Synthesis of (±)-likonide B (smenochromene D) using a regioselective Claisen rearrangement, separation of the enantiomers and stereochemical assignment

Article abstract of DOI:10.1039/b901358j

A synthesis of the unusual ansa-bridged farnesyl hydroquinone derivative likonide B in racemic form is described. The natural product, also known as smenochromene D, was obtained from geranylacetone by a route in which the key steps are a regioselective m

Full text of DOI:10.1039/b901358j

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Synthesis of ( )-likonide B (smenochromene D) using a regioselective Claisen
rearrangement, separation of the enantiomers and stereochemical assignment†
Marjorie Bruder,a Stephen J. Smith,b Alexander J. Blakea and Christopher J. Moody*a
Received 21st January 2009, Accepted 25th February 2009
First published as an Advance Article on the web 27th March 2009
DOI: 10.1039/b901358j
A synthesis of the unusual ansa-bridged farnesyl hydroquinone derivative likonide B in racemic form is
described. The natural product, also known as smenochromene D, was obtained from geranylacetone
by a route in which the key steps are a regioselective microwave-mediated Claisen rearrangement of an
aryl propargyl ether to deliver the chromene ring, and macrocyclization via an intramolecular
Mitsunobu reaction. Subsequent HPLC on a chiral stationary phase gave the pure (+)- and
(-)-enantiomers, that were studied by CD spectroscopy, thereby shedding some light on the true
stereochemical nature of the two natural products (-)-smenochromene D and (+)-likonide B.
Introduction
Sesquiterpenoid quinone and hydroquinone derivatives occur
widely in nature.1–3 In 1991 Faulkner and Clardy and col-
leagues reported the isolation, and structure determination,
of a series of unusual ansa-bridged farnesyl hydroquinones,
the smenochromenes A–D (1–4), from a Seychelles sponge
Smenospongia sp.4 Some years later, Kashman and co-workers
reported the isolation of two compounds, named likonide A and
B (5 and 6), from a marine sponge Hyatella sp. found off the coast
of Likoni, Kenya (Fig. 1).5
The structures and absolute configurations of the likonides
were determined by detailed spectroscopic studies,5 but their close
similarity to the smenochromenes was not commented upon.
Specifically, the structure and spectroscopic data for one of these
compounds, smenochromene D 4, appeared to be extremely simi-
lar to those of likonide B 6 in all respects except optical rotation:
smenochromene D, [a]D -68.5 (c 0.35, CH2Cl2);4 likonide B, [a]D
+27 (c 0.08, MeOH).5 This apparent confusion over the identity, or
otherwise, of the two natural products has recently been resolved
by the synthesis of ( )-smenochromene D by Trauner and co-
workers,6,7 which clearly established that smenochromene D and
likonide B are identical in terms of relative stereochemistry. Hence
the natural products appear to be enantiomers, or possibly, given
the large discrepancy in optical rotation, to have an enantiomeric
Fig. 1 Reported structures of the smenochromenes and the likonides
(ref. 5 and 6).
excess in the opposite sense.
Intriguingly, it was also noted that likonides A and B are
formally related by a [3,3]-sigmatropic process, since Claisen
rearrangement of likonide B should give likonide A (Scheme 1).
However, Trauner and co-workers have recently shown that
heating of likonide B 6 (= smenochromene D 4) does not result
in such a Claisen rearrangement, but rather in an alternative
rearrangement to give the ring skeleton of smenochomene B.7
It has also been proposed that another pericyclic process might
be responsible for the facile racemization of smenochromene A 1
(Scheme 1),6 since the compound was isolated as a racemate.4
In view of the continuing interest in these and other sesquiter-
pene quinones and hydroquinones,8–10 we report the details of a
new synthesis of ( )-likonide B.11 In continuation of our interest
in the wide and varied use of the Claisen rearrangement in
the synthesis of natural products,12–22 a regioselectve Claisen
rearrangement to form the chromene is a key step in our approach.
We also describe the separation and properties of the individual
aSchool of Chemistry, University of Nottingham, University Park, Notting-
ham, U.K. NG7 2RD. E-mail: c.j.moody@nottingham.ac.uk; Fax: +44 115
951 3564
bProcess Research and Development, AstraZeneca R & D Charnwood,
Bakewell Road, Loughborough, U.K. LE11 5RH
† Electronic supplementary information (ESI) available: Copies of 1H
and 13C NMR spectra. CCDC reference number 717575. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b901358j
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Scheme 2
Scheme 1 Possible involvement of pericyclic processes in the interconver-
sion of the likonides, and the racemization of smenochromene A.
cleaved using LDA in THF at low temperature.31 Gratifyingly,
the resulting phenolic propargylic ether 16 underwent a highly
selective Claisen rearrangement upon microwave heating in N,N-
enantiomers, thereby shedding some light on the true stereochem-
ical nature of the two natural products (-)-smenochromene D and
(+)-likonide B.
◦
diethylaniline at 140 C for 40 min to give the desired chromene
17 in 87% yield with no evidence for the formation of the
alternative regioisomer. Thereafter the silyl protecting group was
removed from the side chain using hexafluorosilicic acid to give the
precursor 18 for the macrocyclization reaction. The cyclization was
effected by means of an intramolecular Mitsunobu reaction using
tri-n-butylphosphine, 1,1¢-azodicarbonyl dipiperidine (ADDP) in
toluene and gave likonide B 6 (smenochromene D) in 27% yield,
the poor yield probably reflecting the strained nature of the ansa-
ring. A dimer, assigned as structure 19 (mixture of diastereomers),
was also isolated (Scheme 3).
The NMR spectroscopic data for synthetic 6 were identical to
those described for the natural products smenochromene D and
likonide B,4,5 and the aforementioned synthetic racemic material
prepared by Olson and Trauner.6 Final confirmation came from a
single crystal X-ray structure determination (Fig. 2).
