Synthesis of novel quinone-amino acid hybrids via cross-enyne metathesis and Diels-Alder reaction as key steps

Article abstract of DOI:10.1002/ejoc.200600970

A "Building Block Approach" for the synthesis of various quinone-amino acid hybrids through ethylene cross-enyne metathesis and Diels-Alder reaction as key steps is described. A library of comformationally constrained quinone-based phenylalanine derivativ

Full text of DOI:10.1002/ejoc.200600970

FULL PAPER
DOI: 10.1002/ejoc.200600970
Synthesis of Novel Quinone–Amino Acid Hybrids via Cross-Enyne Metathesis
and Diels–Alder Reaction as Key Steps
Sambasivarao Kotha,*[a] Kalyaneswar Mandal,[a] Shaibal Banerjee,[a] and
Shaikh M. Mobin[a]
Keywords: Quinone–amino acid hybrids / Cross-enyne metathesis / Cycloaddition / Fullerenes
A “Building Block Approach” for the synthesis of various
quinone-amino acid hybrids through ethylene cross-enyne
metathesis and Diels–Alder reaction as key steps is de-
scribed. A library of comformationally constrained quinone-
based phenylalanine derivatives and dicarba analogs of cys-
tine have been generated starting from a common precursor
using Grubbs’ catalysts. This methodology has also been ex-
tended for the synthesis of fullerene-based dicarba analogs
of cystine.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
ing blocks in cytotoxic peptide analogs.[13] To this end, the
application of metathesis for the synthesis of novel qui-
none–amino acid hybrids has been envisaged.
Introduction
In recent years, synthesis of hybrid natural products has
gained momentum. Generally, it is expected that combining
features of more than one biologically active natural seg-
ments in a single molecule may result in pronounced phar-
macological activity.[1] Quinones are an important class of
natural compounds that show a wide range of applications
in medicinal chemistry,[2] photochemistry, and redox sys-
tems.[3] They are present in several enzymes and is responsi-
ble for exhibiting various intricate biological properties.[4–6]
The quinone component is also a useful tool for under-
standing the mechanism of various biological processes oc-
curring in nature and can be successfully incorporated in
hybrid molecules.[7–8] For example, enzymes containing qui-
none moiety play a critical role in oxidative deamination
of biogenic amines.[9] Similarly, pyrrolo-quinoline quinone
(PQQ, 1), a hybrid of quinone and amino acid, serves as a
redox cofactor for several bacterial dehydrogenases (Fig-
ure 1).[10] The extensive applications of quinone–amino acid
hybrids in diverse fields make it worthwhile for the organic
chemist to pursue their synthesis. However, limited reports
are available describing quinone-containing amino acids.[11]
Kotha et al. have reported a useful methodology for the
synthesis of quinone-based amino acid derivatives by intra-
molecular alkylation of Schiff base with the o-xylylene di-
bromide derivative.[12] Similarly, Bittner and co-workers
have synthesized various napthaquinoyl heterocyclic amino
acids (such as 2, Figure 1), some of which are crucial build-
Figure 1. Biologically relevant quinone-based amino acid deriva-
tives.
With the availability of well-defined and commercially
available metal carbene complexes such as 3[14a], 4[14b] and
5[14c] (Figure 2), the metathesis strategy has received a re-
newed interest and has opened up several new retrosyn-
thetic pathways in organic synthesis.[15] Although RCM has
[a] Department of Chemistry, Indian Institute of Technology,
Bombay,
Powai, Mumbai 400076, India
Fax: +91-22-2572-3480
E-mail: srk@chem.iitb.ac.in
Figure 2. Ruthenium carbene complexes used in metathesis reac-
tions.
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Novel Quinone–Amino Acid Hybrids
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gained popularity, enyne metathesis, and more specifically, tion using Grubbs’ first-generation catalyst 3 in DCM at
cross-enyne metathesis (CEM) with ethylene is less ex- room temp. to obtain the required diene building block 7,
plored.[16–18]
which on reaction with suitable dienophiles containing the
Towards the synthesis of novel quinone–amino acid hy- quinone moiety delivered the DA adducts. Subsequent aro-
brids the ‘Building Block Approach’ has been conceived for matization of the DA adduct with MnO2 gave the Phe de-
the generation of a diverse range of quinone-containing rivatives in good yield (Table 1).
phenylalanine (Phe) derivatives and conformationally con-
strained dicarba analogs of cystine.[19] To this end, CEM
and Diels–Alder (DA) reactions have been used as key
steps. Here, the benzophenoneimine glycine ethyl ester 9 has
been utilized as a glycine equivalent, which has been suit-
ably modified by appending an acetylenic moiety.[20] The
diene building blocks required here was prepared through
Grubbs’ catalyst induced CEM of alkynyl mono- and bis-
(amino acid) derivatives with ethylene. DA reaction of the
resulting dienes (e.g. 7 and 11) with various dienophiles and
the subsequent aromatization protocol delivered conforma-
tionally constrained quinones containing Phe and dicarba
analogs of cystine derivatives 6 and 12, respectively
(Scheme 1).
Scheme 2. Synthetic route to functionalized Phe derivatives based
on CEM with ethylene.
Table 1. List of various quinone–phenylalanine hybrids prepared
through DA strategy.
Scheme 1. Strategy for the synthesis of quinone–amino acid hy-
brids.
Results and Discussion
To begin with, the glycine equivalent, ethyl N-(diphenyl-
methylene)glycinate (9) was alkylated with propargyl bro-
mide under phase-transfer catalysis (PTC) condition, using
K2CO3 as a base to obtain the acetylene derivative 13
(Scheme 2).[20] Hydrolysis of the unsaturated amino acid de-
rivative 13 with 1  HCl delivered the expected hydrochlo-
ride salt, which was further neutralized with triethylamine
and subsequently tosylated with pTsCl in one pot to obtain
the requisite tosyl derivative 8. The propargylated amino
acid derivative 8 was then subjected to ethylene CEM reac- Isolated overall yield after DA and aromatization step.
[a] DA reaction was carried out by heating in toluene at 90 °C. [b]
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Similar conditions were employed to prepare the diene (Scheme 3).[21] The stereochemistry of 10b was assigned as
building block 11 suitable for the synthesis of dicarba ana- meso based on its crystal structure, hence compound 10a is
logs of cystine derivatives such as 12. Alkynylation of racemic.
benzophenone imine 9 with 1,4-dibromo-2-butyne (22) was
accomplished with potassium carbonate in refluxing aceto-
nitrile in the presence of tetrabutylammonium hydrogen sul-
fate (TBAHS) as a PTC (Scheme 3). Attempts to purify the
bis(amino acid) derivative 23 were unsuccessful due to its
rapid hydrolysis on a silica-gel or neutral alumina column.
Therefore, compound 23 was hydrolyzed with 1  HCl in
diethyl ether to get the corresponding amino acid derivative
as its hydrochloride salt (Scheme 3). Neutralization of 24
with aqueous ammonia to deliver the free amino acid was
avoided due to high solubility of the free amine in water.
The bis(amino acid) derivatives 10a and 10b were then
subjected to CEM in presence of ethylene with the aid of
Ru catalysts 3, 4 and 5. When compounds 10a and 10b were
subjected to CEM with Grubbs’ first-generation catalyst 3
in presence of ethylene in DCM only minor amount (1.5%)
of diene formation was observed. Even after prolonged stir-
ring at room temp. (Table 2, entry 1–2), there was no im-
provement in conversion. Treatment with a more reactive
Hoveyda–Grubbs’ second-generation catalyst 5 afforded the
desired CEM product 11 in good yield at room temp. under
usual stirring conditions (Table 2, entry 3–6).
Surprisingly, with catalyst 5, the racemic diastereomer
10a was found to be less reactive as compared to the meso
isomer 10b. High catalyst loading (20 mol-%, DCM, room
temp.) was necessary to deliver 80% conversion of the start-
ing material in the case of racemic diastereomer (Table 2,
entry 3). However, complete conversion with low catalyst
loading was achieved by performing the reaction at elevated
temperature (80 °C, benzene) in a sealed tube (Table 2, en-
try 5). On the other hand in the case of the meso dia-
stereomer, room temp. stirring in DCM or benzene was
found to be sufficient to achieve the complete conversion
of the starting material by using Hoveyda–Grubbs catalyst
(Table 2, entries 4, 6).[22]
With the requisite diene building blocks 11a and 11b in
hand, the DA reaction with various dienophiles was per-
formed to obtain a diverse collection of conformationally
rigid dicarba analogs of cystine.[23] Both the racemic and
the meso dienes were treated individually with different
dienophiles at toluene reflux to afford the corresponding
DA adducts. In some instances the DA adducts were con-
taminated with aromatized products. Hence, the crude DA
adducts were aromatized with activated MnO2 to obtain the
dicarba analogs of cystine (Table 3).
