Synthesis of a carbon analogue of scytonemin

Article abstract of DOI:10.1248/cpb.c14-00838

The synthesis of a carbon analogue of scytonemin was accomplished on the basis of molybdenum-mediated intramolecular double Pauson-Khand type reaction of bis(allenyne), followed by the double aldol condensation of the formed double Pauson-Khand type adduct.

Full text of DOI:10.1248/cpb.c14-00838

Vol. 63, No. 4
Chem. Pharm. Bull. 63, 273–277 (2015)
273
Regular Article
Synthesis of a Carbon Analogue of Scytonemin
Chisato Mukai,* Katsuya Arima, Shuichi Hirata, and Shigeo Yasuda
Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University; Kakuma-machi,
Kanazawa 920–1192, Japan.
Received December 9, 2014; accepted January 19, 2015
The synthesis of a carbon analogue of scytonemin was accomplished on the basis of molybdenum-
mediated intramolecular double Pauson–Khand type reaction of bis(allenyne), followed by the double aldol
condensation of the formed double Pauson–Khand type adduct.
Key words scytonemin; allene; [2+2+1] cycloaddition; alkyne; molybdenum; aldol condensation
Scytonemin (1) is the cyanobacterial dimeric alkaloid could not be detected in the reaction mixture.
pigment, whose chemical structure has been elucidated by
We now report the short-step synthesis of 2, a carbon
Gerwick and co-workers in 1993,1) over 100 years after its dis- analogue of scytonemin (1), by taking advantage of the in-
covery. Scytonemin has an intriguing novel structural feature, tramolecular double carbonylative [2+2+1] cycloaddition of
which consists of a two 1,1′-linked cyclopent[b]indole-2(1H)- the bis(allenyne) derivative 7,27,28) which should provide the
one framework possessing 4-hydroxybenzylidenes at the central linked two tricyclic framework, namely the dimeric
3-positions of the fused tricyclic systems. The biosynthetic 1H-cyclopent[a]inden-2-one 8, in one operation. The outline
studies of scytonemin have been recently made by Walsh and of our synthetic plan is depicted in Chart 3. The double Pau-
Balskus.2,3) In 2011, Mårtensson and colleagues achieved the son–Khand type reaction (PKTR) of bis(allenyne) 7 would
first total synthesis of scytonemin by taking advantage of the proceed under the conditions shown in Chart 2 as is the case
tandem Heck carbocyclization/Suzuki–Miyaura coupling and of 3 to afford 8. The successive aldol condensation of 8 with
a bioinspired oxidative dimerization.4) Of particular interest the suitably protected 4-hydroxybenzaldehyde 9 and several
is its interesting biological features. Scytonemin is a UV- manipulations would lead to 2.
absorbing pigment that protects important cellular components
in a cyanobacteria against harmful UV radiation.5–8) Besides
Results and Discussion
this important function, scytonemin exhibits a biological ac-
The Sonogashira coupling reaction of 1-bromo-2-iodoben-
tivity as a small molecule inhibitor of polo-like kinase 19) and zene (10) with trimethylsilylacetylene produced 1-bromo-2-
possesses anti-inflammatory and antiproliferative properties.10) [2-(trimethylsilyl)ethynyl]-benzene (11) in quantitative yield.
During our studies on the syntheses of various kind of alka- Treatment of 11 with butyllithium was followed by iodination
loids,11–19) we became very interested in the highly conjugated to afford 12, which was then used for the second Sonogashira
and characteristic dimeric structure of scytonemin as well as coupling reaction with propargyl alcohol resulting in the for-
its biological activity. We postulated that the origin of the bio- mation of the cross-coupling adduct 13 in 84% overall yield
logical activity of scytonemin (1) might be elucidated by com- from 11. The exposure of 13 to Cu(OAc)2·H2O effected the
parison with its carbon analogue, in which two nitrogen atoms consecutive removal of the trimethylsilyl (TMS) group and
are replaced by two carbon atoms. Therefore, our endeavor homo-coupling of the terminal alkyne moiety29) to afford the
was directed toward the synthesis of 2, a carbon analogue of tetrayne 14 in 89% yield. The Mitsunobu reaction of 14 with
scytonemin (1) (Chart 1).
