Chemoenzymatic synthesis of each enantiomer of orthogonally protected 4,4-difluoroglutamic acid: A candidate monomer for chiral Bronsted acid peptide-based catalysts

Article abstract of DOI:10.1021/jo2018679

We have accomplished an asymmetric synthesis of each enantiomer of 4,4-difluoroglutamic acid. This α-amino acid has been of interest in medicinal chemistry circles. Key features of the synthesis include highly scalable procedures, a Reformatsky-based coupling reaction, and straightforward functional group manipulations to make the parent amino acid. Enantioenrichment derives from an enzymatic resolution of the synthetic material. Conversion of the optically enriched compounds to orthogonally protected forms allows for the selective formation of peptide bonds. 4,4-Difluoroglutamic acid, in a suitably protected form, is also shown to exhibit enhanced catalytic activity in both an oxidation reaction and a reduction reaction, in comparison to the analogous glutamic acid derivative.

Full text of DOI:10.1021/jo2018679

Article
pubs.acs.org/joc
Chemoenzymatic Synthesis of Each Enantiomer of Orthogonally
Protected 4,4-Difluoroglutamic Acid: A Candidate Monomer for
Chiral Brønsted Acid Peptide-Based Catalysts
Yang Li and Scott J. Miller*
Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States
S
* Supporting Information
ABSTRACT: We have accomplished an asymmetric synthesis of
each enantiomer of 4,4-difluoroglutamic acid. This α-amino acid
has been of interest in medicinal chemistry circles. Key features of
the synthesis include highly scalable procedures, a Reformatsky-
based coupling reaction, and straightforward functional group
manipulations to make the parent amino acid. Enantioenrichment
derives from an enzymatic resolution of the synthetic material.
Conversion of the optically enriched compounds to orthogonally
protected forms allows for the selective formation of peptide
bonds. 4,4-Difluoroglutamic acid, in a suitably protected form, is also shown to exhibit enhanced catalytic activity in both an
oxidation reaction and a reduction reaction, in comparison to the analogous glutamic acid derivative.
needed more rapid access to large quantities of the material and
unambiguously in each enantiomeric form. Additionally, the
parent compound 4,4-difluoroglutamic acid per se cannot be
incorporated into a peptide directly, without being protected
orthogonally. This unglamorous, though necessary, aspect was
not well-described in the chemical literature.
INTRODUCTION
■
One of the foci of the research in our laboratory is the use of
amino acids and peptides as catalysts for synthetic organic
transformations.1 Central to the function of these peptides are
specific catalytically active amino acids that, in and of
themselves, may mediate the chemical transformation of
interest. In some respects, this strategy may be analogous to
the roles of catalytic residues in enzymes.1c,2 Recently, we have
been studying the potential catalytic activity of peptides
containing carboxylic acid side chains, in the forms of aspartic
or glutamic acids, and have found their applications in the
epoxidation of olefins3 and the Baeyer−Villiger oxidation of
ketones.4 In these processes, we have gained evidence that the
carboxylic acid side chain may engage in transient conversion to
a peracid intermediate (Figure 1a).5 Notably, aspartic and
glutamic acid moieties could also be relevant for the
development of chiral Brønsted acid-based catalysts, a subfield
of asymmetric catalysis that has seen explosive interest in recent
years.6 Of course, the role of these amino acid side chains in
enzymatic proton transfer catalysis, and as H-bond donors or
acceptors, is also ubiquitous.7 The most successful non-
enzymatic Brønsted acid catalysts reported to date appear to
exhibit pKa values that are lower than typical aspartic or
glutamic acid residues.8 Therefore, we wondered if 4,4-
difluoroglutamic acid, by virtue of the inductive effect of the
fluorine atoms,9 could provide a boost in catalytic activity for
Brønsted acid-catalyzed processes, over its proteinogenic
glutamic counterpart. Such a residue then might be inserted
into peptide libraries, facilitating the search for new chiral
Brønsted acid catalysts (Figure 1b).
RESULTS AND DISCUSSION
■
We were very much attracted to the simplicity and robustness
of the racemic synthesis developed by Tsukamoto and
Coward10b and therefore based our work on this efficient
route (Scheme 1). Our synthesis began from chlorodifluoro-
acetic acid 1, an inexpensive commercially available acid. Its
diethylamide derivative 2 was subjected to a Reformatzky
reaction to give an N,O-acetal 3. For this step, we found that
the original procedure,11 which heats acid-washed zinc powder
with reactants at 65 °C, was not suitable for large-scale
synthesis. The zinc insertion into 2 is highly exothermic, yet it
does not take place unless being heated to ∼50 °C;
consequently, the reaction is prone to thermal runaway. We
examined experimentally various physical and chemical
methods of zinc activation,12 including ultrasound, Zn/Cu
couple, Zn/Ag couple, TMSCl, and 1,2-dibromoethane as
additives. None were particularly effective. Eventually, we found
that adding a catalytic amount of CeCl3 allowed the reaction to
proceed smoothly at room temperature13 and gave an
acceptable yield of 3 in 53%. This modification should make
for a safer procedure and one that is more easily scalable to the
desired 20 g level. The N,O-acetal 3 was subsequently
The compound of interest 4,4-difluoroglutamic acid has been
synthesized before, in both racemic and optically pure forms.10
Excellent as these pioneering precedents are, we felt that we
Received: September 13, 2011
Published: October 31, 2011
© 2011 American Chemical Society
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according to the multistep procedure developed by Tsukamoto
and Coward to give 4,4-difluoroglutamic acid 9. We have made
two minor modifications to their procedure to suit our needs.
