Enantioselective Synthesis of a Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 5 (mGluR5) Receptor via Dynamic Kinetic Resolution of α-Amino Ketones

Article abstract of DOI:10.1002/adsc.201600329

The concise synthesis of a pharmaceutical candidate is described. The chiral core of the molecule is assembled using an aza-benzoin condensation and a dynamic kinetic resolution (DKR) as the key reactions. This enables superb control of the regio-, diastereo- and enantioselectivity of the synthesis. Both biocatalysts and transition metal catalysts are remarkably effective in the key asymmetric reduction step. Similar approaches could be considered in the synthesis of other 1,2-amino alcohols where traditional approaches based on functionalization of alkenes, epoxides or aziridines may suffer from selectivity issues. (Figure presented.) .

Full text of DOI:10.1002/adsc.201600329

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DOI: 10.1002/adsc.201600329
Enantioselective Synthesis of a Positive Allosteric Modulator of
the Metabotropic Glutamate Receptor 5 (mGluR5) Receptor via
Dynamic Kinetic Resolution of a-Amino Ketones
Francisco Gonzꢀlez-Bobes,a,* Ronald Hanson,a Neil Strotman,a Zhiwei Guo,a
and Animesh Goswamia
a
Chemical & Synthetic Development, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, NJ 08903, USA
Fax : (+1)-732-227-3932; phone: (+1)-732-227-7926; e-mail: francisco.gonzalezbobes@bms.com
Received: March 25, 2016; Revised: April 25, 2016; Published online: && &&, 0000
Dedicated to Professor Josꢁ Barluenga.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600329.
Abstract: The concise synthesis of a pharmaceutical
candidate is described. The chiral core of the mole-
cule is assembled using an aza-benzoin condensa-
tion and a dynamic kinetic resolution (DKR) as the
key reactions. This enables superb control of the
regio-, diastereo- and enantioselectivity of the syn-
thesis. Both biocatalysts and transition metal cata-
lysts are remarkably effective in the key asymmetric
reduction step. Similar approaches could be consid-
ered in the synthesis of other 1,2-amino alcohols
where traditional approaches based on functionali-
zation of alkenes, epoxides or aziridines may suffer
from selectivity issues.
as a potential candidate for pre-clinical development
(Figure 1).[4]
Figure 1. mGluR5 modulator 1.
Keywords: asymmetric synthesis; biotransforma-
tions; homogenous catalysis; regioselectivity; umpo-
lung
The initial route to 1 relied on the osmium-cata-
lyzed aminohydroxylation of trans alkene 3 (Figure 2)
to set both the absolute and relative configuration of
the chiral centers on the target molecule.[5] This reac-
tion occurred with modest regioselectivity (3:1) and
~90% ee, negatively impacting the overall yield and
throughput of the synthesis. Herein, we report a ste-
reoselective synthesis of 1 avoiding the use of the
Glutamate is the major excitatory neurotransmitter in toxic osmium catalyst and precluding the formation of
the mammalian brain, playing an important role in undesired regioisomers (Scheme 1). These results may
a wide variety of physiological process.[1] Glutamater- prove useful towards the asymmetric synthesis of the
gic neurotransmission is predominantly mediated popular 1,2-amino alcohol motif where approaches
through activation of cell surface receptors including based on the functionalization of alkenes, epoxides or
ligand-gated ion channels (ionotropic receptors) and aziridines often are challenged with selectivity issues.
metabotropic glutamate G protein coupled receptors
Two major strategic challenges to accomplish a se-
(mGluRs).[2] Within this family, the mGluR5 receptor lective synthesis of 1 were recognized. The first was
is expressed broadly throughout the central nervous to identify a highly enantioselective method to set the
system (CNS) and has attracted interest for a number vicinal stereocenters with the desired relative stereo-
of therapeutic indications with implications in differ- chemistry. The second was to devise an approach that
ent behavioral and cognitive processes.[3] During the would not form regioisomers, thus preventing unde-
course of a program directed to the discovery of sired yield losses. To address the enantioselectivity
mGluR5 modulators, oxazolidinone 1 was identified challenge, we were drawn to explore the asymmetric
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Figure 2. Synthetic approaches for the preparation of 1.
action optimization, 6 was prepared in two steps using
pyridine 7 as bench-stable surrogate for the reactive
intermediate Boc- and Cbz-imines and the readily
available aldehyde 8 under thioazolium-based cataly-
sis (Scheme 1).
