Asymmetric Synthesis of Netarsudil: A New Therapeutic for Open-Angle Glaucoma

Article abstract of DOI:10.1055/s-0037-1610310

The asymmetric synthesis of a Rho kinase/norepinephrine transport inhibitor, netarsudil, the active component in the recently FDA-approved product Rhopressa, is described herein. This concise six-step synthetic route utilizes the 2,4-dimethylbenzoate ester of a phenylacetic acid as the backbone of the β-amino acid's framework. A chiral enolate of the Evans auxiliary, (R)-4-benzyloxazolidin-2-one, is used to direct the formation of the (S)-stereocenter by incorporating the N -Boc-protected β-amino methyl arm with high diastereoselectivity (96:4 dr) using N -Boc-1-aminomethylbenzotriazole as the electrophile. Uniquely, 2,2,2-trichloro-1,1-dimethylethyl chloroformate is used as a non-racemizing activating agent for the coupling reaction between the chiral (S)- N -Boc-protected 2,4-dimethylbenzoyloxymethyl phenyl propanoic acid and 6-aminoisoquinoline to provide N -Boc-protected netarsudil in good yield and excellent enantiomeric purity (63%, 98% ee). Final acidic deprotection and recrystallization provides netarsudil (>99% ee), an ophthalmic agent used for the treatment of patients with open-angle glaucoma.

Full text of DOI:10.1055/s-0037-1610310

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–G
paper
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en
M. A. deLong, J. M. Sturdivant
Paper
Synthesis
Asymmetric Synthesis of Netarsudil: A New Therapeutic for
Open-Angle Glaucoma
Mitchell A. deLong
Jill M. Sturdivant*
O
0
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0-0
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2-6
7
6
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HO
Aerie Pharmaceuticals Inc., 4301 Emperor Blvd., Suite 400,
Durham, NC 27703, USA
jsturdivant@aeriepharma.com
N
O
O
N
H
Netarsudil
NH2
Received: 05.09.2018
Accepted: 28.09.2018
Published online: 29.10.2018
DOI: 10.1055/s-0037-1610310; Art ID: ss-2018-m0594-op
function of the trabecular meshwork, through increased
stiffness and fibrosis, which the above-mentioned thera-
pies do not treat.6
Recently, Rhopressa™ was approved by the FDA for the
reduction of elevated IOP in patients with open-angle glau-
coma or ocular hypertension.7 Its active agent, netarsudil,
directly targets the afflicted trabecular meshwork by inhib-
iting Rho-associated protein kinase (ROCK), which relaxes
the trabecular meshwork cells, increases aqueous humor
outflow and ultimately lowers IOP.6,8
Netarsudil is an α-aryl β-amino isoquinoline amide that
is a potent ROCK inhibitor.9 It was uniquely designed to en-
compass the properties required for an effective once-daily
topical eye drop, including aqueous solubility, stability and
the ability to penetrate the protective corneal layer. The ra-
cemic synthesis has recently been described.9b The key
steps in that synthesis include an alkylation with N-(bro-
momethyl)phthalimide which incorporates the β-amino
arm, followed by formation of the aminoisoquinoline amide
through a standard coupling reaction.9b
Abstract The asymmetric synthesis of a Rho kinase/norepinephrine
transport inhibitor, netarsudil, the active component in the recently
FDA-approved product Rhopressa™, is described herein. This concise
six-step synthetic route utilizes the 2,4-dimethylbenzoate ester of a
phenylacetic acid as the backbone of the β-amino acid’s framework. A
chiral enolate of the Evans auxiliary, (R)-4-benzyloxazolidin-2-one, is
used to direct the formation of the (S)-stereocenter by incorporating
the N-Boc-protected β-amino methyl arm with high diastereoselectivity
(96:4 dr) using N-Boc-1-aminomethylbenzotriazole as the electrophile.
Uniquely, 2,2,2-trichloro-1,1-dimethylethyl chloroformate is used as a
non-racemizing activating agent for the coupling reaction between the
chiral (S)-N-Boc-protected 2,4-dimethylbenzoyloxymethyl phenyl pro-
panoic acid and 6-aminoisoquinoline to provide N-Boc-protected netar-
sudil in good yield and excellent enantiomeric purity (63%, 98% ee). Fi-
nal acidic deprotection and recrystallization provides netarsudil (>99%
ee), an ophthalmic agent used for the treatment of patients with open-
angle glaucoma.
Key words netarsudil, ROCK, Rho kinase, β-amino acids, glaucoma
The flexible nature of that synthesis enabled rapid ac-
cess to SAR around various α-aryl β-amino isoquinoline an-
alogs and resulted in the identification of netarsudil as the
lead compound for further development.9
Glaucoma affects approximately 2.5 million people in
the US and 70 million worldwide.1 High intraocular pres-
sure (IOP) is a trademark symptom of glaucoma which in-
creases the risk of optic nerve damage that can lead to
blindness.2 Over the last 20 years, patients have been treat-
ed with prostaglandins3 as the first line therapy, or in a
combination regimen with a beta blocker or alpha agonist.4
These therapies lower IOP by reducing the amount of aque-
ous humor production and/or enhancing its outflow
through the uveoscleral outlet.5 However the uveoscleral
drainage pathway is secondary to the trabecular meshwork,
which is the major facilitator of aqueous humor equilibri-
um, adjusting resistance to aqueous outflow to maintain
normal IOP levels. Elevated IOP in glaucoma involves dys-
Herein is described an asymmetric route to the more ac-
tive S-antipode of netarsudil. The synthesis of this β-amino
acid derivative involves several key challenges. First, netar-
sudil contains an α-aryl moiety which lowers the pKa of the
α hydrogen compared to alkyl-branched amino acids.
