Total synthesis of lavendamycin by a [2+2+2] cycloaddition

Article abstract of DOI:10.1002/ejoc.201100131

The total synthesis of the bacterial-derived, pentacyclic, antitumor antibiotic lavendamycin has been achieved through a highly convergent strategy. The key step of this synthesis is a ruthenium-catalyzed [2+2+2] cycloaddition of an electron-deficient nit

Full text of DOI:10.1002/ejoc.201100131

FULL PAPER
DOI: 10.1002/ejoc.201100131
Total Synthesis of Lavendamycin by a [2+2+2] Cycloaddition
Felix Nissen*[a] and Heiner Detert[a]
Dedicated to Prof. Dr. Horst Kunz on the occasion of his 70th birthday
Keywords: Natural products / Total synthesis / Cycloaddition / Regioselectivity / Nitrogen heterocycles
The total synthesis of the bacterial-derived, pentacyclic, anti-
tumor antibiotic lavendamycin has been achieved through a
highly convergent strategy. The key step of this synthesis is
a ruthenium-catalyzed [2+2+2] cycloaddition of an electron-
deficient nitrile to an alkynyl-ynamide to prepare the carb-
oline scaffold. The elaborate cycloaddition substrate is ob-
tained in few steps by an N-ethynylation using alkynyliodon-
ium salt chemistry and two palladium-catalyzed cross-cou-
pling reactions. An efficient synthesis of a halogenated quin-
oline-5,8-dione building block starting from hydroquinone is
presented.
agent, lavendamycin’s beneficial effects are unfortunately
associated with a high general toxicity, which has precluded
its potential clinical use. Therefore, a substantial interest in
a flexible strategy for the total synthesis of lavendamycin
arose recently, elicited by the potential application of struc-
turally related analogs having comparable efficacy but di-
minished toxicity.
Introduction
Lavendamycin (1, Figure 1), a bacterial-derived anti-
tumor antibiotic, was isolated and characterized from
Streptomyces lavendulae in 1981 by Doyle and Balitz.[1] In
initial studies lavendamycin showed activity against several
cancer cell lines and significant activity against topoisomer-
ase I.[2]
A key to the synthesis of lavendamycin lies in the prepa-
ration of the highly substituted pyridine ring of the carb-
oline core. Several strategies have been applied to the synthe-
sis of this heterocyclic system, that is, annulation of a pyr-
idine ring to a preformed indole structure through classic
Pictet–Spengler[13] or Bischler–Napieralski condensation,[14]
ring-closure of the pyrrole ring through a Pd-mediated[7] or
nucleophilic[11] substitution, tandem aza-Wittig/electro-
cyclic ring-closure followed by construction of the pyrrole
ring through a thermolytic nitrene insertion,[10] and modi-
fied Knoevenagel–Stobbe reaction.[9] However, low yields,
not readily available starting materials, or a lack of general-
ity make these strategies unattractive for the systematic syn-
thesis of structurally related analogs. Recently, Behforouz
reported an efficient total synthesis of lavendamycin
through a Pictet–Spengler condensation of 7-(acylamino)-
2-formylquinoline-5,8-dione and β-methyltryptophan.[8]
Based on this approach, over 100 analogs, varied predomi-
nantly by esterification as well as acylation of the 7-amino
group, were synthesized and biologically evaluated. Several
lavendamycin analogues showed a higher specific toxicity
against human cancer cells,[15] as well as anti-HIV reverse
transcriptase activity,[16] compared to the parent molecule.
Inspired by the highly flexible approach to the formation
of annulated pyridines from tethered diynes or cyano-
alkynes in transition-metal-mediated [2+2+2] cycload-
ditions,[17,18] we investigated the possibility of simulta-
Figure 1. Lavendamycin (1) and streptonigrin (2).
These promising biological properties as well as the com-
plex structural features of lavendamycin (1), a highly func-
tionalized pentacyclic structure containing a β-carboline[3]
and a quinoline-5,8-dione moiety, have sparked consider-
able research activities directed toward its total synthesis.
As a result of these efforts, the first total synthesis of laven-
damycin was reported in 1984 by Kende and Ebetino, and
additional total syntheses followed within the next few
years.[4–11] Closely related in structure and biological ac-
tivity to streptonigrin (2),[12] another potent antitumor
[a] Institute for Organic Chemistry, Johannes Gutenberg
University Mainz,
Duesbergweg 10–14, 55099 Mainz, Germany
Fax: +49-6131-3925338
E-mail: detert@uni-mainz.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100131.
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F. Nissen, H. Detert
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neously constructing the pyrrole and the pyridine ring in
the carboline core with a cocycloaddition of a 1,6-diyne and
a nitrile.[19]
Results and Discussion
Our synthetic strategy for lavendamycin is based on the
retrosynthetic analysis shown in Figure 2. The key step of
this synthesis is the formation of the β-carboline core by a
transition-metal-catalyzed [2+2+2] cycloaddition. Ad-
ditional masking of the 7-aminoquinoline-5,8-dione unit by
appropriate group transformations leads retrosynthetically
to the electron-deficient nitrile methyl cyanoformate and
the o,N-dialkynylanilide (alkynyl-ynamide) 3.[20,21] Continu-
ing with the simplification of the structure, diyne 3 can be
traced back by straightforward retrosynthetic disconnec-
tions to the small and readily available starting materials 2-
iodoaniline, hydroquinone, propyne, 3,3-dimethoxyprop-
anoic acid, and ethynyl(phenyl)iodonium triflate 4.[22]
Scheme 1. Reaction sequence leading to 12.
common catalysts for halogen exchange in 2- or 4-chloro-
pyridines, afforded iodoquinoline 12 in excellent yields
(Table 1, Entries 1–3, 87–93%). Remarkably, the use of
acid-free acetyl chloride (distilled from PCl5 followed by
distillation from quinoline) under the same conditions led
to only 10% conversion after 24 h (Entry 4), which shows
for this reaction the importance of an initially formed pro-
tonated species.
Table 1. Investigation of the reaction conditions for the chlorine/
iodine exchange leading to iodoquinoline 12.
Figure 2. Retrosynthetic analysis for lavendamycin (1).
Run
Catalyst
Time [h] Isolated yield [%]
1
2
3
4
2 equiv. AcCl
0.5 equiv. HCl (aqueous)
0.5 equiv. TMSCl
4
4
4
93
87
An important intermediate for the synthesis of the quin-
oline-5,8-dione moiety of lavendamycin was the known
compound 8 (Scheme 1). With some improvements, the syn-
thesis of 8 followed published procedures (see Exp. Sect. for
details). Briefly, this unit was prepared from hydroquinone
(5) by acetylation,[23a] nitration,[23b] methanolysis, and sub-
91
2 equiv. AcCl (acid-free)
24
10[a]
1
[a] Not isolated; conversion determined by H NMR.
