Efficient syntheses of naphthoquinone-dipeptides

Article abstract of DOI:10.1055/s-0029-1220012

Naphthoquinone-dipeptides are synthesized in 76-89% yield from naphthoquinone-amino acid conjugates by N-acylbenzotriazole methodology in aqueous media at 20°C. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1220012

PAPER
2011
Efficient Syntheses of Naphthoquinone-Dipeptides
Efficient
S
ynthese
l
s
of
N
a
a
phthoquino
n
ne-Dipeptides R. Katritzky,* Longchuan Huang, Rajeev Sakhuja
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
Fax +1(352)3929199; E-mail: katritzky@chem.ufl.edu
Received 22 December 2009; revised 6 March 2010
Some human tumors are hormone-dependent and contain
the corresponding hormone receptors; some of these, in-
cluding luteinizing hormone-releasing hormone (LH-
RH),7 somatostatin,8 bombesin,9 vasoactive intestinal
peptide10 and growth factors, including epidermal11 and
insulin-like substances,12 have been detected in prostate,
breast, pancreas, ovary, lung, colon, and brain tumors.13 In
view of the abundance of tumors bearing LH-RH recep-
tors, related target chemotherapy has gained considerable
attention. Analogues of LH-RH, agonists and antagonists,
when conjugated to cytotoxic compounds such as alkylat-
ed nitrogen mustard,14 anticancer antibiotics and quinone
derivatives,15 have exhibited diverse specific binding af-
finities towards LH-RH receptors. The cytotoxicity of
peptide–drug conjugates can be markedly augumented in
vitro, far beyond that of the drug component alone.16
Abstract: Naphthoquinone-dipeptides are synthesized in 76–89%
yield from naphthoquinone–amino acid conjugates by N-acylben-
zotriazole methodology in aqueous media at 20 °C.
Key words: quinones, amino acids, peptides, coupling, conjuga-
tion
In the biochemistry of living cells, quinones play many vi-
tal roles including respiration, photosynthesis and cellular
defense against bacteria, fungi, and parasites.1 Quinone
derivatives are used as medicines for bacterial and fungal
diseases and can exhibit potent antimalarial capacity.2
Many quinones, some naturally occurring (Figure 1), are
antitumor agents and those approved for clinical use in-
clude: menadione (1), anthracycline-glycosides [doxoru-
bicin (2), daunorubicin, and aclacinomycin A],
benzoquinone derivatives [mitomycin C (3), carba-
zilquinone, and diaziquone] and more complex quinones
[mitoxantrone (4), streptonigrin, and actynomicin D].3–5
The cell cytotoxicity of quinones is due to their ability to
(a) undergo a reversible one-electron reduction to a semi-
quinone radical anion, and (b) to associate and intercalate
with DNA duplexes, thus impairing appropriate template
function and nucleic acid synthesis.6
Preliminary findings indicate that quinonyl-amino acids
incorporated into a biological active peptide showed cyto-
toxic and anticancer activity,8 and this aroused our interest
in the synthesis of quinone-amino acid dipeptides. Several
such peptides with quinone moieties attached through the
e-amino side chain of a D-lysine residue possess cytotoxic
activity against human breast and prostate cancer cell
lines.15,17
Bittner and coworkers reported the linking of several free
and blocked amino acids to a quinone moiety, and studied
free radical generation via chemical and enzymatic meth-
ods.2a,6,7,17,18 Tandon and Maurya have recently reported
the unprecedented nucleophilic substitution of 1,4-quino-
nes with amino acids in aqueous suspension.19 N-(1,4-
Naphthoquinonyl)glycyl-glycine (8a) and N-(2-chloro-
O
O
OH
O
OH
OH
O
H
O
MeO
O
OH
menadione (1)
doxorubicin (2)
OH
1,4-naphthoquinonyl)glycyl-glycine
(8b)
were
synthesized17 by reaction of glycyl-glycine with 1,4-naph-
thoquinone (5a) and 2,3-dichloro-1,4-naphthoquinone
(5b), respectively, in aqueous ethanol during 24–48 hours
at room temperature. The initially formed hydroquinone
conjugates (7a and 7b) were spontaneously oxidized by
excess of 1,4-naphthoquinone to the naphthoquinone–
dipeptide conjugates (8a and 8b; 63% and 48%, respec-
tively; Scheme 1).