Therefore, controlled synthetic steps preventing racemiza-
tion of this labile α center are required. Second, the 6-ami-
noisoquinoline is expensive, an unreactive nucleophile, and
is poorly soluble in many standard organic solvents, so am-
ide formation next to the α carbon presents another note-
worthy challenge. Finally, incorporation of the 2,4-dimeth-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

B
M. A. deLong, J. M. Sturdivant
Paper
Synthesis
ylbenzoate early in the synthesis is preferred, but the inher-
ent instability of the ester may require a lengthier
protection/deprotection strategy (Scheme 1).
with an [H2NCH2]+ equivalent using the Evans oxazolidi-
none chiral auxiliary.15 We envisioned that netarsudil could
be prepared from intermediate 8 enabling the 6-aminoiso-
quinoline to be appended late in the synthesis. N-Boc-α-
aryl-β-amino acid 8 could be synthesized from the 2,4-di-
methylbenzoate ester of phenyl acetic acid 4 which incor-
porates the 2,4-dimethylbenzoate early in the sequence
(Scheme 2).
Compound 4 is synthesized from commercially available
4-(hydroxymethyl)phenylacetic acid (1). Fischer esterifica-
tion with H2SO4 in MeOH provided methyl ester 2 (98%) and
coupling with 2,4-dimethylbenzoic acid (2,4-DMBA) fur-
nished 3 (79%). Final hydrolysis with LiOH·H2O gave the 2,4-
dimethylbenzoyloxy methyl ester of phenyl acetic acid 4
(97%) (Scheme 3).
lability of the
2,4-dimethylbenzoate
O
O
O
Netarsudil
H
N
H2N
N
α-aryl moiety
coupling of the
6-aminoisoquinoline
CO2H
CO2Me
CO2Me
CO2H
EDC, DMAP
Scheme 1 Netarsudil: The active ingredient in Rhopressa™
LiOH·H2O
H2SO4
MeOH
2,4-DMBA
pyridine
There are not as many asymmetric routes reported for
β2-amino acids (2-substituted) as there have been for the β3
(3-substituted) amino acid class.10 Even less accessible are
routes to α-aryl (β2) β-amino acids. Stefani and co-workers
prepared α-aryl β-amino acids by developing a Suzuki–
Miyaura, Pd(OAc)2-catalyzed cross-coupling reaction using
potassium aryltrifluoroborates and substituted 5-iodo-2,3-
dihydro-5(H)-pyrimidin-4-ones.11 Williams and co-workers
also used palladium-catalyzed allylic substitution to pre-
HO
HO
O
O
1
2, 98%
O
O
3, 79%
4, 97%
Scheme 3 Synthesis of 2-{4-[(2,4-dimethylbenzoyloxy)methyl]phe-
nyl}acetic acid (4)
pare various α-aryl analogs of the β2 amino acid class.12
A
We chose the more economical and readily available
Evans chiral auxiliary, (R)-4-benzyloxazolidin-2-one to set
the S-stereocenter at the α carbon (Scheme 4).16 Addition of
oxalyl chloride to 4 in THF with a catalytic amount of DMF
provided acid chloride 5 which was used immediately. The
lithium anion of (R)-4-benzyloxazolidin-2-one was formed
with n-BuLi at –78 °C and added to a solution of acid chlo-
ride 5 in THF at –78 °C to yield acylated (R)-4-benzyloxazo-
lidin-2-one 6 (76%). Formation of the lithium enolate with
LiHMDS at –78 °C and stereoselective alkylation with N-
Boc-protected 1-aminomethylbenzotriazole at –30 °C to
–25 °C provided a mixture of (S,R)-7 and its diastereomer
(R,R)-7D (75% yield) in a 96:4 diastereomeric ratio.17a Col-
umn chromatography was used to easily separate and puri-
fy 7 (4.1 g, 71%) from the R,R diastereomer (7D, 191 mg)
(Scheme 4). As observed by Wyatt and co-workers, increas-
ing the temperature above –20 °C during the alkylation re-
action led to lower yields due to decomposition, presum-
ably through the ketene, resulting in the deacylated chiral
auxiliary.15 The N-Boc-protected 1-aminomethylbenzotri-
azole electrophile 11 was prepared by reacting 1-hy-
droxymethylbenzotriazole with tert-butyl carbamate in re-
fluxing toluene using a Dean–Stark apparatus. Evaporation
and recrystallization from toluene provided pure 11
(64%).15 Removal of the chiral auxiliary from 7 was accom-
plished using Evans’ hydroperoxide anion conditions (LiOH,
few catalytic asymmetric approaches have been reported
including a Hantzsch ester induced conjugate reduction of
β-nitro acrylates to the corresponding β-nitro esters and a
rhodium-carbenoid-induced C–H activation/insertion of N-
protected methylamines.13,14
We used a modified synthetic route developed by Wyatt
and co-workers which entails alkylation of a chiral enolate
O
O
O
O
O
8
H
N
H2N
BocHN
OH
O
N
Netarsudil
O
O
4
OH
O
Scheme 2 Retrosynthetic analysis of netarsudil
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

C
M. A. deLong, J. M. Sturdivant
Paper
Synthesis
H2O2, H2O)16a without loss of enantiomeric purity or loss of
the benzoate ester to give the (S)-N-Boc 2,4-dimethylben-
zoate methyl phenyl propanoic acid 8 (90%, >99% ee).17b
Next, coupling 6-aminoisoquinoline to 8 while main-
taining optical purity during the coupling reaction posed a
significant challenge, as did isolating the product in an ac-
ceptable yield. Several standard coupling agents were used,
which either resulted in low yields or loss of enantiomeric
integrity (Table 1).18
2,2,2-trichloro-1,1-dimethylethyl chloroformate is most
notably used as a N-protecting group,19b,c but it has also
been used to prepare novel biologically active com-
pounds.19d These data herein demonstrate for the first time
Table 1 Standard Coupling Reactions Between 8 and 6-Aminoisoquin-
oline
reagents
condition
Compound 9
Compound 8
The use of ethyl chloroformate (A) as a coupling agent
with model compound N-Boc-2-phenylpropanoic acid (12)
and 6-aminoisoquinoline in DMF gave 6-aminoisoquinoline
amide 13 with a high ee value (96%), but in low yield (40%).
