A short and efficient total synthesis of the naturally occurring coumarins siderin, kotanin, isokotanin A and desertorin C

Article abstract of DOI:10.1055/s-2003-41027

Starting from methyl 2-hydroxy-4-methoxy-6-methyl-benzoate (6) and its regioisomeric dehydrodimers 7-9, readily available by an oxidative coupling reaction of 6, the naturally occurring coumarins siderin (1), kotanin (2), isokotanin A (3) and desertorin C (4) were synthesized in a novel and highly efficient three-step transformation. In the case of kotanin (2) both atropisomers were prepared from the pure atropisomers of 7.

Full text of DOI:10.1055/s-2003-41027

PAPER
1803
A Short and Efficient Total Synthesis of the Naturally Occurring Coumarins
Siderin, Kotanin, Isokotanin A and Desertorin C
Efficient
S
ynthesis of 4,
o
4 -Dimethox
l
ybicou
f
a
Institut für Biotechnologie 2, Forschungszentrum Jülich GmbH, 52425 Jülich
Fax +49(2461)613870; E-mail: mi.mueller@fz-juelich.de
b
Institut für Anorganische Chemie, Rheinische Friedrich-Wilhelms-Universität, 53121 Bonn
Received 25 June 2003
Dedicated to Professor Wolfgang Steglich on the occasion of his 70th birthday.
Abstract: Starting from methyl 2-hydroxy-4-methoxy-6-methyl-
benzoate (6) and its regioisomeric dehydrodimers 7–9, readily
available by an oxidative coupling reaction of 6, the naturally occur-
ring coumarins siderin (1), kotanin (2), isokotanin A (3) and deser-
torin C (4) were synthesized in a novel and highly efficient three-
step transformation. In the case of kotanin (2) both atropisomers
were prepared from the pure atropisomers of 7.
O
O
O
O
A. niger,
A. clavatus,
A. alliaceus
*
2
kotanin (2)
Key words: atropisomerism, biaryls, oxidative phenolic coupling,
natural coumarins
O
O
O
2
*
A. alliaceus
R
O
O
O
O
O
The biaryl unit is a widely distributed structure element in
R = H : 5
R = Me: siderin (1)
isokotanin A (3)
many natural product classes.1 However, its chemical syn-
thesis often requires multistep procedures especially if the
synthesis has to be atropselective. The polyketide-
derived2 dehydro-metabolites discussed in this work are
regioisomeric dimers of the trisubstituted coumarin sid-
erin (1). They and their demethyl derivatives are produced
by different Aspergillus species: kotanin (2) was isolated
from A. clavatus, A. niger and A. alliaceus;3 isokotanin A
(3) was found in A. alliaceus and its teleomorph Petromy-
ces alliaceus;4 and the constitutionally unsymmetric
dimer desertorin C (4) was obtained from Emericella de-
sertorum (Scheme 1).5 The biosynthesis of 2–4 is as-
sumed to proceed through dehydrodimerization of a
monomeric precursor like siderin (1) or its demethyl de-
rivative 5.
O
Emericella
desertorum
O
O
O
O
*
O
O
O
desertorin C (4)
Scheme 1 Regioisomeric bicoumarins isolated from filamentous
fungi and their putative monomeric precurors in biosynthesis
three regioisomeric bicoumarins 2–4 could be realized ef-
ficiently.
For a study on the stereo- and regioselective dimerization
of these coumarins in filamentous fungi, an analytical as-
say had to be established. Therefore, a short and simple
chemical access to both the monomeric and the oxidative
coupled coumarins was required. Even though racemic
and atropselective syntheses of these compounds have
been reported in the literature,6–9 these methods include
multistep procedures and were not suitable for our pur-
pose.10 Here we describe a consistent and efficient new
access to the monomeric and dimeric 4,7-dimethoxy cou-
marins 1–4 (see Scheme 4). Since the biaryl precursors 7–
9 are available in a single step by an unselective oxidative
phenol coupling11 of readily available methyl 2-hydroxy-
4-methoxy-6-methylbenzoate (6), the syntheses of the
For the transformation of benzoate 6 into 4-hydroxy-
coumarin 12, acetic ester enolate should be added to the
ester moiety followed by acidic hydrolysis and cycliza-
tion. However, neither the conversion of 6 with the lithi-
um enolate of tert-butyl acetate nor treatment of acetate
10 with LDA gave the desired product (Scheme 2).12
OH
O
LDA
O
O
O
O
O
O
12
O
10
Synthesis 2003, No. 12, Print: 02 09 2003. Web: 13 08 2003.
Art Id.1437-210X,E;2003,0,12,1803,1808,ftx,en;T05603SS.pdf.
DOI: 10.1055/s-2003-41027
Scheme 2 Attempted cyclization of 10 to 4-hydroxycoumarin 12
with LDA
© Georg Thieme Verlag Stuttgart · New York

1804
W. Hüttel et al.
PAPER
In a further attempt, we used acetonitrile as an acetic ester two-proton signal at = 7.18 in the 1H NMR spectrum of
equivalent13 to obtain a compound in 80% yield, which compound 11 (DMSO-d6) suggests the presence of an
proved to be the intramolecular cyclization product 11 of amino group as expected for an aminochromenone. Since
the expected -keto nitrile (Scheme 3).
