An improved synthesis of chiral α-(4-bromobenzyl)alanine ethyl ester and its application to the synthesis of LFA-1 antagonist BIRT-377

Full text of DOI:10.1021/jo0013913

J . Org. Chem. 2001, 66, 1903-1905
1903
alanine can be used as the starting material to synthesize
2 either in cis or trans configuration.
An Im p r oved Syn th esis of Ch ir a l
r-(4-Br om oben zyl)a la n in e Eth yl Ester a n d
Its Ap p lica tion to th e Syn th esis of LF A-1
An ta gon ist BIRT-377
A careful examination of the literature, describing
several applications of Seebach’s protocol, showed a very
confusing trend regarding the stereoselectivity of the
formation of the oxazolidinone template 2. Using the
same two-step approach, Seebach5 reported cis as a major
isomer (4:1, R ) t-Bu, X ) Ph), whereas Fadel6 (7.5:1, R
) X ) Ph) and Mutter7 (2.5:1, R ) Ph, X ) BnO) reported
trans as the major product and Davies8 obtained cis
isomer (R ) ferrocenyl, X ) t-Bu) as the only product.
Due to these inconsistencies and the fact that these
procedures are carried out in two distinct steps, we
decided to examine a one-step procedure developed first
by Karady9a and later modified by Shrader9b and J ones,10
each of whom reported cis as the major isomer. Unlike
Karady, both Shrader and J ones condensed a carbamate-
protected amino acid with an acetal in the presence of
excess of BF3 etherate to obtain the template 2 (R ) Ph,
X ) BnO) in high yield. However, the drawback of this
method is that it uses a corrosive acid at a very low
temperature (-78 °C) in ether. Since we hoped to scale
this reaction up to multikilogram scale, we needed to
modify the reaction conditions in order to avoid the low
temperature conditions, the hazardous ether solvent, and
highly corrosive BF3.
Suresh R. Kapadia,* Denice M. Spero, and
Magnus Eriksson
Department of Chemical Development, Boehringer Ingelheim
Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368,
Ridgefield, Connecticut 06877
skapadia@rdg.boehringer-ingelheim.com
Received September 19, 2000
In tr od u ction
Recently BIRT-377 (1) was identified as a potent
inhibitor of the interaction between intercellular adhe-
sion molecule-1 (ICAM-1) and lymphocyte function-
associated antigen-1 (LFA-1), and thus it could play an
important role in the treatment of a number of inflam-
matory and immune disorders.1,2 To facilitate preclinical
studies, a practical synthesis of 1 was needed. Because
hydantoins can easily be prepared from amino acids, our
initial target was the corresponding amino acid bearing
a quaternary asymmetric center in the R position. A
number of syntheses have been reported in the literature
for this type of compounds.3 We found the synthesis based
on oxazolidinone chemistry to be very attractive for its
simplicity. It takes advantage of the protocol called Self-
Regeneration of Stereocenters devised and extensively
studied by Seebach.4 On the basis of this strategy, we
envisioned the synthesis of 1 as shown in Scheme 1.
Resu lts a n d Discu ssion
With this goal in mind, we decided to screen commonly
used Lewis acids. n-Butyl ether was chosen as the solvent
because of its low flammability, and all the reactions were
run at 0 °C. We looked at number of common Lewis acids
derived from titanium, boron, aluminum, zinc, and yt-
terbium. Only ZnCl2 and ZnBr2 provided the oxazolidi-
none 4 in appreciable yield. Around this time, we came
across a report by Micheel11 describing the use of thionyl
chloride to effect a similar cyclization. When we used 1
equiv of thionyl chloride in the presence of anhydrous
ZnCl2, we were delighted to find that the yield increased
to 66% with a cis/trans ratio of 5.5:1. Changing the
solvent to THF and some more fine-tuning of the reaction
conditions gave 4 in 76% crude yield with a cis/trans ratio
ranging from 15:1 to 25:1 (Scheme 2).
Sch em e 1
Sch em e 2
Thus, 1 can be synthesized from the amino acid 1a ,
which, in turn, can be obtained from 2 by alkylation with
4-bromobenzyl bromide followed by hydrolysis. Acylated
* To whom correspondence should be addressed.