Formation of the ethyl ester of compound 12 was the main
by-product observed in the reaction. Modifying the amount
of the coupling agent, its concentration, the base and the
temperature did not improve the yield of 13 (Table 2).
Other chloroformates and anhydrides were investigated
as activating agents, including di-tert-butyl dicarbonate (B),
4-fluorophenyl chloroformate (C), and isopropenol chloro-
formate (D), but the coupling yields remained low (23–40%)
(Table 2). 2,2,2-Trichloro-1,1-dimethylethyl chloroformate
(Troc-Cl) (E), a reagent that has not previously been de-
scribed as a coupling reagent, was successfully used to cou-
ple the 6-aminoisoquinoline with model compound 12 to
give amide 13 in good yield (62–63%) and excellent enan-
tiomeric purity (>95% ee). The expected by-products from
this coupling reaction are HCl, CO2 and 1,1,1-trichloro-2-
methylpropan-2-ol, based on kinetic studies of the solvoly-
ses of 2,2,2-trichloro-1,1-dimethylethyl chloroformate.19a It
was expected that 1,1,1-trichloro-2-methylpropan-2-ol
would be less nucleophilic than ethanol, which is generated
from ethyl chloroformate. In accordance, we did not ob-
serve any formation of the trichloro 2-methylpropanol es-
ter by-product in the coupling reaction. In the literature,
H2N
N
Reagents (equiv), conditionsa,b,c
Yield (%) ee (%)d
HATU (1.6), 2,4,6-trimethylpyridine (2.0), HOAt (1.2),
DMF
68
±
HATU (1.6), DMAP (0.2), DMF
EDC (1.6), DMAP (0.2), pyridine (337 mM)
EDC (1.6), HOBt (1.3), DMF
13
98
27
60
±
41
DCC (1.6), HOAt (1.2), DMF
76
±
PyAOP (1.6), DIEA (2.0), DMF, 4 h
PyAOP (1.6), HOAt (1.2), DMF
PyAOP (1.6), 2,4,6-trimethylpyridine (2.0), DMF, 3.5 h
DMTMM (1.5), THF (230 mM)
DMTMM (1.5), DMF, 5 h
93
±
<10e
56
NDf
±
11
85
85
NDf
11
CDI (1.4), DMF
<10e
a Reaction concentration is 288 mM unless noted.
b Reaction time is 24 h unless noted.
c See Ref. 18 for a review of peptide coupling reagents.
d The ee values were determined by chiral LC; ± = racemized.
e Yield based on LC-MS.
f ND = not determined.
O
O
NH
Bn
O
O
O
O
Cl
O
Cl
O
O
O
O
O
O
n-BuLi
O
O
N
THF, –78 °C
HO
Cl
DMF, THF
6, 76%
5, >95%
4
Bn
O
O
LiHMDS
N
2,4,6-TMP
O
O
O
O
O
O
N
LiOH·H2O
H2O2
N
O
CCl3
Cl
O
N
HO
11
NHBoc
H2N
THF, H2O, 0 °C
8, 90%
7, 71%
NHBoc
NHBoc
THF, –78 to –25 °C
Bn
N
DMF, 0 °C
O
O
O
N
O
MsOH
CH2Cl2
N
O
O
2 MsOH
N
N
H
H
10, 93%, >99% ee
9, 63%, 98% ee
NH2
NHBoc
Scheme 4 Asymmetric synthesis of netarsudil
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

D
M. A. deLong, J. M. Sturdivant
Paper
Synthesis
that this chloroformate can be successfully used as a cou-
pling agent for a less reactive amine, resulting in a high
yield of the desired product with a minimal loss of optical
purity.
Table 2 Optimization of the Coupling Reaction Between Model Com-
pound 12 and 6-Aminoisoquinolinea
A, B, C, D, E
DMF
Based on these studies, (S)-N-Boc 2,4-dimethylbenzoate
methyl phenyl propanoic acid (8) was coupled with 6-ami-
noisoquinoline using 2,2,2-trichloro-1,1-dimethylethyl
chloroformate to give (S)-N-Boc phenylacetate 6-aminoiso-
quinoline amide 9 (63% yield, >95% purity) with high enan-
tiomeric excess (98% ee).17b Recrystallization from EtOAc/
hexanes gave 9 (>99% ee, 47%). Final deprotection using
methanesulfonic acid in CH2Cl2 and recrystallization from
isopropanol provided pure netarsudil dimesylate (10) (93%,
>99% ee).17b
In summary, a scalable asymmetric synthesis of netar-
sudil is described. The six-step synthetic route originates
from the 2,4-dimethylbenzoate phenyl acetic acid starting
material. The (S)-stereocenter is set using the chiral enolate
of the Evans (R)-4-benzyloxazolidin-2-one chiral auxiliary
to direct alkylation of N-Boc 1-aminomethyl benzotriazole
(11) incorporating the β-amino arm. Hydrolytic removal of
the auxiliary and coupling the (S)-N-Boc α-aryl β-amino
acid with 6-aminoisoquinoline using 2,2,2-trichloro-1,1-di-
methylethyl chloroformate as the activating agent is accom-
plished in good yield and excellent ee. This is the first use of
2,2,2-trichloro-1,1-dimethylethyl chloroformate as the acti-
vating agent for a chiral amidation reaction. Final acidic
deprotection provides enantiomerically pure (S)-netarsudil
dimesylate (>99% ee). This six-step synthetic route and the
use of 2,2,2-trichloro-1,1-dimethylethyl chloroformate as
the coupling agent can be used on a kilo-scale for the pro-
cess preparation of netarsudil as a single enantiomer.20
2,4,6-collidine
H
BocHN
OH
BocHN
N
N
*
*
H2N
O
O
N
13
model compound 12
A = ethyl chloroformate; B = di-tert-butyl dicarbonate, C = 4-fluorophenyl
chloroformate; D = isopropenol chloroformate; E = 2,2,2-trichloro1,1-dimethylethyl
chloroformate
