Total synthesis of coprinol

Article abstract of DOI:10.1021/acs.jnatprod.6b00277

The first synthesis of coprinol has been achieved from 2-methoxy-3,5-dimethylbenzaldehyde via the intermediacy of an indanone derivative where dialkylation, Friedel-Crafts acylation, demethylation, and regioselective formation of a primary -OH group from a chloroacetyl group are the key steps.

Full text of DOI:10.1021/acs.jnatprod.6b00277

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Total Synthesis of Coprinol
Muthiah Suresh,† Navin Kumar,† Gorre Veeraraghavaiah,‡ Sunit Hazra,† and Raj Bahadur Singh*,†
†Centre for Applied Chemistry, Central University of Jharkhand, Brambe, Ranchi 835205, India
‡School of Chemistry, University of Hyderabad, Central University P.O., Hyderabad 500046, India
S
* Supporting Information
ABSTRACT: The first synthesis of coprinol has been achieved from 2-methoxy-3,5-
dimethylbenzaldehyde via the intermediacy of an indanone derivative where
dialkylation, Friedel−Crafts acylation, demethylation, and regioselective formation of
a primary −OH group from a chloroacetyl group are the key steps.
lludalane sesquiterpenes are a class of secondary metabolites
of both fungi of the Basidiomycotina subdivision and ferns of
Scheme 1. Retrosynthtic Approach to Coprinol (1)
I
the Pteridaceae family.1 They are characterized by the presence
of a benz-fused functionalized cyclopentane derivative as shown
in Figure 1. These sesquiterpenes are reported to show
Figure 1. Chemical structure of coprinol and the skeleton of
illudalane.
alloy following a literature procedure10 to get the correspond-
ing hydrocinnamic acid (6) in 95% yield. The indanone
derivative (3) was obtained in 88% yield by a polyphosphoric
acid-mediated cyclization11 of compound 6. NaH/MeI-
mediated12 dimethylation of 3 produced α,α-dimethylated
indanone (7), in 83% yield, which on Clemmensen reduction13
gave substituted indane (2), in 90% yield. Compound 2 on
treatment with chloroacetyl chloride in the presence of AlCl3 in
carbon disulfide solvent afforded the advanced precursor 8 in
97% yield (Scheme 2).5
With compound 8 in hand, we thought that regioselective
formation of a primary −OH group5 followed by demethylation
of the aromatic methoxy group will complete the synthesis of
coprinol (1). Thus, when compound 8 was treated with NaBH4
in ethanol, the desired hydroxy compound 9 was produced in
79% yield.5 However, the attempted aromatic methoxy
demethylation14 of compound 9 resulted in formation of
bromo derivative 10 (obtained from bromination of the
primary OH group of coprinol) as the major product along
with our target compound 1 in 37% yield. Formation of side
product could not be minimized even at lower temperature
(down to −78 °C). Use of other Lewis acids such as AlCl3 in
dichloromethane (DCM) and AlCl3−NaI in acetonitrile in
refluxing conditions resulted in incomplete reaction even after
cytotoxic2,3 and antispasmodic4 activities along with DNA-
binding properties by some of them and their synthetic
analogues.5,6 In a search for new illudalane sesquiterpenes,
Pettit et al. recently isolated coprinol (1) (Figure 1) along with
two new sesquiterpenes.7 Coprinol (1) contains an indane
nucleus with a fully substituted aromatic ring. Although the
biological activity and the presence of densely functionalized
groups have made them attractive targets to synthetic organic
chemists,8 to the best of our knowledge there is no report on
the synthesis of illudalanes with a hydroxy group on the
aromatic ring. Herein we report the first synthesis of coprinol
(1), a representative of this class of illudalane sesquiterpenes
(Figure 1).
Our retrosynthetic plan showed coprinol (1) could be
synthesized from an indane derivative (2) via Friedel−Crafts
acylation and functional group modification. The indane
derivative (2) could be obtained from an indanone derivative
(3) via α,α-dimethylation followed by reduction of the carbonyl
group. Cinnamic acid (4) was chosen as a precursor for
indanone (3). Compound 4 can be obtained from a
Knoevenagel condensation of 2-methoxy-3,5-dimethylbenzal-
dehyde (5) with malonic acid (Scheme 1).
According to the plan in Scheme 1, we started with the
conversion of 2-methoxy-3,5-dimethylbenzaldehyde (5)9 to a
cinnamic acid derivative (4) by the Knoevenagel condensation.
