A simple approach for the synthesis of new pyrimidinyl α-amino acids

Article abstract of DOI:10.1016/j.tet.2009.11.077

A simple synthetic method for the preparation of optically active pyrimidinyl α-amino acids is presented. A nucleophilic ipso-substitution reaction between 2-(benzylsulfonyl)-4-isopropoxypyrimidines and a nucleophilic side chain of several protected natural α-amino acids is investigated to obtain new pyrimidin-2-yl α-amino acids. A detailed optimisation study of this reaction is discussed. Moreover, the selective O-alkylation of 2-(benzylsulfanyl)-4(3H)pyrimidinones with a hydroxylic side chain of some natural α-amino acids under Mitsunobu conditions is studied as a method to prepare new pyrimidin-4-yl α-aminoesters.

Full text of DOI:10.1016/j.tet.2009.11.077

Tetrahedron 66 (2010) 612–623
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A simple approach for the synthesis of new pyrimidinyl a-amino acids
*
Abdelatif Elmarrouni, Mireia Gu¨ell, Cristina Collell, Montserrat Heras
Department of Chemistry, Faculty of Science, University of Girona, Campus de Montilivi, Girona E-17071, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 October 2009
Received in revised form 16 November 2009
Accepted 17 November 2009
Available online 20 November 2009
A simple synthetic method for the preparation of optically active pyrimidinyl
a
-amino acids is presented.
A
nucleophilic ipso-substitution reaction between 2-(benzylsulfonyl)-4-isopropoxypyrimidines and
a nucleophilic side chain of several protected natural a-amino acids is investigated to obtain new pyr-
imidin-2-yl
selective O-alkylation of 2-(benzylsulfanyl)-4(3H)pyrimidinones with a hydroxylic side chain of some
natural -amino acids under Mitsunobu conditions is studied as a method to prepare new pyrimidin-4-yl
-aminoesters.
a-amino acids. A detailed optimisation study of this reaction is discussed. Moreover, the
a
Keywords:
Non-proteinogenic amino acids
Pyrimidines
a
Ó 2009 Elsevier Ltd. All rights reserved.
Nucleophilic ipso-substitution
Mitsunobu reaction
Chiral pool
1. Introduction
acids have been reported.18 These methods are mainly based on the
enantioselective transformation of prochiral starting materials or
In drug discovery, interest in non-proteinogenic amino acids is
increasing as a result of their intrinsic biological propertiesdanti-
biotic, antiviral and antitumour1dand their utility as building
blocks and molecular scaffolds in the synthesis of combinatorial
libraries of non-peptidic compounds.2 Many of these non-protei-
nogenic amino acids are also critical components in pharmaceuti-
cals and developmental drugs.3 Furthermore, their incorporation
into biologically active peptides has been used to improve the ac-
tivity, stability, bioavailability and selectivity of peptides in their
use as a therapeutic agents.4 For these reasons, research into
methods that will allow the efficient synthesis of novel non-pro-
teinogenic amino acids is crucial.5 From among the various non-
on chiral pool synthesis by transformation of natural a-amino acids.
HN
NH2
N
N
HO
N
HET
NH2
CO2H
OH
n
NH2
N
N
O
I
HO2C
n=1, Heteroarylalanines
L
-Azatyrosine
Discadenine
O
NH
NH2
HO
N
proteinogenic amino acids, such as
a,a-disubstituted a-amino
NH2
N
O
N
N
CO2H
acids,6 arylglycines,7
b and g
-amino acids,8 proline derivatives9 and
CO2H
CO2H
O
conformationally restricted amino acids10 we have focused our
attention on the heterocyclic amino acids type I (Fig. 1), a class of
NH2
Iboteic acid
L
-Lathyrine
NH2
Willardiine
non-proteinogenic a-amino acids, substituted on the side chain by
Figure 1. Examples of heterocyclic
a-amino acids.
an heterocyclic ring.11 Many of these compounds are natural and
have been discovered and isolated from natural sources.12 Exam-
ples include willardiine,13 discadenine,14 -azatyrosine15
L , L-lath-
Pyrimidine rings are present in some important natural
biologically active compounds19 and synthetic pyrimidine de-
rivatives have important pharmaceutical and agrochemical prop-
erties.20 Apart from willardiine13 and lathyrine analogues16,21 only
a small number of synthetic methods for obtaining new unnatural
yrine16 and ibotenic acid17 (Fig. 1), which all displayed a wide range
of biological properties such as antibacterial or antitumour activi-
ties. Moreover, in recent years a number of stereoselective methods
for rendering new synthetic enantiopure heterocyclic
a-amino
pyrimidinyl a
-amino acids are reported in the literature.22
One of our research interest lies in the development of efficient
methods for the preparation of pyrimidinyl compound libraries
with a high degree of molecular diversity through solution or solid-
* Corresponding author. Tel.: þ34 972418274; fax: þ34 972418150.
E-mail address: montserrat.heras@udg.edu (M. Heras).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.077

A. Elmarrouni et al. / Tetrahedron 66 (2010) 612–623
613
phase synthesis.23 The highlight in our synthetic sequences include
selective O-alkylation of 2-(alkylsulfanyl)-4(3H)pyrimidinones 1
with alkyl halides under basic conditions or with alcohols under
Mitsunobu conditions, followed by chemical transformations at
position 4 of the pyrimidine ring and a final nucleophilic ipso-
substitution step of the oxidised sulfur with a variety of nucleo-
philes (Scheme 1). This last step is used not only for introducing
molecular diversity but also as cleavage reaction in solid-phase
synthesis. Both nucleophilic ipso-substitution reaction of alkylsul-
fonyl groups and Mitsunobu reaction are versatile and useful
methods currently employed in the development of synthetic
strategies for the construction of highly functionalised pyrimi-
dines.24 In this connection, we have recently described the syn-
thesis of novel N-pyrimidinyl arylglycines type
2 through
subsequent Mitsunobu, Petasis and ipso-substitution reactions25
(Scheme 1).
Chemical
transformation
OR4
OR3
N
O
N
i) R3X / Base
N
n
HN
N
R1
R1
or
R1
N
R2
S
O
R2
R2
S
S
ii) R3OH / PPh3 / DIAD
1
n= 1, 2
R1= Bn, Merrifield resin
R2= H, Me, Ph
Oxidation
Ph
NuH
Figure 2. X-ray crystal structure of compound 5c.
CO2Me
R3
OR4
N
N
O
N
R2
R1
N(p
) or N(
s
) atoms and consequently two regioisomers would be
) derivative is often the major product
N
isolated. Although the N(
s
Nu
R2
N
N
resulting from steric factors, it is rarely exclusive. However, in all
cases (Table 1, entries 1–5) the reaction was completely regiose-
2
O
lective in favour of the N(s) derivative. The unambiguous assign-
Scheme 1. Synthesis of highly functionalised pyrimidines.
ment of the structures 5a–c was achieved by X-ray analysis of
compound 5c. As evidenced in Figure 2, the histidine residue is
As a part of our research aimed at synthesising novel, modified
antimicrobial peptides by incorporation of unnatural -amino
acids, we centred our attention on the synthesis of novel, unnatural
pyrimidinyl -amino acids. Specifically, we prepared a series of
pyrimidines substituted at position 2 and/or 4 with an -amino acid
attached to position 2 of the pyrimidine ring by the N(
imidazole ring.
s) of the
a
In our initial experiments with Na-Boc-tyrosine methyl ester 4b,
we first studied the nucleophilic ipso-substitution reaction by
employing several bases and starting from 2-benzylsufonylpyr-
imidine 3a. No reaction took place when potassium tert-butoxide
was used as a base (Table 1, entry 6). Better results were obtained
using both NaH and potassium carbonate affording pyrimidinyl
amino ester 5d without appreciable racemisation (Table 1, entries 7
and 8). In the case of potassium carbonate, reaction required
heating at 50 ꢀC for completion. These reaction conditions were
then extended to 2-benzylsufonylpyrimidines 3b and 3c, which
afforded the corresponding pyrimidinyl aminoesters 5e and 5f in
good yields (Table 2, entries 9 and 10). Unfortunately compound 5f
was obtained with a high degree of racemisation (60:40 enantio-
meric ratio). In order to avoid racemisation the temperature re-
action was decreased. When this reaction was carried out at 40 ꢀC
a substantial reduction in racemisation was observed (87:13 en-
antiomeric ratio) whereas at room temperature pyrimidinyl amino
ester 5f was obtained without appreciable racemisation but with
a lower yield (Table 1 entries 11 and 12). It was possible to obtain an
X-ray analysis of structure 5f (Fig. 3) in which the tyrosine residue
links to position 2 of the pyrimidine ring by the phenoxy group
could be seen.
a
a
residue, following the method described by our research group. The
results of this investigation are disclosed herein.
2. Results and discussion
Consistent with our goal, we reasoned that the incorporation
of an
a-amino acid residue at position 2 of a pyrimidine ring
could be achieved by nucleophilic ipso-substitution of the sul-
fones 3 with a nucleophilic side chain of several protected natural
a
-amino acid. For this purpose, the easily available 2-(benzylsul-
fonyl)-4-isopropoxypyrimidines23c 3 were treated under basic
conditions, with Na-Boc-aminoesters 4 with an amine (lysine), an
heteroaryl (histidine and tryptophan), an alcohol (serine) or
a phenol (tyrosine) functions in the side chain in order to obtain
the corresponding pyrimidinyl
entries 1–32).
a-aminoesters type 5 (Table 1,
When a ring nitrogen of the imidazole of the Na-Boc-histidine
methyl ester 4a was employed as a nucleophile the best results
were obtained using DBU as a base and heating at 50 ꢀC (Table 1,
entries 2–5). Under these conditions all compounds 5a–c were
isolated in good yields and without appreciable racemisation ex-
cept for compound 5c, which contained a phenyl group at position
6 of pyrimidine ring that showed a substantial degree of race-
misation (Table 1, entry 4). It proved possible to avoid racemisation
of 5c carrying out the reaction at room temperature (Table 1, entry
5). The two nitrogen atoms of the imidazole ring of histidine are not
equivalent. The nucleophilic attack could, in principle, take place by
In the case of Na-Boc-lysine methyl ester (Table 1, entries 9–
12) we used the commercially available Na-Boc-lysine methyl
ester acetate salt 4c. For this reason the ipso-substitution reaction
between 2-benzylsulfonylpyrimidines 3 and amino ester 4c also
needed basic conditions. The reaction was not complete even
after several days heating at 50 ꢀC when Et3N and DIEA were
employed as a base and the corresponding pyrimidinyl amino
ester 5g was isolated in poor yield (Table 1, entries 13 and 14). It

614
A. Elmarrouni et al. / Tetrahedron 66 (2010) 612–623
Table 1
Synthesis of pyrimidinyl aminoesters 5
O
OR2
NHBoc
OCH(CH3)2
OCH(CH3)2
HX
n
4
N
N
R2O2C
Bn
DMF / Base
nX
N
R1
S
N
3
R1
O
O
5
NHBoc
R1= H, Me, Ph
Entry
1
Amino acid 4
R1
Base (equiv)
KOtBu (1.1)
Time (h)
Temp (ꢀC)
50
Product 5
Yielda (%)
37
Enantiomeric ratiof
(70:30)
15
5a
H
H
Me
Ph
Ph
O
2
3
4
5
DBU (1.2)
DBU (1.2)
DBU (1.2)
DBU (1.2)
8
8
24
24
50
50
50
rt
5a
5b
5c
5c
80
79
79b
58
πN
OCH3
NHBoc
N
τ
H
4a
4b
4c
6
KOtBu (1.1)
24
80
5d
d
H
H
H
Me
Ph
Ph
Ph
O
7
8
9
10
11
12
NaH (1.2)
18
24
24
24
24
24
rt
5d
5d
5e
5f
5f
5f
60
79
60
K2CO3 (2.4)
K2CO3 (2.4)
K2CO3 (2.4)
K2CO3 (2.4)
K2CO3 (2.4)
50
50
50
40
rt
OCH3
NHBoc
90b
58b
40
(60:40)
(87:13)
HO
13
Et3N (2.0)
96
50
5g
14
H
H
H
H
Me
Ph
O
14
15
16
17
18
DIEA (2.0)
DBU (1.2)
K2CO3 (4.0)
DBU (1.2)
DBU (1.2)
48
28
24
24
24
50
50
40
50
50
5g
5g
5g
5h
5i
16
60b
88
43
42
H2N
(89:11)
OCH3
NHBoc
19
KOtBu (1.2)
1
50
5j
5c
H
O
20
21
22
23
24
25
26
H
H
H
H
H
Me
Ph
DBU (1.2)
DBU (1.2)
NaH (1.2)
K2CO3 (2.4)
K2CO3 (2.4)
DBU (1.2)
DBU (1.2)
24
24
24
24
24
24
24
50
rt
rt
50
rt
50
50
5j
5j
5j
5j
5j
5k
5l
50e
50e
34e
37b,d
19d
40e
57e
(50:50)
(50:50)
(50:50)
(75:25)
OBn
NHBoc
N
H
4d
(50:50)
(50:50)
O
40d
40d
35d
OCH3
NHBoc
27
28
29
H
H
H
K2CO3 (4.0)
K2CO3 (4.0)
K2CO3 (4.0)
24
48
7 days
40
40
rt
5m
5m
5m
N
H
4e
30
KOtBu (1.2)
KOtBu (1.2)
24
rt
5n
d
H
H
H
O
31
32
48
24
80
rt
5n
5n
d
d
HO
OCH3
4f NHFmoc
NaH (1.2)
a
Isolated yields.
b
c
d
e
f
Partial racemisation observed.
t
Na-Boc-tryptophan Bu ester isolated as a major product reaction.
About 50% of starting sulfone 3a recovered.
Complete racemisation observed.
Determined by HPLC of dipeptide derivatives 8.
was possible to improve yield and reduce reaction time using
DBU and heating at 50 ꢀC. Under these conditions compounds 5h
and 5i were obtained in moderate yields and without appreciable
racemisation (Table 1, entries 15, 17 and 18). However compound
5g was isolated with a noticeable degree of racemisation (89:11
enantiomeric ratio). The racemisation of compound 5g was
completely avoided by employing K2CO3 as a base. In addition,
this reaction afforded Na-Boc-aminoester 5g in good yield (Table
1, entry 16).
The nucleophilic ipso-substitution reaction between sulfones 3
and Na-Boc-tryptophan was first studied using the commercially
available benzyl ester 4d. When this reaction was carried out with
sulfone 3a in the presence of potassium tert-butoxide at 50 ꢀC, the
desired amino ester 5j was obtained in only 5% yield. The major
compound isolated was the transesterification product Na-Boc-
tryptophan tert-butyl ester (Table 1, entry 19). By employing DBU or
NaH as a base the corresponding aminoesters 5j–l were obtained in
moderate yields. However, DBU and NaH caused the complete
racemisation of compounds 5j–l even at room temperature (Table
1, entries 20–22, 25 and 26). The degree of racemisation was sub-
stantially reduced when sulfone 3a and tryptophan 4d were treated
with K2CO3 at 50 ꢀC (75:25 enantiomeric ratio), while at room
temperature pyrimidinyl amino ester 5j was obtained without
appreciable racemisation but in low yield (Table 1 entries 23 and
24). We continued our studies using Na-Boc-tryptophan methyl
ester 4e instead of benzyl ester derivative 4d. Treatment of sulfone
3a with 4e in the presence of an excess of K2CO3 (4 equiv) at 40 ꢀC
afforded amino ester 5m in a moderate yield without appreciable
racemisation (Table 1, entry 27). These results clearly indicate that
using K2CO3 racemisation can be completely avoided by performing
the ipso-substitution reaction below 40 ꢀC. The main cause of low
yields of compounds 5j and 5m employing K2CO3 could be