(1) Kelly, T. A.; J eanfavre, D. D.; McNeil, D. W.; Woska, J . R.; Reilly
P. L.; Mainolfi, E. A.; Kishimoto K. M.; Nabozny, G. H.; Zinter, R.;
Bormann, B. J . and Rothlein, R. J . Immunology 1999, 163, 5173.
(2) Yee, N. K. Org. Lett. 2000, 2, 2781.
(3) Seebach, D.; Imwinkelreid, R.; and Weber, T. Modern Synthetic
Methods; Scheffold, R., Ed.; Springer Verlag: Heidelberg, 1986; Vol.
4, p 125. (b) Schollkopf, U, Topics in Current Chemistry; Boschka, F.
L., Ed.; Springer-Verlag, Heidelberg, 1983; Vol. 109, p 6. (c) Williams,
R. M. Synthesis of Optically Active R-Amino Acids; Pergamon Press:
Oxford, 1989. (d) Spero, D. M.; Kapadia, S. R. J . Org. Chem. 1996, 61,
7398.
(5) Seebach, D.; Fadel, A. Helv. Chim. Acta 1985, 68, 1243.
(6) Fadel, A.; Salaun, J . Tetrahedron Lett. 1987, 28, 2243.
(7) Mutter, M.; Altmann, E.; Nebel, K. Helv. Chim. Acta 1991, 800.
(8) Alonso, F.; Davies, S. G. Tetrahedron: Asymmetry 1995, 6, 353.
Exclusive cis selectivity was obtained but ferrocenecarboxaldehyde is
extremely expensive.
(9) (a) Karady, S.; Amato, J . S.; Weinstock, L. M. Tetrahedron Lett.
1984, 25, 4373. (b) Shrader, W. D.; Marlowe, C. K. Bioorg. Med. Chem.
Lett. 1995, 5, 2207.
(4) Seebach, D.; Sting, A.; Hoffmann, M. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2708.
(10) J ones, J . B.; Keitz, P.; Cheng, H. J . Org. Chem. 1994, 59, 7671.
(11) Micheel, F.; Meckstroth, W. Chem. Ber. 1959, 1675.
10.1021/jo0013913 CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/30/2001

1904 J . Org. Chem., Vol. 66, No. 5, 2001
Notes
Sch em e 4
A preliminary study of this reaction indicated that both
the ZnCl2 and thionyl chloride are needed for the reaction
to occur. Without at least an equivalent amount of each,
the reaction remained incomplete. Oxalyl chloride can
also be used in place of thionyl chloride. The reaction also
occurs in other solvents such as ethyl acetate and
acetonitrile. However, THF gives the highest cis/ trans
ratio. Scheme 2 shows the optimized reaction conditions.
At first, the use of thionyl chloride with the amino acid
3 led us to believe that the acid chloride could be the
intermediate in this reaction. However, 1H NMR experi-
ments in d8-THF showed a fast reaction, <20 min at room
temperature, between SOCl2 and benzaldehyde dimethyl
acetal in the presence of ZnCl2 to yield R-chloro ether 5.12
Furthermore, when ZnCl2 is added to a mixture of Cbz-
alanine, SOCl2 and benzaldehyde dimethyl acetal, 5 is
observed before the appearance of any 4 as determined
by 1H NMR. Thus, in the presence of ZnCl2, 5 reacts with
3 to afford the cyclized product 4 (presumably through
6) as shown in Scheme 3.
Sch em e 3
Hydrolysis of the crude alkylated template was ac-
complished by stirring with 30% HBr in acetic acid at
room temperature for 20 h to give the amino acid
hydrobromide. Amino ester 8 was obtained by stirring
the hydrobromide salt in ethanol at 70 °C in the presence
of HCl gas. Treatment of 8 with 3,5-dichlorophenyl
isocyanate in the presence of sodium carbonate provided
the hydantoin skeleton in high yield. Methylation with
methyl iodide completed the synthesis of 1.