Reduction of cinnamic acid (4) was carried out by a Ni−Al
Received: April 2, 2016
© XXXX American Chemical Society and
American Society of Pharmacognosy
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DOI: 10.1021/acs.jnatprod.6b00277
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Journal of Natural Products
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a
Scheme 2. Synthesis of Key Intermediates
a
Reagents and conditions: (i) CH2(COOH)2, pyridine, catalytic piperidine, reflux for 4 h, 98%; (ii) Ni−Al alloy, 10% NaOH(aq), overnight, 95%;
(iii) polyphosphoric acid, heat at 70−-80 °C for 4 h, 88%; (iv) NaH, MeI, THF room temp, 83%; (v) Zn amalgam, conc. HCl, toluene, reflux for 4 h,
90%; (vi) chloroacetyl chloride, AlCl3, CS2, 0 °C to room temp, 1 h, 97%.
12 h with the formation of a nonpolar uncharacterized side
product.
EXPERIMENTAL SECTION
■
General Experimental Procedures. All reagents were purchased
from commercial sources and used as received without purification
except tetrahydrofuran (THF) and DCM. The column chromatog-
raphy was carried out using silica gel (100−200 mesh) with hexane
and ethyl acetate as eluent. All reactions were monitored by thin-layer
chromatography (TLC) on 0.25 mm silica plates (F-254) visualizing
a
Scheme 3. Synthesis of Coprinol
1
with UV light and KMnO4(aq). H NMR (400, 500 MHz) and 13C
NMR (125 MHz) spectra were recorded on Bruker-AVANCE- 400
and Bruker-AVANCE- 500 spectrometers in deuterochloroform
(CDCl3) except the target molecule coprinol, which was recorded in
deuteromethanol (CD3OD). HRMS spectra were recorded on a
Bruker MaXis ESI-TOF spectrometer.
3-(2-Methoxy-3,5-dimethylphenyl)prop-2-enoic Acid (4). In
a 250 mL round-bottom flask 3.8 g (23.17 mmol) of 5 and 5.2 g (50
mmol) of malonic acid were taken and dissolved in a mixture of a
catalytic amount of 0.5 mL of piperidine and 40 mL of pyridine. The
mixture was heated under reflux for 4 h, and the completion of
reaction was monitored by TLC. After completion, the reaction
mixture was cooled and poured over cold water containing excess
hydrochloric acid, and the solid cinnamic acid 4 was filtered, washed
with excess cold water, and dried. The yield was 4.6 g (98%), and the
a
Reaction conditions: (i) NaBH4, ethanol, room temp, 24 h, 80%; (ii)
1 M solution of BBr3 in dichloromethane, 1.5 equiv, −20 °C to room
temp.
In order to avoid formation of side product, the synthetic
route was modified. In a modified route, the Friedel−Crafts-
acylated indane (8) was demethylated using BBr3 in DCM,
which furnished the expected product 11 in 90% yield (Scheme
4). Compared with the synthetic route mentioned above, this
1
melting point 164−167 °C. H NMR (500 MHz, CDCl3) δ 2.27 (s,
3H), 2.28 (s, 3H), 3.72 (s, 1H), 6.46 (d, 1H J = 16 Hz), 7.03 (s, 1H),
7.22 (s, 1H), 7.97 (d, 1H J = 16.5 Hz); 13C NMR (125 MHz, CDCl3)
δ 15.7, 20.6, 61.3, 118.8, 125.8, 127.2, 131.3, 133.5, 134.1, 140.6, 155.6,
170.2; HRMS (ESI) exact mass calcd for C12H14O3 + NH4 (M +
NH4)+ 224.1287, found 224.1287.
a
Scheme 4. Modified Route to Compound 1
3-(2-Methoxy-3,5-dimethylphenyl)propanic Acid (6). In a 250
mL RB flask 2 g (9.71 mmol) of 4 was dissolved in 60 mL of 10%
NaOH(aq) solution. The flask was connected with an adapter that was
attached to a balloon. Ni−Al alloy (2 g) was added portionwise over
10 min to the stirred solution. The completion of the reaction was
monitored by TLC, and after completion, the reaction mixture was
filtered through a Celite bed on a sintered funnel and washed
thoroughly with NaOH(aq) solution. The filtrate was poured into
water containing enough concentrated HCl to neutralize the base. The
aqueous solution was extracted by ethyl acetate and evaporated, and
a
Reaction conditions: (i) 1 M solution of BBr3 in dichloromethane,
1.5 equiv, −20 °C to room temp; (ii) NaBH4, ethanol, room temp, 24
h.