A. Elmarrouni et al. / Tetrahedron 66 (2010) 612–623
615
Ph
OCH(CH3)2
H
OCH(CH3)2
N
Ph
O
NH2
O
N
N
7a
a
O
b
H2N
5
R1
HO2C
N
nX
N
nX
N
R1
H
8a
NH2
6
NHBoc
HPLC two peaks ratio 1:1
Ph
OCH(CH3)2
H
N
Ph
NH2
O
N
7b
O
b
H2N
N
nX
N
8b
R1
H
O
NH2
no racemisation HPLC one peak
Scheme 2. Solid-phase synthesis of dipeptides 8. Reagents and conditions: (a) LiOH,
THF/MeOH/H2O (1:2:2), rt, 3–4 h. (b) (i) HBTU, DIEA, DMF, rt, 3 h; (ii) TFA/H2O/TIS
(95:2.5:2.5), rt, 2 h.
OCH(CH3)2
OCH(CH3)2
N
N
a, b, c
MeO2C
HO2C
nX
N
nX
N
5
NHFmoc
NHBoc
9
Figure 3. X-ray crystal structure of compound 5f.
Scheme 3. Synthesis of Na-Fmoc-pyrimidinyl amino acids 9. Reagents and conditions:
(a) LiOH, THF/MeOH/H2O (1:2:2), rt, 3–4 h. (b) TFA, CH2Cl2, 0 ꢀC, 1-2 h. (c) Fmoc-Osu,
Na2CO3 (pH 7), 1,4-dioxane, rt, 8–12 h.
attributed to incomplete reactions. In general, the conversion of
starting sulfone 3a was about 50%. However, an increase in reaction
time did not improve reaction conversion (Table 1, entries 28 and
29).
Table 2
Yields of Na-Fmoc-pyrimidinyl amino acids 9
Disappointingly, no reaction took place when Na-Boc-serine
methyl ester 4f was employed as nucleophile in any of the experi-
mental conditions tested (Table 1, entries 30–32). In all cases,
starting sulfone 3a was totally recovered whereas basic conditions
and high temperature caused dehydratation of Na-Boc-serine
methyl ester 4f (Table 1, entry 31).
Entry
Na-Boc-amino ester 5
Product 9
OCH(CH3)2
Yielda (%)
96
1
5a
N
O
N
N
HO
9a
N
FmocHN
The optical purity of compounds 5 was verified by coupling the
2
3
5b
5c
57
77
O
new pyrimidinyl
a-amino acids 6 with both racemic phenylalanine
OCH(CH3)2
HO
and -phenylalanine in order to measure the degree of racemisation
L
by HPLC. Thus, samples of Na-Boc-aminoesters 5 were deprotected
using lithium hydroxide to give free Na-Boc-amino acids 6 in
quantitative yield. These compounds were first coupled to resin
bound racemic phenylalanine 7a using standard protocols for solid-
phase peptide synthesis following Fmoc/tert-butyl strategy. After
cleavage from the resin, the HPLC analyses of the resulting
dipeptides 8a showed the formation of two diastereoisomers.
Dipeptides 8b were then synthesised analogously by coupling Na-
N
N
FmocHN
9b
O
N
OCH(CH3)2
NHFmoc
HO
N
N
H
9c
O
OCH(CH3)2
O
HO
N
Boc-amino acids 6 to L-phenylalanine resin bound 7b. When no
4
5d
77
reasonable racemisation occurred during the synthesis of 5, HPLC
analyses of 8b showed the formation of one single diastereoisomer
(Scheme 2). However, Na-Boc-amino acids 6 are not useful tools for
solid-phase peptide synthesis following Fmoc/tert-butyl strategy.
To circumvent this problem we explored the synthesis of the Na-
Fmoc-protected derivatives 9. For this purpose, we selected amino
FmocHN
N
N
9d
a
Isolated yields.
ester 5a, 5d, 5g and 5m, each with a different a-amino acid residue
treated with PPh3 and diisopropyl azodicarboxylate (DIAD) in
anhydrous THF (Scheme 4, Table 3). Under these conditions only
14% yield of the substitution product 10a was obtained (Table 3,
entry 1).
The major compound isolated was the dehydroalanine de-
rivative 11a, produced from serine by b-elimination through the
at position 2 of the pyrimidine ring. First, methyl ester of com-
pounds 5 was deprotected using lithium hydroxide. After cleavage
of Na-Boc protecting group by treatment with TFA, the free amino
group was reprotected with Fmoc-Osu leading the expected Na-
Fmoc-amino acids 9 in high yields (Scheme 3, Table 2).
On the other hand, we expected that an amino acid residue
with an hydroxyl function in the side chain could be easily in-
corporated at position 4 of a pyrimidine ring by selective O-al-
action of DIAD and PPh3 (Scheme 4). To circumvent this side re-
action a literature search of serine-based Mitsunobu reaction was
carried out. We found that Cherney et al. had demonstrated that
a Mitsunobu reaction performed with both Na-phenylfluorenyl and
kylation of 2-(benzylsulfanyl)-4(3H)pyrimidinones
1
under
Na-trityl-serine completely prevents
b-elimination reaction,
a Mitsunobu reaction. We have shown previously that Mitsunobu
reactions between pyrimidinones 1 and bulky alcohols are com-
pletely regioselective in favour of O-alkylated derivative.23 Ini-
tially, Na-Boc methyl serinate 4f and 4(3H)-pyrimidinone 1a were
whereas a Mitsunobu reaction using Na-Boc-serine methyl ester
afford a large amount of dehydroalanine 11a.26 In good agreement
with this study, when Na-trityl-serine methyl ester27 4g was used

616
A. Elmarrouni et al. / Tetrahedron 66 (2010) 612–623
R3
O
O
N
O
N
OCH3
R2
R3
O
HN
R2
HN
CO2CH3
HN
N
a
+
+
Bn
Bn
S
R1
HO
OCH3
S
R1
R3
HN
1
R2
10
11
4
R1= H, Me, Ph
11a R2= Boc, R3= H
11b R2= Trt, R3= Me
4f R2= Boc, R3= H
4g R2= Trt, R3= H
4h R2= Trt, R3= Me
Scheme 4. Synthesis of pyrimidines 10 substituted at position 4 with an amino acid
residue. Reagents and conditions: (a) Ph3P, DIAD, THF, 0 ꢀC to rt, 4–6 h.
Table 3
Yields of pyrimidinyl amino ester 10
Entry
Amino ester 4
R1
Product 10
Yielda (%)
1
2
3
5
5
4e
4f
4f
4f
4g
H
H
Me
Ph
H
10a
10b
10c
10d
10e
14
97
64
93
17
a
Isolated yields.
instead of the Na-Boc derivative 4f, the desired compounds 10b–
d were isolated in high yields (Table 3, entries 2–4) as the sole
reaction products. We then examined the same Mitsunobu reaction
using Na-trityl threonine methyl ester 4h. In this case, the sub-
stitution product 10e was obtained in only a 17% yield along with
a large amount of the elimination derivative 11b (Table 3, entry 5).
In order to increase the molecular diversity of aminoesters 10 at
position 2 of the pyrimidine ring, we examined the nucleophilic
displacement of the activated benzylsulfanyl group using the
methodology described previously. Accordingly, compounds 10b–
d were treated with 2.5 equiv of m-CPBA at 0 ꢀC to afford the
corresponding sulfones 12a–c (Scheme 5). Compound 12b was
crystallised giving crystals suitable for X-ray analysis (Fig. 4). This
was not only unambiguous proof of the constitution and configu-
ration of sulfone derivatives 12 but also their aminoesters 10
precursors. As expected the Na-trityl methyl serinate residue was
attached to position 4 of the pyrimidine ring by the alcohol
Figure 4. X-ray crystal structure of compound 12b.
function. This clearly confirmed that Mitsunobu reaction was
completely regioselective in favour of O-regioisomer.
The subsequent nucleophilic ipso-substitution displacement of
sulfones 12 with morpholine afforded the pyrimidinyl aminoesters
13 in good yields. In addition, compounds 12 were treated with Na-
Boc methyl tyrosinate 4b and Na-Boc methyl histidinate 4a under
previously optimised reaction conditions, leading the desired py-
rimidines 14 and 15, with an amino acid residue at position 2 and 4
of the pyrimidine ring, in moderate yields (Scheme 5). Compounds
14 and 15 were obtained as a sole diastereoisomer. No other
diastereoisomer could be detected by 1H NMR. This result proved
O
O
O
O
OCH3
NHTrt
O
OCH3
O
OCH3
a
NHTrt
b
NHTrt
N
N
N
Bn
Bn
R1
N
N
13
R1
S
N
10
R1
S
N
12
O
O
O
12a R1= H (71%)
12b R1= Me (50%)
12c R1= Ph (45%)
13a R1= H (83%)
13b R1= Me (63%)
13c R1= Ph (62%)
O
O
N
OCH3
NHBoc
OCH3
NHBoc
c
d
N
H
HO
(36%)
O
O
O
OCH3
NHTrt
O
O
N
OCH3
NHTrt
N
H3CO
BocHN
14a R1= H (73%)
14b R1= Me (40%)
N
O
N
N
O
R1
H3CO
BocHN
N
15
Scheme 5. Functionalisation of pyrimidines 10 at position 2. Reagents and conditions: (a) m-CPBA, CH2Cl2, 0 ꢀC to rt, 2–4 h. (b) morpholine, 1,4-dioxane, 60 ꢀC, 12–15 h. (c) NaH,
DMF, rt, 12–15 h; d) DBU, DMF, 50 ꢀC, 15 h.