Having established a convenient procedure for the con-
sequent methylation with diazomethane[23c] to yield 1,4-di- struction of the quinoline-5,8-dione part of lavendamycin,
methoxy-2,6-dinitrobenzene (7) in 55% yield over 4 steps. we next turned our attention to the preparation of 1,6-diyne
Thereafter, a selective reduction of one of the nitro groups 3. Based on Witulski’s route to carbazoles through a rho-
was achieved by transfer hydrogenation with cyclohexene in dium-catalyzed cross-cyclotrimerization,[30] 1,6-diyne 16
the presence of 5 mol-% Pd/C (10%) in ethanol at 50 °C was synthesized in three steps starting from 2-iodoaniline
(95% yield).[24]
(13) (Scheme 2). A Sonogashira reaction with propyne fol-
Once the substitution pattern of the A-ring of lavenda- lowed by N-tosylation afforded sulfonamide 15, which was
mycin was established, a DCC (N,NЈ-dicyclohexylcarbo- then deprotonated with potassium hexamethyldisilazane
diimide)/DMAP (4-dimethylaminopyridine)-mediated am- (KHMDS) and alkynylated with alkynyliodonium salt 4 to
idation of 8 with 3,3-dimethoxypropanoic acid afforded 9 in
93% yield.[25] The projected Knorr cyclization[26] proceeded
efficiently by treating 9 with concentrated H2SO4 at room
temperature for 2 h to give quinolinone 10 in 97% yield.
Chlorination of 10 with 10 equiv. of POCl3 in DMF (di-
methylformamide) cleanly furnished 11 (95% yield). To op-
timize the cross-coupling reactivity, 11 was converted to the
more reactive 2-iodoquinoline 12. A series of experiments
were carried out to find an optimal catalyst for this reac-
tion. Treatment of 11 with sodium iodide in acetonitrile at
60 °C for 2 h in the presence of either acetyl chloride,[27]
trimethylsilyl chloride (TMSCl),[28] or hydrochloric acid,[29] Scheme 2. Reaction sequence leading to 3.
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Total Synthesis of Lavendamycin by a [2+2+2] Cycloaddition
Table 2. Transition-metal-catalyzed [2+2+2] cycloaddition of diyne 3 and methyl cyanoformate (17).
Run Catalyst (amount [mol-%]) Temperature [°C]
Nitrile 17 [equiv.]
Regioisomeric ratio (β-18/γ-19)
Isolated yield (%)
1
2
3
4
[Rh(cod)2]BF4/BINAP (6)
[Rh(cod)2]BF4/BINAP (6)
[Rh(cod)2]BF4/BINAP (6)
Cp*RuCl(cod) (2)
20
60
80
20
10
10
10
5
27:73
30:70
38:62
100:0
92
87
81
92
obtain 1,6-diyne 16. This diyne was coupled smoothly un-
der Negishi conditions[31] with the 2-iodoquinoline building
block 12 to finally give diyne 3 in 53% overall yield.
With 1,6-diyne 3 in hand, we began investigating its reac-
tion with methyl cyanoformate (17) to give the desired
pentacyclic precursor of lavendamycin. Although reactions
of α,ω-diynes with electron-deficient nitriles are known to
be efficiently mediated by Cp*RuCl(cod)[32] or cationic RhI
catalysts,[33] this case was complicated by the sterically and
electronically complex features of 1,6-diyne 3. Assuming
that the presence of the electronically modified alkyne unit
and the fully unsymmetrical substitution of 1,6-diyne 3
would facilitate the chemo- and regioselective outcome of
this reaction, we carried out the [2+2+2] cycloaddition with
17 in the presence of 6 mol-% [Rh(cod)2]BF4/BINAP [2,2Ј-
bis(diphenylphosphanyl)-1,1Ј-binaphthyl] in CH2Cl2 at
room temperature (Table 2). A regioisomeric mixture of the
corresponding β-carboline 18 and its γ-isomer 19 was ob-
tained in excellent yield (92%), but with the undesired γ-
carboline 19 as the major product (Table 2; Entry 1; β/γ =
27:73). Attempts to influence the regiochemical outcome of
this reaction by varying the temperature were unsuccessful
(Table 2, Entries 2 and 3). Remarkably, the regioselectivity
of this reaction was completely reversed when the cycload-
dition was promoted by the ruthenium(II) complex
Cp*RuCl(cod).
Scheme 3. Proposed reaction path leading to β-carboline 18.
Having demonstrated the synthesis of the pentacyclic
core of lavendamycin through a [2+2+ 2] cycloaddition,
only a few remaining group transformations were needed
to complete the total synthesis of lavendamycin (Scheme 4).
Removal of the N-tosyl protecting group with 3 equiv. of
tetrabutylammonium fluoride (TBAF) in tetrahyrofuran
(THF) at room temperature afforded 22 in 91% yield.[34]
Then, the C-7 nitro group was reduced with hydrogen in
the presence of Pd/C, and the resulting amino group was
acetylated. First attempts at the direct oxidative demethyl-
ation of 23 to generate the quinoid system were carried out
with cerium ammonium nitrate (CAN) in a mixture of
acetonitrile and water.[35] Although the CAN oxidation af-
With a catalyst loading of only 2 mol-% Cp*RuCl(cod),
the desired β-carboline 18 was formed under mild condi-
tions (room temperature, 5 equiv. of nitrile in CH2Cl2) in
very high yield (92%) without any detectable trace of γ-
isomer 19 (Entry 4). In agreement with previously reported
Cp*RuCl-catalyzed cycloadditions of unsymmetrical α,ω-
diynes,[32] the origin of this excellent regioselectivity might
be rationalized by considering the [2+2] addition of the
electron-deficient nitrile to asymmetric metallacyclic inter-
mediate 20 leading to the intermediates 21A or 21B
(Scheme 3). If the nitrile attacks the Ru–C-α bond B, inter-
mediate 21B will form, but the sterically more demanding
substituent R2 will come close to the bulky Cp* ligand. Ad-
dition to the Ru–C-α bond A will avoid this steric repulsion
and lead to the formation of β-carboline 18 via intermedi-
ate 21A.
Scheme 4. Reaction sequence leading to lavendamycin methyl ester
(25).
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F. Nissen, H. Detert
FULL PAPER
forded the corresponding quinoline-5,8-dione 24 in an ers are separated from the next layer of 25A by a layer of
acceptable yield of 64%, this process was significantly im- parallel 25B molecules with an interstrand distance of half
proved when 23 was treated with 4 equiv. of (diacetoxy- of the b-axis. Channels between the B-layers are filled with
iodo)benzene (DIB) to give 24 in 88% yield.[36] Finally, to two molecules of the solvent CHCl3.
complete the formal total synthesis of lavendamycin, the C-
7 acetamido group was hydrolyzed in a mixture of H2SO4/
water (4:3) at 60 °C according to a procedure reported by
Behforouz.[8a]
Lavendamycin methyl ester (25) was obtained in 97%
yield, and the physical and spectroscopic data were identical
to those reported in the literature.[1a,7a,8a] In addition, struc-
ture and connectivity was unequivocally evidenced by two-
dimensional NMR spectroscopy and X-ray crystal structure
analysis (Figure 3).
Figure 4. Arrangement of lavendamycin methyl ester (25) in the
crystal.