1
method was convenient and short and formation of the
brominated side product 10 was eliminated. Compound 11 was
subjected to a NaBH4 reduction,5 which yielded 77% of
coprinol (1). The 1H and 13C NMR data of synthesized
coprinol (1) matched perfectly with literature data.7
In conclusion, we have accomplished the first total synthesis
of coprinol with 41% overall yield in eight linear steps from 2-
methoxy-3,5-dimethylbenzaldehyde, where Friedel−Crafts acy-
lation, alkylation, demethylation, and regioselective reduction of
a chloroacetyl group to a primary −OH are the key steps.
Further application of our synthetic route to other illudalane
sesquiterpenes is currently under way.
the yield of 6 was 1.92 g (95%): melting point 59−62 °C; H NMR
(400 MHz, CDCl3) δ 2.25 (s, 3H), 2.26 (s, 3H), 2.68 (t, 2H, J = 7.6
Hz), 2.93 (t, 2H, J = 8.4 Hz), 3.72 (s, 3H), 6.83 (s, 1H), 6.87 (s, 1H);
13C NMR (125 MHz, CDCl3) δ 16.1, 20.7, 25.3, 34.9, 60.4, 128.1,
130.4, 130.8, 132.7, 133.4, 154.6, 179.6; HRMS (ESI) exact mass calcd
for C12H16O3 + Na (M + Na)+ 231.0997, found 231.0990.
4-Methoxy-5,7-dimethylindan-1-one (3). A mixture of 3.45 g
(24.5 mmol) of P2O5 and 3.8 mL of orthophosphoric acid was stirred
under anhydrous conditions in an oil bath at 90−95 °C for about 1 h,
and the resulting polyphosphoric acid was cooled to 70 °C. To this
was added compound 6 (1 g, 4.81 mmol). After stirring at 70 °C for 4
h the reaction mixture was cooled, poured over ice, extracted with
ethyl acetate, washed with NaHCO3, dried over Na2SO4, and
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DOI: 10.1021/acs.jnatprod.6b00277
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Journal of Natural Products
Note
1
evaporated. The yield was 0.8 g (88%). H NMR (500 MHz, CDCl3)
δ 2.33 (s, 3H), 2.55 (s, 3H), 2.67−2.65 (m, 2H), 3.07 (t, 2H, J = 6.5
Hz), 3.82 (s, 3H), 6.93 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 16.1,
17.6, 22.3, 36.9, 59.9, 132.6, 133.8, 134.1, 137.2, 147.6, 153.6, 207.3;
HRMS (ESI) exact mass calcd for C12H14O2 + H (M + H)+ 191.1072,
found 191.1068.
added 0.170 g of NaBH4 (4.49 mmol), and the mixture stirred
overnight at room temperature. The progress of the reaction was
monitored by TLC. After completion, the reaction mixture was dried
under vacuum, and the resulting white solid residue dissolved in water,
neutralized with saturated NH4Cl solution, and extracted with ethyl
acetate. The organic layer was dried over Na2SO4, and the product
purified by column chromatography, giving a yield of 1 of 0.067 g
4-Methoxy-2,2,5,7-tetramethylindan-1-one (7). In a 50 mL
two-neck round-bottom flask 0.25 g of NaH (55−60% suspension in
mineral oil) was placed and closed with septum. The NaH was washed
twice with dry hexane, and 10 mL of dry THF was added. To this was
added 0.2 g (1.05 mmol) of 3 in 3 mL of THF, and the mixture stirred
for 20 min, followed by addition of excess MeI drop by drop; this was
then stirred for a further 30 min and quenched with crushed ice,
extracted with ethyl acetate, evaporated, and purified by column
chromatography, which furnished 0.19 g of the desired product 7
1
(77%). Mp = 132−134 °C (lit. =159−160 °C); H NMR (500 MHz,
CD3OD) δ 1.14 (s, 6H), 2.12 (s, 3H), 2.17 (s, 3H), 2.62 (s, 2H), 2.63
(s, 2H), 2.88 (t, 2H, J = 8 Hz), 3.54 (t, 2H, J = 8.5 Hz), 4.63 (s, 1H);
13C NMR (125 MHz, CD3OD) δ 12.1, 15.8, 29.7, 34.3, 40.3, 45.6,
62.2, 122.5, 124.8, 127.7, 134.6, 141.9, 150.1; HRMS (ESI) exact mass
calcd for C15H22O2 + H (M + H)+ 235.1698, found 235.1694.