With the a-amino ketone derivatives in hand, the
asymmetric reduction of 6 was then explored. Table 1
summarizes the results obtained when exploring
a range of commercially available enzymatic catalysts
such as ketoreductases and selected yeast strains.[10]
We hypothesized that either the syn or the anti amino
alcohol, resulting from the respective syn or anti hy-
dride additions,[11] could be productively cyclized to
make the oxazolidinone with retention[12] or inver-
Scheme 1. Synthesis of protected a-amino ketones via aza-
benzoin condensation. Conditions: (a) (1 equiv.),
(1.05 equiv.), 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-
ium chloride (5–7 mol%), NEt3 (5 equiv.), CH2Cl2, 08C,
78% yield of 6a, 75% yield of 6b.
7
8
reduction of an adequately protected a-amino sion[13] at the C-2 stereocenter.
ketone.[6] This approach would need to both over-
A number of catalysts, including isolated ketore-
come the potential formation of syn and anti iso- ductases and yeast strains, proved highly selective to
mers,[7] and be amenable to a dynamic kinetic resolu- prepare either enantiomer of the syn 2a’ and anti iso-
tion (DKR) that theoretically could generate a single mers 2a (Table 1, entries 1–4 and 5–9, respectively).
enantiomer of the desired amino alcohol from race- Importantly, the Cbz-protected amino ketone 6b
mic amino or amido ketone.[8] To test the feasibility of could also be transformed in excellent stereoselectivi-
this idea, an efficient synthesis of protected a-amino ties (entry 10).[15] Collectively, these results represent
ketone 6 was required. The convergent disconnection a breakthrough in the area. Attaining of high enantio-
À
of C-1 C-2 was particularly attractive as it would pre- selectivities with concomitant modulation of syn/anti
vent the formation of any undesired regioisomer. To selectivities in protected substrates using other reduc-
this end, the aza-benzoin condensation was chosen tion methods has remained an unsolved synthetic
due to its operational simplicity, avoidance of oxida- challenge. In general, mixtures of syn and anti adducts
tion state adjustments, and the easy access to all the are formed and stereochemical outcomes are difficult
required precursors and catalysts.[9] After minimal re- to predict.[16]
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Table 1. Enzymatic reduction of protected amino ketones.
Table 2. Ru-catalyzed DKR of protected amino ketone 6b.[a]
En- Sub- Catalyst
try strate (wt%)[a]
dr
ee
(2:2’)[b] [%][b]
1
6a
KRED-NADH-107
(100)
9:91
97 (1R,2R)
2
3
4
5
6
7
8
9
6a
6a
6a
6a
6a
6a
6a
6a
KRED-148 (500)
Pichia anomala
Rhodococcus sp.
ES-KRED-112 (100)
KRED-145 (500)
CRED-A131 (100)
Pichia methanolica
Actinosynnema pretio-
sum
11:89
29:71
4:96
96:4
98:2
98:2
97 (1R,2R)
>99 (1R,2R)
97 (1S,2S)
>99 (1R,2S)
>99 (1R,2S)
>99 (1S,2R)
Entry
Solvent
Catalyst
dr (2b:2b’)[b]
ee [%][b]
1
2
3
4
5
6
7
THF
A
A
A
B
B
B
C
120:1
>200:1
164:1
>200:1
>200:1
>200:1
>200:1
À94
À95
À94
À98
À91
À92
À97
DCM
MeCN
THF
DCM
MeCN
MeCN
>200:1 >99 (1R,2S)
>200:1 >99 (1S,2R)
10 6b
KRED-145 (40)
>200:1 >99
(1R,2S)[c}
[a]
Screening conducted with 3 mol% (R,R)-catalyst,
HCO2H (3 equiv.) and DABCO (5 equiv.) at room tem-
perature.
Determined by HPLC. 100% conversion observed in all
cases in <48 h.
[a]
Screening conditions for commercial ketoreductase en-
zymes: 1 mg ketone dissolved in 0.02 mL DMSO, 1 mM
NADP or NAD, 5 mg glucose, 0.05 mg glucose dehydro-
genase,1 mM dithiothreitol and 0.98 mL 0.1M KPi pH 7,
20–87 h, 308C. For microbial screening 2 mg ketone in
0.02 mL DMSO was added to 1-day-old 2 mL cultures
and incubated for 2 days. Conversion and enzyme load-
ing for each case are shown in the Supporting Informa-
tion.
