Concise asymmetric synthesis of a (1R,2S)-1-amino-2- vinylcyclopropanecarboxylic acid-derived sulfonamide and ethyl ester

Article abstract of DOI:10.1039/c3ob41394b

The development and demonstration of short, robust and chromatography-free sequences for the preparation of a (1R,2S)-1-amino-2-vinylcyclopropane- carboxylic acid-derived sulfonamide and ethyl ester in ≥99% ee are described. Both compounds are common buil

Full text of DOI:10.1039/c3ob41394b

Organic &
Biomolecular Chemistry
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Concise asymmetric synthesis of a (1R,2S)-1-amino-
2-vinylcyclopropanecarboxylic acid-derived
sulfonamide and ethyl ester†
Cite this: Org. Biomol. Chem., 2013, 11,
6796
Sha Lou,* Nicolas Cuniere, Bao-Ning Su‡ and Lindsay A. Hobson
The development and demonstration of short, robust and chromatography-free sequences for the prepa-
ration of a (1R,2S)-1-amino-2-vinylcyclopropane-carboxylic acid-derived sulfonamide and ethyl ester in
≥99% ee are described. Both compounds are common building blocks in multiple preparations of potent
HCV NS3 protease inhibitors. The robustness of the asymmetric cyclopropanation of (E)-N-benzylidene-
glycine ethyl ester under phase transfer catalysis conditions is significantly improved based on a detailed
mechanistic investigation that included an analysis of the catalyst decomposition pathway, a postulated
model for the stereo-selectivity that was guided by calculations and rigorous quality control of the start-
ing materials and reagents. Wet milling has been demonstrated to dramatically accelerate this phase
transfer reaction. A bench stable benzylidene-protected primary 1-amino-2-vinylcyclopropane amide
intermediate was isolated and its reliable enantiomeric enrichment was achieved by a controlled crystalli-
zation process. A chemical resolution procedure was identified using di-p-toluoyl-(D)-tartaric acid to
access (1R,2S)-1-amino-2-vinyl-cyclopropanecarboxylic ester in high ee.
Received 7th July 2013,
Accepted 14th August 2013
DOI: 10.1039/c3ob41394b
www.rsc.org/obc
Introduction
Hepatitis C virus (HCV) is estimated to affect more than
175 million people worldwide and is a frequent cause of liver
failure and hepatocellular carcinoma.1 In the United States,
more people now die from hepatitis each year than from AIDS,
according to a news report from the Centers for Disease
Control and Prevention.2 Eleven different genotypes of the
virus have been identified and genotype 1 (subtypes 1a and 1b)
is by far the most frequent worldwide.3a The current standard
of care for chronic hepatitis C infection is based on a combi-
nation of a pegylated form of interferon (IFN)-α and ribavirin.
This combination cures approximately 80% of infections in
patients infected with HCV genotype 2 or 3, but only 40%–50%
in patients infected with genotypes 1 or 4.3 To improve the
overall cure rate and broaden the spectrum of antiviral activi-
ties against HCV genotypes, several potent HCV NS3/4a
protease inhibitors have recently been developed (Fig. 1),
including asunaprevir (BMS-650032),4 vaniprevir (MK-7009),5
Chemical Development, Bristol-Myers Squibb, One Squibb Drive, New Brunswick,
New Jersey 08903, USA. E-mail: sha.lou@bms.com; Fax: +01-732-227-3936;
Tel: +01-732-227-5510
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
for compounds 1b, 2, 3, 4a and 8, and chiral HPLC chromatograms for 1b, 2, 3
and 4a. See DOI: 10.1039/c3ob41394b
‡Current address: WuXi AppTec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao
Free Trade Zone, Shanghai 200131, China.
Fig. 1 Selected HCV NS3 protease inhibitors.
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macrocyclic BILN 2061,6 and danoprevir (ITMN-191).7
Common structural motifs present in these NS3 protease
inhibitors are (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic
acid (vinyl-ACCA 1a) and its corresponding sulfonamide 1b.
The pendant vinyl group of vinyl-ACCA can be elaborated via
ring-closing metathesis to form a macrocyclic series or further
functionalized for structure–activity relationship studies.
For this reason, the synthesis of chiral vinyl-ACCA deriva-
tives has drawn considerable attention both from academic
and pharmaceutical industrial labs. Synthetic routes leading
to enantioenriched vinyl-ACCA via the enzymatic resolution of
a Boc-protected 1-amino-2-vinylcyclopropanecarboxylic ester
were recently reported by Bristol-Myers Squibb4f and Boehrin-
ger-Ingelheim.5b Although these processes have been success-
fully executed on a kilogram scale, a significant drawback of
this approach is the loss of 50% of the input material in the
enzymatic resolution. To overcome this issue, transition metal-
catalyzed asymmetric syntheses of vinyl-ACCA derivatives have
been reported, including Pd-catalyzed ring opening of 3,4-
epoxy-1-butene with glycine equivalents,8 Pd-catalyzed allylic
alkylation of 1,4-dichlorobut-2-ene with α-aminoacetonitriles,9
along with Cu(I)-catalyzed cyclopropanation of methyl nitro-
acetate-derived phenyliodonium ylides with 1,3-butadiene.10
However, these approaches present several challenges for
implementation on the preparation scale to supply clinical
studies due to the formation of side products, moderate
selectivity, high cost and limited commercial availability of the
raw materials. An enantioenriched vinylcyclopropane dicarb-
oxylic ester can also be prepared starting from (S)-1,2,4-butane-
triol which is elaborated via a Curtius rearrangement to
generate vinyl-ACCA.11 Despite all these advances, a short and
concise asymmetric synthesis of vinyl-ACCA is still highly
desirable. Herein, we report our results on the identification,
development and optimization of a route to vinyl-ACCA ester
and its corresponding sulfonamide. We believe that this will
facilitate the preparation of potential next-generation HCV NS3
protease inhibitors and enable the investigation of their
pharmaceutical potency, safety and bioavailabilities.
Scheme 1 Retrosynthesis of (1R,2S)-1-amino-2-vinyl-cyclopropane-carboxylic
acid-derived sulfonamide 1b.