A. Elmarrouni et al. / Tetrahedron 66 (2010) 612–623
617
that both Mitsunobu reaction and nucleophilic ipso-substitution
displacement proceeded without racemisation.
reverse-phase column (4.6ꢂ40 mm; 3.5
m
m particle size). Flash
chromatography purifications were performed on silica gel 60
(230–400 mesh, Merck).
3. Conclusion
A simple synthetic strategy to prepare new Na-Boc-pyrimidin-
2-yl aminoesters 5 via an ipso-substitution reaction between
sulfones 3 and a nucleophilic side chain of several Na-Boc-amino-
esters 4 has been described. The results of this investigation show
that the base and reaction temperature play a crucial role in
obtaining the target compounds 5 in good yield and without rac-
emisation. In the case of histidine derivatives 5a–c, the described
4.2. Synthesis of pyrimidin-4(3H)-ones 1a–c and pyrimidines
3a–c
The synthesis of these compounds were described in Ref. 23c.
reaction proved to be totally regioselective in favour of N(s)
regioisomer. Na-Boc-pyrimidin-2-yl aminoesters 5 were easily
converted into Na-Fmoc-pyrimidin-2-yl amino acids 9 using stan-
dard deprotecting and protecting group procedures. The Na-Fmoc-
protected derivatives 9a–d are useful building blocks for the
solid-phase peptide synthesis following Fmoc/tert-butyl strategy.
The effect of its incorporation into bioactive peptides is currently
underway. We have also described the synthesis of highly
functionalised Na-trityl-pyrimidin-4-yl aminoesters 13 via a sub-
sequent Mitsunobu and ipso-substitution reaction. Best results
were obtained when Mitsunobu reaction was carried out
employing Na-trityl-serine methyl ester 4g. Finally, the synthesis of
new pyrimidines substituted at position 2 and 4 by an amino ester
residue 14 and 15 has been achieved applying the synthetic
strategies optimised in this work.
4.3. Representative procedure for the synthesis of Na-Boc-
pyrimidin-2-yl aminoesters 5a–m
The appropriate Na-Boc-aminoester 4a–f (1.1–1.2 equiv) was
dissolved in dry DMF (2.5 mL/mmol) under a nitrogen atmosphere.
The corresponding base (1.2–4.0 equiv) was added and the result-
ing mixture was stirred at room temperature for 15 min. Then,
pyrimidinyl sulfone 3a–c (1 equiv) was added as a DMF solution
(1 mL/mmol 3a–c). The resulting mixture was stirred under nitro-
gen at the temperature specified in Table 1. Upon completion of the
reaction (TLC monitoring; reaction time specified in Table 1), the
solvent was removed under reduced pressure, and the resulting
residue was purified by flash chromatography (n-hexane/ethyl
acetate 10:1–1:1) to afford Na-Boc-pyrimidinyl aminoesters 5.
4. Experimental section
4.1. General information
4.3.1. tert-Butyl (S)-1-(methoxycarbonyl)-2-(1-(4-isopropoxypyrimidin-
2-yl)-1H-imidazol-4-yl)ethylcarbamate (5a). Synthesised according to
general procedure from pyrimidinyl sulfone 3a (292.4 mg, 1.0 mmol),
Na-Boc-(S)-histidine methyl ester 4a (296.2 mg, 1.1 mmol) and DBU
(1.52 mL, 1.2 mmol), 324 mg (80%) of compound 5a was obtained as
All commercially available chemicals were used as purchased
without further purification. DMF and dioxane were dried over
activated molecular sieves (4 Å). THF was dried over Na/benzo-
phenone prior use. Melting points (capillary tube) were measured
with an Electrothermal digital melting point apparatus IA 91000
and are uncorrected. IR spectra were recorded on a Mattson-Gal-
axy Satellite FT-IR using a single reflection ATR system as a sam-
pling accessory. Bands are characterized as broad (br), strong (s),
medium (m) and weak (w). NMR spectra were recorded on
a Brucker DPX Advance spectrometer. 1H NMR spectra were
recorded at 400 or 200 MHz. 13C NMR spectra and DEPT experi-
ments were determined at 100 or 50 MHz. Spectra recorded in
CDCl3 were referenced to residual CHCl3 at 7.26 ppm for 1H or
77.0 ppm for 13C. Spectra recorded in DMSO-d6 were referenced to
residual DMSO-d6 at 2.49 ppm for 1H or 39.5 ppm for 13C. Coupling
constants (J) are given in Hertz (Hz). The following abbreviations
were used for spin multiplicity: s¼singlet, d¼doublet, t¼triplet,
q¼quarter, sept¼septet, m¼multiplet, dd¼double doublet,
br¼broad. ESI mass spectra were recorded using a Navigator
quadrupole instrument. High resolution mass spectra (HRMS)
were determined under conditions of ESI on a Brucker MicroTof-Q
instrument using a lock-spray source. Elemental analyses were
performed on an apparatus from Thermo Instruments, model
EA1110-CHNS. Optical rotations were measured on a Perkin–Elmer
a colourless solid. Mp 100–101 ꢀC. TLC: Rf¼0.19 (n-hexane/ethyl ace-
25
tate, 1:1). [
a
]
þ8.19 (c¼0.5, MeOH). IR (ATR): 3264 (w), 2980 (w),
D
1744 (m), 1700 (s), 1586 (m), 1562 (s), 1473 (m), 1437 (s), 1366 (s), 1349
(m), 1315 (w), 1275 (m), 1248 (m), 1215 (w), 1174 (s), 1092 (m), 1056
(m), 1022 (s), 971 (w), 948 (m), 823 (m) cmꢁ1 1H NMR (200 MHz,
.
CDCl3):
3.14 (m, 2H, CH2-
d
¼1.43 (d, J¼6.2 Hz, 6H, CH(CH3)2), 1.46 (s, 9H, C(CH3)3), 3.11–
b
), 3.74 (s, 3H, OCH3), 4.60–4.64 (m, 1H, CH- ), 5.42
a
(sept, J¼6.2 Hz, 1H, CH(CH3)2), 5.86 (d, J¼8.0 Hz, 1H, NH), 6.54
(d, J¼5.8 Hz, 1H, H(5)pym), 7.61 (d, 1H, 4J¼1.2 Hz, H(5)imid), 8.32
(d, J¼5.8 Hz, 1H, H(6)pym), 8.46 (d, 1H, 4J¼1.2 Hz, H(2)imid). 13C NMR
(50 MHz, DMSO-d6):
d
¼21.4 (q, 2C), 28.0 (q, 3C), 29.6 (t), 51.8 (q), 53.4
(d), 70.2 (d), 78.3 (s), 106.2 (d), 113.9 (d), 135.3 (d), 139.1 (s), 153.4 (s),
155.3 (s), 159.1 (d), 169.5 (s), 172.4 (s). MS (ESI) m/z: 405.9 [MþH]þ.
Calcd for C19H27N5O5: C, 56.28; H, 6.71; N, 17.27. Found: C, 56.35; H,
6.58; N, 17.42.
4.3.2. tert-Butyl (S)-1-(methoxycarbonyl)-2-(1-(4-isopropoxy-6-methyl-
pyrimidin-2-yl)-1H-imidazol-4-yl)ethylcarbamate
(5b). Synthesised
according to general procedure from pyrimidinyl sulfone 3b
(306.0 mg, 1.0 mmol), Na-Boc-(S)-histidine methyl ester 4a
(296.2 mg, 1.1 mmol) and DBU (1.52 mL, 1.2 mmol), 330 mg (79%)
of compound 5b was obtained as a colourless solid. Mp 110–
25
111 ꢀC. TLC: Rf¼0.29 (n-hexane/ethyl acetate, 1:1). [
a
]
þ10.23
D
polarimeter 241. Specific rotation [
a
]
D
are given in 10ꢁ1 cm2 gꢁ1
,
(c¼0.17, MeOH). IR (ATR): 3344 (w), 2978 (w), 1711 (m), 1600 (s),
and the concentration (c) are expressed in g per 100 mL. Analytical
thin layer chromatography (TLC) analyses were carried out on
0.25 mm thick precoated plates (Merk Fertigplatten Kieselgel
60F254) and spots were visualized with UV light (254 nm) and/or
stained with a solution of potassium permanganate (1.5 g/100 mL
H2O). High performance liquid chromatography (HPLC) was per-
formed on a Summit Dionex instruments composed of P680 binary
pump, UVD 170U 4-Channel UV–vis Detector, ASI-100 Autosampler
and the Chromaleon 6.60 software from Dionex, on a C18 Kromasil
1554 (m), 1481 (s), 1450 (m), 1401 (s), 1366 (m), 1311 (s), 1164 (s),
1102 (m), 1042 (m), 1014 (s), 866 (m) cmꢁ1 1H NMR (200 MHz,
.
CDCl3):
2.43 (s, 3H, CH3), 3.11–3.13 (m, 2H, CH2-
4.59–4.63 (m, 1H, CH-
), 5.39 (sept, J¼6.2 Hz, 1H, CH(CH3)2), 5.86
(br, 1H, NH), 6.38 (s, 1H, H(5)pym), 7.63 (s, 1H, H(5)imid), 8.48 (s, 1H,
H(2)imid). 13C NMR (50 MHz, CDCl3):
d
¼1.41 (d, J¼6.2 Hz, 6H, CH(CH3)2), 1.46 (s, 9H, C(CH3)3),
b
), 3.75 (s, 3H, OCH3),
a
d
¼22.4 (q, 2C), 24.4 (q), 29.0
(q, 3C), 31.0 (t), 52.9 (q), 54.1 (d), 70.7 (d), 80.3 (s), 105.3 (d), 114.8
(d), 136.6 (d), 139.1 (s), 154.2 (s), 156.2 (s), 169.7 (s), 171.0 (s), 173.2

618
A. Elmarrouni et al. / Tetrahedron 66 (2010) 612–623
(s). MS (ESI) m/z: 419.9 [MþH]þ. Calcd for C20H29N5O5: C, 57.17; H,
(368.4 mg,1.1 mmol), Na-Boc-(S)-tyrosine methyl ester4b(354.4 mg,
1.2 mmol) and K2CO3 (136.7 mg, 1.2 mmol), 202 mg (40%) of com-
6.97; N, 16.70. Found: C, 57.35; H, 7.09; N, 16.82.
pound 5f was obtained as a colourless oil. TLC: Rf¼0.52 (n-hexane/
25
4.3.3. tert-Butyl (S)-1-(methoxycarbonyl)-2-(1-(4-isopropoxy-6-phenyl-
ethyl acetate, 1:1). [
a
]
ꢁ6.23 (c¼0.26, MeOH). IR (ATR): 3442 (w),
D
pyrimidin-2-yl)-1H-imidazol-4-yl)ethylcarbamate
(5c). Synthesised
2978 (w), 2928 (w),1744 (w),1713 (s),1580 (s),1549 (s),1503 (s),1453
(w),1431 (w),1356 (s),1324 (s),1250 (w),1212 (s),1164 (s),1095 (w),
1065 (s), 1018 (w), 939 (m), 770 (m), 731 (w) 693 (m) cmꢁ1. 1H NMR
according to general procedure from pyrimidinyl sulfone 3c
(368.4 mg, 1.0 mmol), Na-Boc-(S)-histidine methyl ester 4a
(296.2 mg, 1.1 mmol) and DBU (1.52 mL, 1.2 mmol), 278 mg (58%) of
(200 MHz, CDCl3):
C(CH3)3), 3.16 (d, J¼5.4 Hz, 2H, CH2-
(m, 1H, CH-
d
¼1.35 (d, J¼6.2 Hz, 6H, CH(CH3)2), 1.47 (s, 9H,
compound 5c was obtained as a colourless solid. Mp 133–134 ꢀC.
b
), 3.73 (s, 3H, OCH3), 4.63–4.67
24
TLC: Rf¼0.35 (n-hexane/ethyl acetate, 1:1). [
a]
þ23.28 (c¼0.35,
a
), 4.61 (d, J¼8.2 Hz, 1H, NH), 5.27 (sept, J¼6.2 Hz, 1H,
D
MeOH). IR (ATR): 3344 (w), 2978 (w), 1711 (m), 1600 (s), 1554 (m),
1481 (s), 1450 (m), 1401 (s), 1366 (m), 1311 (s), 1164 (s), 1102 (m),
CH(CH3)2), 6.81 (s, 1H, H(5)pym), 7.21–7.26 (m, 4H, CHAryl), 7.43–7.50
(m, 3H, CHAryl), 7.94–8.01 (m, 2H, CHAryl). 13C NMR (50 MHz, CDCl3):
1042 (m), 1014 (s), 866 (m) cmꢁ1
.
1H NMR (200 MHz, DMSO-d6):
d
¼22.5 (q, 2C), 29.0 (q, 3C), 38.6 (t), 52.8 (q), 55.2 (d), 70.7 (d), 82.1 (s),
d
¼1.45 (s, 9H, C(CH3)3), 1.49 (d, J¼6.2 Hz, 6H, CH(CH3)2), 3.02–3.05
99.3 (d), 122.7 (d, 2C), 127.7 (d, 2C), 129.4 (d, 2C), 130.6 (d, 2C), 131.4
(d), 133.2 (s), 137.1 (s), 153.0 (s), 155.8 (s), 165.7 (s), 167.1 (s), 172.7 (s),
172.9 (s). MS (ESI) m/z: 508 [MþH]þ. Calcd for C28H33N3O6: C, 66.26;
H, 6.55; N, 8.28. Found: C, 66.17; H, 6.41; N, 8.37.
(m, 2H, CH2-b), 3.74 (s, 3H, OCH3), 4.42–4.45 (m, 1H, CH-a), 5.59
(sept, J¼6.2 Hz, 1H, CH(CH3)2), 7.01 (br, 1H, NH), 7.32 (s, 1H,
H(5)pym), 7.45–7.66 (m, 3H, CHAryl), 7.91 (s, 1H, H(5)imid), 8.36–8.38
(m, 2H, CHAryl), 8.77 (s, 1H, H(2)imid). 13C NMR (50 MHz, CDCl3):
d
¼22.5 (q, 2C), 29.0 (q, 3C), 31.1 (t), 52.9 (q), 54.2 (d), 71.2 (d), 80.3
4.3.7. tert-Butyl (S)-1-(methoxycarbonyl)-5-(4-isopropoxy-6-meth-
ylpyrimidin-2-ylamino)pentylcarbamate (5g). Synthesised accord-
ing to general procedure from pyrimidinyl sulfone 3a (292.4 mg,
1.0 mmol), Na-Boc-(S)-lysine methyl ester 4c (384.4 mg,
1.2 mmol) and K2CO3 (275.8 mg, 2.0 mmol), 262 mg (66%) of
(s), 101.9 (d), 114.9 (d),127.6 (d, 2C),129.5 (d, 2C),131.7 (d),136.7 (d),
139.3 (s), 154.5 (s), 156.0 (s), 166.6 (s), 171.7 (s), 173.2 (s). MS (ESI)
m/z: 480.9 [MþH]þ. Calcd for C25H31N5O5: C, 62.36; H, 6.49; N,
14.54. Found: C, 62.45; H, 6.61; N, 14.72.
compound 5g was obtained as a colourless oil. TLC: Rf¼0.27 (n-
25
4.3.4. tert-Butyl (S)-1-(methoxycarbonyl)-2-(4-(4-isopropoxypyri-
midin-2-yloxy)phenyl)ethylcarbamate (5d). Synthesised according
to general procedure from pyrimidinyl sulfone 3a (292.4 mg,
1.1 mmol), Na-Boc-(S)-tyrosine methyl ester 4b (354.4 mg,1.2 mmol)
and K2CO3 (136.7 mg,1.2 mmol), 340 mg (79%) of compound 5d was
hexane/ethyl acetate, 1:1). [
a
]
ꢁ5.6 (c¼0.19, MeOH). IR (ATR):
D
3387 (w), 3316 (w), 2978 (w), 2930 (w), 1739 (m), 1708 (s), 1667
(m), 1579 (s), 1525 (s), 1458 (m), 1422 (m), 1390 (w), 1365 (s),
1302 (m), 1232 (m), 1163 (s), 800 (s) cmꢁ1 1H NMR (200 MHz,
.
CDCl3):
1.53–1.88 (m, 6H, (-CH2)3), 3.38 (q-apparent, J¼6.4 Hz, 2H,
NCH2), 3.75 (s, 3H, OCH3), 4.29–4.32 (m, 1H, CH- ), 5.14 (br, 1H,
d
¼1.34 (d, J¼6.2 Hz, 6H, CH(CH3)2), 1.46 (s, 9H, C(CH3)3),
obtained as a colourless solid. Mp 114–115 ꢀC. TLC: Rf¼0.27 (n-hex-
25
ane/ethyl acetate, 1:1). [
a
]
ꢁ2.80 (c¼0.14, MeOH). IR (ATR): 3360
a
D
(w), 2978 (w), 1739 (s),1699 (s), 1517 (s),1508 (s), 1450 (m), 1383 (s),
1366 (s),1321 (w),1272 (s),1252 (w),1223 (s),1202 (s),1171 (s),1150
(s), 1110 (m), 1041 (s), 1017 (m), 978 (w), 839 (m), 817 (w), 786 (m)
NH), 5.28 (sept, J¼6.2 Hz, 1H, CH(CH3)2), 5.83 (d, 1H, J¼5.6 Hz,
H(5)pym), 6.36 (br, 1H, NH), 7.98 (d, 1H, J¼5.6 Hz, H(6)pym). 13C
NMR (50 MHz, CDCl3):
d
¼22.5 (q, 2C), 23.4 (t), 29.6 (q, 3C), 30.3
cmꢁ1.1H NMR (200 MHz, CDCl3):
d
¼1.34 (d, J¼6.2 Hz, 6H, CH(CH3)2),
1.45 (s, 9H, C(CH3)3), 3.12–3.16 (m, 2H, CH2- ), 3.74 (s, 3H, OCH3),
4.60–4.63 (m, 1H, CH-
), 5.01 (br, 1H, NH), 5.27 (sept, J¼6.2 Hz, 1H,
(t), 33.2 (t), 41.7 (t), 52.8 (q), 53.9 (d), 68.9 (d), 80.5 (s), 98.3 (d),
158.6 (d), 163.1 (s), 170.1 (s), 173.9 (s), 176.3 (s). MS (ESI) m/z:
396.9 [MþH]þ. Calcd for C19H32N4O5: C, 57.56; H, 8.14; N, 14.13.
Found: C, 57.64; H, 8.23; N, 14.17.
b
a
CH(CH3)2), 6.38 (d, J¼5.6 Hz, 1H, H(5)pym), 7.16–7.29 (m, 4H, CHAryl),
8.18 (d, J¼5.6 Hz, 1H, H(6)pym). 13C NMR (50 MHz, CDCl3):
¼22.4 (q,
d
2C), 28.9 (q, 3C), 38.5 (t), 52.9 (q), 55.1 (d), 70.6 (d),104.5 (d),122.5 (d,
2C),130.9 (d, 2C),133.6 (s),152.7 (s),161.7 (s),165.7 (s),171.6 (s),172.9
(s). MS (ESI) m/z: 431.9 [MþH]þ. Calcd for C22H29N3O6: C, 61.24; H,
6.77; N, 9.74. Found: C, 61.39; H, 6.88; N, 9.90.
4.3.8. tert-Butyl (S)-1-(methoxycarbonyl)-5-(4-isopropoxy-6-meth-
ylpyrimidin-2-ylamino)pentylcarbamate (5h). Synthesised accord-
ing to general procedure from pyrimidinyl sulfone 3b (306.4 mg,
1.0 mmol), Na-Boc-(S)-lysine methyl ester 4c (384.4 mg, 1.2 mmol)
and DBU (1.52 mL, 1.2 mmol), 176 mg (43%) of compound 5h was
4.3.5. tert-Butyl
(S)-1-(methoxycarbonyl)-2-(4-(4-isopropoxy-6-
obtained as a colourless oil. TLC: Rf¼0.46 (n-hexane/ethyl acetate,
25
methylpyrimidin-2-yloxy)phenyl)ethylcarbamate (5e). Synthesised
according to general procedure from pyrimidinyl sulfone 3b
(306.4 mg, 1.1 mmol), Na-Boc-(S)-tyrosine methyl ester 4b
(354.4 mg,1.2 mmol) and K2CO3 (136.7 mg,1.2 mmol), 266 mg (60%)
2:1). [
a]
ꢁ12.38 (c¼0.1, MeOH). IR (ATR): 3397 (w), 3317 (w), 2964
D
(w), 2930 (w), 1717 (m), 1687 (s), 1657 (s), 1477 (m), 1435 (w), 1364
(m), 1335 (w), 1259 (m), 1221 (w), 1164 (s), 1098 (m), 1075 (m), 1051
(s), 1018 (s), 798 (s) cmꢁ1
.
1H NMR (200 MHz, CDCl3):
d¼1.34 (d,
of compound 5e was obtained as a colourless oil. TLC: Rf¼0.49 (n-
J¼6.2 Hz, 6H, CH(CH3)2), 1.47 (s, 9H, C(CH3)3), 1.63–2.07 (m, 6H,
(-CH2)3), 2.29 (s, 3H, CH3), 3.38 (q-apparent, J¼6.4 Hz, 2H, NCH2),
27
hexane/ethyl acetate,1:1). [
a]
ꢁ28.6 (c¼0.3, MeOH). IR (ATR): 3355
D
(w), 2979 (w),1744 (m),1712 (s),1596(s),1561 (m),1533 (w),1505 (s),
1452 (w), 1354 (s), 1321 (s), 1247 (m), 1211 (s), 1165 (s),1101 (s), 1075
3.76 (s, 3H, OCH3), 4.30–4.34 (m, 1H, CH-a), 4.97 (br, 2H, NH), 5.26
(sept, J¼6.2 Hz, 1H, CH(CH3)2), 5.83 (s, 1H, H(5)pym). 13C NMR
(m), 1017 (s), 731 (s) cmꢁ1
.
1H NMR (200 MHz, CDCl3):
d
¼1.24 (d,
J¼6.2 Hz, 6H, CH(CH3)2),1.43 (s, 9H, C(CH3)3), 2.34 (s, 3H, CH3), 3.09–
3.12 (m, 2H, CH2- ), 3.71 (s, 3H, OCH3), 4.61 (br, 1H, NH), 5.01–5.08
(m, 1H, CH-
), 5.10 (sept, J¼6.2 Hz, 1H, CH(CH3)2), 6.22 (s, 1H,
H(5)pym), 7.13 (s, 4H, CHAryl). 13C NMR (50 MHz, CDCl3):
(50 MHz, CDCl3):
d
¼21.9 (q, 2C), 22.7 (t), 23.7 (q), 28.1 (q, 3C), 29.4
(t), 32.5 (t), 41.0 (t), 52.2 (q), 53.3 (d), 68.1 (d), 79.8 (s), 96.1 (d),155.3
(s), 162.3 (s), 167.8 (s), 170.0 (s), 173.3 (s). MS (ESI) m/z: 411 [MþH]þ.
Calcd for C20H34N4O5: C, 58.52; H, 8.35; N,13.65. Found: C, 58.65; H,
8.51; N, 13.71.
b
a
d¼22.0 (q,
2C), 23.7 (q), 28.2 (q, 3C), 37.7 (t), 52.7 (q), 54.4 (d), 70.1 (d), 79.9 (s),
101.8 (d),121.7 (d, 2C),130.3 (d, 2C),132.4 (s),152.2 (s),155.0 (s),164.4
(s), 169.6 (s), 171.1 (s), 172.2 (s). MS (ESI) m/z: 446 [MþH]þ. Calcd for
C23H31N3O6: C, 62.01; H, 7.01; N, 9.43. Found: C, 62.19; H, 7.19; N, 9.57.
4.3.9. tert-Butyl (S)-1-(methoxycarbonyl)-5-(4-isopropoxy-6-phe-
nylpyrimidin-2-ylamino)pentylcarbamate (5i). Synthesised accord-
ing to general procedure from pyrimidinyl sulfone 3c (368.4 mg,
1.0 mmol), Na-Boc-(S)-lysine methyl ester 4c (384.4 mg, 1.2 mmol)
and DBU (1.52 mL, 1.2 mmol), 198 mg (42%) of compound 5i was
4.3.6. tert-Butyl
(S)-1-(methoxycarbonyl)-2-(4-(4-isopropoxy-6-
phenylpyrimidin-2-yloxy)phenyl)ethylcarbamate (5f). Synthesised
according to general procedure from pyrimidinyl sulfone 3c
obtained as a colourless oil. TLC: Rf¼0.50 (n-hexane/ethyl acetate,
25
2:1). [
a]
ꢁ18.55 (c¼0.15, MeOH). IR (ATR): 3367 (w), 3315 (w),
D

