Improved Schoellkopf construction of quaternary α-amino acids: efficient enantioselective synthesis of integrin LFA-1 antagonist BIRT-377

Article abstract of DOI:10.1016/j.tetasy.2006.06.019

The Schoellkopf methodology for the asymmetric synthesis of α-amino acids which was previously not applicable to the construction of α,α-dialkylated (quaternary) α-amino acids, has been rendered practical for this purpose and applied in a highly efficient

Full text of DOI:10.1016/j.tetasy.2006.06.019

Tetrahedron: Asymmetry 17 (2006) 1754–1757
¨
Improved Schollkopf construction of quaternary
a-amino acids: efficient enantioselective synthesis
of integrin LFA-1 antagonist BIRT-377
Stamatia Vassilioua and Plato A. Magriotisb,*
aDepartment of Chemistry, Laboratory of Organic Chemistry, University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece
bDepartment of Chemistry, New York University, 110 Washington Square East, New York, NY 10003, USA
Received 25 May 2006; accepted 5 June 2006
Abstract—The Scho¨llkopf methodology for the asymmetric synthesis of a-amino acids which was previously not applicable to the con-
struction of a,a-dialkylated (quaternary) a-amino acids, has been rendered practical for this purpose and applied in a highly efficient
enantioselective synthesis of integrin LFA-1 antagonist BIRT-377.
Ó 2006 Elsevier Ltd. All rights reserved.
O
1. Introduction
Cl
Cl
Br
N
N
The synthesis of a,a-dialkylated (quaternary) a-amino acids
has recently received considerable attention since their
incorporation in modified peptides, often improves both
the biological activity and the pharmacological profile of
the latter, due to the introduction of unusual conformational
constraints which change their secondary or tertiary struc-
ture.1 Furthermore, these peptides are rendered more stable
metabolically due to the decreased rate of proteolysis.2
O
1
Figure 1. Structure of cell adhesion inhibitor BIRT-377.
Prior to the discovery of cell adhesion inhibitor BIRT-377,6
potential therapeutics designed to block the binding of
LFA-1 to ICAM-1 for the treatment of immunological dis-
orders,7 had been mostly mAb based,8 mainly because of
the problems inherent in identifying or designing small
molecules that antagonize protein–protein interactions.9
Specifically, blockade of integrin LFA-1 by monoclonal
antibodies (mAbs) had shown efficacy in animal models
of inflammation and autoimmune diseases such as arthritis,
ischemia/reperfusion injury, and transplant rejection.10
Therefore, an effective antagonist of LFA-1, such as
BIRT-377, may prove useful for the treatment or prophyl-
axis of inflammatory diseases, autoimmune diseases includ-
ing Crohn’s disease,6 tumor metastasis, allograft rejection,
and reperfusion injury.11
Along with recently developed catalytic enantioselective
protocols,3 alkylation of glycine or amino acid chiral eno-
late equivalents stands as one of the most convenient and
general methodologies for the synthesis of enantiomerically
pure a-amino acids, particularly, quaternary a-amino
acids.4 One of the most notable examples of the latter ap-
proach, is the bis-lactim ether methodology developed by
Scho¨llkopf and co-workers.5 Herein, we report an efficient
enantioselective synthesis of the integrin LFA-1 antagonist
BIRT-377 1 (Fig. 1) which is essentially an N-aryl hydan-
toin derivative of such a quaternary a-amino acid by
employing an improved Scho¨llkopf protocol, based on
the use of tert-BuLi instead of n-BuLi5 for the deprotona-
tion of the substituted bis-lactim ether 2 (Scheme 1).
2. Results and discussion
*
Despite a few recent reports describing catalytic enantio-
selective syntheses of BIRT-377,3a,12 we envisioned that
Corresponding author. Tel.: +1 212 998 3591; fax: +1 212 260 7905;
e-mail: plato.magriotis@nyu.edu
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.06.019