First the reaction temperature for the acetylation of
intermediate 5 was raised by 30 °C from room temperature,
which shortened the reaction time from overnight as reported
to half an hour. Secondly we also chose to convert the crude
hydrochloride salt 9 to the Cbz-protected amino acid 10
directly, thus bypassing a laborious ion-exchange chromatog-
raphy step.
From intermediate 10, the key to the eventual orthogonal
protection of 4,4-difluoroglutamic acid was the differential
functionalization of the two carboxylic acids. While we were
unable to find conditions that could selectively esterify the
carboxylic acids in 10, we found that the dimethyl ester
derivative 11 could be readily hydrolyzed to give 12 with total
regioselectivity, due to the activating effect of the geminal
difluoro group.15 From 12, a tert-butyl ester was installed to
give an orthogonally protected difluoroglutamic acid 13.16
We next endeavored to resolve the racemic amino acid ester
13 into the individual enantiomers by enzymatic hydrolysis
(Scheme 2). A survey of the literature revealed that subtilisin,
an inexpensive commercially available enzyme, was often
employed for this purpose.17 There were two issues, however,
that needed to be addressed. First, the substrate 13 is not
appreciably soluble in water, the preferred solvent for
enzymatic reaction; second, while the serine protease subtilisin
Carlsberg is optimal under alkaline conditions, substrate 13 is
sensitive to base. After experimenting unsuccessfully with
organic−aqueous biphasic conditions, we eventually decided to
develop conditions with a homogeneous reaction medium,
which was buffered at neutral pH, and with a water-miscible
cosolvent added to improve the solubility of the substrate.
From a screen of cosolvents (Table 1), we found that the
enzyme was the most active with DMSO as the cosolvent.
Using DMSO as the preferred cosolvent, we next attempted
to optimize other reaction variables (Table 2). The amount of
the sodium phosphate buffer salts, which was critical to the
reaction, was found to be optimal at 1.5 equiv (entries 1−3),
yielding the highest selectivity factor. The enzymatic reaction
was also very sensitive to the water content of the reaction
medium. Using the aforementioned phosphate buffer, we found
that a 60:40 ratio of DMSO to aqueous buffer was optimal
(entry 1). Higher water content caused lower selectivity,
presumably caused by higher background hydrolysis rate (entry
4), while higher DMSO content led to enzyme denaturation
(entry 5). Furthermore, we found that the enzyme was
functioning more selectively at lower temperatures, albeit at a
lower reaction rate (entries 6 and 7), which could be
compensated by increasing the catalyst loading (entry 8).
Finally, we were pleased to discover that the outcome of the
reaction improved when conducted on a larger scale (entry 9).
Under the optimized resolution conditions, the amino acid
ester 13 was obtained in ≥99% ee and the amino acid 14 was
obtained in >90% ee. The recovery of the two compounds was
close to the theoretical limit of 50%. The reaction has since
been run on multigram scale without difficulty (Scheme 2).
Having obtained the protected amino acid L-14, its
enantiomer D-14 could be made by removing the methyl
ester in D-13. In a quite surprising event, unforeseen by us, the
presence of the geminal difluoro group in D-13 made the tert-
butyl ester more susceptible to hydrolysis than the methyl ester.
We have screened a number of reagents and conditions for the
Figure 1. (a) Acid−peracid catalytic cycle. (b) Brønsted acid-catalyzed
reactions.
a
Scheme 1. Synthesis of DL-13
a
Reagents and conditions: (i) SOCl2, DMF, 50−90 °C; Et2NH, Et2O,
0−23 °C; (ii) Zn, CeCl3, Et2SO4, DMF, 0−65 °C; (iii) Amberlyst 15
H, EtOH/H2O, rt; (iv) CH2NO2(COOEt), Et2NH, THF, 0−23 °C;
(v) Ac2O, cat. H2SO4, DCM, 55 °C; (vi) NaBH4, THF, 0 °C; (vii)
Raney Ni, 1 atm H2, EtOH, rt; (viii) 12 M HCl, 100 °C; (ix) CbzCl,
NaHCO3, H2O, 0−23 °C; (x) TMSCHN2, PhMe/MeOH, rt; (xi)
LiOH, MeOH/H2O, 0 °C; (xii) tBuBr, K2CO3, BnNEt3Cl, AcNMe2,
55 °C.
hydrolyzed to give the corresponding hemiacetal 4, by
employing a strong cationic exchange resin Amberlyst 15 as
the catalyst.14 The hemiacetal 4 was then transformed
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a
Scheme 2. Enzymatic Kinetic Resolution of DL-13
a
Reagents and conditions: (i) subtilisin Carlsberg, DMSO/phosphate buffer, pH 7.0, rt; (ii) Me3SnOH, 1,2-DCE, 70 °C.
a
Table 1. Screening of Cosolvent for Enzymatic Resolution
With a robust and scalable synthesis of the monomeric
amino acid in hand, the stage was set for the investigation of its
reactivity and potential catalytic utilities. While these studies are
underway in our laboratory, we wish to present here two
reactions that illustrate the benefit from the increased acidity of
the difluoroglutamic acid: the Baeyer−Villiger oxidation of
cyclobutanones20 and the transfer hydrogenation of imines.21
Both processes are known to be catalyzed by Brønsted acids. In
the experiments presented below, we found that the
difluoroglutamic catalyst gave substantial rate acceleration
over its corresponding identical glutamic counterpart, thus
confirming our initial hypothesis. For example, as shown in
Scheme 3, we observe the 3-phenyloxetanone 16a undergoes
oxidative ring expansion in the presence of glutamic acid
derivative 15a (10 mol %) to give lactone 16b in only 28%
yield within 18 h. On the other hand, the difluorinated catalyst
analogue 15b delivers the product in 79% yield within the same
time frame. By the same token, glyoximine derivative 17 is
reduced upon exposure to the Hantszsch ester and catalyst 15a
(10 mol %) to afford phenylglycine derivative 18 in 20% yield
(Scheme 4). Once again, catalyst 15b exhibits greater activity,
with 18 produced in 68% yield under the analogous conditions.