11 crystallized readily from an aqueous ethanol solution,
the exclusive existence of this tautomer could also be
proved by X-ray structure analysis (Figure 1).
O
LiCH2CN,
CN
THF, -78 °C - RT
6
O
OH
O
OH
?
O
O
NH2
O
O
NH
11
imino-11
Scheme 3 Synthesis and possible tautomers of product 11
The cyclization reaction is described in the literature to
yield both 2-aminochromen-4-ones14 like 11 and the tau-
tomeric 2-iminochromen-4-ols (4-hydroxyiminocoumar-
ins) like imino-11.15
Figure 1 Molecular structure of 11
The acidic hydrolysis of 11 was carried out by refluxing
in a methanol–hydrochloric acid mixture to give the pure
4-hydroxycoumarin 12 in 90% yield. After methylation
However, no NMR data were given for the latter. The
O
O
HCl (32%) /
MeOH (1:1),
∆, 5 h
O
OH
O
LiCH2CN, THF,
-78 °C -> RT
Me2SO4, K2CO3,
acetone, ∆, 4 h
O
80%
90%
81%
O
NH2
O
OH
O
O
O
O
O
O
6
11
12
siderin (1)
FeCl3/SiO2
60 °C, 20 h
O
O
O
OH
O
O
O
Me2SO4, NaH,
HMPT, RT, 2 h
O
" , 13 h
75%
"
59%
75%
O
OH
O
NH2
O
O
O
O
2
2
2
2
7 (17%)
13
16
kotanin (2)
+
O
OH
O
O
2
2
2
2
O
" , 3.5 h
77%
"
"
68%
77%
O
O
O
NH2
O
OH
O
O
O
O
O
O
O
O
8 (33%)
14
17
isokotanin A (3)
+
OH
O
O
O
O
O
NH2
O
O
O
O
O
O
O
O
O
OH
" , 6 h
67%
"
"
55%
66%
O
OH
O
O
O
O
O
OH
O
NH2
15
O
18
O
9 (30%)
desertorin C (4)
Scheme 4 Syntheses of monomeric and dimeric coumarins starting from methyl benzoate 6
Synthesis 2003, No. 12, 1803–1808 © Thieme Stuttgart · New York

PAPER
Efficient Synthesis of 4,4 -Dimethoxybicoumarins
1805
with dimethyl sulfate under standard conditions, siderin both atropisomers were prepared in optically pure form
(1) was obtained in 81% yield (Scheme 4).
from the corresponding isomers of biaryl ester 7.
Encouraged by these results, we adopted this method for
the syntheses of the bicoumarins 2–4 starting from the
corresponding biaryl esters 7–9. The transformation with
the lithium salt of acetonitrile took place as for the mono-
meric compound, albeit in slightly lower yields. For the
acidic hydrolysis of the resulting aminobichromenones
13–15, the reaction time had to be adjusted, since the re-
activity of these compounds decreases from the 6,6 -
dimer 14 to the 8,8 -dimer 13. On the other hand, decar-
boxylation products were observed if the reaction time
was too long. Because of their low solubility even in polar
solvents, the 4,4 -dihydroxybicoumarins 16–18 were used
for the next step without further purification. Due to the
low reactivity of the hydroxy group in 16–18, an opti-
mized method described in the literature was adopted for
the final methylation step using dimethyl sulfate, sodium
hydride, and HMPT (Scheme 4).16 Alternatively, these
highly toxic reagents can be avoided by using acid-cata-
lyzed etherification for O-methylation.17
All reagents were used in analytical grade. Solvents were dried by
standard methods, if necessary. Methyl 2-hydroxy-4-methoxy-6-
methylbenzoate (6)20 and its dimers 7, 8 and 9 were synthesized ac-
cording to published procedures.11 Flash column chromatography
was carried out on silica gel 60 (Merck) (particle size 40–60 m).
NMR spectra were recorded on a Bruker AMX 300 spectrometer
operating at 300 MHz (1H) and 75 MHz (13C). Chemical shifts are
reported in ppm relative to CHCl3 (1H: = 7.25) and CDCl3 (13C:
= 77.23) or to DMSO (1H: = 2.50) and DMSO-d6 (13C:
= 39.51). GC-MS were recorded on a HP 6890 Series GC System
equipped with a HP 5973 Mass Selective Detector (Hewlett Pack-
ard, capillary column HP-5 MS 30 m·250
m; TGC
(injector) = 250 °C, TMS (ion source) = 200 °C, time program (ov-
en):
T0min = 60 °C, T3min = 60 °C, T14min = 280 °C (heating
rate = 20 °C·min–1), T19min = 280 °C, MS: EI, 70 eV). MS and
HRMS (EI) were carried out at the Analytical Department, Che-
mische Institute der Universität Bonn, Germany. Optical rotations
were measured on a Jasco P-1020 polarimeter. CD spectra were re-
corded on a Jasco J-810 Spectropolarimeter in MeCN. Circular
dichroic absorptions
recorded on a Nicolet 360 FTIR spectrometer. Melting points were
are reported in cm2·mol–1. IR spectra were
Moreover, both atropisomers of kotanin (2) were prepared measured on a Büchi B-540 heating unit.