However, the experimental procedure required a specific par-
ticle size of solid NaOH in the alkylation step and chiral pre-
parative SFC (supercritical fluid chromatography) to isolate the
desired enantiomer of vinyl-ACCA ester 4a. Commercially avail-
able powdered NaOH is very hygroscopic and difficult to handle,
therefore freshly milled NaOH had to be prepared before each
use. In our hands, selectivity of the phase-transfer catalyzed
reaction fluctuated quite significantly using the reported pro-
cedure.12 Thus, we describe a short and robust synthetic
sequence run on a 10 g scale using modified phase transfer
conditions to prepare optically active vinyl-ACCA ethyl ester 2
and vinyl-ACCA derived sulfonamide 1b. The route circum-
vents chiral column chromatography and protecting group
manipulations and results in an increased overall yield.
Retrosynthetically sulfonamide 1b could be prepared from
its ester analog 2 in four steps involving Boc protection, sapo-
nification, coupling of the corresponding Boc-protected amino
acid with cyclopropanesulfonamide and Boc deprotection
(Scheme 1).4f Intermediate 2 could be obtained directly via
hydrolysis of ethyl 1-((E)-benzylideneamino)-2-vinylcyclo-
propane-carboxylate 4a. An alternate approach to 1b would
also utilize 4a; however, the benzylidene protecting group
would be retained to generate primary amide 3. Primary amide
Results and discussion
3 could then be converted to the target compound 1b in only 2 We chose to start the investigation of the phase transfer cata-
steps (coupling with cyclopropanesulfonamide followed by lyzed alkylation of 5a to improve its robustness (the reported
hydrolysis of the benzylidene). This alternate approach would results are shown in entry 1, Table 1).12 The reaction con-
reduce the number of steps for accessing sulfonamide 1b by ditions were modified with aqueous (50 wt%) NaOH used in
avoiding the additional protecting group manipulations.
place of solid NaOH to circumvent the particle size control
The synthesis of vinyl-ACCA ester 4a via an asymmetric and potential agglomeration during the course of the reaction.
phase-transfer catalyzed dialkylation of the inexpensive and The reaction temperature was raised to 10 °C in order to
readily available (E)-N-benzylideneglycine ethyl ester 5a with achieve an acceptable reaction rate so that the reaction could
trans-1,4-dibromo-2-butene 6a was recently reported.12,13 be complete within 17 h. trans-1,4-Dibromo-2-butene 6a was
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gave better yield with shorter reaction times (entry 10). A sig-
nificant improvement in reaction rate was observed when
applying a wet milling process using an Ultra-Turrax in-line
disperser/homogenizer (IKa UTL 25), reducing the reaction
time from 17 h to 1.5 h presumably due to the remarkably
improved mixing of the biphasic mixture (entry 11). Such a
strong dependence on the stirring rate and mixing suggested
that the PTC-1-catalyzed reaction is governed by the interfacial
mechanism where the quaternary ammonium ion mainly
resides in the organic phase and the reaction rate is limited by
the rate of hydroxide extraction.15
Table 1 Experimental investigation of asymmetric phase transfer cyclopropa-
nation of 5a with 6a
Yieldb eec
Entrya Experimental
(%)
(%)
After the set of conditions to give reproducible ee were
determined, we established purity control of all inputs and
began tuning the catalyst structure to further enhance the
selectivity of the process (Fig. 2 & Table 2). A series of cincho-
nidine-based phase transfer catalysts were prepared. We found
that the 2,5-substitution pattern on the aromatic ring of the
benzyl group and the electron withdrawing character of the
substituents were primary factors for obtaining good enantio-
selectivity (entries 1–4). For instance, a subtle change from a
CF3 group to a CH3 group on the aromatic C5 position resulted
1
2
3
4
5
6
7
8
Pin-milled NaOH and water at 0 °C (22 h)12 78
77
77–81
55
73
51
—
37
34
60
NaOHaq (50 wt%) at 10 °C (17 h)
NaOHaq (30 wt%)
88
48
84
53
<2
65
84
77
93
87
KOHaq (50 wt%)
CsOHaq (50 wt%)
Cs2CO3 (70 wt%)
2% Et3N in 5a
5% PhCHO in 5a
9
10
11
PTC-1 with 1.4% cinchonidine
PhCl as the solvent
Turrax wet milling (1.5 h)
80
70
a Except entry 1, the reactions were carried out using 6a as the limiting
reagent, 1.20 equiv. of 5a, solvent (16 g per g-LR), and base (15 g per in a decrease in selectivity of the phase-transfer cyclopropana-
g-LR). b Determined by reverse phase HPLC analysis. c Determined by
normal-phase chiral HPLC analysis.
tion (entry 4). Catalysts with different substitution patterns, for
instance 3,5-substitutions (entries 5–7) and 4-NO2-aryl ana-
logue (entry 8), varying the steric bulk of their substituent
set as the limiting reagent and its complete consumption was
required to preclude unselective cyclopropanation of residue
1,4-dibromo-2-butene in a crude mixture with glycine imine 5a
in the amidation step under basic conditions (see eqn (2)).
With these changes in place, an optimized yield of 88% was
obtained with a range of enantioselectivities from 77% to 81%
(entry 2). Using less concentrated NaOH or LiOH (the result is
not shown) led to a slower reaction, increased formation of
saponification by-products and diminished selectivity (entry
3). Other aqueous alkaline bases, for example KOH and CsOH,
were not as effective as NaOH in promoting the cyclopropana-
tion reaction with good selectivity (entries 4 & 5). Weaker car-
bonate bases, such as Cs2CO3, were not able to mediate the
double alkylation process (entry 6). During the investigation of
the phase transfer reaction, the purity of (E)-N-benzylidene-
glycine ethyl ester 5a was found to be a key factor impacting
the enantioselectivity of the reaction. As little as 2 mol%
residual Et3N, a contaminant from the preparation of the
Schiff base 5a was detrimental to the cyclopropanation stereo-
selectivity and promoted significant unselective alkylation
(entry 7). Residual benzaldehyde (5 mol%) in 5a reduced the
selectivity (entry 8) and we speculated that benzaldehyde may
competitively bind with the catalyst.14 The purity of the phase
transfer catalyst was an additional factor which needed to be
controlled to achieve high enantioselectivity. Contamination of
catalyst PTC-1 with cinchonidine led to the production of 4a in
only moderate ee (entry 9). Toluene, a hydrophobic non-polar
solvent, was selected as the solvent considering its inexpensive
cost, and the good enantioselectivity observed during a solvent
screen. However, additional rounds of solvent screening con-
sistently showed that the reactions in chlorobenzene generally
(entries 9–11) or changing their electronic character (entries
5–11) did not provide a meaningful improvement in enantio-
selectivity under the optimized phase transfer conditions.