The products of these reactions, 16b and 18, are not
surprisingly racemic, given the simplicity of the catalyst.
However, once this amino acid is incorporated into peptide
b
b
cosolvent
yield
%
cosolvent
MeCN
yield %
tBuOH
THF
7
1
1
4
3
DMF
10
39
12
1,4-dioxane
acetone
DMSO
[bmim][BF4]
a
Conditions: 26 mM substrate in 40:60 pH 7.0 sodium phosphate
buffer/cosolvent mixture, 0.77 equiv buffer salts, 73U enzyme/mmol
substrate, 37 °C, 20 h. Uncalibrated yield measured by integrating
b
UV 215 nm absorption in HPLC trace.
deprotection of the methyl ester, including LiOH, K2CO3,
TMSOK, and LiI. None were high yielding and selective for
this substrate. Finally, we discovered that trimethyltin
hydroxide could remove the methyl ester in high yield and
without racemization,19 thus giving the other enantiomer of the
protected amino acid. While the entire synthetic sequence is
perhaps lengthy, it only makes uses of four chromatographic
purification steps. Most of the intermediates are carried forward
without purification.
a
Table 2. Optimizing the Reaction Conditions for Enzymatic Resolution
b
c
d
e
entry
enzyme loading (U/mmol)
phosphate (equiv)
DMSO (vol %)
temp (°C)
yield (%)
ee of SM (%)
krel
1
2
3
4
5
6
7
8
77
77
77
77
77
77
77
269
269
0
1.5
3.0
6.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
60
60
60
50
70
60
60
60
60
60
37
37
37
37
37
30
23
23
23
23
53
70
67
67
7
82
94
98
90
4
16
7
12
7
3
46
39
52
53
4
76
60
92
>99
40
58
40
>80
f
9
g
10
ND
a
Reactions were run using 13 mM substrate in DMSO/pH 7.0 sodium phosphate buffer mixture under the specified conditions for 12−17 h.
b
c
Reactions were conducted on 5−10 mg scale. The amount of enzyme used, in enzyme unit, per mmol of substrate. The equivalents of phosphates
d
e
relative to substrate. Uncalibrated yield measured by integrating UV 215 nm absorption in HPLC trace. Nominal selectivity factor calculated using
formula by Kagan.18 Reaction was run at 100 mg scale. Not determined.
f
g
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Proton and carbon NMR chemical shifts were recorded relative to
TMS and were calibrated to either internally added TMS or residual
solvent signal. Fluorine NMR chemical shifts were recorded relative to
FCCl3 and were calibrated automatically by the spectrometer using
solvent deuterium lock signal. Fluorine NMR spectra were recorded
without proton decoupling. All NMR data were acquired at ambient
temperature.
Scheme 3. Difluoroglutamic Acid-Catalyzed Baeyer−Villiger
Oxidation
Infrared spectra were acquired on a Fourier transform spectrometer
equipped with a diamond crystal for attenuated total reflectance
measurement. Only peaks in the carbonyl region are reported.
The procedures leading up to the preparation of 13 and 14 are
described for representive experiments repeated several times on
convenient scale. We have since used this procedure to successfully
make more than 20 g of 13 per batch and have resolved DL-13 on 5 g
scale.
2-Chloro-N,N-diethyl-2,2-difluoroacetamide (2). See Support-
ing Information for a diagram of the apparatus used for this reaction.
Thionyl chloride (65 mL, 0.89 mol) was slowly added from an
addition funnel to a solution of chlorodifluoroacetic acid (50 mL, 0.58
mol) in dry DMF (400 mL). The solution was then heated in an oil
bath to 50 °C with stirring. Chlorodifluoroacetic chloride was
produced as a gas (bp 26 °C), which was condensed via a dry ice
cooled condenser to another flask containing a solution of diethyl-
amine (210 mL, 2.02 mol) in dry diethyl ether (500 mL) at 0 °C. The
temperature of the oil bath was gradually increased from 50 to 90 °C
to maintain a steady rate of chlorodifluoroacetic chloride production.
After 2 h, the oil bath was removed. The reactions were left stirring
overnight. Afterward, the ethereal solution was filtered. The filtrate was
washed with water (3 × 500 mL) and 1 M HCl (3 × 500 mL), dried
over magnesium sulfate, and then evaporated in vacuo to dryness to
give the product as a pale yellow-green liquid (68.7 g, 64%). Proton
and fluorine NMR spectra were recorded in CDCl3 and were
consistent with literature data.11
3-(Dimethylamino)-3-ethoxy-N,N-diethyl-2,2-difluoropropa-
namide (3). [Caution: this is a highly exothermic reaction, and therefore
it is very important to monitor the reaction temperature closely and apply
cooling swiftly if the temperature rises rapidly above 70 °C in order to
avoid thermal runaway.] A solution of diethyl sulfate (50 mL, 374
mmol) in dry DMF (90 mL) was heated under nitrogen at 90 °C for 2
h and then cooled with an ice bath to <10 °C. To the solution α-
chloroamide 2 (34.7 g, 187 mmol), zinc powder (25.0 g, 375 mmol),
and finally anhydrous cerium trichloride (1.86 g, 7.55 mmol) were
added. After stirring under nitrogen at <10 °C for 25 min, the reaction
was taken out of the ice bath. As the reaction mixture warmed up to rt,
the reaction gradually became highly exothermic. An ice bath was used
to cool the reaction mixture when necessary, such that the temperature
never exceeded 60 °C. After the exotherm subsided, the reaction
mixture was further stirred under nitrogen at rt for 2 h. After adding
more anhydrous cerium trichloride (516 mg, 2.09 mmol) to the
reaction mixture, it was heated in a 65 °C oil bath for 1 h and then
filtered to give a viscous dark brown opaque solution. The solution was
continuously extracted with pentane (250 mL) overnight.