Results and discussion
Our synthesis started with the known allylic alcohol 7, readily
available from the allylic oxidation of commercial geranylacetone
with selenium dioxide and tert-butyl hydroperoxide.23,24 Protection
as the tert-butyldimethylsilyl (TBS) ether 8 was followed by
addition of ethynylmagnesium bromide to give tertiary alcohol
9, and acylation with methyl chloroformate to give the tertiary
propargylic alcohol carbonate 10 in preparation for coupling
to a phenol. The first phenol investigated was 3-methoxy-4-tert-
butyldimethylsiloxyphenol 11.25 However, attempts to couple phe-
nol 11 with the propargylic carbonate 10 (or the corresponding tri-
fluoroacetate) in the presence of DBU and copper(II) chloride26,27
gave only poor yields (12–26%) of the desired propargylic ether
12. Nevertheless, sufficient material was obtained to establish
that the planned Claisen rearrangement exhibited the required
regioselectivity.27–29 Thus microwave heating30 of 12 in DMF at
200 ◦C for 30 min gave the chromene 13 in a 4:1 mixture with the
regioisomeric product (Scheme 2).
In order to improve the yield in the key copper catalyzed
coupling step, a number of model studies were performed which
established that the reaction proceeded better if an electron-
withdrawing protecting group was installed on the para-hydroxyl
group. Thus the coupling reaction of propargylic carbonate 10
was repeated using the mesyl protected phenol 14 resulting in
an acceptable yield (73%) of the propargylic ether 15. However,
the Claisen rearrangement of the mesylate derivative 15 exhibited
poor regioselectivity (ratio 2:1), and therefore the mesylate was
With a supply of synthetic racemic likonide B in hand we were
able to separate the two enantiomers by preparative HPLC on a
chiral stationary phase, and this allowed us to study the individual
enantiomers of synthetic likonide B (= smenochromene D). The
two enantiomers were studied by CD spectroscopy, and exhibited
the expected spectra for pairs of enantiomers (Fig. 3). The
(+)-enantiomer exhibited a positive Cotton effect at ca. 275 nm,
and therefore could be assigned as the 3R-enantiomer.5,33 Inter-
25
estingly their specific rotations were [a]D +180 (c 0.31, CH2Cl2)
25
(peak 1) and [a]D -176 (c 0.35, CH2Cl2) (peak 2). These values
are somewhat different for those reported for the natural products:
smenochromene D, [a]D -68.5 (c 0.35, CH2Cl2);4 likonide B, [a]D
+27 (c 0.08, MeOH),5 and confirm earlier suspicions that the
natural products have an enantiomeric excess in the opposite sense,
and were not isolated as pure single enantiomers. This lack of
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Fig. 2 X-ray crystal structure of ( )-likonide B.32
products were obtained optically pure. Although it has been
suggested that similar compounds could undergo racemization by
way of an electrocyclic ring opening–ring closure process, we can
find no evidence that the single enantiomers of likonide B racemize
easily. Hence, although the involvement of pericyclic processes in
the racemization of these ansa-bridged farnesyl hydroquinones is
an attractive proposition, there remains no experimental support
for this.
Experimental section
General
Commercially available reagents were used throughout without
purification unless otherwise stated. Light petroleum refers to
the fraction with bp 40–60 ◦C. Ether refers to diethyl ether.
Reactions were routinely carried out under a nitrogen or argon
atmosphere. Analytical thin layer chromatography was carried
out on aluminium backed plates coated with silica gel, and
visualized under UV light at 254 and/or 360 nm. Chromatography
was carried out on silica gel unless otherwise stated. Fully
characterized compounds are chromatographically homogeneous.
Infrared spectra were recorded in the range 4000–600 cm-1. NMR
spectra were recorded at 400 and 500 MHz (1H frequencies,
corresponding 13C frequencies 100 and 125 MHz). Chemical
shifts are quoted in ppm and are referenced to residual H in the
deuterated solvent as the internal standard. J values are recorded
in Hz. In the 13C NMR spectra, signals corresponding to CH, CH2,
or CH3 groups are assigned from DEPT. High and low resolution
mass spectra were recorded on a time-of-flight mass spectrometer.
Scheme 3
optical purity in the natural products may be due to their facile
racemization, possibly by the electrocyclic ring opening process
proposed by Trauner for smenochromene A (Scheme 1).6 However,
heating our enantiopure material in toluene at 110 ◦C for 2 h left
it unchanged with no evidence for racemization being observed
by HPLC analysis. The use of higher temperatures were precluded
by the alternative thermal rearrangement pathway reported by
Trauner and co-workers.7 Similarly, exposure of enantiopure
likonide B to UV-light over a prolonged period did not result
in racemization either.
(5E,9E)-6,10-Dimethyl-11-tert-butyldimethylsiloxyundeca-5,9-
dien-2-one 8. To a solution of alcohol 723,24 (1.50 g, 7.13 mmol)
in dry dichloromethane (36 mL) under a nitrogen atmosphere
was added 2,6-lutidine (1.83 mL, 1.69 g, 15.69 mmol) and tert-
butyldimethylsilyl triflate (1.80 mL, 2.07 g, 7.84 mmol) dropwise
at room temperature. The reaction mixture was stirred for 1 h
and saturated aqueous ammonium chloride (30 mL) was added.
The aqueous layer was extracted once into dichloromethane
(20 mL) and the combined organic extracts were washed with brine
In summary, we have developed a concise synthesis of
( )-likonide B, also known as smenochromene D, resolved the
compound by HPLC, and, based on the optical properties of
the individual enantiomers, suggest that neither of the natural
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Fig. 3 CD spectra (1.5 mM in methanol) of the two enantiomers of likonide B (smenochromene D) after separation by HPLC.
(20 mL), dried over magnesium sulfate, filtered and evaporated in
vacuo. The residue was purified by chromatography, eluting with
light petroleum/ether (9:1), to give the silyl ether 8 (2.05 g, 89%)
as a colourless oil; (Found: [M+Na]+ 347.2376. C19H36O2Si + Na+
requires 347.2382); nmax (CHCl3)/cm-1 2952, 2928, 2856, 1710,
1602, 1462, 1360, 1259, 1104; dH (400 MHz; CDCl3) 5.35–5.31 (1
H, m, H-9), 5.08–5.05 (1 H, m, H-5), 3.97 (2 H, s, H-11), 2.45–2.41
(2 H, m, H-3), 2.27–2.21 (2 H, m, H-4), 2.11–2.06 (5 H, m, 1-Me,
H-7) 2.00–1.96 (2 H, m, H-8), 1.60 (3 H, s, 10-Me), 1.57 (3 H, s,
6-Me), 0.86 (9 H, s, CMe3), 0.04 (6 H, s, SiMe2); dC (100 MHz;
CDCl3) 208.5 (C), 138.9 (C), 136.2 (C), 124.1 (CH), 122.7 (CH),
68.6 (CH2), 43.4 (CH2), 39.3 (CH2), 29.9 (Me), 26.0 (CH2), 25.8
(Me), 22.4 (CH2), 18.2 (C), 15.9 (Me), 12.7 (Me), -5.0 (Me).