Conclusions
The regio- and chemoselective transition-metal-catalyzed
[2+2+2] cycloaddition of a 1,6-diyne and an electron-de-
ficient nitrile is a new and efficient route for the synthesis
of β- and γ-carbolines. We have proven the efficiency of this
method in the key step for the total synthesis of lavendamy-
cin. Forming three bonds in a single step, this convergent
approach allows the flexible preparation of the highly sub-
stituted pyridine ring of lavendamycin. This method re-
quires simple starting materials and a sequence of reliable
reactions, which should enable the synthesis of a broad vari-
ety of derivatives and analogs for this promising antitumor
antibiotic.
Experimental Section
General Information: Commercially available reagents were used
without further purification. Solvents and gases were dried by stan-
Figure 3. X-ray crystallographic structure of lavendamycin methyl
ester (25).
dard procedures. Yields refer to chromatographically and spectro-
scopically pure compounds unless otherwise stated. 1H and 13C
The crystals of 25 contain two independent molecules
25A and 25B, and the unit cell is filled with two 25A, two
25B, and two molecules of the solvent (Figure 4). Molecules
25A and 25B are nearly identical with the largest deviation
NMR spectra were recorded with Bruker AC 300 (300 MHz),
AV 400, and ARX 400 (400 MHz) spectrometers in CDCl3 and
[D6]DMSO. The proton and carbon signals were assigned on the
basis of DEPT, COSY45, HMQC (Heteronuclear Multiple Quan-
being the angle between the planes of the ester and the car- tum Coherence), and HMBC experiments. Melting points were
measured with a Büchi HWS SG 200, and IR spectra were re-
corded with a JASCO 4100 FTIR (ATR). FD mass spectra were
recorded with a Mat 95 (Finnigan), and HR-ESI mass spectra were
obtained by using a Q-TOF-ULTIMA 3 with a Lock Spray device
(Waters–Micromass) and NaICsI standard as a reference. Elemen-
tal analyses were carried out with a Vario EL. X-ray crystal struc-
ture analyses were performed by using a Turbo CAD-4 with Cu-Kα
radiation and data collection with CAD-4 software (Enraf–Nonius,
1989), structure solution with SIR97 (direct methods), structure
refinement with SHELXL97, and molecular graphics with PLA-
boline unit [25A: N-2–C-3–C-14–O-15 178.2(9)°; 25B: N-2–
C-3–C-14–O-15 144.7(9)°]. A highly coplanar arrangement
of the carboline and the quinolinone unit results from hy-
drogen-bond formation between the pyrrole NH group and
the quinoline N atom, as well as from the amino N-30
group adjacent to the quinine O-29 – the dihedral angle of
the mean planes of the carboline and the quinoline units
amounts to only θ = 3.44°. This hydrogen-bond-stabilized
coplanarity is closely analogous to the structure of strepto-
nigrin (2) in the solid state[37] and in solution.[38] Intermo- TON.[39]
lecular hydrogen bonds from the amine to the ester (N-30–
H–O-15) connect coplanar molecules of 25A to form linear
strands. On both sides of the strand, the 25B molecules are
4-Hydroxy-3,5-dinitrophenyl Acetate (6): 1,4-Diacetoxybenzene[21]
(50 g, 0.26 mol) was added in small portions to fuming HNO3
(150 mL) at –5 °C. After stirring at –5 °C for 30 min, the mixture
attached with hydrogen bonds from the amine N-30A to the was poured on ice and filtered. The residue was washed with water
and dried in air to yield 6 (38 g, 0.16 mol, 61%) as a yellow solid.
quinone O-31B and O-31A to N-30B. Layers with parallel
strands of 25A are arranged in a herringbone fashion, and
the distances of the mean planes of 25A [4.029(5) Å] and
M.p. 95–96 °C (ref.[22] 94 °C).
1,4-Dimethoxy-3,5-dinitrobenzene (7): HCl (12 m, 0.2 mL,
25B [3.496(5) Å] indicate π-stacking interaction. These lay- 0.24 mmol, 6 mol-%) was added to 6 (10 g, 41 mmol) in methanol
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Total Synthesis of Lavendamycin by a [2+2+2] Cycloaddition
(80 mL), and the mixture was heated at reflux for 3 h. The solvent
was removed in vacuo, and the residue was dissolved in diethyl
ether (35 mL) and methanol (35 mL). At 5 °C diazomethane[40]
(approximately 1 m in diethyl ether, 250 mL) was added, and the
reaction mixture was stirred for 4 h. After the addition of acetic
acid (30 mL), the mixture was stirred for an additional 4 h. The
solution was concentrated. Diethyl ether was added, and the mix-
ture was neutralized with NaOH (2 m solution). The organic layer
was separated and then washed with NaOH (2 m solution,
3ϫ30 mL), water, and brine. The organic layer was dried with
MgSO4 and then concentrated to yield 7 (8.97 g, 39 mmol, 95%)
as a yellow solid. M.p. 109–110 °C (hexane/diethyl ether) (ref.[23]
The precipitate was filtered and washed with ice-cold water until
the filtrate was neutral. The resulting solid was dried under vacuum
in a desiccator over P2O5 to provide 10 (6.95 g, 28 mmol, 97%) as
a yellow solid. M.p. 294–297 °C. 1H NMR (400 MHz, [D6]DMSO,
3
25 °C): δ = 11.73 (br. s, 1 H, NH), 8.04 (d, JH,H = 9.7 Hz, 1 H),
3
7.20 (s, 1 H), 6.64 (d, JH,H = 9.7 Hz, 1 H), 3.94 (s, 3 H), 3.82 (s,
3 H) ppm. FD-MS: m/z (%) = 250 (100) [M]+. HRMS (ES+): calcd.
for [M + H]+ 251.0662; found 251.0659. IR (neat, ATR): ν = 3045,
˜
1671, 1574, 1521, 1490, 1357, 1336, 1156, 112, 957, 832 cm–1.
2-Chloro-5,8-dimethoxy-7-nitroquinoline (11): A solution of 10
(10 g, 40 mmol) in DMF (10 mL) was treated with POCl3 (36.7 mL,
62 g, 0.4 mol, 10 equiv.) and heated at 120 °C for 30 min. After
cooling to room temperature, the reaction mixture was poured into
ice-cold water, and NaHCO3 (saturated aqueous solution) was
added until a neutral pH was reached. The precipitate was isolated
by suction filtration, washed with water, and dried under vacuum
in a desiccator over P2O5 to yield 11 (10.22 g, 38 mmol, 95%) as a
1
109–111 °C). Rf = 0.50 (SiO2; hexane/ethyl acetate, 1:1). H NMR
(400 MHz, CDCl3/TMS, 25 °C): δ = 7.58 (s, 2 H), 4.03 (s, 3 H),
3.92 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 154.9 (C),
145.9 (C), 141.1 (C), 114.8 (CH), 65.1 (CH3), 56.8 (CH3) ppm. IR
(neat, ATR): ν = 3092, 1524, 1486, 1417, 1346, 1042, 973, 873,
˜
787 cm–1. FD-MS: m/z (%) = 228 (100) [M]+.
