Total synthesis of luotonin A and 14-substituted analogues

Article abstract of DOI:10.1039/b707684c

A new and concise synthesis of luotonin A was achieved from the previously described compounds ethyl 4-oxo-3,4-dihydroquinazoline-2-carboxylate and 1-(2-nitrophenyl)prop-2-en-1-one. New 14-substituted luotonin A analogues were prepared using 14-chloroluotonin A as the key intermediate. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/b707684c

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Total synthesis of luotonin A and 14-substituted analogues†
Jeffrey J. Mason and Jan Bergman*
Received 22nd May 2007, Accepted 12th June 2007
First published as an Advance Article on the web 29th June 2007
DOI: 10.1039/b707684c
A new and concise synthesis of luotonin A was achieved from the previously described compounds
ethyl 4-oxo-3,4-dihydroquinazoline-2-carboxylate and 1-(2-nitrophenyl)prop-2-en-1-one. New
14-substituted luotonin A analogues were prepared using 14-chloroluotonin A as the key intermediate.
The most commonly stated inadequacies of 1 are associated with
Introduction
poor solubility and an approximately ten-fold lower biological
effect compared to CPT. This has led to the development of
analogues, in an attempt to improve these undesirable qualities.
These analogues were also tested as potential alternatives for
camptothecin-resistant tumour strains. Only a few of the presently
described analogues have shown to be as effective or slightly more
effective than 1. The majority of existing analogues of 1 have
modifications to the E-ring, but alterations to positions in other
rings have also been described.2q,5–7
The natural product luotonin A (1) was first described a decade
ago by Ma and Nomura. It was extracted from the aerial parts
of Peganum nigellasterum (Chinese Bunge), commonly known as
“luo-tuo-hao”, giving the name to this group of compounds.1 Since
then, many alternative approaches to the preparation of luotonin
A have been reported.2 Several reviews have summarized these
synthetic developments as the number of synthetic procedures in
this field has grown.3
Several camptothecin analogues have emerged as approved
therapeutic antineoplastic agents, namely the topotecan and
irinotecan hydrochlorides (Fig. 1), while others are in various
stages of clinical trials. These compounds have been shown to
be effective in treatments for breast, colon, ovarian and small-cell
lung cancer as well as malignant melanomas and leukaemia.8 It
is hoped that analogues of luotonin A can serve as models, or
in some cases as substitutes, for camptothecin-based anti-cancer
agents.
The method described herein provides a new and concise
synthetic route to luotonin A and analogues with substituents at
the C-14 position. There are several different numbering schemes
reported for 1. We chose to adopt the numbering system from
Curran’s work,2q where the assignment is in agreement with other
14-substituted analogues of 1. The same numbering scheme can
also be found in the work by Dallavalle.7
Fig. 1 Structures of luotonin A (1), 20(S)-camptothecin, topotecan and
irinotecan.
Results and discussion
Structural similarities between 1 and camptothecin (CPT) have
been stated since the discovery of 1, but the biological associations,
albeit at a lower inhibitory extent, were confirmed in an elegant
experiment by Hecht and co-workers.4 Like CPT, luotonin A has
been described as a selective (class I) human DNA-topoisomerase
I (Top I) covalent binary complex stabilizer,5 although 1 has been
reported as having a lower Top I selectivity than CPT, with regard
to Top I–Top II inhibitory effects.6
The synthetic route devised involved the sequential formation of
the B, C and D rings of luotonin A. The A and E rings were
derived from 2-nitrobenzaldehyde and ethyl 4-oxo-3,4-dihydro-
quinazoline-2-carboxylate (2), respectively.
The preparation of ethyl 4-oxo-3,4-dihydroquinazoline-2-
carboxylate (2) was modified from previously described
procedures.9 These were reported as giving yields of 57%9a and
90%.9b In our procedure an excess of diethyl oxalate was added to
a melt of 2-aminobenzamide, giving yields consistently above 90%.