Interestingly the use of the O-allylated catalyst in the reaction
afforded the product with negligible enantioselectivity in poor
yield which suggested that the hydrogen bonding ability of the
catalyst was a critical attribute in promoting the reaction
stereoselectively (entry 12). In contrast to PTC-1, the Maruoka
catalyst PTC-13 was not suitable for this phase transfer
Fig. 2 Phase transfer catalysts.
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Table 2 Catalyst survey for asymmetric phase transfer cyclopropanation of 5a
with 6a
Table 3 Substrate survey for asymmetric phase transfer cyclopropanation of 5
with 6
Entrya
Catalyst
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
PTC-1
PTC-2
PTC-3
PTC-4
PTC-5
PTC-6
PTC-7
PTC-8
PTC-9
PTC-10
PTC-11
PTC-12
PTC-13
88
79
91
79
84
80
82
25
81
77
52
15
14
80
60
35
11
51
29
20
35
72
10
17
<2
33
Entrya
5
6
Yieldb (%)
eec (%)
drd
1
2
3
4
5
6
7
8
9
5a
5a
5a
5a
5b
5c
5d
5e
5f
6a
6b
6c
6d
6a
6a
6a
6a
6a
88
33
<5
<5
51
82
<5
15
27
80
64
—
—
10
<5
—
—
<5
>20 : 1
>20 : 1
—
9
10
11
12
13
—
7 : 1
>20 : 1
—
—
10 : 1
a The reactions were carried out using 6a as the limiting reagent, 1.20
equiv. of 5a, toluene (16 g per g-LR), and NaOH (15 g per g-LR).
b Determined by reverse phase HPLC analysis. c Determined by
normal-phase chiral HPLC analysis.
a The reactions were carried out using 6 as the limiting reagent, 1.20
equiv. of 5, toluene (16 g per g-LR), and NaOH (15 g per g-LR).
b Determined by reverse phase HPLC analysis. c Determined by
normal-phase chiral HPLC analysis. d Determined by 1H-NMR.
reaction and promoted the reaction in low yield and selectivity
(entry 13).13
In an effort to attain a better enantioselectivity, we investi-
gated the scope of both electrophiles and nucleophiles
(Table 3). Under our optimized conditions, cyclopropanation
product 4a was always obtained in high dr (entry 1). Its diastereo-
mer underwent an aza-Cope rearrangement and its derived by-
product could be purged in the next step. Commercially avail-
able trans-1,4-dichloro-2-butene 6b was not as competitively
reactive as dibromo butene 6a (entry 2). cis-1,4-Dibromo-2-
butene was not a suitable electrophile giving primarily cyclo-
pentene cyclization product (entry 3) and cis-1,4-diacetoxy-2-
butene was completely unreactive (entry 4). Phase transfer
alkylation of α-aminoacetonitrile-derived imine 5b afforded
the corresponding product in poor ee but good dr (entry 5).
We also synthesized the benzylidene-protected glycinamide 5c,
a bench stable solid compound, and under PTC-1-catalyzed
conditions cyclopropanation did occur and generated amide 3
in good yield (82%) and high dr (>20 : 1) but with low enantio-
selectivity. Benzophenone-derived glycine imines (5d, 5e and
5f) are relatively stable solids. However the cyclopropanation
reactions of these sterically hindered imines were very slow
and often led to stalled reactions at the mono-alkylation stage
or a competing side reaction occurred where the mono-alkyl-
ation intermediate reacted with another equivalent of glycine
imine to form a 2-butene-bridged dimer (entries 7–9).
4a. It was determined that intermediate 7 was a racemic com-
pound during the course of the reaction suggesting that the
first alkylation is either not enantioselective or intermediate 7
is easily racemized. Under the phase transfer conditions, cycli-
zation of isolated racemate 7 produced 4a in 70% yield and
77% ee, which supports the hypothesis that the second alkyl-
ation is both an enantio- and diastereo-defining step.
The degree of diastereoselectivity and enantioselectivity
observed in the phase transfer reaction of 5a with 6a suggests
a catalyst–enolate associated complex with specific steric
requirements. We have developed a model that accounts for
the sense of stereoinduction. We first executed a conformation
search of the catalyst PTC-1 and identified its lowest-energy
conformer which featured a sterically shielded ammonium
functionality (Fig. 4a).17 In addition, we considered the eno-
lates of mono-alkylated intermediate 7 as reactive species in
the second alkylation. Both Z- and E-enolates of 7 were mod-
elled in a reactive conformation with PTC-1 docked by hydro-
gen bonding.18 An MMFF conformation search identified the
lowest-energy conformer of the enolates of 7 complexed with
PTC-1. Upon optimization of the complex structures with DFT
(B3LYP/6-31G*), the E-enolate/PTC-1 complex was significantly
lower in energy than the Z-enolate/PTC-1 complex. According
to this model (Fig. 4b), an orthogonal orientation of the
N-benzylidene moiety relative to the enolate plane would allevi-
ate the allylic strain imposed by the alkyl chain on the enolate
α-carbon. The Br-substituted 2-butenyl group rotated away
A representative reaction progression profile of the phase
transfer reaction is shown in Fig. 3.16 A relatively rapid
accumulation of mono-alkylation intermediate 7 was observed,
accompanied by its slower conversion to the desired product
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from the quinoline ring of the catalyst and the leaving group
bromine atom was pointing towards the positive charge on the
ammonium moiety. Thus, C–C bond formation to generate the
cyclopropane ring favored an attack on the si face of the CvC
double bond of the α-alkyl chain. Our proposed model is con-
sistent with the solution structures of ion pairs formed by
cinchona alkaloid-derived ammonium with small anions
studied by intermolecular NOE correlations in which the pre-
ferred anion occupancy site was determined to be near the
hydroxyl group.19 Although further calculations may be war-
ranted, we suspect that ion pairing may promote subtle confor-
mational changes in the phase transfer catalyst. PTC-1 with a
2,5-substitution pattern on the aryl ring may have lower acti-
vation energy to form the enolate/PTC-1 complex from two free
ions than the catalysts with other substitution patterns.