diisopropyl azodicaroboxylate (DIAD) and N-isopropylidene-
In 2005, Liu and Datta developed the efficient synthesis
of 1H-cyclopent[a]inden-2-one (4a) from 1-ethynyl-2-(1,2-
propadienyl)benzene (3a) through the Mo(CO)3(MeCN)3-
mediated carbonylative [2+2+1] ring-closing reaction at 25°C
in a stoichiometric manner20) (Chart 2). They also reported
the catalytic version of that transformation in the presence
of 5mol% of [RhCl(CO)2]2 at 90°C to furnish 4a in 62%
yield along with the by-production of 2-methylnaphthalene
(5), the latter of which should be arisen from the Myers–
Saito cycloaromatization21–25) of 3a. We have independently
reported that treatment of 3-(2-ethynylphenyl)prop-2-ynyl
benzenesulfinate (6) with 2.5mol% of [RhCl(CO)2]2 at 40°C
in an atmosphere of CO effected the successive 2,3-sigma-
tropic rearrangement and carbonylative [2+2+1] ring-closing
reaction of the resulting allenyne species 3b to afford the
8-(phenylsulfonyl)-1H-cyclopent[a]inden-2-one (4b) in a high
yield.26) In this case, the formation of 2-methylnaphthalene
Chart 1. Structures of Scytonemin (1) and Its Carbon Analogue (2)
*To whom correspondence should be addressed. e-mail: mukai@p.kanazawa-u.ac.jp
© 2015 The Pharmaceutical Society of Japan

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Chem. Pharm. Bull.
Vol. 63, No. 4 (2015)
Chart 2. Synthesis of 1H-Cyclopent[a]inden-2-one Derivatives 4 by PKTR of Allenynes 3
Chart 3. Strategy for the Synthesis of 2
Chart 4. Synthesis of Bis(allenyne) 7
Table 1. Optimization of Reaction Conditions for Double Carbonylative
[2+2+1] Cycloaddition of 7
N′-2-nitrobenzenesulfonyl hydrazine (IPNBSH) was followed
by hydrolysis under trifluoroethanol (TFE)/water conditions30)
to produce the bis(allenyne) 7, a substrate of PKTR, in 63%
yield (Chart 4).
Our endeavor then focused on the intramolecular double
carbonylative [2+2+1] cycloaddition of 7 (Table 1). Treatment
of 7 with 10mol% of [RhCl(CO)2]2, which was effective for
the PKTR of allenynes 320,26) (Chart 2), in toluene at 70°C
produced the desired product 8 in 22% yield along with the
formation of unidentified by-products31) (entry 1). Lowering
the reaction temperature for suppression of the undesired reac-
tions was not effective. The reaction at 30°C in CH2Cl2 led
to a result similar to entry 1 with a prolonged reaction time
(entry 2), while no reaction occurred at 0°C (entry 3). The
reaction with 2 equiv of Mo(CO)3(MeCN)3,32) being effective
for the PKTR of allenynes 320) (Chart 2), at room temperature
afforded 8 in 19% yield (entry 4). A slightly higher yield was
recorded when treated at 0°C (entry 5). Dimethyl sulfoxide
(DMSO) was found to be an effective additive.33) Indeed, the
reaction in the presence of 4 equiv of Mo(CO)3(MeCN)3 and
CO
(atm)
Temp. Time
Yield
(%)a)
Entry
Metal reagent (eq)
(°C)
(h)
1b)
2
[RhCl(CO2)]2 (0.10)
[RhCl(CO2)]2 (0.20)
1
1
70
30
0
4
23
19
1
22
18
nr
3
[RhCl(CO2)]2 (0.10)
1
4
Mo(CO)3(MeCN)3 (2.0)
Mo(CO)3(MeCN)3 (2.0)
Mo(CO)3(MeCN)3 (4.0)
Mo(CO)3(MeCN)3 (4.0)
Mo(CO)3(MeCN)3 (4.0)
—
—
—
1
rt
0
19
28
44
59
61
5
5.5
8
6c)
7c)
8b,c)
0
0
24
24
1
0
a) Yield of the isolated product. b) Reaction was performed in toluene. c) Reaction
was carried out with 8eq of DMSO. nr=no reaction.