Scheme 3. Preparation of the diene building block 11.
The increasing number of chemical and biological studies
of the carbon cluster C60 (fullerene) in the recent years has
drawn our attention towards the synthesis of fullerene-
based dicarba analogs of cystine by a DA approach
(Scheme 4).[24]
One-pot neutralization and acetyl protection of the
amine groups present in 24 was achieved by using triethyl-
amine and acetic anhydride in the presence of a catalytic
amount of 4-(dimethylamino)pyridine (DMAP). Careful
column chromatography afforded the two diastereomers
Treatment of dienes 11a and 11b with C60 fullerene (25)
10a and 10b (1:1; RR/SS and RS/SR) in 30% overall yield at toluene reflux temperature furnished stable cycloadducts
after steps (combined yields of 10a and 10b) 26a and 26b, respectively, in good yield (Scheme 4). The
3
Table 2. List of conditions for cross-enyne metathesis of 10 with ethylene mediated by a Ru catalyst.
Entry
Substrate
Ru catalyst
Conditions[a]
Conversion
Yield[b]
1
2
3
4
5
6
10a
10b
10a
10b
10a
10b
3 (10 mol-%)
3 (10 mol-%)
5 (20 mol-%)
5 (10 mol-%)
5 (7 mol-%)
5 (7.5 mol-%)
DCM, room temp., 72 h
DCM, room temp., 72 h
DCM, room temp., 24 h
DCM, room temp., 24 h
benzene, 80 °C, 24 h
1.5%[c]
1.5%[c]
80%
100
100
100
–
–
68%, (85%)[d]
98%
96%
97%
benzene, room temp., 24 h
1
[a] All reactions were carried out in ethylene atmosphere (p = 1 atm). [b] Isolated yield. [c] Percentage conversion indicated from the H
NMR analysis. [d] Yields mentioned in the parentheses refer to the yield based on starting material recovered.
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Novel Quinone–Amino Acid Hybrids
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Table 3. List of various dicarba analogs of cystine synthesized from diene 11.[a]
[a] DA reaction was carried out in toluene reflux or heating in a sealed tube at 110 °C. [b] Isolated overall yield after DA reaction and
aromatization.
structures of both of these compounds have been estab- of the ring inversion is faster than the NMR time scale at
lished unambiguously by complementary spectroscopic room temp. (Figure 4).[25] The 13C spectrum of 26a showed
data. The molecular ion peak (m/z) observed at 1089 [M + the presence of 26 signals of which 17 correspond to sp2
H]+ for both the isomers in QTof-MS confirmed the forma- carbons, indicating that the molecule has an average C2v
tion of 1:1 adduct. The appearance of the peak at 527 cm–1 symmetry resulting from the fast flipping motion of the cy-
characteristic of C60 core and peaks at 1739 cm–1 and clohexene ring connecting the C60 cage to the organic ad-
1652 cm–1 in IR absorption spectra of compound 26b and dend. In addition to the ester and amide carbonyl carbon
1736 cm–1 and 1656 cm–1 for compound 26a indicated the atoms which appear at δ = 172.4 and 170.6 ppm, the signal
presence of an ester and amide moiety in the molecule. Both at δ = 44.8 (cyclohexene ring CH2 carbon) and a peak at δ
the diastereomers showed a typical weak absorption band = 65.9, characteristic of the quaternary sp3-hybridized ful-
around 430 nm in the UV/Vis spectrum, similar to that of lerene carbon atoms to which the substituents are attached,
most dihydrofullerenes.[25]
were also observed. However, broadened AB systems (cen-
The 1H NMR spectra of the diastereomer rac-26a tered at δA = 3.92 and δB = 4.12 ppm), corresponding to
showed a broad singlet at δ ≈ 4.4 ppm corresponding to the methylene protons of cyclohexene ring were observed in
four protons (cyclohexene ring methylene protons), which the 1H NMR spectra of the meso diastereomers 26b at room
could be attributed to a rapid boat-to-boat interconversion temp., indicating the restricted boat-to-boat interconversion
of the cyclohexene ring (Figure 3) indicating that the rate of the cyclohexene ring in the molecule (Figure 4). The 13C
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S. Kotha, K. Mandal, S. Banerjee, S. M. Mobin
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Scheme 4. Synthesis of fullerene-based dicarba analogs of cystine.
Figure 3. Boat-to-boat interconversion of the cyclohexene ring.
1
Figure 4. Expanded AB signals of 26a and 26b in 300-MHz H-NMR spectra at room temp.
stereomers by H NMR and 13C NMR spectroscopy were
not successful due to a close similarity of their chemical
shift values. It was considered that employment of a CSR
might be helpful in assigning the stereochemistry of the two
diastereomers where the chiral atoms are separated by four
carbon units. As expected, it was observed that upon ad-
dition of Eu(tfc)3 to a CDCl3 solution of compound 10a
the signals were split into two sets of lines of equal intensity,
for the racemic isomer (Figure 5, B), even the meso com-
pound was also found to split into two set of lines with
varying separation as shown in Table 4.[26] Literature re-
ports also suggest that in the presence of CSR the meso
isomer becomes “internally diastereotopic” and thus ani-
sochronous.[27]
1
spectrum of 26b exhibited signals for 32 C atoms (24 lines,
8 with double integral) for the fullerene sp2-C atoms as well
as a peak at δ = 65.9 ppm characteristic of those quaternary
sp3-hybridized C atom that constitute the 6–6 fusion point
of attachment of the cyclohexenyl moiety which further
confirmed the Cs symmetry of the molecule (Figure 3).[25]
Effect of Addition of Chiral Shift Reagent (CSR) on the
Two Diastereomers
Determining the stereochemistry of the two dia-
stereomers 10a and 10b (rac and meso) appeared to be a
non-trivial task. Attempts to differentiate these two dia-
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Novel Quinone–Amino Acid Hybrids
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Figure 5. Splitting of the ester methyl proton triplet in the 300-MHz 1H-NMR spectrum upon addition of the CSR; (A) 10a in the
absence of CSR, (B) 10a: CSR (1:0.75), (C) 10b in the absence of CSR, (D) 10b: CSR (1:0.70).
1
Table 4. Effect of addition of CSR on H NMR chemical shift.
[a]
CSR/substrate ratio
Change in chemical shift (in ppm) of 10a ∆δ = (δCSR+10a – δCSR)
NHAc
CHNH
OCH2CH3
CHaHbCϵC
COCH3
OCH2CH3
Ha
0.32
Hb
0.51
0.24:1
0.47:1
0.75:1
1.06
2.08
3.26
1.5
0.24
0.48
0.74
1.04
2.12
0.10
0.12
0.19
0.22
0.29
0.34
1.33
2.72
–
0.48
0.63
0.69
0.93
0.91
1.2
1.43
3.15
3.36
1.93
[a]
Change in chemical shift (in ppm) of 10b ∆δ = (δCSR+10b – δCSR
)
0.22:1
0.50:1
0.70:1
0.89
2.12
3.48
1.2
0.19
0.45
0.75
0.27
0.66
1.60
0.93
2.16
0.075
0.079
0.18
0.19
0.29
0.31
2.84
4.65
0.61
0.94
1.05
2.41
2.7
3.54
3.76
1
[a] H NMR were recorded in CDCl3 at room temp.
Stereochemical Assignment of 10a and 10b
The stereochemistry of 10b was assigned as meso based
on its crystal structure as shown in Figure 6. Compound
10a was obtained as racemic diastereomer.
Conclusions
We have prepared the new building blocks 7 and 11 suit-
able for the synthesis of quinone–amino acid hybrids. More
specifically, various conformationally constrained quinone-
containing dicarba analogs of cystine and Phe derivatives
have been synthesized via ethylene cross-enyne metathesis
using Grubbs’ catalyst and DA reaction as key steps. Also,
we have extended this methodology for the synthesis of ful-
lerene-based dicarba analog of cystine. The stereochemistry
of the meso diastereomer of the dicarba analog of cystine
was assigned based on its crystal structure. We anticipate
Figure 6. ORTEP diagram of compound 10b.
