Total syntheses of multicaulins via oxidative photocyclization of stilbenes

Article abstract of DOI:10.1021/np5001158

The Wittig reaction of 3-isopropyl-4-methoxybenzaldehyde and 2,3-dimethylbenzylphosphonium bromide afforded the corresponding stilbene mixture 16. Oxidative photocyclization of stilbene 16 with iodine facilitated the first total synthesis of 7-isopropyl-6

Full text of DOI:10.1021/np5001158

Note
pubs.acs.org/jnp
Total Syntheses of Multicaulins via Oxidative Photocyclization of
Stilbenes
Hatice Seci̧ nti, Serdar Burmaoglu, Ramazan Altundas,̧ and Hasan Secȩ n*
̆
Department of Chemistry, Faculty of Sciences, Ataturk University, 25240 Erzurum, Turkey
S
* Supporting Information
ABSTRACT: The Wittig reaction of 3-isopropyl-4-methoxybenzalde-
hyde and 2,3-dimethylbenzylphosphonium bromide afforded the
corresponding stilbene mixture 16. Oxidative photocyclization of
stilbene 16 with iodine facilitated the first total synthesis of 7-
isopropyl-6-methoxy-1,2-dimethylphenanthrene, multicaulin (1). The
O-demethylation of 1 with BBr3 afforded the 7-isopropyl-1,2-
dimethylphenanthren-6-ol, O-demethylmulticaulin (2).
Salvia is a common genus among medicinal plants. More than
700 secondary metabolites from Salvia species include various
terpenoids, steroids, and polyphenols, and their biological
activities have recently been reviewed.1 These metabolites
possess acetylcholinesterase (AChE) inhibitory, antitumor,
antifeedant, antihypertensive, cardiovascular, antileishmanial,
antimicrobial, antioxidant, cytotoxic, and anti-HIV activities. In
1997, Ulubelen and co-workers2 isolated four new aromatic
norditerpenoids (1−4), two new abiatene diterpenoids (5, 6),
and a new pimarene diterpenoid (7) along with a series of
known compounds from Salvia multicaulis. Compounds 1−7
were tested against the Mycobacterium tuberculosis strain H37Rv
and exhibited strong antituberculous activity, with MIC values
ranging from 0.46 to 7.3 μg/mL. Among these compounds, O-
demethylmulticaulin (2) exhibited the strongest antitubercu-
lous activity, with an MIC value of 0.46 μg/mL. Sairafianpour
and co-workers3 isolated compound 2 and its dihydro
derivative 8 from Salvia hydrangea as new 20-norabiatenes.
Only two reports describing the isolation of multicaulins from
nature are known. To date, synthesis pathways toward the
formation of either 1 or 2 have not been described. The
synthesis of 1 and 2 was attempted due to their high
antituberculosis activities.
Figure 1. Structures of natural compounds 1−8.
Our synthesis is based on a convergent method in which the
relevant stilbene 16, which possesses all of the required
functionalities, was first prepared. Therefore, 2-isopropylphenol
(9) was O-methylated with Me2SO4 to yield 2-isopropylanisole
(10) (93% yield). Bromination of electron-rich aromatic
compound 10 using molecular Br2 afforded bromoanisole 11
in low yield along with several side products. However, the
bromination of 2-isopropylanisole (10) with LiBr/(NH4)2Ce-
(NO3)64 selectively yielded 4-bromo-2-isopropylanisole (11) in
97% yield. Subsequent lithiation of 11 with n-BuLi followed by
formylation with N-formylpiperidine instead of conventionally
used DMF5 afforded 3-isopropyl-4-methoxybenzaldehyde (12)
in 90% yield (Scheme 1).
of benzaldehyde 13 with LiAlH4 afforded 2,3-dimethybenzyl
alcohol (14) (89% yield), which was converted to 2,3-
dimethylbenzyl bromide (15) in 93% yield via treatment with
PBr3 (Scheme 2).
2,3-Dimethylbenzyl bromide (15) was converted to the
corresponding phosphonium salt, which was used in the next
step without further purification. The Wittig reaction between
the phosphonium salt and 3-isopropyl-4-methoxybenzaldehyde
(12) resulted in (E/Z)-stilbene mixture 16 in a yield of 90%.