[b]
to the ancillary h6 arene ligand, developed by Ikariya
(B) and Wills (C), also provided excellent selectivity
(entries 4–7).[21]
We prepared 2b with high diastereo- and enantio-
meric purity using the (S,S)-isomer of catalyst B. As
anticipated, the anti isomer could be easily converted
to the desired oxazolidinone intermediate 9 via cycli-
[b]
[c]
Diastereomeric ratios and enantiomeric excess were de-
termined by HPLC.[14]
Experiment run on a 1-g scale.
Despite the high selectivities observed, the relative- zation with inversion of configuration at the C-2
ly low catalyst turnovers of the ketoreductases[14,17] center[13] thus intercepting a known intermediate in
prompted us to consider the use of a stereoselective the previous synthesis. The synthesis of 1 was com-
hydrogenation via DKR. We evaluated a series of or- pleted via a palladium-catalyzed Sonogashira[22] cou-
ganometallic catalysts under typical transfer hydroge- pling reaction (Scheme 2).[5] Overall, the target com-
nation conditions using formic acid as the hydrogen pound was obtained in 5 steps and 35% overall yield.
donor and 1,4-diazabicyclo[2.2.2]octane (DABCO) as
In conclusion, we have reported the concise enan-
tioselective synthesis of a pharmaceutical candidate
the base (Table 2).[18]
Derivatives of Noyoriꢃs ruthenium transfer hydro- via the asymmetric reduction of an a-amino ketone
genation catalysts were employed,[19] since these were derivative. The use of an aza-benzoin condensation to
expected to provide high anti-selectivity in the rapidly build the key carbon-carbon bond enabled an
DKR.[20] A survey of several commercial variants of efficient convergent synthesis that precluded the for-
this catalyst revealed three that offered high enantio- mation of undesired regioisomers.
and diastereoselectivities in different solvents (en-
Both transition metal and biocatalysis-based routes
tries 1–7, Table 2). In addition to obtaining high selec- provided exceptional diastereo- and enantiocontrol in
tivity with a pentafluorophenyl variant of Noyoriꢃs the preparation of the key amino alcohol intermedi-
RuCl(p-cymene)Ts-DPEN catalyst (catalyst A, en- ate and circumvented the limitations of the original
tries 1–3), variants with the diamine ligand tethered aminohydroxylation-based approach.
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128.5, 127.8, 120.0, 72.0, 66.4, 21.3; HR-MS: m/z=475.0311,
calculated for C21H20O4N2Br: 475.0322.
Preparation of Benzyl [1-(5-Bromopyridin-3-yl)-2-
(2,5-difluorophenyl)-2-oxoethyl]carbamate (6b)
Dichloromethane (225 mL) was added to a vessel containing
7b (15 g, 1 equiv.) and 3-benzyl-5-(2-hydroxyethyl)-4-methyl-
thiazol-3-ium chloride (0.6 g, 0.07 equiv.). 2,5-Difluoroben-
zaldehyde (8, 3.61 mL,1.05 equiv.) was then added and the
resulting mixture was cooled in an ice-water bath. Triethyl-
AHCTUNGTREGaNNUN mine (22 mL, 5 equiv.) was then added drop-wise leading
to the formation of a deep yellow solution. The mixture was
held at 08C for 12 h and then warmed up to room tempera-
ture. The reaction was then quenched with aqueous sodium
chloride (200 mL, 10%), the phases were split and the or-
ganic layer was dried over anhydrous sodium sulfate. After
concentration 6b was isolated as a white solid by ISCO
column chromatography (gradient from 5% to 20% ethyl
acetate in n-hexane); yield: 11.4 g (78%); mp (from n-
hexane/ethyl acetate): 155–1608C. 1H NMR (600 MHz,
DMSO-d6): d=8.65 (d, J=2.2 Hz, 1H), 8.57 (d, J=8.3 Hz,
1H), 8.56 (t, J=1.5 Hz, 1H), 8.02 (br s, 1H), 7.65 (m, 1H),
7.52 (m, 1H), 7.39 (dt, J=9.5, 4.1 Hz, 1H), 7.31 (m, 3H),
7.24 (d, J=6.9 Hz, 2H), 6.17 (d, J=8.3 Hz, 1H), 5.06 ( d,
J=12.0 Hz, 1H), 5.03 (d, J=12.0 Hz, 1H); 13C NMR
(151 MHz, DMSO-d6): d=193.2 (d, JC,F =2.8 Hz), 158.0 (d,
Scheme 2. Synthesis of 1 from a-amino ketone derivative
6b. Conditions: (a) 6b, DMSO, H2O, 1M potassium phos-
phate buffer pH 8, glucose, DTT (1 mM), NADP (0.5 mM),
glucose dehydrogenase, and 40 wt% KRED-145, 308C. 80%
yield, >99% ee, >200:1 2b:2b’. (b) Transfer hydrogenation:
1.5 mol% catalyst (S,S)-Ts-DENEB, THF, DABCO
(5 equiv.), HCO2H (3 equiv.), room temperature, 80%,
98.5% ee and >200:1 2b:2b’. (c) Ms2O (3 equiv.), pyridine,
65–708C, 78%. (d) PdCl2(PPh3)2 (5 mol%), CuI (5 mol%),
PPh3 (19 mol%), MeCN, NEt3, 808C, 93%.