A. Elmarrouni et al. / Tetrahedron 66 (2010) 612–623
619
2977 (w), 2930 (w), 1739 (m), 1709 (s), 1578 (s), 1559 (m), 1497 (m),
1459 (w), 1391 (m), 1366 (m), 1319 (w), 1210 (s), 1164 (s), 909 (w),
1552 (s), 1518 (s), 1465 (s), 1389 (s), 1369 (s), 1321 (w), 1286 (m),
1245 (s), 1210 (m), 1158 (m), 1101 (m), 1014 (w), 958 (w), 766 (m),
771 (w), 733 (s) cmꢁ1
.
1H NMR (200 MHz, CDCl3):
d
¼1.39 (d,
738 (s), 691 (m) cmꢁ1. 1H NMR (200 MHz, DMSO-d6):
d
¼1.41 (s, 9H,
C(CH3)3), 1.55 (d, J¼6 Hz, 6H, CH(CH3)2), 3.25–3.30 (m, 2H, CH2- ),
4.49–4.53 (m, 1H, CH-
), 5.21 (s, 2H, OCH2Ph), 5.61 (sept, J¼6 Hz,
1H, CH(CH3)2), 7.30–7.55 (m, 13H, 8CHAryl, H(5)pym, NH, H(2)ind,
J¼6.2 Hz, 6H, CH(CH3)2), 1.47 (s, 9H, C(CH3)3), 1.66–2.07 (m, 6H,
b
(–CH2)3), 3.49 (q-apparent, J¼6.4 Hz, 2H, NCH2), 3.76 (s, 3H, OCH3),
a
4.27–4.33 (m, 1H, CH-
a
), 5.15 (br, 2H, NH), 5.37 (sept, J¼6.2 Hz, 1H,
CH(CH3)2), 6.41 (s, 1H, H(5)pym), 7.38–7.47 (m, 3H, CHAryl), 7.95–8.00
H(5)ind, H(6)ind), 8.23–8.39 (m, 3H, 3CHAryl, H(7)ind), 8.85 (d, 1H,
(m, 2H, CHAryl). 13C NMR (50 MHz, CDCl3):
d
¼22.1 (q, 2C), 23.1 (t),
J¼8.2 Hz, H(4)ind). 13C NMR (50 MHz, DMSO-d6):
¼21.6 (q, 2C), 26.4
d
29.0 (q, 3C), 30.5 (t), 32.7 (t), 41.3 (t), 52.3 (q), 53.4 (d), 68.4 (d), 80.0
(s), 93.6 (d), 126.9 (d, 2C), 128.9 (d, 2C), 131.0 (d), 138.1 (s), 155.4 (s),
162.7 (s), 165.6 (s), 170.9 (s), 173.4 (s). MS (ESI) m/z: 473 [MþH]þ.
Calcd for C25H36N4O5: C, 63.54; H, 7.68; N, 11.86. Found: C, 63.67; H,
7.71; N, 11.81.
(t), 28.0 (q, 3C), 54.0 (d), 65.9 (t), 69.9 (d), 78.3 (s), 98.5 (d), 115.3 (s),
115.7 (d), 118.7 (d), 121.8 (d), 123.7 (d), 124.4 (d), 127.60 (d, 2C),127.8
(d, 2C),128.2 (d),128.5 (d, 2C),128.9 (d, 2C),130.5 (s),131.1 (d),134.9
(s), 135.8 (s), 136.1 (s), 155.4 (s), 156.3 (s), 165.1 (s), 170.4 (s), 172.0
(s). MS (ESI) m/z: 545.0 [MþH]þ. Calcd for C36H38N4O5: C, 71.27; H,
6.31; N, 9.23. Found: C, 70.99; H, 6.56; N, 9.31.
4.3.10. tert-Butyl (S)-1-((benzyloxy)carbonyl)-2-(1-(4-isopropoxypy-
rimidin-2-yl)-1H-indol-3-yl)ethylcarbamate (5j). Synthesised accord-
ing to general procedure from pyrimidinyl sulfone 3a (292.4 mg,
1.0 mmol), Na-Boc-(S)-tryptophan benzyl ester 4d (433.8 mg,
1.1 mmol) and DBU (1.52 mL, 1.2 mmol), 265 mg (50%) of compound
4.3.13. tert-Butyl (S)-1-(methoxycarbonyl)-2-(1-(4-isopropoxypyrimidin-
2-yl)-1H-indol-3-yl)ethylcarbamate (5m). Synthesised according to
general procedure from pyrimidinyl sulfone 3a (292.4 mg,1.0 mmol),
N-Boc-(S)-tryptophan methyl ester 4e (350 mg, 1.1 mmol) and K2CO3
(276 mg, 2.0 mmol), 182 mg (40%) of compound 5m was obtained as
5j was obtained as a colourless solid. Mp 103–104 ꢀC. TLC: Rf¼0.71 (n-
25
hexane/ethyl acetate, 2:1). [
a
]
racemic. IR (ATR): 3365 (w), 2973
a colourless solid. Mp 88–89 ꢀC. TLC: Rf¼0.61 (n-hexane/ethyl acetate,
D
24
(w), 1735 (m), 1695 (s), 1565 (s), 1506 (m), 1470 (m), 1447 (s), 1434 (s),
1372 (m), 1254 (m), 1293 (m), 1166 (s), 1140 (s), 1106 (m), 1017 (m),
940 (w), 816 (m), 743 (s), 703 (m) cmꢁ1. 1H NMR (200 MHz, DMSO-
2:1). [
a
]
þ9.90 (c¼0.11, MeOH). IR (ATR): 3645 (w), 3371 (m), 2978
D
(w),1735 (w),1690 (s),1572 (m),1518 (w),1465(m),1425 (s),1360 (m),
1304 (m), 1271 (w), 1247 (s), 1159 (s), 1136 (w), 1107 (w), 1091 (m),
1076 (w),1006 (s), 986 (w), 816 (w), 738 (m) cmꢁ1.1H NMR (400 MHz,
CDCl3, 25 ꢀC):
C(CH3)3), 3.31 (m, 2H, CH2-
d6):
(m, 2H, CH2-
d
¼1.41 (s, 9H, C(CH3)3), 1.51 (d, J¼6 Hz, 6H, CH(CH3)2), 3.21–3.26
b
), 4.45–4.48 (m, 1H, CH- ), 5.20 (s, 2H, OCH2Ph), 5.52
a
d¼1.44 (d, J¼6.20 Hz, 6H, CH(CH3)2), 1.47 (s, 9H,
(sept, J¼6 Hz,1H, CH(CH3)2), 6.75 (d, J¼5.6 Hz,1H, H(5)pym), 7.30–7.55
(m, 8H, 5CHaryl, NH, H(5)ind, H(6)ind), 7.70 (d, 1H, J¼7.6 Hz, H(7)ind),
8.24 (s, 1H, H(2)ind), 8.61 (d, J¼5.6 Hz, 1H, H(6)pym), 8.77 (d, 1H,
b
), 3.70 (s, 3H, OCH3), 4.70 (m, CH- ), 5.15
a
(d, J¼7.81 Hz, 1H, NH), 5.51 (sept, J¼6.20 Hz, 1H, CH(CH3)2), 6.32 (d,
J¼5.70 Hz, 1H, H(5)pym), 7.14–7.18 (m, 1H, H(5)ind), 7.23–7.27 (m, 1H,
H(6)ind), 7.55 (d, 1H, J¼7.73 Hz, H(7)ind), 8.05 (s, 1H, H(2)ind), 8.36 (d,
J¼5.70 Hz, 1H, H(6)pym), 8.73 (d, 1H, J¼7.63 Hz, H(4)ind). 13C NMR
J¼8.0 Hz, H(4)ind). 13C NMR (50 MHz, DMSO-d6):
¼21.5 (q, 2C), 26.4
d
(t), 28.0 (q, 3C), 54.0 (d), 65.8 (t), 69.8 (d), 78.3 (s), 103.6 (d), 115.3 (s),
118.6 (d),121.8 (d),123.7 (d),124.2 (d),127.6 (d, 2C),127.9 (d),128.2 (d,
2C),130.4 (s),134.8 (s),135.8 (s),155.4 (s),156.3 (s),158.8 (d),169.0 (s),
172 (s). MS (ESI) m/z: 531.0 [MþH]þ. Calcd for C30H34N4O5: C, 67.91;
H, 6.46; N, 10.56. Found: C, 67.84; H, 6.58; N, 10.62.
(100 MHz, CDCl3, 25 ꢀC):
d
¼20.8 (q, 3C), 27.0 (t), 28.0 (q, 2C), 51.2 (q),
52.9 (d), 68.8 (d), 78.8 (s),102.7 (d),113.3 (s), 115.1 (d), 117.8 (d), 120.8
(d),122.8 (d),123.3 (d),130.1 (s),134.6 (s),154.2 (s),156.0 (s),156.9 (d),
168.5 (s), 171.5 (s). HRMS (ESI): m/z calcd for C24H30N4NaO4 [MþNa]þ
477.2108, found 477.2121; calcd for C24H31N4O54 [MþH]þ 455.2289,
found 455.2292.
4.3.11. tert-Butyl (S)-1-((benzyloxy)carbonyl)-2-(1-(4-isopropoxy-6-
methylpyrimidin-2-yl)-1H-indol-3-yl)ethylcarbamate
(5k). Synthesised according to general procedure from pyrimidinyl
sulfone 3b (306.4 mg, 1.1 mmol), Na-Boc-(S)-tryptophan benzyl
ester 4d (433.8 mg, 1.1 mmol) and DBU (1.52 mL, 1.2 mmol), 217 mg
(40%) of compound 5k was obtained as a colourless oil. TLC:
4.4. Representative procedure for the synthesis
of dipeptides 8
Dipeptides 8 were prepared manually by solid-phase method
using Fmoc-Rink-MBHA resin (0.64 mmol/g) as solid support fol-
lowing standard Fmoc-strategy. Coupling of amino acids were
mediated by HBTU (3 equiv) and DIEA (3 equiv) in DMF at room
temperature for 3 h. Monitoring was carried out by ninhydrin
test.28 Washings were performed with DMF (6ꢂ1 min). Fmoc group
was removed by treating the resin with 30% piperidine in DMF (v/v)
and washed with DMF (6ꢁ1 min). The Fmoc-Rink-MBHA resin
(10 mg) was placed into a plastic syringe fitted with a poly-
propylene frit to remove the Fmoc group and subsequently couple
Fmoc-Phe-OH 7. After Fmoc group removal resin was treated with
pyrimidinyl amino acid 6 under coupling conditions. The resulting
dipeptides were deprotected and cleaved from resin by treatment
with TFA/H2O/TIS (95:2.5:2.5) for 2 h. Then the solvents were
evaporated to dryness and the crude dipeptides 8 were dissolved in
H2O, lyophilized and tested for purity on HPLC. Electrospray ion-
isation mass spectrometry was used to confirm peptide identity.
Rf¼0.59 (n-hexane/ethyl acetate, 2:1). [
a]
25 racemic. IR (ATR): 3438
D
(w), 2976 (w), 1709 (m), 1588 (s), 1558 (m), 1458 (s), 1390 (s), 1323
(s), 1162 (s), 1102 (m), 1014 (w), 977 (w), 884 (w), 741 (s), 703 (m)
cmꢁ1
.
1H NMR (200 MHz, CDCl3):
d
¼1.47 (s, 9H, C(CH3)3), 1.49 (d,
J¼6 Hz, 6H, CH(CH3)2), 2.52 (s, 3H, CH3), 3.34–3.36 (m, 2H, CH2- ),
4.73–4.77 (m,1H, CH- ), 5.22 (s, 2H, OCH2Ph), 5.32 (br,1H, NH), 5.51
b
a
(sept, J¼6 Hz, 1H, CH(CH3)2), 6.32 (s, 1H, H(5)pym), 7.30–7.55 (m, 7H,
5CHaryl, H(5)ind, H(6)ind), 7.59 (d, 1H, J¼7.8 Hz, H(7)ind), 8.11 (s, 1H,
H(2)ind), 8.80 (d, 1H, J¼8.4 Hz, H(4)ind). 13C NMR (50 MHz, CDCl3):
d
¼22.5 (q, 2C), 24.6 (q), 28.8 (t), 28.9 (q, 3C), 55.0 (d), 67.7 (t), 70.1
(d), 80.1 (s), 102.6 (d), 114.3 (s), 116.8 (d), 119.3 (d), 122.3 (d), 124.3
(d), 125.2 (d), 128.80 (d), 128.85 (d), 129.1 (d, 2C), 131.4 (s), 135.8 (s),
136.2 (s), 156.4 (s), 157.8 (s), 168.9 (s), 170.6 (s), 172.6 (s). MS (ESI)
m/z: 545.0 [MþH]þ. Calcd for C31H36N4O5: C, 68.36; H, 6.66; N,
10.29. Found: C, 68.18; H, 6.90; N, 10.23.
4.3.12. tert-Butyl (S)-1-((benzyloxy)carbonyl)-2-(1-(4-isopropoxy-6-
phenylpyrimidin-2-yl)-1H-indol-3-yl)ethylcarbamate
(5l). Synthesised according to general procedure from pyrimidinyl
sulfone 3c (368.4 mg, 1.0 mmol), Na-Boc-(S)-tryptophan benzyl
ester 4d (433.8 mg, 0.55 mmol) and DBU (1.52 mL, 1.2 mmol),
4.5. Representative procedure for the synthesis of Na-Fmoc-
pyrimidin-2-yl amino acids 9a–d
LiOH monohydrate (2.5 equiv) was added to a solution of ap-
propriate Na-Boc-amino methyl ester 5 (1 equiv) in THF/MeOH/
water (1:2:2) (8 mL/mmol), and the reaction mixture was stirred at
room temperature for 3–4 h. Upon completion of the reaction (TLC
310 mg (57%) of compound 5j was obtained as a colourless solid.
25
Mp 140–141 ꢀC. TLC: Rf¼0.53 (n-hexane/ethyl acetate, 2:1). [
a]
D
racemic. IR (ATR): 3378 (w), 2977 (w), 1731 (m), 1682 (s), 1582 (s),

