An improved synthesis of N-aryl-hydantoin LFA-1 antagonists via the enantiospecific alkylation of an isobutyraldehyde-derived imidazolidinone template

Article abstract of DOI:10.1016/S0957-4166(01)00009-X

An improved and cost-effective process for the synthesis of N-aryl-hydantoin LFA-1 antagonists is described. Key transformations include the synthesis and stereospecific alkylation of the trans-isobutyraldehyde-derived template 4, and the one-pot hydrolys

Full text of DOI:10.1016/S0957-4166(01)00009-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 101–104
An improved synthesis of N-aryl-hydantoin LFA-1 antagonists
via the enantiospecific alkylation of an isobutyraldehyde-derived
imidazolidinone template
Rogelio P. Frutos,* Sandra Stehle, Laurence Nummy and Nathan Yee
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road/PO Box 368,
Ridgefield, CT 06877-0368, USA
Received 16 November 2000; accepted 13 December 2000
Abstract—An improved and cost-effective process for the synthesis of N-aryl-hydantoin LFA-1 antagonists is described. Key
transformations include the synthesis and stereospecific alkylation of the trans-isobutyraldehyde-derived template 4, and the
one-pot hydrolysis of intermediate 6. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
ceeded efficiently and in high-yield up to multi kilogram
scale,6 the major drawback of this process was the high
cost of pivalaldehyde,7 and more significantly, the lim-
ited number of bulk suppliers.8 Anticipating the possi-
bility that bulk commercial availability of pivalaldehyde
could become an issue, and to reduce the cost of the
process, we decided to investigate the use of the isobu-
tyraldehyde-derived imidazolidinone template 4 for the
synthesis of 1 and analogues.
In a search for novel therapeutic agents for ailments
related to inflammation and immunology, our discovery
group recently identified an important series of hydan-
toin small molecules that act as antagonists to the
binding of intracellular adhesion molecules such as
ICAM-1 with leukointegrin LFA-1.1 The selection of
BIRT377 1 as a candidate for further pre-clinical stud-
ies gave rise to a program designed to develop a reliable
and cost-effective process for their synthesis and the
synthesis of similar chiral, non-racemic hydantoins. Of
the synthetic methods investigated,2–4 a modification of
Seebach’s self regeneration of stereocenters principle5
resulted in a reliable process suitable for the multi
kilogram synthesis of 1 and structurally related LFA-1
antagonists. This process development has been
described in a previous report from our laboratories
(Fig. 1).6
2. Results and discussion
The alkylation of 2-isopropyl-imidazolidinones, which
are derived from isobutyraldehyde and glycine, is
reported to proceed with lower stereoselectivity than
with the corresponding pivalaldehyde-derived ana-
logues.9 This is presumably due to the reduced bulk of
the isopropyl group. As a result, 2-tert-butyl-imidazo-
lidinones have become the templates of choice in the
synthesis of amino acids and related compounds. How-
A key feature of molecules like 1 is the N-aryl-substi-
tuted hydantoin bearing a quaternary stereogenic cen-
ter. The process originally developed for the synthesis
of (+)-1 relied on the stereospecific alkylation of the
pivalaldehyde-derived imidazolidinone template
5
(Scheme 1).6 Imidazolidinone 5 was prepared by the
condensation of amino acid amide 2 and pivalaldehyde,
followed by N-protection as the trifluoracetamide.
Although all reactions in the eight-step process pro-
* Corresponding
ingelheim.co
author.
E-mail:
rfrutos@rdg.boehringer-
Figure 1. BIRT377 1.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00009-X

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R. P. Frutos et al. / Tetrahedron: Asymmetry 12 (2001) 101–104
Scheme 1. (a) Ref. 6. (b) Isobutyraldehyde, toluene, 55°C; crystallization from methanol/hexanes (76%). (c) TFAA, Et3N, THF
(98%). (d) LiN(TMS)2, 4-bromo-benzylbromide, THF, −20°C (95%). (e) tert-BuOK (2 equiv.), H2O (1.3 equiv.), THF; conc.