NH2
O
H
N
N
NH
OH
OH
O
O
HN
HN
OH
O
H2N
O
O
O
OH
N
H
H2N
mitomycin C (3)
mitoxantrone (4)
We felt that, in view of the potential clinical significance
of quinone-bearing peptides in targeted chemotherapy, it
was important to increase the arsenal of related natural
naphthoquinonyl–amino acids, to synthesize them in good
yields and to study their spectral properties. Herein, we re-
port an efficient N-acylbenzotriazole-mediated prepara-
tion of naphthoquinone–dipeptides in yields of 76–89%
starting from naphthoquinone-a-amino acid conjugates in
aqueous media at 20 °C.
Figure 1 Naturally occurring antitumor quinones
SYNTHESIS 2010, No. 12, pp 2011–2016
Advanced online publication: 25.05.2010
DOI: 10.1055/s-0029-1220012; Art ID: M06709SS
© Georg Thieme Verlag Stuttgart · New York
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x.
x
x
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A. R. Katritzky et al.
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H
OH
OH
O
O
O
N
COOH
H2N
R1
R1
R1
6
[O]
O
H
H
N
COOH
N
COOH
R2
N
H
N
H
O
O
O
5a R1 = R2 = H
5b R1 = R2 = Cl
8a R1 = H; 63%
8b R1 = Cl; 48%
7a–b
Scheme 1
Naphthoquinone–amino acid conjugates 10a–d were syn- column chromatographic purification. The benzotriazole
thesized starting from naphthoquinone (5a) and L-amino derivatives did not pass elemental analysis (1H NMR
acids 9a–d by a modified literature procedure20 in aque- showed minor amounts of DCU); hence, the compounds
ous ethanol at room temperature for 10–12 hours in the were used directly for dipeptide formation. The use of N-
presence of triethylamine. The reaction mixtures were ethyl-N¢-(3-dimethylaminopropyl)carbodiimide (EDC) as
purified by column chromatography to first yield naph- a coupling reagent produced equally good results, but the
thoquinone–amino acid triethyl ammonium salts, which, high sensitivity toward moisture of the EDC hydrochlo-
after washing with aqueous hydrochloric acid solution, ride salt led to a limited shelf-life, and therefore DCC was
yielded the expected naphthoquinone–amino acid conju- preferred.
gates 10a–d in 58–79% yields (Scheme 2, Table 1).
The coupling of N-acylbenzotriazole derivatives (12a–d)
with various natural amino acids (9a–f) in aqueous aceto-
O
O
O
nitrile–triethylamine at 20 °C for four hours, yielded
naphthoquinone dipeptides 13a–j in good to excellent
yields (Scheme 4, Table 3).
H
O
N
(i)
OH
H2N
+
OH
R
(ii)
R
O
O
O
O
O
O
10a: R = Bn
10b: R = i-Bu
10c: R = Me
10d: R = H2C
5a
9a–d
H
H
N
N
(i)
OH
N
N
N
BtH
R
R
11
O
O
N
10a–d
12a: R = Bn
H
12b: R = i-Bu
12c: R = Me
Scheme 2 Reagents and conditions: (i) Et3N, EtOH–H2O, r.t., 12 h;
(ii) HCl (10% solution).
BtH = benzotriazole
12d: R =
H2C
N
Table 1 Naphthoquinone–Amino Acid Conjugates 10a–d
H
Entry Amino acid 9
Conjugate 10 Yield (%) Mp (°C)
Scheme 3 Reagents and conditions: (i) DCC, CH2Cl2, r.t., 4 h.
1
L-phenylalanine
(9a)
10a
72
200–203
Table 2 Naphthoquinone Amino Acyl Benzotriazoles 12a–d
Entry Conjugate 10 Benzotriazole 12 Yield (%) Mp (°C)
2
3
4
L-leucine (9b)
L-alanine (9c)
10b
10c
79
64
58
115–117
137–139a
208–211b
1
2
3
4
10a
10b
10c
10d
12a
12b
12c
12d
86
84
87
83
115–117
a
–
L-tryptophan (9d) 10d
a
a Lit.6 139.0–142.0 °C.
b Lit.20 210.0–213.0 °C.
–
114–115
a Not isolated in pure form; used crude for the next coupling reaction.
Naphthoquinone–amino acid conjugates 10a–d were acti-
vated by conversion into naphthoquinone aminoacyl ben-
zotriazole derivatives 12a–d in 83–87% yield. The
conversion of 10 into 12 was initially attempted with (i)
BtH, SOCl2, THF at room temperature for 2–5 hours and
(ii) BtSO2Me, THF, Et3N, reflux, 8–12 hours, but com-
plex mixtures were obtained in each case. Finally, the N-
acyl benzotriazole derivatives were obtained in dichlo-
romethane at room temperature in four hours using N,N-
dicyclohexylcarbodiimide (DCC) as the coupling agent
(Scheme 3, Table 2). The products were isolated without
All the reactions were carried at 20 °C and the products
were isolated by washing the reaction mixtures with 4 M
HCl to remove benzotriazole followed by precipitation of
the organic layer with hexane.