J
C,F =179.6 Hz), 156.0 (d, JC,F =190.6 Hz), 155.8, 149.9, 148.2,
138.6, 134.1, 136.7, 128.3, 127.9, 127.5, 125.2 (dd, JC,F =15.1,
6.9 Hz), 119.9, 118.7 (dd, JC,F =25.7, 8.2 Hz), 116.6 (dd, JC,F
Experimental Section
=
General Information
25.7, 1.8 Hz), 65.9, 60.1 (d, JC,F =4.6 Hz); HR-MS: m/z=
461.0304, calculated for C21H16O3N2BrF2: 461.0307.
Experiments were run under a positive nitrogen atmos-
phere. All reagents were used as received without further
purification. Reaction progress and final product purity
were monitored using HPLC. KRED-NADH-107, KRED-
148 and KRED-145 were purchased from Codexis. ES-
KRED-112 was purchased from Enzysource and CRED-
A131 was purchased from Almac. Determinations of ee and
dr were done by reverse phase HPLC. Specific conditions of
analysis are provided in the Supporting Information.
Preparation of Benzyl [(1R,2S)-1-(5-Bromopyridin-3-
yl)-2-(2,5-difluorophenyl)-2-hydroxyethyl]carbamate
(2b)
Biotransformation: Carbamate 6b (1 g, 1 equiv.), 100 mL
DMSO, 350 mL water, 50 mL of 1M KPi pH 8, 5 g of glu-
cose, 77 mg of DTT (1 mM), 191 mg of NADP (0.5 mM),
20 mg of glucose dehydrogenase and 400 mg of KRED-145
were stirred for 41 h at 308C. After extractive work-up with
EtOAc, crude 2b was obtained in quantitative yield. The
product was recrystallized from ethyl acetate/n-hexane mix-
tures to afford 2b as a white solid; yield: 0.8 g (80%).
Transfer hydrogenation: In a 25-mL vessel, 6b (165 mg,
1 equiv.) and DABCO (195 mg, 5 equiv.) were dissolved in
THF (2.5 mL). (S,S)-Ts-DENEB (3.5 mg, 0.015 equiv.) was
then added followed by formic acid (40 mL, 3 equiv.). The
resulting mixture was stirred at room temperature for 24 h.