Vol. 63, No. 4 (2015)
Chem. Pharm. Bull.
275
DMSO (8eq) afforded 8 in 44% yield (entry 6). The reaction was used for chromatography. Organic extracts were dried
in a CO atmosphere increased the yield to 59% (entry 7). The over anhydrous Na2SO4.
highest yield of 8 (61%) was attained when the reaction was
performed in toluene (entry 8).
1-Bromo-2-[2-(trimethylsilyl)ethynyl]-benzene (11) To
a solution of 1-bromo-2-iodobenzene (10, 1.0mL, 8.0mmol)
The next task was the introduction of 4-hydroxybenzylidene in THF (50mL) were added PdCl2(PPh3)2 (112mg, 0.16mmol),
moieties to the α-positions of the two carbonyl groups of 8 CuI (15mg, 0.080mmol), trimethylsilylacetylene (1.4mL,
(Chart 5). Treatment of 8 with 4-benzoyloxybenzaldehyde (9a) 8.8mmol) and iPr2NH (7.8mL, 56mmol) at room temperature.
in the presence of sodium hydroxide resulted in an intractable After being stirred for 5h, the mixture was quenched by ad-
mixture. The reaction with 4-acetoxybenzaldehyde (9b) gave dition of saturated aqueous NH4Cl and extracted with hexane.
a similar result. Gratifyingly, the MOM-protected 4-hydroxy- The extract was washed with water and brine, dried and con-
benzaldehyde 9c (MOM: methoxymethyl) was shown to afford centrated to dryness. The residue was chromatographed with
the desired condensation product 1534) in 51% yield. Finally, hexane to give 11 (2.28g, quantitative yield) as a pale yellow
1
the exposure of 15 to acidic conditions resulted in the removal oil: H-NMR (400MHz, CDCl3) δ: 7.61 (d, 1H, J=8.1Hz), 7.53
of the MOM group to provide 2, the carbon analogue of scyto- (dd, 1H, J=7.8, 1.4Hz), 7.28 (dd, 1H, J=7.8, 7.8Hz), 7.19 (dd,
nemin (1), in 91% yield.35)
1H, J=8.1, 7.8Hz), 0.32 (s, 9H). NMR data is identical to lit-
In summary, we have completed the short-step synthesis erature data.36)
of a carbon analogue of scytonemin from the commercially
3-[2-(2-(Trimethylsilyl)ethynyl)phenyl]-2-propyn-1-ol
available 1-bromo-2-iodobenzene (10). The significant features (13) To a solution of 11 (2.03g, 8.0mmol) in THF (42mL)
of this synthesis are (i) the intramolecular double PKTR of was added butyllithium (1.61M in hexane, 7.0mL, 11mmol)
bis(allenyne), which enabled us to straightforwardly construct at −78°C. After being stirred for 30min, I2 (3.0g, 12mmol)
the 3,3′-linked dimeric 1H-cyclopent[a]inden-2-one skeleton, was added to the reaction mixture at –78°C. The mixture
and (ii) the stereoselective introduction of the arylidene moi- was stirred for 2h at room temperature, quenched by addi-
ety by aldol condensation. The biological studies of 2 are now tion of saturated aqueous Na2S2O3 and extracted with hexane.
in progress.