yellow solid. M.p. 181–182 °C (diethyl ether). Rf = 0.43 (SiO2; hex-
1
2,5-Dimethoxy-3-nitroaniline (8): Pd/C (10%, 1.17 g, 1.1 mmol, ane/ethyl acetate, 2:1). H NMR (400 MHz, [D6]DMSO, 25 °C): δ
3
5 mol-%) and cyclohexene (13 mL, 10.5 g, 0.13 mol, 6 equiv.) were
added to a solution of 7 (5 g, 22 mmol) in ethanol (150 mL) at
45 °C. The starting material was completely consumed after 5 h
(TLC), and the mixture was filtered through silica and concen-
trated in vacuo. The resulting residue was redissolved in diethyl
ether and then filtered a second time through silica. Concentration
of the mixture, and recrystallization of the solid from diethyl ether
yielded 8 (4.13 g, 21 mmol, 95%) as dark-red solid. M.p. 88–89 °C
(ref.[23] 87.5–89.5 °C). Rf = 0.38 (SiO2; diethyl ether). 1H NMR
= 8.60 (d, JH,H = 9.1 Hz, 1 H), 7.77 (d, 3JH,H = 9.1 Hz, 1 H), 7.47
(s, 1 H), 4.10 (s, 3 H), 4.01 (s, 3 H) ppm. 13C NMR (100 MHz,
[D6]DMSO, 25 °C): δ = 151.6 (C), 150.9 (C), 143.6 (C), 142.0 (C),
141.4 (C), 135.1 (CH), 124.5 (CH), 121.8 (C), 100.2 (C), 63.7
(CH3), 56.9 (CH3) ppm. FD-MS: m/z (%) = 268 (100) [M]+. HRMS
(ES+): calcd. for [M + H]+ 269.0324; found 269.0320. IR (neat,
ATR): ν = 3111, 3084, 2953, 1601, 1577, 1521, 1359, 1161, 1081,
˜
832 cm–1.
2-Iodo-5,8-dimethoxy-7-nitroquinoline (12): A suspension of 11
(5.0 g, 19 mmol) and NaI (11.2 g, 75 mmol, 4 equiv.) in acetonitrile
(100 mL) was treated with acetyl chloride (0.7 mL, 10 mmol,
0.5 equiv.), and the reaction mixture was heated to 60 °C. After
3.5 h, the starting material had been consumed (1H NMR), and a
5% aqueous NaHCO3/NaS2O3 solution was added. The aqueous
phase was extracted with CH2Cl2 (3ϫ), and the combined organic
phases were washed with water (2ϫ), dried with MgSO4, and fil-
tered through silica. After removal of the solvent under reduced
pressure and crystallization of the residue from CH2Cl2/hexane, 12
(6.22 g, 17 mmol, 93%) was obtained as a dark yellow solid. M.p.
4
(400 MHz, CDCl3/TMS, 25 °C): δ = 6.73 (d, JH,H = 3.0 Hz, 1 H),
4
6.50 (d, JH,H = 3.0 Hz, 1 H), 4.11 (br. s, 2 H, NH2), 3.86 (s, 3 H),
3.77 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3/TMS, 25 °C): δ =
155.8 (C), 144.1 (C), 143.0 (C), 135.1 (C), 106.3 (CH), 98.4 (CH),
61.3 (CH3), 55.9 (CH3) ppm. FD-MS: m/z (%) = 198 (100) [M]+.
HRMS (ES+): calcd. for [M + H]+ 199.0713; found 199.0712. IR
(neat, ATR): ν = 3485, 3387, 2941, 1631, 1598, 1518, 1340, 1235,
˜
1038, 991 cm–1. C8H10N2O4 (198.18): calcd. C 48.48, H 5.09, N
14.14; found C 48.48, H 5.09, N 14.06.
N-(2,5-Dimethoxy-3-nitrophenyl)-3,3-dimethoxypropanamide (9): To
a solution of 8 (1.37 g, 6.9 mmol) and 3,3-dimethoxypropanoic acid
(1.11 g, 8.3 mmol, 1.2 equiv.) in CH2Cl2 (7 mL) at 0 °C was added
DMAP (82 mg, 0.7 mmol, 10 mol-%) and a solution of DCC
1
166–167 °C. Rf = 0.43 (SiO2; hexane/ethyl acetate, 2:1). H NMR
(400 MHz, CDCl3/TMS): δ = 8.15 (d, J = 8.8 Hz, 1 H), 7.86 (d, J
= 8.8 Hz, 1 H), 7.14 (s, 1 H), 4.27 (s, 3 H), 4.02 (s, 3 H) ppm. 13C
(1.71 g, 8.3 mmol, 1.2 equiv.) in CH2Cl2 (3.5 mL). The mixture was NMR (100 MHz, CDCl3/TMS): δ = 151.1 (C), 144.4 (C), 143.8
stirred at 0 °C for 30 min and at room temperature for an ad-
ditional 14 h. Diethyl ether was added, and the precipitated urea
was removed by filtration through a pad of silica. After removal of
the solvent under reduced pressure, the residue was crystallized
from diethyl ether/hexane to give 9 (2.03 g, 6.5 mmol, 95%) as a
colorless solid. M.p. 75–76 °C. Rf = 0.21 (SiO2; hexane/ethyl acet-
(C), 142.8 (C), 134.0 (CH), 132.3 (CH), 123.1 (C), 120.7 (C), 99.8
(CH), 64.2 (CH3), 56.5 (CH3) ppm. FD-MS: m/z (%) = 359 (100)
[M]+. HRMS (ES+): calcd. for [M + H]+ 360.9680; found 360.9673.
IR (neat, ATR): ν = 3106, 2941, 1566, 1520, 1455, 1350, 1319,
˜
1161, 979, 923 cm–1. C11H9IN2O4 (360.10): calcd. C 36.69, H 2.52,
N 7.78; found C 36.67, H 2.53, N 7.75.
1
ate, 2:1). H NMR (300 MHz, CDCl3/TMS, 25 °C): δ = 9.12 (s, 1
2-(Prop-1-yn-1-yl)aniline (14): Into a Schlenk tube were introduced
2-iodoaniline (5.0 g, 23 mmol), PdCl2(PPh3)2 (800 mg, 1.15 mmol,
5 mol-%), CuI (435 mg, 2.3 mmol, 10 mol-%), dry Et3N (50 mL),
and dry DMF (30 mL). The reaction mixture was cooled to –78 °C,
and condensed propyne (1.75 mL, 1.17 g, 29 mmol, 1.3 equiv.),
measured by condensing the gas in a precooled (–78 °C) graduated
cylinder, was added. The reaction mixture was stirred at room tem-
perature for 13 h. Then the mixture was worked up by evaporating
the solvent, adding diethyl ether and water, and extracting with
diethyl ether (3ϫ). The organic phases were washed with brine and
4
4
H, NH), 8.34 (d, JH,H = 3.1 Hz, 1 H), 7.10 (d, JH,H = 3.1 Hz, 1
H), 4.71 (t, JH,H = 4.5 Hz, 1 H), 3.89 (s, 3 H, OCH3), 3.83 (s, 3 H,
OCH3), 3.48 (s, 6 H), 2.80 (d, 3JH,H = 4.5 Hz, 2 H) ppm. 13C NMR
(75 MHz, CDCl3/TMS, 25 °C): δ = 167.8 (C), 155.8 (C), 143.1 (C),
136.7 (C), 134.7 (C), 111.4 (CH), 104.3 (CH), 102.0 (CH), 62.7
(CH3), 56.2 (CH3), 54.8 (CH3), 42.2 (CH2) ppm. FD-MS: m/z (%)
= 314 (100) [M]+. IR (neat, ATR): ν = 3252, 2945, 2836, 1656,
˜
1583, 1527, 1477, 1112, 1081, 1052 cm–1. C13H18N2O7 (314.29):
calcd. C 49.68, H 5.77, N 8.91; found C 49.82, H 5.77, N 8.95.