S. Vassiliou, P. A. Magriotis / Tetrahedron: Asymmetry 17 (2006) 1754–1757
1755
1. tert-BuLi
THF, -78 ºC
H3CO
N
H3CO
6
3
N
N
2. p-Bromobenzyl bromide
OCH3
N
OCH3
THF, -78 ºC
0 ºC
H3C
CH3
Br
3
2
TFA
CH3CN/H2O
25 ºC
1. 3,5-Dichlorophenyl
isocyanate, DMSO
R
N
O
O
H2N
CH3
N
OCH3
Br
Na2CO3, 120 ºC, 12 h
2. LiHMDS, DMF, 0 ºC
MeI, 25 ºC, 2 h
O
Cl
H3C
5, R = H
1, R = CH3
Br
4
Cl
Scheme 1. Scho¨llkopf-type enantioselective synthesis of cell adhesion inhibitor BIRT-377.
the more established chiral auxiliary-based methodology
might lead to an improved enantioselective route to
BIRT-377.13 Thus, deprotonation of chiral auxiliary 2 with
tert-BuLi followed by alkylation of the resulting anion with
p-bromobenzyl bromide, provided 3 in 85% yield and very
high diastereoselectivity (ꢀ95%, Scheme 1). Notably, the
yield of this alkylation using n-BuLi as the base was only
60%.14 This significant yield disparity is most likely due
to the exclusively basic action of tert-BuLi toward the less
hindered C-3 hydrogen as opposed to the C-6 one, as well
as its negligible nucleophilicity toward the imino esters.
Hydrolysis of 3 with TFA,5b and reaction of the derived
a-amino ester 4 with 3,5-dichlorophenyl isocyanate, gave
rise to hydantoin derivative 5 in 90% yield which was
N-methylated to furnish the requisite LFA-1 antagonist
BIRT-377 1 (100% yield, Scheme 1).15
ciently converted to the useful integrin LFA-1 antagonist
BIRT-377.6,7,10,11,16
4. Experimental
4.1. General
All of the compounds, for which analytical and spectro-
scopic data are quoted, were homogenous by TLC. TLC
analyses were performed using silica gel plates (E. Merck
silica gel 60 F-254) and components were visualized by
the following methods: ultraviolet light absorbance, and
ninhydrin spray. Column chromatography was carried
out on silica gel (E. Merck, 70–230 mesh), height 42 cm,
diameter 2.3 cm. All the compounds were characterized
by 1H and 13C NMR spectroscopy. 1H and 13C NMR spec-
tra were recorded on a 200 MHz Mercury Varian spec-
trometer. Electron spray mass spectroscopy (ESMS) was
performed on a Surveyor MSQ instrument. Optical rota-
tions were recorded on a Perkin–Elmer 349 Polarimeter
(k = 589 nm, 1 dm cell). HPLC was carried out using a
Pharmacia LKB-HPLC consisting of a Waters 2487-dual
k Absorbance Detector and a 224B Pump.
The asymmetric synthesis of BIRT-377 described herein is
highly competitive with both previously reported chiral
auxiliary-based syntheses,16 and the more recent catalytic
approaches.3a,12,13
The high efficiency of this method relies on both the ready
availability of 2 (E. Merck),17 and the two-step, one-pot
conversion of 3 to 5 in >90% isolated yield.
4.2. (3R,6S)-3-(4-Bromobenzyl)-6-isopropyl-5-methoxy-3-
methyl-3,6-dihydro-2-pyrazinyl methyl ether 3
3. Conclusion
To a solution of (6S)-6-isopropyl-5-methoxy-3-methyl-3,6-
dihydro-2-pyrazinyl methyl ether (2, 0.30 g, 1.52 mmol) in
dry THF (3 ml) under argon at ꢁ78 °C was added tert-
BuLi (1.6 M, 0.95 ml, 1.52 mmol) dropwise. The resulting
solution was stirred at ꢁ78 °C for 1 h and treated slowly
We have shown that the Scho¨llkopf methodology can be
conveniently employed for the enantioselective construc-
tion of quaternary a-amino acids in a practical manner,4,5
and we have applied this protocol to the synthesis of qua-
ternary a-amino ester 4 (Scheme 1),18 which has been effi-
with
a solution of 4-bromobenzyl bromide (0.50 g,