12b
Coupling
Concn
agent (equiv) (mM)
Base
(equiv)
Temp
Yield
(%)
ee
(%)c
R
S
A (1.1)
A (1.1)
A (1.1)
A (1.1)
A (1.1)
A (2.0)
B (1.2)
B (2.5)
B (1.5)
C (1.3)
D (1.2)
D (1.5)
E (1.1)
E (1.4)
E (1.6)
E (1.6)
E (1.3)
E (1.3)
A (1.3)
309
312
316
337
176
220
238
244
247
248
254
241
244
245
243
243
246
246
132
1.0
1.0
1.0d
1.0
1.0
2.0
1.0
2.3
1.5
1.35
1.1
1.4
1.0
1.3
1.5
1.5
1.2
1.3
1.3
0 °C to RT
40
40
96
99
–
0 °C to RT
0 °C to RT
–40 °C to RT
0 °C to RT
0 °C to RT
0 °C to RT
0 °C to RT
0 °C to RT
0 °C to RT
0 °C to RT
0 °C to RT
0 °C to RT
0 °C to RT
0 °C to RT
0 °C to RT
0 °C to RT
0 °C to RT
0 °C
±
±
±
±
±
±
±
±
S
NCe
NCe
37
–
–
NCe
23
–
–
NCe
25
–
–
NCe
35
–
–
R
±
±
±
R
S
40
–
48
–
56
–
55
–
44
–
63
–
S
62
>95
All reactions were conducted under a nitrogen atmosphere unless
otherwise noted. Anhydrous tetrahydrofuran, dimethylformamide,
and methylene chloride were acquired from Acros and used without
further purification. Unless otherwise stated, reagents were commer-
cially available and used as purchased. n-Butyllithium in hexanes
(nominally 1.6 M) was purchased from Aldrich and titrated before
use.21 Normal-phase column chromatography was carried out using
Davisil silica gel (40–63 micron) or using an automated Teledyne ISCO
Combiflash RF200 with RediSep normal-phase silica flash columns.
Melting points were obtained using a Mel-Temp apparatus. Optical
rotations were recorded at SGS (Fairfield, NJ). Infrared spectra were
obtained on an ATR cell using a Nicolet iS10 FT-IR spectrometer. 1H
and 13C NMR spectra were recorded on a 500 or 600 MHz Varian Inova
spectrometer or on an 800 MHz Varian/Agilent DirectDrive 2 spec-
trometer. Analytical LC-MS spectra were obtained using a Waters Ac-
quity QDA MS ESI instrument with an Alliance 2695 HPLC and a 2998
photodiode array detector. Elemental analyses were carried out by
Atlantic Microlab (Norcross, GA).
8 Sf
<25%
a To 12 in DMF was added the base followed by the coupling agent. The re-
action was stirred for 30 min and then 6-aminoisoquinoline (in DMF) was
added.
b Optically pure or racemic compound 12.
c The ee values were determined by chiral LC.
d Pyridine was used in place of 2,4,6-trimethylpyridine.
e NC = no change in yield based on LC.
f Compound 8 was used following the experimental procedure used for
product 9. Ethyl chloroformate was added last.
Methyl 2-[4-(Hydroxymethyl)phenyl]acetate (2)
To 2-[4-(hydroxymethyl)phenyl]acetic acid (1) (5 g, 30.1 mmol) in
MeOH (30 mL) cooled to 0 °C was added H2SO4 (3 mL) and the solu-
tion was stirred for 1 h at 0 °C. The solution was then poured into H2O
and EtOAc and washed with H2O (2×). The aqueous layer was back-
extracted with EtOAc (2×). The combined EtOAc layers were washed
with NaHCO3 (sat.) (3×). The organics were dried (Na2SO4), filtered
and evaporated to give methyl 2-[4-(hydroxymethyl)phenyl]acetate
(2) (5.3 g, 98%) as an oil.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

E
M. A. deLong, J. M. Sturdivant
Paper
Synthesis
1H NMR (600 MHz, CDCl3): δ = 7.35 (d, J = 6.0 Hz, 2 H), 7.29 (d, J = 6.0
(R)-4-[2-(4-Benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl]benzyl 2,4-
Hz, 2 H), 4.69 (s, 2 H), 3.71 (s, 3 H), 3.65 (s, 3 H).
Dimethylbenzoate (6)
13C NMR (150 MHz, CDCl3): δ = 172.1, 139.8, 133.4, 129.5, 127.3, 65.1,
52.1, 40.1.
To (R)-4-benzyloxazolidin-2-one (2.5 g, 14.1 mmol) in THF (28 mL) at
–78 °C was added n-BuLi [1.37 M (titrated), 10.4 mL, 14.2 mmol]
slowly down the sides of the flask and the reaction was stirred at
–78 °C for 20 min. Next, the solution containing the lithium anion of
(R)-4-benzyloxazolidin-2-one in THF was cannulated into a precooled
(–78 °C) solution of 4-(2-chloro-2-oxoethyl)benzyl 2,4-dimethylben-
zoate (5) (5.3 g, 16.9 mmol) dissolved in THF (25 mL). The reaction
was stirred at –78 °C for 1 h and then poured into NH4Cl (sat.)/HCl (1
M) (3:1) and extracted with EtOAc. The combined extracts were dried
(Na2SO4), filtered and evaporated. Purification using an automated
column (Teledyne ISCO, Rf 200, 80 g RediSep cartridge, 0–25% EtOAc/
hexanes) gave pure (R)-4-[2-(4-benzyl-2-oxooxazolidin-3-yl)-2-ox-
oethyl]benzyl 2,4-dimethylbenzoate (6) (4.9 g, 76%) as a white solid.
4-(2-Methoxy-2-oxoethyl)benzyl 2,4-Dimethylbenzoate (3)
To methyl 2-[4-(hydroxymethyl)phenyl]acetate (2) (5.3 g, 29.4 mmol)
in pyridine (87 mL) were added 2,4-dimethylbenzoic acid (2,4-DMBA)
(5.3 g, 35.3 mmol), EDC (10.1 g, 53 mmol), and DMAP (718 mg, 5.9
mmol) and the solution was flushed with N2, capped and stirred over-
night. The mixture was poured into EtOAc/HCl (1 M) and washed with
HCl (1 M, 3×). Next, the organic layer was washed with NaHCO3 (sat.)
