An efficient synthesis of N-arylated, orthogonally protected racemic aspartates

Article abstract of DOI:10.1016/j.tetlet.2007.11.060

A brief and efficient synthesis of variously N-arylated racemic aspartates has been achieved by two consecutive reactions in one-pot, in which imine or equivalent, formed in situ from various anilines and ethyl glyoxylate, reacted with the Reformatsky rea

Full text of DOI:10.1016/j.tetlet.2007.11.060

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 296–299
An efficient synthesis of N-arylated, orthogonally
protected racemic aspartates
*
Guanglin Luo, Ling Chen, Rita Civiello and Gene M. Dubowchik
Department of Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT, USA
Received 6 February 2007; revised 8 November 2007; accepted 9 November 2007
Available online 17 November 2007
Abstract—A brief and efficient synthesis of variously N-arylated racemic aspartates has been achieved by two consecutive reactions
in one-pot, in which imine or equivalent, formed in situ from various anilines and ethyl glyoxylate, reacted with the Reformatsky
reagent, tert-butyl 2-bromozinc acetate. Notably the two esters are orthogonally protected for the convenience of further
derivatization.
Ó 2007 Elsevier Ltd. All rights reserved.
7
N-Aryl-a-amino acids are common pharmacophores in
a number of medicinally important agents. Many of
their derivatives, including non-nucleoside reverse trans-
of aspartic acid in acceptable yield. The key to success
was the formation of a soluble salt in dimethylacet-
amide, dimethylformamide, or acetonitrile. Recently
this transformation was achieved with water as solvent,
1
criptase inhibitor Opaviraline 1, insulin sensitizer Farg-
2
3
8
litazar 2, anticoagulant factor Xa inhibitor 3, and
albeit with low yield (32%) in the case of aspartic acid.
platelet aggregation inhibitor GP IIb/IIIa antagonist
Lotrafiban (SB-214857) 4, shown in Figure 1, possess
a wide range of biological activities.
Our initial attempt to utilize these conditions failed in
cases of more complicated, functionalized bromides.
What is more, these coupling reactions use commercial
4
One of our recent medicinal chemistry programs
required an efficient method of accessing various N-aryl
aspartic acid derivatives as intermediates for further
elaboration at two acid or ester functional groups. Our
first thought was a direct coupling of various aryl
bromides with aspartic acid or esters. N-Arylation of
amino acids or esters was initially achieved by Ma using
a copper-catalyzed coupling reaction of aryl halides and
amino acids or esters (CuI and K CO in dimethylacet-
H
N
O
O
H
N
F
N
O
O
O
N
O
O
OH
1
(Opaviraline)
2 (Farglitazar)
OH
O
O
2
3
5
amide). However, these conditions were only successful
for amino acids bearing hydrophobic side groups (exem-
plified by valine, phenylalanine, and proline) and failed
for those with hydrophilic substituents (glutamic acid,
serine, or glycine). Later, intra-molecular N-arylation
of an aspartic acid derivative for the synthesis of 4
H
O
H N
N
O
2
N
H
S NH2
NH
3 (Anticoagulant)
6
was achieved under these conditions. Conditions were
O
OH
further developed by Hayes substituting K CO with
tetrabutylammonium hydroxide to effect N-arylation
HN
2
3
H
N
O
N
O
N
Keywords: Ethyl glyoxylate; Imine; N-Aryl aspartate; Reformatsky
reagent.
4
(Lotrafiban)
*
Corresponding author. Tel.: +1 230 677 6640; fax: +1 203 677
702; e-mail: guanglin.luo@bms.com
7
Figure 1. Selected biologically active N-arylated aminoacids.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.060