In conclusion, we have demonstrated that the oxazo-
lidinone 4 can be synthesized with very high cis selectiv-
ity. The key to this method is the use of ZnCl2 as the
Lewis acid in combination with thionyl chloride. Under
this condition, cis isomer is obtained in >15:1 selectivity,
which after crystallization from aqueous ethanol provided
oxazolidinone 4 in >98% purity. Starting with pure cis
isomer, 1 is obtained in >99% chemical and chiral
purity14 on a multigram scale. Thus, we accomplished a
practical synthesis of ΒΙRΤ-377.
We also found that a 3:1 cis/trans mixture can be
enriched to 8:1 simply by stirring it with ZnCl2 in THF
at room temperature for 20 h. This indicates that the cis
isomer is the thermodynamic product. As shown in
Scheme 2, the isolated product has a cis/ trans ratio of
15:1 to 25:1, considerably higher than 8:1. Our prelimi-
nary results indicate that the improvement of the ratio
may take place when the reaction mixture is quenched
with water, through selective hydrolysis of the trans
diastereomer.13
Exp er im en ta l Section
Gen er a l P r oced u r es. 1H and 13C spectra were measured at
400 MHz using TMS as standard. The commercial chemicals
were used as received without further purification, and all
solvents were dried by standard methods prior to use. Column
chromatography was carried out on silica gel 60 (E. Merck, 230-
400 mesh). All melting points are uncorrected.
With the desired cis oxazolidinone 4 in hand, comple-
tion of the synthesis was carried out as shown in Scheme
4.
Using the method of Karady and co-workers,9a addition
of the 4-bromobenzyl bromide to the preformed enolate
of 4 in THF at -27 °C gave a very low yield of the
alkylated product. The low yield was attributed to the
unstable nature of the enolate. However, the addition of
the mixture of 4 and 4-bromobenzyl bromide in THF to
the base at -27° C afforded the product 7 in 75% yield
after flash column chromatography. The alkylation takes
place at the face of the enolate opposite the phenyl ring
and is completely stereoselective. Since the alkylated
product was somewhat unstable to silica gel, the crude
material was generally used in the next step.
(S,S)-4-Met h yl-5-oxo-2-p h en yl-oxa zolid in e-3-ca r b oxyl-
ic Acid Ben zyl Ester (4). Thionyl chloride (3.27 mL, 44.8 mmol)
was added to a stirring solution of Cbz-L-alanine (10.00 g, 44.8
mmol) and benzaldehyde dimethyl acetal (6.73 mL, 44.8 mmol)
in dry THF (75 mL) at 0 °C. After stirring for 5 min, anhydrous
ZnCl2 (6.11 g, 44.8 mmol) was added, and the reaction mixture
was stirred at this temperature for 3 h. At this stage, 0.2 equiv
each of SOCl2 (0.65 mL, 9.0 mmol) and anhydrous ZnCl2 (1.22
g, 9.0 mmol) were added, and the reaction mixture was stirred
for an additional 1 h.
The reaction mixture was quenched by dropwise addition of
water so that the reaction temperature did not exceed 10 °C. It
was extracted with ether (200 mL). The ether extract was
washed with water until almost neutral, with a saturated
solution of NaHCO3, and with water and finally dried over
anhydrous Na2SO4. Evaporation of the solvent furnished light
(12) The formation of 5 is very slow, ca. 40% after 18 h, in the
absence of ZnCl2.
(13) HPLC monitoring of samples withdrawn from the reaction
mixture during quench showed a gradual increase in the cis:trans ratio.
More details will be provided in a forthcoming full paper.
(14) Chiral purity: HPLC-Chiralpak AD, hexane:ethyl alcohol:
diethylamine (95: 5: 0.5) Chemical purity: HPLC-Reverse phase
C-18, 90% MeOH with 0.1% triethylamine.