In summary, we report a general method for the syntheses
of naphthoquinone-dipeptides via benzotriazole method-
ology and have applied it to several combinations of ami-
no acids. The previous reported method is restricted to the
Synthesis 2010, No. 12, 2011–2016 © Thieme Stuttgart · New York

PAPER
Efficient Syntheses of Naphthoquinone-Dipeptides
2013
R2
O
O
O
O
O
H
H
N
N
(i)
R2
COOH
N
N
H
R1
R1
13a–j
N
N
O
H2N
COOH
9a: R2 = Bn
12a: R1 = Bn
12b: R1 = i-Bu
12c: R1 = Me
9b: R2 = i-Bu
9c: R2 = Me
H C
9d: R2
=
12d: R1
H C
=
2
2
N
N
H
H
9e: R2 = i-Pr
9f: R2 = CH2CH2COOMe
Scheme 4 Reagents and conditions: (i) Et3N, MeCN–H2O, r.t., 4 h (for designation of 13a–j, see Table 3).
Naphthoquinone–Amino Acid Conjugates 10a–d; General Pro-
cedure
synthesis of naphthoquinone-glycyl-glycine dipeptides in
moderate yield. Our method allows the use of free amino
acids as coupling components, does not require anhydrous
conditions and, thus, is cost-effective. The advantages of
using Bt-activation include: (a) excellent yields, (b) sim-
ple preparative and purification procedures, (c) short reac-
tion times, (d) applicability to a variety of amino acids, (e)
low cost, and (f) use of aqueous conditions.
To a solution of 2-naphthalene-1,4-dione (5a; 20 mmol) dissolved
in EtOH (200 mL), L-amino acid (9a–d; 10 mmol), Et3N (20 mmol)
and H2O (10 mL) were added, and the mixture was stirred at r.t. for
12 h. The resulting solution was dried under reduced pressure and
the residue was subjected to column chromatography. Elution with
EtOAc–hexane (2:8), removed the nonpolar impurities, and elution
with 100% EtOAc, yielded naphthoquinone–amino acid triethylam-
monium salts, which were subsequently dissolved in CH2Cl2 (50
mL), and washed with 4 M HCl (3 × 30 mL) and then brine (2 × 30
mL). The organic layers were dried over anhydrous MgSO4. The
solvent was evaporated and the residue was dried overnight under
vacuum to yield the corresponding naphthoquinone–amino acid
conjugates 10a–d.
Table 3 Synthesis of Naphthoquinone-dipeptides
12
Amino acid 9
NQ–dipep- Yield Mp
tide 13
(%)
(°C)
12a
12a
12b
12b
12b
12b
12c
12d
12d
12d
L-valine
(9e)
13a
81
175–
177
(S)-2-(1,4-Dioxo-1,4-dihydronaphthalen-2-ylamino)-3-phenyl-
propanoic Acid (10a)
Yield: 2.31 g (72%); black solid; mp 200.0–203.0 °C.
L-tryptophan
(9d)
13b
13c
13d
13e
13f
13g
13h
13i
81
78
81
89
81
82
79
76
81
215–
217
1H NMR (300 MHz, DMSO-d6): d = 3.22 (t, J = 7.5 Hz, 2 H), 4.48–
4.54 (m, 1 H), 5.74 (s, 1 H), 7.01–7.26 (m, 6 H), 7.74 (t, J = 7.5 Hz,
1 H), 7.84 (t, J = 7.5 Hz, 1 H), 7.91 (d, J = 7.5 Hz, 1 H), 7.96 (d,
J = 7.5 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 35.9, 55.7, 101.2, 125.6, 126.2,
126.8, 128.4, 129.4, 130.3, 132.6, 132.9, 135.2, 137.0, 147.6, 172.0,
181.4, 182.0.
L-phenylalanine
(9a)
161–
164
L-tryptophan
(9d)
223–
225
L-alanine
(9c)
173–
174
(S)-2-(1,4-Dioxo-1,4-dihydronaphthalen-2-ylamino)-4-methyl-
pentanoic Acid (10b)
Yield: 2.27 g (79%); black solid; mp 115.0–117.0 °C.