structures, there are ample opportunities for creating highly
enantioselective catalysts, as we have demonstrated numerous
times before in related systems.1a−c,3 These preliminary
observations confirm our original hypothesis and provide the
basis of our ongoing studies with the title compound.
CONCLUSIONS
■
We have developed a robust and scalable synthesis of a key
amino acid for studies in asymmetric Brønsted acid catalysis. Of
additional significance, 4,4-difluoroglutamic acid derivatives
have proven of interest in medicinal chemistry settings,22 and
the synthesis we report here may prove useful to chemists
beyond the context of our specific goals. In this context, we
have synthesized both enantiomers of orthogonally protected
4,4-difluoroglutamic acids in a protected form suitable for use
in peptide coupling. The synthesis yields products with high
optical purity and requires few purification steps. Preliminary
experiments have demonstrated that the difluoroglutamic acid
is a promising strong Brønsted acid catalyst. We are currently
engaged in the study of peptides incorporating this amino acid.
EXPERIMENTAL SECTION
■
General Information. Anhydrous CeCl3 was prepared by slowly
flame drying the commercially available heptahydrate under vacuum
and then cooled to rt under vacuum. Purchased zinc powder was
purified by first washing with 2 M HCl, then rinsing with water,
acetone, and diethyl ether, and finally flame-dried under vacuum. All
other reagents and solvents were used as received without purification,
unless otherwise noted.
The enzyme subtilisin Carlsberg (EC 3.4.21.62) from Bacillus
licheniformis was purchased and was used as received. Enzyme activity
was assayed by the manufacturer. One unit enzyme is defined by the
manufacturer as the amount of enzyme that can hydrolyze casein to
produce 1.0 μmol of tyrosine per minute at pH 7.5 and 37 °C, as
detected colorimetrically by Folin−Ciocalteu reagent.
The extract was evaporated in vacuo to remove pentane. To the
residual liquid was added saturated aqueous sodium bicarbonate
solution (100 mL) and diethyl ether (100 mL). The resulting
heterogeneous mixture was filtered. The organic layer was separated
Unless otherwise noted, all reactions were carried out at benchtop
conditions without exclusion of air or moisture.
Scheme 4. Difluoroglutamic Acid-Catalyzed Transfer Hydrogenation
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out. The aqueous layer was extracted with diethyl ether (2 × 100 mL).
The combined ethereal extract was washed with water (2 × 50 mL)
and brine (50 mL), dried over sodium sulfate, and concentrated to
give a dark red viscous oil as the crude product. The crude product was
distilled under vacuum (1.9 Torr). Product 3 was collected at 80 °C as
a clear colorless liquid (24.8 g, 53%). Proton and fluorine NMR
spectra were recorded in CDCl3 and were consistent with literature
data.11
possible. In the end, a viscous yellow green oil was obtained as the
crude difluoroglutamic acid 9.
The crude 9 was dissolved in water (550 mL) at 0 °C. To it was
added sodium bicarbonate (54.5 g, 647 mmol) portionwise. To the
alkaline suspension, benzyl chloroformate (24 mL, 163 mmol) was
then added. The suspension was stirred at rt overnight. Afterward, the
reaction suspension was then washed with chloroform (100 mL × 5).
The aqueous phase was acidified in an ice bath with 12 M HCl (70
mL) and then extracted with EtOAc (150 mL × 4). The aqueous
phase was saturated with brine (250 mL) and then extracted again
with EtOAc (150 mL). The combined organic extract was washed with
brine (100 mL), dried over magnesium sulfate, and evaporated in
vacuo to dryness to give a clear yellow oil. The oil gradually solidified
under vacuum to give dicarboxylic acid 10 as a pale red-orange solid
(13.74 g, 54% from 7). Proton and fluorine NMR spectra were
recorded in CD3OD. The product was ∼90% pure by visual inspection
of its NMR spectra. The compound’s proton and fluorine NMR
spectra, as well as its mass spectrum, were consistent with literature
data.15
Dimethyl N-Benzyloxycarbonyl-4,4-difluoro-DL-glutamate
(11). To a solution of dicarboxylic acid 10 (5.95 g, 18.8 mmol) in
5:2 toluene/methanol (175 mL) was added dropwise an excess
amount (∼25 mL) of a 2 M solution of trimethylsilyldiazomethane in
hexanes, until gas evolution ceased, and the reaction solution stayed
golden yellow in color. Acetic acid was then added dropwise to the
reaction solution, until gas evolution ceased and the golden yellow
color disappeared. The reaction solution was concentrated to give a
viscous oil, which was then diluted with ethyl acetate (300 mL),
washed with saturated aqueous solution of sodium bicarbonate (100
mL) and brine (100 mL), dried over magnesium sulfate, and
evaporated to give a viscous oil. The oil was purified by flash
chromatography on silica gel (8−66% ethyl acetate in hexanes) to give
diester 11 as a clear colorless oil, which gradually solidified into a white
waxy solid (4.89 g, 76%). Rf 0.62 (2:1 hexanes/EtOAc). 1H NMR (400
MHz, CDCl3): δ 7.40−7.28 (m, 5H), 5.44 (d, J = 8.3 Hz, 1H), 5.13,
5.10 (ABq, J = 12.2 Hz, 2H), 4.61 (td, J = 7.8, 4.8 Hz, 1H), 3.774 (s,
4-Ethoxycarbonyl-N,N-diethyl-2,2-difluoro-4-nitrobutana-
mide (7). To a solution of N,O-acetal 3 (41.5 g, 164 mmol) in
ethanol (370 mL) was added Amberlyst 15 resin (33.0 g, 4.99 mequiv
H+/g) and water (6.0 mL, 333 mmol). After stirring at rt overnight,
the mixture was filtered. The resulting brown solution was
concentrated in vacuo to dryness and then redissolved in diethyl
ether (300 mL). A copious amount of anhydrous potassium carbonate
was added to the solution, which was then vigorously stirred for 3 h.