Formation of 1-(2-nitrophenyl)propenone (3) was achieved via a
method described by Danishefsky,10 using 2-nitrobenzaldehyde
as the starting material in 86% over two steps. The Michael
addition of 2 with the propenone compound 3 occurs rapidly,
and an intramolecular Claisen condensation followed to produce
compound 4 (Scheme 1).
Unit for Organic Chemistry, Department of Biosciences and Nutrition,
Karolinska Institute, SE-14157, Huddinge, Sweden. E-mail: jabe@
biosci.ki.se; Fax: +46 8-608-1501; Tel: +46 8-608-9204
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectral data. See DOI: 10.1039/b707684c
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Table 1 Nucleophilic substitutions of 14-chloroluotonin A
R
Conditions
Product
Yield (%)
81
Neat, excess amine
8
Scheme 1 Reagents and conditions: i) THF, −70 ◦C, vinylmagnesium
bromide. ii) Jones reagent, 86% over 2 steps. iii) DMF, t-BuOK, 60 ◦C.
iv) 3, 83%.
Neat, excess amine
9
79
Catalytic hydrogenation of 4 with Pd/C in DMF produced
compound 5 in quantitative yield. Chlorination of 5 using
phosphorus oxychloride gave 14-chloroluotonin A (6). Reduction
of 6 to the target molecule 1 (84%) was found to work best
using freshly activated Raney nickel catalyst at room temperature
(Scheme 2).
DMF, K2CO3
DMF, K2CO3
10
11
87
86
Nucleophilic substitutions of 6 were performed under two
different sets of conditions, depending on the nature of the
reactant. The more volatile amines were refluxed neat (N,N-
dimethyl-1,3-diaminopropane and piperidine), producing com-
pounds 8 and 9 respectively. The other substitution conditions
used benzylamine or methyl mercaptoacetate, in DMF with
K2CO3, giving compounds 10 and 11 (Table 1).
The structure of 8 is strikingly reminiscent of other groups
of polycyclic quinoline-based structures such as nitracrines15
and some quindoline derivatives.16 The nitracrines are a group
of hypoxia-selective cytotoxic compounds that display in vitro
activity, while the quindoline derivatives have shown activ-
ity towards stabilizing G-quadruplex DNA of certain on-
cogenes.
Two different reactions involving palladium catalysts demon-
strated the potential of 6 in transition-metal-catalyzed reactions.
Attempted dechlorination of 6 with Pd/C in acetic acid produced
the coupled product, 14,14ꢀ-bisluotonin A (12), quantitatively
(Scheme 3). This is presumed to occur via an acidic modification
of the Wurtz-type coupling between the heteroaromatic halide
subunits.17
Scheme 2 Reagents and conditions: i) Pd/C, H2, DMF, 1 h, 96%.
ii) POCl3, reflux, 1 h, 99%. iii) Raney nickel, dioxane, 1 h, 84%. iv) Raney
nickel, dioxane, reflux, 1 h (or rt, >4 h).
Furthermore, reduction of 6 or luotonin A with Raney nickel
generated compound 7 (Scheme 2). The structure was confirmed
as 7,8,9,10-tetrahydroluotonin A, using HMBC analysis. A cor-
relation was found between the C-11 carbonyl and the protons
associated with the C-10 carbon. Compound 7 has been previously
reported as 16,17,18,19-tetrahydroluotonin A,5 and biological
screening returned a lower Top I inhibitory response than 1.11
The halo-substituent of 6 can undergo various modifications.
An equivalent CPT analogue, 7-chlorocamptothecin, has been
described.12 Substituents in this position have been shown to in-
fluence the solubility and biological effect of the CPT analogues.13
To test the reactivity of 6, a small group of established reactions
were performed. Initially, nucleophilic substitutions with amines
and a sulfur compound were investigated, since analogues of
CPT with alkyl, alkyl amino and alkyl imino chains have been
synthesized, and some of these compounds displayed superior
Top I inhibition compared to CPT.14
Scheme 3 Reagents and conditions: i) Pd/C, HOAc, 40 ◦C, 3 h, 100%.