from the pure atropisomers of dimeric ester 711 in 24%
and 10% yield,18 respectively (Scheme 5). P-(+)-Kotanin
(P-2) was obtained from P-(+)-7 and M-(–)-kotanin (M-2)
from the M-(–)-isomer of 7.19
2-Amino-7-methoxy-5-methyl-4H-chromen-4-one (11)
Under argon, n-BuLi (2.5 M in hexane, 8.16 mL, 20.4 mmol) was
added dropwise to a solution of anhyd MeCN (1.13 mL, 20.39
mmol) in anhyd THF (50 mL) at –78 °C. After stirring for 45 min
at –78 °C, a solution of methyl 2-hydroxy-4-methoxy-6-methylben-
zoate (6; 1.00 g, 5.10 mmol) in THF (20 mL) was added over a 10
min period. After stirring for 30 min at –78 °C, the reaction mixture
was allowed to warm to r.t. and was stirred for a further 60 min. The
reddish suspension was hydrolyzed with aq NH4Cl solution (120
mL) and diluted with EtOAc (120 mL). The aqueous layer was sep-
arated and extracted with EtOAc (3 × 70 mL). The combined organ-
In summary, we have developed a new, consistent and
highly efficient synthetic access to the naturally occurring
coumarins siderin (1), kotanin (2), isokotanin A (3) and
desertorin C (4) starting from benzoate 6 and its readily
available dehydrodimers 7–9. It is based on a new and
straightforward synthetic approach from 2-hydroxyben-
zoates to 4-hydroxycoumarins. In the case of kotanin (2) ic layers were dried (MgSO4) and the solvent was removed at
reduced pressure. The crude product was purified by flash column
Scheme 5 Syntheses of P- and M-kotanin (2) and CD spectra (acetonitrile) (*For reaction conditions, see Scheme 4)
Synthesis 2003, No. 12, 1803–1808 © Thieme Stuttgart · New York

1806
W. Hüttel et al.
PAPER
2,2 -Diaminobichromenones 13–15; General Procedure
chromatography (EtOAc–propan-2-ol, 10:1) and recrystallization
(EtOAc) to give product 11 as colorless needles (833 mg, 80%);
Rf 0.29; mp 225–226 °C.
IR (KBr): 3347, 3117, 1655, 1616 cm–1.
1H NMR: (DMSO-d6): = 2.68 (s, 3 H, CH3), 3.79 (s, 3 H, OCH3),
5.04 (s, 1 H, CH), 6.62 (‘s’, 2 H, ArH), 7.18 (s, 2 H, NH2).
13C NMR: (DMSO-d6): = 22.4 (CH3), 55.5 (OCH3), 85.8 (CH),
98.5 (CH), 114.56 (Cq), 114.65 (CH), 140.7, 156.3, 160.7, 163.4,
177.5 (Cq).
Under argon, n-BuLi was added dropwise to a solution of anhyd
MeCN in anhyd THF at –78 °C. After stirring for 45 min at –78 °C,
the appropriate biaryl orsellinate 7–9, dissolved (suspended in the
case of 7) in THF, was added during 10 min. After stirring for 30
min at –78 °C, the reaction mixture was allowed to warm to r.t. and
stirred for a further 60 min. The reddish suspension was hydrolyzed
with aq NH4Cl solution and diluted with EtOAc. The aqueous layer
was separated and extracted with EtOAc (3 ×). The organic layers
were combined and dried (MgSO4). After removal of the solvent,
the crude product was purified by flash column chromatography
(EtOAc–propan-2-ol, 3:1) to yield the product as a yellowish solid.
The product can be recrystallized (MeOH–EtOAc) to obtain color-
less needles.
MS (EI): m/z (%) = 205 (M+, 100), 164 (M+ – C3H2N, 10).
HRMS (EI): m/z calcd for C11H11NO3: 205.0739; found: 205.0741.
X-ray Structure Analysis21
C11H13NO4: colorless crystals, crystal dimension 0.15 × 0.30 × 0.40
mm3; M = 223.22; monoclinic, space group P21/c (No. 14),
a = 10.6943(3), b = 8.1814(3), c = 12.9573(5) Å, = 114.006(2)°,
V = 1035.63(7) Å3, Z = 4, (MoK ) = 0.110 mm–1, T = 123(2) K,
F(000) = 472. 4804 reflections up to 2 max = 50° were measured on
a Nonius KappaCCD diffractometer with MoK radiation, 1824 of
which were independent and used for all calculations. The structure
was solved by direct methods and refined to F2 anisotropically, the
H atoms were refined with a riding model [H(O, N) free]. The final
quality coefficient wR2(F2) for all data was 0.0884, with a conven-
tional R(F) = 0.0354 for 158 parameters and 4 restraints.