2-(7-Methoxy-2,2,4,6-tetramethylindan-5-yl)ethanol (9). To
an ethanolic solution of compound 8 (0.46 g, 1.64 mmol) was added
0.74 g (19.6 mmol) of NaBH4, and the mixture stirred overnight at
room temperature. The progress of the reaction was monitored by
TLC. After completion, the reaction mixture solvent was evaporated
under vacuum, and the resulting white solid material dissolved in water
and extracted with ethyl acetate. The organic layer was dried over
Na2SO4 and evaporated, and the product purified by column
1
(yield 83%): H NMR (500 MHz, CDCl3) δ 1.21 (s, 6H), 2.32 (s,
3H), 2.55 (s, 3H), 2.94 (s, 2H), 3.80 (s, 3H), 6.95 (s, 1H); 13C NMR
(125 MHz, CDCl3), δ 16.2, 17.6, 25.6, 39.4, 45.6, 59.9, 132.3, 132.7,
134.5, 137.3, 144.4, 153.6, 211.4; HRMS (ESI) exact mass calcd for
C14H18O2 + H (M + H)+ 219.1385, found 219.1378.
4-Methoxy-2,2,5,7-tetramethylindane (2). To prepare the zinc
amalgam, in a 250 mL round-bottom (RB) flask 22.5 g of zinc powder
was added and washed twice with 20 mL of 50% HCl. Then 2.5 g of
HgCl2, 40 mL of water, and 7.5 mL of concentrated HCl were added
to the washed Zn dust, and the resulting mixture was stirred vigorously
for 1 h at room temperature. To this was added 0.5 g (2.29 mmol) of
compound 7 in 40 mL of toluene followed by 37.5 mL of concentrated
HCl. The reaction mixture was refluxed, and after each 2 h interval 2.5
mL of concentrated HCl was added; the completion of the reaction
was monitored by TLC. After completion, the reaction mixture was
cooled, the liquid was separated from the solid residue, and the
aqueous layer was saturated with NaCl and extracted with ethyl
acetate. The combined organic layer was evaporated and purified by
column chromatography. The yield of 2 was 0.423 g (90%): 1H NMR
(500 MHz, CDCl3) δ 1.16 (s, 6H), 2.14 (s, 3H), 2.22 (s, 3H), 2.61 (s,
2H), 2.77 (s, 2H), 3.72 (s, 3H), 6.78 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ 15.8, 18.6, 29.4, 40.1, 45.2, 46.5, 59.8, 128.0, 129.3, 130.2,
134.5, 142.1, 153.2; HRMS (ESI) exact mass calcd for C14H20O + H
(M + H)+ 205.1592, found 205.1593.
2-Chloro-1-(7-methoxy-2,2,4,6-tetramethylindan-5-yl)-
ethanone (8). In a 25 mL RB flask 0.5 g (2.45 mmol) of 2 in 5 mL of
CS2 was cooled to 0 °C, and 1.2 mL (14.71 mmol, 6 equiv) of
chloroacetyl chloride in 5 mL of CS2 added followed by 1.96 g of AlCl3
(14.71 mmol, 6 equiv) added portionwise for 30 min; the mixture was
stirred 30 min at ambient temperature. After completion of the
reaction it was quenched with crushed ice and extracted with ethyl
acetate, and the organic layer was washed with saturated NaHCO3
solution and evaporated under high vacuum. The yield was 0.665 g
(97%). Mp = 52−53 °C; 1H NMR (500 MHz, CDCl3) δ 1.16 (s, 6H),
2.05 (s, 3H), 2.11 (s, 3H), 2.62 (s, 2H), 2.79 (s, 2H), 3.72 (s, 3H),
4.40 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 12.7, 16.0, 29.1, 39.9,
45.3, 46.5, 50.2, 59.8, 124.0, 124.5, 136.1, 138.2, 143.3, 153.2; HRMS
(ESI) exact mass calcd for C16H21O2Cl + H (M + H)+ 281.1308,
found 281.1307.