Coupling 6 with 1-hexyne using a copper-free Sonogashira
reaction produced compound 13 (Scheme 4).18
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HCl (0.01 M, 100 ml), concentrated under vacuum to 200 ml,
extracted with Et2O–diethyl ether (3 × 300 ml), dried over MgSO4
and evaporated, giving a dark oil, 1-(2-nitrophenyl)prop-2-en-1-ol
(14.33 g, assumed quantitative yield). This was used immediately
in the oxidation reaction to the corresponding ketone.
A solution of Jones reagent (2.67 M) was prepared and 20 ml
was added dropwise to 1-(2-nitrophenyl)prop-2-en-1-ol (14.30 g,
79.8 mmol) in ac◦etone (200 ml) at 3 ◦C, such that the reaction
did not exceed 8 C. The reaction was complete within 1 h. The
solution was treated with i-PrOH (10 ml) and stirred at room
temperature for 10 minutes. This was then passed through a pad
of Celite and the solvent was evaporated to give 3, as a dark oil
(11.92 g, 67.3 mmol, 86%). This substance was used immediately
after isolation in the preparation of 4. Spectral data were in
agreement with previously published results.10
Scheme 4 Reagents and conditions: i) Pd(OAc)2, rac-BINAP, K2CO3,
benzene, reflux, 18 h, 87%.
Conclusions
A new method for the total synthesis of luotonin A was suc-
cessful using straightforward and cost-effective operations. More
importantly, several new 14-substituted analogues of luotonin A
were synthesized and a technique for generating novel and diverse
libraries of luotonin A analogues has been described.
Preparation of compound 4
The ester 2 (13.093 g, 60.0 mmol) was dissolved in DMF
(200 ml) and warmed to 60 ◦C. Potassium tert-butoxide (7.407 g,
66.0 mmol) was dissolved in DMF (50 ml) and added to the
solution. After 30 minutes the acrylic nitro-compound 3 (11.70 g,
66 mmol) was added and stirred at 60 ◦C for 2 hours. The solvent
was removed under vacuum to relative dryness, treated with water
(300 ml) and stirred for 2 hours at room temperature. The solution
was filtered and treated with 1 M HCl (ca. 65 ml) to pH 4. This
gave a precipitate that was filtered and collected. Concentration
of the liquor to 50 ml gave a further 10% of precipitate. The solid
collected was dissolved in refluxing 95% ethanol (600 ml), cooled
and collected. The filtrate was washed with absolute ethanol (2 ×
100 ml) and Et2O (2 × 50 ml) to give the desired compound 4 as
a white powder (17.53 g, 50.2 mmol, 83%), mp 215 ◦C (dec.); IR
mmax/cm−1 1661, 1604, 1518, 1432, 1342 and 1275; Anal. calcd. for
C18H11N3O5: C, 61.9; H, 3.2; N, 12.0. Found: C, 61.8; H, 3.3; N,
12.0; 1H NMR (300 MHz, DMSO-d6) dH 4.72 (2H, s), 7.59–7.64
(2H, m), 7.75–7.93 (4H, m) 8.22–8.26 (2H, m); 13C NMR (75 MHz,
DMSO-d6) dC 46.3, 115.3, 120.8, 124.0, 126.1, 126.9, 127.4, 128.8,
130.9, 134.5, 134.8, 136.7, 146.0, 148.1, 153.4, 154.9, 158.6, 186.4;
HRMS-FAB: m/z calcd for C18H11N3O5 + H, 350.0771; found
350.0773 [M + H]+.
Experimental
General
Solvents and reagents were commercially sourced and used
without further purification or preparation, with the exception of
THF, which was freshly distilled over sodium and benzophenone.
Melting points were taken using a Bu¨chi Melting Point B-545
capillary apparatus in open capillary tubes and are uncorrected.
IR spectra were acquired (neat) using a Thermo Nicolet Avatar 330
FT-IR instrument. NMR data was recorded at 300.13 MHz for 1H,
and 75.5 MHz for 13C, or at a frequency of 500.16 MHz for 1H, and
125.8 MHz for 13C, for 2D analyses with the specified deuterated
solvents. Elemental analyses and mass spectrum services were
externally sourced.