1H NMR (300 MHz, DMSO-d6): d = 0.87 (d, J = 6.0 Hz, 3 H), 0.92
(d, J = 6.3 Hz, 3 H), 1.65–1.71 (m, 2 H), 1.88–1.96 (m, J = 8.4 Hz,
1 H), 4.07–4.11 (m, 1 H), 5.68 (s, 1 H), 7.31 (d, J = 8.1 Hz, 1 H),
7.74 (td, J = 1.5, 7.5 Hz, 1 H), 7.83 (td, J = 1.5, 7.5 Hz, 1 H), 7.94
(dd, J = 1.2, 7.5 Hz, 1 H), 8.00 (dd, J = 1.2, 7.5 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 21.6, 22.7, 24.6, 53.4, 100.7,
125.4, 126.0, 130.3, 132.5, 132.8, 134.9, 148.1, 172.9, 181.3, 181.7.
HRMS: m/z [M + H]+ calcd for C16H18NO4: 288.1320; found:
288.1233.
L-glutamic acid methyl ester
(9f)
153–
155
L-tryptophan
(9d)
243–
245
L-leucine
(9b)
114–
120
L-glutamic acid methyl ester
(9f)
104–
111
L-phenylalanine
(9a)
13j
121–
123
(S)-2-(1,4-Dioxo-1,4-dihydronaphthalen-2-ylamino)propanoic
Acid (10c)
Yield: 1.57 g (64%); red solid; mp 137.0–139.0 °C (Lit.6 139.0–
142.0 °C).
Melting points were determined with a capillary point apparatus
equipped with a digital thermometer and are uncorrected. NMR
spectra were recorded in CDCl3, acetone-d6 or DMSO-d6 with TMS
as internal reference for 1H (300 MHz) and 13C (75 MHz) nuclei.
Synthesis 2010, No. 12, 2011–2016 © Thieme Stuttgart · New York

2014
A. R. Katritzky et al.
PAPER
1H NMR (300 MHz, DMSO-d6): d = 1.31 (d, J = 2.7 Hz, 3 H), 3.60–
3.80 (m, 1 H), 5.58 (s, 1 H), 7.43 (d, J = 6.0 Hz, 1 H), 7.71 (t,
J = 7.5 Hz, 1 H), 7.82 (t, J = 7.2 Hz, 1 H), 7.92–7.99 (m, 2 H).
to the resulting solution. The precipitated solid was filtered and
dried under vacuum to yield naphthoquinone–dipeptides 13a–j.
(S)-2-[(S)-2-(1,4-Dioxo-1,4-dihydronaphthalen-2-ylamino)-3-
phenylpropanamido]-3-methylbutanoic Acid (13a)
Yield: 0.34 g (81%); red solid; mp 175.0–177.0 °C.
13C NMR (75 MHz, DMSO-d6): d = 17.1, 51.5, 99.1, 125.3, 125.8,
130.2, 132.0, 133.3, 134.8, 146.5, 173.6, 181.0, 181.6.
(S)-2-(1,4-Dioxo-1,4-dihydronaphthalen-2-ylamino)-3-(1H-in-
dol-3-yl)propanoic Acid (10d)
1H NMR (300 MHz, acetone-d6): d = 0.97 (t, J = 5.4 Hz, 6 H), 2.16–
2.27 (m, 1 H), 3.23 (dd, J = 7.8, 13.8 Hz, 1 H), 3.36 (dd, J = 5.1,
13.8 Hz, 1 H), 4.47–4.60 (m, 2 H), 5.72 (s, 1 H), 6.68 (d, J = 7.2 Hz,
1 H), 7.16–7.34 (m, 5 H), 7.65–7.81 (m, 2 H), 7.83 (t, J = 13.9 Hz,
1 H), 8.02 (t, J = 7.5 Hz, 2 H).
13C NMR (75 MHz, acetone-d6): d = 18.2, 19.5, 31.6, 38.6, 57.77,
57.84, 58.1, 102.6, 126.5, 126.6, 126.8, 127.7, 129.3, 129.5, 130.3,
131.5, 133.1, 134.2, 135.5, 137.7, 147.9, 170.9, 172.8, 182.2, 182.7.
Yield: 2.09 g (58%); black solid; mp 208.0–211.0 °C (Lit.19 210.0–
213.0 °C).
