Synthesis of 4-fluoro-β(4-fluorophenyl)-l-phenylalanine by an asymmetric phase-transfer catalyzed alkylation: Synthesis on scale and catalyst stability

Article abstract of DOI:10.1021/op060190j

4-Fluoro-β-(4-fluorophenyl)-L-phenylalanine 1 was synthesized by the asymmetric phase-transfer catalyzed alkylation of tert-butyl glycinate-benzophenone Schiff base using the cinchona alkaloid derived catalyst 6. Upon scaling, it was observed that to achieve high levels of enantioselectivity, it was necessary to add the catalyst or base last. From these studies, insight into the stability of the catalyst 6 under the reaction conditions was gained.

Full text of DOI:10.1021/op060190j

Organic Process Research & Development 2007, 11, 624−627
Communications to the Editor
Synthesis of 4-Fluoro-â-(4-fluorophenyl)-L-phenylalanine by an Asymmetric
Phase-Transfer Catalyzed Alkylation: Synthesis on Scale and Catalyst Stability
Daniel E. Patterson,* Shiping Xie, Lynda A. Jones, Martin H. Osterhout, Christopher G. Henry, and Thomas D. Roper
Chemical DeVelopment, GlaxoSmithKline, FiVe Moore DriVe, P.O. Box 13398, Research Triangle Park, North Carolina
27709-3398
Abstract:
auxiliary, which lowers costs and minimizes waste. In
addition, the typical reaction conditions are mild, do not
require the use of metal catalyst, and utilize only inexpensive
and readily available reagents.
4-Fluoro-â-(4-fluorophenyl)-L-phenylalanine 1 was synthesized
by the asymmetric phase-transfer catalyzed alkylation of tert-
butyl glycinate-benzophenone Schiff base using the cinchona
alkaloid derived catalyst 6. Upon scaling, it was observed that
to achieve high levels of enantioselectivity, it was necessary to
add the catalyst or base last. From these studies, insight into
the stability of the catalyst 6 under the reaction conditions was
gained.
Unnatural amino acid 4-fluoro-â-(4-fluorophenyl)-L-phe-
nylalanine 1 is a key intermediate in the synthesis of a lead
drug candidate in development. Initial supplies of this
compound were synthesized by employing, as the key step,
an asymmetric azidation mediated by a chiral auxiliary.5
Subsequent hydrolysis of the chiral auxiliary, followed by
reduction of the azide gave amino acid 1. This route to 1
was deemed unacceptable for larger-scale synthesis both
because of its length as well as safety issues related to the
stability of azide intermediates on scale. For this reason, it
was necessary to develop a new route to 1 that would be
safe and amenable to scale-up. Several synthetic strategies
were considered, including resolution6 and hydrogenation7
routes, but it was decided to initially investigate the use of
asymmetric PTC1 using a cinchonidine-derived chiral catalyst
to synthesize the desired amino acid because this route could
be quickly assessed and offered rapid access to the desired
structure.4f Using the asymmetric PTC route, the synthesis
of 1 could be achieved by reaction of tert-butyl glycinate-
benzophenone Schiff base 2 with bromide 3 in the presence
of a cinchonidine-derived chiral catalyst, which, after hy-
drolysis of the product, would give the desired amino acid
1 (Scheme 1).
Asymmetric phase transfer catalysis (PTC) has been
successfully applied to a number of important synthetic
transformations.1,2 This method has been particularly valuable
for the synthesis of natural and unnatural R-amino acids by
the alkylation of glycinate ester Schiff bases.3,4 The most
successful examples of syntheses of amino acids using PTC
have used catalysts derived from cinchona alkaloids.3,4 Use
of PTC for the synthesis of amino acids has several
advantages over alternative methods, especially for synthesis
on large scale. There is no need for a stoichiometric chiral
* To
whom
correspondence
should
be
addressed.
E-mail:
daniel.e.patterson@gsk.com. Telephone: (919) 483-1266. Fax: (919) 483-3706.
(1) For a review of asymmetric phase-transfer catalysis see: O’Donnell, M.J.
In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York; 1993.
(2) (a) Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc. 1984,
106, 446. (b) Hughes, D. L.; Dolling, U.-H.; Ryan, K. M.; Schoenewaldt,
E. F.; Grabowski, E. J. J. J. Org. Chem. 1987, 52, 4745. (c) Corey, E. J.;
Zhang, F.-Y. Agnew. Chem., Int. Ed. 1999, 38, 1931. (d) Corey, E. J.; Bo,
Y.; Busch-Petersen, J. J. Am. Chem. Soc. 1998, 120, 13000. (e) Zhang,
F.-Y.; Corey, E. J. Org. Lett. 2000, 2, 1097. (f) Perrard, T.; Plaquevent,
J.-C.; Desmurs, J.-R.; Hebrault, D. Org. Lett. 2000, 2, 2959.