was stirred for further 30 min and methyl chloroformate (83 ml,
101 mg, 1.07 mmol) was added at -20 C. The reaction mixture
◦
was stirred for 1.5 h and allowed to reach room temperature. Water
(10 mL) and dichloromethane (10 mL) were added, the organic
phase separated and the aqueous phase extracted with ether (2 ¥
10 mL). The combined organic layers were dried over magnesium
sulfate, filtered and evaporated in vacuo. The residue was purified
by chromatography, eluting with light petroleum/ether (9:1), to
give the methyl carbonate 10 (301 mg, 86%) as a colourless oil;
(Found: [M+Na]+ 431.2585. C23H40O4Si + Na+ requires 431.2594);
n
max (CHCl3)/cm-1 3305, 2955, 2856, 1750, 1461, 1376, 1288, 1161,
1071; dH (400 MHz; CDCl3) 5.38–5.34 (1 H, m, H-10), 5.15–5.11
(1 H, m, H-6), 4.00 (2 H, s, H-12), 3.76 (3 H, s, OMe), 2.59 (1 H, s,
H-1), 2.24–2.17 (2 H, m, H-5), 2.14–2.09 (2 H, m, H-9), 2.03–1.95
(3 H, m, H-8, H-4), 1.88–1.80 (1 H, m, H-4), 1.72 (3 H, s, 3-Me),
1.62 (3 H, s, 11-Me), 1.59 (3 H, s, 7-Me), 0.90 (9 H, s, CMe3), 0.05
(6 H, s, SiMe2); dC (100 MHz; CDCl3) 153.5 (C), 135.9 (C), 134.4
(C), 124.2 (CH), 122.9 (CH), 83.1 (C), 76.9 (C), 73.9 (CH), 68.6
(CH2), 54.3 (Me), 41.2 (CH2), 39.3 (CH2), 26.2 (Me), 26.0 (Me),
25.9 (CH2), 22.7 (CH2), 18.4 (C), 15.9 (Me), 13.4 (Me), -5.3 (Me).
(6E,10E)-12-tert-Butyldimethylsiloxy-3,7,11-trimethyldodeca-
6,10-dien-1-yn-3-ol 9. To a solution of ether 8 (2.00 g, 6.16 mmo◦ l)
in an anhydrous mixture of THF/ether (1:1) (20 mL) at -10 C
was added ethynylmagnesium bromide (0.5 M in THF; 18.5 mL,
9.25 mmol) dropwise over a 10 min period while stirring under
a nitrogen atmosphere. The mixture was stirred for further 5 h
◦
below 0 C, and quenched with a mixture of saturated aqueous
ammonium chloride (5 mL) and a hydrochloric acid (2 M;
1 mL). The mixture was extracted with ether (2 ¥ 20 mL) and
the combined organic layers were dried over magnesium sulfate,
filtered and evaporated in vacuo. The residue was purified by
chromatography, eluting with light petroleum/ether (100% to
80:20), to give the propargylic alcohol 9 (1.84 g, 85%) as a
colourless oil (lit.,34 oil); (Found: [M+Na]+ 373.2530. C21H38O2Si
+ Na+ requires 373.2539); nmax (CHCl3)/cm-1 3598, 3304, 2929,
2956, 1462, 1361, 1107; dH (400 MHz; CDCl3) 5.37–5.34 (1 H,
m, H-10), 5.20–5.16 (1 H, m, H-6), 3.99 (2 H, s, H-12), 2.45 (1
H, s, H-1), 2.35–2.10 (5 H, m, H-4, OH, H-5), 2.04–2.00 (2 H,
m, H-9), 1.75–1.65 (5 H, m, H-8, 3-Me), 1.59 (3 H, s, 11-Me),
1.50 (3 H, s, 7-Me), 0.90 (9 H, s, CMe3), 0.05 (6 H, s, SiMe2); dC
(100 MHz; CDCl3) 136.0 (C), 134.4 (C), 124.6 (CH), 124.0 (CH),
87.6 (C), 71.4 (CH), 68.6 (CH2), 68.2 (C), 43.1 (CH2), 39.3 (CH2),
30.2 (Me), 26.0 (CH2), 25.9 (Me), 23.4 (CH2), 18.4 (C), 16.0 (Me),
13.8 (Me), -5.3 (Me).
4-tert-Butyldimethylsiloxy-3-methoxyphenol 11. (a) To a solu-
tion of vanillin (1.00 g, 6.57 mmol) in anhydrous dichloromethane
(30 mL) under nitrogen was added diisopropylethylamine (2.54 g,
3.40 mL, 19.72 mmol) and tert-butyldimethylsilyl triflate (1.81 mL,
2.08 g, 7.89 mmol) dropwise at room temperature. The mixture
was stirred for 1.5 h, the solvent was removed in vacuo and the
residue taken up in light petroleum. After filtration, the solvent
was evaporated in vacuo and the resulting oil purified by chro-
matography, eluting with light petroleum/ethyl acetate (9:1), to
give 4-tert-butyldimethylsiloxy-3-methoxybenzaldehyde (1.57 g,
89%) as a yellow oil (lit.,35 yellow oil); (Found: [M+Na]+ 289.1215.
C14H22O3Si + Na+ requires 289.1236); nmax (CHCl3)/cm-1 2931,
2859, 1682, 1593, 1506, 1464, 1392, 1294, 1154, 1124, 898; dH
(400 MHz; CDCl3) 9.86 (1 H, s, CHO), 7.41 (1 H, d, J 1.8, H-2),
7.39 (1 H, dd, J 8.0, 1.8, H-6), 6.97 (1 H, d, J 8.0, H-5), 3.88 (3
H, s, OMe), 1.01 (9 H, s, CMe3), 0.20 (6 H, s, SiMe2); dC (100 MHz;
CDCl3) 191.0 (CH), 151.3 (C), 151.0 (C), 131.0 (C), 126.2 (CH),
120.7 (CH), 110.1 (CH), 55.4 (Me), 25.6 (Me), 18.3 (C), -4.6 (Me).
