A One-Pot Synthesis of Symmetrical and Unsymmetrical Dipeptide Ureas

Article abstract of DOI:10.1002/ejoc.201500589

We describe a flexible and high yielding synthesis of 1,3-disubstituted ureas that allows for the construction of both symmetrical and unsymmetrical dipeptide ureas, including easy access to ¹³C-labelled ureas, from amino acids and carbon dioxide at atmospheric pressure. We describe a flexible and high yielding synthesis of 1,3-disubstituted ureas, that allows for the construction of both symmetrical and unsymmetrical dipeptide ureas, including easy access to ¹³C labelled ureas, from amino acids and carbon dioxide at atmospheric pressure.

Full text of DOI:10.1002/ejoc.201500589

FULL PAPER
DOI: 10.1002/ejoc.201500589
A One-Pot Synthesis of Symmetrical and Unsymmetrical Dipeptide Ureas
Antoine Abou Fayad,[a,b] Cristina Pubill-Ulldemolins,[a] Sunil V. Sharma,[a] David Day,[b] and
Rebecca J. M. Goss*[a]
Keywords: Peptides / Dipeptide / Urea / Isotopic labelling
We describe a flexible and high yielding synthesis of 1,3-
disubstituted ureas that allows for the construction of both
symmetrical and unsymmetrical dipeptide ureas, including
easy access to 13C-labelled ureas, from amino acids and car-
bon dioxide at atmospheric pressure.
the uridyl peptide antibiotics [of which pacidamycin 4 (3) is
Introduction
a member].[10–12] In the uridyl peptide series of antibiotics
The usefulness of ureas in materials chemistry,[1–3] phar- the incorporation of a diamino acid N to N inverts the sense
maceutical chemistry,[4–6] and biology[7,8] is evident from of the peptide, the N to C directionality is restored by the
the publication of many more than a thousand papers re- incorporation of a urea; this double inversion in the sense
porting their synthesis and applications. These diverse series of the peptide potentially confers a level of resistance to
of compounds have wide series of applications ranging from degradation by proteases.[12]
plasticisers to pharmaceuticals. Importantly, ureas are also
The vast majority of methods to synthesise ureas rely
a key component of several bioactive natural products (Fig- upon the use of phosgene or isocyanates as staring materi-
ure 1),[9] including mozamide A (1), oscillamide Y (2) and als.[13–20] Alternatively, approaches based on activated carb
Figure 1. Urea-containing natural products. Mozamide A (1), oscillamide Y (2) and pacidamycin 4 (3), the urea moiety is highlighted.
[a] School of Chemistry, University of St Andrews,
St Andrews, KY16 9ST, UK
amates which can be generated from various carbonylation
reagent such as carbonates[21] chloroformates[22] and N,N-
carbonyldiimidazole (CDI)[23] have been described for the
synthesis of peptide ureas. Newer methods have been devel-
oped using carbon monoxide or carbon dioxide with transi-
tion metal catalysts.[24–27] These procedures are generally
E-mail: rjmg@st-andrews.ac.uk
http://rjmg.wp.st-andrews.ac.uk/
[b] School of Chemistry, University of East Anglia,
Norwich, NR4 7TJ, UK
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500589.
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FULL PAPER
accompanied by the disadvantage that they require either great impact on the overall yield (Table 1). Under the same
the use of very high temperatures or pressures, expensive reaction conditions, low yields were obtained at –10 °C and
catalysts, highly specialised apparatus or do not afford the –50 °C (Table 1, entries 2 and 15 respectively). A slightly
flexibility to synthesise unsymmetrical ureas.
increase in the total yield was afforded at –30 °C (Table 1,
Herein, we describe a simple procedure that allows for entry 13) but, to our delight, when the reaction was per-
the ready formation of symmetrical and unsymmetrical formed at –20 °C the yield dramatically increased to 74%
ureas from amino acids or amines and carbon dioxide.
(Table 1, entry 6). The need for the subtle tuning of tem-
perature is curious and can perhaps be explained by low
reactivity and/or solubility of the reactants at –30 °C, bal-
anced against the instability and decomposition of interme-
diates at the higher temperature of –10 °C.
Results and Discussion
Our simple one-pot, sequential, low temperature and at-
mospheric pressure route to ureas is inspired by the work
of McGhee et al.,[28] which involves first the deprotonation
of an amine with base and reaction with carbon dioxide to
form the carbamate anion, followed by its conversion to an
isocyanate using thionyl chloride (Scheme 1).
Table 1. Reaction optimisation; compound 4, aa1 = Ala, aa2 = Trp.
SOCl2, Yield [%][a][b]
equiv.
Scheme 1. Conversion of amines to isocyanate using thionyl chlor-
ide.[28]
Entry Temp.
[°C]
DBU,
equiv.
Pyridine,
equiv.
1
2
3
4
5
6
7
8
–10
–10
–10
–10
–10
–20
–20
–20
–20
–20
–20
–20
–30
–30
–50
3
5
5
3
5
5
8
3
5
5
5
5
5
5
5
2
3
3
2
2
3
3
3
4
5
3
3
3
3
3
1.5
1.5
3
15
22
28
22
35
74
20
69
8
The utility of this route to access carbamates has been
elegantly demonstrated by Taylor et al.[29,30] In the present
work, once the isocyanate is formed, by removal of the sol-
vent and all volatiles, in vacuo, re-dissolving the residue in
pyridine and then introducing a second amino acid, we
demonstrated that ready access to the urea formation could
be afforded. This approach enabled us to access a series of
1,3-disubstituted urea analogues (Scheme 2).
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2
9
10
11
12
13
14
15
6
73
76
40
42
15
3
1.5
3
1.5
[a] Reactions were carried out using l-alanine benzyl ester p-tolu-
enesulfonate (1 equiv.) and l-tryptophan methyl ester hydrochlo-
ride (1 equiv.) in DCM as specified above. [b] Isolated yields are
reported after flash chromatography.
Scheme 2. Synthesis of unsymmetrical 1,3-disubstituted ureas.
Firstly, optimisation of the reaction conditions was car-
ried out by exploring the synthesis of the unsymmetrical
Keeping –20 °C as the optimal temperature, we then
alanine-urea-tryptophan (4) as a model system. Dried car- studied the effect of the concentration of reagents. We
bon dioxide, generated from CO2(s) was bubbled into a found that for DBU, the best yield was obtained upon using
cooled solution of l-alanine benzyl ester p-toluenesulfonate 5 equiv. since, under the same reaction conditions, neither
in dichloromethane (DCM) with 1,8-diazabicycloundec-7- the use of an increased amount (8 equiv.) nor a decreased
ene (DBU) and pyridine. It is noteworthy that DBU facili- amount (3 equiv.) was beneficial to the overall reaction
tates the formation and stabilisation of the carbamate anion yield (Table 1, entries 6, 7 and 8 respectively). In the case
adduct of the amine with CO2(g), whereas pyridine liberates of pyridine, the optimal quantity was found to be 3 equiv.
the free amine from its p-toluenesulfonate salt. Thionyl since increased amounts (4 and 5 equiv.) resulted in very
chloride was then added and the reaction was warmed to poor yields (Table 1, entries 6, 9 and 10 respectively). This
room temperature. Volatiles were removed under reduced effect could be attributed to the reaction of the overexcess
pressure, anhydrous pyridine was added to solvate the iso- base with SOCl2, thus lowering the concentration of the
cyanate, and then l-tryptophan methyl ester hydrochloride later for the generation of the desired isocyanate. Addition
was added as a solution in anhydrous pyridine. Using this of 1.5 equiv. of SOCl2 was enough to afford high yields of
pre-optimized method, next, the effect of altering tempera- the desired urea compound (Table 1, entry 6). Upon using
ture and reagent concentrations was systematically investi- a larger excess of this reagent (2 and 3 equiv.) the obtained
gated. This screening revealed that the temperature at which yields were comparable (Table 1, entries 11 and 12 respec-
the carbon dioxide and thionyl chloride are added have a tively). It is important to note that a high excess of SOCl2
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A One-Pot Synthesis of Dipeptide Ureas
resulted in a very dark reaction mixture and further prob- these, a range of ureas were prepared in modest to good
lems in the workup procedure. Thus, 1.5 equiv. of SOCl2 yields (Table 4, entries 1–11).
was determined as the optimal amount as demonstrated
Table 4. One-pot synthesis of unsymmetrical urea analogues.
through the reactions reported in Table 1.