In order to investigate the asymmetric PTC alkylation
route to 1, it was first necessary to synthesize the requisite
bromide 3.8 For initial lab-scale experiments, the bromide
was prepared by treating 4,4′-difluorobenzhydrol 4 with a
solution of boron tribromide in methylene chloride. Although
this method was effective, the workup was highly exother-
mic, and the large excess of base needed to quench the
reaction would lower the throughput in larger equipment.
As an alternative, 4 was treated with 48% hydrobromic acid
(3) For a review of the synthesis of amino acids by asymmetric phase-transfer
catalysis see: (a) Maruoka, K.; Ooi, T. Chem. ReV. 2003, 103, 3013. (b)
O’Donnell, M. J. Aldrichimica Acta 2001, 34, 3.
(4) (a) O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc. 1989, 111,
2353. (b) Lipkowitz, K. B.; Cavanaugh, M. W.; Baker, B.; O’Donnell, M.
J. J. Org. Chem. 1991, 56, 5181. (c) Imperiali, B.; Prins, T. J.; Fisher, S. L.
J. Org. Chem. 1993, 58, 1613. (d) O’Donnell, M.J.; Wu, S.; Huffman, J.C.
Tetrahedron 1994, 50, 4507. (e) Lygo, B.; Wainwright, P. G. Tetrahedron
Lett. 1997, 38, 8595. (f) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem.
Soc. 1997, 119, 12414. (g) Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron
Lett. 1998, 39, 5347. (h) O’Donnell, M. J.; Delgado, F.; Hostettler, C.;
Schwesinger, R. Tetrahedron Lett. 1998, 39, 8775. (i) Horikawa, M.; Busch-
Petersen, J.; Corey, E. J. Tetrahedron Lett. 1999, 40, 3843; (j) Lygo, B.;
Crosby, J.; Peterson, J. A. Tetrahedron Lett. 1999, 40, 1385. (k) Lygo, B.;
Crosby, J.; Peterson, J. A. Tetrahedron Lett. 1999, 40, 8671. (l) Ooi, T.;
Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 1999, 121, 6519. (m)
O’Donnell, M. J.; Delgado, F.; Pottorf, R. S. Tetrahedron 1999, 55, 6347.
(n) Okino, T.; Takemoto, Y. Org. Lett. 2001, 3, 1515. (o) Chen, G.; Deng,
Y.; Gong, L.; Mi, A.; Cui, X.; Jiang, Y.; Choi, M. C. K.; Chan, A. S. C.
Tetrahedron: Asymmetry 2002, 12, 1567. (p) Jew, S.-s.; Yoo, M.-S.; Jeong,
B.-S.; Park, I. Y.; Park, H.-g Org. Lett. 2002, 4, 4245. (q) Lee, J-H; Jeong,
B.-S.; Ku, J-M, Jew, S-s; Park, H.-g J. Org. Chem. 2006, 71, 6690.
(5) Evans, D. A.; Britton, T. C. J. Am. Chem. Soc. 1987, 109, 6881.
(6) For a patent claiming the synthesis of the title compound by a resolution of
the N-acetyl amino acid see, Beylin, V.; Chen, H. G.; Goel, O. P.; Topliss,
J. G. U.S. Patent 5,198,548, 1993.
(7) For reviews of synthesis of amino acids by hydrogenation of dehydro-amino
acid derivatives see, (a) Tungler, A.; Fodor, K. Catal. Today 1997, 37, 191.
(b) Nagel, U.; Albrecht, J. Top. Catal. 1998, 5, 3. (c) Kruezfeld, H. J.;
Doebler, C.; Schmidt, U.; Krause, H. W. Amino Acids 1996, 11, 269.
(8) Gascoyne, J. M.; Mitchell, P. J.; Phillips, L. J. Chem. Soc., Perkin Trans.
2 1977, 8, 1051.
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10.1021/op060190j CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/20/2006

Scheme 1. Retrosynthesis of 4-fluoro-â-(4-fluorophenyl)-L-
phenylalanine 1
Scheme 3. PTC Alkylation of tert-butyl glycinate
benzophenone Schiff base 2
Scheme 2. Synthesis of 4,4′-difluorobenzhydrylbromide 3
Scheme 4. Catalyst decomposition studies
in water at room temperature to give the desired product 3.