(b) To a solution of 4-tert-butyldimethylsiloxy-3-methoxy-
benzaldehyde (1.00 g, 3.75 mmol) in anhydrous dichloromethane
(15 mL) under a nitrogen atmosphere was added mCPBA (1.26 g,
5.63 mmol) portionwise at 0 ◦C. Following the addition, the
(6E,10E)-12-tert-Butyldimethylsiloxy-3,7,11-trimethyldodeca-
6,10-dien-1-yn-3-ol methyl carbonate 10. To a solution of alcohol
9 (300 mg, 0.86 mmol) in anhydrous THF (7.5 mL) at -35 ◦C
was added n-butyllithium (2.5 M in THF; 0.43 mL, 1.07 mmol)
dropwise, while stirring under a nitrogen atmosphere. The mixture
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reaction mixture was heated at reflux (40 ◦C) for 2 h. The mixture
was washed with saturated aqueous sodium hydrogen carbonate
(2 ¥ 10 mL), saturated aqueous sodium thiosulfate (2 ¥ 10 mL)
and again, saturated aqueous sodium hydrogen carbonate (2 ¥
10 mL). The organic phase was dried over magnesium sulfate,
filtered and the solvent was removed in vacuo. The residual formate
(0.94 g, 3.33 mmol) was taken up in anhydrous methanol (30 mL)
and anhydrous potassium carbonate (602 mg, 4.36 mmol) was
added at room temperature. The reaction mixture was stirred for
10 min and quenched with saturated aqueous ammonium chloride
(30 mL). The aqueous phase was extracted several times with
dichloromethane (2 ¥ 25 mL), the combined organic phases dried
over magnesium sulfate, filtered and evaporated in vacuo. The
resulting brown oil was taken up in a minimum of light petroleum
to give, on cooling, colourless crystals (800 mg, 94%) of the title
compound 11; mp 59–60 ◦C (lit.,25 colourless oil); (Found: [M+H]+
255.1386. C13H22O3Si + H+ requires 255.1416); nmax (CHCl3)/cm-1
3599, 3426, 2929, 2834, 1600, 1500, 1462, 1390, 1296, 1150, 1116;
dH (400 MHz; CDCl3) 6.69 (1 H, d, J 8.5, H-5), 6.40 (1 H, d, J 2.8,
H-2), 6.26 (1 H, d, J 8.5, 2.8, H-6), 4.78 (1 H, s, OH), 3.75 (3 H, s,
OMe), 0.98 (9 H, s, CMe3), 0.12 (6 H, s, SiMe2); dC (100 MHz;
CDCl3) 151.5 (C), 150.3 (C), 138.7 (C), 120.9 (CH), 106.3 (CH),
100.6 (CH), 55.4 (Me), 25.7 (Me), 18.4 (C), -4.7 (Me).
chromatography, eluting with light petroleum/ether (8:2–6:4), to
give the title compound 12 (22 mg, 26%) as a colourless oil; (Found:
[M+NH4]+ 604.4207. C34H58O4Si2 + NH4+ requires 604.4212); nmax
(CHCl3)/cm-1 3304, 2929, 2856, 1601, 1504, 1463, 1361, 1309,
1153, 1110; dH (400 MHz; CDCl3) 6.76 (1 H, d, J 2.6, H-2), 6.72
(1 H, d, J 8.6, H-5), 6.67 (1 H, dd, J 2.6, 8.6, H-6), 5.39–5.35 (1 H,
m, H-10¢), 5.18–5.15 (1 H, m, H-6¢), 4.00 (2 H, s, H-12¢), 3.76 (3
H, s, OMe), 2.55 (1 H, s, H-1¢), 2.33–2.22 (2 H, m, H-5¢), 2.16–2.10
(2 H, m, H-9¢), 2.04–2.00 (2 H, m, H-8¢), 1.94–1.77 (2 H, m, H-4¢),
1.63 (3 H, s, 11¢-Me), 1.60 (3 H, s, 7¢-Me), 1.53 (3 H, s, 3¢-Me), 0.99
(9 H, s, CMe3), 0.91 (9 H, s, CMe3), 0.13 (6 H, s, SiMe2), 0.06 (6
H, s, SiMe2); dC (100 MHz; CDCl3) 150.7 (C), 149.8 (C), 140.8 (C),
135.5 (C), 134.3 (C), 124.3 (CH), 123.6 (CH), 120.1 (CH), 113.8
(CH), 107.3 (CH), 85.7 (C), 75.7 (CH), 74.6 (C), 68.6 (CH2), 55.4
(Me), 42.4 (CH2), 39.3 (CH2), 26.9 (Me), 26.1 (CH2), 26.0 (Me),
25.7 (Me), 23.0 (CH2), 18.4 (C), 16.0 (Me), 13.4 (Me), -4.7 (Me),
-5.3 (Me).
6-tert-Butyldimethylsilyl-2-[(3¢E,7¢E)-9¢-tert-butyldimethyl-
siloxy-4¢,8¢-dimethyl-nona-3¢,7¢-dienyl]-7-methoxy-2-methyl-2H-
chromen-6-ol 13. A solution of propargyl aryl ether 12 (38 mg,
0.65 mmol) in DMF (1 mL) in a sealed tube was heated at
200 ◦C for 30 min at 300 W in a microwave reactor. The reaction
mixture was diluted with ether (5 mL), washed with brine (3 ¥
5 mL), water (5 mL), dried over magnesium sulfate, filtered and
evaporated in vacuo. The oil was purified by chromatography,
eluting with light petroleum/ether (9:1), to give the chromene
13 (22 mg, 52%) as an inseparable 4:1 mixture of regioisomers,
as a colourless oil; (Found: [M+Na]+ 609.3740. C34H58O4Si2 +
Na+ requires 609.3771); nmax (CHCl3)/cm-1 2929–2857, 1614, 1573,
1499, 1462, 1450, 1388, 1362, 1327, 1286, 1260, 1171, 1128, 1102;
dH (400 MHz; CDCl3) major regioisomer 6.45 (1 H, s, H-5), 6.35 (1
H, s, H-8), 6.23 (1 H, d, J 9.8, H-4), 5.42 (1 H, d, J 9.8, H-3), 5.37–
5.34 (1 H, m, H-7¢), 5.14–5.10 (1 H, m, H-3¢), 4.00 (2 H, s, H-9¢),
3.75 (3 H, s, OMe), 2.12–2.08 (4 H, m, H-2¢, H-6¢), 2.01–1.97 (2
H, m, H-5¢), 1.76–1.62 (2 H, m, H-1¢), 1.59 (3 H, s, 8¢-Me), 1.57 (3
H, s, 4¢-Me), 1.37 (3 H, s, 2-Me), 0.99 (9 H, s, CMe3), 0.91 (9 H, s,
CMe3), 0.13 (6 H, s, SiMe2), 0.06 (6 H, s, SiMe2); the following
peaks were assigned to the minor regioisomer 6.61 (1 H, d, J 10.0,
H-4), 6.60 (1 H, d, J 8.7, H-7), 6.42 (1 H, d, J 8.7, H-8), 5.59 (1
H, J 10.0, H-3), 3.77 (3 H, s, OMe), 1.00 (9 H, s, CMe3), 0.16 (6
H, s, SiMe2); dC (100 MHz; CDCl3) 151.3 (C), 147.9 (C), 138.3 (C),
135.0 (C), 134.3 (C), 127.0 (CH), 124.3 (CH), 124.2 (CH), 122.5
(CH), 118.0 (CH), 113.4 (C), 100.9 (CH), 78.2 (C), 68.6 (CH2),
55.4 (Me), 41.0 (CH2), 39.3 (CH2), 26.12 (CH2), 26.07 (Me), 26.0
(Me), 25.8 (Me), 22.6 (CH2), 18.41 (C), 18.37 (C), 15.9 (Me), 13.4
(Me), -4.7 (Me), -5.3 (Me).