1756
S. Vassiliou, P. A. Magriotis / Tetrahedron: Asymmetry 17 (2006) 1754–1757
2.00 mmol) in dry THF (4 ml). The reaction mixture was
stirred at ꢁ78 °C for 10 h, allowed to slowly warm to ambi-
ent temperature, and was quenched with saturated NH4Cl.
The aqueous layer was extracted with Et2O twice. The
combined organic layers were washed with brine and
dried over Na2SO4. After removal of solvent under
reduced pressure, the residue was purified by column chro-
matography (silica gel, CH2Cl2) to afford 3 (0.47 g, 85%).
iodomethane (10 ll, 0.150 mmol) were added and stirred
at ambient temperature for 2 h. The reaction mixture was
diluted with water and extracted with ethyl acetate. The
organic phase was dried over Na2SO4, concentrated, and
purified by column chromatography (silica gel, light petro-
leum ether/ethyl acetate = 60:30) to afford 1 as solid
25
(45 mg, quantitative). Mp: 135–136 °C ½aꢂD ¼ þ127:1 (c
1
1, EtOH). H NMR (200 MHz, CDCl3): d 1.61 (s, 3H),
25
1
½aꢂD ¼ ꢁ70:0 (c 1, CH2Cl2). H NMR (200 MHz, CDCl3):
d 0.57 (d, 3H, J = 6.6), 0.93 (d, 3H, J = 6.6), 1.44 (s, 3H),
2.22–2.17 (m, 1H), 2.71, 3.05 (AB, 2H, JAB = 12.5), 3.27 (d,
1H, J = 3.7), 3.65 (s, 6H), 6.87 (d, 2H, J = 8.1), 7.28 (d,
2H, J = 8.1). 13C NMR (50 MHz, CDCl3): d 16.8, 19.4,
28.8, 30.8, 46.8, 52.1, 52.3, 59.8, 60.7, 120.5, 130.9, 131.9,
136.8, 162.3, 164.0. MS (EI): 367.1 (M+).
2.89, 3.12 (AB, 2H, JAB = 13.9), 3.06 (s, 3H), 6.83 (d,
2H, J = 1.5), 6.94 (d, 2H, J = 8.8), 7.28 (t, 1H, J = 1.5),
7.44 (d, 2H, J = 8.8). 13C NMR (50 MHz, CDCl3): d
21.3, 25.6 40.9, 65.9, 122.2, 124.8, 128.6, 131.3, 132.1,
133.0, 135.3, 153.7, 173.6. MS (EI): 442.9 (MH+). HPLC
(Daicel Chiralcel OD, hexane/isopropanol/Et2NH =
90:9.9:0.1, flow rate 0.8 ml/min, k = 254 nm): tR =
17.30 min (ꢁ), (BIRT-377, ent-3), tR = 20.40 min (+),
(BIRT-377, 1).
4.3. Methyl (2R)-2-amino-3-(4-bromophenyl)-2-methylpro-
panoate 4
To a solution of compound 3 (0.30 g, 0.87 mmol) in aceto-
nitrile–water 3:1 (4 ml), trifluoroacetic acid (0.5 ml) was
added and the resulting solution was stirred at ambient
temperature for 10 h. It was then evaporated to dryness
and the residue diluted with ethyl acetate and water. The
aqueous layer was neutralized with NaHCO3 5% solution
and extracted with CH2Cl2. The organic layer was dried
over Na2SO4. After removal of solvent under reduced pres-
sure, the residue was purified by column chromatography
Acknowledgements
This work was supported in part by the Laboratory of
Organic Chemistry of the University of Athens and by
the special account for research grants of the University
of Athens. Professor James W. Canary (NYU) is warmly
thanked for generous donation of both laboratory space
and consumables. We also thank Dr. Dionisios Abatis
for HPLC assistance and Professor Athanasios Yiotakis
for sustained encouragement and advice as well as gener-
ous donation of consumables.
(silica gel, CH2Cl2/MeOH = 95/5) to afford 4 as solid
25
(0.23 g, 97%). Mp: 40–42 °C. ½aꢂD ¼ þ16:7 (c 1, CH2Cl2).
1H NMR (200 MHz, CDCl3): d 1.35 (s, 3H), 1.69 (br s,
2H), 2.73, 3.02 (AB, 2H, JAB = 13.1), 3.66 (s, 3H), 6.99
(d, 2H, J = 8.1), 7.37 (d, 2H, J = 8.1). 13C NMR
(50 MHz, CDCl3): d 26.7, 46.4, 52.4, 58.9, 121.2, 131.6,
131.9, 135.8, 177.4. MS (EI): 273.9 (MH+).
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