1H NMR (300 MHz, DMSO-d6): d = 3.36–3.38 (m, 2 H), 4.45–4.52
(m, 1 H), 5.74 (s, 1 H), 6.91–6.97 (m, 2 H), 7.05 (t, J = 7.8 Hz, 1 H),
7.18 (d, J = 2.4 Hz, 1 H), 7.32 (dd, J = 0.6, 8.1 Hz, 1 H), 7.52 (d,
J = 8.1 Hz, 1 H), 7.74 (t, J = 7.5 Hz, 1 H), 7.83 (t, J = 7.5 Hz, 1 H),
7.92–8.00 (m, 2 H), 10.90 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 26.1, 55.2, 100.9, 108.8, 111.4,
118.1, 118.4, 120.9, 124.0, 125.3, 125.9, 127.2, 130.0, 132.3, 132.7,
134.9, 136.0, 147.2, 172.1, 181.1, 181.7.
HRMS: m/z [M + H]+ calcd for C24H25N2O5: 421.1758; found:
421.1778.
(S)-2-[(S)-2-(1,4-Dioxo-1,4-dihydronaphthalen-2-ylamino)-3-
phenylpropanamido]-3-(1H-indol-3-yl)propanoic Acid (13b)
Yield: 0.41 g (81%); red solid; mp 215.0–217.0 °C.
1H NMR (300 MHz, DMSO-d6): d = 3.06–3.14 (m, 3 H), 3.23 (dd,
J = 5.1, 5.4 Hz, 1 H), 4.31–4.38 (m, 1 H), 4.52–4.59 (m, 1 H), 5.57
(s, 1 H), 6.93 (t, J = 7.2 Hz, 1 H), 7.00–7.04 (m, 1 H), 7.14–7.24 (m,
5 H), 7.32 (d, J = 7.8 Hz, 2 H), 7.53 (d, J = 7.8 Hz, 2 H), 7.73 (t,
J = 7.5 Hz, 1 H), 7.82 (t, J = 7.5 Hz, 1 H), 7.91 (d, J = 7.2 Hz, 1 H),
7.97 (d, J = 7.5 Hz, 1 H), 8.65 (d, J = 8.1 Hz, 1 H), 10.87 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 27.1, 37.1, 53.0, 56.6, 100.9,
109.5, 111.3, 116.4, 118.1, 118.3, 120.8, 123.6, 124.5, 125.3, 125.7,
125.9, 126.0, 126.4, 127.1, 128.1, 128.5, 129.1, 130.0, 132.3, 132.6,
134.8, 136.0, 136.9, 147.2, 169.6, 172.8, 180.9, 181.6.
Naphthoquinone–Amino AcylBenzotriazoleDerivatives12a–d;
General Procedure
To a solution of naphthoquinone–amino acid conjugate (10a–d; 5
mmol) in anhydrous CH2Cl2 (30 mL), benzotriazole (11; 5 mmol,
595 mg) and DCC (5 mmol, 1.03 g) were added. The reaction mix-
tures were stirred at r.t. for 4 h and then filtered through Celite at
least twice. The organic layers were concentrated in vacuo and the
residues were recrystallized from EtOAc–hexane to yield naphtho-
quinone-aminoacyl benzotriazole derivatives 12a–d.
(S)-2-{1-(1H-Benzo[d][1,2,3]triazol-1-yl)-1-oxo-3-phenylpro-
pan-2-ylamino}naphthalene-1,4-dione (12a)
Yield: 1.82 g (86%); black solid; mp 115.0–117.0 °C.
HRMS: m/z [M + H]+ calcd for C30H26N3O5: 508.1867; found:
1H NMR (300 MHz, CDCl3): d = 3.37 (dd, J = 7.5, 13.8 Hz, 1 H),
3.60 (dd, J = 4.8, 13.8 Hz, 1 H), 5.76 (s, 1 H), 5.56–5.82 (m, 1 H),
6.55 (d, J = 7.8 Hz, 1 H), 7.17–7.33 (m, 5 H), 7.54–7.72 (m, 4 H),
8.04 (t, J = 6.0 Hz, 2 H), 8.20 (t, J = 7.5 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 38.9, 56.6, 103.0, 114.4, 120.8,
126.4, 126.6, 127.1, 127.9, 129.1, 129.3, 130.5, 131.0, 131.3, 132.5,
133.2, 134.8, 134.9, 146.3, 146.6, 169.6, 181.3, 183.3.
508.1886.
(S)-2-[(S)-2-(1,4-Dioxo-1,4-dihydronaphthalen-2-ylamino)-4-
methylpentanamido]-3-phenylpropanoic Acid (13c)
Yield: 0.34 g (78%); red solid; mp 161.0–164.0 °C.
