Diarylketone ketoreductase screen and synthesis demonstration to access mglu2 receptor potentiators

Article abstract of DOI:10.1021/op2002479

This communication describes proof of concept for an enantioselective enzyme-based synthesis of diarylmethanol (S)-1 to access mGlu2 receptor potentiators. A ketoreductase (KRED) screen was applied to benzophenone 8 to afford chiral diarylmethanol (S)-9,

Full text of DOI:10.1021/op2002479

COMMUNICATION
pubs.acs.org/OPRD
Diarylketone Ketoreductase Screen and Synthesis Demonstration to
Access mGlu2 Receptor Potentiators
Nicholas A. Magnus,* D. Scott Coffey, Amy C. DeBaillie, Chauncey D. Jones, Iwona A. Kaluzna,‡
Spiros Kambourakis,§ Yangwei J. Pu, Lin Wang, and James P. Wepsiec
Eli Lilly and Company, Chemical Product Research and Development Division, Indianapolis, Indiana 46285, United States
S Supporting Information
b
(KREDs) to prepare enantiomerically enriched diarylmethanols
ABSTRACT: This communication describes proof of con-
cept for an enantioselective enzyme-based synthesis of
diarylmethanol (S)-1 to access mGlu2 receptor potentia-
tors. A ketoreductase (KRED) screen was applied to benzo-
phenone 8 to afford chiral diarylmethanol (S)-9, which is a
useful intermediate for the preparation of chiral diaryl-
methanol (S)-1. In addition, a more practical synthesis of
benzophenone 8 was demonstrated utilizing FriedelꢀCrafts
acylation and radical bromination chemistry.
via reduction of benzophenones under ambient conditions in
aqueous media indicated that such an approach would be more
attractive.4
’ RESULTS AND DISCUSSION
The goal of this research was to achieve proof of concept for an
enantioselective enzyme-based synthesis of diarylmethanol (S)-1
with potential for scale-up. To that end, benzophenone 8 was
identified as a suitable substrate for screening in KRED reduc-
tions to give chiral diarylmethanol (S)-9 (Scheme 2), which
could be further converted to (S)-1 via selective activation of the
primary alcohol. For the KRED screening study, benzophenone
8 was synthesized using a standard ketone synthesis, and a
reference sample of diarylmethanol (S)-9 was prepared by
deprotecting 7 (see Supporting Information). The ketone 8
was reacted with KREDs from an enzyme kit supplied by Codexis
(Table 1). Table 1 summarizes selected results from a screen of
60 KREDs for the conversion of 8 to 9. Only those reductions
giving the highest levels of enantioselectivity are reported.
From the KRED screen for the reduction of ketone 8, two
enzymes were identified as highly S-selective, producing a ratio of
99:1 for S- to R-alcohols. These enzymes are KRED 111 and
KRED 115. Both enzymes catalyzed reduction at moderate to
good rates, with KRED 111 being the best at 0.62 U/mg, a rate
that should be sufficient for scale-up.5 In addition, eight KREDs
were identified that were highly R-selective.
’ INTRODUCTION
The excitatory amino acid L-glutamate mediates most of the
excitatory neurotransmission within the central nervous system.
Glutamate receptors are classified into two main types, iono-
tropic (iGlu) which are glutamate-mediated ion channels, and
metabotropic (mGlu) which are a class of G-protein-coupled
receptors.1 The mGlu receptors have been divided into three
main groups (IꢀIII) with the group II mGlu receptors (mGlu2
and mGlu3) being largely presynaptic and inhibitors of neuro-
transmission.2 To access mGlu2 receptor potentiators to fund
Lilly’s research directed towards potential therapies for the
treatment of migraine headaches, efficient syntheses were needed
to prepare the ether-linked diarylmethanol (S)-1.