1-tert-Butyldimethylsiloxy-4-[(6¢E,10¢E)-12¢-tert-butyl-
dimethylsiloxy-3¢,7¢,11¢-tri-methyldodeca-6¢,10¢-dien-1¢-
yn-3¢-yloxy]-2-methoxybenzene 12.
Method A. To a solution of propargylic alcohol 9 (200 mg,
0.57 mmol) in anhydrous acetonitrile (0.4 mL) cooled to be-
low -5 ◦C was added DBU (110 mL, 112 mg, 0.74 mmol)
under a nitrogen atmosphere. Trifluoroacetic anhydride (80 mL,
121 mg, 0.57 mmol) was added dropwise while maintaining the
temperature below 2 ◦C. The resulting solution was allowed to
stir at 0 ◦C for 1 h. Separately, to a solution of the 4-tert-
butyldimethylsiloxy-3-methoxyphenol 11 (126 mg, 0.49 mmol) in
anhydrous acetonitrile (0.4 mL) cooled to below -4 ◦C were added
DBU (90 mL, 92 mg, 0.61 mmol) and copper(II) chloride dihydrate
(1 mg) under a nitrogen atmosphere. The solution containing the
trifluoroacetate (described above) was then added over a 5 min
period while maintaining the temperature below 0 ◦C. After being
stirred for 5 h below 0 ◦C, the mixture was concentrated in vacuo
and the residue partitioned between water (2 mL) and ethyl acetate
(6 mL). The organic layer was washed with hydrochloric acid (2 M;
2 mL), aqueous sodium hydroxide (2 M; 2 mL) and brine (2 mL),
dried over magnesium sulfate, filtered and evaporated in vacuo.
The crude product was purified by chromatography, eluting with
light petroleum/ether (9:1), to give the title compound 12 (64 mg,
22%) as a colourless oil; data given below.
4-Methanesulfonyloxy-3-methoxyphenol 14. (a) To a solution
of vanillin (1.00 g, 6.57 mmol) in anhydrous dichloromethane
(20 mL) under an argon atmosphere was added mCPBA (2.20 g,
9.86 mmol) portionwise. Following the addition, the reaction
mixture was stirred for 2.5 h at room temperature. The mixture
was washed with saturated aqueous sodium hydrogen carbonate
(2 ¥ 10 mL), saturated aqueous sodium thiosulfate (2 ¥ 10 mL) and
saturated aqueous sodium hydrogen carbonate (2 ¥ 10 mL). The
organic phase was dried over magnesium sulfate, filtered and the
solvent was removed in vacuo to give 4-hydroxy-3-methoxyphenyl
formate (0.80 g, 73%) as a colourless crystals, mp 58–59 ◦C (lit.,36
no mp given); (Found: [M+H]+ 169.0495. C8H9O4 + H+ requires
Method B. To a solution of the 4-tert-butyldimethylsiloxy-3-
methoxyphenol 11 (38 mg, 0.15 mmol) in anhydrous acetonitrile
(0.5 mL) cooled at -20 ◦C were added DBU (30 mL, 31 mg,
0.20 mmol) and anhydrous copper(II) chloride (0.1% mol) under
a nitrogen atmosphere. After 20 min stirring, a solution of methyl
carbonate 10 (74 mg, 0.18 mmol) in acetonitrile (0.◦25 mL) was
added dropwise. After being stirred for 5 h below 0 C and 18 h
at room temperature, the mixture was concentrated in vacuo and
the residue partitioned between water (2 mL) and ethyl acetate
(6 mL). The organic layer was dried over magnesium sulfate,
filtered and evaporated in vacuo. The crude product was purified by
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169.0492); nmax (CHCl3)/cm-1 3695, 3544, 2941, 2358, 1738, 1602,
1507, 1451, 1369, 1276, 1154, 1103; dH (400 MHz; CDCl3) 8.30 (1
H, s, CHO), 6.96 (1 H, d, J 8.5, H-5), 6.67 (1 H, d, J 2.6, H-2), 6.64
(1 H, dd, J 8.5, 2.6, H-6), 5.50 (1 H, s, OH), 3.88 (3 H, s, OMe);
dC (100 MHz; CDCl3) 159.7 (CH), 146.7 (C), 143.8 (C), 142.8 (C),
114.4 (CH), 113.3 (CH), 104.6 (CH), 56.1 (Me).
(CH), 75.6 (C), 68.6 (CH2), 55.9 (Me), 42.4 (CH2), 39.3 (CH2),
38.0 (Me), 26.7 (Me), 26.05 (Me), 25.96 (CH2), 22.9 (CH2), 18.4
(C), 15.9 (Me), 13.4 (Me), -5.3 (Me).