(rac)-2,2 -Diamino-7,7 -dimethoxy-5,5 -dimethyl-4H,4 H-8,8 -
bichromene-4,4 -dione (13)
Compound 13 was obtained from (rac)-dimethyl 2,2 -dihydroxy-
6,6 -dimethoxy-4,4 -dimethyl-1,1 -biphenyl-3,3 -dicarboxylate (7;
100 mg, 0.26 mmol), MeCN (84 mg, 2.05 mmol) and n-BuLi (2.5
M in hexane, 0.82 mL, 2.05 mmol) in THF (15 mL) according to the
general procedure; yield: 79 mg (75%); Rf 0.41; mp 335 °C (dec.).
IR (KBr): 3475, 1648, 1619, 1581 cm–1.
1H NMR: (DMSO-d6): = 2.80 (s, 6 H, 2 × CH3), 3.74 (s, 6 H, 2 ×
OCH3), 4.98 (s, 2 H, 2 × CH), 6.88 (s, 2 H, 2 × ArH), 6.89 (s, 4 H,
2 × NH2).
13C NMR: (DMSO-d6): = 22.9 (2 × CH3), 55.9 (2 × OCH3), 85.4
(2 × CH), 107.0 (2 × Cq), 111.3 (2 × CH), 114.8, 140.1, 153.4, 158.3,
163.3, 177.7 (12 × Cq).
MS (EI): m/z (%) = 408 (M+, 100), 393 (M+ – CH3, 58), 377 (M+ –
OCH3, 19).
4-Hydroxy-7-methoxy-5-methyl-2H-chromen-2-one (12)
2-Amino-7-methoxy-5-methyl-4H-chromen-4-one (11; 500 mg,
2.44 mmol) was dissolved in a mixture of MeOH (25 mL) and HCl
(32%, 25 mL) and refluxed for 5 h. From the resulting suspension,
the MeOH was evaporated at reduced pressure and H2O was added
(50 mL). The colorless precipitate was filtered off, washed with dil.
HCl (1%, 30 mL) and air dried at 60 °C to yield the crude product
as a colorless solid (455 mg, 90%), pure enough to be applied for
the next step. For further purification, the crude product was recrys-
tallized from MeOH as colorless needles (68%); mp 289 °C (dec.).
HRMS (EI): m/z calcd for C22H20N2O6: 408.1321; found: 408.1330.
(rac)-2,2 -Diamino-7,7 -dimethoxy-5,5 -dimethyl-4H,4 H-6,6 -
bichromene-4,4 -dione (14)
Compound 14 was obtained from (rac)-dimethyl 4,4 -dihydroxy-
6,6 -dimethoxy-2,2 -dimethyl-1,1 -biphenyl-3,3 -dicarboxylate (8;
500 mg, 1.28 mmol), MeCN (468 mg, 11.4 mmol) and n-BuLi (1.6
M in hexane, 7.13 mL, 11.4 mmol) in THF (60 mL) according to the
general procedure; yield (after recrystallization): 403 mg (77%);
Rf 0.36; mp 262 °C (dec.).
1H NMR: (DMSO-d6): = 2.60 (s, 3 H, CH3), 3.80 (s, 3 H, OCH3),
4
5.39 (s, 1 H, CH), 6,69 (d, 1 H, J = 2.6 Hz, ArH), 6.74 (d, 1 H,
4J = 2.6 Hz, ArH), 12.20 (s, 1 H, OH).
13C NMR: (DMSO-d6): = 22.8 (CH3), 55.7 (OCH3), 88.7 (CH),
98.7 (CH), 107.6 (Cq), 114.8 (CH), 138.6, 157.0, 161.7, 161.8,
168.9 (Cq).
IR (KBr): 3386, 3152, 1654, 1602, 1547 cm–1.
MS (EI): m/z (%) = 206 (M+, 97), 178 (M+ – CO, 6), 164 (M+ –
1H NMR: (DMSO-d6): = 2.30 (s, 6 H, 2 × CH3), 3.69 (s, 6 H, 2 ×
OCH3), 5.07 (s, 2 H, 2 × CH), 6.79 (s, 2 H, 2 × ArH), 7.17 (s, 4 H,
2 × NH2).
13C NMR: (DMSO-d6): = 17.4 (2 × CH3), 55.9 (2 × OCH3), 86.1
(2 × CH), 97.0 (2 × CH), 114.4, 123.0, 138.9, 155.8, 158.9, 163.1,
177.8 (14 × Cq).
C2H2O, 100), 136 (M+ – C3H2O2, 24).
4,7-Dimethoxy-5-methyl-2H-chromen-2-one (Siderin, 1)
4-Hydroxy-7-methoxy-5-methyl-2H-chromen-2-one (12; 250 mg,
1.21 mmol), K2CO3 (610 mg, 4.41 mmol) and dimethyl sulfate
(0.32 mL, 3.41 mmol) were suspended in acetone (50 mL) and re-
fluxed for 4 h. The mixture was then diluted with H2O and extracted
with CHCl3 (4 × 75 mL). The combined organic layers were dried
(MgSO4) and the solvent was evaporated at reduced pressure. After
purification by flash column chromatography (CHCl3–EtOAc, 10:
1) product 1 was obtained as colorless needles (216 mg, 81%); Rf
0.45; mp 191 °C.