620
A. Elmarrouni et al. / Tetrahedron 66 (2010) 612–623
monitoring), the organic solvents were removed under reduced
pressure. The pH of the resulting aqueous solution was then ad-
justed to 4 with glacial acetic acid, and the solution was extracted
with CH2Cl2 (3ꢂ5 mL). The combined organic layer was dried
(MgSO4), filtered and concentrated under reduced pressure. Then,
the free Na-Boc-amino acid 6 was dissolved in CH2Cl2 (1.5 mL/
mmol) and the solution was cooled in an ice bath. TFA (1.5 mL/
mmol) was added dropwise and the resulting mixture was stirred
at 0 ꢀC for 1–2 h. Upon completion of the reaction (TLC monitoring),
the solvent was removed under reduced pressure. Next, the crude
material was dissolved in 1,4-dioxane (3 mL/mmol). The resulting
solution was adjusted to pH 7 with aqueous Na2CO3 (5%). Fmoc-Osu
(1.05 equiv) was added slowly. During Fmoc-Osu addition, pH was
readjusted to 7 with aqueous Na2CO3 (5%). The resulting mixture
was stirred at room temperature for 8–12 h. Upon completion of
the reaction (TLC monitoring), the solvent was removed under re-
duced pressure. The resulting residue was dissolved in water
(10 mL) and extracted with ethyl acetate (3ꢂ5 mL). The combined
organic layer was back extracted with saturated NaHCO3 solution
(3ꢂ5 mL). Then the aqueous layer was acidified to pH 1–2 with
aqueous HCl (1%), and extracted with ethyl acetate (3ꢂ5 mL). The
combined organic layer was dried (MgSO4), filtered and concen-
trated under reduced pressure. The resulting residue was purified
by flash chromatography (n-hexane/ethyl acetate/acetic acid 4:1:0–
0:20:1) to afford Na-Fmoc-amino acids 9.
131.0 (d, 2C), 133.5 (s), 141.7 (s, 2C), 144.1 (s), 144.3 (s), 152.2 (s),
156.3 (s), 158.0 (d), 165.0 (s), 171.6 (s), 174.6 (s). HRMS (ESI): m/z
calcd for C31H30N3O6 [MþH]þ 540.2129, found 540.2131.
4.5.3. (S)-Na-Fmoc-6-(4-isopropoxypyrimidin-2-ylamino)-2-amino-
hexanoic acid (9c). Synthesised according to general procedure
from Na-Boc-amino methyl ester 5g (158 mg, 0.40 mmol), 155 mg
(77%) of compound 9c was obtained as a colourless solid. Mp 54–
57 ꢀC. TLC: Rf¼0.57 (ethyl acetate/methanol/acetic acid, 10:3:0.2).
25
[a
]
ꢁ5.91 (c¼0.10, MeOH). IR (ATR) 3385 (w), 3343 (w), 3316 (w),
D
2358 (w), 2325 (w), 1674 (s), 1640 (s), 1474 (m), 1461 (m), 1400 (w),
1323 (w), 1201 (s), 1180 (s), 1130 (s), 841 (w), 799 (m), 750 (w), 721
(m), 694 (w), 643 (w), 615 (w), 561 (w). 1H NMR (400 MHz, DMSO-
d6):
d
¼1.30 (d, J¼6.0 Hz, 6H, CH(CH3)2), 1.66–1.68 (m, 2H, CH2),
1.69–1.70 (m, 2H, CH2), 1.73–1.75 (m, 2H, CH2-
b
), 3.25–3.29 (m, 2H,
NCH2), 4.25–4.33 (m, 3H, OCH2, CHFmoc), 5.27 (sept, J¼6.0 Hz, 1H,
CH(CH3)2), 5.94 (d, J¼5.6 Hz, 1H, H(5)pym), 7.37 (t, J¼7.6 Hz, 2H,
CHaryl), 7.46 (t, J¼7.2 Hz, 2H, CHaryl), 7.67 (d, J¼8.0 Hz, 1H, NH), 7.77
(d, J¼7.2 Hz, 2H, CHaryl), 7.93 (t, J¼7.6 Hz, 2H, CHaryl), 7.99 (d,
J¼5.6 Hz, 1H, H(6)pym), 12.63 (br, 1H, OH). 13C NMR (100 MHz,
DMSO-d6):
d
¼21.8 (q, 2C), 23.5 (t), 29,1 (t), 32.0 (t), 41.8 (t), 48.0 (d),
55.8 (d), 68.5(t), 73.3 (d), 99.4 (d), 120.9 (d), 126.2 (d), 128.0 (d, 2C),
128.4 (d, 2C), 142.1 (s, 2C), 145.1 (s, 2C), 147.4 (s), 157.2 (s), 157.7 (d),
162.5 (s), 172.3 (s). HRMS (ESI): m/z calcd for C28H32N4NaO5
[MþNa]þ 527.2265, found 527.2244; calcd for C28H33N4O5 [MþH]þ
505.2445, found 505.2435.
4.5.1. (S)-Na-Fmoc-2-amino-3-(1-(4-isopropoxypyrimidin-2-yl)-1H-
imidazol-4-yl)propanoic acid (9a). Synthesised according to general
procedure from Na-Boc-amino methyl ester 5a (162 mg,
0.40 mmol), 197 mg (96%) of compound 9a was obtained as a col-
4.5.4. (S)-Na-Fmoc-2-amino-3-(1-(4-isopropoxypyrimidin-2-yl)-1H-
indol-3-yl) propanoic acid (9d). Synthesised according to general
procedure from Na-Boc-amino methyl ester 5m (182 mg,
0.40 mmol), 173 mg (77%) of compound 9d was obtained as a col-
ourless solid. Mp 80–83 ꢀC. TLC: Rf¼0.50 (ethyl acetate/methanol/
25
acetic acid, 5:3:0.2). [
a]
þ5.50 (c¼0.23, MeOH). IR (ATR): 3363
ourless solid. Mp 174–176 ꢀC. TLC: Rf¼0.77 (ethyl acetate/methanol/
D
25
(w), 3337 (w), 1710 (m), 1592 (m), 1562 (m), 1486 (w), 1444 (s), 1380
(m), 1310 (m), 1248 (w), 1214 (m), 1188 (w), 1097 (m), 1046 (w),
acetic acid, 10:3:0.2). [
a]
þ4.38 (c¼0.14, MeOH). IR (ATR): 3342
D
(m), 1731 (m), 1686 (m), 1577 (m), 1559 (m), 1537 (m), 1469 (m),
1430 (s), 1361 (s), 1305 (m), 1235 (s), 1223 (s), 1140 (w), 1103 (w),
1087 (m), 1032 (m), 1000 (w), 945 (w), 756 (m), 733 (s) cmꢁ1. 1H
1026 (m), 986 (w), 947 (m), 823 (w), 757 (m), 738 (s), 539 (w) cmꢁ1
.
1H NMR (400 MHz, DMSO-d6):
d¼1.28 (d, J¼6.2 Hz, 3H, CH(CH3)2),
1.31 (d, J¼6.2 Hz, 3H, CH(CH3)2), 2.90 (dd, 1H, J¼14.5 Hz, J0¼9.3 Hz,
NMR (400 MHz, DMSO-d6):
d
¼1.40 (d, J¼6.0 Hz, 3H, CH(CH3)2), 1.42
1H, CH2-
b
), 3.04 (dd, 1H, J¼14.5 Hz, J0¼3.7 Hz, 1H, CH2-
b
), 4.17–4.29
(d, J¼6.0 Hz, 3H, CH(CH3)2), 3.11 (dd, J¼14.8 Hz, J0¼10.4.0 Hz, 1H,
(m, 4H, CHFmoc, OCH2, CH-
a
), 5.34 (sept, J¼6.2 Hz, 1H, CH(CH3)2),
CH2-
b
), 3.26 (dd, J¼14.8 Hz, J0¼4.4.0 Hz, 1H, CH2-
b), 4.12–4.20 (m,
6.76 (d, J¼5.8 Hz, 1H, H(5)pym), 7.18–7.38 (m, 4H, CHaryl), 7.60–7.64
(m, 3H, NH, CHaryl), 7.68 (s, 1H, H(5)imid), 7.85 (d, J¼7.5 Hz, 2H,
CHaryl), 8.43 (d, J¼5.8 Hz, 1H, H(6)pym), 8.46 (s, 1H, H(2)imid). 13C
3H, OCH2, CHFmoc), 5.40 (sept, J¼6.0 Hz, 1H, CH(CH3)2), 6.61 (d,
J¼5.6 Hz, 1H, H(5)pym), 7.14 (t, 1H, J¼7.6 Hz, H(5)ind), 7.23–7.30 (m,
2H, CHaryl), 7.35–7.42 (m, 3H, CHaryl, H(6)ind), 7.56 (d, J¼7.6 Hz, 1H,
H(7)ind), 7.61 (d, J¼7.6 Hz, 1H, NH), 7.67 (d, J¼7.6 Hz, 1H, CHaryl),
7.82–7.87 (m, 3H, CHaryl), 8.18 (s, 1H, H(2)ind), 8.46 (d, J¼5.60 Hz, 1H,
H(6)pym), 8.66 (d, 1H, J¼8.4 Hz, H(4)ind), 12.84 (br, 1H, OH). 13C NMR
NMR (100 MHz, DMSO-d6):
d
¼21.5 (q, 2C), 29.6 (t), 46 (d), 53.4 (d),
65.4 (t), 70.0 (d),105.9 (d),113.5 (d),119.7 (d, 2C),124.9 (d, 2C),126.7
(d, 2C), 127.2 (d, 2C), 135.0 (d), 139.3 (s), 140.3 (s, 2C), 143.4 (s, 2C),
153.2 (s), 155.6 (s), 158.8 (d), 169.2 (s), 173.1 (s). HRMS (ESI): m/z
calcd for C28H28N5O5 [MþH]þ 514.2085, found 514.2071.
(75 MHz, [DMSO-d6):
d
¼21.49 (q), 21.52 (q), 26.5 (t), 46.5 (d), 53.9
(d), 65.7 (t), 69.7 (d), 103.5 (d),115.7 (d),118.8 (d),119.9 (d, 2C),121.8
(d), 123.6 (d), 124.1 (d), 125.11 (d), 125.16 (d), 126.8 (d), 126.9 (d),
127.4 (d), 127.5 (d), 130.5 (s), 134.8 (s), 140.6 (s), 143.6 (s), 143.7 (s),
156.0 (s), 156.3 (s), 158.7 (d), 169.0 (s), 173.4 (s). HRMS (ESI): m/z
calcd for C33H30N4NaO5 [MþNa]þ 477.2108, found 477.2121; calcd
for C33H31N4O5 [MþH]þ 585.2108, found 585.2107.
4.5.2. (S)-Na-Fmoc-3-(4-(4-isopropoxypyrimidin-2-yloxy)phenyl)-2-
amino propanoic acid (9b). Synthesised according to general pro-
cedure from Na-Boc-amino methyl ester 5d (172 mg, 0.40 mmol),
123 mg (57%) of compound 9b was obtained as a colourless solid.
Mp 72–74 ꢀC. TLC: Rf¼0.71 (ethyl acetate/methanol/acetic acid,
10:3:0.2). [
a
]
þ5.92 (c¼0.32, MeOH). IR (ATR) 3745 (w), 3709 (w),
4.6. Synthesis of (S)-Na-triphenylmethylserine
methyl ester 4g
25
D
3474 (w), 3414 (w), 3355 (w), 3327 (w), 2977 (w), 1711 (m), 1586
(m), 1563 (m), 1506 (m), 1451 (m), 1384 (s), 1324 (m), 1275 (s), 1245
(w), 1200 (s), 1143 (w), 1105 (m), 1046 (s), 893 (w), 759 (m), 739 (s),
The synthesis of this compound was described in Ref. 27.
539 (w), 515 (m) cmꢁ1
.
1H NMR (200 MHz, DMSO-d6):
d
¼1.33 (d,
), 4.21–4.28 (m.
1H, CHFmoc), 4.42–4.55 (m, 2H, OCH2), 4.74–4.76 (m, 1H, CH- ), 5.20
J¼6.0 Hz, 6H, CH(CH3)2), 3.20–3.22 (m, 2H, CH2-
b
4.7. Representative procedure for the synthesis of Na-trityl-
pyrimidin-4-yl aminoesters 10b–d
a
(sept, J¼6.0 Hz, 1H, CH(CH3)2), 5.54 (br, 1H, NH), 6.41 (d, J¼5.6 Hz,
1H, H(5)pym), 7.30–7.46 (m, 4H, CHaryl), 7.69–7.78 (m, 4H, CHaryl),
7.59–7.62 (m, 2H, CHaryl), 7.76–7.80 (m, 2H, CHaryl), 7.16–7.29 (m, 4H,
CHAryl), 8.20(d, J¼5.6 Hz, 1H, H(6)pym). 13C NMR (50 MHz, CDCl3):
The appropriate 2-(benzylsulfanyl)pyrimidin-4(3H)-ones 1a–c
(1.0 equiv) was dissolved in dry THF (3 mL/mmol pyrimidinone)
under a nitrogen atmosphere, and the solution was cooled in
an ice bath. Triphenylphosphine (1.1 equiv) and (S)-Na-triphenyl-
methylserine methyl ester 4g (1.1 equiv) were added. DIAD
d
¼22.0 (q, 2C), 37.7 (t), 47.6 (d), 55.1 (d), 67.4 (t), 70.9 (d), 104.3 (d),
120.4 (d, 2C), 122.2 (d, 2C), 125.5 (d, 2C), 127.5 (d, 2C), 128.2 (d, 2C),