Depending upon reagent availabilities, rather than gener-
ate the CO2(g) from CO2(s), dry CO2(g) from a cylinder can
be directly used. We noted that upon using a CO2(g) cylin-
der an improvement of 10% in yield was obtained (Table 1,
entry 6 was elevated from 74 to 85% yield).
Finally, we explored the effect of replacing thionyl chlor-
ide with p-toluenesulfonyl chloride (pTsCl) or 1-[bis(di-
Entry
aa1
aa2
Yield [%][a],[b]
methylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridin-
ium 3-oxide hexafluorophosphate (HATU) as alternative
activators (Table 2). In all cases, formation of the desired
product was observed but generally the isolated yields were
considerably lower, even upon using larger excess, in com-
parison to the use of SOCl2 (Table 2, entries 2 to 6 and 1,
respectively).
1
2
3
4
5
6
7
8
Ala
Ala
Ala
Ala
Ala
Ala
Ala
Met
Met
Leu
Leu
Trp
Phe
Met
5-Br-Trp
5-Cl-Trp
5-F-Trp
7-I-Trp
Phe
Trp
Phe
74Ϯ0.8 (4)
78Ϯ0.5 (8)
68Ϯ1.0 (9)
55Ϯ0.8 (10)
52Ϯ1.1 (11)
58Ϯ0.5 (12)
72Ϯ0.9 (13)
60Ϯ0.7 (14)
63Ϯ0.5 (15)
55Ϯ0.9 (16)
40Ϯ1.2 (17)
90 (18)
9
Table 2. Screening of alternative activators for synthesis of com-
pound 4; aa1 = Ala, aa2 = Trp.
10
11
12
Met
Ala (13CO2) Trp
Entry
Activator
Equiv.
Yield [%][a][b]
[a] Reactions were carried out using aa1 (1 equiv.), aa2 (1 equiv.),
DBU (5 equiv.), pyridine (3 equiv.) and SOCl2 (1.5 equiv.) in DCM
as specified above. [b] Isolated yields are reported after flash
chromatography from reactions carried out in triplicate.
1
SOCl2
pTsCl
pTsCl
pTsCl
HATU
HATU
1.5
1.5
2
3
1.5
2
74
28
35
30
45
48
2
3
4
5[c]
6
As shown in Table 4, reacting Ala as aa1 with Trp (Tryp-
tophan), Phe (Phenylalanine) and Met (Methionine) as aa2
afforded high yields of the corresponding 1,3-disubstituted
urea analogues (Table 4, entries 1, 2 and 3).
Notably, the coupling of Ala as aa1 with halogenated Trp
(generated by biocatalysis through a well-established proto-
col previously developed in our group)[31,32] as aa2 also af-
forded the corresponding desired urea analog in moderate
yields (Table 4, entries 4 to 7).
Changing aa1 to Leu (Leucine) and Met successfully re-
sulted in formation of the desired urea product but in lower
yields (Table 4, entries 8–11, respectively). This decrease in
yield upon changing aa1 could be explained mainly due to
the steric effects of the side chain in α position (R1).
Remarkably, in all cases, this one-pot method is highly
reproducible as shown by the very low error obtained from
performing the reactions in triplicate.
[a] Reactions were carried out using l-alanine benzyl ester p-tolu-
enesulfonate (1 equiv.), l-tryptophan methyl ester hydrochloride
(1 equiv.), DBU (5 equiv.), pyridine (3 equiv.) in DCM at –20 °C as
specified above. [b] Isolated yields are reported after flash
chromatography. [c] A slightly different procedure was used, see
experimental section.
Using the optimized conditions with thionyl chloride, ac-
cess to symmetrical ureas was shown to be particularly high
yielding, over 90% in all cases (Table 3, entries 1–3).
Table 3. One-pot synthesis of symmetrical urea analogues, aa1 = aa2.
Most importantly, using 13C carbon dioxide we success-
fully generated isotopically labelled urea in almost a quanti-
tative manner (Table 4, entry 12). The obtained higher yield
over the unlabelled system (90% and 74% respectively) can
be rationalised by the fact that rigorously dry 13CO2(g) was
provided directly from a gas cylinder rather from simply
evaporating and drying CO2(s).
Entry R1
R2
Bn
aa1 = aa2
Yield [%][a][b]
1
2
3
Me
Me
Bn
Phe
96 Ϯ 0.03 (5)
93 Ϯ 0.1 (6)
95 Ϯ 0.07 (7)
CH2CH2SCH3 Met
Me Ala
[a] Reactions were carried out using aa1 (1 equiv.), aa2 (1 equiv.),
DBU (5 equiv.), pyridine (3 equiv.) and SOCl2 (1.5 equiv.) in DCM
as specified above. [b] Isolated yields are reported after flash
chromatography from reactions carried out in triplicate.
Conclusions
Encouraged by these results, we next focused on ex-
In summary, we have developed a simple and efficient
panding the scope of the reaction on the synthesis of un- synthetic approach enabling easy access to symmetrical and
symmetrical ureas. A series of six methyl ester and benzyl the more challenging unsymmetrical 1,3-disubstiuted ureas
ester protected amino acids were synthesised and using from amino acids and carbon dioxide in moderate to high
Eur. J. Org. Chem. 2015, 5603–5609
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R. J. M. Goss et al.
FULL PAPER
3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 175.0, 173.4, 156.8,
135.9, 135.2, 128.5, 128.3, 128.1, 127.4, 123.6, 121.9, 119.3, 118.4,
111.4, 109.2, 67.2, 53.1, 52.3, 48.5, 28.0, 19.0 ppm. HRMS (ESI,
+ve) C23H25N3O5 [M + Na]+ calculated for 446.1679, found
446.1680.
yields at atmospheric pressure. Moreover, the utility of this
one-pot approach for accessing 13C labelled urea has also
been demonstrated. Although the current methodology is
applied to the synthesis of dipeptide ureas, in principle, it
could potentially be extended to other types of building
blocks to generate 1,3 disubstituted ureas apart from amino
acids.
N,NЈ-Carbonylbis(L-phenylalanine Methyl Ester) (5): N,NЈ-Carb-
onylbis(l-phenylalanine methyl ester) (5) (0.09 g, 0.23 mmol, 96%),
white powder, was prepared following the same procedure as de-
1
scribed for compound (4). H NMR (500 MHz, CDCl3): δ = 7.20–
Experimental Section
7.30 (m, 6 H), 7.09 (d, J = 7.1 Hz, 4 H), 5.51 (d, J = 8.4 Hz, 2 H),
4.82 (dt, J = 8.4, 5.8 Hz, 2 H), 3.63 (s, 6 H), 3.00 (d, J = 5.9 Hz, 4
H) ppm. 13C NMR (126 MHz, CDCl3): δ = 173.3, 156.2, 136.1,
129.3, 128.4, 126.9, 53.9, 52.2, 38.7 ppm. HRMS (ESI, +ve)
C21H24N2O5 [M + H]+ calculated for 385.1758, found 385.1761.