1H NMR: (CDCl3): = 2.56 (s, 3 H, CH3), 3.79 (s, 3 H, OCH3), 3.89
(s, 3 H, OCH3), 5.48 (s, 1 H, CH), 6.55 (d, 1 H, 4J = 2.6 Hz, ArH),
6.60 (d, 1 H, 4J = 2.6 Hz, ArH).
13C NMR: (CDCl3): = 23.6 (CH3), 55.7 (OCH3), 56.1 (OCH3),
87.6 (CH), 98.8 (CH), 108.0 (Cq), 115.7 (CH), 138.6, 156.8, 162.0,
163.3, 169.9 (Cq).
MS (EI): m/z (%) = 408 (M+, 30), 393 (M+ – CH3, 100), 377 (M+ –
OCH3, 26).
(rac)-2,2 -Diamino-7,7 -dimethoxy-5,5 -dimethyl-4H,4 H-6,8 -
bichromene-4,4 -dione (15)
Compound 15 was obtained from (rac)-dimethyl 2,4 -dihydroxy-
6,6 -dimethoxy-2 ,4-dimethyl-1,1 -biphenyl-3,3 -dicarboxylate (9;
500 mg, 1.28 mmol), MeCN (468 mg, 11.4 mmol) and n-BuLi (1.6
M in hexane, 7.13 mL, 11.4 mmol) in THF (60 mL) according to the
general procedure; yield (after recrystallization): 347 mg (66%);
Rf 0.38; mp 264 °C (dec.).
IR (KBr): 3386, 3152, 1655, 1604, 1546 cm–1.
MS (EI): m/z (%) = 220 (M+, 100), 205 (M+ – CH3, 3), 192 (M+ –
1H NMR: (DMSO-d6): = 2.38 (s, 3 H, CH3), 2.79 (s, 3 H, CH3),
3.70 (s, 3 H, OCH3), 3.72 (s, 3 H, OCH3), 4.96 (s, 1 H, CH), 5.06 (s,
CO, 43), 177 (M+ – CO, CH3, 28).
Synthesis 2003, No. 12, 1803–1808 © Thieme Stuttgart · New York

PAPER
Efficient Synthesis of 4,4 -Dimethoxybicoumarins
1807
1 H, CH), 6.79 (s, 1 H, ArH), 6.84 (s, 1 H, ArH), 6.86 (s, 2 H, NH2),
7.14 (s, 2 H, NH2).
O-Methylation of the 4,4 -Dihydroxybicoumarins 16–18; Gen-
eral Procedure
To a stirred solution of 4,4 -dihydroxybicoumarin in anhyd hexa-
methylphosphoric acid triamide (HMPT) under argon was added
NaH. After the evolution of gas had ceased dimethyl sulfate was
added and stirring was continued for 2 h. The reaction mixture was
diluted with EtOAc (15 mL), washed with 2 M HCl (2 × 15 mL) and
brine (15 mL). The brine washing was extracted with CHCl3 (10
ml). The combined organic layers were dried (MgSO4) and the sol-
vent was evaporated at reduced pressure. The residue was purified
by flash column chromatography (CHCl3–EtOAc, 3:1) to yield the
product as a colorless solid.
13C NMR: (DMSO-d6): = 17.8 (CH3), 22.8 (CH3), 55.85 (OCH3),
55.88 (OCH3), 85.4 (CH), 86.0 (CH), 97.0 (CH), 110.5 (Cq), 111.0
(CH), 114.5, 114.8, 119.3, 139.4, 140.0, 153.1, 156.0, 157.9, 159.3,
163.0, 163.3, 177.64, 177.72 (Cq).
MS (EI): m/z (%) = 408 (M+, 100), 393 (M+ – CH3, 21), 377 (M+ –
OCH3, 70).
HRMS (EI): m/z calcd for C22H20N2O6: 408.1321; found: 408.1330.
Acidic Hydrolysis of the 2,2 -Diaminobichromenones 13–15;
General Procedure
4,4 ,7,7 -Tetramethoxy-5,5 -dimethyl-2H,2 H-8,8 -bichromene-
2,2 -dione (Kotanin) (2)
Racemic Kotanin (2)
Racemic kotanin (2) was obtained from (rac)-16 (55 mg, 0.13
mmol), NaH (60% in oil, 14 mg, 0.33 mmol), dimethyl sulfate (51
mg, 0.40 mmol) and HMPT (0.8 mL) according to the general pro-
cedure; yield: 35 mg (59%); Rf 0.31; mp 360 °C (dec.).
The aminochromenone was dissolved in a mixture of MeOH and
32% HCl (1:1) and refluxed for several hours. From the resulting
suspension, the MeOH was evaporated at reduced pressure and H2O
was added. The colorless precipitate was filtered off, washed with
dil. HCl (1%) and air dried at 60 °C to yield a crude product as a col-
orless solid which is pure enough to be used in the next step.