4-[(6¢E,10¢E)-12¢-tert-Butyldimethylsiloxy-3¢,7¢,11¢-trimethyl-
dodeca-6¢,10¢-dien-1¢-yn-3¢-yloxy]-2-methoxyphenol 16. To a so-
lution of mesylate 15 (368 mg, 0.67 mmol) in dry THF (5.6 mL)
at -78 ◦C was added a freshly prepared LDA solution (3.95 mL,
2.14 mmol)‡ under an argon atmosphere. The reaction mixture
was stirred for 2 h at that temperature and quenched with saturated
aqueous ammonium chloride (5 mL). The mixture was extracted
into ethyl acetate (2 ¥ 5 mL), dried over magnesium sulfate, filtered
and the solvent removed in vacuo. The residue was purified by
chromatography, eluting with light petroleum/ether (7:3), to give
the title compound 16 (244 mg, 76%) as an orange-yellow oil;
(Found: [M+Na]+ 495.2903. C28H44O4Si + Na+ requires 495.2901);
(b) To a solution of 4-hydroxy-3-methoxyphenyl formate (1.77 g,
10.5 mmol) in dichloromethane (50 mL) under an argon at-
mosphere was added diisopropylethylamine (2.10 mL, 1.57 g,
12.1 mmol) and methanesulfonyl chloride (0.86 mL, 1.27 g,
11.0 mmol) dropwise at 0 ◦C. The reaction mixture was stirred
for 0.5 h and washed with water. The organic layer was dried
over magnesium sulfate, filtered and the solvent was removed in
vacuo. The crude product was used without further purification
and taken up in a (4:1) mixture of methanol and THF (25 mL).
Anhydrous potassium hydrogen carbonate (618 mg, 6.17 mmol)
was added at room temperature and the reaction mixture was
stirred for 15 min. Saturated aqueous ammonium chloride (15 mL)
was used to quench the reaction. The aqueous phase was extracted
with ethyl acetate (3 ¥ 25 mL), the combined organic layers were
dried over magnesium sulfate, filtered and evaporated in vacuo.
The resulting oil was dissolved in ethyl acetae–light petroleum (1:1)
(5 mL) and quickly filtered through a thin layer of silica, the filtrate
evaporated, and the residue crystallised from cold light petroleum
to afford the title compound 14 (1.52 g, 66%) as colourless crystals;
n
max (CHCl3)/cm-1 3686, 3553, 3307, 2929, 2856, 2351, 1600, 1502,
1464, 1370, 1154, 1108; dH (400 MHz; CDCl3) 6.80 (1 H, d, J 8.6
H-6), 6.78 (1 H, d, J 2.8, H-3), 6.71 (1 H, dd, J 8.6, 2.8, H-5),
5.39–5.35 (2 H, m, H-10¢, OH), 5.19–5.15 (1 H, m, H-6¢), 4.00 (2
H, s, H-12¢), 3.85 (3 H, s, OMe), 2.56 (1 H, s, H-1¢), 2.35–2.22 (2
H, m, H-5¢), 2.16–2.10 (2 H, m, H-9¢), 2.04–2.00 (2 H, m, H-8¢),
1.94–1.87 (1 H, m, H-4¢), 1.84–1.76 (1 H, m, H-4¢), 1.64 (3 H, s,
7¢-Me), 1.60 (3 H, s, 11¢-Me), 1.53 (3 H, s, 3¢-Me), 0.91 (9 H, s,
CMe3), 0.06 (6 H, s, SiMe2); dC (100 MHz; CDCl3) 148.5 (C), 146.1
(C), 141.7 (C), 135.5 (C), 134.3 (C), 124.3 (CH), 123.6 (CH), 114.9
(CH), 113.6 (C), 106.6 (CH), 85.6 (C), 76.1 (C), 74.8 (CH), 68.6
(CH2), 55.9 (Me), 42.3 (CH2), 39.3 (CH2), 26.9 (CH2), 26.1 (Me),
26.0 (Me), 23.1 (CH2), 18.4 (C), 16.0 (Me), 13.4 (Me), -5.2 (Me).
◦
mp 92–94 C; (Found: [M-H]- 217.0173. C8H10O5S - H requires
217.0165); nmax (CHCl3)/cm-1 3592, 2940, 2838, 2231, 2072, 1618,
1505, 1434, 1367, 1305, 1151, 1110; dH (400 MHz; CDCl3) 7.11 (1
H, d, J 8.8, H-5), 6.48 (1 H, d, J 2.7, H-2), 6.34 (1 H, d, J 8.8,
2.7, H-6), 4.88 (1 H, s, OH), 3.85 (3 H, s, OMe), 3.15 (3 H, s, Me);
dC (100 MHz; CDCl3) 158.9 (C), 153.8 (C), 132.7 (C), 125.7 (CH),
107.8 (CH), 101.7 (CH), 56.3 (Me), 38.0 (3 H, s, Me).
2-[(3¢E,7¢E)-9¢-tert-Butyldimethylsiloxy-4¢,8¢-dimethylnona-3¢,
7¢-dienyl]-7-methoxy-2-methyl-2H-chromen-6-ol 17. A solution
of the propargyl ether 16 (98 mg, 0.21 mmol) in N,N-diethylaniline
(3.5 mL) in a sealed tube was heated at 140 ◦C for 40 min at 300
W in a microwave reactor. The reaction mixture was concentrated
and the residue was purified by chromatography, eluting with light
petroleum/ether (8:2), to give the title compound 17 (85 mg, 87%)
as a orange-yellow oil; (Found: [M+Na]+ 495.2917. C28H44O4Si +
Na+ requires 495.2901); nmax (CHCl3)/cm-1 3630, 3553, 2929, 2856,
1628, 1583, 1501, 1458, 1360, 1290, 1124; dH (400 MHz; CDCl3)
6.56 (1 H, s, H-5), 6.41 (1 H, s, H-8), 6.27 (1 H, d, J 9.8, H-4),
5.47 (1 H, d, J 9.8, H-3), 5.38 (1 H, m, H-7¢), 5.19 (1 H, s, OH),
5.16–5.13 (1 H, m, H-3¢), 4.02 (2 H, s, H-9¢), 3.86 (3 H, s, OMe),
2.14–2.10 (4 H, m, H-2¢, H-6¢), 2.03–2.00 (2 H, m, H-4¢), 1.75–1.66
(2 H, m, H-1¢), 1.61 (6 H, s, 4¢-Me, 8¢-Me), 1.39 (3 H, s, 2-Me),
0.93 (9 H, s, CMe3), 0.08 (6 H, s, SiMe2); dC (100 MHz; CDCl3)
146.7 (C), 146.6 (C), 139.2 (C), 135.0 (C), 134.3 (C), 127.6 (CH),
124.3 (CH), 122.4 (CH), 121.5 (CH), 113.9 (CH), 111.7 (C), 100.0
(CH), 78.1 (C), 68.6 (CH2), 55.9 (Me), 40.9 (CH2), 39.3 (CH2),
26.0 (CH2), 25.9 (Me), 25.8 (Me), 22.6 (CH2), 18.4 (C), 15.9 (Me),
13.4 (Me), -5.3 (Me).