5,8-Dimethoxy-7-nitroquinolin-2(1H)-one (10): Compound 9 (9.0 g, then dried with MgSO4. Purification by column chromatography
29 mmol) was introduced portionwise to concentrated H2SO4
(90 mL), and the resulting solution was stirred at room tempera-
ture. After 2 h, the mixture was poured into ice-cold water (1.5 L).
(SiO2; pentane/diethyl ether, 10:1) afforded 14 (2.71 g, 21 mmol,
90%) as a yellow oil. Rf = 0.45 (SiO2; pentane/diethyl ether, 3:1).
1H NMR (400 MHz, CDCl3/TMS): δ = 7.42 (dd, J = 7.8 Hz, J =
Eur. J. Org. Chem. 2011, 2845–2853
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2849

F. Nissen, H. Detert
FULL PAPER
1.5 Hz, 1 H), 7.25 (dt, J = 7.8 Hz, J = 1.5 Hz, 1 H), 6.80–6.88 (m,
for 30 min, and thereafter the reaction mixture was treated with a
2 H), 4.33 (s, 2 H), 2.28 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3/ solution of Pd2dba3·CHCl3 (148 mg, 0.16 mmol, 2.5 mol-%), PPh3
TMS): δ = 148.2 (C), 132.4 (CH), 129.3 (CH), 118.2 (CH), 114.6 (170 mg, 0.64 mmol, 10 mol-%), and 12 (2.18 g, 6.1 mmol, 1 equiv.)
(CH), 109.4 (C), 91.4 (C), 76.7 (C), 4.9 (CH3) ppm. FD-MS: m/z in THF (60 mL). After 3 h, the solvent was removed under reduced
(%) = 131 (100) [M+]. MS (ES+): m/z = 132 [M + H]+. HRMS
pressure, and the residue was dissolved in water and CH2Cl2. The
aqueous phase was extracted with CH2Cl2 (3ϫ), and the combined
organic phases were dried with MgSO4 and concentrated under
reduced pressure. The resulting solution was applied to a short sil-
ica column and eluted with CH2Cl2 followed by diethyl ether. Re-
moval of the solvent under reduced pressure and washing of the
residue with a small amount of diethyl ether yielded 3 (2.97 g,
5.5 mmol, 90%) as a bright yellow solid. M.p. 165–167 °C (CH2Cl2/
hexane). Rf = 0.61 (SiO2; hexane/ethyl acetate, 1:1). 1H NMR
(ES+): calcd. for [M + H]+ 132.0808; found 132.0806. IR (KBr): ν
˜
= 3470, 3375, 3029, 1613, 1493, 1455, 1306 cm–1.
N-[2-(Prop-1-yn-1-yl)phenyl]toluenesulfonamide (15): Tosyl chloride
(3.68 g, 19 mmol, 2 equiv.) was added to a solution of 14 (1.25 g,
9.5 mmol) in THF (100 mL) and pyridine (50 mL). The mixture
was stirred at room temperature for 3 d. The solution was concen-
trated, and CH2Cl2 (50 mL) and water (100 mL) were added. The
aqueous layer was extracted with CH2Cl2 (3ϫ), and the combined
organic layers were washed with brine and dried with MgSO4. Puri-
fication by column chromatography (SiO2; pentane/diethyl ether,
5:1) afforded 15 (2.44 g, 8.6 mmol, 90%) as colorless crystals. M.p.
3
(400 MHz, CDCl3/TMS): δ = 8.46 (d, JH,H = 8.8 Hz, 1 H), 7.84
3
3
(d, JH,H = 8.8 Hz, 2 H), 7.51 (d, JH,H = 8.8 Hz, 1 H), 7.32–7.43
(m, 6 H), 7.09 (s, 1 H), 4.27 (s, 3 H, CO2CH3), 4.02 (s, 3 H, OCH3),
2.46 (s, 3 H, TsCH3), 1.75 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3/TMS): δ = 150.9 (C), 145.4 (C), 145.3 (C), 144.1 (C), 143.7
(C), 142.8 (C), 138.3 (C), 134.6 (C), 133.5 (CH), 131.2 (CH), 129.8
(CH), 129.6 (CH), 129.5 (CH), 128.8 (CH), 128.5 (CH), 125.4
(CH), 123.9 (C), 122.3 (C), 99.1 (CH), 93.2 (C), 85.8 (C), 75.2 (C),
72.7 (C), 64.2 (CH3), 56.4 (CH3), 21.8 (CH3), 4.6 (CH3) ppm. FD-
MS: m/z (%) = 541 (100) [M]+. HRMS (ES+): calcd. for [M +
1
111–113 °C. Rf = 0.35 (SiO2; pentane/diethyl ether, 3:1). H NMR
(400 MHz, CDCl3/TMS): δ = 2.05 (s, 3 H, CH3), 2.35 (s, 3 H,
TsCH3), 6.97 (dt, J = 7.6 Hz, J = 1.1 Hz, 1 H), 7.16–7.28 (m, 5 H),
7.53 (d, J = 7.6 Hz, 1 H), 7.67 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3/TMS): δ = 143.8 (C), 137.5 (C), 136.2 (C), 131.8
(CH), 129.4 (CH), 128.7 (CH), 127.2 (CH), 124.1 (CH), 119.4
(CH), 114.9 (C), 93.1 (C), 74.5 (C), 21.4 (CH3), 4.4 (CH3) ppm.
MS (ES+): m/z = 308.0688 [M + Na]+, 593.1538 [2M + Na]+.
HRMS (ES+): calcd. for [M + Na]+ 308.0716; found 308.0721. IR
H]+ 542.1380; found 542.1370. IR (neat, ATR): ν = 2949, 2232,
˜
1604, 1576, 1518, 1350, 1163, 1072, 984, 766 cm–1. C25H18N4O5
(454.43): calcd. C 64.31, H 4.28, N 7.76, S 5.92; found C 63.91, H
4.28, N 7.56, S 5.49.
(KBr): ν = 3278, 3257, 2917, 1493, 1397, 1158 cm–1.