Notes
J . Org. Chem., Vol. 66, No. 5, 2001 1905
yellow oil (21:1 cis by 1H NMR) which solidified on stirring with
hexane (75 mL). The product was filtered and dried under
reduced pressure (9.12 g, 65%, 29:1 cis by 1H NMR). The product
was finally purified by crystallization from ethanol/water to give
colorless needles, mp 52-53 °C (6.70 g, 48%, .50:1 cis by 1H
NMR). 1H NMR (CDCl3) δ 1.59 (s, 3H), 4.47-4.52 (m, 1H), 5.14-
5.21 (m, 2H), 6.65 (bs, 1H), 7.34-7.41 (m, 10 H). 13C NMR
(CDCl3) δ 52.5, 68.4, 89.4, 126.6, 127.0, 128.5, 128.9, 129.0, 129.2,
129.3, 130.3, 135.8, 137.3 and 172.9. MS (CI) 312 (MH+). Anal.
Calcd for C18H17NO4: C, 69.44; H, 5.50 and N, 4.49. Found: C,
69.40; H, 5.52 and N, 4.40.
(R,S)-4-(4-Br om oben zyl)-4-m eth yl-5-oxo-2-p h en yl-oxa zo-
lid in e-3-ca r boxylic Acid Ben zyl Ester (7). A solution of
oxazolidinone 4 (51.62 g, 0.166 mol) and 4-bromobenzyl bromide
(41.41 g, 0.166 mol) in dry THF (100 mL) was added to a stirring
solution of potassium hexamethyldisilazane (0.38 M/toluene,
0.174 mol, 457 mL, 1.05 equiv) in dry THF (400 mL) at -30 °C
at such a rate that the internal temperature remained between
-27.5 °C and -26.5 °C. The addition was complete in 1.5 h. The
reaction mixture was stirred at this temperature for 1 h followed
by stirring at room temperature for 1 h. The reaction mixture
was then poured into 1 L of ice cold saturated NaHCO3 and
extracted with ether (700 mL). The organic layer was separated
and dried over anhydrous Na2SO4, and the solvent was evapo-
rated to give crude 7 as yellow oil (80.0 g, 100%). Analytically
pure sample was obtained by silica gel column chromatography
using 10% ethyl acetate/hexane as the eluent to give colorless
solid, mp. 59-60 °C. 1H NMR (CDCl3) two rotamers (∼3:1) δ
1.88 (s, 0.75H), 1.94 (s, 2.25H), 2.99-3.06 (m, 1H), 3.35 (d, 0.25H,
J ) 13.6 Hz), 3.71(d, 0.75H, J ) 13.6 Hz), 4.89 (d, 0.75H, J )
13.6 Hz), 5.04-5.06 (m, 1H), 5.41-5.46 (m, 1.25H), 6.70 (m, 1H),
6.93-6.96 (m, 4H), 7.19-7.47 (m, 9H). 13C NMR (CDCl3) δ_23.9,
24.9, 40.2, 67.2, 68.1, 89.3, 89.5, 126.7, 128.2, 128.3, 128.5, 128.7,
After evaporation of alcohol, the residue was dissolved in
water (250 mL) and extracted with ether (300 mL). The ether
extract was discarded. The aqueous phase was basified with solid
NaHCO3, and the product was extracted with CH2Cl2. It was
dried over anhydrous Na2SO4 and concentrated to a light brown
oil which solidified on standing. Amino ester 8 was finally
purified by crystallization from light petroleum ether to give
colorless crystals, mp 42-43 °C (31.5 g, 66% over three steps,
chemical purity 95%, ee >99%), [R]25D ) +5.12° (c ) 1.0, EtOH),
1H NMR (CDCl3) δ 1.28 (t, 3H, J ) 7.0 Hz), 1.39 (s, 3H), 2.75 (d,
1H, J ) 13.2 Hz), 3.09 (d, 1H, J ) 13.2 Hz), 4.11-4.22 (m, 2H),
7.07 (d, 2H, J ) 8.35 Hz) and 7.42 (d, 2H, J ) 8.35 Hz). 13C
NMR (CDCl3) δ 14.2, 26.6, 46.0, 58.4, 61.1, 120.9, 131.3, 131.7,
135.6 and 176.8. MS (CI) 286 (MH+). Anal. Calcd for C12H16
-
BrNO2 : C, 50.37; H, 5.64 and N, 4.89. Found: C 50.28; H, 5.51
and 4.83.