Synthesis of Enzymatic Substrate 8. Due to the utility of
benzophenone 8 for the preparation of (S)-1 and the positive
screening results for the KRED-mediated enantioselective re-
duction of 8, a synthesis of 8 was developed beginning with
toluene (Scheme 3). 3-Cyanobenzoyl chloride 10 in toluene was
treated with AlCl3 to induce FriedelꢀCrafts acylation at the para
position of toluene to afford benzophenone 11 in 80% yield.6
The benzylic methyl group of 11 was subjected to radical
bromination with AIBN and 1,3-dibromo-5,5-dimethylhydan-
toin in CH3CN to give a mixture of mono- (12) and bis-bro-
mination (13).7 The bromination reaction mixture was treated
with diisopropylethylamine and diethyl phosphite to selectively
reduce 13 to 12 in 80% overall yield.8 The bromine atom of 12
was replaced with actetate in a mixture of NaOAc and DMF to
give 14 in 98% yield. Acetate 14 was subjected to methanolysis in
a mixture of MeOH, water, and K2CO3 to afford 8 in 91% yield.9
The published syntheses of diarymethanols related to (S)-1
initially utilized chiral chromatography which was improved
upon through the development of an enantioselective aryl-
transfer process.3 This process involved using cryogenic condi-
tions and pyrophoric reagents to convert arylbromide 2 into
aryllithium 3, which is converted to an arylboroxine 4 and then to
an arylalkyl zinc species 5 to make the carbonꢀcarbon bond of
diarylmethanol 7 in the presence of a chiral ligand 6 (Scheme 1).
The number of steps, conditions, and reagents required for the
aryl-transfer process led us to investigate biocatalytic methods as
an alternative. In particular, reports on the use of ketoreductases
Received: July 19, 2011
Published: October 08, 2011
r
2011 American Chemical Society
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Scheme 1. Aryl-transfer process
Scheme 2. Enantioselective KRED reduction of benzophe-
none 8
generate the intermediate bromide (the bromide was observed to
react more productively than the mesylate in ether couplings)
(Scheme 4). The bromide was reacted with the potassium
phenolate of resorcinol 17 to give (()-1 in 75% yield.10
’ CONCLUSIONS
The KRED screen for the enantioselective reduction of ben-
zophenone 8 demonstrated that chiral diol (S)-9 could be
generated in 98% ee from the prochiral ketone 8, and the rate
of conversion indicated utility for development to larger scale.
Due to the potential of the enzyme chemistry, a scalable synthesis
of benzophenone 8 was devised with four steps and 57% overall
yield employing FriedelꢀCrafts acylation of toluene and radical
bromination as key transformations. In addition, (S)-9 was
shown to be useful for the preparation of diarylmethanol (S)-1
via activation and ether coupling of (()-9 to afford diarylmetha-
nol (()-1 in 75% yield. Last, the goal of demonstrating proof of
concept for an enantioselective enzyme-based synthesis of
diarymethanol (S)-1 with potential for scale-up was achieved.
Table 1. Results of screening KREDs for enantioselective
reduction of ketone 8a
KREDb
U/mgc
yieldd (%)
Sd (%)
Rd (%)
101
108
111
112
113
114
115
116
117
118
119
120
127
128
0.167
0.012
0.62
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
97
<2
99
96
95
97
99
<2
<2
<2
<2
<3
<2
<2
3
>98
1
0.072
0.018
0.66
4
5
3
0.416
0.014
0.012
0.096
0.274
0.007
0.07
1
’ EXPERIMENTAL SECTION
>98
>98
>98
>98
>97
>98
>98
General. 1H and 13C NMR spectra were obtained on a Varian
spectrometer at 400 and 101 MHz respectively. HPLC condi-
tions: Instrument: Agilent 1100 series. Column: Zorbax SB-C8.
Flow: 1.5 mL/min. A = 0.1% H3PO4, B = CH3CN. Gradient:
95% A/5% B to 50% A over 10 min; change to 5% A over 5 min.
Hold at 5% A for 5 min. Return to 95% A using a 3 min post time.