The extract was washed with water and brine, dried and
concentrated to dryness. To a solution of the residue in THF
(50mL) were added PdCl2(PPh3)2 (109mg, 0.16mmol), CuI
Experimental
General Melting points were measured with Yanagimoto (15mg, 0.078mmol), propargyl alcohol (0.70mL, 12mmol)
(Tokyo, Japan) micro melting point apparatus, and were un- and iPr2NH (7.7mL, 55mmol) at room temperature. After
corrected. Infrared spectra were measured with a Shimadzu being stirred for 25h, the mixture was quenched by addition
FTIR-8700 spectrometer (Kyoto, Japan) for samples in CHCl3. of saturated aqueous NH4Cl, and extracted with AcOEt. The
1H-NMR spectra were measured with JNM-ECS400 or JNM- extract was washed with water and brine, dried and concen-
ECA600 spectrometers for samples in CDCl3. Tetramethyl- trated to dryness. The residue was chromatographed with
silane (0.00ppm) for compounds with a phenyl group or CHCl3 hexane–AcOEt (5:1) to give 13 (1.53g, 84% yield from 11) as
1
(7.26ppm) were used as an internal reference. 13C-NMR a yellow oil: H-NMR (400MHz, CDCl3) δ: 7.48–7.41 (m, 2H),
spectra were measured with JNM-ECS400 or JNM-ECA600 7.27–7.24 (m, 2H), 4.54 (brs, 2H), 0.27 (s, 9H). NMR data is
spectrometers for samples in CDCl3. CDCl3 (77.00ppm) was identical to literature data.37)
used as an internal reference. High-resolution mass spectra
2,2′-(Buta-1,3-diyne-1,4-diyl)bis[(3-hydroxypropynyl)ben-
(HR-MS) and MS were measured with JMS-SX102A (FAB) zene] (14) To a solution of 13 (2.20g, 9.6mmol) in MeOH
or JMS-T100TD (Direct Analysis in Real Time: DART) mass (30mL) and pyridine (30mL) was added Cu(OAc)2·H2O (3.9g,
spectrometers. UV visible absorption spectra were measured 19mmol) at room temperature. After stirring for 9h at 60°C,
with UV-3150 (Shimadzu). Commercially available anhydrous the reaction was quenched by addition of 10% aqueous HCl,
tetrahydrofuran (THF), CH2Cl2, and toluene were employed and extracted with Et2O. The extract was washed with water
for reactions. DMSO was distilled from CaSO4. [RhCl(CO)2]2 and brine, dried, and concentrated to dryness. The residue
was purchased from Kanto Chemical Co. (Tokyo, Japan). was chromatographed with hexane–AcOEt (2:1) to afford 14
Other reagents were commercially available and used without (1.32g, 89% yield) as a pale brown solid: mp 105–106°C; IR
further purification. All reactions were carried out under a 3601, 3420, 2399, 1522, 1475, 1448, 1383, 1022, 951, 930cm−1;
nitrogen atmosphere. Silica gel (silica gel 60, 230–400 mesh) 1H-NMR (600MHz, CDCl3) δ: 7.51 (d, 2H, J=6.9Hz), 7.42 (d,
Chart 5. Completion of the Synthesis of 2

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Chem. Pharm. Bull.
Vol. 63, No. 4 (2015)
2H, J=7.2Hz), 7.31–7.26 (m, 4H), 4.58 (d, 4H, J=5.8Hz), 2.97 p-TsOH·H2O (156mg, 0.82mmol) at room temperature. After
(t, 2H, J=5.8Hz); 13C-NMR (151MHz, CDCl3) δ: 132.7, 131.8, stirring for 4h at 60°C, EtOH was evaporated off. The residue
128.9, 128.1, 126.3, 124.3, 92.3, 83.7, 81.2, 77.5, 51.5; DART was dissolved in acetone, extracted with CH2Cl2, washed with
MS m/z 311 (M++1, 29.0); DART HR-MS Calcd for C22H15O2 water and brine, dried, and concentrated to dryness. The resi-
311.1072, Found 311.1077.