(R)-5-(4-Br om oben zyl)-3-(3,5-dich lor oph en yl)-1,5-dim eth -
ylim id a zolid in e-2,4-d ion e (BIRT-377) (1). To a stirring solu-
tion the amino ester 8 (4.55 g, 16 mmol) in dry DMSO (25 mL)
at room temperature was added 3,5-dichlorophenyl isocyanate
(3.0 g, 16 mmol). After stirring for 1 h, sodium carbonate (3.40
g, 32.0 mmol) was added, and the reaction mixture was heated
at 120° C for 1 h. The cooled reaction mixture was diluted with
ethyl acetate, washed thoroughly with water, and dried over
anhydrous Na2SO4. Evaporation of the solvent furnished the
crude hydantoin (6.80 g, 98%), which was used as such in the
next step.
To a solution of the crude hydantoin (6.80 g, from above) in
dry DMF (20 mL) was added sodium hexamethyldisilazane (1M/
THF, 16 mmol, 16 mL). After stirring the mixture for 15 min at
room temperature, methyl iodide (1.20 mL, 19.20 mmol) was
added and was stirred for 2 h. The reaction mixture was
quenched with ice, diluted with water, and extracted with ethyl
acetate. The organic layer was dried over anhydrous Na2SO4,
and the solvent was evaporated to give a crude material. It was
purified using silica gel column and 20% ethyl acetate/hexane
as eluent to give a colorless solid. It was finally purified by
crystallization from ethyl acetate to give 1 as colorless crystals,
mp 135-136 °C (5.87 g, 13.3 mmol, 83% over two steps, chemical
128.9, 131.1, 131.3, 131.9 and 132.0. Anal. Calcd for C25H22
-
BrNO4: C, 62.51; H, 4.62 and N, 2.92. Found: C, 62.29; H, 4.70
and N, 2.77.
(R)-2-Am in o-2-m eth yl-3-(4-br om op h en yl)p r op ion ic Acid
Eth yl Ester (8). HBr/acetic acid (30 wt %, 100 mL) was added
over 20 min to a stirring solution of crude alkylated oxazolidi-
none 7 (80.0 g, from above) in glacial acetic acid (150 mL) at
room temperature, and the reaction mixture was stirred for 20
h. Solvent was evaporated, and the residue was dissolved in
water (600 mL). 2 N HBr (100 mL) was also added. It was
extracted with ether (600 mL), which was discarded. The
aqueous phase was evaporated to dryness to give the amino acid
hydrobromide as an off-white solid (49.20 g, crude).
HCl gas was bubbled through a solution of the amino acid
hydrobromide (49.20 g, from above) in ethyl alcohol (400 mL) at
room temperature for 45 min. The reaction mixture was stirred
at 70 °C (bath temp) for 24 h. To complete the reaction,
additional HCl gas was bubbled through the reaction mixture
(15 min) and stirred for an additional 10 h at 70 °C.
purity: >99%, chiral purity: >99%). [R]25 ) +134.3° (c ) 1.0
D
EtOH) 1H NMR (CDCl3) δ 1.61 (s, 3H), 2.96 (d, 1H, J ) 14 Hz),
3.06 (s, 3H), 3.08 (d, 1H, J ) 14 Hz), 6.84 (d, 2H, J ) 1.8 Hz),
6.94 (br d, 2H, J ) 8.3), 7.28 (t, 1H, J ) 1.8 Hz) and 7.42 (br d,
2H, J ) 8.3 Hz). 13C NMR (CDCl3) δ 21.0, 25.2, 40.6, 65.6, 121.9,
124.4, 128.3, 131.0, 131.0, 132.8, 132.9, 135.0, 153.4 and 173.3.
Anal. Calcd for C18H15BrCl2N2O2: C, 48.89; H, 3.41 and N, 6.33.
Found: C, 48.88; H, 3.06 and N, 6.28.
Ack n ow led gm en t. We thank Dr. Vittorio Farina for
helpful discussions.
J O0013913