Kaliakoudas and co-workers6 developed a successful I2-
oxidative photocyclization of stilbenes to afford substituted
2,3-Dimethylbenzyl bromide (15) was synthesized in two
steps starting from 2,3-dimethylbenzaldehyde (13). Reduction
Received: February 6, 2014
Published: August 20, 2014
© 2014 American Chemical Society and
American Society of Pharmacognosy
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Journal of Natural Products
Note
a
a
Scheme 1. Synthesis of Compound 12
Scheme 3. Synthesis of Multicaulins 1 and 2
a
Reaction conditions and reagents: (i) Me2SO4, NaOH(aq), 90 °C, 4
h, 93%; (ii) LiBr/(NH4)2Ce(NO3)6, CH3CN, 20 °C, 2 h, 97%; (iii) n-
BuLi, −78 °C, N-formylpiperidine, THF; then rt, 12 h, 90%.
a
Scheme 2. Synthesis of 2,3-Dimethylbenzyl Bromide (15)
a
Reaction conditions and reagents: (i) PPh3, CH3CN, N2 atm, reflux,
24 h; (ii) NaH, 0 °C, N2 atm, 1 h; then benzaldehyde 12, rt, 48 h,
90%; (iii) I2, t-BuOH/benzene (9:1), 25 °C, hν, 120 h, 41%; (iv) BBr3,
CH2Cl2, N2 atm, 0 °C → rt, 12 h, 93%.
a
Reaction conditions and reagents: (i) LiAlH4, THF, 0 °C → rt, 4 h,
89%; (ii) PBr3, CH2Cl2, 0 °C → rt, 12 h, 93%.
EXPERIMENTAL SECTION
■
phenanthrenes. By applying this methodology, the (E/Z)-
stilbene mixture 16 was converted to multicaulin (1) in a yield
of 41%. The 1H NMR spectrum of 1 displayed two singlets for
H-8 (δ 7.66) and H-5 (δ 7.95) and two AB systems for H-4/H-
3 (δ 8.38 and δ 7.42) and H-10/H-9 (δ 7.86 and 7.69), which
are in agreement with the data reported by Ulubelen and co-
workers.2 However, the 13C NMR spectrum of the synthetic
multicaulin (1) was quite different from that reported by
Ulubelen and co-workers for the natural product.2 In this
context, both spectra exhibit eight quaternary and six tertiary
olefinic carbons. However, the spectrum of the natural product
1 contains three carbons above 140 ppm (140.0, 147.8, 151.4),
while the spectrum of our synthetic compound 1 contains only
one carbon (156.9) in that region. Compound 17, a
regioisomer of compound 1, was not observed in the oxidative
cyclization most likely due to the steric effect of the isopropyl
group. O-Demethylation of multicaulin (1) by treatment with
General Experimental Procedures. Solvents were purified and
dried by standard methods. Reactions were monitored via TLC. The
1H NMR and 13C NMR spectra were recorded on a 400(100) MHz
Varian spectrometer. Column chromatography was performed on
silica gel 60 (70−230) mesh ASTM, and thin-layer chromatography
was carried out on silica gel (254−366 mesh ASTM).
Syntheses. 2-Isopropylanisole (10). A solution of NaOH (9.18 g,
229 mmol) in H2O (47 mL) was added to a solution of 2-
isopropylphenol (9) (10.0 g, 73.4 mmol) in H2O (30 mL), and the
mixture was heated to 90 °C. Me2SO4 (10.65 g, 7.7 mL, 84.4 mmol)
was added, and the resulting mixture was stirred for 4 h at the same
temperature. The reaction mixture was allowed to cool to rt, and the
solution was extracted with EtOAc (3 × 50 mL). The combined
organic phases were dried over Na2SO4, filtered, and concentrated in
vacuo to yield 2-isopropylanisole (10) as a pale yellow liquid (10.19 g,
93%): Rf 0.86 (1:4 EtOAc−hexanes). The H NMR and 13C NMR
1
spectra are in agreement with reported data.7
4-Bromo-2-isopropylanisole (11). Ammonium cerium(IV) nitrate
(18.96 g, 34.6 mmol) and LiBr (3.00 g, 34.5 mmol) were placed in a
250 mL flask, and CH3CN (50 mL) was added under N2. 2-
Isopropylanisole (10) (4.71 g, 31.4 mmol) was dissolved in CH3CN
(50 mL) and added dropwise to the reaction mixture under N2. The
mixture was stirred for 2 h at rt, and the solvent was removed under
reduced pressure. The crude product was dissolved in EtOAc (50 mL),
washed with H2O (2 × 25 mL) and a solution of saturated aqueous
NaHCO3 (50 mL), and dried over Na2SO4. The solvent was removed
under reduced pressure to afford 4-bromo-2-isopropylanisole (11) as a
1
BBr3 yielded O-demethylmulticaulin (2) in 93% yield. The H
NMR spectrum of O-demethylmulticaulin (2) was in good
agreement with the spectra reported by the Ulubelen2 and
Sairafianpour3 groups. Although the 13C NMR spectrum was
different from that reported by the Ulubelen group, the 13C
NMR spectrum of synthetic 2 was in perfect agreement with
that reported by the Sairafianpour group.3 The latter authors
properly discussed the conflicting 13C NMR data and predicted
that the alternative structural isomer for O-demethylmulticaulin
(2) reported from S. multicaulis by Ulubelen and co-workers2
may be 7-isopropyl-1,2-dimethylphenanthren-5-ol.3 Our results
confirm the results reported by Sairafianpour and co-workers3
and provide confirmation of the structures of 1 and 2.