The solution was then purified by ISCO column chromatog-
raphy (gradient from 10% to 35% EtOAc in n-hexanes)
yielding 2b an off-white solid; yield: 132 mg (82%); mp
(from EtOAc/hexane): 150–1558C. 1H NMR (600 MHz,
DMSO-d6): d=8.57 (d, J=2.2 Hz, 1H), 8.35 (d, J=1.6 Hz,
1H), 8.28 (t, J=2.2 Hz, 1H), 8.01 (d, J=9.4 Hz, 1H), 7.35–
7.25 (m, 3H), 7.21 (dt, J=8.8, 2.2 Hz, 1H), 7.19 (d, J=
7.5 Hz, 2H), 7.15 (dddd, J=8.8, 8.5, 4.5, 3.3 1H), 7.01 (ddd,
J=8.5, 5.6, 3.3 Hz, 1H), 5.91 (d, J=5.5 Hz, 1H), 4.99 (dd,
J=7.4, 5.5 Hz, 1H), 4.97 (dd, J=12.8, 1.6 Hz, 1H), 4.90 (d,
J=12.8 Hz, 1H), 4.87 (dd, J=9.4, 7.4 Hz, 1H); 13C NMR
(151 MHz, DMSO-d6): d=158.0 (d, JC,F =240 Hz), 155.6 (d,
Preparation of Benzyl [(5-Bromopyridin-3-yl)(tosyl)-
methyl]carbamate (7b)
5-Bromonicotinaldehyde (10.00 g, 1.0 equiv.) was dissolved
in acetonitrile (300 mL). Sodium-p-toluenesulfinate (14.37 g,
1.5 equiv.), benzyl carbamate (12.19 g, 1.5 equiv.) and chlor-
otrimethylsilane (13.7 mL, 2.0 equiv.) were sequentially
added and the resulting mixture was stirred at room temper-
ature for 18 h. Water (500 mL) was then added and the re-
sulting slurry was aged for 6 h, then filtered and washed
twice with acetonitrile:water (3:5 v/v, 150 mL) then water
(2ꢄ150 mL). The resulting solid was dried under vacuum at
room temperature and then at 608C. Carbamate 7b was ob-
tained as a white solid; yield: 21.3 g (83%); mp (from aceto-
nitrile:H2O): 1808C (decomposition). 1H NMR (500 MHz,
DMSO-d6): d=9.17 (d, J=10.6 Hz, 1H), 8.82–8.70 (m, 3H),
8.41–8.38 (m, H), 8.1 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.1 Hz,
2H), 7.39–7.30 (m, 3H), 7.20 (d, J=6.2 Hz, 2H), 6.31 (d, J=
10.6 Hz, 1H), 4.92 (d, J=12.5 Hz, 1H), 4.87 (d, J=12.5 Hz,
1H), 2.41 (s, 3H); 13C NMR (126 MHz, DMSO-d6): d=
155.2, 151.1, 149.0, 145.4, 139.4, 136.3, 133.0, 129.8, 129.3,
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J
C,F =240 Hz), 155.4, 149.0, 147.9, 138.0, 137.5, 136.9, 131.3
night. The mixture was filtered through celite and the ethyl
acetate solution was solvent switched into n-heptane. The
resulting solid was filtered and crystallized from acetone
and water to afford 1 as a light brown solid; yield: 0.96 g
(d, JC,F =17.7 Hz), 128.3, 127.8, 127.4, 119.7, 116.6 (dd, JC,F
=
25.0, 8.0 Hz), 115.7 (dd, JC,F =25.0, 8.0 Hz), 114.7 (JC,F =25.0,
5.0 Hz), 68.2, 65.4, 56.7; [a]2D0: +27.7 (c=0.0072 gmLÀ1,
1
MeOH);
HR-MS:
m/z=463.0459,
calculated
for
(93%). H NMR (400 MHz, DMSO-d6) d=8.76 (d, J=2 Hz,
C21H18O3N2BrF2: 463.0463.
1H), 8.58–8.53 (m, 2H), 8.06 (t, J=2 Hz, 1H), 7.68–7.55 (m,
2H), 7.50–7.30 (m, 6H), 5.66 (d, J=6.6 Hz, 1H), 5.03 (d, J=
6.6 Hz, 1H).
The chiral purity was determined with the following
HPLC method: Phenomenex Lux Cellulose-1 (3 mmꢄ4.6ꢄ
250 mm). Mobile phase : 0.1% diethylamine in 20 mM aque-
ous ammonium carbonate (pH 8.8)/MeCN (40v/60v). Iso-
cratic. Wavelength: 281 nm. Injection volume: 10 mL, flow:
1 mLminÀ1. Oven temperature: 408C. Retention times
1 10.30 min, undesired enantiomer 12.73 min.
The chiral purity was determined with the following
HPLC method: Phenomenex Lux u Cellulose (3 mmꢄ4.6ꢄ
150 mm). Mobile phase A: 0.05 TFA in H2O/MeCN (95v/
5v), mobile phase B 0.05% TFA in H2O/MeCN 5v/95v).