Column temperature: 40 °C. Wavelength: 220 nm. HPLC
method for chiral analysis of compound 9: Column: Chiralpak
AD 250 mm ꢁ4.6 mm, 10 μm particle size. Flow rate: 1 mL/min.
Column temperature: ambient. Wavelength: 280 nm. Mobile
phase: heptane/2-propanol/TFA (60:40:0.01 v/v/v.
General KRED Screening Conditions for the Conversion
of 3-(4-(Hydroxymethyl)benzoyl)benzonitrile (8) to (S) or (R)-
3-(Hydroxy(4-(hydroxymethyl)phenyl)methyl)benzonitrile
(9). Screening was carried out by incubating the diaryl ketone 8
(5 mg) in a reaction mixture under ambient conditions with
individual KRED enzymes overnight (12ꢀ16 h). Reaction
mixtures contained 10 mM ketone, 2 mg/mL KRED, 200 mM
potassium phosphate buffer pH 6.9, 100 mM glucose, 0.5 mg/mL
0.72
a See Experimental Section for screening conditions. b KRED number
corresponds to the Codexis catalog number. c Unit definition: 1U =
1 μmol substrate conversion/mg of enzyme x minꢀ1. These activities
were measured in cuvette assays where the rate of NADPH consumption
(as measured by the rate of decrease at 340 nm) was measured after
incubation of the enzyme with the substrate in the presence of NADPH.
d Yield and percent for S or R by normal phase chiral HPLC.
To demonstrate the viability of diarylmethanol (S)-9 for the
preparation of (S)-1, diol (()-9 (prepared by standard condi-
tions see Supporting Information) was exposed to Ms2O in the
presence of TEA in 2-butanone to give selective mesylation of
the primary alcohol which was reacted with TBAB and KBr to
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Scheme 3. FriedelꢀCrafts/radical bromination-based synthesis of benzophenone 8
Scheme 4. Selective activation and ether synthesis to prepare (()-1
glucose dehydrogenase (for recycling of the cofactor), and
1.5 mM NADPH cofactor. The diaryl ketone substrate was first
dissolved in DMSO at 200 mM concentration and was subse-
quently added to the reaction mixture giving 5% (v/v) DMSO
concentration and 10 mM final ketone concentration. The re-
actions were extracted with EtOAc (10 mL) and evaporated to
afford the products for analysis. Note that the substrate did not
completely dissolve and a heterogeneous mixture formed upon
substrate addition, but this did not impede the screening. All
reactions gave complete product formation (100% conversion to
alcohol) after overnight reaction.
3-(4-Methylbenzoyl)benzonitrile (11). Under a nitrogen at-
mosphere, 3-cyanobenzoyl chloride 10 (5.00 g, 30.20 mmol) was
dissolved in toluene (75 mL) at 22 °C to give a colorless solution.
Aluminum trichloride (6.10 g, 45.30 mmol) was added to the
reaction mixture. After 0.5 h, water (125 mL) was added over
0.5 h to the dark, greenish-yellow reaction mixture causing the
color to change to amber and the temperature to rise to 31 °C.
EtOAc (100 mL) was added to the mixture, giving clean phase
separation. The organic phase was separated and dried with
Na2SO4. Distillation to remove EtOAc at 40 °C in vacuo caused
the product to crystallize. The resulting slurry was cooled to 0 °C,
and the solids were filtered and washed with cold toluene
(10 mL). The solids were dried in a vacuum oven at 46 °C to
afford 4.54 g of crystalline product 11. The mother liquor from
the crystallization was concentrated to leave a solid which was
dissolved in hot toluene (10 mL) to afford a second crop of
crystals on cooling to 0 °C. The second crop of crystals was
filtered, washed with cold toluene, and dried in a vacuum oven at
46 °C to afford a further 0.85 g of crystalline product 11. A total
of 5.39 g of product 11 was isolated as a colorless crystalline solid
in 80% yield. Mp 139ꢀ140 °C. IR (neat) 3066, 2232, 1644, 1600,
1421 cmꢀ1. 1H NMR (400 MHz, DMSO-d6) 8.12ꢀ8.08 (m, 2
H), 7.98 (ddd, J = 7.9, 1.4, 1.5 Hz, 1 H), 7.74 (dd, J = 7.8, 7.8 Hz, 1
H), 7.66 (d, J = 8.2 Hz, 2 H), 7.38 (d, J = 8.2 Hz, 2 H), 2.40 (s, 3
H). 13C NMR (101 MHz, DMSO-d6) 194.1, 144.4, 138.9, 136.0,
134.2, 133.8, 133.2, 130.5, 130.3, 129.8, 118.6, 112.4, 21.7. HRMS
(ESI) calcd for C15H11NO (M+) 222.0913, found 222.0917.