1H NMR: (CDCl3): = 2.70 (s, 6 H, 2 × CH3), 3.79 (s, 6 H, 2 ×
OCH3), 3.92 (s, 6 H, 2 × OCH3), 5.50 (s, 2 H, 2 × CH), 6.71 (s, 2 H,
2 × ArH).
13C NMR: (CDCl3): = 24.3 (2 × CH3), 56.1 (2 × OCH3), 56.3 (2 ×
OCH3), 87.9 (2 × CH), 107.6, 108.6 (4 × Cq), 111.6 (2 × CH), 138.7,
153.7, 159.7, 163.3, 170.1 (10 × Cq).
(rac)-4,4 -Dihydroxy-7,7 -dimethoxy-5,5 -dimethyl-2H,2 H-8,8 -
bichromene-2,2 -dione (16)
(rac)-2,2 -Diamino-7,7 -dimethoxy-5,5 -dimethyl-4H,4 H-8,8 -bi-
chromene-4,4 -dione (13; 69 mg, 0.16 mmol) was refluxed for 13 h
in the hydrolytic mixture (20 mL) according to the general proce-
dure; yield: 45 mg (67%); mp >350 °C.
1H NMR: (DMSO-d6): = 2.75 (s, 6 H, 2 × CH3), 3.75 (s, 6 H, 2 ×
OCH3), 5.38 (s, 2 H, 2 × CH), 6.97 (s, 2 H, 2 × ArH), 12.27 (s, 2 H,
2 × OH).
+
MS (EI): m/z (%) = 438 (M+, 57), 421 (C24H21O7 , 15), 407
+
(C23H19O7 , 100).
Atropisomerically pure P-(+)- and M-(–)-kotanin (P-2, M-2) were
obtained from the corresponding isomerically pure biarylic esters
P-(+)-7 and M-(–)-7 in 10% and 24% overall yield, respectively, as
described for the racemic compound.
13C NMR: (DMSO-d6): = 23.2 (2 × CH3), 56.1 (2 × OCH3), 88.6
(2 × CH), 106.4, 107.9 (4 × Cq), 111.2 (2 × CH), 138.6, 153.7, 159.3,
161.6, 169.1 (10 × Cq).
MS (EI): m/z (%) = 410 (M+, 100), 369 (98), 327 (93), 295 (83), 269
(75).
P-(+)-Kotanin (P-2)
25
20
Mp >320 °C; [ ]D +27.6 (c = 0.4, CHCl3) {Lit.7b [ ]D +38.4
(rac)-4,4 -Dihydroxy-7,7 -dimethoxy-5,5 -dimethyl-2H,2 H-6,6 -
bichromene-2,2 -dione (17)
(rac)-2,2 -Diamino-7,7 -dimethoxy-5,5 -dimethyl-4H,4 H-6,6 -bi-
chromene-4,4 -dione (14; 100 mg, 0.24 mmol) was refluxed for 3.5
h in the hydrolytic mixture (10 mL) according to the general proce-
dure; yield: 73 mg (73%); mp 206–208 °C.
(c = 0.44, CHCl3); Lit.3 [ ]D23 +40.0 (c = 1.65, CHCl3)}.
CD:
(
) = 206 (–55), 215 (–20), 220 (–26), 232 (+7), 238 (+6),
260 (+24), 291 (–17), 322 nm (+32).
MS and NMR spectra identical to those of racemic 2.
M-(–)-Kotanin (M-2)
1H NMR: (DMSO-d6): = 2.22 (s, 6 H, 2 × CH3), 3.70 (s, 6 H, 2 ×
OCH3), 5.47 (s, 2 H, 2 × CH), 6.94 (s, 2 H, 2 × ArH), 12.30 (s, 2 H,
2 × OH).
13C NMR: (DMSO-d6): = 18.2 (2 × CH3), 56.2 (2 × OCH3), 89.1,
97.6 (4 × CH), 107.6, 122.7, 136.8, 156.6, 159.9, 161.7, 169.2
(14 × Cq).
Mp >320 °C; [ ]D25 –37.2 (c = 0.3, CHCl3).
CD:
(
) = 206 (+79), 215 (+30), 220 (+37), 232 (–10), 238 (–8),
260 (–34), 291 (+23), 322 nm (–46).
MS and NMR spectra identical to those of racemic 2.
(rac)-4,4 ,7,7 -Tetramethoxy-5,5 -dimethyl-2H,2 H-6,6 -bichro-
mene-2,2 -dione (Isokotanin A, 3)
Racemic isokotanin A (3) was obtained from (rac)- 17 (55 mg, 0.13
mmol), NaH (60% in oil, 14 mg, 0.34 mmol), dimethyl sulfate (51
mg, 0.40 mmol) and HMPT (0.8 mL) according to the general pro-
cedure; yield: 35 mg (68%); Rf 0.37; mp 321 °C (dec.).