General Experimental Methods: TLC analysis was carried out on
Merck aluminium-backed silica gel 60 F254 and was visualised by
ultraviolet light (UV) using a model UVGL-58 MINERLIGHT®
LAMP multiband UV-254/365 nm, by ninhydrin stain (50 mg of
ninhydrin dissolved in 40 mL of acetone). Column chromatography
was carried out on Davisil® chromatographic silica media LC60A
40–63 μm. Anhydrous DCM was obtained using a MBRAUN SPS
800 filtered through pre-packed alumina columns. Anhydrous pyr-
idine was distilled from over calcium hydride under argon atmo-
sphere and stored over activated 4 Å molecular sieves. Anhydrous
DMF was purchased. All other solvents were SLR grade and used
without further purification unless stated otherwise. When anhy-
drous solvents were used, all glassware was oven dried and cooled
under argon. l-7-Iodotryptophan, l-5-bromotryptophan, l-5-chlo-
rotryptophan, and l-5-fluorotryptophan were prepared as de-
scribed previously.[31,32]
N,NЈ-Carbonylbis(L-methionine Methyl Ester) (6): N,NЈ-Carb-
onylbis(l-methionine methyl ester) (6) (0.16 g, 0.46 mmol, 93%),
white powder, was prepared following the same procedure as de-
1
scribed for compound (4). H NMR (500 MHz, CDCl3): δ = 5.67
(d, J = 8.2 Hz, 2 H), 4.60 (td, J = 7.7, 5.0 Hz, 2 H), 3.76 (s, 6 H),
2.53 (t, J = 7.5 Hz, 4 H), 2.06–2.17 (m, 8 H), 1.94 (dq, J = 14.6,
7.4 Hz, 2 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 173.8, 156.8,
52.5, 52.2, 32.3, 29.9, 15.4 ppm. HRMS (ESI, +ve) C13H24N2O5S2
[M + H]+ calculated for 353.1199 found 353.1202.
N,NЈ-Carbonylbis(L-alanine Benzyl Ester) (7): N,NЈ-Carbonylbis(l-
alanine benzyl ester) (7) (0.10 g, 0.27 mmol, 95%), white powder,
was prepared following the same procedure as described for com-
pound (4). H NMR (500 MHz, CDCl3): δ = 7.32–7.40 (m, 10 H),
N-({(1S)-1-[(Benzyloxy)carbonyl]ethyl}aminocarbonyl)-L-trypto-
1
phan Methyl Ester (4): Dry ice was placed in a 500 mL round-
bottom flask connected to a paraffin oil bubbler then to a drying
tube containing pellets of activated 4 Å molecular sieves. Using Tef-
lon® tubing, CO2(g) derived from dry ice was bubbled into a stirred
solution of l-alanine benzyl ester p-toluenesulfonate salt (0.20 g,
0.57 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.43 mL,
2.85 mmol) and pyridine (0.14 mL, 1.71 mmol) in anhydrous DCM
(30 mL) at –20 °C, for a period of 30 min whilst keeping the mix-
ture at –20 °C. Subsequently, a solution of thionyl chloride
(0.08 mL, 1.14 mmol) in anhydrous DCM (5 mL) was carefully
added to the reaction over a period of 20 min under an atmosphere
of argon. The reaction was then left stirring under an atmosphere
of argon for 2 h while it was warmed up to room temperature.
Upon addition of thionyl chloride, the color of the reaction mixture
gradually changed from clear to yellow to brown as the reaction
warms up to room temperature. Afterwards, the solvent was re-
moved under reduced pressure and the brown, oily residue was dis-
solved in anhydrous pyridine (8 mL). Under an atmosphere of ar-
gon, a solution of l-tryptophan methyl ester hydrochloride salt
(0.15 g, 0.57 mmol) in anhydrous pyridine (2 mL) was added over
a period of 10 min at room temperature. The mixture was left stir-
ring under an atmosphere of argon at room temperature for 4 h.
The solvent was then removed under reduced pressure and the
brown residue was dissolved in ethyl acetate (50 mL) and washed
five times with a saturated sodium hydrogen carbonate solution
(40 mL). The organic layer was dried with magnesium sulfate, fil-
tered, concentrated under reduced pressure and purified using flash
chromatography (SiO2, hexane/ethyl acetate, 3:1 to 1:1, ninhydrin/
UV) to yield the target compound (4)(0.19 g, 0.44 mmol, 74%) as
a white powder. 1H NMR (500 MHz, CDCl3): δ = 8.62 (s, 1 H),
7.48 (d, J = 7.9 Hz, 1 H), 7.29–7.36 (m, 4 H), 7.19–7.21 (m, 2 H),
7.15 (t, J = 7.6 Hz, 1 H), 7.07 (t, J = 7.4 Hz, 1 H), 6.87 (s, 1 H),
5.78 (d, J = 8.4 Hz, 1 H), 5.64 (d, J = 8.0 Hz, 1 H), 5.06 (d, J =
5.35 (d, J = 7.7 Hz, 2 H), 5.22 (d, J = 12.4 Hz, 2 H), 5.15 (d, J =
12.4 Hz, 2 H), 4.55 (p, J = 7.3 Hz, 2 H), 1.39 (d, J = 7.2 Hz, 6 H)
ppm. 13C NMR (126 MHz, CDCl3): δ = 174.1, 156.4, 135.4, 128.6,
128.3, 128.1, 67.0, 48.8, 18.9 ppm. HRMS (ESI, +ve) C21H24N2O5
[M + H]+ calculated for 385.1758, found 385.1761.
N-({(1S)-1-[(Benzyloxy)carbonyl]ethyl}aminocarbonyl)-L-phenyl-
alanine Methyl Ester (8): N-({(1S)-1-[(Benzyloxy)carbonyl]-
ethyl}aminocarbonyl)-l-phenylalanine methyl ester (8) (0.17 g,
0.42 mmol, 78%), white powder, was prepared following the same
procedure as described for compound (4). 1H NMR (500 MHz,
CDCl3): δ = 7.34–7.39 (m, 5 H), 7.22–7.26 (m, 3 H), 7.11 (d, J =
7.1 Hz, 2 H), 5.24–5.08 (m, 4 H), 5.02 (d, J = 8.1 Hz, 1 H), 4.80
(dt, J = 5.7, 8.2 Hz, 1 H), 4.50–4.58 (m, 1 H), 3.71 (s, 3 H), 3.09
(dd, J = 2.6, 5.8 Hz, 2 H), 1.37 (d, J = 7.5 Hz, 3 H) ppm. 13C
NMR (126 MHz, CDCl3): δ = 173.8, 172.9, 156.1, 135.9, 135.4,
129.3, 128.6, 128.5, 128.3, 128.1, 127.0, 67.0, 53.8, 52.2, 48.8, 38.5,
19.0 ppm. HRMS (ESI, +ve) C21H24N2O5 [M + Na]+ calculated
for 407.1565, found 407.1566.