H2SO4 (3 equiv.), reflux (96%). (f) ClCO2CH3, Et3N, NaOMe, THF (95%). (g) KN(TMS)2, MeI, THF (74%).
ever, literature reports on the use of 2-isopropyl-imida-
zolidinone templates are few, and unlike 4, the tem-
plates investigated do not have an aryl group at the
3-position.9–11 Moreover, we were not aware of any
studies related to the use of 2-isopropyl-imidazolidi-
nones for the synthesis of a-disubstituted amino acids
and related compounds. This was surprising, since the
cost associated with the use of pivalaldehyde-derived
templates is high, and a highly stereospecific alkylation
of a novel isobutyraldehyde-derived template would
make the synthesis of a-disubstituted amino acid
derivatives significantly more affordable. Herein, we
report our studies on the successful synthesis and alkyl-
ation of isopropyl-derived template 4, and further
manipulations of the alkylated product 6 that led to an
improved synthesis of N-aryl-hydantoin LFA-1 antago-
nists such as 1.
alkylation of 4 with 4-bromobenzylbromide (LiN-
(TMS)2, THF, −20°C) gave intermediate 6 in good
yield as a single isomer. The enantiospecificity of the
alkylation is noteworthy, because, as Seebach pointed
out,9 the isopropyl group is rather small with an ‘A
value’ of 2.1 kcal/mol, much closer to a methyl group
(1.7 kcal/mol) than a tert-butyl group (ꢀ5 kcal/mol).
Nevertheless, our results clearly demonstrate that,
under the right conditions, alkylation of a 2-isopropyl-
imidazolidinone such as 4 can occur with the same
degree of enantiospecificity as the corresponding tert-
butyl analogue, such as 5 previously used by Yee.6
The next step of the synthesis involved hydrolysis of the
imidazolidinone ring of 6. However, this proved less
easy than hydrolysis of the analogous pivalaldehyde-
derived compound;6 hence, treatment of
6 with
BnMe3NOH and aqueous NaOH, followed by addition
of 6N HCl, failed to give any of the hydrolysis product
7. This observation was rather surprising since we
initially expected the less sterically demanding isobu-
tyraldehyde-derived intermediate 6 to be more suscepti-
ble to hydrolysis than the pivalaldehyde-derived
analogue. We speculate that upon removal of the trifl-
uoroacetate group from 6, the resulting imidazolidinone
ring could open and tautomerize to form a relatively
stable tri-substituted enamine;16 this is not possible with
the pivalaldehyde-derived analogue, and could account
for the difference in reactivity between the two sub-
strates. Nevertheless, a one-pot hydrolysis sequence was
developed based on the modified Gassman’s procedure
for the hydrolysis of amides.17 Accordingly, treatment
of 6 with potassium tert-butoxide (2 equiv.) and H2O
(1.3 equiv.) in THF resulted in the successful removal
of the trifluoroacetate protecting group, and subsequent
The alkylation of the isopropyl-derived imidazolidinone
4 was applied to the synthesis of 1, as shown in Scheme
1. Amino amide 2 was prepared in two steps from
Boc-D
-alanine as previously reported by Yee.6 Conden-
sation of amino amide 2 with isobutyraldehyde in tolu-
ene at 55°C afforded imidazolidinone 312 in good yield.
Crude imidazolidinone 3 was initially obtained as a
disappointing 3:2 mixture of trans- and cis-isomers.13
However, under our crystallization conditions (reflux in
methanol/hexanes, cooled to 4°C) the mixture was com-
pletely converted to the trans-isomer.14 This is possible
because an equilibrium mixture of both isomers exists
in solution, but the trans-isomer selectively crystallizes
out of the mixture, resulting in the complete formation
of pure trans-3. Acylation of 3 (trifluoroacetic anhy-
dride, Et3N, THF, room temperature) afforded tem-
plate 415 as a crystalline solid in good yield, and

R. P. Frutos et al. / Tetrahedron: Asymmetry 12 (2001) 101–104
103
addition of H2SO4 at reflux temperature resulted in the
formation of the hydrolysis product 7 in good yield.
Amino amide 7 was then converted to (+)-118 in two
steps by reported procedures.6
135.4, 138.7, 174.9; anal. calcd for C13H16Cl2N2O: C,
54.37; H, 5.62; N, 9.75. Found C, 54.44; H, 5.43; N,
9.63%.