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S. Kotha, K. Mandal, S. Banerjee, S. M. Mobin
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H, 2 Me), 2.36 (s, 3 H, ArCH3), 3.08 (d, 1/2ABq, J = 6.4, 14 Hz,
1 H, CHCHaHb), 3.18 (d, 1/2ABq, J = 5.6, 13.8 Hz, 1 H,
CHCHaHb), 4.01 (q, J = 7.1 Hz, 2 H, -OCH2CH3), 4.19–4.21 (m,
1 H, CHCH2), 5.18 (d, J = 8.8 Hz, 1 H, N-H), 7.20 (d, J = 8.0 Hz,
2 H, 2 ArH), 7.47 (d, J = 7.6 Hz, 1 H, ArH), 7.61 (d, J = 8.0 Hz,
2 H, 2 ArH), 7.75 (s, 1 H, ArH), 7.95 (d, J = 7.6 Hz, 1 H, ArH)
ppm. 13C NMR (100.6 MHz, CDCl3): δ = 13.1, 14.1, 21.7, 39.6,
56.5, 62.4, 126.7, 127.2, 127.4, 129.8, 131.2, 132.2, 134.8, 136.6,
that these new advances for the preparation of quinone–
amino acid hybrids might allow the synthesis of novel pepti-
domimetics and artificial proteins.
Experimental Section
141.6, 143.5, 143.7, 143.9, 170.6, 184.7, 184.9 ppm. IR (neat): ν =
˜
1738 (ester C=O), 1659 cm–1 (ArC=O). UV (CHCl3): λmax (ε) =
270 nm (12400 mol–1dm3cm–1). HRMS (Q-Tof): m/z calcd. for
C24H26NO6S [M + H] 456.1481, found 456.1487.
General Remarks: All reactions were monitored by thin-layer
chromatography (TLC) carried out on glass plates coated with
Acme’s silica gel GF 254 (containing 13% calcium sulfate as a
binder). Visualization of the spots on TLC plates was achieved
either by exposure to iodine vapor or UV light. Flash chromatog-
raphy was performed using Acme’s silica gel (100–200 mesh). Petro-
leum ether refers to fraction with the boiling range 60–80 °C. Me-
tathesis catalysts were purchased from Sigma–Aldrich (Milwaukee,
USA). All the commercial-grade reagents were used without fur-
ther purification. Infrared spectra were recorded on a Nicolet Im-
Ethyl 3-(9,10-Dioxo-9,10-dihydroanthracen-2-yl)-2-[(4-methylphen-
yl)sulfonamido]propanoate (19): 1,4-Naphthoquinone (15) (33 mg,
0.21 mmol) was added to a solution of diene 7 (27 mg, 0.08 mmol),
in dry toluene (5 mL) was heated (90 °C, 24 h). Then, the solvent
was concentrated under reduced pressure and the crude product
obtained was purified by flash silica gel column chromatography
(EtOAc/petroleum ether 25%) to afford DA adduct. Subsequent
oxidation of the DA adduct (34 mg, 0.07 mmol) was carried out
with MnO2 (250 mg, 2.79 mmol) in refluxing dioxane (14 mL) for
30 h. Then, the solvent was removed under reduced pressure and
the crude product was purified by flash silica-gel column
chromatography (EtOAc/petroleum ether 25%) to afford the aro-
matized product 19 (30 mg, 77%) as a yellow solid; Rf = 0.48 (silica
gel, EtOAc/petroleum ether, 1:3); m.p. 181–182 °C. 1H NMR
(400 MHz, CDCl3, 25 °C, TMS): δ = 1.17 (t, J = 7.2 Hz, 3 H,
-OCH2CH3), 2.26 (s, 3 H, Ar-CH3), 3.10–3.28 (m, 2 H, CHCH2),
4.07 (q, J = 6.4 Hz, 2 H, -OCH2CH3), 4.22–4.24 (m, 1 H, CHCH2),
5.27 (d, J = 8.4 Hz, 1 H, NH), 7.17 (d, J = 8 Hz, 2 H, 2 ArH),
7.59–7.60 (m, 3 H, 3 ArH), 7.80–7.83 (m, 2 H, 2 ArH), 7.97 (s, 1
H, ArH), 8.18 (d, J = 8 Hz, 1 H, ArH), 8.31–8.36 (m, 2 H, 2 ArH)
ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C, TMS): δ = 14.2, 21.6,
39.6, 56.6, 62.5, 127.3, 128.0, 128.4, 129.79, 129.81, 130.33, 130.35,
133.5, 134.5, 135.3, 135.4, 135.7, 136.6, 142.7, 143.9, 170.7, 182.8,
1
pact 400 FT-IR spectrometer in KBr/CHCl3/CCl4. H NMR (300,
400 MHz) and 13C NMR (75, 100 MHz) spectra were determined
at room temp. on a Varian VXR 300 or AX 400 mercury plus in
CDCl3 solutions. Coupling constants (J values) are given in Hertz
(Hz). Chemical shifts are expressed in δ values downfield from in-
ternal reference tetramethylsilane. High-resolution mass spectra
were determined on Micromass Q-Tof spectrometer.
Ethyl 4-Methylene-2-[(4-methylphenyl)sulfonamido]hex-5-enoate (7):
The amino ester 8 (41 mg, 0.13 mmol) in dichloromethane (10 mL)
was degassed with nitrogen for 10 min and then degassed with eth-
ylene for 10 min. Grubbs’ first-generation catalyst 3 (6.2 mg,
0.008 mmol, 6 mol-%) was added and finally, the vessel was kept
under pressure with ethylene (balloon pressure: 1 atm). The reac-
tion mixture was then stirred at room temp. for 24 h. After comple-
tion of the reaction (TLC monitoring), the solvent was concen-
trated and the crude product was purified by flash silica-gel column
chromatography (EtOAc/petroleum ether 20%) to afford a brown-
ish liquid 7 (31 mg, 68%); Rf = 0.32 (silica gel, EtOAc/petroleum
182.9 ppm. IR (neat): ν = 1732 (ester C=O), 1660 cm–1 (ArC=O).
˜
UV (CHCl3): λmax (ε) = 258 nm (18916 mol–1dm3cm–1). HRMS (Q-
Tof): m/z calcd. for C26H23NNaO6S [M + Na] 500.1147, found
500.1144.
1
ether, 1:5). H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 1.10 (t,
J = 7.2 Hz, 3 H, -OCH2CH3), 2.41 (s, 3 H, Ar-CH3) 2.58–2.62 (m,
2 H, CHCH2), 3.90 (q, J = 7.2 Hz, 2 H, -OCH2CH3), 4.06–4.12
(m, 1 H, CH-CH2), 5.02–5.22 [m, 5 H, CH2CHC(=CH2)CH2, NH],
6.27 (dd, J = 14, 10.8 Hz, 1 H, -CH=CH2), 7.28 (d, J = 8 Hz, 2 H,
2 ArH), 7.69 (d, J = 8.2 Hz, 2 H, 2 ArH). 13C NMR (100.6 MHz,
CDCl3): δ = 14.0, 21.7, 35.9, 54.8, 61.7, 114.5, 120.0, 127.5, 129.7,
Ethyl 3-(5,12-Dioxo-5,12-dihydrotetracen-2-yl)-2-[(4-methylphenyl)-
sulfonamido]propanoate (20): 1,4-Anthraquinone (16) (26 mg,
0.13 mmol) was added to a solution of diene 7 (31, mg, 0.10 mmol),
in dry toluene (5 mL) and was heated (90 °C, 24 h). Then, the sol-
vent was concentrated under reduced pressure and the crude prod-
uct obtained was purified by flash silica gel column chromatog-
raphy (EtOAc/petroleum ether 30%) to afford the DA adduct. Sub-
sequent oxidation of the DA adduct (47 mg, 0.09 mmol) was car-
136.9, 137.7, 140.3, 143.7, 171.4 ppm. IR (neat): ν = 1737 (ester
˜
C=O), 1645 cm–1 (ArC=O). HRMS (Q-Tof ES+): m/z calcd. for
C16H21NNaO4S [M + Na] 346.1089, found 346.1105.