(3×). The combined organics were dried (Na2SO4), filtered and evapo-
rated. Column chromatography (15% EtOAc/hexanes) gave pure 4-(2-
methoxy-2-oxoethyl)benzyl 2,4-dimethylbenzoate (3) (7.2 g, 79%) as
a white solid.
Mp 70–71 °C.
IR (ATR): 1779, 1713, 1693, 1613 cm–1
.
Mp 44–45 °C.
1H NMR (500 MHz, CDCl3): δ = 7.88 (d, J = 7.9 Hz, 1 H), 7.44 (d, J = 8.1
Hz, 2 H), 7.36 (d, J = 8.1 Hz, 2 H), 7.31–7.24 (m, 3 H), 7.14 (d, J = 6.9 Hz,
2 H), 7.06 (s, 1 H), 7.03 (d, J = 8.2 Hz, 1 H), 5.33 (s, 2 H), 4.69 (m, 1 H),
4.33 (dd, J = 15.6, 36.9 Hz, 2 H), 4.24–4.17 (m, 2 H), 3.27 (dd, J = 3.1,
13.3 Hz, 1 H), 2.77 (dd, J = 9.4, 13.4 Hz, 1 H), 2.59 (s, 3 H), 2.35 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 171.2, 167.1, 153.4, 142.6, 140.5,
135.6, 135.1, 133.4, 132.5, 130.9, 129.9, 129.4, 128.9, 128.4, 127.3,
126.4, 126.4, 66.2, 65.9, 55.3, 41.3, 37.7, 21.8, 21.4.
IR (ATR): 1735, 1713, 1613, 1450, 1437 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.89 (d, J = 8.0 Hz, 1 H), 7.43 (d, J = 8.1
Hz, 2 H), 7.32 (d, J = 8.1 Hz, 2 H), 7.08 (s, 1 H), 7.06 (d, J = 8.0 Hz, 1 H),
5.33 (s, 2 H), 3.72 (s, 3 H), 3.66 (s, 2 H), 2.60 (s, 3 H), 2.37, (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 171.9, 167.2, 142.7, 140.6, 135.2,
133.9, 132.6, 130.9, 129.5, 128.5, 126.5, 126.4, 65.9, 52.1, 40.9, 21.9,
21.4.
Anal Calcd for C19H20O4: C, 73.06; H, 6.45. Found: C, 72.95; H, 6.48.
LC-MS (ES+): m/z = 480 [M + 23]+.
Anal Calcd for C28H27NO5: C, 73.51; H, 5.95; N, 3.06. Found: C, 73.53;
H, 5.93; N, 3.06.
2-{4-[(2,4-Dimethylbenzoyloxy)methyl]phenyl}acetic Acid (4)
To 4-(2-methoxy-2-oxoethyl)benzyl 2,4-dimethylbenzoate (3) (7.2 g,
23 mmol) in MeCN (27.3 mL) and 1,4-dioxane (27.3 mL) cooled to 0 °C
was added LiOH·H2O (1.16 g, 27.7 mmol) dissolved in H2O (27.3 mL).
The solution was warmed to room temperature and stirred for 40
min. TLC (hexanes/EtOAc, 80:20) indicated completion of the reac-
tion. HCl (2 M) was added until the pH was about 4–5 (pH paper) and
the solvents were evaporated. The remaining solution was poured
into EtOAc and HCl (1 M) and the aqueous layer was extracted with
EtOAc (2×). The combined organics were dried (Na2SO4), filtered and
evaporated to give 2-{4-[(2,4-dimethylbenzoyloxy)methyl]phe-
nyl}acetic acid (4) (6.6 g, 97%) as a white solid.
4-{(S)-1-[(R)-4-Benzyl-2-oxooxazolidin-3-yl]-3-[(tert-butoxycar-
bonyl)amino]-1-oxopropan-2-yl}benzyl 2,4-Dimethylbenzoate (7)
To a solution of LiHMDS (1.0 M, 11.9 mL, 11.9 mmol) in THF (5.8 mL)
cooled to –78 °C was added a cooled (–78 °C) solution of (R)-4-[2-(4-
benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl]benzyl 2,4-dimethylbenzo-
ate (6) (4.6 g, 10.0 mmol) in THF (22 mL) via cannula and this mixture
was stirred at –78 °C for 30 min. Next, a solution of tert-butyl [(1H-
benzo[d][1,2,3]triazol-1-yl)methyl]carbamate (11) (2.9 g, 11.9 mmol)
in THF (18.1 mL), also cooled to –78 °C, was added via cannula. This
solution was warmed to –25 to –30 °C and stirred for 1.5–2 h. The
mixture was poured into EtOAc and NH4Cl (sat.)/HCl (1 M) (3:1) and
the aqueous phase was further extracted one more time with EtOAc.
The combined organics were dried (Na2SO4), filtered and evaporated.
Purification using an automated column (Teledyne ISCO Rf 200, 80 g
RediSep cartridge, 0–4% EtOAc/CH2Cl2) gave pure 4-{(S)-1-[(R)-4-ben-
zyl-2-oxooxazolidin-3-yl]-3-[(tert-butoxycarbonyl)amino]-1-oxopro-
pan-2-yl}benzyl 2,4-dimethylbenzoate (7) (4.1 g 71%) as a soft white
solid and the diastereomer 4-{(R)-1-[(R)-4-benzyl-2-oxooxazolidin-
3-yl]-3-[(tert-butoxycarbonyl)amino]-1-oxopropan-2-yl}benzyl 2,4-
dimethylbenzoate (7D) (191 mg, 3.2%) as a soft white solid. The de of
the reaction was 96:4 based on the isolated yields.
Mp 95–96 °C.