1
chromatography; the yield of 9 was 0.32 g (79%). H NMR (500
MHz, CDCl3) δ 1.16 (s, 6H), 2.18 (s, 3H), 2.25 (s, 3H), 2.66 (s, 2H),
2.78 (s, 2H), 2.96 (t, 2H, J = 7.5 Hz), 3.70 (s, 3H), 3.74 (t, 2H, J = 7.5
Hz); 13C NMR (125 MHz, CDCl3), δ 12.3, 16.3, 29.5, 33.4, 39.6, 45.3,
47.5, 60.0, 62.1, 127.4, 128.6, 132.8, 134.0, 142.3, 153.2; HRMS (ESI)
exact mass calcd for C16H24O2 + NH4 (M + NH4)+ 266.2120, found
266.2123.
6-(2-Bromoethyl)-2,2,5,7-tetramethylindan-4-ol (10) and 6-
(2-Hydroxyethyl)-2,2,5,7-tetramethylindan-4-ol (coprinol) (1).
A solution of compound 9 (0.1 g, 0.4 mmol) in 5 mL of DCM was
cooled at −20 °C, and 1.5 equiv (0.60 mmol, 0.60 mL) of BBr3 was
added. The reaction mixture was stirred at −20 °C for 30 min and for
a further 2 h at room temperature, followed by quenching with
crushed ice and extracting with ethyl acetate. The organic layer was
dried over Na2SO4, evaporated, and purified by column chromatog-
raphy. The yield of compound 1 was 0.035 g (37%); that of 10 was
0.061 g (52%). The 1H and 13C NMR and HRMS data for compound
10 were as follows: 1H NMR (500 MHz, CDCl3) δ 1.17 (s, 6H), 2.14
(s, 3H), 2.21 (s, 3H), 2.63 (s, 2H), 2.69 (s, 2H), 3.17−3.21 (m, 2H),
3.33−3.37 (m, 2H), 4.32 (s, 1H); 13C NMR (125 MHz, CDCl3) δ
11.7, 15.8, 29.6, 30.2, 34.2, 39.7, 44.0, 47.7, 120.3, 124.6, 126.4, 135.2,
141.8, 148.5; HRMS (ESI) exact mass calcd for (C15H21BrO − H)− =
295.0703, found 295.0706.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jnat-
prod.6b00277.
1H and 13C NMR spectra for compounds 4, 6, 3, 7, 2, 8,
9, and 10 (PDF)
2-Chloro-1-(7-hydroxy-2,2,4,6-tetramethylindan-5-yl)-
ethanone (11). A solution of compound 8 (0.1 g, 0.36 mmol) in 5
mL of DCM was cooled at −20 °C, and 0.54 mL of a 1 M solution of
BBr3 in dichloromethane (0.54 mmol, 1.5 equiv) was added. The
reaction mixture was stirred at −20 °C for 30 min, followed by 1 h at
room temperature. After that, the reaction mixture was quenched with
crushed ice and extracted with ethyl acetate. The organic layer was
dried over Na2SO4, evaporated, and purified by column chromatog-
AUTHOR INFORMATION
Corresponding Author
*E-mail (R. B. Singh): rajbahadur.iitb@gmail.com. Phone: +91-
8877019873.
■
Notes
The authors declare no competing financial interest.
1
raphy. The yield of 11 was 0.0864 g (90%). Mp = 158−160 °C; H
NMR (500 MHz, CDCl3) δ 1.18 (s, 6H), 2.02 (s, 3H), 2.09 (s, 3H),
2.65 (s, 4H), 4.39 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 12.5, 15.8,
29.4, 40.2, 43.9, 46.9, 50.3, 117.5, 121.3, 129.4, 138.2, 142.6, 148.5,
201.0; HRMS (ESI) exact mass calcd for C15H19O2Cl + Na (M + Na)+
289.0971, found 289.0963.
ACKNOWLEDGMENTS
■
Financial support for this work was provided by Grant SB/FT/
CS-045/2013 from the Department of Science and Technol-
ogy, India, and is gratefully acknowledged. M.S. thanks CSIR-
New Delhi for his junior research fellowship. N.K. thanks DST,
India, for his fellowship.
6-(2-Hydroxyethyl)-2,2,5,7-tetramethylindan-4-ol (Coprinol)
(1). To the ethanolic solution of compound 11 (0.1 g, 0.37 mmol) was
C
DOI: 10.1021/acs.jnatprod.6b00277
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