Ethyl 3-(6,7-Dimethyl-5,8-dioxo-5,8-dihydronaphthalen-2-yl)-2-[(4- ried out with MnO2 (150 mg, 1.72 mmol) in refluxing dioxane
methylphenyl)sulfonamido]propanoate (18): 2,3-Dimethylbenzoqui-
none (14) (15 mg, 0.11 mmol), was added to a solution of diene 7
(11 mg, 0.03 mmol), in toluene (5 mL) and the mixture was heated
(90 °C, 24 h). Then, the solvent was concentrated under reduced
pressure and the crude product obtained was purified by a flash
column chromatography (silica gel, EtOAc/petroleum ether 25%)
to afford the DA adduct as a semi solid. Subsequent oxidation of
the DA adduct (15 mg, 0.03 mmol) was carried out with MnO2
(100 mg, 1.15 mmol) in refluxing dioxane (14 mL) for 30 h. Then,
the solvent was removed under reduced pressure and the crude
product was purified by flash silica gel column chromatography
(EtOAc/petroleum ether 25%) to afford the aromatized product 18
(12 mg, 81%) as a yellow solid. Rf = 0.41 (silica gel, EtOAc/petro-
(14 mL) for 30 h. Then the solvent was removed under reduced
pressure and the crude product was purified by flash silica-gel col-
umn chromatography (EtOAc/petroleum ether 30%) to afford the
aromatized product 20 (46 mg, 93%) as a yellow solid; Rf = 0.39
(silica gel, EtOAc/petroleum ether, 1:3), m.p. 230 °C. 1H NMR
(CDCl3, 300 MHz, 25 °C, TMS): δ = 1.19 (t, J = 6.8 Hz, 3 H,
-OCH2CH3), 2.25 (s, 3 H, ArCH3), 3.13 (d, 1/2ABq, J = 13.6,
7.2 Hz, 1 H, CHCHaHb), 3.26 (d, 1/2ABq, J = 13.8, 5.4 Hz, 1 H,
CHCHaHb), 4.05 (q, J = 5.6 Hz, 2 H, -OCH2CH3), 4.24–4.28 (m,
1 H, CHCH2), 5.27 (d, J = 8.4 Hz, 1 H, NH), 7.17 (d, J = 8.4 Hz,
2 H, 2 ArH), 7.60–7.62 (m, 3 H, 3 ArH), 7.71 (dd, J = 6.6, 3.2 Hz,
2 H, 2 ArH), 8.05–8.12 (m, 3 H, 3 ArH), 8.25 (d, J = 8 Hz, 1 H,
ArH), 8.84 (s, 1 H, ArH), 8.86 (s, 1 H, ArH) ppm. 13C NMR
leum ether, 1:4); m.p. 160–162 °C. 1H NMR (300 MHz, CDCl3, (100.6 MHz, CDCl3, 25 °C, TMS): δ = 14.2, 21.5, 39.6, 56.6, 62.5,
25 °C, TMS): δ = 1.14 (t, J = 6.8 Hz, 3 H, -OCH2CH3), 2.17 (s, 6 127.32, 127.39, 127.4, 127.7, 128.1, 129.8, 132.5, 133.52, 133.56,
1250
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1244–1255

Novel Quinone–Amino Acid Hybrids
133.6, 134.3, 134.4, 135.6, 136.5, 142.6, 143.9, 170.6, 182.9, 18.0 Hz, 2 H, 2 CHCHaHb) 4.26 (q, J = 7.2 Hz, 4 H, 2 OCH2CH3),
FULL PAPER
183.0 ppm. IR (neat): ν
= 3409 (NH), 1736 (ester C=O),
4.90 (dt, J = 8.8, 4.0 Hz, 2 H, 2 CHNHAc), 7.25 (d, J = 8.8 Hz, 2
˜
max
1649 cm–1 (ArC=O). UV (CHCl3): λmax (ε)
=
292 nm H, 2 NH) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 14.2, 22.9,
(18666 mol–1dm3cm–1). HRMS (Q-Tof ES+): m/z calcd. for
C30H26NO6S [M + H] 528.1481, found 528.1486.
23.6, 50.4, 62.0, 78.5, 170.5, 172.2 ppm. IR (neat): ν = 3308 (NH),
˜
1726 (ester C=O), 1650 cm–1 (amide C=O). UV (CHCl3): λmax (ε)
= 208 nm (1698 mol–1dm3cm–1). HRMS (Q-Tof): m/z calcd. for
C16H24N2NaO6 [M + Na]: 363.1532, found 363.1518.
Dimethyl
4-{3-Ethoxy-2-[(4-methylphenyl)sulfonamido]-3-oxo-
propyl}phthalate (21): Dimethyl acetylenedicarboxylate (17) (29 mg,
0.20 mmol) was added to a solution of diene 7 (30 mg, 0.09 mmol),
in dry toluene (5 mL) was heated (90 °C, 18 h). Then the solvent
was concentrated under reduced pressure and the crude product
obtained was purified by flash silica gel column chromatography
(ethyl acetate/petroleum ether 40%) mixture to afford the Diels–
Alder adduct. Subsequent oxidation of the DA adduct (31 mg,
0.06 mmol) was carried out with MnO2 (232 mg, 2.6 mmol) in re-
fluxing dioxane (dry) (14 mL) for 30 h. Then the solvent was re-
moved under reduced pressure and the crude product was purified
by flash silica-gel column chromatography (EtOAc/petroleum ether
40%) to afford the aromatized product 21 (29 mg, 67%) as a color-
less liquid. Rf = 0.30 (silica gel, EtOAc/petroleum ether, 1:3). 1H
NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 1.02 (t, J = 6.9 Hz, 3
H,-OCH2CH3), 2.36 (s, 3 H, Ar-CH3), 3.05–3.11 (m, 2 H, CH-
CH2), 3.89 (s, 3 H, -CO2CH3), 3.90 (s, 3 H, -CO2CH3), 3.98 (q, J
= 7.3 Hz, 2 H, -OCH2CH3), 4.12–4.19 (m, 1 H, CH-CH2), 5.17 (d,
J = 8.8 Hz, 1 H, NH), 7.22 (d, J = 8.0 Hz, 2 H, 2 ArH), 7.28–7.31
(m, 1 H, ArH), 7.41 (d, J = 1.5 Hz, 1 H, ArH), 7.59–7.62 (m, 3 H,
3 ArH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C, TMS): δ =
14.0, 21.6, 39.0, 52.7, 52.8, 56.5, 62.3, 127.2, 129.26, 129.78, 130.01,
130.72, 132.30, 132.34, 136.4, 139.3, 143.9, 167.8, 167.9, 170.6 ppm.
meso-Diethyl 2,7-Bis(acetamido)oct-4-yne-1,8-dioate (10b): Rf
=
0.31 (silica gel, EtOAc); m.p. 134 °C. 1H NMR (300 MHz, CDCl3):
δ = 1.30 (t, J = 7.2 Hz, 6 H, 2 OCH2CH3), 2.13 (s, 6 H, 2 COCH3),
2.66 (d, 1/2ABq, J = 5.2, 2 Hz, 2 H, 2 CHCHaHb), 2.69 (d, 1/2ABq,
J = 5.2, 2.8 Hz, 2 H, 2 CHCHaHb), 4.25 (q, J = 7.0 Hz, 4 H, 2
OCH2CH3), 4.78 (dt, J = 8.4, 4.4 Hz, 2 H, 2 CHNHAc), 6.56 (d,
J = 8.4 Hz, 2 H, 2 NH) ppm. 13C NMR (75.4 MHz, CDCl3): δ =
14.2, 23.09, 23.14, 50.7, 61.9, 77.9, 170.9 ppm. IR (neat): ν = 3332
˜
(NH), 1734 (ester C=O), 1647 cm–1 (amide C=O). UV (CHCl3):
λmax (ε) = 208 nm (1658 mol–1dm3cm–1). HRMS (Q-Tof): m/z calcd.
for C16H24N2NaO6 [M + Na]: 363.1532, found 363.1543.
rac-Diethyl
2,7-Diacetamido-4,5-dimethyleneoctane-1,8-dioate
(11a): The amino ester 10a (83 mg, 0.244 mmol) in dry benzene
(7 mL) was degassed with nitrogen for 15 min and then with ethyl-
ene gas for 10 min in a sealed tube. Hoveyda’s catalyst 5 (11 mg,
0.0175 mmol, 7.0 mol-%) was then added and finally, the vessel was
kept under ethylene pressure (1 atm) and capped tightly. The reac-
tion mixture was then heated to 80 °C. After completion of the
reaction (24 h, TLC monitoring), the pressure was released and the
resulting brown solution was concentrated under reduced pressure
and the crude product was purified by silica gel flash column
chromatography (EtOAc/petroleum ether 80%) to afford rac-11a as
a white crystalline solid (86 mg, 96%). Rf = 0.26 (silica gel, EtOAc);
IR (neat): ν
= 1729 (ester C=O), 1435 cm–1. HRMS (Q-Tof):
˜
max
m/z calcd. for C22H25NNaO8S [M + Na] 486.1199, found 486.1186.