A. Elmarrouni et al. / Tetrahedron 66 (2010) 612–623
621
(1.1 equiv) was added dropwise as a THF solution (1 mL/mmol
DIAD). The resulting mixture was warmed to room temperature
and stirred under nitrogen. Upon completion of the reaction (TLC
monitoring), the solvent was removed under reduced pressure, and
the resulting residue was purified by flash chromatography (n-
hexane/ethyl acetate 10:1–1:1) to afford pyrimidin-4-yl amino-
esters 10.
638 [MþH]þ. Calcd for C40H35N3O3S: C, 75.33; H, 5.53; N, 6.59; S,
5.03. Found: C, 75.17; H, 5.64; N, 6.48; S, 5.41.
4.8. Representative procedure for the synthesis
of sulfone derivatives 12a–c
The appropriate pyrimidinyl aminoesters 10b–d (1.0 equiv) was
dissolved in CH2Cl2 (5 mL/mmol). The solution was cooled in an ice
bath and m-CPBA (2.2 equiv) was added in small portions. The
resulting mixture was warmed to room temperature and stirred
during 2–3 h. Upon completion of the reaction (TLC monitoring),
the solvent was removed under reduced pressure and the residue
was dissolved in AcOEt (20 mL), washed with saturated NaHCO3
solution (2ꢂ10 mL) and brine (1ꢂ10 mL). The organic layer was
dried (MgSO4), filtered and concentrated under reduced pressure.
The resulting residue was purified by flash chromatography
(n-hexane/ethyl acetate 10:1–1.1) to afford sulfones 12.
4.7.1. (S)-Methyl 3-(2-(benzylsulfanyl)pyrimidin-4-yloxy)-2-(trityl-
amino)propanoate (10b). Synthesised according to general pro-
cedure from pyrimidin-4(3H)-one 1a (218 mg, 1.0 mmol), (S)-Na-
triphenylmethylserine methyl ester 4g (400 mg, 1.1 mmol), PPh3
(289 mg, 1.1 mmol) and DIAD (0.21 mL, 1.1 mmol), 545 mg (97%) of
compound 10b was obtained as a colourless solid. Mp 62–63 ꢀC.
25
TLC: Rf¼0.43 (n-hexane/ethyl acetate, 1:1). [
a
]
D
þ79.91 (c¼0.38,
MeOH). IR (ATR): 3432 (w), 3058 (w), 3030 (w), 2949 (w), 1736 (m),
1554 (m), 1492 (m), 1433 (s), 1313 (s), 1227 (m), 1206 (s), 1173 (m),
1027 (m), 981 (w), 775 (m), 695 (s) cmꢁ1 1H NMR (200 MHz,
.
CDCl3):
(m, 1H, CH-
d
¼2.90 (d, J¼10.4 Hz, 1H, NH), 3.21 (s, 3H, OCH3), 3.72–3.83
4.8.1. (S)-Methyl 3-(2-(benzylsulfonyl)pyrimidin-4-yloxy)-2-(trityl-
amino)propanoate (12a). Synthesised according to general pro-
cedure from pyrimidinyl amino ester 10b (337 mg, 0.6 mmol),
252 mg (71%) of compound 12a was obtained as a colourless solid.
Mp 71–72 ꢀC. TLC: Rf¼0.45 (n-hexane/ethyl acetate, 1:1). IR (ATR):
3029 (w), 2950 (w), 2923 (w),1736 (m),1578 (s),1541 (w),1491 (w),
1466 (s),1446 (s),1323 (s), 1203 (m),1123 (s),1026 (w), 985 (w), 776
a
), 4.42 (s, 2H, SCH2), 4.49 (dd, J¼10.6 Hz, J0¼6.4 Hz, 1H,
OCH2), 4.71 (dd, J¼10.6 Hz, J0¼5.4 Hz, 1H, OCH2), 6.43 (d, J¼5.6 Hz,
1H, H(5)pym), 7.21–7.57 (m, 20H, CHAryl), 8.27 (d, J¼5.6 Hz, 1H,
H(6)pym). 13C NMR (50 MHz, CDCl3):
d
¼35.9 (t), 52.6 (q), 56.3 (d),
68.7 (t), 71.6 (s), 104.6 (d), 127.2, 127.8, 128.6, 129.2, 129.4, 129.6 (d,
20C), 138.4 (s), 146.2 (s, 3C), 158.2 (d), 168.9 (s), 171.9 (s), 173.8 (s).
MS (ESI) m/z: 562 [MþH]þ. Calcd for C34H31N3O3S: C, 72.70; H, 5.56;
N, 7.48; S, 5.71. Found: C, 72.63; H, 5.43; N, 7.33; S, 6.06.
(w), 747 (w), 696 (s) cmꢁ1. 1H NMR (200 MHz, CDCl3):
d
¼3.23 (s, 3H,
OCH3), 3.82 (dd, J¼6.6 Hz, J0¼5.0 Hz, 1H, CH-
), 4.49 (dd, J¼10.8 Hz,
a
J0¼6.6 Hz, 1H, OCH2), 4.69 (s, 2H, S(O)2CH2), 4.83 (dd, J¼10.8 Hz,
J0¼5.0 Hz, 1H, OCH2), 6.90 (d, J¼5.8 Hz, 1H, H(5)pym), 7.22–7.55 (m,
20H, CHAryl), 8.61 (d, J¼5.8 Hz, 1H, H(6)pym). 13C NMR (50 MHz,
4.7.2. (S)-Methyl 3-(2-(benzylsulfanyl)-6-methylpyrimidin-4-yloxy)-
2-(tritylamino)propanoate (10c). Synthesised according to general
procedure from pyrimidin-4(3H)-one 1b (232 mg, 1.0 mmol), (S)-
Na-triphenylmethylserine methyl ester 4g (400 mg, 1.1 mmol),
PPh3 (289 mg, 1.1 mmol) and DIAD (0.21 mL, 1.1 mmol), 368 mg
DMSO-d6):
d
¼51.7 (q), 55.1 (d), 56.2 (t), 68.2 (t), 70.3 (s), 111.5 (d),
126.4, 127.4, 128.3, 128.4, 128.5, 131.3 (d, 20C), 127.9 (s), 145.4 (s, 3C),
159.0 (d), 164.0 (s), 169.2 (s), 172.1 (s). MS (ESI) m/z: 594 [MþH]þ.
Calcd for C34H31N3O5S: C, 68.78; H, 5.26; N, 7.08; S, 5.40. Found: C,
68.92; H, 5.48; N, 7.17; S, 5.78.
(64%) of compound 10c was obtained as a colourless solid. Mp 62–
25
63 ꢀC. TLC: Rf¼0.43 (n-hexane/ethyl acetate, 1:1). [
a
]
þ58.05
D
(c¼0.42, MeOH). IR (ATR): 3422 (w), 3038 (w), 3027 (w), 2951 (w),
1736 (m), 1578 (m), 1547 (s), 1492 (w), 1445 (m), 1406 (m), 1346 (s),
1282 (s), 1206 (s), 1197 (m), 1161 (s), 1041 (m), 774 (m), 745 (m), 704
4.8.2. (S)-Methyl 3-(2-(benzylsulfonyl)-6-methylpyrimidin-4-yloxy)-
2-(tritylamino)propanoate (12b). Synthesised according to general
procedure from pyrimidinyl amino ester 10c (345 mg, 0.6 mmol),
(s) cmꢁ1. 1H NMR (200 MHz, CDCl3):
d
¼2.39 (s, 3H, CH3), 2.80 (br,
1H, NH), 3.19 (s, 3H, OCH3), 3.72–3.78 (m, 1H, CH-
a
), 4.40 (s, 2H,
182 mg (50%) of compound 12b was obtained as a colourless solid.
25
SCH2), 4.46 (dd, J¼10.6 Hz, J0¼6.4 Hz,1H, OCH2), 4.66 (dd, J¼10.6 Hz,
Mp 78–79 ꢀC. TLC: Rf¼0.42 (n-hexane/ethyl acetate, 1:1). [
a]
D
J0¼5.2 Hz, 1H, OCH2), 6.27 (s, H(5)pym), 7.19–7.55 (m, 20H, CHAryl).
þ66.01 (c¼0.32, MeOH). IR (ATR):3421 (w), 3058 (w), 3031 (w), 2951
(w),1733 (s),1591 (s),1491 (w),1445 (m),1409 (m),1351 (s),1325 (s),
1205 (w), 1173 (m), 1138 (s), 1025 (s), 1042 (m), 776 (s), 747 (m), 696
13C NMR (50 MHz, CDCl3):
d
¼23.6(q), 35.2 (t), 51.7 (q), 55.7 (d), 67.9
(t), 70.9 (s), 102.6 (d), 126.4, 127.5, 128.5, 128.8, 128.9, 129.2 (d, 20C),
137.8 (s), 145.6 (s, 3C),167.8 (s), 168.7 (s), 170.4 (s),173.0 (s). MS (ESI)
m/z: 576 [MþH]þ. Calcd for C35H33N3O3S: C, 73.02; H, 5.78; N, 7.30;
S, 5.57. Found: C, 73.14; H, 5.91; N, 7.41; S, 5.80.
(s) cmꢁ1. 1H NMR (200 MHz, CDCl3):
d
¼2.56 (s, 3H, CH3), 3.23 (s, 3H,
OCH3), 3.60 (br,1H, NH), 3.81 (dd, J¼6.6 Hz, J0¼5.0 Hz,1H, CH-
a), 4.56
(dd, J¼10.8 Hz, J0¼6.6 Hz,1H, OCH2), 4.70 (s, 2H, S(O)2CH2), 4.81 (dd,
J¼10.8 Hz, J0¼5.0 Hz,1H, OCH2), 6.72 (s, H(5)pym), 7.21–7.99 (m, 20H,
4.7.3. (S)-Methyl 3-(2-(benzylsulfanyl)-6-phenylpyrimidin-4-yloxy)-
2-(tritylamino)propanoate (10d). Synthesised according to general
procedure from pyrimidin-4(3H)-one 1c (294 mg, 1.0 mmol), (S)-
Na-triphenylmethylserine methyl ester 4g (400 mg, 1.1 mmol),
PPh3 (289 mg, 1.1 mmol) and DIAD (0.21 mL, 1.1 mmol), 592 mg
CHAryl). 13C NMR (50 MHz, CDCl3):
d
¼23.7 (q), 51.9 (q), 55.4 (d), 57.2
(t), 69.2 (t), 70.9 (s),109.5 (d),126.6,128.6,129.0,131.2 (d, 20C),126.9
(s), 145.4 (s, 3C), 163.9 (s), 169.3 (s), 170.1 (s), 172.6 (s). MS (ESI) m/z:
608 [MþH]þ. Calcd for C35H33N3O5S: C, 69.17; H, 5.47; N, 6.91; S, 5.28.
Found: C, 69.25; H, 6.70; N, 7.02; S, 5.79.
(93%) of compound 10d was obtained as a colourless solid. Mp 77–
25
78 ꢀC. TLC: Rf¼0.55 (n-hexane/ethyl acetate, 1:1). [
a]
þ87.17
4.8.3. (S)-Methyl 3-(2-(benzylsulfonyl)-6-phenylpyrimidin-4-yloxy)-
2-(tritylamino)propanoate (12c). Synthesised according to general
procedure from pyrimidinyl amino ester 10d (382 mg, 0.6 mmol),
D
(c¼0.11, MeOH). IR (ATR): 3431 (w), 3053 (w), 3029 (w), 2948 (w),
1737 (m), 1567 (s), 1536 (s), 1492 (m), 1448 (w), 1407 (w), 1351 (m),
1267 (w), 1204 (s), 1022 (m), 776 (m), 749 (m), 693 (s) cmꢁ1
.
1H
180 mg (45%) of compound 7c was obtained as a colourless solid.
25
NMR (200 MHz, CDCl3):
d
¼2.92 (d, J¼10.4 Hz, 1H, NH), 3.22 (s, 3H,
Mp 77–78 ꢀC. TLC: Rf¼0.53 (n-hexane/ethyl acetate, 1:1). [
a]
D
OCH3), 3.73–3.84 (m, 1H, CH-
a
), 4.52 (s, 2H, SCH2), 4.55 (dd,
þ38.17 (c¼0.042, MeOH). 1H NMR (200 MHz, CDCl3, 25 ꢀC):
d
¼2.41
J¼10.6 Hz, J0¼6.4 Hz, 1H, OCH2), 4.75 (dd, J¼10.6 Hz, J0¼5.2 Hz, 1H,
(br,1H, NH), 3.25 (s, 3H, OCH3), 3.38 (apparent t, J¼5.2 Hz,1H, CH-
a),
OCH2), 6.83 (s, H(5)pym), 7.20–7.57 (m, 23H, CHAryl), 8.03–8.08 (m,
4.66 (dd, J¼10.6 Hz, J0¼6.4 Hz,1H, OCH2), 4.82 (s, 2H, S(O)2CH2), 4.87
2H, CHAryl). 13C NMR (50 MHz, CDCl3):
d
¼36.1 (t), 52.6 (q), 56.4 (d),
(dd, J¼10.6 Hz, J0¼4.8 Hz, 1H, OCH2), 7.18–7.57 (m, 24H, H(5)pym
,
69.0 (t), 71.7 (s), 99.8 (d), 127.2, 127.7, 128.6, 128.8, 129.2, 129.4,
129.6, 130.0, 131.4 (d, 25C), 137.2 (s), 138.6 (s), 145.3 (s, 3C), 165.6 (s),
170.2 (s), 171.6 (s), 173.8 (s). MS (ESI) m/z: 696 [MþCH3CNþNH4]þ,
CHAryl), 8.09–8.14 (m, 2H, CHAryl). 13C NMR (50 MHz, CDCl3, 25 ꢀC):
d
¼52.0 (q), 55.5 (d), 57.3 (t), 69.6 (t), 71.0 (s), 105.5 (d), 126.6, 127.3,
128.0, 128.7, 128.8, 129.1, 131.3, 131.8 (d, 25C), 127.0 (s), 134.7 (s),