1H NMR (300 MHz, DMSO-d6): d = 3.83 (d, J = 3.0 Hz, 3 H), 0.90
(d, J = 3.0 Hz, 3 H), 1.47–1.62 (m, 2 H), 1.70–1.78 (m, 1 H), 2.89
(dd, J = 6.3, 13.8 Hz, 1 H), 3.08 (dd, J = 4.5, 13.8 Hz, 1 H), 3.98–
4.05 (m, 1 H), 4.44–4.50 (m, 1 H), 5.74 (s, 1 H), 6.99 (d, J = 8.4 Hz,
1 H), 7.06–7.11 (m, 1 H), 7.15–7.20 (m, 4 H), 7.75 (t, J = 7.5 Hz,
1 H), 7.85 (t, J = 7.5 Hz, 1 H), 7.95–8.02 (m, 2 H), 8.51 (d, J = 8.1
Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 21.7, 22.4, 24.1, 36.4, 53.1,
54.1, 100.7, 125.1, 125.7, 126.0, 127.8, 128.9, 130.0, 132.2, 132.5,
134.7, 137.0, 147.2, 170.4, 172.2, 180.9, 181.5.
HRMS: m/z [M + H]+ calcd for C25H27N2O5: 435.1914; found:
435.1934.
(S)-2-{1-(1H-Benzo[d][1,2,3]triazol-1-yl)-3-(1H-indol-3-yl)-1-
oxopropan-2-ylamino}naphthalene-1,4-dione (12d)
Yield: 1.92 g (83%); yellow solid; mp 114.0–115.0 °C.
1H NMR (300 MHz, CDCl3): d = 3.60 (dd, J = 7.6, 15.0 Hz, 1 H),
3.80 (dd, J = 4.8, 14.7 Hz, 1 H), 5.72 (s, 1 H), 5.92 (q, J = 4.8 Hz,
1 H), 6.61 (d, J = 8.1 Hz, 1 H), 7.00 (t, J = 7.5 Hz, 1 H), 7.10–7.17
(m, 2 H), 7.29 (d, J = 8.4 Hz, 1 H), 7.45 (d, J = 7.8 Hz, 1 H), 7.54–
7.72 (m, 5 H), 8.02 (d, J = 7.8 Hz, 1 H), 8.18 (t, J = 6.9 Hz, 2 H),
8.26 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 29.3, 56.1, 103.0, 111.7, 114.6,
118.5, 120.3, 120.8, 122.9, 123.7, 126.5, 126.7, 127.1, 131.4, 132.6,
135.0, 147.0, 170.1.
HRMS: m/z [M + H]+ calcd for C27H20N5O3: 462.1561; found:
462.1556.
(S)-2-[(S)-2-(1,4-Dioxo-1,4-dihydronaphthalen-2-ylamino)-4-
methylpentanamido]-3-(1H-indol-3-yl)propanoic Acid (13d)
Yield: 0.38 g (81%); red solid; mp 223–225.0 °C.
1H NMR (300 MHz, DMSO-d6): d = 0.82 (d, J = 6.3 Hz, 3 H), 0.89
(d, J = 6.0 Hz, 3 H), 1.52–1.61 (m, 2 H), 1.64–1.75 (m, 1 H), 3.06
(dd, J = 5.4, 14.4 Hz, 1 H), 3.19 (dd, J = 5.4, 14.4 Hz, 1 H), 4.01–
4.08 (m, 1 H), 4.51–4.54 (m, 1 H), 5.73 (s, 1 H), 6.90–7.03 (m,
3 H), 7.14 (d, J = 2.1 Hz, 1 H), 7.29 (d, J = 7.5 Hz, 1 H), 7.51 (td,
J = 1.5, 7.5 Hz, 1 H), 7.74 (td, J = 1.5, 7.5 Hz, 1 H), 7.84 (td,
J = 1.2, 7.5 Hz, 1 H), 7.95 (dd, J = 1.2, 8.1 Hz, 1 H), 8.00 (dd,
J = 1.2, 7.8 Hz, 1 H), 8.47 (d, J = 8.1 Hz, 1 H), 10.81 (s, 1 H).
Naphthoquinone–Dipeptides 13a–j; General Procedure
A solution of L-amino acid (1 mmol; 9a–f) and Et3N (1.2 mmol) in
H2O (4 mL) was added to a solution of N-acyl benzotriazole deriv-
ative (1 mmol; 12a–d) in MeCN (50 mL). The reaction was stirred
at r.t. for 3–4 h and then quenched with 4 M HCl (2 mL). The reac-
tion mixture was concentrated, diluted with EtOAc (100 mL), and
washed with 4 M HCl (3 × 30 mL), and brine (2 × 30 mL). The or-
ganic layer was concentrated and cold hexane (30 mL) was added
13C NMR (75 MHz, DMSO-d6): d = 22.0, 22.7, 24.3, 53.0, 54.4,
100.8, 109.6, 111.4, 118.1, 118.3, 120.8, 123.6, 125.4, 126.0, 127.2,
130.3, 132.4, 132.8, 134.9, 136.1, 147.6, 170.7, 172.9, 181.2, 181.8.