Although the catalyst PTC-1 is not commercially available,
its precursor 2,5-bis(trifluoromethyl)benzyl bromide is readily
available and synthesis of PTC-1 in high purity has been
demonstrated on a 10 g scale (see the Experimental section).20
In our optimized phase transfer procedure, premixing the cata-
lyst with glycinate Schiff base 5a to minimize the exposure
time of free catalyst to NaOH in the interface appeared to be
an important factor to achieve good enantioselectivity. We
reasoned that such a procedure mitigated catalyst degradation.
Indeed formation of 8 (70%) occurred when PTC-1 was sub-
jected to aqueous NaOH for 3–5 hours. Epoxide 8 was isolated
after holding the phase transfer reaction stream for an
extended period (Scheme 2)21 and its formation appears to be
the major decomposition pathway of the PTC catalyst. Neither
allyl ether 9 that could be generated from a reaction of the
catalyst PTC-1 with 1,4-dibromo-2-butene 6a nor its sub-
sequent Hoffman elimination product 10 was observed.22
Albeit epoxide 8 lacks the ammonium moiety to form an ion
pair with the enolate, it is an organic base that proves to be a
competent catalyst that promotes an unselective alkylation of
5a to generate racemic 4a.
Fig. 3 Reaction profile of the phase transfer alkylation of 5a.
Fig. 4 Calculated ground state conformations of catalyst PTC-1 and the PTC-1/
enolate of 7 complex.
Scheme 2 Plausible catalyst degradation pathways.
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ð1Þ
With enantioenriched Schiff base 4a in hand, we first con-
sidered accessing vinyl-ACCA sulfonamide 1b through its ester
analog 2 given the known synthetic sequence.4f In order to
prepare material of the required purity (>90% ee), a robust
chemical resolution strategy to further upgrade the chiral
purity of vinyl-ACCA ethyl ester 2 was developed (eqn (1)).
Upon a survey of a range of chiral acids and solvents, we were
delighted to find that di-p-toluoyl-(D)-tartaric acid (D-DTTA)
was a suitable acid for the hydrolysis of Schiff base 4a in a
mixture of acetonitrile–water resulting in the formation of the
2/D-DTTA salt which exhibited the desired low solubility in this
solvent system. By careful control of solvent composition
(CH3CN–water = 9 : 1), the 2/D-DTTA salt was reproducibly iso-
lated in high enantiomeric purity (94% ee). An additional
recrystallization afforded 2/D-DTTA in >99% ee with good
material recovery. As described earlier (see Scheme 1), 2 can be
converted to 1b in 4 steps.4f This process suffers from lower
throughput yield, low overall yield and long cycle time due to
additional Boc protection–deprotection steps. In addition,
multiple isolations involving acid–base salt formation to
isolate the corresponding Boc-protected carboxylic acid and
salt breaking for the peptide coupling step are necessary.
Fig. 5 Conglomerate phase diagram of amide 3 at rt.
is most favorable for achieving a successful enantiomeric
enrichment by fractional crystallization from a non-racemic
mixture. Such
a conglomerate phase diagram generally
suggests that only two crystal solid forms are present in solu-
tion,24 one being (1R,2S)-3 and the other being its enantiomer,
(1S,2R)-3. The triangle edges are given in vol% of solvents
(EtOH and cyclohexane) and mole fractions of (R)/(S) enantio-
mers.25 Each point inside the triangle describes a ternary
mixture consisting of all three components. For conglomer-
ates, the diagram consists of three region types: a single under-
saturated liquid phase region (A) close to the top vertex, two
two-phase regions (B) on each side which contain an enantio-
pure solid phase and a saturated liquid phase with one or both
enantiomers, and a three-phase region (C) where under equili-
brium conditions the liquid phase is a saturated solution of a
racemic mixture and the solid phase is a mixture of two
enantiomeric crystal forms. The diagram depicted in Fig. 4
suggests that to ensure isolation of enantiopure 3, the isolation
needs to be conducted above the solubility of the racemic frac-
tion of the enantioenriched mixture present in the process
stream and that the isolation yield can be improved by increas-
ing the anti-solvent volume percentage, cyclohexane in this
case, within the B-phase regions.
The final two steps in the improved route to 1b were rela-
tively straightforward (Scheme 3). The sulfonylation to furnish
11 was carried out by treating amide 3 with cyclopropanesulf-
onyl chloride in the presence of a strong base. The main
impurity in this step is the α-aminonitrile derivative, a dehy-
dration product of the primary amide 3. Typically 7–10 mol%
of this side product was formed and its downstream hydrolysis
product was successfully purged during the crystallization of
1b. It was found that using lithium tert-butoxide as a base sig-
nificantly mitigated the formation of α-aminonitrile. However,
lithium tosylate formed in the hydrolysis step has higher solu-
bility in EtOAc and could not be effectively purged by filtration
ð2Þ
Having vinyl-ACCA sulfonamide 1b as our final target, we
set out to identify and develop a shorter sequence that allowed
the use of the N-benzylidene protecting group and thus avoid
extra protection–deprotection steps. Vinyl-ACCA ester 4a is not
a stable intermediate and was not isolated. Instead, the
process stream containing 4a was subjected to amidation with
a mixture of formamide and sodium methoxide in MeOH
(MeOH is required) to form a stable and isolable primary
amide 3 in 70% yield and >99% ee upon crystallization from
ethanol and cyclohexane (eqn (2)).23 To test the efficiency of
this process in upgrading optical purity, primary amide 3 with
a range of ee values was subjected to the EtOH–cyclohexane
crystallization conditions. Impressively, input 3 with ≥70% ee
could be recrystallized under controlled conditions to provide
>99% ee material. A conglomerate phase diagram was deter-
mined for primary amide 3 (Fig. 5). In fact only 5 to 10% of
the compounds have a conglomerate forming property which
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Experimental section
General information
The following reagents were purchased and used without
further purification: cinchonidine (Aldrich), 2,5-bis(trifluoro-
methyl)benzyl bromide (SynQuest), benzaldehyde (Aldrich),
glycine ester hydrochloride (Aldrich), trans-1,4-dibromo-2-
butene (AK Scientific), NaOH (50 wt% aq., Alfa Aesar), toluene
(J. T. Baker), formamide (Aldrich), NaOMe (25 wt% in MeOH,
Aldrich), cyclopropanesulfonyl chloride (AK Scientific) and
TsOH monohydrate (Aldrich). (E)-N-Benzylideneglycine ethyl
ester was prepared according to a literature procedure6,25 and
the spectral data are in agreement with reported values.6 HPLC
analysis was carried out using a Shimadzu Prominence system.