622
A. Elmarrouni et al. / Tetrahedron 66 (2010) 612–623
145.5 (s, 3C),164.7 (s),165.9 (s), 171.0 (s), 172.6 (s). MS (ESI) m/z: 728
[MþCH3CNþNH4]þ, 670 [MþH]þ. Calcd for C40H35N3O5S: C, 71.73;
H, 5.27; N, 6.27; S, 4.79. Found: C, 71.86; H, 5.53; N, 6.38; S, 5.10.
165.4 (s), 170.3 (s), 173.7 (s). MS (ESI) m/z: 601 [MþH]þ. HRMS (ESI):
m/z calcd. For C37H36N4NaO4 [MþNa]þ 623.2629, found 623.2596.
4.10. Synthesis of (S)-methyl 3-(2-(4-(2-(S)-tert-
4.9. Representative procedure for synthesis of pyrimidinyl
aminoesters 13a–c
butoxycarbonylamino-2-methoxycarbonylethyl)imidazol-1-
yl)pyrimidinin-4-yloxy)-2-(tritylamino)propanoate (15)
The appropriate sulfone derivatives 12a–c (1.0 equiv) was dis-
solved in dry 1,4-dioxane (5 mL/mmol sulfone) under a nitrogen
atmosphere. Morpholine (2.5 equiv) was added and the reaction
mixture was stirred under a nitrogen atmosphere at 60 ꢀC. Upon
completion of the reaction (TLC monitoring), the solvent was re-
moved under reduced pressure, and the resulting residue was pu-
rified by flash chromatography (n-hexane/ethyl acetate 10:1–1:1)
to afford compounds 13.
Na-Boc-(S)-histidine methyl ester 4a (64.6 mg, 0.24 mmol) was
dissolved in dry DMF (2.5 mL/mmol) under a nitrogen atmosphere.
DBU (0.39 mL, 0.26 mmol) was added and the resulting mixture
was stirred at room temperature for 15 min. Then, sulfone de-
rivative 12a (119 mg, 0.2 mmol) was added as a DMF solution
(1 mL/mmol) and the resulting reaction was heated to 50 ꢀC until
total consumption of the starting material (TLC monitoring). The
solvent was removed under reduced pressure, and the resulting
residue was purified by flash chromatography (n-hexane/ethyl ac-
4.9.1. (S)-Methyl 3-(2-morpholinopyrimidin-4-yloxy)-2-(tritylamino)-
propanoate (13a). Synthesised according to general procedure from
sulfone derivative 12a (178 mg, 0.3 mmol), 131 mg (83%) of com-
etate 10:1–1:1) to give compound 15 (51 mg, 36%) as a colourless
25
solid. Mp 81–83 ꢀC. TLC: Rf¼0.11 (n-hexane/ethyl acetate, 1:1). [
a]
D
þ65.98 (c¼0.47, MeOH). IR (ATR): 3350 (w), 3041 (w), 2974 (w)
1736 (m), 1711 (s), 1588 (s), 1569 (s), 1486 (s), 1424 (s), 1361 (m),
1316 (m), 1251 (m), 1204 (m), 1160 (s), 1028 (m), 705 (m) cmꢁ1. 1H
pound 13a was obtained as a colourless solid. Mp 68–69 ꢀC. TLC:
25
Rf¼0.39 (n-hexane/ethyl acetate, 1:1).
[a]
þ93.48 (c¼0.352,
D
MeOH). IR (ATR): 3027 (w), 2955 (w), 2923 (w), 1591 (m), 1564 (s),
1514 (w), 1466 (w), 1432 (s), 1339 (s), 1319 (m), 1309 (m), 1272 (w),
1257 (m), 1235 (m), 1210 (m), 1118 (s), 1029 (s), 991 (m), 799 (s), 776
NMR (400 MHz, CDCl3):
d
¼1.37 (s, 9H, C(CH3)3), 2.83 (d, J¼9.8 Hz,
1H, NH), 3.02 (dd, J¼14.9 Hz, J0¼5.0 Hz, 1H, CH2-bhistidine), 3.10 (s,
3H, OCH3), 3.07–3.12 (m,1H, CH2-bhistidine), 3.67 (s, 3H, OCH3), 3.72–
3.73 (m, 1H, CH-aserine), 4.42 (dd, J¼10.7 Hz, J0¼6.8 Hz, 1H, CH2-
bserine), 4.52–4.56 (m, 1H, CH-ahistidine), 4.67 (dd, J¼10.7 Hz,
J0¼5.4 Hz, 1H, CH2-bserine), 5.87 (d, J¼8.2 Hz, 1H, NH), 6.53 (d,
J¼5.7 Hz, 1H, H(5)pym), 7.10–7.22 (m, 9H, CHAryl), 7.42–7.46 (m, 6H,
CHAryl), 7.50 (s, 1H, H(5)imid), 8.27 (d, J¼5.7 Hz, 1H, H(6)pym), 8.38 (s,
(m), 704 (s) cmꢁ1. 1H NMR (200 MHz, CDCl3):
d
¼2.89 (d, J¼10.4 Hz,
1H, NH), 3.14 (s, 3H, OCH3), 3.74–3.80 (m, 8H, 2ꢂOCH2CH2N), 3.80–
3.85 (m, 1H, CH-
a
), 4.41 (dd, J¼10.6 Hz, J0¼7.4 Hz, 1H, OCH2), 4.73
(dd, J¼10.6 Hz, J0¼5.8 Hz, 1H, OCH2), 6.02 (d, J¼5.6 Hz, 1H, H(5)pym),
7.34–7.57 (m, 15H, CHAryl), 8.08 (d, J¼5.6 Hz, 1H, H(6)pym). 13C NMR
(50 MHz, CDCl3):
d
¼44.9 (t, 2C), 52.4 (q), 56.2 (d), 67.4 (t, 2C), 67.7 (t),
1H, H(2)imid). 13C NMR (50 MHz, CDCl3):
d
¼28.4 (q), 30.1 (t), 52.1
71.5 (s), 97.7 (d), 127.2, 128.5, 129.4 (d, 15C), 146.3 (s, 3C), 158.7 (d),
162.0 (s), 170.0 (s), 174.2 (s). MS (ESI) m/z: 525 [MþH]þ. HRMS (ESI):
m/z calcd for C31H32N4NaO4 [MþNa]þ 547.2316, found 547.2290.
(q), 52.3 (q), 53.4 (d), 55.4 (d), 68.5 (t), 71.0 (s), 79.7 (s), 106.2 (d),
114.3 (d), 126.7 (d, 3C),128.0 (d, 6C), 128.7 (d, 6C), 135.9 (d), 145.5 (s,
3C), 153.7 (s), 155.6 (s), 158.6 (d), 170.0 (s), 172.4 (s), 173.0 (s). MS
(ESI) m/z: 707 [MþH]þ. HRMS (ESI): m/z calcd for C39H43N6O7
[MþH]þ 707.3188, found 707.3201; HRMS (ESI): m/z calcd for
C39H42N6NaO7 [MþNa]þ 729.3007, found 729.2999.
4.9.2. (S)-Methyl 3-(6-methyl-2-morpholinopyrimidin-4-yloxy)-2-
(tritylamino)propanoate (13b). Synthesised according to general
procedure from sulfone derivative 12b (151 mg, 0.25 mmol), 85 mg
(63%) of compound 13b was obtained as a colourless oil. TLC: Rf¼0.41
4.11. Representative procedure for the synthesis
of pyrimidinyl aminoesters 14a–b
27
(n-hexane/ethyl acetate, 1:1). [
a
]
þ88.46 (c¼0.25, MeOH). IR (ATR):
D
3046 (w), 2953 (w), 1735 (m), 1570 (s), 1491 (m), 1445 (m), 1394 (m),
1343 (s), 1275 (m), 1243 (w), 1207 (w), 1158 (s), 1115 (m), 906 (s), 728
Na-Boc-(S)-tyrosine methyl ester 4b (1.2 equiv) was dissolved in
dry DMF (2.5 mL/mmol) under a nitrogen atmosphere. NaH
(1.2 equiv) was added and the resulting mixture was stirred at
room temperature for 15 min. Then, the appropriate sulfone 7a–b
(1.0 equiv) was added as a DMF solution (1 mL/mmol) and the
resulting reaction was stirred at room temperature. Upon com-
pletion of the reaction (TLC monitoring), the solvent was removed
under reduced pressure, and the resulting residue was purified by
flash chromatography (n-hexane/ethyl acetate 10:1–1:1) to afford
pyrimidinyl aminoesters 14a–b.
(s), 705 (s) cmꢁ1. 1H NMR (200 MHz, CDCl3):
d
¼2.09 (s, 3H, CH3), 2.87
(d, J¼10.4 Hz, 1H, NH), 3.17 (s, 3H, OCH3), 3.64–3.79 (m, 8H,
2ꢂOCH2CH2N), 3.82–3.87(m,1H, CH-
a
), 4.40 (dd, J¼10.8 Hz, J0¼7.4 Hz,
1H, OCH2), 4.72 (dd, J¼10.6 Hz, J0¼5.8 Hz, 1H, OCH2), 5.89 (s, 1H,
H(5)pym), 7.21–7.37 (m, 9H, CHAryl), 7.53–7.57 (m, 6H, CHAryl). 13C NMR
(50 MHz, CDCl3):
d
¼24.0 (q), 44.3 (t, 2C), 51.7 (q), 55.6 (d), 66.8 (t, 2C),
67.0 (t), 70.8 (s), 95.6 (d),126.5,127.8,128.7 (d,15C),146.7 (s, 3C),161.4
(s), 168.2 (s), 169.5 (s), 173.7 (s). MS (ESI) m/z: 539 [MþH]þ. HRMS
(ESI): m/zcalcdforC32H34N4NaO4 [MþNa]þ 561.2472, found 561.2462.
4.9.3. (S)-Methyl 3-(2-morpholino-6-phenylpyrimidin-4-yloxy)-2-
(tritylamino)propanoate (13c). Synthesised according to general
procedure from sulfone derivative 12c (167 mg, 0.25 mmol), 93 mg
4.11.1. (S)-Methyl 3-(2-(4-(2-(S)-tert-butoxycarbonylamino-2-meth-
oxycarbonylethyl)phenoxy)pyrimidinin-4-yloxy)-2-(tritylamino)pro-
panoate (14a). Synthesised according to general procedure from
sulfone derivative 12a (119 mg, 0.2 mmol), Na-Boc-(S)-tyrosine
methyl ester 4b (70.9 mg, 0.24 mmol) and NaH (6 mg, 0.24 mmol),
(62%) of compound 13c was obtained as a colourless oil. TLC:
25
Rf¼0.58 (n-hexane/ethyl acetate, 1:1). [
a
]
D
þ72.01 (c¼0.05, MeOH).
IR (ATR): 3042 (w), 2955 (w), 2921 (w), 1735 (w), 1571 (s), 1557 (s),
1491 (m),1446 (m),1392 (m),1348 (m),1264 (m),1207 (s),1114 (m),
1024 (s), 993 (w), 769 (s), 744 (m), 696 (s) cmꢁ1. 1H NMR (200 MHz,
107 mg (73%) of compound 14a was obtained as a colourless solid.
26
Mp 90–91 ꢀC. TLC: Rf¼0.49 (n-hexane/ethyl acetate, 1:1). [
a]
D
þ46.77 (c¼0.41, MeOH). IR (ATR): 3045 (w), 2949 (w), 2927 (w),
1738 (m), 1711 (m), 1572 (s), 1503 (w), 1444 (m), 1381 (s), 1339 (m),
1271 (s), 1206 (s), 1162 (s), 1048 (m), 1025 (m), 816 (w), 744 (w), 704
CDCl3):
d
¼2.87 (d, J¼10.6 Hz, 1H, NH), 3.18 (s, 3H, OCH3), 3.79–3.84
(m, 9H, 2ꢂOCH2CH2N, CH-
a
), 4.45 (dd, J¼10.8 Hz, J0¼7.4 Hz, 1H,
OCH2), 4.76 (dd, J¼10.6 Hz, J0¼5.6 Hz, 1H, OCH2), 6.46 (s, 1H,
(s) cmꢁ1. 1H NMR (200 MHz, CDCl3):
d
¼1.35 (s, 9H, C(CH3)3), 2.79 (d,
H(5)pym), 7.21–7.33 (m, 10H, CHAryl), 7.45–7.58 (m, 8H, CHAryl), 7.99–
J¼12 Hz, 1H, NH), 3.03–3.06 (m, 2H, CH2), 3.12 (s, 3H, OCH3), 3.65 (s,
3H, OCH3), 3.65–3.71 (m, 1H, CH-aserine), 4.42 (dd, J¼10.0 Hz,
J0¼6.0 Hz, 1H, OCH2), 4.46–4.47 (m, 1H, CH-atyrosine), 4.61 (dd,
J¼10.0 Hz, J0¼6.0 Hz, 1H, OCH2), 4.92 (br, 1H, NH), 6.38 (d, J¼6.0 Hz,
8.04 (m, 2H, CHAryl). 13C NMR (100 MHz, CDCl3):
d
¼44.3 (t, 2C), 51.8
(q), 55.6 (d), 66.9 (t, 2C), 67.3 (t), 70.8 (s), 95.5 (d), 126.5, 126.9,
127.9, 128.5, 128.7, 130.1 (d, 20C), 137.7 (s), 145.7 (s, 3C), 161.5 (s),