3-(4-(Bromomethyl)benzoyl)benzonitrile (12). Under a ni-
trogen atmosphere at 20 °C, the ketone 11 (0.50 g, 2.26 mmol)
was combined with 1,3-dibromo-5,5-dimethylhydantoin (0.58 g,
1.98 mmol), 2,20-azo-bis-isobutyronitrile (0.02 g, 0.11 mmol),
followed by CH3CN (5 mL). The slurry was heated to 80 °C.
After 2.0 h, an aliquot of reaction mixture was dissolved in
CH3CN for HPLC analysis which indicated a mixture of mono-
and bis-bromination products, with <1% of the starting ketone
remaining. The reaction mixture was cooled to 0 °C, and
diisopropylethylamine (0.30 mL, 1.69 mmol) and diethyl phos-
phite (0.22 mL, 1.69 mmol) were added to the reaction mixture,
followed by removal of the cooling bath. After 4.0 h at 21 °C, an
aliquot of reaction mixture was dissolved in CH3CN for HPLC
analysis which indicated mainly the desired benzyl bromide 12,
with <1% of the bis-bromination product remaining. Water (3 mL)
was added to the reaction mixture. A few seeds of 12 were added
to the reaction mixture causing rapid nucleation of white solids.
To the slurry was added a further amount of water (2 mL) over 0.5 h
to further promote the crystallization. The solids were filtered and
washed with a 1:1 mixture of CH3CN and water (2 mL). After
drying the resulting solids in a vacuum oven at 40 °C, 0.55 g of off-
white crystals of 12 were isolated in 80% yield. Mp 94ꢀ96 °C. IR
(neat) 3073, 3036, 2232, 1652, 1600, 1414 cmꢀ1. 1H NMR (400
MHz, DMSO-d6) 8.13ꢀ8.11 (m, 2 H), 8.01 (ddd, J = 8.0, 1.5, 1.5
Hz, 1 H), 7.77ꢀ7.73 (m, 3 H), 7.62 (d, J = 8.2 Hz, 2 H), 4.78 (s, 2
H). 13C NMR (101 MHz, DMSO-d6) 193.9, 143.8, 138.4, 136.2,
136.0, 134.3, 133.4, 130.8, 130.4, 130.0, 118.5, 112.3, 33.6. HRMS
(ESI) calcd for C15H10BrNO (M+) 300.0019, found 300.0024.
4-(3-Cyanobenzoyl)benzyl Acetate (14). Under a nitrogen
atmosphere at 21 °C, benzyl bromide 12 (1.00 g, 3.33 mmol) was
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dissolved in DMF (5 mL) followed by the addition of potassium
acetate (0.65 g, 6.66 mmol). After 15.0 h, an aliquot of reaction
mixture was diluted with CH3CN for HPLC which indicated
complete conversion of 12 to a slightly more polar product.