In conclusion, we report the first total synthesis of
multicaulin (1) in seven steps with 30% overall yield. O-
Demethylmulticaulin (2) was also obtained via simple O-
demethylation of 1 (93% yield). In addition, our synthesis
resolves the dispute between the Ulubelen2 and Sairafianpour3
groups regarding the structure elucidation of 1 and 2. Our
methodology may find application in the syntheses of more
potent multicaulin derivatives to combat the tuberculosis
epidemic.
1
yellow liquid (7.02 g, 97%): Rf 0.85 (1:9 EtOAc−hexanes). The H
NMR and 13C NMR spectra are in agreement with reported data.8
3-Isopropyl-4-methoxybenzaldehyde (12). A solution of 4-bromo-
2-methoxyanisole (11) (6.78 g, 29.6 mmol) in THF (30 mL) was
cooled to −78 °C under N2. Then, n-BuLi (2.5 M, 14.1 mL, 35.2
mmol) was added dropwise at the same temperature. After stirring for
1 h at −78 °C, N-formylpiperidine (6.1 mL, 6.63 g, 55.6 mmol) was
added. The reaction mixture was allowed to reach rt and then stirred
for 12 h. After monitoring with TLC, the mixture was quenched by a
saturated solution of NH4Cl (10 mL), and the solvent was removed
under reduced pressure. The crude mixture was extracted with EtOAc
(3 × 75 mL). The combined organic layers were dried over Na2SO4.
After removal of the solvent under reduced pressure, the residue was
purified by silica gel chromatography (1:20 EtOAc−hexanes) to yield
3-isopropyl-4-methoxybenzaldehyde (12) as a pale yellow liquid (4.75
g, 90%): Rf 0.41 (1:9 EtOAc−hexanes). The H NMR and 13C NMR
1
spectra are in agreement with reported data.9
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Journal of Natural Products
Note
2,3-Dimethylbenzyl Alcohol (14). To a suspension of LiAlH4 (281
mg, 7.45 mmol) in THF (15 mL) was added dropwise a solution of
2,3-dimethylbenzaldehyde (13) (1.00 g, 7.5 mmol) in THF (20 mL)
at 0 °C under N2, and the mixture was allowed to reach rt and then
stirred for 4 h. After monitoring with TLC, the reaction mixture was
cooled to 0 °C, and a saturated solution of NH4Cl (10 mL) was added,
followed by the addition of EtOAc (20 mL). The precipitate was
filtered, and the organic phase was washed with H2O (2 × 20 mL) and
dried over Na2SO4. The solvent was removed under reduced pressure
to yield 2,3-dimethylbenzyl alcohol (14) as a yellow crystalline solid
(913 mg, 89%): mp 62−64 °C; lit.6 63−65 °C; Rf 0.51 (1:4 EtOAc−
NMR (100 MHz, CDCl3) δ 156.8 (C-6); 138.0 (s); 134.0 (s); 132.4
(s); 131.1 (s); 130.2 (s); 128.7 (d); 128.4 (s); 126.5 (d); 126.0 (s);
125.6 (d); 120.5 (d); 120.2 (d); 102.0 (d); 55.6 (OCH3); 27.3
(CHMe2); 23.0 (CHMe2); 21.1 (CH3); 15.3 (CH3).