4.2. Preparation of (2R,5R)-3-(3,5-dichloro-phenyl)-2-
isopropyl-5-methyl-1-(2,2,2-trifluoro-acetyl)-imidazolidin-
4-one 4
3. Conclusions
In conclusion, we have developed a more effective
process for the synthesis of N-aryl-hydantoin LFA-1
inhibitors such as BIRT377 1 via the enantiospecific
alkylation of 2-isopropyl-imidazolidinone 4. To the best
of our knowledge, this is the first successful use of an
isobutyraldehyde-derived imidazolidinone template for
the asymmetric stereospecific synthesis of an a-disubsti-
tuted amino acid derivative. Furthermore, our results
argue against current conventional wisdom, which sug-
gests that 2-tert-butyl-imidazolidinones are always
superior templates for alkylation than the correspond-
ing 2-isopropyl analogues. In addition, a relatively mild
one-pot hydrolysis method for the hydrolysis of 6 was
implemented.19 Finally, the process described herein is
more cost effective than the previous process6 due to
the lower cost of isobutyraldehyde, which is available in
bulk from a number of suppliers.20 The scope and
limitations of the use of isobutyraldehyde-derived tem-
plates for the synthesis of analogues of 1, as well as
other quaternary a-amino acid derivatives, is currently
under investigation and will be reported in due course.
Trifluoroacetic anhydride (40 mL, 283 mmol) was
added dropwise to a stirred solution of 3 (79.6 g, 277
mmol), triethylamine (39.4 mL, 283 mmol) and THF
(600 mL) at 0°C over a period of 90 min. The resulting
solution was allowed to reach ambient temperature and
stirred for 90 min. The mixture was concentrated under
reduced pressure to afford 185 g of an orange oil. The
above oil was dissolved in ethyl acetate (1 L) and
washed sequentially with 0.5N HCl, 0.5N NaOH, water
and brine. The organic portion was concentrated under
reduced pressure to afford 129 g (98%) of a colorless oil
that solidified upon standing: mp 87–89°C; [h]2D0=+87
1
(c=7.15, CH2Cl2); H NMR (400 MHz, CDCl3) l 0.74
(d, J=7.2 Hz, 3H), 0.91 (d, J=6.8 Hz, 3H), 1.68 (d,
J=6.4 Hz, 3H), 2.42 (m, 1H), 4.57 (q, J=6.6 Hz, 1H),
6.18 (s, 1H), 7.30 (m, 1H), 7.45 (br s, 2H); 13C NMR
(100 MHz, CDCl3) l 15.8, 18.1, 20.2, 57.0, 78.0, 122.4,
127.3, 135.7, 137.4, 168.7; anal. calcd for
C15H15Cl2F3N2O2: C, 47.02; H, 3.95; N, 7.31. Found C,
47.16; H, 3.82; N, 7.24%.
4.3. Preparation of (2R,5R)-5-(4-bromo-benzyl)-3-(3,5-
dichloro-phenyl)-2-isopropyl-5-methyl-1-(2,2,2-trifluoro-
acetyl)-imidazolidin-4-one 6
4. Experimental
Unless otherwise specified, all reactions were carried
out in oven-dried glassware under an atmosphere of
nitrogen. NMR spectra were recorded on a Bruker
DPX-400 NMR spectrometer. Shifts are reported in
ppm relative to trimethylsilane; coupling constants (J)
are reported in hertz, refer to apparent peak multiplic-
ities, and may not necessarily be true coupling con-
stants. The commercially available starting materials
were used as received without further purification and
all solvents were dried by standard methods prior to
use. All melting points were recorded using a Fisher–
Johns melting point apparatus and are uncorrected.