EtOAc (10 mL) and water (5 mL) were added to the reaction to
give two phases. The organic layer was separated and washed
with water (2 ꢁ 5 mL) to remove DMF. The organic phase was
dried with Na2SO4 and the solvent removed in vacuo to leave a
yellow oil that crystallized under vacuum (0.92 mg) to afford a
98% yield of 14. A sample of 14 (300 mg) was recrystallized from
hot IPA (5 mL), and the following analytical data were collected:
Mp 78ꢀ80 °C. IR (neat) 3073, 2940, 2232, 1727, 1652, 1451,
1421 cmꢀ1. 1H NMR (400 MHz, DMSO-d6) 8.13ꢀ8.11 (m, 2
H), 8.01 (ddd, J = 7.8, 1.5, 1.4 Hz, 1 H), 7.77ꢀ7.73 (m, 3 H), 7.54
(d, J = 8.0 Hz, 2 H), 5.18 (s, 2 H), 2.09 (s, 3 H). 13C NMR (101
MHz, DMSO-d6) 194.1, 170.6, 142.2, 138.5, 136.2, 135.9, 134.3,
133.4, 130.5, 130.3, 128.2, 118.5, 112.3, 65.2, 21.1. HRMS (ESI)
calcd for C17H13NO3 (M+) 280.0968, found 280.0972.
3-(4-(Hydroxymethyl)benzoyl)benzonitrile (8) from Acetate
(14). Acetate 14 (0.25 g, 0.90 mmol) was suspended in MeOH
(5 mL), heated to 45 °C to give a homogeneous solution, and
cooled to 21 °C. At 21 °C, K2CO3 (0.27 g, 1.97 mmol) in water
(0.5 mL) was added to the reaction mixture, giving an exotherm
to 24 °C, a light-brown color, and precipitation of solids. After
0.5 h, a sample of the reaction mixture was dissolved in CH3CN
for HPLC that indicated complete conversion to the alcohol 8.
Water (0.5 mL) and saturated aqueous citric acid (2 mL) were
added to the reaction mixture, causing further solids to precipi-
tate. The solids were filtered, washed with water, and dried in a
vacuum oven at 40 °C to afford 8 (0.19 g) in 91% yield. Mp
134ꢀ135 °C. IR (neat) 3426, 3068, 2235, 1644, 1599, 1577,
1421 cmꢀ1. 1H NMR (400 MHz, DMSO-d6) 8.12ꢀ8.09 (m, 2
H), 7.99 (ddd, J = 7.8, 1.4, 1.2 Hz, 1 H), 7.77ꢀ7.22 (m, 3 H), 7.50
(d, J = 8.2 Hz, 2 H), 5.40 (t, J = 5.7 Hz, 1 H), 4.6 (d, J = 5.7 Hz, 2
H). 13C NMR (101 MHz, DMSO-d6) 194.3, 149.0, 138.9, 136.1,
134.8, 134.2, 133.3, 130.4, 130.3, 126.8, 118.6, 112.3, 62.8.
HRMS (ESI) calcd for formula C15H12NO2 (M+) 238.0863,
found 238.0860.
(()-3-((4-((4-Acetyl-3-hydroxy-2-propylphenoxy)methyl)phe-
nyl)(hydroxy)methyl)benzonitrile (1) from (()-9. Mesylate
Formation. Under a nitrogen atmosphere at 20 °C, diol (()-9
(1.00 g, 4.18 mmol) was dissolved in 2-butanone (10 mL) and
TEA (0.86 g, 8.50 mmol). The resulting mixture was cooled to
2ꢀ3 °C, and a solution of methanesulfonic anhydride (1.10 g,
6.31 mmol) in 2-butanone (5 mL) was added to the reaction
mixture over 0.25 h. After 1.0 h at 2ꢀ3 °C, 2% citric acid in water
(10 mL) and 2-butanone (10 mL) was added to the reaction
mixture to give two phases. The organic phase was separated and
washed with saturated aqueous NaHCO3 (10 mL) and 5% NaCl
in water (10 mL). The organic phase was transferred to an
addition funnel with the aid of 2-butanone (5 mL), which was
attached to a reactor.