IR (ATR): 1719, 1693, 1612, 1448 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.89 (d, J = 7.9 Hz, 1 H), 7.43 (d, J = 8.0
Hz, 2 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.07 (s, 1 H), 7.05 (d, J = 8.0 Hz, 1 H),
5.32 (s, 2 H), 3.68 (s, 2 H), 2.60 (s, 3 H), 2.36 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 177.5, 167.2, 142.7, 140.6, 135.5,
133.1, 132.5, 130.9, 129.5, 128.4, 126.4, 126.3, 65.9, 40.6, 21.8, 21.4.
LC-MS (ES+): m/z = 321 [M + 23]+.
Anal Calcd for C18H18O4: C, 72.47; H, 6.08. Found: C, 72.35; H, 6.10.
4-(2-Chloro-2-oxoethyl)benzyl 2,4-Dimethylbenzoate (5)
Compound 7 (S,R)
To 2-{4-[(2,4-dimethylbenzoyloxy)methyl]phenyl}acetic acid (2) (5.0
g, 16.9 mmol) in THF (55 mL) at 0 °C was added oxalyl chloride (1.8
mL, 20.2 mmol) and DMF (132 μL, 1.69 mmol), and the solution was
stirred for 1.25 h at 0 °C in a flask fitted with a drying tube. The sol-
vents were evaporated and the residue dried to give 4-(2-chloro-2-
oxoethyl)benzyl 2,4-dimethylbenzoate (5) as a off-white solid which
was used immediately for the next step.
Mp 45–50 °C; Rf = 0.45 (CH2Cl2/EtOAc, 97:3).
IR (ATR): 1778, 1693, 1613, 1498 cm–1
1H NMR (500 MHz, CDCl3): δ = 7.87 (d, J = 7.9 Hz, 1 H), 7.36 (m, 6 H),
7.30 (m, 1 H), 7.23 (d, J = 7.2 Hz, 2 H), 7.06 (s, 1 H), 7.04 (d, J = 8.2 Hz, 1
H), 5.29 (s, 2 H), 5.24–5.18 (m, 1 H), 4.88–4.81 (m, 1 H), 4.65–4.61 (m,
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

F
M. A. deLong, J. M. Sturdivant
Paper
Synthesis
1 H), 4.13–4.05 (m, 2 H), 3.81–3.73 (m, 1 H), 3.57–3.54 (m, 1 H), 3.35–
(S)-4-{3-[(tert-Butoxycarbonyl)amino]-1-(isoquinolin-6-ylami-
3.32 (m, 1 H), 2.88–2.84 (m, 1 H), 2.59 (s, 3 H), 2.36 (s, 3 H), 1.44 (s, 9
H).
13C NMR (125 MHz, CDCl3): δ = 172.6, 167.1, 155.6, 152.4, 142.7,
140.6, 135.9, 135.6, 135.1, 132.5, 130.8, 129.4, 129.0, 128.9, 128.5,
127.4, 126.4, 126.3, 79.5, 65.9, 65.7, 55.6, 49.8, 43.8, 37.9, 28.3, 21.8,
21.4.
no)-1-oxopropan-2-yl}benzyl 2,4-Dimethylbenzoate (9)
To (S)-3-[(tert-butoxycarbonyl)amino)]-2-(4-{[(2,4-dimethylbenzo-
yl)oxy]methyl}phenyl)propanoic acid (8) (2.3 g, 5.5 mmol) in DMF
(33 mL) cooled to 0 °C was added 6-aminoisoquinoline (1.0 g, 7.1
mmol) and 2,4,6-trimethylpyridine (947 μL, 7.1 mmol). After 10 min
at 0 °C, a solution of 2,2,2-trichloro-1,1-dimethylethyl chloroformate
(1.7 g, 7.1 mmol) in DMF (8.6 mL) was added and the reaction stirred
at 0 °C for 2 h. The mixture was poured into NaHCO3 (sat.)/EtOAc and
extracted with EtOAc. The organic layers were then washed with NaCl
(sat.), dried (Na2SO4) filtered and evaporated. Column chromatogra-
phy (70% EtOAc/hexanes) gave pure (S)-4-{3-[(tert-butoxycarbon-
yl)amino]-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl}benzyl 2,4-
dimethylbenzoate (9) (1.93 g, 63%, 98% ee) as a off-white solid. Re-
crystallization from EtOAc/hexanes gave 9 (1.43 g, 47%, 99.7% ee, S,S-
Whelk-01) as a off-white crystalline solid.
LC-MS (ES+): m/z = 609.2 [M + 23]+.
Anal Calcd for C34H38N2O7: C, 69.61; H, 6.53; N, 4.77. Found: C, 69.57;
H, 6.47; N, 4.78.
Compound 7D (R,R)
Mp 45–50 °C; Rf = 0.25 ((CH2Cl2/EtOAc), 97:3).
IR (ATR): 1778, 1693, 1613, 1498 cm–1
.
1H NMR (800 MHz, CDCl3): δ = 7.88 (d, J = 7.9 Hz, 1 H), 7.45–7.41 (m, 4
H), 7.21–7.17 (m, 3 H), 7.05 (s, 1 H), 7.03 (d, J = 8.1 Hz, 1 H), 6.99–6.98
(m, 2 H), 5.32 (s, 2 H), 5.16–5.10 (m, 1 H), 4.83–4.79 (m, 1 H), 4.77–
4.75 (m, 1 H), 4.21–4.20 (m, 1 H), 4.09–4.08 (m, 1 H), 3.75–3.73 (m, 1
H), 3.60–3.54 (m, 1 H), 3.17–3.15 (m, 1 H), 2.62–2.60 (m, 1 H), 2.59 (s,
3 H), 2.35 (s, 3 H), 1.42 (s, 9 H).
13C NMR (125 MHz, CDCl3): δ = 172.6, 167.2, 155.6, 152.4, 142.7,
140.6, 135.9, 135.6, 134.7, 132.5, 130.9, 129.3, 129.0, 128.9, 128.5,
127.3, 126.4, 126.3, 79.4, 65.9, 65.8, 54.8, 49.9, 43.5, 37.9, 28.3, 21.8,
21.4.