A. Elmarrouni et al. / Tetrahedron 66 (2010) 612–623
3. (a) Ma, J. S. Chim. Oggi 2003, 65–68; (b) Beck, G. Synlett 2002, 837–850.
623
1H, H(5)pym), 7.01–7.23 (m, 13H, CHAryl), 7.41–7.46 (m, 6H, CHAryl),
4. (a) Jones, M. A.; Notta, J. K.; Cobbold, M.; Palendira, M.; Hislop, A. D.; Wilkie,
J.; Snaith, J. S. J. Pept. Sci. 2008, 14, 313–320; (b) Hicks, R. P.; Bhonsle, J. B.;
Venugopal, D.; Koser, B. W.; Magill, A. L. J. Med. Chem. 2007, 50, 3026–3036;
(c) Kumar, A.; Wang, Y.; Lin, X.; Sun, G.; Parang, K. Chem. Med. Chem. 2007, 2,
1346–1360; (d) D’Ursi, A. M.; Giannecchini, S.; Esposito, C.; Alcaro, M. C.;
Sichi, O.; Armenante, M. R.; Carotenuto, A.; Papini, A. M.; Bendinelli, M.;
Rovero, P. ChemBioChem 2006, 7, 774–779; (e) Ishida, H.; Kyakuno, M.; Oishi,
S. Biopolymers 2004, 76, 69–82; (f) Adessi, C.; Soto, C. Curr. Med. Chem. 2002,
9, 963–978; (g) Oh, J. E.; Lee, K. H. Bioorg. Med. Chem. 1999, 7, 2985–2990; (h)
Latham, P. W. Nat. Biotechnol. 1999, 17, 755–757.
8.36 (d, J¼6.0 Hz,1H, H(6)pym). 13C NMR (50 MHz, CDCl3):
¼29.0 (q,
d
3C), 38 (t), 52.6 (q), 52.9 (q), 55.1 (d), 56.3 (d), 69.2 (t), 71.7 (s), 80.7
(s), 104.2 (d), 122.4, 127.2, 128.6, 129.4, 131.1 (d, 19C), 133.8 (s), 146.3
(s, 3C), 152.6 (s), 159.5 (d), 165.5, 171.8, 172.9, 173.6 (s, 5C). MS (ESI)
m/z: 733 [MþH]þ. HRMS (ESI): m/z calcd for C42H44N4NaO8
[MþNa]þ 755.3051, found 755.3018.
4.11.2. (S)-Methyl 3-(2-(4-(2-(S)-tert-butoxycarbonylamino-2-meth-
oxycarbonylethyl)phenoxy)-6-methylpyrimidinin-4-yloxy)-2-(trityl-
amino)propanoate (14b). Synthesised according to general
procedure from sulfone derivative 12b (121 mg, 0.2 mmol),
Na-Boc-(S)-tyrosine methyl ester 4b (70.9 mg, 0.24 mmol) and
NaH (6 mg, 0.24 mmol), 60 mg (40%) of compound 14b was
5. Haldar, D. Curr. Org. Synth. 2008, 5, 61–80; (b) Perdih, A.; Sollner Dolenc, M.
Curr. Org. Chem. 2007, 11, 801–832; (c) Najera, C.; Sansano, J. M. Chem. Rev. 2007,
107, 4584–4671.
6. Vogt, H.; Bra¨se, S. Org. Biomol. Chem. 2007, 5, 406–430.
7. (a) Beenen, M. A.; Weix, D. J.; Ellman, J. A. J. Am. Chem. Soc. 2006, 128, 6304–
6305; (b) Shang, G.; Yang, Q.; Zhang, X. Angew. Chem., Int. Ed. 2006, 45, 6360–
6362 and references cited therein; (c) Williams, R. M.; Hendrix, J. A. Chem. Rev.
1992, 92, 889–917.
obtained as a colourless oil. TLC: Rf¼0.41 (n-hexane/ethyl acetate,
8. (a) Katritzky, A. R.; Tao, H.; Jiang, R.; Suzuki, K.; Kirichenko, K. J. Org. Chem. 2007,
27
1:1). [
a
]
ꢁ72.69 (c¼0.18, MeOH). IR (ATR): 3441 (w), 3359 (w),
´
D
72, 407–414; (b) Ordonez, M.; Cativiela, C. Tetrahedron: Asymmetry 2007, 18,
3–99; (c) Liljeblad, A.; Kanerva, L. T. Tetrahedron 2006, 62, 5831–5854; (d)
Fu¨lo¨p, F.; Martinek, T. A.; To´th, G. K. Chem. Soc. Rev. 2006, 35, 323–334.
9. (a) Onomura, O.; Kirira, P. G.; Tanaka, T.; Tsukada, S.; Matsumura, Y.; Demizu, Y.
Tetrahedron 2008, 64, 7498–7503; (b) van Esseveldt, B. C. J.; Vervoort, P. W. H.;
van Delft, F. L.; Rutjes, F. P. J. T. J. Org. Chem. 2005, 70, 1791–1795.
10. (a) Trabocchi, A.; Scarpi, D.; Guarna, A. Amino Acids 2008, 34, 1–24; (b) Meyer,
U.; Bisel, P.; Bra¨uner-Osborne, H.; Madsen, U.; Ho¨fner, G.; Wanner, K. T.; Frahm,
A. W. Chirality 2005, 17, 99–107; (c) Hruby, V. J., Soloshonok V. A. Eds. Asym-
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3042 (w), 2976 (w), 2952 (w), 1738 (m), 1712 (m), 1596 (s), 1564
(m) 1505 (m), 1446 (w), 1362 (s), 1343 (s), 1246 (w), 1210 (s), 1164
(s), 1079 (w), 908 (m), 728 (s), 706 (s) cmꢁ1 1H NMR (200 MHz,
.
CDCl3):
d
¼1.46 (s, 9H, C(CH3)3), 2.37 (s, 3H, CH3), 2.89 (br, 1H,
NH), 3.13–3.16 (m, 2H, CH2), 3.21 (s, 3H, OCH3), 3.71–3.74 (m, 1H,
CH-aserine), 3.74 (s, 3H, OCH3), 4.43 (dd, J¼10.6 Hz, J0¼6.0 Hz,
1H, OCH2), 4.59 (dd, J¼10.6 Hz, J0¼5.0 Hz, 1H, OCH2), 4.71–4.61
(m, 1H, CH-atyrosine), 5.32 (br, 1H, NH), 6.35 (s, 1H, H(5)pym), 7.11–
7.33 (m, 13H, CHAryl), 7.50–7.54 (m, 6H, CHAryl). 13C NMR (50 MHz,
11. (a) Adlington, R. M.; Baldwin, J. E.; Catterick, D.; Pritchard, G. J.; Tang, L.
T. J. Chem. Soc., Perkin Trans.
1 2000, 303–305; (b) Adlington, R. M.;
CDCl3):
d
¼23.3 (q), 28.9 (q, 3C), 38.5 (t), 52.5 (q), 52.8 (q), 55.1
Baldwin, J. E.; Catterick, D.; Pritchard, G. J. J. Chem. Soc., Perkin Trans. 1 2000,
299–302; (c) Kolar, P.; Petric, A.; Tisler, M. J. Heterocycl. Chem. 1997, 34,
1067–1098.
(d), 56.3 (d), 68.9 (t), 71.6 (s), 80.6 (s), 102.4 (d), 122.2, 127.1,
128.5, 129.4, 130.7 (d, 19C), 133.8 (s), 146.3 (s, 3C), 152.7 (s), 155.7
(s), 164.8 (s), 170.6 (s), 171.9 (s), 172.8 (s), 173.6 (s). MS (ESI) m/z:
747 [MþH]þ. HRMS (ESI): m/z calcd for C43H46N4NaO8 [MþNa]þ
769.3208, found 769.3197.
12. Wagner, I.; Musso, H. Angew. Chem., Int. Ed. Engl. 1983, 22, 816–828.
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Acknowledgements
Abdelatif E is the recipient of a predoctoral fellowship (FI) from
the Generalitat of Catalonia. This work was supported by grant
AGL2006-13564-C02-02/AGR from MICINN of Spain. We are also
grateful to the Serveis Tecnics de Recerca of the University of Girona
for X-ray analyses and NMR spectra.
`
18. (a) Suhartono, M.; Weidlich, M.; Stein, T.; Karas, M.; Du¨rner, G.; Go¨bel, M. W.
Eur. J. Org. Chem. 2008, 1608–1614; (b) Krebs, A.; Ludwing, V.; Pfizer, J.; Du¨rner,
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Science of Synthesis. Six-Membered Hetarenes with Two Identical Heteroatoms:
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Chem. Biodivers. 2005, 2, 1–50.
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Supplementary data
Representative 1H and 13C NMR spectra of synthesised
compounds, X-ray crystallographic details of compounds 5c, 5f and
12b and representative HPLC and MS (ESI) of dipeptides 8. CCDC-
724139, CCDC-724138, and CCDC-724137 contain the supplemen-
tary data for compounds 5c, 5f and 12b, respectively. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supplementary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2009.11.077.
22. (a) Dinsmore, A.; Doyle, P. M.; Young, D. W. Tetrahedron Lett. 1995, 36, 7503–
7506; (b) Blank, B.; Caldwell, W. T. J. Org. Chem. 1959, 24, 1137–1138.
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1443; (b) Font, D.; Heras, M.; Villalgordo, J. M. J. Comb. Chem. 2003, 5, 311–321;
(c) Font, D.; Heras, M.; Villalgordo, J. M. Synthesis 2002, 1833–1842.
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