Bromide Formation. Under a nitrogen atmosphere at 20 °C,
the reactor was charged with KBr (0.60 g, 5.04 mmol) and TBAB
(0.30 g, 0.93 mmol), and the mesylate/2-butanone solution was
added and rinsed in with 2-butanone (5 mL). The resulting
mixture was stirred for 21.0 h to complete the bromide formation.
Ether Formation. Under a nitrogen atmosphere at 20 °C,
resorcinol 17 (0.85 g, 4.38 mmol) and K2CO3 (0.70 g, 5.06
mmol) were added to the bromide/2-butanone solution, and the
resulting slurry was heated to 55 °C. After 5.0 h at 55 °C, the
mixture was cooled to 20 °C, and a solution of 5% citric acid in
water (15 mL) was added to the reaction (pH of the aqueous
layer was 5). The reaction mixture was transferred to an addition
funnel and rinsed in with 2-butanone (10 mL). The organic
phase was separated, washed with 5% NaCl in water (15 mL),
and concentrated on a roto-vap to give a yellow oil (2.25 g). The
oil was dissolved in MeOH (10 mL) and seeded with (()-1 at
20 °C. After 0.5 h a thin slurry was produced which was stirred for
16.0 h to produce a thick slurry. The slurry was cooled to 0 °C,
stirred for 1.0 h, filtered, and washed with cold MeOH (2 mL).
The resulting off-white solids were dried under vacuum to afford
(()-1 (1.31 g, 75%). Mp 138ꢀ139 °C. IR (neat) 3366, 3314,
2957, 2923, 2224, 1625, 1495, 1417, 1268 cmꢀ1. 1H NMR (400
MHz, DMSO-d6) 12.82 (s, 1H), 7.82 (bs, 1H), 7.76 (d, J = 9.0
Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.50 (t,
J = 7.8 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H),
6.68 (d, J = 9.1 Hz, 1H), 6.15 (d, J = 4.0 Hz, 1H), 5.78 (d, J = 4.0
Hz, 1H), 5.19 (s, 2H), 2.56 (t, J = 7.4 Hz, 2H), 2.54 (s, 3H), 1.46
(sextet, J = 7.4 Hz, 2H), 0.84 (t, J = 7.4 Hz, 3H). 13C NMR (101
MHz, DMSO-d6) 14.5, 21.9, 24.4, 26.8, 69.8, 73.5, 104.4, 111.6,
114.2, 117.3, 119.3, 126.9, 127.6, 129.9, 130.0, 131.1, 131.5,
131.6, 136.1, 144.9, 147.6, 161.5, 162.5, 204.4. HRMS (ESI)
calcd for formula C26H25NO4 (M+) 416.1864, found 416.1856.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
spectral data for compounds 8, (S)-9, and (()-9. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
Telephone: 317-651-1470. Fax: 317-276-4507. E-mail: magnus_
nicholas_a@lilly.com.
Present Addresses
‡DSM Innovative Synthesis B.V., Poststraat 1, 6135 KR Sittard,
the Netherlands.
§Synthetic Genomics, Inc., 11149 N. Torrey Pines Rd., La Jolla,
CA 92037, U.S.A.
’ ACKNOWLEDGMENT
We are grateful to Dr. Rui Lin Gu for instruction on conduct-
ing enzyme reactions. Mr. Eric D. Crockett for performing all of
the high-resolution mass spectrometer experiments, and Dr. Lars
Magnusson, Mr. Keith Galyan, and Mr. John L. Bowers for
analytical and chromatography support.
’ REFERENCES
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057870 A1 20060601, 2006 (b) Magnus, N. A.; Anzeveno, P. B.; Coffey,
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(9) The current synthesis is not desirable for scale-up as described in
the Experimental Section with operations such as concentration to
dryness and the use of drying agents. However, development of
azeotropic solvent exchanges to afford drying and further development
of the crystallizations would enable a fully scalable synthesis.
(10) While we demonstrated that (()-9 can be converted to (()-1,
and therefore (S)-9 can be converted into (S)-1, the project was no
longer funded to develop the single enantiomer process.
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