Daicel CHIRALCEL® columns or Daicel CHIRALPAK®
columns (internal diameter 4.6 mm, column length 250 mm,
particle size 5 μm) were used for chiral HPLC analysis. All reac-
tions were carried out in oven-dried glassware or a clean and
nitrogen-dried Chemglass jacketed 1 L process reactor under
an atmosphere of nitrogen.
Scheme 3 Synthesis of 1b from 3.
N-[2,5-Bis(trifluoromethyl)benzyl]cinchonidinium bromide
(PTC-1). The title compound was prepared according to a
reported procedure12 with an additional reslurry process to
prior to crystallization of 1b. The presence of LiOTs in the reac- upgrade its purity. To a 3-neck RBF equipped with a thermo-
tion stream either resulted in a low isolated yield or 1b con- couple and a condenser were added cinchonidine (10.0 g [lim-
taminated with LiOTs. Reactions using other strong bases, iting reagent]; 1.0 equiv.; 34.0 mmoles) and toluene (15.0 mL
such as organolithium reagents, lithium bis(trimethylsilyl)- per g-bulk-LR; 150 mL). 2,5-Bis(trifluoromethyl)benzyl
amide, Grignard reagents, and DBU, did not afford 1b in com- bromide (1.20 equiv.; 40.8 mmoles; 7.48 mL; 12.5 g) was added
parable yield. Finally, sodium tert-butoxide was chosen for the to the RBF via a syringe. The solution was heated to 110 °C
sulfonylation step and the resulting insoluble NaOTs were (internal solution temperature) and stirred for 4.0 h. The reac-
efficiently removed by filtration. Hydrolysis of the N-benzyl- tion was monitored by HPLC until <5.0 RAP cinchonidine was
idene Schiff base with TsOH·H2O yielded sulfonamide 5 as a reached. The reaction mixture was cooled to rt over 2.0 h and
shelf-stable TsOH salt in high purity.
stirred at rt for 1.0 h. The resulting white solid was filtered and
washed with toluene (60.0 mL). The cake was air-dried for
5.0 min. Its purity was determined by HPLC and contained
3.50 RAP cinchonidine. The purity of the catalyst was further
upgraded by a reslurry procedure: 20.1 g was treated with
Conclusions
In summary, a 4-step chromatography-free sequence to rapidly EtOH–MTBE (10.0 mL g−1, 100 mL, 1 : 1). The resulting slurry
access (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic sulfon- was stirred overnight and filtered. The cake was washed with
amide 1b in ≥99% ee and 51% overall yield has been develo- EtOH–MTBE (1.0 mL g−1, 10.0 mL, 1 : 1) and MTBE (2.0 mL
ped. The robustness of the asymmetric cyclopropanation g−1, 20.0 mL). The resulting cake was dried in a vacuum oven
under phase transfer catalysis conditions was significantly at 50 °C and 25.0 inHg for 2.0 h. N-[2,5-Bis(trifluoromethyl)-
improved from the previously reported process by a deliberate benzyl]cinchonidinium bromide was obtained as a white solid
procedure design based upon mechanistic investigations and (15.4 g, 77% yield, purity >99% with <0.05 RAP of cincho-
understanding the quality of the starting materials and the nidine). Reverse phase HPLC analysis: Phenomenex Luna
catalyst. Amidation of the vinylcyclopropanecarboxylic ester 4a 3 µm 100AC18, 4.6 × 50 mm; solvent pair: A = 0.05% TFA in
with sodium formamide afforded a bench stable benzylidene- water–MeOH 80 : 20, B = 0.05% TFA in CH3CN–MeOH–water
protected primary amide 3 and its excellent optical purity 75 : 20 : 5; gradient: start % B = 0, 0.5 Min. 0%, 5 Min. 10%,
enrichment to ≥99% ee was achieved by controlled crystalliza- 10 Min. 100%, 12 Min. 100%; flow rate = 2 ml min−1; wave-
tion conditions. In addition, a robust chemical resolution length = 254 nm; retention time: 1.45 min (cinchonidine),
using D-DTTA following the asymmetric phase transfer reaction 7.58 min (PTC-1), 7.80 min (dihydro-PTC-1); sampling: about
was developed to access (1R,2S)-1-amino-2-vinylcyclopropane- 10 mg solid was dissolved in 10 mL MeOH in a volumetric
1
carboxylic ester 2 in ≥94% ee and ≥99% ee upon recrystalliza- flask; H NMR (500 MHz, DMSO-d6) δ 8.99 (d, J = 4.4 Hz, 1H),
tion. Both chiral vinylcyclopropanecarboxylic sulfonamide and 8.60 (s, 1H), 8.37 (d, J = 8.2 Hz, 1H), 8.25 (s, 2H), 8.11 (dd, J =
ester are valuable synthons for the preparation of HCV pro- 8.4, 1.1 Hz, 1H), 7.85 (td, J = 7.6, 0.9 Hz, 1H), 7.81 (d, J =
tease inhibitors.
4.4 Hz, 1H), 7.74 (ddd, J = 8.4, 6.9, 1.1 Hz, 1H), 6.88 (d,
6802 | Org. Biomol. Chem., 2013, 11, 6796–6805
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J = 3.2 Hz, 1H), 6.57 (br. s., 1H), 5.66 (ddd, J = 17.2, 10.9, J = 7.1 Hz, 3H); 13C NMR (126 MHz, DMSO-d6) δ 169.2, 159.4,
6.0 Hz, 1H), 5.57–5.50 (m, 1H), 5.49–5.41 (m, 1H), 5.25 (d, J = 135.9, 134.3, 130.8, 128.6 (2C), 127.9 (2C), 117.4, 60.7, 53.5,
17.3 Hz, 1H), 4.94 (d, J = 10.4 Hz, 1H), 4.37 (m, 1H), 4.14–4.02 35.3, 21.5, 14.1; IR (KBr) 3419, 2990, 1717, 1635, 1577, 1462,
(m, 2H), 3.51 (t, J = 11.2 Hz, 1H), 3.25–3.13 (m, 1H), 2.67 (br. 1368, 1291, 1174, 1144, 1025, 916, 758, 702 cm−1; HRMS (EI)
s., 1H), 2.17–2.03 (m, 2H), 2.01 (br. s., 1H), 1.81–1.70 (m, 1H), calcd for C15H18NO2 (M + 1+) 244.13321, found 244.13292.