Lithium bis(trimethylsilyl)amide (282 mL of a 1 M
solution in THF, 282 mmol) was added dropwise to a
stirred solution of 4 (128 g, 268 mmol), 4-bromo-benzyl
bromide (68.5 g, 268 mmol) and THF (585 mL) at
−20°C over a period of 1 h. The mixture was allowed to
reach ambient temperature and concentrated under
reduced pressure to afford 280 g of an oil. The crude
product was partitioned between ethyl acetate (1.2 L)
and water (400 mL). The organic layer was stored and
the aqueous layer was extracted further with ethyl
acetate (2×200 mL). The combined organic extract was
washed with brine (200 mL), dried (Na2SO4) and con-
centrated under reduced pressure to afford 155 g of 6 as
a yellow oil that solidified upon standing: [h]2D0=+95
4.1. Preparation of (2S,5R)-3-(3,5-dichloro-phenyl)-2-
isopropyl-5-methyl-imidazolidin-4-one 3
1
(c=9.5, CH2Cl2); mp 143–145°C; H NMR (400 MHz,
CDCl3) l 0.55 (d, J=7.0 Hz, 3H), 0.92 (d, J=7.0 Hz,
3H), 1.95 (s, 3H), 2.07 (m, 1H), 3.02 (d, J=13.7 Hz,
1H), 3.72 (d, J=13.7 Hz, 1H), 5.10 (br, 1H), 6.76 (d,
J=1.6 Hz, 2H), 6.81 (d, J=8.3 Hz, 2H), 7.3 (br, 1H),
7.37 (d, J=8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3)
l 14.3, 20.1, 22.3, 36.3, 39.1, 70.2, 78.2, 121.8, 123.9,
128.1, 131.2, 131.8, 134.0, 135.6, 137.3, 169.9; anal.
calcd for C22H20BrCl2F3N2O2: C, 47.85; H, 3.65; N,
5.07. Found C, 47.69; H, 3.68; N, 4.87%.
Isobutyraldehyde (40.1 mL, 442 mmol) was added
dropwise over a period of 30 min to a stirred solution
of amino amide 26 and toluene (420 mL) at room
temperature. The mixture was heated to 50°C and
stirred for 12 h. Concentration under reduced pressure
afforded 123 g of crude product as a solid. Recrystal-
lization from methanol (28 mL) and hexanes (570 mL)
afforded 80.6 g (76%) of product as a yellow solid: mp
1
123–125°C; [h]2D0=+19 (c=5.1, CH2Cl2). H NMR (400
MHz, CDCl3) l 0.79 (d, J=6.8 Hz, 3H), 0.99 (d, J=6.8
Hz, 3H), 1.38 (d, J=6.8 Hz, 3H), 2.02–1.95 (m, 2H),
3.72 (q, J=6.1 Hz, 1H), 5.02 (d, J=1.96, 1H), 7.17 (m,
1H), 7.41 (d, J=1.96 Hz, 2H); 13C NMR (100 MHz,
CDCl3) l 14.1, 18.1, 18.4, 30.5, 56.2, 78.1, 120.8, 125.5,
4.4. Preparation of (R)-2-amino-3-(4-bromo-phenyl)-N-
(3,5-dichloro-phenyl)-2-methyl-propionamide 7
Potassium tert-butoxide (343 mL of a 1 M solution in
THF, 343 mmol) was added to a stirred solution of 5

104
R. P. Frutos et al. / Tetrahedron: Asymmetry 12 (2001) 101–104
g, 267 mmol), THF (290 mL) and water (5.3 mL) at
room temperature and the resulting mixture was stirred
for 30 min. The resulting mixture was filtered and
concentrated under reduced pressure to afford 238 g of
an amber oil. The above oil was dissolved in ethanol
(1.2 L) and conc. sulfuric acid (54 mL, 972 mmol) was
added over a period of 10 min at ambient temperature.
The mixture was then refluxed for 30 min and allowed
to reach room temperature. The mixture was placed
over an ice bath and 50% NaOH (1.63 mol) was added
dropwise. The mixture was filtered and concentrated
under reduced pressure to afford an oil. The crude oil
was partitioned between ethyl acetate (700 mL) and
water (250 mL). The organic layer was set aside and the
aqueous layer was extracted with ethyl acetate (2×200
mL). The combined organic portions were washed
sequentially with saturated aqueous NaHCO3 and
brine, dried (Na2SO4) and concentrated under reduced
pressure to afford 111 g of product as an oil.21
as suppliers of bulk pivalaldehyde. To the best of our
knowledge, the only supplier of bulk pivalaldehyde avail-
able when this manuscript was prepared was Inspec Fine
Chemicals, Ltd. in England.