N-({(1S)-1-[(Benzyloxy)carbonyl]ethyl}aminocarbonyl)-L-methionine
Methyl Ester (9): N-({(1S)-1-[(Benzyloxy)carbonyl]ethyl}-
aminocarbonyl)-l-methionine methyl ester (9) (0.15 g, 0.40 mmol,
68%), white powder, was prepared following the same procedure
1
as described for compound (4). H NMR (500 MHz, CDCl3): δ =
7.30–7.40 (m, 5 H), 5.57 (d, J = 8.1 Hz, 1 H), 5.48 (d, J = 7.7 Hz,
1 H), 5.11–5.24 (m, 2 H), 4.62 (td, J = 7.7, 4.9 Hz, 1 H), 4.51–4.58
(m, 1 H), 3.76 (s, 3 H), 2.53 (t, J = 7.5 Hz, 2 H), 2.06–2.16 (m, 4
H), 1.93 (dq, J = 14.6, 7.4 Hz, 1 H), 1.39 (d, J = 7.1 Hz, 3 H) ppm.
13C NMR (126 MHz, CDCl3): δ = 174.0, 173.9, 156.6, 135.4, 128.6,
128.3, 128.0, 67.0, 52.5, 52.2, 48.9, 32.3, 29.9, 18.9, 15.4 ppm.
HRMS (ESI, +ve) C17H24N2O5S[M + Na]+ calculated for
391.1292, found 391.1290.
12.3 Hz, 1 H), 4.85 (dt, J = 7.9, 5.3 Hz, 1 H), 4.72 (d, J = 12.3 Hz, N-({(1S)-1-[(Benzyloxy)carbonyl]ethyl}aminocarbonyl)-
1 H), 4.64 (p, J = 7.4 Hz, 1 H), 3.62 (s, 3 H), 3.28 (dd, J = 14.8, tryptophan Methyl Ester (10): N-({(1S)-1-[(Benzyloxy)carbonyl]-
5.3 Hz, 1 H), 3.18 (dd, J = 14.8, 5.1 Hz, 1 H), 1.30 (d, J = 7.3 Hz, ethyl}aminocarbonyl)-l-5-bromotryptophan methyl ester (10)
L-5-bromo-
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A One-Pot Synthesis of Dipeptide Ureas
(0.08 g, 0.16 mmol, 55%), white powder, was prepared following
N-({(1S)-1-[(Benzyloxy)carbonyl]-4-(methylthio)propyl}amino-
carbonyl)- -phenylalanine Methyl Ester (14): N-({(1S)-1-[(Benz-
the same procedure as described for compound (4). 1H NMR
L
(500 MHz, CDCl3): δ = 8.74 (s, 1 H), 7.58 (s, 1 H), 7.31–7.35 (m, yloxy)carbonyl]-4-(methylthio)propyl}aminocarbonyl)-l-phenylal-
3 H), 7.13–7.23 (m, 4 H), 6.86 (s, 1 H), 5.86 (d, J = 8.7 Hz, 1 H), anine methyl ester (14) (0.07 g, 0.16 mmol, 60%), white powder,
5.67 (d, J = 7.9 Hz, 1 H), 5.04 (d, J = 12.3 Hz, 1 H), 4.83 (dt, J = was prepared following the same procedure as described for com-
1
7.9, 5.0 Hz, 1 H), 4.63–4.73 (m, 2 H), 3.68 (s, 3 H), 3.21 (dd, J = pound (4). H NMR (500 MHz, CDCl3): δ = 7.36–7.41 (m, 5 H),
14.9, 5.0 Hz, 1 H), 3.12 (dd, J = 14.9, 5.0 Hz, 1 H), 1.35 (d, J =
7.2 Hz, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 175.2, 173.0,
156.7, 135.0, 134.4, 129.1, 128.5, 128.4, 128.0, 125.0, 124.7, 121.0,
7.25–7.29 (m, 3 H), 7.11 (d, J = 6.6 Hz, 2 H), 5.23 (d, J = 12.2 Hz,
1 H), 5.17 (d, J = 12.1 Hz, 1 H), 5.02 (d, J = 8.0 Hz, 1 H), 4.87 (d,
J = 8.0 Hz, 1 H), 4.78 (dt, J = 7.9, 5.6 Hz, 1 H), 4.63 (td, J = 7.7,
112.8, 112.6, 108.8, 67.4, 52.9, 52.4, 48.5, 27.9, 19.2 ppm. HRMS 4.9 Hz, 1 H), 3.73 (s, 3 H), 3.11 (d, J = 5.6 Hz, 2 H), 2.44–2.55 (m,
(ESI, +ve) C23H24BrN3O5 [M + Na]+ calculated for 524.0786, 2 H), 2.10–2.18 (m, 1 H), 2.04 (s, 3 H), 1.89–1.97 (m, 1 H) ppm.
found 524.0788.
13C NMR (126 MHz, CDCl3): δ = 174.1, 173.0, 156.1, 142.6, 135.8,
135.5, 129.3, 128.6, 128.5, 128.4, 128.3, 127.0, 67.3, 53.9, 52.4, 52.2,
38.4, 29.8, 15.4 ppm. HRMS (ESI, +ve) C23H28N2O5S[M + Na]+
calculated for 467.1608, found 467.1606.
N-({(1S)-1-[(Benzyloxy)carbonyl]ethyl}aminocarbonyl)-L-5-chloro-
tryptophan Methyl Ester (11): N-({(1S)-1-[(Benzyloxy)carbonyl]-
ethyl}aminocarbonyl)-l-5-chlorotryptophan methyl ester (11)
(0.09 g, 0.2 mmol, 52%), white powder, was prepared following the
same procedure as described for compound (4). 1H NMR
(400 MHz, CDCl3): δ = 8.84 (s, 1 H), 7.42 (d, J = 2.0 Hz, 1 H),
7.30–7.34 (m, 3 H), 7.21 (d, J = 8.6 Hz, 1 H), 7.13–7.20 (m, 2 H),
7.07 (dd, J = 8.6, 2.0 Hz, 1 H), 6.87 (d, J = 2.4 Hz, 1 H), 5.97 (d,
J = 7.9 Hz, 1 H), 5.77 (d, J = 7.9 Hz, 1 H), 5.05 (d, J = 12.3 Hz,
1 H), 4.84 (dt, J = 7.9, 5.0 Hz, 1 H), 4.61–4.74 (m, 2 H), 3.66 (s, 3
H), 3.21 (dd, J = 14.9, 5.1 Hz, 1 H), 3.11 (dd, J = 14.9, 5.0 Hz, 1
H), 1.33 (d, J = 7.2 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 175.3, 173.1, 135.0, 134.2, 128.5, 128.4, 128.3, 128.0, 125.2,
125.1, 122.1, 117.9, 112.4, 108.9, 67.4, 52.9, 52.4, 48.5, 27.9, 19.1
ppm. HRMS (ESI, +ve) C23H24ClN3O5 [M + H]+ calculated for
458.1477, found 458.1478.
N-({(1S)-1-[(Benzyloxy)carbonyl]-4-(methylthio)butyl}amino-
carbonyl)-L-tryptophan Methyl Ester (15): N-({(1S)-1-[(Benzyloxy)-
carbonyl]-4-(methylthio)propyl} aminocarbonyl)-l-tryptophan
methyl ester (15) (0.07 g, 0.15 mmol, 63%), white powder, was pre-
pared following the same procedure as described for compound (4).