4-Methanesulfonyloxy-3-methoxy-((6¢E,10¢E)-12¢-tert-butyldi-
methylsiloxy-3¢,7¢,11¢-trimethyldodeca-6¢,10¢-dien-1¢-yn-3¢-yloxy)
benzene 15. To a solution of 4-methanesulfonyl-3-methoxy-
phenol 14 (250◦mg, 1.14 mmol) in anhydrous acetonitrile (2.5 mL)
cooled to -20 C was added DBU (205 mL, 209 mg, 1.37 mmol)
and anhydrous copper(II) chloride (0.15 mg, 0.1% mol) under a
nitrogen atmosphere. The mixture was stirred for 15 min and a
solution of the carbonate 10 (562 mg, 1.37 mmol) in acetonitrile
(3 mL) was slowly added at 0 ◦C. The reaction mixture was stirred
below 0 ◦C for 5 h and at room temperature for 12 h. Water (10 mL)
was added, and after extraction with ethyl acetate (2 ¥ 10 mL),
the organic layers were dried over magnesium sulfate, filtered and
evaporated in vacuo. The residue was purified by chromatography,
eluting with light petroleum/ether (7:3) to give the title compound
(459 mg, 73%) as a colourless oil; (Found: [M+Na]+ 573.2594.
C29H46O6SSi + Na+ requires 573.2682); nmax (CHCl3)/cm-1 3303,
2929, 2856, 1603, 1498, 1450, 1367, 1329, 1301, 1152, 1107, 1034;
dH (400 MHz; CDCl3) 7.20–7.17 (1 H, m, H-5), 6.86–6.83 (2 H,
m, H-2, H-6), 5.39–5.35 (1 H, m, H-10¢), 5.18–5.14 (1 H, m, H-6¢),
4.00 (2 H, s, H-12¢), 3.85 (3 H, s, OMe), 3.15 (3 H, s, Me), 2.64
(1 H, s, H-1¢), 2.36–2.18 (2 H, m, H-4¢), 2.15–2.10 (2 H, m, H-8¢),
2.04–2.00 (2 H, m, H-9¢), 1.98–1.91 (1 H, m, H-5¢), 1.88–1.80 (1
H, m, H-5¢), 1.63 (3 H, s, 7¢-Me), 1.59 (6 H, s, 11¢-Me, 3¢-Me),
0.90 (9 H, s, CMe3), 0.06 (6 H, s, SiMe2); dC (100 MHz; CDCl3)
155.3 (C), 151.5 (C), 135.8 (C), 134.3 (C), 133.4 (C), 124.2 (CH),
124.1 (CH), 123.2 (CH), 112.5 (CH), 106.2 (CH), 84.7 (C), 75.7
2-[(3¢E,7¢E)-9¢-Hydroxy-4¢,8¢-dimethylnona-3¢,7¢-dienyl]-7-
methoxy-2-methyl-2H-chromen-6-ol 18. To a solution of silyl
ether 17 (242 mg, 0.51 mmol) in acetonitrile (10 mL) was added
‡ Lithium diisopropylamide (LDA) was prepared by the following pro-
cedure: to THF (15 mL) cooled to -78 ◦C was added diisopropylamine
(1.97 mL, 1.47 g, 1.20 equiv) followed by n-butyllithium (1.61 M in hexane;
7.76 mL, 1.00 equiv). The solution was stirred at -78 ◦C for 30 min and
used immediately.
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hexafluorosilicic acid (35% w/w in water; 319 mL, 1.02 mmol) at
0 C. The reaction mixture was stirred for 40 min and quenched
1.92–1.83 (1 H, m, H-5¢), 1.68–1.64 (1 H, m, H-4), 1.62–1.53 (5
H, m, H-8, H-15, H-4¢), 1.41 (3 H, s, H-13), 1.32 (3 H, s, H-14);
dC (100 MHz; DMSO) 153.0 (C), 149.8 (C), 138.9 (C), 131.2
(CH), 131.0 (C), 129.6 (C), 126.3 (CH), 125.6 (CH), 123.2 (CH),
118.9 (CH), 112.9 (C), 99.9 (CH), 78.9 (CH), 78.6 (C), 55.3 (Me),
40.7 (CH2), 38.5 (CH2), 29.7 (Me), 24.0 (CH2), 22.5 (CH2), 14.2
(Me), 13.9 (Me); and (ii) a dimer assigned as 19 (13 mg, 13%) as
a colourless oil (mixture of diastereoisomers); (Found: [M+Na]+
703.3943. C44H56O6 + Na+ requires 703.3969); dH (400 MHz;
CDCl3) 6.48 (1 H, s, ArH), 6.44 (1 H, s, ArH), 6.36 (1 H, s, ArH),
6.35 (1 H, s, ArH), 6.17 (2 H, 2d, J 9.8, 9.8, 2 ¥ CH), 5.41–5.31
(4 H, 2d, J 9.8, 9.8, 2 ¥ CH, m, 2 ¥ CH=), 5.06–5.00 (2 H, m,
2 ¥ CH=), 4.45–4.27 (4 H, m, 2 ¥ CH2OAr), 3.79 (6 H, s, 2 ¥
OMe), 2.12–1.94 (12 H, m, 2 ¥ =C(Me)CH2CH2, 2¥ =CHCH2),
1.66–1.60 (10 H, m, 2 ¥ Me, 2 ¥ =CHCH2CH2), 1.50 (6 H, s, 2 ¥
Me), 1.37 (3 H, s, Me), 1.33 (3 H, s, Me); dC (100 MHz; CDCl3)
150.5 (C), 150.4 (C), 147.6 (C), 141.6 (C), 141.5 (C), 134.1 (C),
131.3 (C), 131.0 (C), 128.3 (CH), 128.0 (CH), 127.3 (CH), 127.2
(CH), 125.0 (CH), 124.9 (CH), 122.4 (CH), 113.5 (CH), 112.9
(C), 100.9 (CH), 100.8 (CH), 78.3 (C), 78.1 (C), 75.8 (CH2), 75.7
(CH2), 55.9 (Me), 40.6 (CH2), 40.2 (CH2), 38.8 (CH2), 38.7 (CH2),
30.3 (Me), 29.7 (Me), 26.1 (Me), 25.9 (Me), 25.3 (CH2), 25.2
(CH2), 22.5 (CH2), 22.3 (CH2), 15.6 (Me), 15.5 (Me), 13.7 (Me).