The mixture was filtered through Celite and then concentrated in
vacuo to give the crude hemiacetal 4 as a clear yellow oil (36.7 g).
The oil 4 was dissolved in dry THF (200 mL). To the solution in an
ice bath, ethyl nitroacetate (18.5 mL, 167 mmol) and diethylamine
(24.0 mL, 230 mmol) were added. The solution was stirred at rt under
nitrogen overnight. Afterward, the volatile components in the reaction
solution were evaporated in vacuo. In an ice bath, to the residual oil
was added 0.6 M HCl solution (400 mL). The mixture was extracted
with EtOAc (3 × 200 mL). The organic extract was washed with 0.5 M
HCl solution (3 × 100 mL) and brine (100 mL), dried over MgSO4,
and concentrated in vacuo to give crude alcohol 5 as a viscous red oil
(50.9 g). [N.B.: thorough removal of diethylamine from the crude product
mixture by vacuum drying is critical for the subsequent acetylation
reaction.]
The oil 5 was dissolved in dry DCM (150 mL). To it acetic
anhydride (20.5 mL, 211 mmol) and 18 M sulfuric acid (0.45 mL, 8.1
mmol) were added. The resulting solution was heated to reflux (55
°C). After 30 min, the reaction solution was poured into water (300
mL) and extracted with EtOAc (3 × 200 mL) and then DCM (200
mL). The combined organic phase was washed with brine (3 × 100
mL), dried over MgSO4, and concentrated in vacuo to give acetylated
alcohol 6 as a viscous red oil.
3H), 3.766 (s, 3H), 2.79 (qd, J = 15.5, 4.7 Hz, 1H), 2.64 (qd, J = 15.4,
2
7.3 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 170.9, 164.2 (t, JCF
=
1
32.3 Hz), 155.6, 136.0, 128.5, 128.2, 128.1, 114.8 (t, JCF = 251.5 Hz),
The oil 6 was dissolved in dry THF (750 mL). To the solution at 0
°C, sodium borohydride (6.32 g, 165 mmol) was added. The resulting
solution was stirred under nitrogen at 0 °C. After 2 h, the reaction
solution was concentrated in vacuo to dryness. The residual material
was redissolved in EtOAc (200 mL). To the solution was added
carefully 1 M HCl (300 mL). After vigorous stirring, the organic phase
was separated out. The aqueous phase was extracted with EtOAc (2 ×
200 mL). The combined organic phase was washed with brine (100
mL), dried over MgSO4, and concentrated in vacuo to give crude
product 7 as a viscous yellow oil, which was purified by flash column
(i.d. 13 cm × L 26 cm) chromatography on silica gel, eluting with
16:100 to 20:100 EtOAc/hexanes. The purified product was a clear
colorless oil (23.9 g, 49% from 3). Proton and fluorine NMR spectra
were recorded in CDCl3 and were consistent with literature data.10b
N-Benzyloxycarbonyl-4,4-difluoro-DL-glutamic Acid (10). A
slurry of Raney nickel in water (35 mL wet volume) was centrifuged.
The supernatant water was removed. The metallic residue was
resuspended in absolute ethanol (35 mL). The centrifugation−
suspension cycle was repeated two more times to obtain a suspension
of Raney nickel in ethanol. The suspension was added to a solution of
nitro compound 7 (23.9 g, 80.7 mmol) in absolute ethanol (200 mL).
The mixture was stirred at rt overnight under a balloon of hydrogen.
The reaction mixture was then filtered through Celite to give a cloudy
green solution, which was evaporated in vacuo to dryness to give crude
amide 8 as a viscous green oil.
67.1, 53.4, 52.8, 48.9 (t, JCF = 4.9 Hz), 36.1 (t, JCF = 23.5 Hz). 19F
3
2
3
NMR (376 MHz, CDCl3): δ −104.12 (t, JHF = 15.6 Hz). IR (FT-
ATR): 1769, 1732, 1685 cm−1. MS (ESI) calculated for [C15H17F2NO6
+ H]+ 346.1102; found 346.1105.