1H NMR (500 MHz, CDCl3): δ = 8.59 (s, 1 H), 7.48 (d, J = 7.9 Hz,
1 H), 7.29–7.41 (m, 4 H), 7.15–7.21 (m, 3 H), 7.09 (t, J = 7.5 Hz,
1 H), 6.89 (s, 1 H), 5.81 (d, J = 8.9 Hz, 1 H), 5.63 (d, J = 8.0 Hz,
1 H), 5.03 (d, J = 12.2 Hz, 1 H), 4.87 (dt, J = 8.6, 5.2 Hz, 1 H),
4.77 (td, J = 8.3, 4.8 Hz, 1 H), 4.69 (d, J = 12.2 Hz, 1 H), 3.64 (s,
3 H), 3.30 (dd, J = 14.9, 5.1 Hz, 1 H), 3.20 (dd, J = 14.9, 5.2 Hz,
1 H), 2.40–2.47 (m, 2 H), 2.00–2.10 (m, 4 H), 1.83 (dq, J = 14.5,
7.5 Hz, 1 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 174.0, 173.1,
156.9, 135.9, 135.0, 128.6, 128.5, 128.4, 127.4, 123.5, 122.0, 119.4,
118.4, 111.4, 109.2, 67.5, 53.2, 52.3, 51.9, 32.4, 29.8, 28.0, 15.4 ppm.
HRMS (ESI, +ve) C25H29N3O5S[M + Na]+ calculated for
506.1717, found 506.1715.
N-({(1S)-1-[(Benzyloxy)carbonyl]ethyl}aminocarbonyl)-L-5-fluoro-
tryptophan Methyl Ester (12): N-({(1S)-1-[(Benzyloxy)carbonyl]-
ethyl}aminocarbonyl)-l-5-fluorotryptophan methyl ester (12)
(0.10 g, 0.23 mmol, 58%), white powder, was prepared following
the same procedure as described for compound (4). 1H NMR
(400 MHz, CDCl3): δ = 8.73 (s, 1 H), 7.32 (m, 3 H), 7.16–7.25 (m,
3 H), 7.10 (dd, J = 9.8, 2.6 Hz, 1 H), 6.87–6.92 (m, 2 H), 5.89 (d,
J = 8.5 Hz, 1 H), 5.71 (d, J = 8.1 Hz, 1 H), 5.07 (d, J = 12.4 Hz,
1 H), 4.83 (dt, J = 8.0, 5.1 Hz, 1 H), 4.75 (d, J = 12.4 Hz, 1 H),
4.61–4.70 (m, 1 H), 3.65 (s, 3 H), 3.20 (dd, J = 14.9, 5.1 Hz, 1 H),
3.12 (dd, J = 14.9, 5.0 Hz, 1 H), 1.32 (d, J = 7.2 Hz, 3 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 175.1, 173.2, 156.8, 156.7 (d, J
= 32.2 Hz), 133.8 (d, J = 277.9 Hz), 128.5, 128.3, 128.0, 127.8 (d,
J = 9.6 Hz), 125.5, 123.9, 112.04 (d, J = 9.7 Hz), 110.30 (d, J =
26.2 Hz), 109.37 (d, J = 4.7 Hz), 103.2 (d, J = 23.6 Hz), 67.3, 53.0,
52.4, 48.5, 28.0, 19.1 ppm. 19F NMR (377 MHz, CDCl3, decoupled
N-{(1S)-1-[(Benzyloxy)carbonyl]-4,4-(dimethyl)propyl}amino-
carbonyl-L-phenylalanine Methyl Ester (16): N-({(1S)-1-[(Benz-
yloxy)carbonyl]-4,4-(dimethyl)propyl}aminocarbonyl)-l-pheny-lal-
anine methyl ester (16) (0.08 g, 0.18 mmol, 55%), white powder,
was prepared following the same procedure as described for com-
1
pound (4). H NMR (500 MHz, CDCl3): δ = 7.32–7.42 (m, 5 H),
7.20–7.27 (m, 3 H), 7.07–7.12 (m, 2 H), 5.20 (d, J = 12.3 Hz, 1 H),
5.09–5.15 (m, 3 H), 4.82 (dt, J = 8.1, 5.5 Hz, 1 H), 4.55 (td, J =
8.9, 5.2 Hz, 1 H), 3.69 (s, 3 H), 3.08 (t, J = 5.5 Hz, 2 H), 1.63–1.71
(m, 1 H), 1.58 (ddd, J = 13.6, 8.4, 5.2 Hz, 1 H), 1.44 (ddd, J =
13.5, 9.3, 5.7 Hz, 1 H), 0.90 (dd, J = 8.2, 6.5 Hz, 6 H) ppm. 13C
NMR (126 MHz, CDCl3): δ = 174.2, 172.9, 156.4, 135.9, 135.4,
129.4, 128.5, 128.4, 128.3, 128.1, 127.0, 67.0, 53.9, 52.2, 51.6, 41.9,
38.5, 24.7, 22.8, 21.8 ppm. HRMS (ESI, +ve) C24H30N2O5 [M +
H]+ calculated for 427.2227, found 427.2226.
1H): δ = –124.89 ppm. 19F NMR (377 MHz, CDCl3, coupled H):
1
δ = –124.90 (td, J = 9.4, 4.3 Hz) ppm. HRMS (ESI, +ve)
C23H24FN3O5 [M + H]+ calculated for 442.7713, found 442.7768.
N-({(1S)-1-[(Benzyloxy)carbonyl]-4,4-(dimethyl)propyl}amino-
carbonyl)-L-methionine Methyl Ester (17): N-({(1S)-1-[(Benzyloxy)-
N-({(1S)-1-[(Benzyloxy)carbonyl]ethyl}aminocarbonyl)-L-7-iodo-
tryptophan Methyl Ester (13): N-({(1S)-1-[(Benzyloxy)carbonyl]-
ethyl}aminocarbonyl)-l-7-iodotryptophan methyl ester (13)
(0.11 g, 0.19 mmol, 72%), white powder, was prepared following
the same procedure as described for compound (4). 1H NMR
(400 MHz, CDCl3): δ = 8.64 (s, 1 H), 7.50 (d, J = 7.5 Hz, 1 H),
7.43 (d, J = 7.9 Hz, 1 H), 7.35 (m, 2 H), 7.25–7.32 (m, 3 H), 6.91
(d, J = 2.4 Hz, 1 H), 6.83 (t, J = 7.7 Hz, 1 H), 5.79 (d, J = 8.1 Hz,
1 H), 5.66 (d, J = 8.2 Hz, 1 H), 5.11 (d, J = 12.4 Hz, 1 H), 4.91
(dt, J = 8.2, 5.0 Hz, 1 H), 4.80 (d, J = 12.3 Hz, 1 H), 4.70 (apparent
p, J = 7.4 Hz, 1 H), 3.59 (s, 3 H), 3.23 (dd, J = 14.8, 4.9 Hz, 1 H),
3.14 (dd, J = 14.9, 5.3 Hz, 1 H), 1.29 (d, J = 7.2 Hz, 2 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 174.9, 173.3, 156.7, 137.8, 135.3,
130.5, 128.6, 128.4, 128.1, 127.5, 124.1, 121.0, 118.6, 110.9, 76.7,
67.2, 52.9, 52.3, 48.5, 28.5, 19.1 ppm. HRMS (ESI, +ve)
C23H24IN3O5 [M + H]+ calculated for 550.0833, found 550.0826.
carbonyl]-4,4-(dimethyl)propyl}aminocarbonyl)-l-methionine
methyl ester (17) (0.10 g, 0.24 mmol, 40%), white powder, was pre-
pared following the same procedure as described for compound (4).