Unfortunately, this material was contaminated with ap-
proximately 25% of the dibenzyl ether byproduct 5. This
byproduct could easily be converted to the desired bromide
by heating to 80 °C in 48% aqueous HBr. In practice, the
bromide was synthesized by treating 4,4′-difluorobenzhydrol
4 with 48% aqueous HBr for 1 h at room temperature,
followed by 2 h at 80 °C (Scheme 2). A simple extractive
workup provided a dichloromethane solution of 3, which was
carried directly into the PTC.
With a synthesis of bromide 3 in hand, the alkylation of
tert-butyl glycinate-benzophenone Schiff base 2 with bromide
3 was examined using the cinchonidine-derived chiral phase
transfer catalyst 6.4e,9 Using literature conditions (10 mol %
catalyst, CsOH as base, in DCM at -78 °C),4f the alkylation
of 2 with bromide 3 resulted in the isolation of racemic
product 7.10 Further experimentation showed that when the
reaction was carried out using the same catalyst under
modified conditions4f (biphasic mixture of dichloromethane
and 45% potassium hydroxide), the desired product 7 was
formed in 80:20 enantiomeric ratio.10-12 The product 7 could
be crystallized out of the reaction mixture in >99% ee from
ethyl acetate and heptane. The reaction was carried out by
dissolving 2 and 10 mol % of the catalyst 6 in dichlo-
romethane, followed by addition of 10 equiv of 45% aqueous
potassium hydroxide. The reaction was then cooled to 0 °C,
and bromide 3 was added. The reaction was stirred until
completion as determined by TLC, and then extractive
workup followed by crystallization from 20% ethyl acetate/
heptane provided up to 55% yield of optically pure 7 as a
white crystalline solid (Scheme 3).
When the PTC reaction was run on kilogram scale, the
reaction proceeded sluggishly, and surprisingly, the product
7 was isolated in racemic form (65% yield)! At this point, it
was necessary to determine why the reaction deviated so
much from lab scale to large scale and to devise conditions
that would be amenable to running on large scale. One
significant difference between small and large scale was the
rate of cooling to 0 °C prior to addition of the bromide. The
cooling time was 5-10 min on lab scale to upwards of 30-
60 min on larger batches. We hypothesized that during the
extended cooling down period, prior to the addition of the
bromide 3, the catalyst might be completely decomposing
to an unselective catalyst.
This hypothesis was confirmed when a test reaction in
the lab was cooled to 0 °C over 45 min prior to the addition
of bromide 3, and only racemic product was obtained. To
further confirm the decomposition of the catalyst, the phase
transfer catalyst 6 was dissolved in dichloromethane and
treated with 45% KOH. Under these conditions, the catalyst
was quantitatively converted to a new product, which was
identified to be enol ether 8 by LC-MS (M+ ) 524) and
NMR analysis (Scheme 4). Enol ether 8 arises by base-
catalyzed Hoffman elimination of the catalyst, a decomposi-
tion pathway that has been observed for related catalysts.2b
In a second study, a mixture of the catalyst 6, imine 2, and
45% KOH in dichloromethane was stirred at room temper-
ature for 1 h. Analysis of the reaction mixture by LC-MS
(9) The catalyst was either bought from Aldrich or, for larger-scale studies,
was synthesized in two steps from cinchonidine.
(10) The enantiomeric ratio was determined by chiral HPLC.
(11) Several other cinchonidine-derived phase transfer catalysts were investigated,
but 6 gave the highest selectivities.
(12) A solvent screen showed that 1,2-dichloroethane gave higher levels of
enantioselectivity (>90:10 er) versus dichloromethane; however dichlo-
romethane was used based on ease of removal by distillation and due to
the fact that 1,2-dichloroethane is not a green solvent of choice and presents
some toxicity issues versus dichloromethane.
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Scheme 5. Synthesis of 4-fluoro-â-(4-fluorophenyl)-
L-phenylalanine 1
crystallized from the aqueous layer in 85% yield as the
hydrochloric acid salt 11 (Scheme 5).
4-Fluoro-â-(4-fluorophenyl)-L-phenylalanine 1 was syn-
thesized as its HCl salt in enantiomerically pure form in two
steps from the commercially available tert-butyl glycinate-
benzophenone Schiff base 2 in 48% overall yield via an
asymmetric phase transfer alkylation followed by hydrolysis.