Preparation of ethyl 4-oxo-3,4-dihydroquinazoline-2-carboxylate
(2)
Diethyl oxalate (410 ml, 3.0 mol) was carefully poured, in a
portionwise fashion, into a melt of 2-aminobenzamide (136.15 g,
1.0 mol). The mixture was stirred at reflux for 8 h, and monitored
by TLC [DCM–Et2O (1 : 1)]. The solution was allowed to cool
to room temperature and the excess diethyl oxalate was removed
under vacuum. The remaining solid was suspended in EtOH and
filtered. Recrystallization from EtOH produced 2 (200 g, 92%)
Preparation of 5H,12H-5,6,11a-triazadibenzo[b,h]fluoren-11,14-
dione (5)
as fine white needles, mp 190–191 C (lit.,9a 179–180 ◦C); IR
mmax/cm−1 1639 and 1609; H NMR (300 MHz, DMSO-d6) dH
1.33–1.38 (3H, t, J 7.1), 4.35–4.42 (2H, q, J 7.1), 7.61–7.66 (1H,
m), 7.80–7.91 (2H, m) 8.16–8.19 (1H, dd, J 7.9, 1.1), 12.61 (1H,
s); 13C NMR (75 MHz, DMSO-d6) dC 13.9, 62.6, 122.9, 126.0,
128.3, 128.6, 134.8, 143.4, 147.2, 160.2, 161.0; MS(ESI) m/z 219
[M + H]+.
◦
The pyrroloquinazolinone 4 (6.986 g, 20.0 mmol) was suspended in
1
DMF (100 ml) and reduced using Pd/C 10% (0.6 g) and hydrogen
◦
(20 bar). The reaction proceeded for 1 h at 50 C. The solution
was filtered through a pad of Celite and the product was washed
out with hot DMF until the solution was clear of any UV-active
compound by TLC. The solvent was evaporated to relative dryness
and boiled in 95% ethanol (200 ml). The cooled solution was
filtered, and the collected solid was washed with absolute ethanol
(2 × 50 ml), then Et2O (2 × 50 ml) to give the desired compound 5
(5.79 g, 96%) as a white powder, mp >400 ◦C; IR mmax/cm−1 1675,
Preparation of 1-(2-nitrophenyl)prop-2-en-1-ol and
1-(2-nitrophenyl)prop-2-en-1-one (3)
◦
1
Under an atmosphere of argon, 2-nitrobenzaldehyde (12.09 g,
80 mmol) was dissolved in freshly distilled THF (400 ml) and
cooled to −70 ◦C. Vinyl magnesium bromide in THF (1.0 M,
100 mmol) was added, so that the internal temperature did
not exceed −60 ◦C. After 1 h the solution was quenched with
1584 and 1461; H NMR (300 MHz, DMSO-d6, 90 C) dH 4.97
(2H, s), 7.39–7.44 (1H, m), 7.61–7.67 (1H, m), 7.72–7.77 (1H, m),
7.87–7.96 (3H, m), 8.24–8.27 (1H, dd, J 0.9, 8.1), 8.30–8.33 (1H,
dd, J 0.9, 8.1), 12.74 (1H, s); 13C NMR (75 MHz, D2SO4) dC 50.9,
118.1, 119.5, 121.0, 121.2, 121.6, 124.5, 128.7, 132.5, 133.5, 136.0,
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136.1, 140.2, 140.2, 141.1, 149.1, 158.9, 166.9; HRMS-FAB: m/z
Method B. Reaction conditions and treatment were as for the
formation of 1 (above) but the solution was heated to reflux, giving
7 (80 mg, 92%).
calcd for C18H11N3O2 + H, 302.0924; found 302.0921 [M + H]+.
Preparation of 14-chloroluotonin A (6)
Method C. A sample of 1 (50 mg) was reacted using method
A and isolated, giving 7 (33 mg, 65%).