1H NMR (CDCl3): = 2.22 (s, 6 H, 2 × CH3), 3.71 (s, 6 H, 2 ×
OCH3), 3.93 (s, 6 H, 2 × OCH3), 5.58 (s, 2 H, 2 × CH), 6.77 (s, 2 H,
2 × ArH).
13C NMR: (CDCl3): = 18.9 (2 × CH3), 56.2 (4 × OCH3), 88.1 (2 ×
CH), 97.6 (2 × CH), 108.3, 123.6, 137.4, 156.5, 160.3, 163.3, 170.3
(14 × Cq).
(rac)-4,4 -Dihydroxy-7,7 -dimethoxy-5,5 -dimethyl-2H,2 H-6,8 -
bichromene-2,2 -dione (18)
(rac)-2,2 -Diamino-7,7 -dimethoxy-5,5 -dimethyl-4H,4 H-6,8 -bi-
chromene-4,4 -dione (15; 320 mg, 0.78 mmol) was refluxed for 6 h
in the hydrolytic mixture (32 mL) according to the general proce-
dure; yield: 215 mg (67%); mp >350 °C.
1H NMR: (DMSO-d6): = 2.26 (s, 3 H, CH3), 2.74 (s, 3 H, CH3),
3.68 (s, 3 H, OCH3), 3.76 (s, 3 H, OCH3), 5.40 (s, 1 H, CH), 5.48 (s,
1 H, CH), 6.94 (s, 1 H, ArH), 6.97 (s, 1 H, ArH), 12.30 (br s, 2 H, 2
× OH).
13C NMR: (DMSO-d6): = 18.2 (CH3), 23.3 (CH3), 56.07 (OCH3),
56.14 (OCH3), 88.7 (CH), 89.1 (CH), 97.6 (CH), 107.6, 108.0,
110.3 (Cq), 111.1 (CH), 119.2, 137.1, 138.5, 153,5, 156.7, 159.0,
160.1, 161.66, 161.71 (Cq), 169.2 (2 × Cq).
MS (EI): m/z (%) = 438 (M+, 100), 410 (C23H22O7 , 8).
+
(rac)-4,4 ,7,7 -Tetramethoxy-5,5 -dimethyl-2H,2 H-6,8 -bichro-
mene-2,2 -dione (Desertorin C, 4)
a) According to the General Procedure: Racemic desertorin C (4)
was obtained from (rac)-18 (150 mg, 0.37 mmol), NaH (60% in oil,
MS (EI): m/z (%) = 410 (M+, 100), 382 (45), 368 (90), 351 (94), 295
(69).
Synthesis 2003, No. 12, 1803–1808 © Thieme Stuttgart · New York

1808
W. Hüttel et al.
PAPER
(8) Isokotanin A(3) (a) Racemic: Lin, G.-Q.; Zhong, M. Acta
30 mg, 0.73 mmol), dimethyl sulfate (111 mg, 0.88 mmol) and
HMPT (2 mL) according to the general procedure; yield: 88 mg
(55%); Rf 0.34.
Chim. Sin. 1997, 55, 97; Chem. Abstr. 1997, 126, 211942.
(b) Stereoselective: Lin, G.-Q.; Zhong, M. Tetrahedron Lett.
1996, 37, 3015. (c) Stereoselective: Bringmann, G.;
Hinrichs, J.; Henschel, P.; Kraus, J.; Peters, K.; Peters, E.-M.
Eur. J. Org. Chem. 2002, 1096.
b) From 6,8 -Aminobichromenone 15: (rac)-15 (30 mg, 0.07 mmol)
was dissolved in MeOH (2 mL) and HCl (37%, 1 mL) and refluxed
for 4.5 h. The mixture was diluted with MeOH (2 mL) and dimethyl
carbonate (2.7 mL, 32.0 mmol), and acetyl chloride (0.38 mL, 5.4
mmol) was added dropwise. After refluxing for a further 24 h, the
reaction mixture was poured into H2O (30 mL) and extracted with
EtOAc (3 × 15 mL). The combined organic layers were dried
(MgSO4) and the solvent was evaporated under reduced pressure.
The residue was purified by preparative thin layer chromatography
(CHCl3–MeOH–formic acid, 30:2:1) to yield desertorin C (4) as a
colorless solid (11 mg, 34%); Rf 0.57; mp 332 °C (dec.).
1H NMR: (CDCl3): = 2.26 (s, 3 H, CH3), 2.71 (s, 3 H, CH3), 3.68
(s, 3 H, OCH3), 3.77 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 3.92 (s, 3
H, OCH3), 5.50 (s, 1 H, CH), 5.53 (s, 1 H, CH), 6.70 (s, 1 H, ArH),
6.74 (s, 1 H, ArH).
13C NMR: (CDCl3): = 19.4 (CH3), 24.3 (CH3), 56.09 (OCH3),
56.15 (OCH3), 56.17 (OCH3), 56.21 (OCH3), 87.9 (CH), 88.0 (CH),
97.7 (CH), 108.3, 108.6 (Cq), 111.3 (CH), 111.5, 119.5, 137.8,
138.4, 153,5, 156.7, 159.4, 160.5, 163.1, 163.4, 169.9, 170.4 (Cq).