G. Luo et al. / Tetrahedron Letters 49 (2008) 296–299
297
O
aspartic acid or the dimethyl ester as starting materials
and further steps are required to differentiate the two
acid or ester groups as we require.
O
R
O
R
N
NH2
O
Another useful amino ester N-arylation method was
9
5
developed by Lam, in which arylboronic acids reacted
O
with a-amino esters using Cu(OAc) as a catalyst. Com-
2
pared to the CuI-catalyzed coupling reaction, the advan-
tage of this method is minimum racemization of the
amine chiral center. Again, in the case of aspartate, dif-
ferentiation of 2 equiv esters is needed and availability
of a variety of arylboronic acids is limited.
R
O
BrZn
O
NH
O
O
O
O
6
With the aim of differentiating the ester groups from the
beginning, we envisioned a simple reaction sequence, in
Scheme 1. Proposed synthesis of N-arylated aspartates.
Table 1. Conversion of anilines 5 to N-aryl aspartates 6
a
Entries
1
Aniline 5
Imine synthesis method
Product 6
Yield (%)
O
O
NH
O
A
82
NH2
O
O
5
a
O
6
a
Br
Br
2
B
83
NH
O
NH2
O
O
5b
O
6
b
N
N
3
4
5
B
A
C
82
65
65
NH
O
NH2
Br
O
O
5
c
O
6c
Br
O
HO
Br
HO
Br
NH
O
NH2
O
5d
O
6d
N
HN
N
HN
NH
O
O
NH2
O
O
5
e
O
6
e
O
N
N
6
7
B
B
85
91
H2N
N
O
HN
O
N
O
O
O
O
O
5
f
O
6
f
OH
OH
NH2
NH
O
O
O
5
g
O
6
g
a
Isolated yield of pure compound for two steps.

298
G. Luo et al. / Tetrahedron Letters 49 (2008) 296–299
which imine intermediates formed in situ between ethyl
glyoxylate and widely available anilines react with com-
mercially available Reformatsky reagent tert-butyl
bromozinc acetate, as shown in Scheme 1. Reaction of
Reformatsky reagents with different electrophiles
including imines have long been known in the
generate a new aniline anion which attacks the ethyl
ester to form the 5-membered ring imidazolone 7.
No 6-membered ring product was observed. Compound
7 appeared to be a single diastereomer, though no
rigorous efforts were attempted to assign relative
stereochemistry.
1
5
1
0
literature.
Owing to the presence of a 2-hydroxymethyl substituent
in 5g (entry 7), the intermediate formed in the reaction
sequence is most likely a 6-membered cyclic semi-aminal
instead of imine (Scheme 3), reaction of which with tert-
butyl 2-bromozinc acetate also proceeded well to afford
6g in 91% yield. Compound 6g or analogs can be con-
verted to benzodiazepinones such as Lotrafiban 4 using
Our first attempt, using p-anisidine 5a met with good
success (Table 1, entry 1). Synthesis of the correspond-
˚
ing imine according to literature procedures with 4 A
1
1
molecular sieves as a dehydrating reagent, followed
1
2
by reaction with tert-butyl 2-bromozinc acetate, affor-
ded the desired aspartate 6a in 82% yield after purifica-
tion. In subsequent reactions with various aniline
derivatives, it was found that imine formation was crit-
ical for the success of the subsequent reaction with the
Reformatsky reagent. Various conditions for the forma-
tion of imines were then surveyed but not optimized
7
,16
known procedures.
Inspired by the success with the putative semi-aminal
intermediate in Scheme 3, we were interested in proceed-
ing through semi-aminal adducts with methanol instead
of imines which are sometimes unstable, especially when
the aniline is electron-deficient. The formation of one
successful methanol semi-aminal had been described in
1
3
among the aniline derivatives shown in Table 1. Gen-
1
erally, analytical means (TLC, LCMS, or H NMR)
were taken to make sure that the formation of imines
was sufficiently clean and complete.
1
7
the literature. In the case of 3,5-dichloroaniline (5h)
from which formation of the imine was not successful,
a stable intermediate 8 was obtained in ca. 50% isolated
The crude imines generally reacted with the Reformat-
sky reagent very well to afford a variety of N-arylated
1
5
yield (Scheme 4).
Reaction of 8 with tert-butyl
1
4
aspartates as shown in Table 1. It is noteworthy that
an free phenol group (entry 4) or indazole NH group
2-bromozinc acetate went well to afford the desired
(
entry 5) did not require protection as long as an extra
equivalent of Reformatsky reagent was used. An aniline
1
5
O
O
(
5f) with ortho-substitution, amide and BOC func-
tional groups (entry 6) also proceeded smoothly to the
desired product. However, when an insufficient amount
of Reformatsky reagent was used, a new product could
be formed. In the case of 3,5-dimethyl aniline, a highly
OH
O
HN
NH2
O
O
1
5
5g
substituted imidazolone 7 was formed (Scheme 2). Pre-
sumably after the addition of Reformatsky reagent to
the imine, the resulting N-centered anion could react
with another equivalent of imine, when available, to
O
O
OH
BrZn
O
NH
O
O
O
THF
O
6
g
O
O
O
Scheme 3. Proposed semi-aminal intermediate.
BrZn
O
N
O
O
N
O
O
O
Cl
O
N
O
Cl
O
O
HN
Cl
Cl
NH2
O
O
MeOH
0 C, 18 h
5
h
o
O
6
8
50%
O
O
O
O
Cl
O
N
O
O
O
O
N
BrZn
O
O
O
N
O
Cl
NH
O
O
N
O
THF
40 C - 0 C
o
o
O
-
6
h
7
1.5 h, 63%
Scheme 2. Formation of a densely substituted imidazolone.
Scheme 4. Proposed semi-aminal intermediate and reaction.