The dione 5 (5.5 g, 18.25 mmol) was refluxed in POCl3 (30 ml) for
1 h. The solvent was removed under vacuum and the remaining
compound was treated with ice-water (20 ml). The mixture was
neutralized with aq. NaHCO3 (50 ml) and the solid product
filtered. This was washed with water (2 × 30 ml), absolute ethanol
(2 × 25 ml) and diethyl ether (2 × 25 ml). The dried substance
was recrystallized with copious amounts of chloroform to give 6
(5.80 g, 99%) as a white powder, mp 287 ◦C (dec.); IR mmax/cm−1
Preparation of compound 8
To a sealed vessel 6 (96 mg, 300 lmol) was dissolved in 3-
N-(dimethylamino)propylamine (1.0 ml) and heated at 145 ◦C
for 2 hours. TLC: DCM–MeOH (99 : 1). The solution was
evaporated to dryness under vacuum, dissolved in DCM (30 ml),
treated with aq. NaHCO3 (10 ml), and brine (10 ml). The organic
phase was dried over MgSO4, filtered, evaporated to dryness, and
recrystallized from acetonitrile, giving 8 (94 mg, 81%), mp 258 ◦C
(dec.); IR mmax/cm−1 2818, 1677, 1572, 1466, 1433, 1367 and 1336;
1H NMR (300 MHz, DMSO-d6) dH 1.80-1.89 (2H, m), 2.20 (6H,
s), 2.39–2.43 (2H, m), 3.67–3.72 (2H, m), 5.41 (2H, s), 7.49–7.59
(2H, m), 7.67–7.77 (2H, m), 7.84–7.91 (2H, m), 7.94–7.98 (1H, dd,
J 8.4, 1.0 Hz), 8.15–8.18 (1H, d, J 8.4), 8.22–8.25 (1H, m); 13C
NMR (75 MHz, DMSO-d6) dC 25.2, 40.9, 42.3, 42.3, 47.9, 54.5,
109.0, 119.0, 120.8, 122.4, 125.4, 125.8, 126.7, 127.9, 129.8, 129.9,
134.4, 147.0, 149.1, 149.3, 151.6, 153.7, 159.5; HRMS-FAB: m/z
calcd for C23H23N5O + H, 386.1975; found 386.1973 [M + H]+.
1
1684, 1626, 1605, 1466 and 1329; H NMR (300 MHz, CDCl3)
dH 5.37 (2H, s), 7.57–7.62 (1H, m), 7.78–7.94 (3H, m), 8.12–8.15
(1H, dd, J 0.5, 8.3), 8.36–8.39 (1H, dd, J 1.0, 8.4), 8.45–8.48 (1H,
dd, J 1.2, 8.4), 8.51–8.54 (1H, dd, J 0.6, 8.5); 13C NMR (75 MHz,
D2SO4, DMSO-d6) dC 57.2, 124.2, 126.9, 127.7, 131.6, 134.1, 135.9,
138.4, 138.7, 140.2, 140.8, 141.5, 144.9, 145.4, 146.5, 153.9, 159.3,
163.0; HRMS-FAB: m/z calcd for C18H10ClN3O + H, 320.0585;
found 320.0581 [M + H]+.
Preparation of luotonin A (1)
Compound 6 (96 mg, 300 lmol) was suspended in 1,4-dioxane
(50 ml) at room temperature. Activated Raney nickel (0.5 g) was
added and the vessel sealed whilst being stirred vigorously. The
reaction was monitored via TLC [hexane–DCM (1 : 15)] and was
found to be complete after approximately 1 hour. Filtration of the
mixture through a pad of Celite and evaporation to dryness gave
the crude compound, which was then redissolved in DCM and
purified by chromatography using a gradient system of hexane–
DCM (1 : 20) → DCM. The fractions containing the major
component were combined and evaporated to dryness giving 1
as a fine white powder (72 mg,◦ 84%), mp 255–257 ◦C (dec.)
from (CHCl3–acetone), (lit.,1 252 C (dec.)); 1H NMR (300 MHz,
DMSO-d6) dH 5.30 (2H, s), 7.59–7.65 (1H, m), 7.72–7.77 (1H, dd,
J 7.6 and 7.3 Hz), 7.87–7.93 (3H, m), 8.13–8.16 (1H, d, J 8.1 Hz),
8.24–8.29 (2H, m), 8.74 (1H, s); 13C NMR (75 MHz, DMSO-d6) dC
47.5, 121.0, 125.9, 127.1, 128.0, 128.2, 128.4, 128.4, 129.6, 130.4,
130.9, 131.7, 134.4, 148.3, 149.0, 151.4, 153.0, 159.6; HRMS-FAB:
m/z calcd for C18H11N3O + H, 286.0975; found 286.0991 [M + H]+.