1
Diethyl 2,7-Bis(acetamido)oct-4-yne-1,8-dioate (10): To a solution
of ethyl 2-[(diphenylmethylene)amino]acetate (9) (7.7 g, 29 mmol)
in dry acetonitrile (30 mL) was added 1,4-dibromobut-2-yne (22)
(2.8 g, 13.0 mmol), potassium carbonate (10 g, 72 mmol) and cata-
lytic amount of TBHAS. The resulting heterogeneous mixture was
then allowed to reflux. After completion of the reaction (20 h, TLC
monitoring), the reaction mixture was cooled, filtered, and the fil-
trate was concentrated under reduced pressure to give 23 as a
brown color liquid which was directly used in the next step without
further purification. A suspension of compound 23 (used as it is
obtained from the earlier step) in diethyl ether (30 mL) was added
1  HCl (40 mL). The reaction mixture was stirred at room temp.
for 24 h. The ether layer was discarded and the aqueous layer was
concentrated under reduced pressure by using a rotary evaporator
and finally dried under high vacuum to give the bis(amino acid)
hydrochloride salt 24. This crude hydrochloride salt was directly
used in the next step without further purification: To a suspension
of crude 24 in dry dichloromethane (50 mL) was added triethyl-
amine (3 g, 29.7 mmol), a catalytic amount of DMAP and acetic
anhydride (4.9 g, 48.4 mmol); the temperature of the reaction mix-
ture was kept at ice temperature. The resulting mixture was then
allowed to warm up to room temp. and stirred for another 24 h.
Then, the mixture was concentrated and the residue was directly
(without any aqueous work up) charged on a silica gel column
(length of the column: 25 cm, diameter: 5.5 cm, amount of silica
gel: 430 g). Careful elution of the column with 80% EtOAc/petro-
leum ether afforded compounds 10a and 10b (1:1, 1.31 g, 30%,
overall yield after three steps).
m.p. 136 °C. H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 1.32
(t, J = 7.2 Hz, 6 H, 2 OCH2CH3), 2.02 (s, 6 H, 2 COCH3), 2.75 (d,
1/2ABq, J = 14.3, 5.9 Hz, 2 H, 2 CHCHaHb), 2.90 (d, 1/2ABq, J
= 14.1, 5.1 Hz, 2 H, 2 CHCHaHb), 4.13 (q, 1/2ABq, J = 10.7,
7.2 Hz, 2 H, 2 OCHaHbCH3), 4.25 (q, 1/2ABq, J = 10.7, 7.2 Hz, 2
H, 2 OCHaHbCH3), 4.74 (dt, J = 8.7, 6.0 Hz, 2 H, 2 CHNHAc),
5.00 (s, 2 H, 2 C=CHaHb), 5.24 (s, 2 H, 2 C=CHaHb), 6.72 (d, J =
8.4 Hz, 2 H, 2 NH) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 14.2,
23.0, 36.4, 51.2, 61.6, 117.1, 141.2, 170.0, 172.5 ppm. IR (neat): ν
˜
= 3414 (NH), 1732 (ester C=O), 1657 cm–1 (amide C=O). UV
(CHCl3): λmax (ε) = 235 nm (6568 mol–1dm3cm–1). HRMS (Q-Tof):
m/z calcd. for C18H28N2NaO6 [M + Na]: 391.1845, found 391.1839.
meso-Diethyl
2,7-Diacetamido-4,5-dimethyleneoctane-1,8-dioate
(11b): The amino ester 10b (65 mg, 0.191 mmol) in dry benzene
(10 mL) was degassed with nitrogen for 15 min and then with ethyl-
ene gas for 10 min. Hoveyda’s catalyst 5 (9 mg, 0.014 mmol,
7.5 mol-%) was then added and finally, the vessel was kept under
ethylene pressure (1 atm). The reaction mixture was stirred at room
temp. After completion of the reaction (24 h, TLC monitoring), the
pressure was released and the resulting brown solution was concen-
trated under reduced pressure and the crude product was purified
by silica gel flash column chromatography. Elution of the column
(EtOAc in petroleum ether 80%) to afford meso-11b as a white
crystalline solid (68 mg, 97%). Rf = 0.28 (silica gel, EtOAc); m.p.
1
154 °C. H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 1.29 (t, J
= 7.2 Hz, 6 H, 2 OCH2CH3), 2.02 (s, 6 H, 2 COCH3), 2.52 (d,
1/2ABq, J = 14.7, 8.7 Hz, 2 H, 2 CHCHaHb), 2.88 (d, 1/2ABq, J
= 14.7, 4.8 Hz, 2 H, 2 CHCHaHb), 4.14–4.25 (m, 4 H, 2
OCH2CH3), 4.73 (dt, J = 12.3, 4.2 Hz, 2 H, 2 CHNHAc), 5.05 (s,
2 H, 2 =CHaHb), 5.26 (s, 2 H, 2 = CHaHb), 6.45 (d, J = 7.5 Hz, 2
rac-Diethyl 2,7-Bis(acetamido)oct-4-yne-1,8-dioate (10a): Rf = 0.32
1
(silica gel, EtOAc); m.p. 134 °C. H NMR (300 MHz, CDCl3): δ =
1.31 (t, J = 7.2 Hz, 6 H, 2 OCH2CH3), 2.14 (s, 6 H, 2 COCH3), H, 2 NH) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 14.2, 23.0, 36.8,
2.59 (1/2ABq, J = 16.4 Hz, 2 H, 2 CHCHaHb), 2.67 (1/2ABq, J =
51.1, 61.5, 115.8, 141.6, 170.3, 172.2 ppm. IR (neat): ν = 3326
˜
Eur. J. Org. Chem. 2007, 1244–1255
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1251

S. Kotha, K. Mandal, S. Banerjee, S. M. Mobin
FULL PAPER
(NH), 1749 (ester C=O), 1651 cm–1 (amide C=O). UV (CHCl3):
(100.6 MHz, CDCl3, 25 °C, TMS): δ = 13.0, 14.2, 23.1, 35.3, 53.1,
λmax (ε) = 235 nm (5232 mol–1dm3cm–1). HRMS (Q-Tof): m/z calcd. 62.1, 128.5, 130.7, 141.6, 143.6, 170.3, 171.5, 184.6 ppm. IR
for C18H28N2NaO6 [M + Na]: 391.1845, found 391.1855.
(KBr): ν = 3383 (NH), 1756 (ester C=O), 1725 (ArC=O),
˜
1661 cm–1 (amide C=O). UV (CHCl3): λmax (ε)
= 260 nm
General Experimental Procedure for the DA Reaction and Aromati-
zation: To a solution of the diene 11a–b (1 equiv.) in dry toluene
or 1,2-dichlorobenzene was added the dienophile (2–7 equiv.) and
the reaction mixture was heated to reflux. After completion of the
reaction (TLC monitoring), the solution was concentrated under
reduced pressure. The crude reaction mixture was then dissolved in
dry dioxane and activated MnO2 (excess) was added. The reaction
mixture was stirred at room temp. for 48 h and then filtered
through a celite pad. The residue was washed with dioxane (3 ϫ
5 mL) and the solvent removed under reduced pressure. The crude
product was purified by silica gel flash column chromatography.
Elution of the column with appropriate mixture of EtOAc in petro-
leum ether afforded the desired aromatized cycloadduct.