9. Seebach, D.; Juaristi, E.; Miller, D. D.; Schickli, C.;
Weber, T. Helv. Chim. Acta 1987, 70, 237.
10. Juaristi, E.; Anzorena, J. L.; Boog, A.; Madrigal, D.;
Seebach, D.; Garcia-Baez, E. V.; Garcia-Barradas, O.;
Gordillo, B.; Steiner, A. K. I.; Zurcher, S. J. Org. Chem.
1995, 60, 6408.
11. Mu¨ller, W.; Lowe, D. A.; Neijt, H.; Urwyler, S.; Her-
rling, P. L.; Blaser, D.; Seebach, D. Helv. Chim. Acta
1992, 75, 855.
12. All new compounds were characterized by 1H and 13C
NMR, mass spectra and elemental analysis. The structure
of intermediate 5 was confirmed by X-ray analysis.
1
13. The cis/trans ratio was determined by H NMR.
14. The cis- and trans-imidazolidinone isomers of 3 are
epimers at the C-2 position. The stereogenic center bear-
ing the methyl group does not epimerize under the crys-
tallization conditions; otherwise, epimerization at the C-5
position would result in racemic 3. Therefore, conversion
to the trans-isomer must occur by opening of the imida-
zolidinone and condensation. Please see Ref. 6 for a
similar preparation of the pivalaldehyde-derived imidazo-
lidinone analogue as a single enantiomer.
15. The e.e. of (+)-4 was determined to be >99%. Chiral
HPLC column, Chiralpak OD (250×4.6 mm); mobile
phase, 7% EtOH and 0.1% trifluoroacetic acid in hexane;
flow rate 1.0 mL/min; ambient temperature; retention
time, (+)-4=4.08 min; (−)-4=5.07 min.
Acknowledgements
The authors want to thank Dr. Vittorio Farina for
helpful discussions. Thanks are also due to Mrs. Lisa
DeLattre for chiral HPLC measurements and Mr.
Denis Byrne for early experimental work.
References
16. No attempts were made to isolate and characterize any
intermediates resulting from the removal of the tri-
fluoroacetate group.
17. Gassman, P. G.; Hodgson, P. K. G.; Balchunis, R. J. J.
Am. Chem. Soc. 1976, 98, 1275.
18. The e.e.s of (−)-8 and (+)-1 were determined by chiral
HPLC to be >99%. See Ref. 6 for details on the HPLC
methods.
19. The standard hydrolysis method involves heating the
hydantoin in concentrated acid at 175–180°C in a sealed
tube.
20. At the time this manuscript was written, isobutyralde-
hyde was offered in multi kilogram quantities by a num-
ber of suppliers, including the Aldrich Chemical
Company Inc., Acros Organics, Alfa Aesar, EM Science,
Fluka, Pfaltz & Bauer, Inc. and Crescent Chemical Co.,
Inc.
21. The analytical data of intermediate 7 were identical to
data previously reported for that compound. See Ref. 6
for details.
1. Kelly, T. A.; Jeanfavre, D. D.; McNeil, D. W.; Woska,
Jr., J. R.; Bormann, B.-J.; Rothlein, R. J. Immunol. 1999,
163, 5173.
2. Frutos, R. P.; Spero, D. M. Tetrahedron Lett. 1998, 39,
2475–2478.
3. Spero, D. M.; Kapadia, S. R. J. Org. Chem. 1996, 61,
7398–7401.
4. For a review on the synthesis of a-disubstituted amino
acids and derivatives see: Cativiela, C.; Diaz-de-Villegas,
M. D. Tetrahedron: Asymmetry 1998, 9, 3517.
5. Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2709.
6. Yee, N. K. Org. Lett. 2000, 2, 2781.
7. As a rough price comparison, one can look at the prices
quoted by the Aldrich Chemical Co. At the time this
manuscript was written the cost for 100 mL of pivalalde-
hyde was $321.90, whereas 100 mL of isobutyraldehyde
costs only $40.00.
8. We were unable to purchase multi kilogram quantities of
pivalaldehyde from companies listed in previous reports5
.
.