Preparation of compound 9
In piperidine (1 ml), 6 (65 mg, 200 lmol) was refluxed for 4 hours.
The solution was evaporated to dryness, extracted with DCM (3 ×
20 ml), washed with aq. NaHCO3 (10 ml) and brine (10 ml). The
organic extracts were dried with MgSO4, filtered, evaporated to
dryness, and triturated in diethyl ether to give 9 (58 mg, 79%),
mp 306–308 ◦C (dec.); IR mmax/cm−1 2925, 1672, 1606, 1566, 1504,
1465, 1385, 1335 and 1102; 1H NMR (300 MHz, DMSO-d6, 50 ◦C)
dH 1.73–1.88 (6H, m), 3.46–3.49 (4H, m), 5.50 (2H, s), 7.58–7.69
(2H, m), 7.78–7.84 (1H, m), 7.91–7.94 (2H, m), 8.12–8.16 (2H,
m), 8.28–8.31 (1H, m); 13C NMR (75 MHz, DMSO-d6, 50 ◦C)
dC 23.5, 25.9, 25.9, 47.51, 52.1, 52.1, 120.3, 120.7, 124.2, 124.3,
125.7, 126.6, 126.7, 127.8, 129.7, 129.9, 134.2, 149.1, 150.0, 151.7,
152.7, 153.0, 159.3; HRMS-FAB: m/z calcd for C23H20N4O + H,
369.1710; found 369.1712 [M + H]+.
Preparation of compound 10
Preparation of 7,8,9,10-tetrahydroluotonin A (7)
In DMF, 6 (96 mg, 300 lmol) was refluxed with benzylamine
(48 mg, 450 lmol) and K2CO3 (125 mg) for 18 hours. The solution
was evaporated to dryness and washed with water (3 × 5.0 ml).
The compound was filtered and washed with hot et◦hanol, giving
10 (102 mg, 87%) as an amorphous solid, mp 300 C (dec.); IR
mmax/cm−1 3267, 1683, 1634, 1567, 1466, 1453, 1423, 1390 and
Method A. The procedure for the formation of 1 was used
but the reaction time was increased to 4 hours. TLC showed
the starting material was no longer luotonin A (Rf 0.5) and was
completely transformed. The solution was passed through a pad
of Celite and evaporated to dryness, giving 7 (84 mg, 94%) as
◦
a fine granular substance, mp 272–273 C (dec.), (lit.,5 275 ◦C
1348; H NMR (300 MHz, DMSO-d6) dH 4.92–4.94 (2H, d, J
1
(dec.)); IR mmax/cm−1 2940, 1667, 1625, 1609, 1468, 1456, 1377
6.3 Hz), 5.24 (2H, s), 7.25–7.29 (1H, m), 7.34–7.42 (4H, m), 7.55–
7.63 (2H, m), 7.75–7.80 (1H, m), 7.87–7.88 (2H, m), 8.03–8.05
(1H, d, J 8.0 Hz), 8.14–8.21 (2H, m), 8.47–8.50 (1H, d, J 8.5 Hz);
13C NMR (75 MHz, DMSO-d6) dC 46.4, 47.6, 108.6, 119.0, 120.8,
122.2, 125.7, 125.8, 125.9, 125.9, 126.7, 127.1, 127.9, 128.8, 128.8,
129.9, 130.0, 134.3, 140.4, 147.3, 149.2, 149.3, 151.6, 153.5, 159.4;
HRMS-FAB: m/z calcd for C25H18N4O + H, 391.1553; found
391.1562 [M + H]+.