7-Isopropyl-1,2-dimethylphenanthren-6-ol (2). To a solution of
multicaulin (1) (100 mg, 0.36 mmol) in CH2Cl2 (30 mL) was added
dropwise BBr3 (110 mg, 0.04 mL, 0.44 mmol) under N2 at 0 °C, and
the mixture stirred for 12 h at room temperature. After monitoring
with TLC, 10 mL of MeOH was added, the solvent removed under
reduced pressure, and the crude product dissolved in EtOAc (90 mL),
washed with H2O (2 × 30 mL), and dried over Na2SO4. The removal
of the solvent under reduced pressure yielded 7-isopropyl-1,2-
dimethylphenanthrene-6-ol (2) as a yellow, viscous oil (88 mg,
93%): Rf 0.55 (1:4 EtOAc−hexanes); 1H NMR (400 MHz, CDCl3) δ
8.28 (d, 1 H, H-4, J = 8.4 Hz); 7.91 (s, 1 H, H-5); 7.84 (d, 1 H, H-10, J
= 9.1 Hz); 7.68 (d, 1 H, H-9, J = 9.1 Hz); 7.67 (s, 1 H, H-8); 7.40 (d,
1 H, H-3, J = 8.4 Hz); 3.38 (septet, 1 H, CHMe2, J = 7.0 Hz); 2.64 (s,
3 H, CH3); 2.52 (s, 3 H, CH3); 1.39 (d, 6 H, CHMe2, J = 7.0 Hz); the
1H NMR spectrum is in agreement with reported data;2,3 13C NMR
(100 MHz, CDCl3) δ 152.6 (s); 135.6 (s); 134.2 (s); 132.4 (s); 131.1
(s); 130.4 (s); 128.8 (d); 128.0 (s); 126.5 (d); 126.5 (s); 126.2 (d);
120.6 (d); 120.2 (d); 107.1 (d); 27.7 (CHMe2); 22.7 (CHMe2); 21.1
(CH3); 15.2 (CH3); the 13C NMR spectrum is in agreement with
reported data.3
1
hexanes). The H NMR and 13C NMR spectra are in agreement with
reported data.10
2,3-Dimethylbenzyl Bromide (15). To a solution of 2,3-
dimethylbenzyl alcohol (14) (950 mg, 6.98 mmol) in CH2Cl2 (50
mL) was added dropwise PBr3 (2.07 g, 0.72 mL, 7.67 mmol) at 0 °C.
The reaction mixture was stirred for 12 h at rt. After monitoring with
TLC, H2O (50 mL) was added, the organic layer was separated and
dried over Na2SO4, and the solvent was removed under reduced
pressure to afford 2,3-dimethylbenzyl bromide (15) as a yellow liquid
1
(1.28 g, 93%): Rf 0.66 (1:9 EtOAc−hexanes); the H NMR spectrum
is in agreement with reported data;6 13C NMR (100 MHz, CDCl3) δ
137.9; 136.1; 135.9; 130.9; 128.1; 126.0; 33.6 (CH2Br); 20.7 (CH3);
15.1 (CH3).
(2,3-Dimethylbenzyl)triphenylphosphonium Bromide. To a sol-
ution of 2,3-dimethylbenzyl bromide (15) (2.52 g, 12.72 mmol) in
CH3CN (100 mL) was added PPh3 (3.67 g, 14.0 mmol), and the
reaction mixture was refluxed for 24 h under N2. After monitoring with
TLC, the solvent was removed under reduced pressure to afford (2,3-
dimethylbenzyl)triphenylphosphonium bromide as a white solid (6.19
g). The salt was used for the next step without further purification.