˜
N-Ethynyl-N-[2-(prop-1-yn-1-yl)phenyl]toluenesulfonamide
(16):
Methyl 1-(5,8-Dimethoxy-7-nitroquinolin-2-yl)-4-methyl-9-tosyl-β-
carboline-3-carboxylate (β-18): To a solution of 3 (1.0 g, 1.8 mmol)
and methyl cyanoformate (17, 0.44 mL, 5.5 mmol, 3 equiv.) in
CH2Cl2 (10 mL) was added Cp*RuCl(cod) (35 mg, 92 μmol, 5 mol-
%). The mixture was stirred at room temperature for 14 h, and
diethyl ether (20 mL) was added. The resulting precipitate was iso-
lated by suction filtration and recrystallized from CH2Cl2/diethyl
ether to yield 18 (1.06 g, 1.7 mmol, 92%) as a bright yellow solid.
M.p. 268–269 °C. Rf = 0.47 (SiO2; hexane/ethyl acetate, 1:1). 1H
NMR (300 MHz, CDCl3/TMS): δ = 8.81 (d, 3JH,Hv = 8.6 Hz, 1 H),
KHMDS (0.5 m solution) in toluene (18.9 mL, 9.5 mmol,
1.2 equiv.) was added dropwise at 0 °C to a solution of 15 (2.25 g,
7.9 mmol) in toluene (760 mL) . After 15 min of stirring at 0 °C, a
solution of alkynyliodonium salt 4[22] (4.75 g, 11 mmol, 1.3 equiv.)
in CH2Cl2 (380 mL) was added dropwise, and the reaction mixture
was stirred at room temperature overnight. The mixture was
worked up by concentration, addition of CH2Cl2 (50 mL) and
water (100 mL), and extraction with CH2Cl2. The organic layer was
dried with MgSO4. Column chromatography (SiO2; pentane/diethyl
ether, 4:1) yielded a colorless oil (2.31 g, 6.1 mmol, 77%). The oil
was dissolved in wet THF (240 mL), and at 0 °C TBAF (1 m solu-
tion) in THF (7.9 mL, 7.9 mmol, 1.3 equiv.) was added dropwise.
After 15 min, diethyl ether and brine were added, and the layers
were separated. The aqueous layer was extracted with diethyl ether,
and the combined organic layers were dried with MgSO4. Purifica-
tion by column chromatography (SiO2; pentane/diethyl ether, 10:1)
afforded 16 (1.79 g, 5.8 mmol, 73% over 2 steps) as a white solid.
M.p. 57–58 °C. Rf = 0.3 (SiO2; pentane/diethyl ether, 3:1). 1H NMR
3
3
8.44 (d, JH,H = 8.6 Hz, 1 H), 8.16 (d, JH,H = 8.1 Hz, 1 H), 8.07
3
(d, JH,H = 8.1 Hz, 1 H), 7.55–7.63 (m, 1 H), 7.40–7.46 (m, 1 H),
7.18 (s, 1 H), 7.10 (d, 3JH,H = 8.3 Hz, 2 H), 6.91 (d, 3JH,H = 8.3 Hz,
2 H), 4.44 (s, 3 H), 4.06 (s, 3 H), 4.05 (s, 3 H), 2.96 (s, 3 H), 2.21
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3/TMS): δ = 167.1 (C),
160.1 (C), 151.0 (C), 146.3 (C), 145.3 (C), 145.2 (C), 144.1 (C),
142.9 (C), 142.6 (C), 142.0 (C), 138.0 (C), 135.7 (C), 132.8 (C),
132.5 (CH), 129.7 (CH), 129.3 (CH), 129.1 (C), 127.3 (C), 126.9
(CH), 125.8 (CH), 124.1 (C), 123.7 (C), 123.4 (CH), 118.4 (CH),
99.3 (CH), 65.2 (CH3), 56.4 (CH3), 53.0 (CH3), 21.6 (CH3), 16.3
(CH3) ppm. FD-MS: m/z (%) = 626 (100) [M]+. HRMS (ES+):
3
(400 MHz, CDCl3/TMS): δ = 7.73 (d, JH,H = 8.3 Hz, 2 H, Ts),
7.25–7.40 (m, 6 H), 2.83 (s, 1 H, CCH), 2.45 (s, 3 H, TsCH3), 1.81
(s, 3 H, CCCH3) ppm. 13C NMR (100 MHz, CDCl3/TMS): δ =
144.8 (C), 138.6 (C), 135.0 (C), 133.5 (CH), 129.5 (CH), 129.4
(CH), 129.2 (CH), 128.6 (CH), 128.4 (CH), 123.9 (C), 92.8 (C),
76.1 (CH), 75.3 (C), 58.6 (C), 21.7 (CH3), 4.5 (CH3) ppm. MS
(ES+): m/z = 332.0703 [M + Na]+, 641.1520 [2 M + Na]+. HRMS
(ES+): calcd. for [M + Na]+ 332.0721; found: 332.0703. IR (KBr):
calcd. for [M + H]+ 627.1544; found 627.1557. IR (neat, ATR): ν
˜
= 2943, 1721, 1603, 1530, 1457, 1364, 1236, 1173, 1092, 936, 765,
741 cm–1. C32H26N4O8S (626.64): calcd. C 61.33, H 4.18, N 8.94,
S 5.12; found C 60.92, H 4.16, N 8.71, S 4.60.
Methyl 4-(5,8-Dimethoxy-7-nitroquinolin-2-yl)-1-methyl-5-tosyl-γ-
carboline-3-carboxylate (γ-19): In a Schlenk tube, [Rh(cod)2]BF4
(2.7 mg, 6 mol-%) and BINAP (4.1 mg, 6 mol-%) were dissolved in
dry, nitrogen-saturated CH2Cl2 (1.2 mL). The solution was stirred
vigorously under H2 for 20 min and then concentrated to dryness.
The residue was dissolved in CH2Cl2 (1.2 mL), and methyl cyano-
ν = 3259, 2229, 2123, 1595, 1484, 1446, 1366, 1183, 1163, 1091,
˜
926, 762, 669, 584 cm–1.
N-[(5,8-Dimethoxy-7-nitroquinolin-2-yl)ethynyl]-N-[2-(prop-1-ynyl)-
phenyl]tolouenesulfonamide (3): A freshly prepared solution of
LiHMDS (0.5 m in THF, 19.4 mL, 9.7 mmol, 1.5 equiv.) was added formate (17) (88 μL, 1.1 mmol, 10 equiv.) and a solution of 3
to a solution of 16 (2.0 g, 6.5 mmol, 1.1 equiv.) in THF (90 mL) at
–78 °C over 3 min. The mixture was stirred at –40 °C for 30 min,
and a solution of anhydrous ZnBr2 (1.60 g, 7.1 mmol, 1.1 equiv.)
in THF (4 mL) was added. The mixture was stirred without cooling
(60 mg, 0.22 mmol) in CH2Cl2 (2.4 mL) were added. After 13 h,
the solvent was removed under reduced pressure, and the residue
was purified by column chromatography (SiO2; hexane/ethyl acet-
ate, 3:2) to yield β-18 (17 mg, 0.27 mmol, 25%) and γ-19 (46 mg,
2850
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2845–2853

Total Synthesis of Lavendamycin by a [2+2+2] Cycloaddition
0.08 mmol, 67%) as bright yellow solids. γ-19: M.p. 226–229 °C
(CH2Cl2/diethyl ether). Rf = 0.33 (SiO2; hexane/ethyl acetate, 1:1).