(16700 mol–1dm3cm–1). HRMS (Q-Tof): m/z calcd. for C26H33N2O8
[M + H]: 501.2237, found 501.2237.
rac-Diethyl 3,3Ј-(9,10-Dioxo-9,10-dihydroanthracene-2,3-diyl)bis(2-
acetamidopropanoate) (28a): 1,4-Napthoquinone (15) (30 mg,
0.19 mmol) was added to a solution of the diene 11a (28 mg,
0.076 mmol) in dry toluene (7 mL) and the reaction mixture was
heated (110 °C, 72 h). The solution was concentrated under re-
duced pressure. The crude reaction mixture was then dissolved in
dry dioxane (5 mL) and activated MnO2 (100 mg, 1.15 mmol) was
added. The reaction mixture was stirred at room temp. for 12 h and
then filtered through a celite pad. The residue was washed with
dioxane (3 ϫ 5 mL) and the solvent was removed under reduced
pressure. The crude product was purified by silica gel flash column
chromatography (EtOAc/petroleum ether 80%) to afford com-
pound 28a (34 mg, overall yield 86%) as a yellow crystalline solid.
Rf = 0.23 (silica gel, EtOAc); m.p. 270–272 °C (dec.). 1H NMR
(300 MHz, CDCl3): δ = 1.27 (t, J = 7.2 Hz, 6 H, 2 OCH2CH3),
1.94 (s, 6 H, 2 COCH3), 3.23 (d, 1/2ABq, J = 14.1, 8.1 Hz, 2 H, 2
CHCHaHb), 3.40 (d, 1/2ABq, J = 14.3, 5.9 Hz, 2 H, 2 CHCHaHb),
4.24 (q, 4 H, J = 7.1 Hz, 2 OCH2CH3), 4.92 (dt, J = 6.8, 6.8 Hz,
2 H, 2 CHNHAc), 6.47 (d, J = 7.2 Hz, 2 H, 2 NH), 7.79 (dd, J =
5.9, 3.2 Hz, 2 H, C6-H, C7-H), 7.80 (s, 2 H, C1-H, C4-H), 8.28 (dd,
J = 5.9, 3.5 Hz, 2 H, C5-H, C8-H) ppm. 13C NMR (100.6 MHz,
CDCl3, 25 °C, TMS): δ = 14.3, 23.0, 35.5, 52.6, 62.2, 127.3, 129.2,
rac-Diethyl
3,3Ј-(6,7-Dimethyl-5,8-dioxo-5,8-dihydronaphthalene-
2,3-diyl)bis(2-acetamidopropanoate) (27a): 2,3-Dimethylbenzoqui-
none (14) (26 mg, 0.19 mmol) was added to a solution of the diene
11a (28 mg, 0.076 mmol) in dry toluene (3 mL) in a sealed tube
and the reaction mixture was heated (110 °C, 48 h). The solution
was concentrated under reduced pressure. The crude reaction mix-
ture was then dissolved in dry dioxane (7 mL) and activated MnO2
(200 mg, 2.29 mmol) was added. The reaction mixture was stirred
at room temp. for 48 h and then filtered through a celite pad. The
residue was washed with dioxane (3 ϫ 5 mL) and the solvent was
removed under reduced pressure. The crude product was purified
by silica gel flash column chromatography (EtOAc/petroleum ether
80%) to afford compound 27a (30 mg, overall yield 79%) as a light
yellow crystalline solid. Rf = 0.30 (silica gel, EtOAc); m.p. 214–
132.1, 133.6, 134.3, 142.6, 170.4, 171.6, 184.8 ppm. IR (neat): ν =
˜
3272 (NH), 1736 (ester C=O), 1656 (amide C=O), 1674 cm–1
(ArC=O). UV (CHCl3): λmax (ε) = 266 nm (18085 mol–1dm3cm–1).
HRMS (Q-Tof): m/z calcd. for C28H31N2O8 [M + H]: 523.2080,
found 523.2073.
1
215 °C. H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 1.26 (t, J
= 7.1 Hz, 6 H, 2 OCH2CH3), 1.93 (s, 6 H, C2,3-CH3), 2.15 (s, 6 H,
2 COCH3), 3.16 (d, 1/2ABq, J = 14.1, 8.4 Hz, 2 H, 2 CHCHaHb),
3.34 (d, 1/2ABq, J = 14.3, 5.9 Hz, 2 H, 2 CHCHaHb), 4.17–4.27
(m, 4 H, 2 OCH2CH3), 4.88 (dt, J = 7.1, 7.1 Hz, 2 H, 2 CHNHAc),
meso-Diethyl
3,3Ј-(9,10-Dioxo-9,10-dihydroanthracene-2,3-diyl)-
bis(2-acetamidopropanoate) (28b): 1,4-Napthoquinone (15) (27 mg,
6.46 (d, J = 7.2 Hz, 2 H, 2 NH), 7.82 (s, 2 H, C5,8-H) ppm. 13C 0.169 mmol) was added to a solution of the diene 11b (25 mg,
NMR (100.6 MHz, CDCl3, 25 °C, TMS): δ = 13.1, 14.3, 23.0, 35.4, 0.068 mmol) in dry toluene (7 mL) and the reaction mixture was
52.6, 62.1, 128.2, 130.8, 141.4, 143.7, 170.3, 171.6, 184.7 ppm. IR
(KBr): ν = 3272 (NH), 1748 (ester C=O), 1726 (ArC=O), 1655
heated (110 °C, 48 h). The solution was concentrated under re-
duced pressure and the crude reaction mixture was then dissolved
˜
cm–1 (amide C=O). UV (CHCl3): λmax (ε)
=
262 nm in dry dioxane (5 mL) and activated MnO2 (96 mg, 1.1 mmol) was
(11000 mol–1dm3cm–1). HRMS (Q-Tof): m/z calcd. for C26H33N2O8
[M + H]: 501.2237, found 501.2256.
added. The reaction mixture was stirred at room temp. for 12 h and
then filtered through a celite pad. The residue was washed with
dioxane (3 ϫ 5 mL) and the solvent was removed under reduced
pressure. The crude product was purified by silica gel flash column
chromatography (EtOAc/petroleum ether 80%) to afford com-
pound 28b (32 mg, overall yield 81%) as a yellow crystalline solid.
Rf = 0.23 (silica gel, EtOAc); m.p. 246–248 °C (dec.). 1H NMR
(300 MHz, CDCl3, 25 °C, TMS): δ = 1.24 (t, J = 7.1 Hz, 6 H, 2
OCH2CH3), 1.99 (s, 6 H, 2 COCH3), 3.26 (d, 1/2ABq, J = 14.1,
6.9 Hz, 2 H, 2 CHCHaHb), 3.38 (d, 1/2ABq, J = 14.3, 5.9 Hz, 2 H,
2 CHCHaHb), 4.18–4.26 (m, 4 H, 2 OCH2CH3), 4.90 (dt, J = 7.8,
6.9 Hz, 2 H, 2 CHNHAc), 6.49 (d, J = 7.8 Hz, 2 H, 2 NH), 7.80
(dd, J = 5.9, 3.2 Hz, 2 H, C6-H, C7-H), 8.06 (s, 2 H, C1-H, C4-
H), 8.29 (dd, J = 6.0, 3.3 Hz, 2 H, C5-H, C8-H) ppm. 13C NMR
(100.6 MHz, CDCl3, 25 °C, TMS): δ = 14.2, 23.2, 35.6, 53.2, 62.2,
127.4, 129.5, 132.1, 133.7, 134.3, 142.6, 170.3, 171.6, 182.9 ppm.
meso-Diethyl 3,3Ј-(6,7-Dimethyl-5,8-dioxo-5,8-dihydronaphthalene-
2,3-diyl)bis(2-acetamidopropanoate) (27b): 2,3-Dimethylbenzoqui-
none (14) (33 mg, 0.24 mmol) was added to a solution of the diene
11b (33 mg, 0.09 mmol) in dry toluene (3 mL) and the reaction mix-
ture was heated (110 °C, 48 h). The solution was concentrated un-
der reduced pressure. The crude reaction mixture was then dis-
solved in dry dioxane (10 mL) and activated MnO2 (200 mg,
2.29 mmol) was added. The reaction mixture was stirred at room
temp. for 48 h and then filtered through a celite pad. The residue
was washed with dioxane (3 ϫ 5 mL) and the solvent was removed
under reduced pressure. The crude product was purified by silica
gel flash column chromatography (EtOAc/petroleum ether 80%) to
afford compound 27b (37 mg, overall yield 82%) as a light yellow
crystalline solid. Rf = 0.30 (silica gel, EtOAc); m.p. 219–220 °C. 1H
NMR (300 MHz, CDCl3): δ = 1.24 (t, J = 7.2 Hz, 6 H, 2
OCH2CH3), 1.98 (s, 6 H, C2,3-CH3), 2.15 (s, 6 H, 2 COCH3), 3.19
(d, 1/2ABq, J = 13.8, 6.6 Hz, 2 H, 2 CHCHaHb), 3.32 (d, 1/2ABq,
J = 14.0, 6.5 Hz, 2 H, 2 CHCHaHb), 4.15–4.25 (m, 4 H, 2
IR (neat): ν = 3305 (NH), 1739 (ester C=O), 1671 (ArC=O); 1655
˜
cm–1 (amide C=O). UV (CHCl3): λmax (ε)
=
267 nm
(16643 mol–1dm3cm–1). HRMS (Q-Tof): m/z calcd. for C28H31N2O8
[M + H]: 523.2080, found 523.2092.