Mp 155–156 °C.
IR (ATR): 1713, 1644, 1527 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 9.14 (s, 1 H), 8.39 (d, J = 5.7 Hz, 1
H), 8.38 (s, 1 H), 8.02 (d, J = 8.7 Hz, 1 H), 7.75 (d, J = 7.9 Hz, 1 H), 7.69–
7.66 (m, 2 H), 7.43 (s, 4 H), 7.11 (s, 1 H), 7.07 (d, J = 8.4 Hz, 1 H), 7.02
(br t, J = 5.4 Hz, 1 H), 5.25 (s, 2 H), 4.13–4.10 (m, 1 H), 3.58–3.53 (m, 1
H), 3.34–3.30 (m, 1 H), 2.49 (s, 3 H), 2.29 (s, 3 H), 1.32 (s, 9 H).
13C NMR (125 MHz, DMSO-d6): δ = 171.0, 166.4, 155.8, 151.5, 143.2,
142.4, 140.4, 139.5, 137.8, 136.1, 135.2, 132.3, 130.4, 128.5, 128.1,
128.0, 126.6, 126.1, 125.0, 121.0, 120.0, 113.1, 77.8, 65.6, 51.7, 42.9,
28.2, 21.2, 20.8.
LC-MS (ES+): m/z = 609.1 [M + 23]+.
Anal Calcd for C34H38N2O7: C, 69.61; H, 6.53; N, 4.77. Found: C, 69.25;
H, 6.57; N, 4.80.
LC-MS (ES+): m/z = 554 [M + 1]+, 576 [M + 23]+.
Anal Calcd for C33H35N3O5: C, 71.59; H, 6.37; N, 7.59. Found: C, 71.54;
H, 6.51; N, 7.58.
(S)-3-[(tert-Butoxycarbonyl)amino]-2-(4-{[(2,4-dimethylbenzo-
yl)oxy]methyl}phenyl)propanoic Acid (8)
To 4-{(S)-1-[(R)-4-benzyl-2-oxooxazolidin-3-yl]-3-[(tert-butoxycar-
bonyl)amino]-1-oxopropan-2-yl}benzyl 2,4-dimethylbenzoate (7)
(4.2 g, 7.1 mmol) in THF (59 mL) and H2O (19 mL) cooled to 0 °C was
added H2O2 (30% in H2O, 3.2 mL, 28.4 mmol) and LiOH·H2O (387 mg,
9.2 mmol). The solution was stirred at 0 °C for 45 min and sodium
sulfite (sat.) (71 mL) was added. The mixture was stirred for an addi-
tional 15 min, then acidified with HCl (2 M) until pH = 5 (pH paper)
and extracted with EtOAc. The combined organics were dried
(Na2SO4), filtered and evaporated. Purification using an automated
column (Teledyne ISCO Rf 200, 80 g RediSep cartridge, 0–28% EtOAc/
hexanes with 1% AcOH) gave pure (S)-3-[(tert-butoxycarbonyl)ami-
no]-2-(4-{[(2,4-dimethylbenzoyl)oxy]methyl}phenyl)propanoic acid
(8) (2.7 g, 90%) as a white solid . Recrystallization from EtOAc/hexanes
gave 8 (2.5 g, 83%, >99% ee, R,R-Whelk-01) as a crystalline white solid.
(S)-4-[3-Amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]ben-
zyl 2,4-Dimethylbenzoate Dimesylate (10)
To(S)-4-{3-[(tert-butoxycarbonyl)amino]-1-(isoquinolin-6-ylamino)-
1-oxopropan-2-yl}benzyl 2,4-dimethylbenzoate (9) (1.0 g, 1.81
mmol, 99.7 % ee) in CH2Cl2 (8.1 mL) was added methanesulfonic acid
(293 μL, 4.52 mL) and the solution was stirred for 22 h at room tem-
perature. The solvents were evaporated and the residue was recrys-
tallized with isopropanol to give pure (S)-4-[3-amino-1-(isoquinolin-
6-ylamino)-1-oxopropan-2-yl]benzyl 2,4-dimethylbenzoate dimesylate
(10) (1.1 g, 93%, >99% ee, Chiralpak AS-H) as a off-white crystalline
solid.
Mp 122–135 °C; [α]D –175 (c 1.0, H2O).
IR (ATR): 1708, 1645, 1613, 1563 cm–1
.
1H NMR (500 MHz, MeOD): δ = 9.49 (s, 1 H), 8.73 (s, 1 H), 8.39 (d, J =
6.7 Hz, 1 H), 8.34 (d, J = 9.1 Hz, 1 H), 8.21 (d, J = 6.7 Hz, 1 H), 8.00 (dd,
J = 3.0, 9.0 Hz, 1 H), 7.73 (d, J = 8.1 Hz, 1 H), 7.53 (dd, J = 8.4, 14.9 Hz, 4
H), 7.03 (s, 1 H), 6.99 (d, J = 8.1 Hz, 1 H), 4.89 (s, 2 H), 4.35 (dd, J = 5.5,
8.7 Hz, 1 H), 3.70 (dd, J = 8.9, 12.8 Hz, 1 H), 3.34 (dd, J = 5.4, 12.9 Hz, 1
H), 2.79 (s, 6 H), 2.46 (s, 3 H), 2.28 (s, 3 H).
13C NMR (125 MHz, MeOD): δ = 172.2, 168.6, 147.5, 146.7, 144.2,
141.9, 141.4, 138.6, 136.5, 133.4, 132.9, 132.4, 131.8, 130.3, 129.6,
127.55, 127.53, 127.46, 125.5, 125.3, 114.9, 66.8, 51.5, 42.8, 39.6, 21.9,
21.3.
Mp 98–100 °C; [α]D –73 (c 1.0, MeOH).