7-N-Acetyllavendamycin Methyl Ester (24): Compound 23 (240 mg,
0.50 mmol) and diacetoxyiodobenzene (DIB, 636 mg, 2 mmol,
4 equiv.) were suspended in a mixture of water (9 mL), acetonitrile
3
1H NMR (400 MHz, CDCl3/TMS): δ = 8.68 (d, JH,H = 8.8 Hz, 1
3
3
H), 8.30 (d, JH,H = 8.4 Hz, 1 H), 7.99 (d, JH,H = 7.5 Hz, 1 H), (9 mL), and methanol (0.45 mL), and the mixture was stirred at
3
3
7.92 (d, JH,H = 8.8 Hz, 1 H), 7.58 (t, JH,H = 7.6 Hz, 1 H), 7.49 room temperature. After 12 h, water (50 mL) was added, and the
3
3
(t, JH,H = 7.6 Hz, 1 H), 7.19 (s, 1 H), 7.13 (d, JH,H = 8.2 Hz, 2
aqueous phase was extracted with CHCl3 (4ϫ50 mL). The com-
3
H), 6.91 (d, JH,H = 8.1 Hz, 2 H), 4.35 (s, 3 H), 4.07 (s, 3 H), 3.72 bined organic phases were washed with brine and dried with
(s, 3 H), 3.01 (s, 3 H), 2.21 (s, 3 H) ppm. 13C NMR (100 MHz,
MgSO4, and the resulting mixture was filtered through a pad of
aluminium oxide. The solvent was removed under reduced pressure,
CDCl3/TMS): δ = 167.9 (C), 157.4 (C), 153.6 (C), 151.1 (C), 148.9
(C), 145.4 (C), 145.0 (C), 144.2 (C), 143.1 (C), 142.5 (C), 141.3 (C), and the residue was washed and centrifuged with diethyl ether (2ϫ)
132.4 (C), 131.1 (CH), 129.4 (CH), 128.6 (CH), 126.9 (CH), 126.3 to yield 24 (198 mg, 0.44 mmol, 84%) as an orange solid. Spectro-
(C), 126.2 (CH), 125.4 (C), 125.0 (CH), 124.0 (C), 123.3 (C), 122.8 scopic and analytical data are in accordance with those in the lit-
(CH), 118.7 (CH), 99.3 (CH), 64.2 (CH3), 56.4 (CH3), 52.9 (CH3), erature.[8a] M.p. 335 °C. Rf = 0.22 (Al2O3 activity II; CH2Cl2/meth-
1
24.1 (CH3), 21.6 (CH3) ppm. FD-MS: m/z (%) = 626 (100) [M]+. anol, 100:1). H NMR (400 MHz, CDCl3/TMS): δ = 11.90 (br. s,
3
3
IR (neat, ATR): ν = 3066, 2939, 1739, 1601, 1523, 1379, 1325,
1 H, NH), 9.14 (d, JH,H = 8.5 Hz, 1 H), 8.55 (d, JH,H = 8.5 Hz,
˜
1173, 750 cm–1.
l H), 8.44 (br. s, l H, NHAc), 8.35 (d, 3JH,H = 8.0 Hz, l H), 8.00 (s,
1 H), 7.78 (d, JH,H = 8.0 Hz, 1 H), 7.68 (t, JH,H = 8.0 Hz, 1 H),
3
3
Methyl
1-(5,8-Dimethoxy-7-nitroquinolin-2-yl)-4-methyl-β-carbo-
3
7.43 (t, JH,H = 8.0 Hz, 1 H), 4.09 (s, 3 H, CO2CH3), 3.23 (s, 3 H),
line-3-carboxylate (22): A suspension of 18 (600 mg, 0.96 mmol)
in THF (90 mL) was treated with TBAF (1 m in THF, 2.88 mL,
2.88 mmol, 3 equiv.), and the reaction mixture was stirred at room
temperature for 2 h. The mixture was concentrated to dryness, and
the residue was dissolved in water and chloroform. The organic
phase was washed with water (3ϫ) and dried with MgSO4. The
solvent was removed under reduced pressure. Crystallization from
chloroform yielded 22 (411 mg, 0.87 mmol, 91%) as a yellow solid.
M.p. 261–262 °C. Rf = 0.47 (SiO2; hexane/ethyl acetate/methanol,
2.38 (s, 3 H, Ac) ppm. FD-MS: m/z (%) = 454 (100) [M]+. HRMS
(ES+): calcd. for [M + Na]+ 477.1169; found 477.1176. IR (neat,
ATR): ν = 3309, 3078, 2950, 1722, 1708, 1503, 1305, 1227, 1074,
˜
1051, 863 cm–1.
Lavendamycin Methyl Ester (25): Compound 24 (105 mg,
0.23 mmol) was dissolved in a mixture of H2SO4/water (4:3, 11 mL)
at 0 °C, and the mixture was heated to 60 °C under N2. After
30 min, NaHCO3 (9% aqueous) was added until pH = 9. The mix-
ture was extracted with CHCl3 (5ϫ30 mL), and the combined or-
ganic phases were dried with MgSO4. Removal of the solvent fol-
1
6:3:1). H NMR (400 MHz, CDCl3/TMS): δ = 12.11 (s, 1 H), 9.01
3
3
(d, JH,H = 9.0 Hz, 1 H), 8.71 (d, JH,H = 9.0 Hz, 1 H), 8.37 (d,
3JH,H = 8.1 Hz, 1 H), 7.71 (d, JH,H = 8.1 Hz, 1 H), 7.62–7.67 (m, lowed by washing and centrifuging the residue with diethyl ether
1 H), 7.37–7.41 (m, 1 H), 7.24 (s, 1 H), 4.38 (s, 3 H), 4.090 (s, 3 gave lavendamycin methyl ester (25) (92 mg, 0.22 mmol, 97%) as a
H), 4.088 (s, 3 H), 3.22 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3/ red solid. Spectroscopic and analytical data are in accordance with
3
TMS): δ = 168.0 (C), 159.1 (C), 151.7 (C), 144.3 (C), 142.7 (C),
142.6 (C), 141.2 (C), 137.8 (C), 136.0 (C), 134.3 (C), 132.9 (C),
132.2 (CH), 130.6 (C), 128.6 (CH), 124.3 (CH), 123.7 (C), 122.5
(C), 121.4 (CH), 121.1 (CH), 112.3 (CH), 99.5 (CH), 63.7 (C), 56.5
(CH3), 52.5 (CH3), 17.0 (CH3) ppm. FD-MS: m/z (%) = 472 (100)
those in the literature.[1a,7a,8a] M.p. 310 °C. Rf = 0.29 (Al2O3;
CH2Cl2/methanol, 20:1). 1H NMR (400 MHz, CDCl3/TMS): δ =
11.97 (br., 1 H, NH), 9.07 (d, J = 8.5 Hz, 1 H, 4Ј-H), 8.54 (d, J =
8.5 Hz, 1 H, 3Ј-H), 8.37 (d, J = 8.5 Hz, 1 H, 5-H), 7.79 (d, J =
8.0 Hz, 1 H, 8-H), 7.66 (t, J = 7.4 Hz, 1 H, 7-H), 7.40 (t, J =
7.4 Hz, 1 H, 6-H), 6.12 (s, 1 H, 6Ј-H), 5.32 (br. s, 2 H, NH2), 4.09
(s, 3 H, OCH3), 3.22 (s, 1 H, 1Ј-H) ppm. 1H NMR (400 MHz,
[D6]DMSO): δ = 11.90 (s, 1 H, NH), 8.77 (d, J = 8.3 Hz, 1 H, 3Ј-
[M]+. IR (neat, ATR): ν = 3338, 3028, 1715, 1601, 1528, 1459,
˜
1338, 1244, 1211, 988, 730 cm–1.