1H NMR (500 MHz, CDCl3): δ = 7.31–7.43 (m, 5 H), 5.12–5.23
(m, 3 H), 4.92 (d, J = 8.5 Hz, 1 H), 4.61 (td, J = 7.7, 4.9 Hz, 1 H),
4.54 (td, J = 8.9, 5.2 Hz, 1 H), 3.77 (s, 3 H), 2.51–2.58 (m, 2 H),
2.08–2.20 (m, 4 H), 1.95 (dq, J = 14.4, 7.4 Hz, 1 H), 1.64–1.73 (m,
2 H), 1.51 (ddd, J = 13.5, 9.2, 5.7 Hz, 1 H), 0.93 (dd, J = 6.5,
4.7 Hz, 6 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 173.9, 173.4,
156.6, 135.4, 128.5, 128.3, 128.1, 67.0, 52.5, 52.3, 51.7, 41.9, 32.2,
29.9, 24.7, 22.8, 21.9, 15.4 ppm. HRMS (ESI, +ve) C20H30N2O5S
[M + Na]+ calculated for 411.1948, found 411.1946.
N-({(1S)-1-[(Benzyloxy)carbonyl]ethyl}(13C)aminocarbonyl)-
L-
tryptophan Methyl Ester (18): N-({(1S)-1-[(Benzyloxy)carbonyl]-
Eur. J. Org. Chem. 2015, 5603–5609
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5607

R. J. M. Goss et al.
ethyl}(13C)aminocarbonyl)-l-tryptophan methyl ester (18) (0.70 g, (0.43 g, 1.14 mmol) in anhydrous DMF (1 mL) was added to the
FULL PAPER
1.65 mmol, 90%), white powder, was prepared following the same
procedure as described for compound (4). 13C labelled carbon diox-
ide, 13CO2, [carbon dioxide (13C, 99%) (Ͻ 1% 18O) purchased from
Cambridge Isotope Laboratories, Inc.] was used instead of CO2
reaction followed by a solution of N,N-diisopropylethylamine, DI-
PEA (0.4 mL, 2.28 mmol) in anhydrous DMF (1 mL) under an at-
mosphere of argon. The reaction was then left stirring under an
atmosphere of argon for 30 min. Subsequently, a solution of l-tryp-
tophan methyl ester hydrochloride salt (0.15 g, 0.57 mmol) in anhy-
1
derived from dry ice. H NMR (500 MHz, CDCl3): δ = 8.62 (s, 1
H), 7.48 (d, J = 7.9 Hz, 1 H), 7.31–7.35 (m, 4 H), 7.19–7.22 (m, 2 drous DMF (2 mL) was added over a period of 10 min at room
H), 7.16 (ddd, J = 8.1, 7.0, 1.1 Hz, 1 H), 7.08 (ddd, J = 8.0, 7.0,
1.0 Hz, 1 H), 6.87 (d, J = 2.4 Hz, 1 H), 5.79 (dd, J = 8.5, 2.4 Hz,
1 H), 5.65 (dd, J = 8.1, 2.4 Hz, 1 H), 5.06 (d, J = 12.3 Hz, 1 H),
temperature. The mixture was left stirring under an atmosphere of
argon at room temperature for 4 h. The solvent was then removed
under reduced pressure and the brown residue was dissolved in
4.86 (dtd, J = 7.9, 5.2, 2.5 Hz, 1 H), 4.70 (d, J = 12.3 Hz, 1 H), ethyl acetate (50 mL) and washed five times with a saturated so-
4.62–4.68 (m, 1 H), 3.62 (s, 3 H), 3.28 (dd, J = 14.9, 5.2 Hz, 1 H), dium hydrogen carbonate solution (40 mL). The organic layer was
3.19 (dd, J = 14.9, 5.1 Hz, 1 H),1.31 (d, J = 7.3 Hz, 3 H) ppm. 13
C
dried with magnesium sulfate, filtered, concentrated under reduced
pressure and purified using flash chromatography (silica, hexane/
ethyl acetate, 3:1 to 1:1, ninhydrin/UV) to yield the target com-
pound (4)(0.11 g, 0.27 mmol, 48%) as a white powder.
NMR (126 MHz, CDCl3): δ = 175.1, 173.3, 156.8, 135.9, 135.2,
128.5, 128.3, 128.1, 127.4, 123.6, 121.9, 119.3, 118.4, 111.4, 109.2,
67.2, 53.1, 52.3, 48.5, 28.0, 19.1 ppm. HRMS (ESI, +ve)
C2213CH25N3O5 [M + Na]+ calculated for 447.1756, found
447.1755.
L-5-Bromotryptophan Methyl Ester (19): Acetyl chloride (0.20 mL,
2.80 mmol) was added over a period of 5 min to a stirred solution
of l-5-bromotryptophan (0.19 g, 0.70 mmol) in methanol (20 mL)
at 0 °C. Following addition, the reaction mixture was warmed up
to room temperature then heated to reflux for 3 h. When no trace
of starting material remained (TLC: silica, methanol, ninhydrin,
Rf 0.6), the solvent was removed under reduced pressure to leave l-
5-bromotryptophan methyl ester (19) (0.20 g, 0.69 mmol, Ͼ95%),
bright red solid. No further purification was required. 1H NMR
(500 MHz, CD3OD): δ = 7.69 (s, 1 H), 7.35 (d, J = 8.6 Hz, 1 H),
7.22–7.30 (m, 2 H), 4.34 (t, J = 6.2 Hz, 1 H), 3.82 (s, 3 H), 3.35–
3.50 (m, 2 H) ppm. 13C NMR (126 MHz, CD3OD): δ = 169.3,
135.4, 128.6, 125.9, 124.2, 120.1, 113.0, 112.0, 105.8, 53.1, 52.3,
25.8 ppm. HRMS (ESI, +ve) C12H13BrN2O2 [M + H]+ calculated
for 297.0226, found 297.0228.
N-({(1S)-1-[(Benzyloxy)carbonyl]ethyl}aminocarbonyl)-L-trypto-
phan Methyl Ester Using p-Toluenesulfonyl Chloride (4). General
Procedure using pTsCl as Activator: Dry ice was placed in a 500 mL
round-bottom flask connected to a paraffin oil bubbler then to a
drying tube containing pellets of 4 Å molecular sieves. Using Tef-
lon® tubing, CO2(g) derived from dry ice was bubbled into a
stirred, solution of l-alanine benzyl ester p-toluenesulfonate salt
(0.20 g, 0.57 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
(0.43 mL, 2.85 mmol) and pyridine (0.14 mL, 1.71 mmol) in anhy-
drous DCM (30 mL) at –20 °C, for a period of 30 min whilst keep-
ing the mixture at –20 °C. Subsequently, a solution of p-tolu-
enesulfonyl chloride (0.22 g, 1.14 mmol) in anhydrous DCM
(5 mL) was added to the reaction over a period of 20 min under an
atmosphere of argon. The reaction was then left stirring under an
atmosphere of argon for 2 h while it was warmed up to room tem-
perature. Upon addition of p-toluenesulfonyl chloride, the color of
the reaction mixture gradually changed from clear to yellow as the
reaction warms up to room temperature. Afterwards, the solvent
was removed under reduced pressure and the brown, oily residue
was dissolved in anhydrous pyridine (8 mL). Under an atmosphere
of argon, a solution of l-tryptophan methyl ester hydrochloride
salt (0.15 g, 0.57 mmol) in anhydrous pyridine (2 mL) was added
L-7-Iodotryptophan Methyl Ester (20): l-7-Iodotryptophan methyl
ester (20)(0.09 g, 0.27 mmol, 92%), white powder, was prepared fol-
lowing the same procedure as described for compound (19). 1H
NMR (400 MHz, CD3OD): δ = 7.56 (dd, J = 14.8, 7.6 Hz, 1 H),
7.34 (s, 1 H), 6.88 (t, J = 7.6 Hz, 1 H), 4.35 (apparent t, J = 6.1 Hz,
1 H), 3.79 (s, 3 H), 3.42 (m, 2 H) ppm. 13C NMR (101 MHz,
CD3OD): δ = 169.2, 138.6, 130.7, 127.2, 125.3, 120.6, 117.8, 107.7,
75.7, 53.2, 52.4, 26.2 ppm. HRMS (ESI, +ve) C12H13IN2O2 [M +
over a period of 10 min at room temperature. The mixture was left H]+ calculated for 345.0094, found 345.0098.
stirring under an atmosphere of argon at room temperature for 4 h.