1.23–1.13 (m, 1H); 13C NMR (126 MHz, DMSO-d6) δ 150.2,
(1R,2S)-1-((E)-Benzylideneamino)-2-vinylcyclopropane carbox-
147.6, 145.0, 137.9, 134.50–133.80 (q, J = 31.25 Hz), 133.7 (d, amide (3). All reagent stoichiometries were calculated based
J = 3.7 Hz), 132.99–132.10 (q, J = 32.5 Hz), 129.9, 129.6 (q, J = on trans-1,4-dibromo-2-butene (10.0 g [limiting reagent]; 1.0
5.5 Hz), 129.5, 128.2 (q, J = 3.7 Hz), 127.4, 127.1, 124.2, 123.5, equiv.; 46.75 mmoles). A solution of 4a was concentrated to
123.4 (q, J = 275 Hz), 123.2 (q, J = 275 Hz), 119.9, 116.4, 68.0, ∼2 mL g−1
.
Tetrahydrofuran (5.0 mL per g-bulk-LR;
64.7, 59.2, 58.3, 51.2, 37.3, 25.3, 24.4, 21.2; Analytical data are 614 mmoles; 50.0 mL; 44.3 g) and formamide (6.0 equiv.;
in agreement with reported values.12
281 mmoles; 11.2 mL; 12.6 g) were charged followed by a slow
(1R,2S)-Ethyl 1-((E)-benzylideneamino)-2-vinylcyclopropane addition of sodium methoxide (2.50 equiv.; 117 mmoles;
carboxylate (4a). To a 1 L reactor was charged toluene (16.0 g 27.2 mL; 25.3 g) via a syringe. The reaction solution was
per g-bulk-LR; 1.73 moles; 178 mL; 160 g) and N-[2,5-bis(tri- heated to 50 °C and stirred for 4.0 h. The reaction was moni-
fluoromethyl)benzyl]cinchonidinium bromide (0.050 equiv.; tored by HPLC until 100% conversion was observed. The reac-
2.34 mmoles; 1.41 g). The catalyst solution was cooled to 5 °C tion mixture was cooled to rt and was quenched with water
and (E)-N-benzylideneglycine ethyl ester (1.20 equiv.; (5.0 mL per g-bulk-LR; 50.0 mL; 50.0 g). The solution pH was
56.1 mmoles; 35.8 g, 30.0 wt% in toluene) was charged via a adjusted from pH ∼ 11 to pH ∼ 9 by adding a saturated
syringe. The mixture was agitated for 15.0 min. A solution of aqueous NH4Cl solution. Methyl t-butyl ether (10.0 mL per
trans-1,4-dibromo-2-butene (10.0
g [limiting reagent]; 1.0 g-bulk-LR; 100 mL; 74.2 g) was charged and the bottom
equiv.; 46.75 mmoles) in toluene (4.0 g per g-bulk-LR; aqueous layer was separated. The organic layer was washed
1.95 moles; 46.0 mL; 40.0 g) was charged via a syringe. Sodium with water (5.0 mL per g-bulk-LR; 50.0 mL; 50.0 g) twice and
hydroxide (15 g per g-bulk-LR; 1.875 moles; 98.3 mL; 150 g; concentrated to ∼50 mL (5.0 mL per g-bulk-LR). The solution
50 wt%) was added via an addition funnel over a period of 1 h was subjected to a constant volume distillation by adding
and the reaction solution temperature was maintained at methyl t-butyl ether (200 mL) over 1 h via an addition funnel
≤5 °C. After the NaOH(aq) charge, the reaction mixture was until the water content reached <0.10 wt% (determined by Karl
warmed to 10 °C and agitated (800–1000 rpm) for 15–17 h. Fischer titration). The solvent was then exchanged to cyclo-
Upon complete consumption of monoalkylation intermediate hexane by adding cyclohexane (200 mL) at such a rate as to
7 (<2.0% RAP relative to product determined by reverse phase maintain the solvent volume at 50 mL (5.0 mL per g-bulk-LR)
HPLC), agitation was stopped and the biphasic reaction at 30 °C. Ethanol (1 mL per g-bulk-LR; 171.76 mmoles;
mixture was allowed to separate for 30 min. The aqueous 10.0 mL; 7.91 g) was charged. The resulting solution was
phase was removed and the organic phase was filtered through heated to 60 °C to obtain a homogeneous solution. The solu-
a Celite® bed to remove any precipitates. The filtrate was used tion was cooled to 45 °C and seeded with (1R,2S)-1-((E)-benzyl-
in the next step without further purification. The solution ideneamino)-2-vinyl-cyclopropanecarboxamide 3 (0.005 g per
yield (88%) was determined by obtaining the wt% of the g-bulk-LR; 50 mg). After aging at 45 °C for 30 min the slurry
product in the stream according to the standard linear cali- was cooled to 20 °C over 2 h and aged at 20 °C for 1 h. The
bration curve. An analytical sample was obtained by column resulting crystallized product was filtered, washed with EtOH–
chromatography (silica gel, eluted with EtOAc in hexanes cyclohexane (1 : 5, 10 mL) and cyclohexane (10 mL). The wet
(5–30% gradient)). Appropriate fractions were combined, con- cake was dried in the vacuum oven at 50 °C and 25 inHg for
centrated and dried under high vacuum. Reverse phase HPLC 4.0 h. (1R,2S)-1-((E)-Benzylideneamino)-2-vinylcyclopropane
analysis: Waters XTerra Phenyl Column, 3.5 µm, 4.6 × 100 mm; carboxamide 3 was obtained as an off-white solid (7.03 g,
solvent pair: A = 0.05% NH4OH in water–MeOH 80 : 20, B = 70.1% yield, >99% ee, and >98 wt% potency). Reverse phase
0.05% NH4OH in CH3CN–MeOH 80 : 20; gradient: start % HPLC analysis: Waters XTerra Phenyl Column, 3.5 µm, 4.6 ×
B = 0, 0.5 Min. 0%, 2 Min. 40%, 10 Min. 60%, 14 Min. 100%; 100 mm; solvent pair: A = 0.05% NH4OH in water–MeOH
flow rate = 1 ml min−1; wavelength = 254 nm; retention time: 80 : 20, B = 0.05% NH4OH in CH3CN–MeOH 80 : 20; gradient:
7.36 min ((E)-N-benzylideneglycine ethyl ester), 9.63 min start % B = 0, 0.5 Min. 0%, 2 Min. 40%, 10 Min. 60%, 14 Min.