5-tert-Butyl 1-Methyl N-benzyloxycarbonyl-4,4-difluoro-DL-
glutamate (DL-13). To a solution of diester 11 (4.89 g, 14.2 mmol)
in methanol (180 mL) at 0 °C was added a solution of lithium
hydroxide monohydrate (0.606 g, 14.2 mmol) in water (60 mL)
portionwise. After stirring for 2 min, 2 M hydrochloric acid (25 mL)
and brine (350 mL) were added to the reaction solution, which was
then extracted with EtOAc (3 × 150 mL). The organic phase was
washed with water (2 × 100 mL) and brine (100 mL), dried over
magnesium sulfate, and evaporated to dryness to give crude monoester
12 as a pale yellow oil, which was then dissolved in N,N-
dimethylacetamide (110 mL). Benzyltriethylammonium chloride
(3.26 g, 14.2 mmol), potassium carbonate (49 g, 351 mmol), and
tert-butyl bromide (79 mL, 687 mmol) were added to the solution.
The mixture was stirred at 55 °C for 18 h. Afterward, the reaction
mixture was partitioned between water (500 mL) and ethyl acetate
(500 mL). The organic phase was washed with water (3 × 250 mL)
and brine (100 mL), dried over magnesium sulfate, and evaporated to
dryness to give a yellow oil, which was purified by flash
chromatography on silica gel (6−50% ethyl acetate in hexanes), to
afford tert-butyl ester DL-13 as a white solid (3.92 g, 71% from 11). Rf
1
0.39 (3:1 hexanes/EtOAc). H NMR (500 MHz, CDCl3): δ 7.38−
The oil 8 was dissolved in 12 M HCl (300 mL) and then stirred at
100 °C overnight. Hydrochloric acid was removed by vacuum
distillation, at temperature not exceeding 100 °C. A yellow oil was
obtained after the distillation. A small amount of water was added to
dissolve the oil. The solution was then evaporated in vacuo to dryness.
This step was repeated several times to remove as much HCl as
7.27 (m, 5H), 5.51 (d, J = 8.1 Hz, 1H), 5.10 (s, 2H), 4.61 (td, J = 7.9,
4.7 Hz, 1H), 3.75 (s, 3H), 2.70 (qd, J = 15.6, 4.7 Hz, 1H), 2.59 (qd, J
= 15.4, 7.6 Hz, 1H), 1.49 (s, 9H). 13C NMR (126 MHz, CDCl3): δ
2
171.1, 162.4 (t, JCF = 31.4 Hz), 155.7, 136.1, 128.6, 128.3, 128.2,
114.8 (t, 1JCF = 252.3 Hz), 85.2, 67.3, 53.0, 49.3 (t, 3JCF = 4.4 Hz), 36.1
2
(t, JCF = 23.6 Hz), 27.7. 19F NMR (376 MHz, CDCl3): δ −103.9,
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2
3
−104.3 (ABX2, JFF = 266 Hz, JHF = 15.7 Hz). IR (FT-ATR): 1750,
1713, 1693 cm−1. MS (ESI) calculated for [C18H23F2NO6 + H]+
388.1572; found 388.1582.
over sodium sulfate, and evaporated in vacuo to dryness to give a clear
colorless oil, which was then dissolved in 1:1 DCM/TFA (5 mL) and
stirred at rt. After 1 h, all volatile components in the reaction solution
was evaporated in vacuo to give a pale yellow oil as the crude product,
which was purified by flash column chromatography (85:15:1 EtOAc/
hexanes/AcOH) on silica gel to afford the product as a white foam
Kinetic Resolution of DL-13. To a solution of DL-13 (1.00 g, 2.58
mmol) in DMSO (120 mL), sodium phosphate buffer (pH 7.0, 400
mM, 10 mL), water (50 mL), and a solution of subtilisin (59.9 mg) in
water (20 mL) were added sequentially. An ice bath was used to keep
the reaction mixture at rt during the addition process. The solution
was stirred at rt for 13 h, then acidified with 10% citric acid solution in
water (300 mL), and saturated with brine (300 mL). The solution was
extracted with ethyl acetate (4 × 200 mL). The organic extract was
washed with water (5 × 300 mL) and brine (300 mL), dried over
sodium sulfate, and evaporated to dryness to yield a clear colorless oil.
The oil was purified by flash column chromatography. The column
was first eluted with 75:25:1 hexanes/EtOAc/AcOH to collect 5-tert-
butyl 1-methyl N-benzyloxycarbonyl-4,4-difluoro-D-glutamate (D-13)
and then with 50:50:1 hexanes/EtOAc/AcOH to collect N-
benzyloxycarbonyl-5-tert-butyl-4,4-difluoro-L-glutamic acid (L-14).
5-tert-Butyl 1-Methyl N-benzyloxycarbonyl-4,4-difluoro-D-
glutamate (D-13). D-13 was obtained as a clear colorless oil (447
mg, 45%), which gradually solidifies into a translucent white solid
upon standing. Its mass spectrum, proton, carbon, and fluorine NMR
spectra were identical to those of the racemic compound DL-13. Rf
(75:25:1 hexanes/EtOAc/AcOH) 0.34. IR (FT-ATR): 1749, 1725,
1714 cm−1. [α]D20 = −1.4° (c = 1.0, chloroform). Chiral HPLC
(Chiralpak OJ-H, 250 × 4.6 mm, 85:15 hexanes/EtOH, 1.0 mL/min,
25 °C, UV 215 nm): tL = 10.4 min, tD = 13.4 min, >99% ee.