◦
1
and 1286; H NMR (300 MHz, DMSO-d6, 90 C) dH 1.78–1.95
(4H, m), 2.86–2.90 (2H, m), 2.96–3.00 (2H, m), 5.05 (2H, s), 7.52–
7.57 (1H, m), 7.79–7.88 (3H, m), 8.22–8.25 (1H, d, J 7.8 Hz); 13
C
NMR (75 MHz, DMSO-d6, 90 ◦C) dC 21.4, 21.8, 28.4, 31.8, 46.7,
120.2, 125.3, 125.9, 127.1, 131.7, 132.6, 133.6, 135.0, 146.8, 148.8,
153.1, 158.8, 159.0; HRMS-FAB: m/z calcd for C18H15N3O + H,
290.1293; found 290.1295 [M + H]+.
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K. Agama, Y. Pommier and D. P. Curran, Synlett, 2005, 18, 2843;
(r) W. R. Bowman, M. R. J. Elsegood, T. Stein and G. W. Weaver, Org.
Biomol. Chem., 2007, 5, 103; (s) A. Servais, M. Azzouz, D. Lopes,
C. Courillon and M. Malacria, Angew. Chem., Int. Ed., 2007, 46,
576.
In DMF (3.0 ml) K2CO3 (210 mg) was added followed by 6
(160 mg, 500 lmol) and refluxed with methyl mercaptoacetate
(80 mg, 750 lmol) for 18 h. The solution was evaporated to dryness
and partitioned between DCM and water. The organic phase was
dried with NaSO4, filtered and evaporated to dryness, giving 11
◦
(167 mg, 86%), mp 236–237 C (dec.); IR mmax/cm−1 1657, 1607,
1
1547, 1498, 1468, 1408, 1◦385, 1342, 1310 and 1257; H NMR
(300 MHz, DMSO-d6, 60 C) dH 3.54 (3H, s), 4.03 (2H, s), 5.40
(2H, s), 7.62–7.67 (1H, m), 7.85–7.99 (4H, m), 8.30–8.35 (2H,
m), 8.55–8.58 (1H, d, J 8.3 Hz); 13C NMR (75 MHz, DMSO-d6,
60 ◦C) dC 35.8, 47.6, 52.0, 120.9, 124.8, 125.6, 127.0, 127.8, 128.9,
129.0, 130.4, 130.4, 134.2, 135.6, 137.4, 148.7, 148.8, 150.6, 152.6,
159.2, 168.9; (ESI) m/z 390 [M + H]+; HRMS-FAB: m/z calcd for
C21H15N3O3S + H, 390.0907; found 390.0908 [M + H]+.
Preparation of 14,14ꢀ-bisluotonin A (12)
3 (a) A. Witt and J. Bergman, Curr. Org. Chem., 2003, 7, 659; (b) Z.
Ma, Y. Hano and T. Nomura, Heterocycles, 2005, 65, 2203; (c) D. J.
Connolly, D. Cusack, T. P. O’Sullivan and P. J. Guiry, Tetrahedron,
2005, 61, 10153; (d) S. B. Mhaske and N. P. Argade, Tetrahedron, 2006,
62, 9787; (e) J. P. Michael, Nat. Prod. Rep., 2007, 24, 223; J. P. Michael,
Nat. Prod. Rep., 2005, 22, 627; J. P. Michael, Nat. Prod. Rep., 2004, 21,
650; J. P. Michael, Nat. Prod. Rep., 2003, 20, 476; J. P. Michael, Nat.
Prod. Rep., 2002, 19, 742; J. P. Michael, Nat. Prod. Rep., 2001, 18, 543;
J. P. Michael, Nat. Prod. Rep., 2000, 17, 603; J. P. Michael, Nat. Prod.
Rep., 1999, 16, 697.
4 A. Cagir, S. H. Jones, R. Gao, B. M. Eisenhauer and S. M. Hecht,
J. Am. Chem. Soc., 2003, 125, 13628.
5 A. Cagir, B. M. Eisenhauer, R. Gao, S. J. Thomas and S. M. Hecht,
Bioorg. Med. Chem., 2004, 12, 6287.