(E/Z)-1-(3-Isopropyl-4-methoxyphenyl)-2-(2,3-dimethylphenyl)-
ethane (16). To a suspension of NaH (366 mg, 15 mmol) in CH2Cl2
(20 mL) was added (2,3-dimethylbenzyl)triphenylphosphonium
bromide (700 mg, 1.51 mmol) in CH2Cl2 (40 mL) at 0 °C, and the
mixture was stirred for 1 h at the same temperature under N2. After 1
h, 3-isopropyl-4-methoxybenzaldehyde (12) (272 mg, 1.53 mmol) in
CH2Cl2 (40 mL) was added, and the reaction mixture was stirred for
48 h at rt. After monitoring with TLC, a saturated solution of NH4Cl
(20 mL) was added dropwise to the mixture to quench the excess
NaH. The organic layer was separated and dried over Na2SO4. The
solvent was removed under reduced pressure, and the crude product
was purified by silica gel chromatography (1:4 EtOAc−hexanes) to
yield an isomeric mixture of stilbene (E/Z)-16 (385 mg, 90%) as a
yellow-colored liquid. This mixture was used for the next step without
further purification. A small amount of the E-isomer of stilbene 16 was
separated by thin-layer silica gel chromatography.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of all new compounds are available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel: +90-442-2314445. Fax: +90-442-2314109. E-mail:
hsecen@atauni.edu.tr.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We wish to thank the Scientific and Research Council of
̈
̇
Turkey (TUBITAK) (Grant No. 108T115). We are grateful to
Prof. Dr. G. Topcu, Faculty of Pharmacy, Bezmialem
1
University, for providing the original H NMR spectrum of
O-demethylmulticaulin (2) for comparison with the spectrum
of our synthetic compound. We wish to thank Assoc. Prof. Dr.
A. C. Goren, National Metrology Institute, TUBITAK, for
helpful discussions. In addition, we wish to thank Prof. Dr. G.
D. Lawrence, Chemistry and Biochemistry Department, Long
Island University, and B. Altundas, Ataturk University, for their
linguistic corrections.
E-Isomer of stilbene 16: 1H NMR (400 MHz, CDCl3) δ 7.41 (bd, 1
H, H-6″, J5″,6″ = 7.0 Hz); 7.36−7.32 (m, 2 H, H-2′, H-5″); 7.26 (d, 1
H, H-2, J1,2 = 16.1 Hz); 7.11 (d, 1 H, H-5′, J5′,6′ = 7.3 Hz); 7.07 (bd, 1
̈
̇
H, H-6′); 6.89 (d, 1 H, H-1, J1,2 = 16.1 Hz); 6.85 (d, 1 H, H-4″, J4″,5″
=
8.1 Hz); 3.86 (s, 3 H, OCH3); 3.33 (septet, 1 H, CHMe2, J = 7.0 Hz);
2.33 (s, 3 H, CH3); 2.32 (s, 3 H, CH3); 1.25 (d, 6 H, CHMe2, J = 7.0
Hz); 13C NMR (100 MHz, CDCl3) δ 156.9 (C-4′); 137.5 (s); 137.4
(s); 136.9 (s); 134.3 (s); 130.8 (d); 130.6 (s); 129.0 (d); 125.8 (d);
125.5 (d); 125.0 (d); 124.8 (d) 123.9 (d); 110.9 (d); 55.7 (OCH3);
27.1 (CHMe2); 22.8 (CHMe2); 20.9 (CH3); 15.7 (CH3).
DEDICATION
■
Dedicated to Prof. Dr. Ayhan Ulubelen on the occasion of her
83rd birthday.
7-Isopropyl-6-methoxy-1,2-dimethylphenanthrene (1). The E/Z
mixture of stilbene 16 (112 mg, 0.40 mmol) was dissolved in 150 mL
of t-BuOH−benzene (9:1), and I2 (101.4 mg, 0.39 mmol) was added.
The reaction mixture was irradiated for 120 h using a 400 W mercury
arc lamp. The solvent was removed under reduced pressure, and the
crude product purified by TLC to afford 7-isopropyl-6-methoxy-1,2-
dimethylphenanthrene (1) as a yellow gum (45 mg, 41%): Rf 0.74 (1:4
EtOAc−hexanes); 1H NMR (400 MHz, CDCl3) δ 8.38 (d, 1 H, H-4, J
= 8.8 Hz); 7.95 (s, 1 H, H-5); 7.86 (d, 1 H, H-10, J = 9.2 Hz); 7.69 (d,
1 H, H-9, J = 9.2 Hz); 7.66 (s, 1 H, H-8); 7.42 (d, 1 H, H-3, J = 8.8
Hz); 4.06 (s, 3 H, OCH3); 3.46 (septet, 1 H, CHMe2, J = 7.0 Hz);
2.65 (s, 3 H, CH3); 2.53 (s, 3 H, CH3); 1.33 (d, 6 H, CHMe2, J = 7.0
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