due was chromatographed with hexane–AcOEt (4:3) to afford
2,2′-(Buta-1,3-diyne-1,4-diyl)bis[(1,2-propadienyl)ben- 2 (67mg, 91% yield) as a dark brown solid: mp 261–262°C; IR
zene] (7) To a solution of 14 (151mg, 0.49mmol) in THF (KBr) 1684, 1664, 1630, 1601, 1580, 1560, 1510, 1437, 1288,
(4.9mL) were successively added PPh3 (498mg, 1.9mmol), 1159, 1088, 1040cm−1; 1H-NMR (600MHz, acetone-d6) δ:
IPNBSH (490mg, 1.9mmol), and DIAD (0.40mL, 1.9mmol) 9.15 (brs, 2H), 7.82 (d, 4H, J=8.6Hz), 7.43 (s, 2H), 7.40–7.35
at 0°C. After stirring for 5h at room temperature, TFE–H2O (m, 6H), 7.30 (d, 2H, J=7.6Hz), 7.10 (dd, 2H, J=6.9, 6.5Hz),
(1:1, 5.0mL) was added to the reaction mixture. After stirring 7.05 (d, 4H, J=8.6Hz); 13C-NMR (151MHz, acetone-d6) δ:
for 1h at room temperature, the reaction was quenched by ad- 194.8, 165.2, 160.2, 149.7, 140.4, 133.5, 133.3, 133.1, 131.4,
dition of water, and the mixture was extracted with AcOEt. 128.22, 128.17, 127.5, 127.4, 125.3, 124.5, 123.6, 116.7; DART
The extract was washed with water and brine, dried, and MS m/z 543 (M++1, 100); DART HR-MS Calcd for C38H23O4
concentrated to dryness. The residue was chromatographed 543.1596, Found 543.1607.
with hexane to afford 7 (57mg, 51% yield) as a pale yel-
low solid: mp 68°C (decomposed); IR 1940, 1481, 1447, 854,
Acknowledgments This work was supported in part by
667cm−1; H-NMR (600MHz, CDCl3) δ: 7.51–7.47 (m, 4H), a Grant-in-Aid for Scientific Research from the Ministry of
7.31 (brs, 2H), 7.16 (brs, 2H), 6.74 (brs, 1H), 5.21–5.20 (m, Education, Culture, Sports, Science and Technology of Japan,
5H); 13C-NMR (151MHz, CDCl3) δ: 210.7, 137.1, 133.3, 129.3, for which we are thankful. We thank Prof. Dr. Akira Odani
126.64, 126.61, 119.4, 92.0, 80.7, 79.1, 78.3; DART MS m/z for UV-visible absorption spectroscopy analysis of 2.
279 (M++1, 42.9); DART HR-MS Calcd for C22H15 279.1174,
1
Found 279.1188.
Conflict of Interest The authors declare no conflict of
[3,3′-Bi(cyclopent[a]inden)]-2,2′(1H,1′H)-dione (8) To a interest.
solution of 7 (29mg, 0.10mmol) in toluene (1.0mL) were
added Mo(CO)3(MeCN)3 (126mg, 0.42mmol) and DMSO
Supplementary Materials The online version of this ar-
(59 µL, 0.83mmol). The reaction mixture was stirred at 0°C ticle contains supplementary materials.
for 24h under CO (1atm). The reaction mixture was chro-
matographed with hexane–CH2Cl2–AcOEt (8:1:1) to afford
8 (21mg, 61% yield) as a red solid: mp over 300°C; IR 1713,
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(d, 4H, J=8.6Hz), 7.11 (s, 2H), 7.06 (dd, 2H, J=7.6, 7.2Hz),
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Vol. 63, No. 4 (2015)
Chem. Pharm. Bull.
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phenyl groups oriented to the opposite side of the carbonyl groups
(see Supplemental Information for details).
35) The UV-visible absorption spectrum of 2 (see Supplemental Infor-
mation) showed strong absorbance peaks around 260nm, which are
different from those of scytonemin (1) exhibiting a characteristic
strong absorbance peak around 400nm (see ref. 1). The above ob-
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