Gradient: 0 min, 35% B; 25 min 50% B, 30 min 100% B,
35 min, 100% B. Wavelength: 271 nm. Injection volume:
10 mL, Flow: 1 mLminÀ1. Oven temperature: 408C. Reten-
tion times 2b’ 10.19 min, 2b 11.44 min.
Preparation of (4R,5R)-4-(5-Bromopyridin-3-yl)-5-
(2,5-difluorophenyl)oxazolidin-2-one (9)[5]
Acknowledgements
Carbamate 2b (210 mg, 1 equiv.) was dissolved in pyridine
(3.1 mL). Ms2O (240 mg, 3 equiv.) was then added and the
resulting mixture was heated to 65–708C. After 18 h, the
mixture was diluted with water (10 mL) and EtOAc
(10 mL). The aqueous layer was back-extracted with EtOAc
(10 mL) and the combined organic phases were sequentially
washed with aqueous citric acid (10 mL, 10%), and brine
(10 mL, 15%) and then dried over anhydrous sodium sul-
fate. After filtration and solvent evaporation the product
was purified by ISCO column chromatography (gradient
from 10% to 35% EtOAc in n-hexanes) affording 9 as an
off-white solid; yield: 125 mg (78%). 1H NMR (400 MHz,
DMSO-d6): d=8.72 (d, J=2.3 Hz, 1H), 8.55–8.53 (m, 2H),
8.15 (t, J=2.3 Hz, 1H), 7.43–7.28 (m, 3H), 5.65 (d, J=
5.3 Hz, 1H), 5.01 (d, J=5.3 Hz, 1H).
The chiral purity was determined with the following
HPLC method: Chiralpak AS-3R (3 mmꢄ4.6ꢄ150 mm).
Mobile phase: 0.01M NH4OAc in MeOH:H2O (20v/80v),
mobile phase B: 0.01M NH4OAc in MeOH:H2O:MeCN
(20v/5v/75v). Gradient: 0 min, 0% B; 30 min 100% B,
35 min 100% B. Wavelength: 220 nm. Injection volume:
10 mL, flow: 1 mLminÀ1. Oven temperature: 258C. Reten-
tion times 9 18.41 min; undesired enantiomer 17.26 min.
We thank Dr. Charles Pathirana for NMR spectroscopy ex-
periments and Mr. Jonathan Marshall for HR-MS data. Pro-
fessor Phil Baran and Drs. Rodney L. Parsons, Antonio
Ramirez, Ian Young, David A. Conlon and Robert E. Walter-
mire are acknowledged for helpful discussions.
References
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Preparation of (4R,5R)-5-(2,5-Difluorophenyl)-4-[5-
(phenylethynyl)pyridin-3-yl]oxazolidin-2-one (1)[5]
Oxazolidinone 9 (0.97 g, 1 equiv.) was added to a vessel con-
taining acetonitrile (8.7 mL) and NEt3 (0.98 mL). Phenylace-
tylene (0.415 g, 1.5 equiv.), triphenylphosphine (0.135 g,
0.19 equiv.), PdCl2(PPh3)2 (0.092 g, 0.05 equiv.) and CuI
(0.025 g, 0.05 equiv.) were sequentially added. The resulting
solution was sparged with nitrogen for ~5 min and was then
heated to 808C. After 5 h the dark solution was cooled to
room temperature and then concentrated to a semi-solid
residue under reduced pressure. Ethyl acetate (5 mL) was
added and the solution was concentrated to dryness yielding
a dark brown solid. The solid was then treated with ethyl
acetate (10 mL) and the resulting mixture was stirred for
10 min at room temperature and then filtered. The filtrate
was sequentially washed with aqueous ammonia (3ꢄ10 mL,
10%), brine (10 mL, 10%), sodium bisulfite (2ꢄ10 mL,
10%) and brine (10 mL, 10%). The organic layer was then
treated with charcoal (~250 mg) at room temperature over-
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Enantioselective Synthesis of a Positive Allosteric
Modulator of the Metabotropic Glutamate Receptor 5
(mGluR5) Receptor via Dynamic Kinetic Resolution of a-
Amino Ketones
7
Adv. Synth. Catal. 2016, 358, 1 – 7
Francisco Gonzꢀlez-Bobes,* Ronald Hanson, Neil Strotman,
Zhiwei Guo, Animesh Goswami
Adv. Synth. Catal. 0000, 000, 0 – 0
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These are not the final page numbers!