OCH2CH3), 4.87 (dt, J = 8.1, 6.6 Hz, 2 H, 2 CHNHAc), 6.55 (d, rac-Diethyl 3,3Ј-(5,12-Dioxo-5,12-dihydrotetracene-2,3-diyl)bis(2-
J = 7.2 Hz, 2 H, 2 NH), 7.82 (s, 2 H, C5,8-H) ppm. 13C NMR acetamidopropanoate) (29a): 1,4-Anthraquinone (16) (27 mg,
1252
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1244–1255

Novel Quinone–Amino Acid Hybrids
FULL PAPER
0.132 mmol) was added to a solution of the diene 11a (27 mg,
gel flash column chromatography (EtOAc/petroleum ether 80%)
0.073 mmol) in dry toluene (7 mL) and the reaction mixture was afforded compound 30a (19 mg, overall yield 72%) as a colorless
heated (110 °C, 24 h). The solution was concentrated under re-
duced pressure. The crude reaction mixture was then dissolved in
dry dioxane (5 mL) and activated MnO2 (188 mg, 2.16 mmol) was
added. The reaction mixture was stirred at room temp. for 30 h and
then filtered through a celite pad. The residue was washed with
dioxane (3 ϫ 5 mL) and the solvent was removed under reduced
pressure. The crude product was purified by silica gel flash column
chromatography (EtOAc/petroleum ether 80%) to afford com-
pound 29a (23 mg, overall yield 55%) as a yellow crystalline solid.
crystalline solid. Rf = 0.17 (silica gel, EtOAc); m.p. 225–226 °C. 1H
NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 1.24 (t, J = 7.1 Hz, 6
H, 2 OCH2CH3), 1.95 (s, 6 H, 2 COCH3), 3.12 (d, 1/2ABq, J =
14.1, 8.1 Hz, 2 H, 2 CHCHaHb), 3.25 (d, 1/2ABq, J = 14.1, 6.3 Hz,
2 H, 2 CHCHaHb), 3.89 (s, 6 H, 2 OCH3), 4.13–4.24 (m, 4 H, 2
OCH2CH3), 4.84 (dt, J = 7.2, 7.2 Hz, 2 H, 2 CHNHAc), 6.41 (d,
J = 8.4 Hz, 2 H, 2 NH), 7.48 (s, 2 H, C3,6-H) ppm. 13C NMR
(100.6 MHz, CDCl3, 25 °C, TMS): δ = 14.0, 22.8, 34.8, 52.3, 52.6,
61.8, 130.4, 130.7, 138.8, 167.6, 170.2, 171.5 ppm. IR (neat): ν =
˜
Rf = 0.21 (silica gel, EtOAc); m.p. 292–294 °C (dec.). 1H NMR 3256 (NH), 1742 (ester C=O), 1650 cm–1 (amide C=O). UV
(300 MHz, [D6]DMSO, 25 °C, TMS): δ = 1.13 (t, J = 7.1 Hz, 6 H,
2 OCH2CH3), 1.81 (s, 6 H, 2 COCH3), 3.16 (d, 1/2ABq, J = 14.3,
(CHCl3): λmax (ε) = 239 nm (8247 mol–1dm3cm–1). HRMS (Q-Tof):
m/z calcd. for C24H32N2NaO10 [M + Na]: 531.1955, found
8.9 Hz, 2 H, 2 CHCHaHb), 3.27–3.40 (m, 2 H, 2 CHCHaHb), 4.08 531.1956.
(q, J = 6.8 Hz, 4 H, 2 OCH2CH3), 4.56 (dt, J = 8.0, 7.1 Hz, 2 H,
meso-Dimethyl 4,5-Bis(2-acetamido-3-ethoxy-3-oxopropyl)phthalate
2 CHNHAc), 7.80 (dd, J = 6.0, 3.2 Hz, 2 H, 2 ArH), 8.13 (s, 2 H,
2 ArH), 8.34 (dd, J = 6.0, 3.3 Hz, 2 H, 2 ArH), 8.52 (d, J = 7.8 Hz,
2 H, 2 NH), 8.87 (s, 2 H, 2 ArH) ppm. 13C NMR (100.6 MHz,
[D6]DMSO): δ = 14.0, 22.4, 33.8, 52.7, 61.1, 128.8, 129.3, 129.6,
130.1, 130.3, 132.4, 134.8, 143.6, 169.9, 171.4, 182.2 ppm. IR
(30b): Dimethyl acetylenedicarboxylate (17) (60 mg, 0.422 mmol)
was added to a solution of the diene 11b (42 mg, 0.114 mmol) in
1,2-dichlorobenzene (5 mL) in a sealed tube, and the reaction mix-
ture was heated (170 °C, 24 h). The solution was concentrated un-
der reduced pressure. The crude reaction mixture was then dis-
solved in dry dioxane (10 mL) and activated MnO2 (60 mg,
0.69 mmol) was added. The reaction mixture was stirred at room
temp. for 12 h and then filtered through a celite pad. The residue
was washed with dioxane (3 ϫ 5 mL) and the solvent was removed
under reduced pressure. The crude product was purified by silica
gel flash column chromatography (EtOAc in petroleum ether 80%)
to afford compound 30b (41 mg, overall yield 71%) as a colorless
crystalline solid. Rf = 0.24 (silica gel, EtOAc); m.p. 128–130 °C. 1H
NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 1.19 (t, J = 7.1 Hz, 6
H, 2 OCH2CH3), 2.0 (s, 6 H, 2 COCH3), 3.18 (s, 2 H, 2
CHCHaHb), 3.20 (s, 2 H, 2 CHCHaHb), 3.89 (s, 6 H, OCH3), 4.10–
4.21 (m, 4 H, 2 OCH2CH3), 4.80 (dt, J = 7.5, 6.9 Hz, 2 H, 2
CHNHAc), 6.48 (d, J = 7.5 Hz, 2 H, 2 NH), 7.49 (s, 2 H, C3,6-H)
ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C, TMS): δ = 13.8, 22.8,
34.8, 52.6, 52.9, 61.8, 130.4, 131.0, 138.9, 167.5, 170.2, 171.4 ppm.
(KBr): ν = 3325 (NH), 1729 (ester C=O), 1678 (ArC=O); 1652
˜
cm–1 (amide C=O). UV (CHCl3): λmax (ε)
=
293 nm
(29101 mol–1dm3cm–1). HRMS (Q-Tof): m/z calcd. for C32H33N2O8
[M + H]: 573.2237, found 573.2240.
meso-Diethyl 3,3Ј-(5,12-Dioxo-5,12-dihydrotetracene-2,3-diyl)bis(2-
acetamidopropanoate) (29b): 1,4-Anthraquinone (16) (23 mg,
0.1 mmol) was added to a solution of the diene 11b (27 mg,
0.073 mmol) in dry toluene (10 mL) and the reaction mixture was
heated (110 °C, 24 h). The solution was concentrated under re-
duced pressure. The crude reaction mixture was then dissolved in
dry dioxane (3 mL) and activated MnO2 (100 mg, 1.15 mmol) was
added. The reaction mixture was stirred at room temp. for 24 h and
then filtered through a celite pad. The residue was washed with
dioxane (3 ϫ 5 mL) and the solvent was removed under reduced
pressure. The crude product was purified by silica gel flash column
chromatography (EtOAc/petroleum ether with 80%) to afford com-
pound 29b (39 mg, overall yield 94%) as a yellow crystalline solid.