N-Benzyloxycarbonyl-5-tert-butyl-4,4-difluoro-L-glutamic
Acid (L-14). L-14 was obtained as a clear colorless oil. The oil was
submerged in hexane and then scratched with a glass rod rapidly. The
oil quickly solidifies into a white solid (451 mg, 47%). Rf (50:50:1
1
(456 mg, 93%). Rf (85:15:1 EtOAc/hexanes/AcOH) 0.23. H NMR
(400 MHz, CDCl3): δ 7.37−7.27 (m, 5H), 6.06 (d, J = 8.5 Hz, 1H),
5.09 (s, 2H), 4.59 (td, J = 8.8, 3.9 Hz, 1H), 3.65−3.34 (m, 4H), 2.55−
2.38 (m, 2H), 2.11−1.77 (m, 6H). 13C NMR (126 MHz, CDCl3): δ
176.7, 170.4, 156.6, 136.4, 128.6, 128.2, 128.0, 67.0, 51.8, 46.7, 46.3,
29.6, 27.6, 26.0, 24.2. IR (FT-ATR): 3278, 1702, 1605 cm−1. [α]D20
=
+3.5° (c = 0.9, chloroform). MS (ESI) calculated for [C17H22N2O5 +
H]+ 335.1607; found 335.1605.
(S)-4-Benzyloxycarbonylamino-2,2-difluoro-5-oxo-5-(1-
pyrrolidinyl)pentanoic Acid (15b). A solution of L-14 (0.38 g, 1.0
mmol), HOBt hydrate (187 mg, 1.20 mmol), EDC·HCl (233 mg, 1.19
mmol), and pyrrolidine (212 μL, 2.39 mmol) in DCM (5 mL) was
stirred overnight at rt. Afterward, the solution was diluted with EtOAc
(100 mL), washed with 10% aqueous citric acid solution (2 × 30 mL),
saturated aqueous sodium bicarbonate solution (30 mL), and brine
(30 mL), dried over sodium sulfate, and evaporated in vacuo to
dryness to give a clear colorless oil. The oil was purified by flash
column chromatography (8:2 hexanes/acetone) to give a clear
colorless oil (398 mg, 92%), a portion of which (299 mg) was then
dissolved in 30:1:1 TFA/Et3SiH/H2O (9.6 mL) and stirred at rt. After
4 h, all volatile components in the reaction solution was evaporated in
vacuo. The residual oil was purified by reverse phase chromatography
on C18 column (2−50% MeCN in H2O, with 0.1% TFA in both
eluents). The product fractions were evaporated in vacuo to give a
white solid. In order to remove the remaining trace amount of TFA,
the product was dissolved in water and evaporated in vacuo for three
times, followed by addition and evaporation of toluene for three times.
It was then dissolved in water/MeOH and lyophilized to give a white
powder (202 mg, 73% overall). The final product was verified to be
free from TFA by fluorine NMR. The compound exhibits multiple
conformers in NMR at rt, the dominant major conformer is as follows:
1H NMR (500 MHz, DMSO): δ 14.7 (br, 1H), 7.80 (d, J = 8.5 Hz,
1
hexanes/EtOAc/AcOH) 0.34. H NMR (500 MHz, CDCl3): δ 10.03
(s, br), 7.38−7.26 (m, 5H), 5.56 (d, J = 8.3 Hz, 1H), 5.11, 5.10 (ABq, J
= 12.3 Hz, 2H), 4.62 (td, J = 8.0, 4.4 Hz, 1H), 2.74 (qd, J = 15.6, 4.3
Hz, 1H), 2.62 (qd, J = 15.3, 7.7 Hz, 1H), 1.48 (s, 9H). 13C NMR (126
2
MHz, CDCl3): δ 175.0, 162.4 (t, JCF = 31.4 Hz), 156.1, 135.8, 128.5,
1
3
128.3, 128.2, 114.6 (t, JCF = 252.3 Hz), 85.4, 67.5, 49.1 (t, JCF = 3.9
Hz), 35.6 (t, JCF = 23.6 Hz), 27.6. 19F NMR (376 MHz, CDCl3): δ
2
−103.7, −104.0 (ABX2, 2JFF = 266 Hz, 3JHF = 15.7 Hz). IR (FT-ATR):
3294, 1758, 1746, 1727, 1716, 1693 cm−1. MS (ESI) calculated for
[C17H21F2NO6 + H]+ 374.1415, found 374.1419. [α]D20 = +0.2° (c =
1.0, chloroform). Chiral HPLC (Chiralcel OD, 250 × 4.6 mm,
950:50:1 hexanes/iPrOH/TFA, 1.0 mL/min, 25 °C, UV 215 nm): tL =
20.8 min, tD = 25.6 min, 92% ee.
1H), 7.39−7.28 (m, 5H), 5.02 (s, 2H), 4.55 (td, J = 8.0, 5.3 Hz, 1H),
3.52 (dt, J = 9.8, 6.8 Hz, 1H), 3.43 (dt, J = 10.0, 6.8 Hz, 1H), 3.32−
3.22 (m, 2H), 2.62−2.46 (m, 1H), 2.43−2.28 (m, 1H), 1.92−1.82 (m,
2H), 1.80−1.70 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 169.6,
164.8 (br), 155.9, 135.9, 128.3, 127.9, 127.7, 115 (v br), 67.0, 47.2,
2
46.8, 46.5, 36.5 (t, JCF = 23.1 Hz), 25.6, 23.8. 19F NMR (376 MHz,
DMSO): δ −103.5, −104.3 (ABX2, 2JFF = 256 Hz, 3JHF = 16.8 Hz). IR
(FT-ATR): 3277, 1708, 1610 cm−1. [α]D20 = −5.1° (c = 1.0,
chloroform). MS (ESI) calculated for [C17H20F2N2O5 + H]+
371.1419; found 371.1422.