Synthesis 2010, No. 12, 2011–2016 © Thieme Stuttgart · New York

PAPER
Efficient Syntheses of Naphthoquinone-Dipeptides
2015
Anal. Calcd for C27H27N3O5: C, 68.48; H, 5.75; N, 8.87. Found: C,
68.58; H, 5.51; N, 8.45.
Anal. Calcd for C27H27N3O5: C, 68.48; H, 5.75; N, 8.87. Found: C,
68.20; H, 5.90; N, 8.47.
(S)-2-[(S)-2-(1,4-Dioxo-1,4-dihydronaphthalen-2-ylamino)-4-
methylpentanamido]propanoic Acid (13e)
Yield: 0.32 g (89%); orange solid; mp 173.0–174.0 °C.
(S)-2-[(S)-2-(1,4-Dioxo-1,4-dihydronaphthalen-2-ylamino)-3-
(1H-indol-3-yl)propanamido]-5-methoxy-5-oxopentanoic Acid
(13i)
Yield: 0.38 g (76%); yellow solid; mp 104.0–111.0 °C.
1H NMR (300 MHz, DMSO-d6): d = 0.85 (d, J = 6.3 Hz, 3 H), 0.92
(d, J = 6.3 Hz, 3 H), 1.23 (d, J = 7.2 Hz, 3 H), 1.55–1.69 (m, 2 H),
1.69–1.80 (m, 1 H), 4.05–4.12 (m, 2 H), 5.73 (s, 1 H), 7.12 (d,
J = 8.4 Hz, 1 H), 7.73 (t, J = 7.5 Hz, 1 H), 7.83 (t, J = 7.5 Hz, 1 H),
7.93 (d, J = 7.5 Hz, 1 H), 7.99 (d, J = 7.5 Hz, 1 H), 8.19 (d, J = 6.9
Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 18.3, 21.9, 22.8, 24.4, 48.8,
54.5, 100.7, 125.4, 126.0, 130.3, 132.4, 132.8, 134.9, 147.8, 169.9,
181.2, 181.8.
1H NMR (300 MHz, DMSO-d6): d = 1.85–1.92 (m, 1 H), 1.98–2.15
(m, 1 H), 2.37 (t, J = 7.2 Hz, 2 H), 3.29–3.38 (m, 2 H), 3.56 (s, 3 H),
4.26–4.40 (m, 2 H), 5.61 (s, 1 H), 6.96 (t, J = 7.2 Hz, 2 H), 7.02 (t,
J = 7.2 Hz, 1 H), 7.25 (s, 1 H), 7.31 (d, J = 8.1 Hz, 1 H), 7.62 (d,
J = 7.8 Hz, 1 H), 7.72 (t, J = 7.2 Hz, 1 H), 7.81 (t, J = 7.2 Hz, 1 H),
7.89 (d, J = 7.5 Hz, 1 H), 7.95 (d, J = 7.5 Hz, 1 H), 8.59 (d, J = 7.8
Hz, 1 H), 10.88 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 26.2, 27.3, 29.6, 51.1, 51.2,
56.1, 100.8, 109.0, 111.3, 118.1, 118.3, 120.9, 124.1, 125.3, 125.8,
127.2, 130.1, 132.3, 132.7, 134.8, 136.1, 147.3, 170.3, 172.5, 181.3,
181.5.
HRMS: m/z [M + H]+ calcd for C19H23N2O5: 359.1601; found:
359.1596.
(S)-2-[(S)-2-(1,4-Dioxo-1,4-dihydronaphthalen-2-ylamino)-4-
methylpentanamido]-5-methoxy-5-oxopentanoic Acid (13f)
Yield: 0.35 g (81%); red solid; mp 153.0–154.0 °C.
Anal. Calcd for C27H25N3O7: C, 64.41; H, 5.00; N, 8.35. Found: C,
64.09; H, 5.05; N, 7.98.
(S)-2-[(S)-2-(1,4-Dioxo-1,4-dihydronaphthalen-2-ylamino)-3-
(1H-indol-3-yl)propanamido]-3-phenylpropanoic Acid (13j)
Yield: 0.41 g (81%); yellow solid; mp 121.0–123.0 °C.