◦
with saturated aqueous sodium hydrogen carbonate (5 mL). The
organic layer was separated, and the aqueous layer extracted
into ethyl acetate (2 ¥ 10 mL). The combined organic layers
were washed with brine (3 ¥ 10 mL), dried over magnesium
sulfate, filtered and evaporated in vacuo. The residue was purified
by chromatography, eluting with light petroleum/ether (1:1), to
give the title compound 18 (157 mg, 83%) as an orange oil;
(Found: [M+Na]+ 381.2052. C22H30O4 + Na+ requires 381.2036);
n
max (CHCl3)/cm-1 3612, 3551, 2926, 2848, 1627, 1583, 1500, 1456,
1380, 1359, 1289, 1164, 1125; dH (400 MHz; CDCl3) 6.56 (1 H, s,
H-5), 6.38 (1 H, s, H-8), 6.26–6.23 (1 H, d, J 9.8, H-4), 5.46–5.43
(1 H, d, J 9.8, H-3), 5.39–5.35 (1 H, m, H-7¢), 5.19 (1 H, s, OH-6),
5.14–5.10 (1 H, m, H-3¢), 3.98 (2 H, s, H-9¢), 3.84 (3 H, s, OMe),
2.13–2.08 (4 H, m, H-5¢, H-1¢), 2.01–1.97 (2 H, m, H-6¢), 1.78–
1.60 (6 H, m, H-2¢, 4¢-Me, OH-9¢), 1.58 (3 H, s, 7¢-Me), 1.36 (3
H, s, 2-Me); dC (100 MHz; CDCl3) 146.7 (C), 146.6 (C), 139.2 (C),
134.9 (C), 134.7 (C), 127.6 (CH), 126.0 (CH), 124.3 (CH), 122.5
(CH), 117.4 (CH), 113.9 (CH), 111.7 (C), 100.1 (CH), 78.2 (C),
69.0 (CH2), 56.0 (Me), 40.9 (CH2), 39.2 (CH2), 26.1 (CH2), 26.0
(Me), 22.6 (CH2), 15.9 (Me), 13.7 (Me).
( )-Likonide B [( )-smenochromene D]. Argon was bubbled
Separation of enantiomers
Column, Chiralpak OJ, 10 ¥ 250 mm; eluant, hexane-2-propanol
(98:2); 10 mg of mixture was dissolved in 1 mL of mobile phase and
injected in 200 mL portions. After separation, the two enantiomers
exhibited the following properties:-
25
Peak 1, Rt = 9.65 min [hexane–2-propanol (99:1)]; [a]D +180
into a stirred 8 mM solution of 2-[(3E,7E)-9-hydroxy-4,8-
dimethylnona-3,7-dienyl]-7-methoxy-2-methyl-2H-chromen-6-ol
18 (50 mg, 0.14 mmol) and 1,1¢-(azodicarbonyl)-dipiperidine
(105 mg, 0.42 mmol) in anhydrous toluene (17.4 mL) for 10 min
at 0 ◦C. A first batch (40 mL) of tri-n-butylphosphine (140 mL,
113 mg, 0.55 mmol) was added dropwise and the reaction mixture
was stirred for 20 min at 0 ◦C followed by the addition of a second
batch of tri-n-butylphosphine (100 mL). The reaction mixture
was allowed to reach room temperature and stirred for 24 h.
A second batch of 1,1¢-(azodicarbonyl)dipiperidine (105 mg,
0.42 mmol) was added at 0 ◦C, tributylphosphine (140 mL,
113 mg, 0.55 mmol) was added over 1 h and the mixture stirred
for 8 h at room temperature. Water was added and the aqueous
phase extracted into ethyl acetate (2 ¥ 15 mL). The combined
organic layers were reduced in vacuo, the crude product was
taken up in light petroleum and filtered. The resulting filtrate
was dried over magnesium sulfate, filtered and evaporated in
vacuo. The residue was purified by chromatography, eluting with
hexane/ethyl acetate (9:1), to give (i) the title compound (13 mg,
27%) as a colourless oil that slowly crystallized to give crystals
suitable for X-ray analysis, mp 107–108 ◦C ( 7 ◦C) (lit.,4 natural
smenochromene D, colourless glass; lit.,5 natural likonide B, oil;
lit.,6,7 synthetic smenochromene D, clear oil); (Found: [M+Na]+
363.1919. C22H28O3 + Na+ requires 363.1931); nmax (DMSO)/cm-1
2930, 1618, 1503, 1450, 1365, 1289, 1124; dH (400 MHz; DMSO)
6.61 (1 H, s, H-16), 6.38 (1 H, d, J 9.8, H-1), 6.34 (1 H, s, H-19),
5.41 (1 H, d, J 9.8, H-2), 4.87–4.85 (1 H, m, H-6), 4.78–4.74 (1
H, m, H-10), 4.38 (1 H, d, J 11.4, H-12), 4.07 (1 H, d, J 11.4,
H-12¢), 3.66 (3 H, s, H-22), 2.12–1.96 (4 H, m, H-9, H-5, H-8),
(c 0.31, CH2Cl2);
25
Peak 2, Rt = 11.4 min [hexane–2-propanol (99:1)]; [a]D -176
(c 0.35, CH2Cl2).
Acknowledgements
We thank Professor Yoel Kashman for helpful exchange of
information including the CD spectra of natural likonide B,
Professor Dirk Trauner for copies of the NMR spectra of synthetic
( )-likonide B, and Professor Mark Searle, Laura Tye and Anita
Rea for help with CD spectroscopy.
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2134 | Org. Biomol. Chem., 2009, 7, 2127–2134
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