This represents only the second example of the use of se-
condary alkyl halides in this type of PTC alkylation.4f Studies
of this reaction show that the chiral catalyst 6 is very sensitive
to base-catalyzed decomposition in the absence of either the
nucleophile or the electrophile. For this reason it is important
to add the base or catalyst last in order to achieve high levels
of enantioselectivity. The asymmetric phase-transfer cata-
lyzed alkylation is a powerful method for the synthesis of
chiral amino acids, but a good understanding of the catalyst
stability is important to successfully use this method,
especially on kilogram scale. Further studies on improving
enantioselectivity and on extending the alkylation to other
secondary alkyl halides is proceeding and will be reported
in due course.
showed that the catalyst had been converted into enol ether
8, alkylation product 10 (M+ ) 485), and byproduct 9 (M+
) 334), as well as the deallylated catalyst (M+ ) 484). These
results led to the conclusion that in the absence of a reactive
halide, the catalyst reacts with base or with the nucleophile
to degrade the PTC catalyst. Tertiary amines 8 and 9 could,
on addition of an alkyl halide, be alkylated to form a new
quarternary ammonium salt that could catalyze the reaction
with little or no selectivity.
Experimental Section
General. All commercial chemicals were used as re-
ceived. Combustion analyses were performed by the Atlantic
Microlab, Inc. All reactions were performed under a nitrogen
atmosphere unless otherwise stated. TLC analysis was
performed on silica gel plate, eluted with 10% ethyl acetate
in hexane. The enantiomeric excess of 7 was determined by
chiral HPLC: column, Bakerbond DNBPG (covalent), 250
cm × 4.6 mm, 5 µm; mobile phase (isocratic) 0.1% methanol
in heptane; flow rate 1.0 mL/min; detection, 250 nm;
temperature 35 °C; retention times, 7: 13.73 min, ent-7:
16.53 min. The enantiomeric excess of 11 was determined
by derivitization with Marfey’s reagent, followed by HPLC
analysis: column, Zorbax Eclipse XDB C18, 150 cm × 4.6
mm, 3.5 µm; Mobile phase (isocratic) 0.5% TFA in water;
flow rate 1.0 mL/min; detection, 340 nm, 8 nm bandwidth;
temperature 40 °C; retention times, desired diastereomer:
17.1 min, undesired: 17.9 min.
Synthesis of 4-Fluoro-â-(4-fluorophenyl)-L-tert-butyl-
phenylalanine Benzophenone Imine 7. A reactor was
charged with 4,4′-difluorobenzhydrol 4 (1.7 kg, 7.72 mol),
followed by 48% HBr in water (5.1 L). The resulting slurry
was stirred for 1 h at 25 °C. The reaction was heated to 80
°C and was stirred at this temperature for 2 h. The reaction
was cooled to 25 °C and water (6.8 L) was added, followed
by dichloromethane (8.5L). The biphasic mixture was stirred,
and the layers were separated. The organic layer was washed
successively with water (5.1 L) and 5% aq sodium bicarbon-
ate (5.1 L). The organic layer was returned to the reactor
and was concentrated under atmospheric pressure to 9.5 L
(5.5 vol). To the above solution of 4,4′difluorobenzhydryl
bromide 3 in dichloromethane was added the tert-butyl
glycinate-benzophenone Schiff base 2 (1.8 kg, 6.10 mol),
followed by the catalyst 6 (0.185 kg, 0.30 mol). Dichlo-
romethane (1.8 L) was added (rinse). The reaction was cooled
to 0 °C over 30 min, and 45% aqueous KOH (7.6 kg, 60.9
mol) was added over 15-30 min while maintaining the
The degradation studies described above suggest that good
selectivity should still be attainable on large scale if all
reactants were added in a defined sequence. Addition of the
catalyst or base last should lead to good selectivity.13 For
convenience, and in order to avoid adding a solid to the
reaction last, it was decided to charge the base last. Under
these conditions, the reaction proceeded smoothly to comple-
tion to give the desired alkylated product with a crude
enantiomeric ratio of 80:20. The reaction was observed to
be faster (5 h) and to require less catalyst than it previously
did. For scaling purposes, 5 mol % catalyst was used, but
subsequent experiments showed that the reaction proceeds
with the same level of selectivity with as low as 2% catalyst.
Interestingly, when the catalyst was monitored during the
reaction, it was observed that the catalyst did not decompose
as long as the starting materials were present, but as soon as
the reaction was complete, the catalyst quickly decomposed
by the Hoffman elimination pathway. This observation
implies that catalyst recycling would be very tenuous,
especially if the reaction is allowed to go to completion at
the temperature range used in these reactions.
From our experiments, the preferred conditions for the
alkylation on scale, are 5 mol % catalyst, 1.2 equiv of the
bromide 3, followed by addition of the base (10 equiv of
45% aqueous KOH) last. On 6 mole scale, the reaction
proceeded smoothly to completion in 5 h (80:20 er), and
workup and crystallization gave the product in >99% ee
(56% yield) as shown in Scheme 5.