IR (ATR): 1712, 1643, 1614, 1528 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.88 (d, J = 7.9 Hz, 1 H), 7.43 (d, J = 8.0
Hz, 2 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.07 (s, 1 H), 7.04 (d, J = 8.4 Hz, 1 H),
5.31 (s, 2 H), 5.00 (br s, 1 H), 3.95–3.83 (m, 1 H), 3.62–3.51 (m, 2 H),
2.59 (s, 3 H), 2.36 (s, 3 H), 1.45 (s, 9 H).
13C NMR (125 MHz, CDCl3): δ = 176.1, 167.2, 158.1, 142.7, 140.6,
136.0, 135.7, 132.5, 130.9, 128.7, 127.9, 126.4, 126.3, 81.5, 65.8, 52.3,
44.6, 28.3, 21.8, 21.4.
LC-MS (ES+): m/z = 450 [M + 23]+.
LC-MS (ES+): m/z = 454 [M + 1 (– 2 CH4O3S)]+, 476 [M + 23 (– 2
CH4O3S)]+.
Anal Calcd for C24H29NO6: C, 67.43; H, 6.84; N, 3.28. Found: C, 67.56;
H, 6.86; N, 3.34.
Anal Calcd for C28H27N3O3.2CH4O3S·H2O: C, 54.29; H, 5.62; N, 6.33; S,
9.66. Found: C, 54.04; H, 5.57; N, 6.21; S, 9.77.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

G
M. A. deLong, J. M. Sturdivant
Paper
Synthesis
tert-Butyl [(1H-benzo[d][1,2,3]triazol-1-yl)methyl]carbamate (11)
Chang, J.; Overby, D. R.; Yuan, F.; Gonzalez, P.; Kopczynski, C. C.;
Farsiu, S.; Stamer, W. D. Eur. J. Pharmacol. 2016, 787, 20.
(c) Wang, R.-F.; Williamson, J. E.; Kopczynski, C.; Serle, J. B.
J. Glaucoma 2015, 24, 51.
To 1-hydroxymethylbenzotriazole (10.3 g, 69.1 mmol) in toluene (180
mL) was added tert-butyl carbamate (8.1 g, 69 .1 mmol) and p-TsOH
(26.3 mg, 0.138 mmol) and the solution was refluxed overnight using
a Dean–Stark apparatus. The solvent was evaporated and the crude
product was recrystallized with toluene to give tert-butyl [(1H-ben-
zo[d][1,2,3]triazol-1-yl)methyl]carbamate (11) (10.9 g, 64%) as a
white solid.
(9) (a) Lin, C.-W.; Sherman, B.; Moore, L. A.; Laethem, C. L.; Lu, D.-
W.; Pattabiraman, P. P.; Rao, P. V.; deLong, M. A.; Kopczynski, C.
C. J. Ocular Pharm Ther. 2018, 34, 40. (b) Sturdivant, J. M.;
Royalty, S. M.; Lin, C.-W.; Moore, L. A.; Yingling, J. D.; Laethem,
C. L.; Sherman, B.; Heintzelman, G. R.; Kopczynski, C. C.; deLong,
M. A. Bioorg. Med. Chem. Lett. 2016, 26, 2475.
(10) Lelais, G.; Seebach, D. Peptide Sci. 2004, 76, 206.
(11) Stefani, H. A.; Amaral, M. F. Z. J.; Reyes-Rangel, G.; Vargas-Capo-
rali, J.; Juaristi, E. Eur. J. Org. Chem. 2010, 6393.
IR (ATR): 1684, 1643, 1614, 1528 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 8.40 (m, 1 H), 8.03 (d, J = 8.4 Hz, 1
H), 7.95 (d, J = 8.4 Hz, 1 H), 7.40 (m, 1 H), 7.56 (m, 1 H), 5.88 (d, J = 6.5
Hz, 2 H), 1.36 (s, 9 H).
13C NMR (125 MHz, DMSO-d6): δ = 155.4, 145.4, 132.1, 127.3, 124.1,
119.0, 111.1, 79.2, 53.3, 27.9.
(12) Bower, J. F.; Jumnah, R.; Williams, A. C.; Williams, J. M. J. J. Chem.
Soc., Perkins Trans. 1 1997, 1411.
(13) Martin, N. J. A.; Cheng, X.; List, B. J. Am. Chem. Soc. 2008, 130,
13862.
(14) Davies, H. M. L.; Venkataramani, C. Angew. Chem. Int. Ed. 2002,
41, 2197.
Acknowledgment
(15) Arvanitis, E.; Ernst, H.; Ludwig (née D’Souza), A. A.; Robinson, A.
J.; Wyatt, P. B. J. Chem. Soc., Perkin Trans. 1 1998, 521.
(16) (a) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 83. (b) Evans, D.
A.; Urpi, F.; Sommers, T. C.; Clark, J. S.; Bilodeau, M. T. J. Am.
Chem. Soc. 1990, 112, 8215. (c) Seebach, D.; Abele, S.;
Gademann, K.; Guichard, G.; Hintermann, T.; Jaun, B.;
Matthews, J. L.; Schreiber, J. V. Helv. Chim. Acta 1998, 81, 932.
(17) (a) Diastereomeric ratio (dr) was determined by isolation of
each diastereomer. (b) Enantiomeric excess (ee) was deter-
mined by chiral LC.
(18) (a) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61,
10827. (b) Albericio, F.; Cases, M.; Alsina, J.; Triolo, S. A.;
Carpino, L. A.; Kates, S. A. Tetrahedron Lett. 1997, 38, 4853.
(c) Kunishima, C.; Kawachi, C.; Iwasaki, F.; Terao, K.; Tani, S. Tet-
rahedron Lett. 1999, 40, 5327. (d) HATU = 1-[Bis(dimethyl-
amino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide
Hexafluorophosphate; HOAT = 1-Hydroxy-7-azabenzotriazole;
DMAP = 4-Dimethylaminopyridine; EDC = N-(3-Dimethylami-
We thank Anthony Ribeiro at the Duke University NMR center for
NMR support.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610310.
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nopropyl)-N-ethylcarbodiimide hydrochloride; HOBT
= 1-
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=
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G