Under argon, 6 (160 mg, 500 lmol) was dissolved in acetic acid
(5.0 ml). 10% Pd/C (20 mg) was added to the solution, which
was warmed to 40 ◦C for 3 hours. Filtration through Celite,
evaporation of the solvent to dryness and recrystallization from
ethanol gave 12 (142 mg, 100%), mp >400 ◦C; IR mmax/cm−1 1681,
1
1584, 1531, 1463, 1402, 1383 and 1336; H NMR (300 MHz,
DMSO-d6) dH 4.67–4.73 (2H, d, J 17.9 Hz), 5.10–5.16 (2H, d, J
17.9 Hz), 7.57–7.69 (6H, m) 7.92–8.03 (6H, m), 8.22–8.25 (2H,
dd, 8.0, 1.0 Hz), 8.48–8.51 (2H, d, J 8.4 Hz); 13C NMR (75 MHz,
DMSO-d6) dC 47.3, 121.0, 125.3, 125.9, 126.0, 127.4, 128.2, 129.3,
130.6, 130.9, 131.0, 134.7, 135.6, 148.8, 149.0, 152.0, 153.3, 159.5;
HRMS-FAB: m/z calcd for C36H20N6O2 + H, 569.1721; found
569.1723 [M + H]+.
6 K. Narco, C. Zha, P. R. Guzzo, R. J. Herr, D. Pearce and T. D. Fredrich,
Bioorg. Med. Chem., 2007, 15, 4237; Z. Ma, Y. Hano, T. Nomura and
Y. Chen, Bioorg. Med. Chem. Lett., 2004, 14, 1193.
7 S. Dallavalle, L. Merlini, G. L. Beretta, S. Tinelli and F. Zunino, Bioorg.
Med. Chem. Lett., 2004, 14, 5757.
8 Y. Pommier, Nat. Rev. Cancer, 2006, 10, 789.
Preparation of 14-(hex-15-ynyl)luotonin A (13)
9 (a) B. R. Baker and P. I. Almaula, J. Org. Chem., 1962, 27, 4672;
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Under an argon atmosphere, a solution of hexyne (2.0 mmol)
in degassed benzene (20.0 ml) was added to a mixture of 7-
chloroluotonin A 6 (160 mg, 500 lmol), Pd(OAc)2 (0.05 mmol),
rac-BINAP (0.1 mmol) and potassium carbonate (1.0 mmol). The
reaction mixture was heated to reflux for 18 h. The solvent was
evaporated and the residue was purified by column chromatogra-
phy [hexane–chloroform–acetone (30 : 10 : 1)], giving 13 (159 mg,
87%) as a white substance, mp 226–227 ◦C (dec.). 1H NMR
(300 MHz, CDCl3) dH 1.02–1.07 (3H, t, J 7.3 Hz), 1.54–1.67 (2H,
m), 1.73–1.83 (2H, m), 2.68–2.73 (2H, t, J 7.1 Hz), 5.34 (2H, s),
7.55–7.60 (1H, m), 7.69–7.74 (1H, m), 7.80–7.88 (2H, m), 8.10–
8.13 (1H, d, J 8.1 Hz), 8.33–8.36 (1H, d, J 8.3 Hz), 8.42–8.46 (2H,
m). 13C NMR (75 MHz, CDCl3) dC 13.8, 19.9, 22.3, 30.7, 47.8, 74.0,
107.8, 121.5, 125.9, 126.6, 127.2, 127.6, 128.7, 128.8, 128.9, 130.8,
131.2, 131.7, 134.7, 149.4, 149.5, 150.6, 153.0, 160.7. HRMS-FAB:
m/z calcd for C24H19N3O + H, 366.1601; found 366.1603 [M + H]+.
10 W. Shen, C. A. Coburn, W. G. Bornmann and S. J. Danishefsky, J. Org.
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11 A. Cagir, S. H. Jones, B. M. Eisenhauer, R. Gao and S. M. Hecht,
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12 E. Winterfeldt, T. Korith, D. Pike and M. Bosch, Angew. Chem., Int.
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2490 | Org. Biomol. Chem., 2007, 5, 2486–2490
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