The alkylated product 7 can be hydrolyzed to the desired
amino acid by refluxing the product in 6 N hydrochloric acid
for several hours. After removal of the benzophenone by
extraction with methyl tert-butyl ether, the amino acid is
(13) Another possibility that could be envisioned to avoid catalyst decomposition
was to simply reduce the concentration of the base, but experiments using
lower base concentration (15% KOH) still showed significant catalyst
decomposition, while slowing the rate of the desired reaction.
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temperature at 0-5 °C. The biphasic reaction was stirred
until complete by TLC (approximately 5 h). The reactor was
then charged with water (1.8 L), and the layers were
separated. The organic layer was washed with brine (5.4 L).
The organic layer was returned to the reactor (rinse with
1.8 L of dichloromethane). The organic solution was
concentrated at atmospheric pressure to 10 L. The reactor
was then charged with 23% ethyl acetate in heptane (9.1 L)
and was concentrated under vacuum to 14.5 L. The reaction
was then seeded. The vacuum distillation was continued to
a final volume of 12.5 L. The vacuum was removed, the
reaction was cooled to 20 °C and held at this temperature
for 1-2 h. The solids were collected by filtration and were
washed with 10% ethyl acetate in heptane (3.6 L). The solids
were dried in a 50 °C vacuum oven to constant weight. The
product 7 is an off-white solid (1.72 kg, 56%, >99% ee).
[R]D ) -206.1° (c ) 2.0, CHCl3). Mp ) 168-171 °C. IR
3100, 2974, 2870, 1724, 1710, 1620, 1601, 1576, 1508, 1392,
(9.0 L) followed by concentrated hydrochloric acid (9.0 L).
The reactor was then charged with 7 (2.0 kg, 4.02 mol) over
5-10 min. The resulting slurry was heated at reflux for 3-4
h. The reaction was cooled to room temperature and washed
with MTBE (2 × 20 L). The aqueous layer was concentrated
under vacuum to 6 L (3 vol), and was cooled at 5 °C for 1
h. Filtration, washing with heptane (3.0 L), and drying at 50
°C afforded the product 11 as an off-white solid (1.07 kg,
85% yield, >99% ee). [R]D ) +56.3° (c ) 2.0, CH3OH).
Mp ) 149 °C dec. IR 3180, 3137, 2820, 2645, 2564, 2462,
1
1715, 1606, 1589, 1536, 1503, 1232, 1192, 827 cm-1. H
NMR (300 MHz, CD3OD) δ 4.47 (d, J ) 10.3 Hz, 1H),
4.85 (d, J ) 10.3 Hz, 1H), 7.07 (t, J ) 8.8 Hz, 2H), 7.16 (t,
J ) 8.8 Hz, 2H), 7.44 (dd, J ) 5.2, 8.8 Hz, 2H), 7.56 (dd,
J ) 5.2, 8.8 Hz, 2H). 13C NMR (300 MHz, DMSO-d6) δ
169.5, 162.4, 162.2, 160.5, 160.2, 135.6, 135.0, 55.3, 51.2.
Anal. Calcd For C15H14ClF2NO2: C, 57.43; H, 4.50; N, 4.46.
Found: C, 57.22; H, 4.48; N, 4.41.
1
1368, 1222, 1161, 1150, 825 cm-1. H NMR (300 MHz,
CDCl3) δ 1.25 (s, 9H), 4.58 (d, J ) 8.3 Hz, 1H), 4.76 (d, J
) 8.3 Hz, 1H), 6.74 (m, 2H), 6.93 (t, J ) 8.8 Hz, 4H), 7.14
Acknowledgment
(m, 2H), 7.28-7.44 (m, 8H), 7.53 (d, J ) 6.7 Hz, 2H). 13
C
NMR (300 MHz, CDCl3) δ 28.0, 53.6, 71.3, 81.6, 115.1,
115.3, 115.5, 128.3, 129.1, 130.5, 131.2, 136.3, 137.7, 139.8,
160.3, 163.5, 170.0, 171.3. Anal. Calcd For C32H29F2NO-2:
C, 76.86; H, 5.82; N, 2.89. Found: C, 76.75; H, 5.76; N,
2.85.
We thank Thomas O’Connell and Jack Thornquest for
NMR and mass spectral studies on the catalyst decomposition
products. We thank Bobby Glover for lab automation
support.
Synthesis of 4-Fluoro-â-(4-fluorophenyl)-L-phenylala-
nine Hydrochloride 11. A reactor was charged with water
OP060190J
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