(9) Desertorin C(4) (a) Racemic: Rizzacasa, M. A.; Sargent, M.
V. J. Chem. Soc., Perkin Trans. 1 1988, 2425.
(b) Stereoselective: Kyasnoor, R. V.; Sargent, M. V. Chem.
Commun. 1998, 2713. (c) Steroselective: Baker, R. W.;
Kyasnoor, R. V.; Sargent, M. V.; Skelton, B. W.; White, A.
H. Aust. J. Chem. 2000, 53, 487.
(10) The total syntheses of the three biaryl coumarins 2–4 require
ca. 25 steps according to the literature.
(11) (a) Drochner, D.; Hüttel, W.; Nieger, M.; Müller, M. Angew.
Chem. Int. Ed. 2003, 42, 931; Angew. Chem. 2003, 115,
961. (b) Drochner, D.; Karl, U.; Nieger, M., Müller, M.;
Steglich, W., manuscript in preparation.
(12) Similar reactions are reported in the literature. However,
yields are low and reaction conditions cannot be applied to
substrate 6., e.g.: Connor, D. T.; Sorenson, R. J. J.
Heterocycl. Chem. 1981, 18, 587.
(13) Long, R. S. J. Am. Chem. Soc. 1947, 69, 990.
(14) Basiski, W. Polish J. Chem. 1995, 69, 376; Chem. Abstr.
1995, 123, 32908.
MS (EI): m/z (%) = 438 (M+, 100), 407 (C23H19O7, 23).
(15) Szabó, V.; Borda, J.; Theisz, E. Acta Chim. Acad. Sci. Hung.
1980, 103, 271; Chem. Abstr. 1981, 94, 103116.
(16) (a) Suzuki, E.; Katsuragawa, B.; Inoue, S. Synthesis 1978,
Acknowledgments
The authors are grateful to Mrs. Petra Geilenkirchen for skillful
technical assistance. The help of Dipl. Chem. Daniel Drochner is
gratefully acknowledged. We thank Prof. Christian Wandrey for his
continuous and generous support.
144. (b) See also Refs.7b,8
.
(17) This was demonstrated for the 6,8 -bisaminochromenone 15,
which was converted to desertorin C (4) in a single step.
Hence, the hydrolytic mixture was dehydrated chemically
with dimethyl carbonate after no starting material could be
detected (TLC). Acetyl chloride was added to generate
additional HCl. The yield (34%) is comparable to the overall
yield of the two-step procedure (36%).
(18) The low yield in the case of M-(–)-2 is mainly due to a
nonoptimized reaction time for acidic hydrolysis.
(19) The isomers of kotanin(2) were erroneously mismatched in
a previous publication.11a
References
(1) Bringmann, G.; Günther, C.; Ochse, M.; Schupp, O.; Tasler,
S. Prog. Chem. Org. Nat. Prod. 2001, 82, 1.
(2) Stothers, J. B.; Stoessl, A. Can. J. Chem. 1988, 66, 2816.
(3) (a) Büchi, G.; Luk, K. C.; Kobbe, B.; Townsend, J. M. J.
Org. Chem. 1977, 42, 244. (b) See also Refs.2,4b,7a
(4) (a) Laakso, J. A.; Narske, E. D.; Gloer, J. B.; Wicklow, D.
T.; Dowd, P. F. J. Nat. Prod. 1994, 57, 128. (b) Nozawa,
K.; Nakajima, S.; Kawai, K.-I.; Udagawa, S. I.; Miyaji, M.
Phytochemistry 1994, 35, 1049.
(5) Nozawa, K.; Seyea, H.; Nakajima, S.; Udagawa, S. I.;
Kawai, K. I. J. Chem. Soc., Perkin Trans. 1 1987, 1735.
(6) Siderin(1): (a) Venturella, P.; Bellino, A.; Piozzi, F.
Tetrahedron Lett. 1974, 15, 979. (b) Chexal, K. K.;
Fouweather, C.; Holker, J. S. E. J. Chem. Soc., Perkin Trans.
1 1974, 554. (c) Ahluwalia, V. K.; Kumar, D. Indian J.
Chem., Sect. B 1976, 14, 589.
(20) (a) Chiarello, J.; Joullié, M. M. Tetrahedron 1988, 44, 41.
(b) Sala, T.; Sargent, M. V. J. Chem. Soc., Perkin
Trans.Trans.1 1981, 855.
(21) Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-215646. Copies of the data can be
obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html [or from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK;
Fax: int. code+44-1223/336-033; e-mail:
deposit@ccdc.cam.ac.uk].
(7) Kotanin(2) (a) Racemic: Büchi, G.; Klaubert, D. H.; Shank,
R. C.; Weinreb, S. M.; Wogan, G. N. J. Org. Chem. 1971,
36, 1143. (b) Stereoselective: Lin, G.-Q.; Zhong, M.
Tetrahedron: Asymmetry 1997, 8, 1369.
Synthesis 2003, No. 12, 1803–1808 © Thieme Stuttgart · New York