N-Benzyloxycarbonyl-5-tert-butyl-4,4-difluoro-D-glutamic
Acid (D-14). To a solution of D-13 (447 mg, 1.15 mmol) in dry 1,2-
dichloroethane (40 mL) under nitrogen at 70 °C, trimethyltin
hydroxide (642 mg, 3.48 mmol) was added. After stirring for 3 h, the
reaction solution was diluted with EtOAc (120 mL) and washed
successively with 10% citric acid solution in water (3 × 50 mL) and
brine (50 mL), dried over magnesium sulfate, and then evaporated to
dryness to afford a clear colorless oil. The oil was purified by flash
chromatography (50:50:1 hexanes/EtOAc/AcOH). After purification,
the afforded product was submerged under hexanes and then
scratched rapidly with a glass rod until all of the product solidified.
The hexanes solvent was evaporated in vacuo to give the product D-14
as a white powder (312 mg, 72%). Its mass spectrum, infrared
spectrum, proton, carbon, and fluorine NMR spectra were identical to
those of its enantiomer L-14. [α]D20 = −1.1° (c = 1.0, chloroform).
Chiral HPLC (Chiralcel OD, 250 × 4.6 mm, 950:50:1 hexanes/
Baeyer−Villiger Oxidation of Cyclobutanone. To a solution
of cyclobutanone 16a23 (28.0 mg, 0.192 mmol) and catalyst 15b (7.1
mg, 0.019 mmol) in CDCl3 (0.50 mL), 30% aqueous hydrogen
peroxide (39.1 μL, 0.383 mmol) was added. The mixture was
vigorously stirred at rt for 18 h, before bromoform (16.8 μL, 0.192
mmol) was added to the reaction mixture. The reaction mixture was
then examined by proton NMR. The product yield (79%) was
determined by comparing the integration of the internal standard
bromoform (singlet at 6.82 ppm) and the carboxylate methylene
protons of the lactone product 16b (dd at 4.67 and 4.27 ppm). The
proton NMR spectrum of the product was consistent with literature
data.23 Chiral HPLC (Chiralpak IA, 250 × 4.6 mm, 99:1 hexanes/
EtOH, 1.0 mL/min, 25 °C, UV 215 nm): t = 41.5, 48.4 min, racemic.
Transfer Hydrogenation of Imine. A mixture of imine 1724
(≥9:1 Z/E mixture of isomers, 53.4 mg, 0.198 mmol), diethyl 1,4-
dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (55 mg, 0.22 mmol),
and a solution of catalyst 15b (7.4 mg, 0.020 mmol) in CDCl3 (0.50
mL) was stirred at rt. The mixture gradually became a homogeneous
solution as it stirred overnight for 17 h. An NMR internal standard
1,3,5-trimethoxybenzene (11.8 mg, 0.0702 mmol) was added to the
reaction solution, which was then examined by proton NMR. The
product yield (68%) was determined by comparing the integration of
iPrOH/TFA, 1.0 mL/min, 25 °C, UV 215 nm): tL = 21.2 min, tD
24.7 min, 99% ee.
=
(S)-4-Benzyloxycarbonylamino-5-oxo-5-(1-pyrrolidinyl)-
pentanoic Acid (15a). A solution of Cbz-Glu(OtBu)-OH (501 mg,
1.47 mmol), HOBt hydrate (583 mg, 3.73 mmol), EDC·HCl (724 mg,
3.70 mmol), and pyrrolidine (freshly distilled, 330 μL, 3.72 mmol) in
DCM (5 mL) was heated by microwave at 60 °C for 20 min.
Afterward, the solution was diluted with EtOAc (100 mL), washed
with 10% aqueous citric acid solution (3 × 30 mL), saturated aqueous
sodium bicarbonate solution (3 × 30 mL), and brine (30 mL), dried
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the aryl protons of the internal standard (singlet at 6.08 ppm) and the
p-methoxyphenyl protons of the product 18 (doublet at 6.53 ppm).
The proton NMR spectrum of the product was consistent with
literature data.14 Chiral HPLC (Chiralpak IB, 250 × 4.6 mm, 90:10
hexanes/iPrOH, 0.5 mL/min, 25 °C, UV 245 nm): t = 14.5, 15.1 min,
racemic.
Richards, N. G. J. J. Org. Chem. 2001, 66, 6381−6388. (d) Meffre, P.;
Dave, R. H.; Leroy, J.; Badet, B. Tetrahedron Lett. 2001, 42, 8625−
8627. (e) Dave, R.; Badet, B.; Meffre, P. Amino Acids 2003, 24, 245−
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(12) (a) Erdik, E. Tetrahedron 1987, 43, 2203−2212. (b) Ocampo,
R.; Dolbier, W. R. Jr. Tetrahedron 2004, 60, 9325−9374.
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(b) Ocampo, R.; Dolbier, W. R. Jr.; Abboud, K. A.; Zuluaga, F. J. Org.
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ASSOCIATED CONTENT
* Supporting Information
NMR spectra and HPLC traces for compounds 11−15; a
diagram of the apparatus to prepare compound 2. This material
is available free of charge via the Internet at http://pubs.acs.org.
■
S
(14) Bijeire, L.; Denier, C.; Mulliez, M.; De Lima, W. T. Phosphorus
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AUTHOR INFORMATION
Corresponding Author
*E-mail: scott.miller@yale.edu.
■
ACKNOWLEDGMENTS
This work is supported by National Institutes of Health,
National Institute of General Medical Sciences (GM096403).
■
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