G. Luo et al. / Tetrahedron Letters 49 (2008) 296–299
299
product 6h in 63% yield (Scheme 4).15 However, though
stable and identifiable, the formation of methanol semi-
aminals was not always achievable. For example, the
dianilino-aminal was found to be the major product in
the case of simple aniline.
Parker, M.; Peishoff, C. E.; Rhodes, G.; Ross, S.; Shu, A.;
Simpson, R.; Takata, D.; Yellin, T. O.; Uzsinskas, I.;
Venslavsky, J. W.; Yuan, C.-K.; Huffman, W. F. J. Med.
Chem. 1996, 39, 4867–4870.
. Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem.
Soc. 1998, 120, 12459–12467.
5
6
7
. Ma, D.; Xia, C. Org. Lett. 2001, 3, 2583.
. Clement, J.-B.; Hayes, J. F.; Sheldrake, H. M.; Sheldrake,
P. W.; Wells, A. S. Synlett 2001, 1423–1427.
In summary, a very short and facile racemic synthesis
has been achieved for N-arylated aspartates through
an imine or semi-aminal intermediate in one-pot. More
critically, the two acid groups were orthogonally
protected as ethyl and tert-butyl esters, which could
be deprotected under basic and acid conditions,
respectively.
8. Lu, Z.; Twieg, R. J. Tetrahedron Lett. 2005, 46, 2997–
3001.
9. Lam, P. Y. S.; Bonne, D.; Vincent, G.; Clark, C. G.;
Combs, A. P. Tetrahedron Lett. 2003, 44, 1691–1694.
0. For a review; see: Erdik, E. Organozinc Reagents in
Organic Synthesis; CRC Press LLC, 1996, pp 207–236.
1. Manhas, M. S.; Ghosh, M.; Bose, A. K. J. Org. Chem.
1
1
1
1
1
990, 55, 575–580.
Acknowledgment
2. tert-Butyl 2-bromozinc acetate (0.50 M in THF) was
commercially available from Reike Metals, Inc.
3. Conditions for the formation of imines: Method A:
Approximately 1.1:1 ratio of ethyl glyoxylate (50% toluene
The authors are grateful to Dr. John E. Macor for his
constant support and encouragement.
˚
solution) and 5 (4.0 mmol) in CH Cl (10 ml) with 4 A
2
2
M.S. till completion, then filtered and concentrated;
Method B: Approximately 1:1 ratio of ethyl glyoxylate
Supplementary data
(
(
50% toluene solution) and 5 (2.0 mmol) in benzene
20 ml) was refluxed for 18 h (or till completion) followed
Supplementary data (analytical data including copies of
H and C NMR spectra for compounds 5f, 6a–6h, 7
and 8) associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2007.11.060.
1
13
by concentration; Method C: Approximately 1.1:1 ratio of
ethyl glyoxylate (50% toluene solution) and 5 (2.0 mmol)
in THF (6 ml) with anhydrous MgSO4 till completion,
then filtered and concentrated.
1
4. General procedures for the synthesis of 6: Intermediate
imine (2.0 mmol) was redissolved in anhydrous THF
(8 ml) and cooled at 0 °C or À20 °C under nitrogen. 1.1 or
References and notes
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