L
-5-Chlorotryptophan Methyl Ester (21): l-5-Chlorotryptophan
The solvent was then removed under reduced pressure and the
brown residue was dissolved in ethyl acetate (50 mL) and washed
five times with a saturated sodium hydrogen carbonate solution
(40 mL). The organic layer was dried with magnesium sulfate, fil-
tered, concentrated under reduced pressure and purified using flash
chromatography (silica, hexane/ethyl acetate, 3:1 to 1:1, ninhydrin/
UV) to yield the target compound (4) (0.08 g, 0.2 mmol, 35%) as
a white powder.
methyl ester (21)(0.12 g, 0.47 mmol, 94%), white powder, was pre-
pared following the same procedure as described for compound
1
(19). H NMR (400 MHz, CD3OD): δ = 7.54 (s, 1 H), 7.38 (d, J =
8.6 Hz, 1 H), 7.29 (s, 1 H), 7.12 (d, J = 7.9 Hz, 1 H), 4.35 (t, J =
5.8 Hz, 1 H), 3.82 (s, 3 H), 3.36–3.48 (m, 2 H) ppm. 13C NMR
(101 MHz CD3OD): δ = 169.3, 135.2, 127.9, 1206.0, 124.7, 121.6,
117.0, 112.5, 105.9, 53.1, 52.3, 25.9 ppm. HRMS (ESI, +ve)
C12H13ClN2O2 [M + H]+ calculated for 253.0738, found 253.0743.
N-({(1S)-1-[(Benzyloxy)carbonyl]ethyl}aminocarbonyl)-L-trypto-
phan Methyl Ester (4). General Procedure Using HATU as Acti-
vator: Dry ice was placed in a 500 mL round-bottom flask con-
nected to a paraffin oil bubbler then to a drying tube containing
pellets of 4 Å molecular sieves. Using Teflon® tubing, CO2(g) de-
rived from dry ice was bubbled into a stirred, solution of l-alanine
benzyl ester p-toluenesulfonate salt (0.20 g, 0.57 mmol), 1,8-diaza-
bicyclo[5.4.0]undec-7-ene (DBU) (0.43 mL, 2.85 mmol) and pyr-
idine (0.14 mL, 1.71 mmol) in anhydrous DCM (30 mL) at –20 °C,
for a period of 30 min whilst keeping the mixture at –20 °C. The
reaction was warmed up to room temperature and the solvent was
removed under reduced pressure. The residue obtained was then
dissolved in anhydrous DMF, (3 mL) and a solution of HATU
L-5-Fluorotryptophan Methyl Ester (22): l-5-Fluorotryptophan
methyl ester (22)(0.10 g, 0.42 mmol, 94%), white powder, was pre-
pared following the same procedure as described for compound
(19). 1H NMR (400 MHz, CD3OD): δ = 7.34–7.41 (dd, J = 8.7,
4.1 Hz, 1 H), 7.29 (s, 1 H), 7.19–7.25 (m, 1 H), 6.93 (t, J = 9.1 Hz,
1 H), 4.34 (t, J = 5.8 Hz, 1 H), 3.82 (s, 3 H), 3.31–3.48 (m, 2
H) ppm. 13C NMR (101 MHz, CD3OD): δ = 169.3, 157.7 (d, J =
233.0 Hz), 133.4, 126.2, 124.8, 112.1 (d, J = 9.6 Hz), 109.6 (d, J =
26.5 Hz), 106.3, 102.2 (d, J = 23.9 Hz), 53.1, 52.3, 26.0 ppm. 19F
NMR (377 MHz, CD3OD, decoupled 1H): δ = –126.98 ppm.
HRMS (ESI, +ve) C12H13FN2O2 [M + H]+ calculated for 237.1034,
found 237.1037.
5608
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 5603–5609

A One-Pot Synthesis of Dipeptide Ureas
-Methionine Benzyl Ester p-Toluenesulfonate (23):[33] To a stirred
[8] E. Mounetou, J. Legault, J. Lacroix, R. C-Gaudreault, J. Med.
Chem. 2003, 46, 5055–5063.
L
solution of l-methionine (0.20 g, 1.34 mmol) and p-toluenesulfonic
acid (0.27 g, 1.60 mmol) in toluene (50 mL), a solution of benzyl
alcohol (0.27 mL, 2.68 mmol) in toluene (10 mL) was added at
room temperature over a period of 10 min. Following addition the
mixture was set to reflux for 20 h while fitted with a Dean–Stark
apparatus to remove water. The reaction mixture was cooled to
room temperature, and then stored in the freezer for 3 h. The pre-
cipitate was filtered and washed with toluene to yield l-methionine
benzyl ester p-toluenesulfonate salt (23) (0.35 g, 0.85 mmol, 75%)
as a white solid. No further purification was required. 1H NMR
(500 MHz, CDCl3): δ = 8.37 (s, 2 H), 7.76 (d, J = 7.9 Hz, 2 H),
7.18–7.35 (m, 5 H), 7.08 (d, J = 7.9 Hz, 2 H), 5.13 (d, J = 12.2 Hz,
1 H), 5.00 (d, J = 12.2 Hz, 1 H), 4.18 (q, J = 5.9 Hz, 1 H), 2.50
(dt, J = 14.6, 7.5 Hz, 1 H), 2.41 (dt, J = 13.9, 7.4 Hz, 1 H), 2.31
(s, 3 H), 2.12 (apparent hep, J = 6.6 Hz, 2 H), 1.84 (s, 3 H) ppm.
13C NMR (126 MHz, CDCl3): δ = 168.9, 141.2, 140.4, 134.7, 128.9,
128.5, 128.4, 128.3, 126.0, 67.9, 52.1, 29.4, 28.9, 21.3, 14.8 ppm.
HRMS (ESI, +ve) C12H17NO2S[M + H]+ calculated for 240.1053,
found 240.1050.
[9] C. G. Boojamra, R. C. Lemoine, J. C. Lee, R. Léger, K. A.
Stein, N. G. Vernier, A. Magon, O. Lomovskaya, P. K. Martin,
S. Chamberland, M. D. Lee, S. J. Hecker, V. J. Lee, J. Am.
Chem. Soc. 2001, 123, 870–874.
[10] E. W. Schmidt, M. K. Harper, D. J. Faulkner, J. Nat. Prod.
1997, 46, 779–782.
[11] T. Sano, K. Kaya, E. C. Division, Tetrahedron Lett. 1995, 36,
5933–5936.
[12] R. H. Chen, A. M. Buko, D. N. Whittern, J. B. Mcalpine, A.
Park, J. Antibiot. 1989, 512–520.
[13] J. J. S. Nowick, N. N. A. Powell, T. M. Nguyen, G. Noronha, J.
Org. Chem. 1992, 57, 7364–7366.
[14] P. Majer, R. S. R. Randad, J. Org. Chem. 1994, 59, 1937–1938.