(product 3), 10.58 (monoalkylation intermediate); chiral HPLC 100%; flow rate = 1 ml min−1; wavelength = 254 nm; retention
analysis: Daicel CHIRALPAK AS-H column, 5 µm, 4.6 × time: 7.79 min (product 3), 9.63 min (starting material 4a);
150 mm; solvent system: 2% IPA in heptanes (0.05% Et2NH); sampling: about 250 mg reaction organic stream was diluted
1.0 mL min−1; retention times: 4.39 min (major), 5.44 min to 25 mL in a volumetric flask with acetonitrile–water = 1 : 1;
(minor); 1H NMR (500 MHz, DMSO-d6) δ 8.35 (s, 1H), chiral HPLC analysis: Daicel CHIRALPAK AD-H column, 5 µm,
7.80–7.72 (m, 2H), 7.51–7.41 (m, 3H), 5.67 (ddd, J = 17.1, 10.3, 4.6 × 150 mm; solvent system: 15% IPA in heptane; 1.0 mL
8.8 Hz, 1H), 5.30 (dd, J = 17.2, 1.4 Hz, 1H), 5.11 (dd, J = 10.4, min−1; retention times: 4.39 min (minor), 6.16 min (major);
1.9 Hz, 1H), 4.21–4.12 (m, 2H), 2.36 (q, J = 8.7 Hz, 1H), 1.87 1H NMR (major diastereomer only, 500 MHz, DMSO-d6) δ 8.07
(dd, J = 7.9, 5.4 Hz, 1H), 1.76 (dd, J = 9.5, 5.4 Hz, 1H), 1.21 (t, (s, 1H), 7.92–7.87 (m, 2H), 7.82 (br. s., 1H), 7.48–7.41 (m, 4H),
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5.90 (ddd, J = 17.3, 10.1, 8.8 Hz, 1H), 5.20 (dd, J = 17.3, 1.9 Hz, 125.4 (2C), 119.7, 41.4, 30.8, 28.9, 20.7, 16.3, 5.7. IR (KBr)
1H), 5.01 (dd, J = 10.4, 1.9 Hz, 1H), 2.07–1.95 (m, 2H), 3428, 3192, 2921, 2832, 2650, 2575, 1707, 1699, 1599, 1518,
1.92–1.87 (m, 1H); 13C NMR (126 MHz, DMSO-d6) δ 171.5, 1479, 1360, 1329, 1190, 1136, 1036, 1010, 882, 815, 783,
154.6, 135.9, 135.7, 130.7, 128.5 (2C), 128.3 (2C), 116.2, 52.3, 686 cm−1
; HRMS (EI) calcd for C9H15N2O3S (M +
1+)
20.4; IR (KBr) 3455, 3282, 2885, 1691, 1578, 1404, 1364, 1210, 231.07979, found 231.07951.
1166, 1001, 914, 904, 777, 765, 698, 636 cm−1; HRMS (EI) calcd
for C13H15N2O (M + 1+) 215.11789, found 215.11765.
(1R,2S)-Ethyl 1-amino-2-vinylcyclopropanecarboxylate di-p-
toluoyl-(D)-tartaric acid salt (2). A (1R,2S)-ethyl 1-((E)-benzy-
(1R,2S)-1-Amino-N-(cyclopropylsulfonyl)-2-vinyl cyclopropane- lideneamino)-2-vinylcyclopropane carboxylate (4a) solution in
carboxamide tosylate salt (1a). To a 3-neck RBF equipped toluene was concentrated to about 84 wt% (determined by
with a thermocouple was charged (1R,2S)-1-((E)-benzylidene- H-NMR). In a 250 mL RBF was charged 4a (10.0 g [limiting
amino)-2-vinylcyclopropane carboxamide 3 (10.0 g [limiting reagent]; 1.0 equiv.; 34.52 mmoles), acetonitrile (18.0 mL per
reagent]; 1.0 equiv.; 46.7 mmoles; 1.00 g) and tetrahydrofuran g-bulk-LR; 190 mL), water (2.0 mL per g-bulk-LR; 20.0 mL) and
(6.0 mL per g-bulk-LR; 73.7 mmoles; 60.0 mL; 53.2 g) and the (+)-di-1,4-toluoyl-D-tartaric acid monohydrate (1.0 equiv.;
solution was cooled to 2 °C in an ice/water bath. Sodium t-but- 34.5 mmoles; 13.5 g). The solution was heated to 75 °C and
oxide (2.20 equiv.; 102.7 mmoles; 9.87 g) in 30.0 mL THF was stirred for 2.0 h until complete conversion of 4 was observed
charged over 15 min via a syringe to control the temperature to by HPLC. The solution was cooled to rt over 3 h and aged at rt
<5 °C. The resulting brown slurry was stirred for 10 min. Cyclo- for 1 h. The resulting white solid was filtered and washed with
propanesulfonyl chloride (1.10 equiv.; 51.3 mmoles; 5.23 mL; acetonitrile–water (18 : 2, 20 mL) and acetonitrile (20 mL). The
7.22 g) in tetrahydrofuran (4.0 mL per g-bulk-LR; 492 mmoles; wet cake was dried in a vacuum oven at 50 °C and 25 inHg for
40.0 mL; 35.4 g) was charged over 10 min at 0–6 °C. The slurry 5 h. The desired product 2 was obtained as a white solid
was stirred at 2 °C for 2.0 h and at 20 °C for 2.0 h until the (13.2 g, 71% yield and 94% ee). Reverse phase HPLC analysis:
reaction was deemed to be complete by HPLC. p-Toluenesulfo- Waters XTerra Phenyl Column, 3.5 µm, 4.6 × 100 mm; solvent
nic acid monohydrate (2.20 equiv.; 102.7 mmoles; 19.5 g) was pair: A = 0.05% NH4OH in water–MeOH 80 : 20, B = 0.05%
charged at 20 °C. The resulting mixture was warmed to 50 °C NH4OH in CH3CN–MeOH 80 : 20; gradient: start % B = 0,
over 15 min and stirred at 50 °C for 3.0 h. The reaction solu- 0.5 Min. 0%, 2 Min. 40%, 10 Min. 60%, 14 Min. 100%; flow
tion was cooled to 20 °C and ethyl acetate (10.0 mL per g-bulk- rate = 1 ml min−1; wavelength = 220 nm; retention time:
LR; 100.0 mL; 90.0 g) was charged. The resulting solid (NaCl 1.18 min (di-1,4-toluoyl-D-tartaric acid), 6.31 min (2), 6.50 min
and NaOTs) was removed by filtration. The filtrate was concen- (benzaldehyde), 9.63 min (3); sampling: about 250 mg reaction
trated to ∼5 mL per g-bulk-LR and subjected to a constant organic stream was diluted to 25 mL in a volumetric flask with
volume distillation with ethyl acetate (10.0 mL per g-bulk-LR; acetonitrile; chiral HPLC analysis: Daicel Chiralpak AD-3R,
100 mL; 90.0 g) at 50 °C until the water content was <0.10 wt% 3 µm, 4.6 × 150 mm; solvent A = 0.01 M NH4OAc in MeOH–
(determined by Karl Fischer titration). The stream was cooled water (20 : 80), solvent B = B2 = 0.01 M NH4OAc in MeOH–water–
to 30 °C and seeded with 1 (0.005 g per g-bulk-LR; 50 mg), CH3CN (20 : 5 : 75); gradient: start % B = 0%, 25% (10 min),
cooled to 10 °C over 2.0 h and aged at 10 °C for 1.0 h. The 35% (20 min), 100% (25 min); 0.8 mL min−1; retention times:
resulting crystals were filtered and washed twice with ethyl 13.83 min (major), 14.96 min (minor); 1H NMR (major diaster-
acetate (1.50 mL per g-bulk-LR; 15.0 mL; 13.5 g). The wet cake eomer only, 500 MHz, DMSO-d6) δ 7.86 (d, J = 7.9 Hz, 4H), 7.34
was dried in a vacuum oven at 50 °C and 25 inHg for 4.0 h to (d, J = 8.2 Hz, 4H), 5.69 (s, 2H), 5.57 (dt, J = 17.2, 9.7 Hz, 1H),
give (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropane- 5.22 (dd, J = 17.0, 1.6 Hz, 1H), 5.06 (dd, J = 10.2, 1.7 Hz, 1H),
carboxamide tosylate salt (13.7 g; 73% yield, >99% ee) as a 4.19–4.06 (m, 2H), 2.38 (s, 6H), 2.16 (q, J = 10.0 Hz, 1H), 1.52
white solid. Reverse phase HPLC analysis: Waters XTerra (dd, J = 9.5, 5.4 Hz, 1H), 1.46 (dd, J = 7.7, 5.5 Hz, 1H), 1.19 (t,
Phenyl Column, 3.5 µm, 4.6 × 100 mm; solvent pair: A = 0.05% J = 7.1 Hz, 3H); 13C NMR (126 MHz, DMSO-d6) δ 169.8, 167.8
NH4OH in water–MeOH 80 : 20, B = 0.05% NH4OH in CH3CN– (2C), 164.8 (2C), 144.0 (2C), 133.5, 129.34 (4C), 129.31 (4C),
MeOH 80 : 20; gradient: start % B = 0, 0.5 Min. 0%, 2 Min. 126.5 (2C), 117.7, 71.7, 61.2, 40.6, 31.7, 21.2 (2C), 20.1, 14.1; IR
40%, 10 Min. 60%, 14 Min. 100%; flow rate = 1 ml min−1
;
(KBr) 3432, 3176, 2945, 1728, 1707, 1612, 1269, 1178, 1110,
wavelength = 254 nm; retention time: 7.79 min (4a); sampling: 750, 694 cm−1; LRMS (EI) calcd for C8H14NO2 (M + 1+)
about 250 mg reaction organic stream was diluted to 25 mL in 156.10184, found 156.10191.
a volumetric flask with acetonitrile–water = 1 : 1; chiral HPLC
analysis: Daicel CHIRALCEL OJ-H column, 5 µm, 4.6 ×
150 mm; solvent system: 20% EtOH in heptane (0.1% TFA);
Acknowledgements
1.0 mL min−1; retention times: 6.17 min (minor), 8.53 min
1
(major); H NMR (major diastereomer only, 500 MHz, DMSO- The authors acknowledge Dr Purushotham Vemishetti,
d6) δ 8.69 (br. s., 2H), 7.55–7.33 (m, 2H), 7.12 (d, J = 7.9 Hz, Dr Shawn B. Brueggemeier, Dr Antonio G. Ramirez, and
2H), 5.68–5.51 (m, 1H), 5.35 (d, J = 17.0 Hz, 1H), 5.27–5.14 (m, Mr Victor W. Rosso for technical support and are grateful to
1H), 3.05–2.90 (m, 1H), 2.35–2.23 (m, 4H), 2.15 (t, J = 7.4 Hz, Dr. David A. Conlon, Dr Sergei Kolotuchin, Dr Martin
1H), 1.59 (dd, J = 9.8, 7.3 Hz, 1H), 1.17–1.01 (m, 4H); 13C NMR D. Eastgate, Dr Robert E. Waltermire, Dr Steven Tymonko, and
(126 MHz, DMSO-d6) δ 166.9, 145.4, 137.8, 131.2, 128.1 (2C), Dr Boguslaw M. Mudryk for helpful discussions.
6804 | Org. Biomol. Chem., 2013, 11, 6796–6805
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10 B. Moreau and A. B. Charette, J. Am. Chem. Soc., 2005, 127,
Notes and references
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of
2,5-bis(trifluoromethyl)benzyl
M. S. Waters, D. Zewge, A. Nolting, D. Zhao, R. A. Reamer,
P. G. Dormer, K. M. Belyk, I. W. Davies, P. N. Devine and
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6 P. L. Beaulieu, J. Gillard, M. D. Bailey, C. Boucher,
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K. Grozinger, I. Houpis, V. Farina, H. Heimroth, T. Krueger
and J. Schnaubelt, J. Org. Chem., 2005, 70, 5869.
bromide: $43.5 per g from Aldrich, $115 per 5 g from
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