Methyl 1-(7-Acetamido-5,8-dimethoxyquinolin-2-yl)-4-methyl-β-car-
boline-3-carboxylate (23): Pd/C (10%, 47 mg, 44 μmol, 5 mol-%)
was added to a suspension of 22 (405 mg, 0.86 mmol) in THF
(170 mL), and the mixture was stirred for 13 h under H2. Ac2O
(5.0 mL) was added, and the mixture was heated to 50 °C. After
3 h, the solvent was removed in vacuo, and the residue was dis-
solved in CH2Cl2. The mixture was filtered through a pad of Celite,
and the filtrate was washed with NaHCO3 (8% aqueous solution,
8 mL). The organic layer was dried with MgSO4 and concentrated.
Crystallization from chloroform/diethyl ether yielded 23 (399 mg,
0.82 mmol, 96%) as a bright yellow solid. M.p. 194–195 °C. Rf =
3
3
H), 8.44 (d, JH,H = 8.3 Hz, 1 H, 4Ј-H), 8.36 (d, JH,H = 8.3 Hz, 1
3
3
H, 5-H), 7.72 (m, JH,H = 8.3 Hz, 1 H, 8-H), 7.67 (dt, JH,H
=
=
3
7.5 Hz, JH,H = 1.2 Hz, 1 H, 7-H), 7.39 (dt, JH,H = 7.5 Hz, JH,H
1.2 Hz, 1 H, 6-H), 5.96 (s, 1 H, 6Ј-H), 3.97 (s, 3 H, OCH3), 3.05 (s,
3 H, CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 180.4 (s,
C-5Ј), 179.8 (s, C-8Ј), 166.8 (s, CO2), 158.0 (s, C-2Ј), 150.5 (s, C-
7Ј), 145.4 (s, C-8aЈ), 140.2 (s, C-8a), 137.4 (s, C-3), 134.4 (s, C-8b),
134.3 (d, C-4Ј), 133.0 (s, C-1), 130.7 (s, C-4a), 129.2 (s, C-4), 128.6
(s, C-4aЈ), 128.4 (d, C-7), 124.3 (d, C-3Ј), 123.6 (d, C-5), 121.1 (s,
C-4b), 120.7 (d, C-6), 111.9 (d, C-8), 102.2 (d, C-6Ј), 51.8 (q,
OCH3), 15.9 (q, CH3) ppm. FD-MS: m/z (%) = 412 (100) [M]+.
MS (ES+): m/z = 435.1068 [M + Na]+. HRMS (ES+): calcd. for
0.12 (SiO2; hexane/ethyl acetate/ethanol, 6:3:1). 1H NMR
3
(400 MHz, CDCl3/TMS): δ = 12.26 (s, 1 H, NH), 8.72 (d, JH,H
=
[M + Na]+ 435.1069; found 435.1068. IR (KBr): ν = 3451, 3329,
˜
8.8 Hz, 1 H), 8.58 (d, 3JH,H = 8.8 Hz, 1 H), 8.34 (d, 3JH,H = 8.1 Hz,
1 H), 8.09–8.13 (m, 2 H), 7.60–7.66 (m, 2 H), 7.34–7.39 (m, 1 H,
CH), 4.19 (s, 3 H), 4.09 (s, 3 H), 4.02 (s, 3 H), 3.19 (s, 3 H), 2.35
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3/TMS): δ = 168.7 (C),
166.7 (C), 157.3 (C), 151.7 (C), 140.8 (C), 140.6 (C), 136.9 (C),
135.7 (C), 135.4 (C), 135.0 (C), 132.3 (C), 131.8 (CH), 129.8 (C),
128.0 (CH), 124.0 (CH), 122.3 (C), 120.6 (CH), 117.3 (C), 117.0
(CH), 111.9 (C), 98.8 (CH), 61.6 (CH3), 56.1 (CH3), 52.4 (CH3),
1713, 1618, 1335, 738 cm–1.
X-ray Crystal Structure Analysis of 25: The analysis was performed
with an Enraf–Nonius Turbo-Cad 4 instrument equipped with a
rotating anode by using a red block. Crystal data: C23H16N4O4·
0.5CHCl3, M = 944.2 gmol–1, 0.064ϫ0.256ϫ0.512 mm, mono-
clinic, space group P21/c, Cu-Kα radiation (graphite-monochro-
mated; λ = 1.54180 Å), T = 193 K, unit-cell dimensions: a =
25.2 (CH3), 16.8 (CH3) ppm. FD-MS: m/z (%) = 484 (100) [M]+. 14.314(4) Å, b = 38.714(5) Å, c = 7.4958(2) Å, β = 92.16(2)°, V =
IR (neat, ATR): ν = 3246, 2948, 1702, 1653, 1618, 1596, 1446,
4159(2) Å3, 1.511 gcm–3, absorption
Z = 4, dcalcd. = μ =
˜
1334, 1275, 1212, 834, 846, 732 cm–1. C25H18N4O5 (454.43): calcd.
C 66.93, H 4.99, N 11.56; found C 66.39, H 4.96, N 11.50.
2.581 mm–1. The θ range for data collection was 2–70°; index ran-
ges were –17 Յ h Յ 17, –47 Յ k Յ 0, –9 Յ l Յ 0. Number of
Eur. J. Org. Chem. 2011, 2845–2853
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2851

F. Nissen, H. Detert
FULL PAPER
[14]
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reflections collected: 8634, independent reflections: 7853 (Rint
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SIR 92, refinement by SHELXL 97).[39] Structure refinement was
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2Fo2]/3, and hydrogen atoms were located from difference Fourier
synthesis and refined isotropically by assuming a riding-motion
model, non-hydrogen atoms were improved with anisotropic refine-
ment. Goodness-of-fit on S = 0.991, maximum range of parameters
0.001e.s.d, final R indices: R1 = 0.1258, wR2 = 0.3849; the final
difference Fourier map showed minimum and maximum values of
1.09 and –0.81 eÅ–3, respectively. CCDC-805338 (for 25) contains
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Supporting Information (see footnote on the first page of this arti-
1
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Acknowledgments
The authors are grateful to Prof. Dr. B. Witulski for initiating this
project, to Dr. D. Schollmeyer for the X-ray analysis, and to H.
Kolshorn for invaluable discussions and NMR spectra.
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