[15] R. A. Aitken, D. P. Armstrong, R. H. B. Galt, S. T. E. Mesher,
J. Chem. Soc. Perkin Trans. 1 1997, 2139–2146.
[16] I.-H. Kim, C. Morisseau, T. Watanabe, B. D. Hammock, J.
Med. Chem. 2004, 47, 2110–2122.
[17] A. K. Singh, R. Chawla, L. D. S. Yadav, Tetrahedron Lett.
2013, 54, 5099–5102.
[18] A. P. Kozikowski, F. Nan, P. Conti, J. Zhang, E. Ramadan,
T. Bzdega, B. Wroblewska, J. H. Neale, S. Pshenichkin, J. T.
Wroblewski, J. Med. Chem. 2001, 44, 298–301.
L
-Leucine Benzyl Ester p-Toluenesulfonate (24):[33] l-Leucine benzyl
[19] a) N. A. Dales, R. S. Bohacek, K. A. Satyshur, D. H. Rich,
Org. Lett. 2001, 3, 2313–2316; b) B. S. Patil, G. R. Vasanthaku-
mar, V. V. Sureshbabu, J. Org. Chem. 2003, 68, 7274–7279; c)
V. V. Sureshbabu, B. S. Patil, R. V. Ramanarao, J. Org. Chem.
2006, 71, 7697–7705; d) V. Semetey, C. Hemmerlin, C. Didier-
jean, A.-P. Schaffner, A. G. Giner, A. Aubry, J.-P. Briand, M.
Marraud, G. Guichard, Org. Lett. 2001, 3, 3843–3846; e) A. C.
Myers, J. A. Kowalski, M. A. Lipton, Bioorg. Med. Chem. Lett.
2004, 14, 5219–5222.
[20] A. P. Kozikowski, J. Zhang, F. Nan, P. A. Petukhov, E.
Grajkowska, J. T. Wroblewski, T. Yamamoto, T. Bzdega, B.
Wroblewska, J. H. Neale, J. Med. Chem. 2004, 47, 1729–1738.
[21] M. Bodanszky, D. T. Fagan, R. Walter, C. W. Smith, J. Med.
Chem. 1978, 21, 306–308.
ester p-toluenesulfonate (24) (0.30 g, 0.76 mmol, 70%), white pow-
derwas prepared following the same procedure as described for
compound (23). 1H NMR (500 MHz, CDCl3): δ = 8.37 (br. s, 2
H), 7.77 (d, J = 7.9 Hz, 2 H), 7.25–7.32 (m, 5 H), 7.08 (d, J =
7.9 Hz, 2 H), 5.12 (d, J = 12.3 Hz, 1 H), 5.04 (d, J = 12.3 Hz, 1
H), 3.97 (t, J = 6.9 Hz, 1 H), 2.32 (s, 3 H), 1.61–1.74 (m, 3 H), 0.75
(dd, J = 7.7, 5.8 Hz, 6 H) ppm. 13C NMR (126 MHz, CDCl3): δ =
169.7, 141.4, 140.2, 134.8, 128.8, 128.4, 128.3, 128.2, 126.1, 67.7,
51.7, 39.2, 24.1, 22.0, 21.9, 21.3 ppm. HRMS (ESI, +ve)
C13H19NO2 [M + H]+ calculated for 222.1485, found 222.1483.
Acknowledgments
The authors gratefully acknowledge financial support from the
Biotechnology and Biological Science Research Council (BBSRC)
(grant number BB/102910/1) and the European Commission (Sev-
[22] M. J. Slater, E. M. Amphlett, D. M. Andrews, P. Bamborough,
S. J. Carey, M. R. Johnson, P. S. Jones, G. Mills, N. R. Parry,
D. O’N. Somers, A. J. Stewart, T. Skarzynski, Org. Lett. 2003,
5, 4627–4630.
enth Framework Programme, Collaborative project “BlueGenics”, [23] D. S. Bhalerao, A. K. R. Arkala, Y. V. Madhavi, M. Nagaraju,
S. R. Gade, U. K. S. Kumar, R. Bandichhor, V. H. Dahanukar,
Org. Process Res. Dev. 2014; DOI: 10.1021/op500065t.
[24] J. Fournier, C. Bruneau, P. H. Dixneuf, S. Lecolier, J. Org.
Chem. 1991, 56, 4456–4458.
grant number 311848). The EPSRC National Mass Spectrometry
Service Centre (Swansea, UK) is thanked for the recording of
HRMS.
[25] B. Zhu, R. J. Angelici, J. Am. Chem. Soc. 2006, 128, 14460–
14461.
[1]
[2]
S. Ozaki, Chem. Rev. 1972, 72, 457–496.
M. R. J. Vos, G. E. Jardl, A. L. Pallas, M. Breurken, O. L.
[26] R. J. Angelici, J. Organomet. Chem. 2008, 693, 847–856.
[27] K. Orito, M. Miyazawa, T. Nakamura, A. Horibata, H. Ush-
ito, H. Nagasaki, M. Yuguchi, S. Yamashita, T. Yamazaki, M.
Tokuda, J. Org. Chem. 2006, 71, 5951–5958.
[28] a) T. E. Waldman, W. D. McGhee, J. Chem. Soc., Chem. Com-
mun. 1994, 957–958; b) W. D. McGhee, Y. Pan, J. J. Talley, Tet-
rahedron Lett. 1994, 35, 839–842.
[29] A. J. Clark, J. Echenique, D. M. Haddleton, T. A. Straw, P. C.
Taylor, J. Org. Chem. 2001, 66, 8687–8688.
[30] O. M. Bratt, P. C. Taylor, J. Org. Chem. 2003, 68, 5439–5444.
[31] D. R. M. Smith, T. Willemse, D. S. Gkotsi, W. Schepens,
B. U. W. Maes, S. Ballet, R. J. M. Goss, Org. Lett. 2014, 16,
2622–2625.
´
Van Asselen, P. H. H. Bomans, P. E. L. G. Leclère, P. M. Fred-
erik, R. J. M. Nolte, N. A. J. M. Sommerdijk, J. Am. Chem.
Soc. 2005, 127, 16768–16769.
N. Chebotareva, P. H. H. Bomans, P. M. Frederik, N. A. J. M.
Sommerdijk, R. P. Sijbesma, Chem. Commun. 2005, 4967–
4969.
[3]
[4] J. L. Kane, B. H. Hirth, B. Liang, B. B. Gourlie, S. Nahill, G.
Barsomian, Bioorg. Med. Chem. Lett. 2003, 13, 4463–4466.
[5] P. Baraldi, Bioorg. Med. Chem. 2003, 11, 4161–4169.
[6] N. Tewari, V. K. Tiwari, R. C. Mishra, R. P. Tripathi, A. K.
Srivastava, R. Ahmad, R. Srivastava, B. S. Srivastava, Bioorg.
Med. Chem. 2003, 11, 2911–2922.
[7] A. D. Borthwick, D. E. Davies, P. F. Ertl, A. M. Exall, T. M.
Haley, G. J. Hart, D. L. Jackson, N. R. Parry, A. Patikis, N.
Trivedi, G. G. Weingarten, J. M. Woolven, J. Med. Chem. 2003,
46, 4428–4449.
[32] R. J. M. Goss, P. L. A. Newill, Chem. Commun. 2006, 4924–4925.
[33] K. Harju, N. Manevski, J. Yli-Kauhaluoma, Tetrahedron 2009,
65, 9702–9706.
Received: May 8, 2015
Published Online: July 30, 2015
Eur. J. Org. Chem. 2015, 5603–5609
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5609