Rf = 0.21 (silica gel, EtOAc); m.p. 262–264 °C (dec.). 1H NMR
(400 MHz, CDCl3): δ = 1.26 (t, J = 7.2 Hz, 6 H, 2 OCH2CH3),
2.01 (s, 6 H, 2 COCH3), 3.28 (d, 1/2ABq, J = 14.0, 6.8 Hz, 2 H, 2
CHCHaHb), 3.40 (d, 1/2ABq, J = 14.2, 7 Hz, 2 H, 2 CHCHaHb),
4.17–4.25 (m, 4 H, 2 OCH2CH3), 4.92 (dt, J = 7.6, 6.8 Hz, 2 H, 2
CHNHAc), 6.63 (d, J = 8.0 Hz, 2 H, 2 NH), 7.69 (dd, J = 6.4,
2.8 Hz, 2 H, 2 ArH), 8.08 (dd, J = 5.8, 3.6 Hz, 2 H, 2 ArH), 8.12
(s, 2 H, 2 ArH), 8.79 (s, 2 H, 2 ArH) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 14.0, 22.9, 35.2, 52.9, 62.0, 129.41, 129.46, 129.51,
129.54, 130.0, 132.7, 135.0, 142.5, 170.2, 171.4, 182.4 ppm. IR
IR (neat): ν = 3370 (NH), 1732 (ester C=O), 1661 cm–1 (amide
˜
C=O). UV (CHCl3): λmax (ε) = 248 nm (6593 mol–1dm3cm–1).
HRMS (Q-Tof): m/z calcd. for C24H32N2NaO10 [M + Na]:
531.1955, found 531.1965.
Fullerene Adduct 26a: Fullerene 25 (30 mg, 0.04 mmol) was added
to a solution of the diene 11a (7.5 mg, 0.02 mmol) in dry toluene
(5 mL) in a sealed tube and the reaction mixture was heated
(110 °C, 36 h). The solvent was removed under reduced pressure
and the crude product was purified by silica gel flash column
chromatography (EtOAc in petroleum ether 75%) to afford com-
pound 26a (13 mg, 60%) as a brown solid. Rf = 0.30 (silica gel,
EtOAc); m.p. Ͼ300 °C. 1H NMR (300 MHz, CDCl3, 25 °C, TMS):
δ = 1.38 (t, J = 7.2 Hz, 6 H, 2 OCH2CH3), 2.16 (s, 6 H, 2 COCH3),
3.01 (br. s, 2 H, 2 CHCHaHb), 3.23 (br. s, 2 H, 2 CHCHaHb), 4.03
(s, 2 H, 2 C60CHaHb), 4.05 (s, 2 H, 2 C60CHaHb), 4.26–4.40 (m, 4
H, 2 OCH2CH3), 4.95 (dt, J = 7.5, 7.5 Hz, 2 H, 2 CHNHAc), 6.73
(br. s, 2 H, 2 NH) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 14.5,
23.3, 35.8, 44.8, 52.0, 62.2, 65.9, 135.4, 140.5, 141.9, 142.3, 142.4,
142.8, 143.3, 143.4, 144.9, 145.6, 145.7, 145.9, 146.5, 146.7, 147.9,
(KBr): ν = 3350 (NH), 1739 (ester C=O), 1673 (ArC=O); 1654
˜
cm–1 (amide C=O). UV (CHCl3): λmax (ε)
=
292 nm
(22636 mol–1dm3cm–1). HRMS (Q-Tof): m/z calcd. for C32H33N2O8
[M + H]: 573.2237, found 573.2220.
rac-Dimethyl 4,5-Bis(2-acetamido-3-ethoxy-3-oxopropyl)phthalate
(30a): Dimethyl acetylenedicarboxylate (17) (50 mg, 0.352 mmol)
was added to a solution of the diene 30a (19 mg, 0.052 mmol) in
1,2-dichlorobenzene (5 mL) in a sealed tube and the reaction mix-
ture was heated (170 °C, 24 h). The solution was concentrated un-
der reduced pressure. The crude reaction mixture was then dis-
solved in dry dioxane (7 mL) and activated MnO2 (70 mg,
0.8 mmol) was added. The reaction mixture was stirred at room
temp. for 12 h and then filtered through a celite pad. The residue
was washed with dioxane (3 ϫ 5 mL) and the solvent was removed
under reduced pressure. The crude product was purified by silica
156.5, 170.6, 172.4 ppm. IR (KBr): ν = 3269 (NH), 1736 (ester
˜
C=O), 1656 (amide C=O), 527 cm–1 (C60). UV (CHCl3): λmax (ε) =
276 nm (35377), 330 nm (32169 mol–1dm3cm–1). MS (Q-Tof): 1089
[M + H].
Fullerene Adduct 26b: Fullerene 25 (30 mg, 0.04 mmol) was added
to a solution of the diene 11b (7.5 mg, 0.02 mmol) in dry toluene
(7 mL) and the reaction mixture was heated (110 °C, 36 h). The
Eur. J. Org. Chem. 2007, 1244–1255
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1253

S. Kotha, K. Mandal, S. Banerjee, S. M. Mobin
FULL PAPER
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solvent was removed under reduced pressure and the crude product
was purified by silica gel flash column chromatography (EtOAc in
petroleum ether 75%) to afford compound 26b (14 mg, 64%) as a
brown solid. Rf = 0.30 (silica gel, EtOAc); m.p. Ͼ300 °C. 1H NMR
(400 MHz, CDCl3, 25 °C, TMS): δ = 1.38 (t, J = 7.2 Hz, 6 H, 2
OCH2CH3), 2.17 (s, 6 H, 2 COCH3), 3.02 (br. s, 2 H, 2 CHCHaHb),
3.18 (br. s, 2 H, 2 CHCHaHb), 3.91 (s, 2 H, 2 C60CHaHb), 4.12 (s,
2 H, 2 C60CHaHb), 4.18–4.40 (m, 4 H, 2 OCH2CH3), 5.00 (dt, J =
7.6, 7.6 Hz, 2 H, 2 CHNHAc), 7.01 (d, J = 7.6 Hz, 2 H, 2 NH)
ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C, TMS): δ = 14.5, 23.4,
37.0, 45.4, 52.4, 62.3, 65.9, 135.8 (2 C), 140.35, 140.41 (2 C), 141.8
(2 C), 142.2, 142.3, 142.4 (2 C), 142.79 (2 C), 142.8, 143.26, 143.33,
144.9 (2 C), 145.5, 145.62, 145.65, 145.67, 145.7 (2 C), 145.9, 146.5
(2 C), 146.7 (2 C), 147.8, 156.4, 156.7, 170.6, 172.4 ppm. IR (neat):
[5]
[6]
[7]
ν = 3404 (NH), 1739 (ester C=O), 1652 (amide C=O), 527 cm–1
˜
(C60). UV (CHCl3): λmax (ε)
= 278 nm (35955), 704 nm
[8]
(96 mol–1dm3cm–1). MS (Q-Tof): 1089 [M + H].
X-ray Crystallographic Data of Compound 10b: The crystallo-
[9]
graphic data presented here is of the half molecule in a unit cell.
¯
C8H12NO3, M = 170.19, triclinic, space group, P1, a = 4.9555(6),
[10]
b = 8.2940(19), c = 11.190(3) Å, β = 97.645(16)°, V = 449.98
(18) Å3, T = 293(2) K, Z = 2, µ(Mo-Kα) = 0.096 mm–1, 4519 reflec-
tions measured, 2045 unique (Rint = 0.0164), observed with
[11]
[12]
IϾ2σ(I) which were used in all refinements; R1 = 0.0874, wR2
=
0.2358 for the observed data.
[13]
[14]
CCDC-621384 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
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Acknowledgments
We thank the Department of Science and Technology (DST), New
Delhi, for the financial support, SAIF-Mumbai for providing spec-
tral facilities and the National Single Crystal X-ray Diffraction Fa-
cility, Mumbai for crystallographic data K. M. and S. B. thank the
Council of Scientific & Industrial Research (CSIR) and University
Grants Commission (UGC), New Delhi, respectively, for the award
of research fellowships. We thank Prof. R. Murugavel, Department
of Chemistry, IIT Bombay, for helpful suggestions regarding crys-
tallographic data analysis.
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1244–1255

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[21] The ratio between the two diastereomers was determined from
1
the H NMR analysis.
[22] Catalyst 4 gave similar results as catalyst 5 for the cross–enyne
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Received: November 6, 2006
Published Online: January 25, 2007
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