1H NMR (300 MHz, DMSO-d6): d = 2.94–3.00 (m, 1 H), 3.05–3.18
(m, 1 H), 3.20–3.28 (m, 2 H), 4.20–4.35 (m, 1 H), 4.51–4.55 (m,
1 H), 5.61 (s, 1 H), 6.90–7.01 (m, 2 H), 7.07 (t, J = 6.9 Hz, 1 H),
7.12–7.25 (m, 6 H), 7.33 (d, J = 7.8 Hz, 1 H), 7.64 (d, J = 7.5 Hz,
1 H), 7.71 (d, J = 6.3 Hz, 1 H), 7.80 (t, J = 7.5 Hz, 1 H), 7.90–7.94
(m, 2 H), 8.70 (d, J = 7.2 Hz, 1 H), 10.88 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 27.9, 37.3, 54.0, 56.7, 101.4,
109.7, 111.9, 118.7, 118.8, 121.5, 124.6, 125.8, 126.4, 126.9, 127.7,
128.6, 129.6, 130.6, 132.8, 133.2, 135.4, 136.6, 137.8, 147.8, 170.7,
173.0, 181.5, 182.1.
1H NMR (300 MHz, DMSO-d6): d = 0.86 (d, J = 6.3 Hz, 3 H), 0.92
(d, J = 6.0 Hz, 3 H), 1.22–1.26 (m, 1 H), 1.58–1.71 (m, 2 H), 1.76–
1.85 (m, 2 H), 2.00–2.03 (m, 1 H), 2.29–2.35 (m, 1 H), 3.51 (s,
3 H), 4.00–4.16 (m, 2 H), 5.75 (s, 1 H), 7.12 (d, J = 8.7 Hz, 1 H),
7.73 (t, J = 7.5 Hz, 1 H), 7.83 (t, J = 7.5 Hz, 1 H), 7.93 (d, J = 7.5
Hz, 1 H), 7.99 (d, J = 7.2 Hz, 1 H), 8.22 (d, J = 7.5 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 13.9, 21.9, 22.1, 22.8, 24.4,
26.9, 29.7, 31.0, 51.2, 52.0, 54.5, 100.9, 125.4, 126.0, 130.3, 132.4,
132.8, 134.9, 147.7, 170.4, 172.9, 181.3, 181.7.
HRMS: m/z [M + H]+ calcd for C22H27N2O7: 431.1813; found:
431.1816.
(S)-2-[(S)-2-(1,4-Dioxo-1,4-dihydronaphthalen-2-ylamino)pro-
panamido]-3-(1H-indol-3-yl)propanoic Acid (13g)
Yield: 0.35 g (82%); red solid; mp 243.0–245.0 °C.
Anal. Calcd for C30H25N3O5: C, 70.99; H, 4.96; N, 8.28. Found: C,
71.26; H, 5.29; N, 7.85.
1H NMR (300 MHz, DMSO-d6): d = 1.36 (d, J = 6.6 Hz, 3 H), 3.08
(dd, J = 5.1, 14.7 Hz, 1 H), 3.22 (dd, J = 5.1, 14.7 Hz, 1 H), 4.12 (t,
J = 7.2 Hz, 1 H), 4.50–4.57 (m, 1 H), 5.60 (s, 1 H), 6.93–7.08 (m,
3 H), 7.16 (d, J = 2.1 Hz, 1 H), 7.31 (d, J = 7.8 Hz, 1 H), 7.52 (d,
J = 7.8 Hz, 1 H), 7.75 (td, J = 1.2, 7.5 Hz, 1 H), 7.85 (td, J = 1.2, 7.5
Hz, 1 H), 7.95 (d, J = 6.6 Hz, 1 H), 8.00 (d, J = 6.9 Hz, 1 H), 8.50
(d, J = 8.1 Hz, 1 H), 10.85 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 17.6, 27.0, 50.8, 52.9, 100.7,
109.5, 111.3, 118.0, 118.3, 120.8, 123.5, 125.3, 125.9, 127.1, 130.2,
132.3, 132.8, 134.8, 136.0, 147.0, 171.0, 172.8, 181.1, 181.6.
Acknowledgment
We thank Dr. C. D. Hall and Dr. Dmytro Fedoseyenko for their va-
luable suggestions.
References
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(S)-2-[(S)-2-(1,4-Dioxo-1,4-dihydronaphthalen-2-ylamino)-3-
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Synthesis 2010, No. 12, 2011–2016 © Thieme Stuttgart · New York