structure of (6)-trans-acetate 4 showing
50% probability ellipsoids. The chloroform molecule has been omitted for clarity.
1
phenyl ring it appears to be less relevant for the assignment.
Furthermore, the DdSR(19F) values calculated for the cis- and
trans-phenoxy MTPA ester resonances are both positive.
Based on H- and 19F-NMR analyses the stereogenic center
of each alcohol, (2)-cis-3 and (1)-trans-2, has the S-configu-
ration.
Fig. 4. CD spectra of (2)-cis-alcohol 3 (blue) and (2)-cis-acetate 5 (red). Two stereoviews of the solid-state structure of (6)-cis-alcohol 3 showing 50% probabil-
ity ellipsoids.
Chirality DOI 10.1002/chir

250
KOHLER ET AL.
17. Iranpoor N, Firouzabadi H, Khalili D, Motevalli S. Easily prepared azo-
CONCLUSION
pyridines as potent and recyclable reagents for facile esterification reac-
tions. An efficient modified Mitsunobu reaction. J Org Chem 2008;
73:4882–4887.
We have developed an effective method for the stereose-
lective ring opening of 1,10-phenanthrolin-5,6-epoxide with
triphenyl borate giving rise to the first cis and trans isomers
of 5,6-dihydro-6-phenoxy-1,10-phenanthrolin-5-ol. The stereo-
selectivity was influenced by the choice of solvent and tem-
perature. Reactions at higher temperature in DMF favored
the cis product (14:1 dr for cis-3), whereas those at lower
temperatures in dichloromethane, chloroform, or acetonitrile
afforded predominantly the trans derivative (>99:1 dr for
trans-2). We identified lipase PSCI from Burkholderia cepacia
as an effective catalyst for the transesterification of racemic
cis- and trans-phenoxy alcohol stereoisomers (97% ee, E >
200). This is the first report for the enzymatic resolution of a
cis-5,6-dihydro-1,10-phenanthroline derivative. The absolute
configuration of all products was corroborated by both CD
and NMR studies. Our results indicate a preference of lipase
PSCI to acetylate the (R)-hydroxyl group. We also report the
first X-ray crystal structures of cis- and trans-5,6-disubsti-
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