Total synthesis of the antifungal natural product mollisin

Article abstract of DOI:10.1002/ejoc.201301088

Mollisin, a bioactive polyketide secondary metabolite of the fungus Mollisia caesia, was synthesized in nine linear steps from commercially available 2,6-dimethyl-γ-pyrone. A key transformation in this first total synthesis of mollisin was the ipso substi

Full text of DOI:10.1002/ejoc.201301088

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301088
Total Synthesis of the Antifungal Natural Product Mollisin
Sonja Schwolow,[a] Horst Kunz,[a] Joachim Rheinheimer,[b] and Till Opatz*[a]
Keywords: Natural products / Total synthesis / Polyketides / Acylation
Mollisin, a bioactive polyketide secondary metabolite of the
fungus Mollisia caesia, was synthesized in nine linear steps
from commercially available 2,6-dimethyl-γ-pyrone. A key
transformation in this first total synthesis of mollisin was the
ipso substitution of an arylstannane, which permitted the
otherwise cumbersome introduction of the characteristic
dichloroacetyl moiety. The fungal fungicide was obtained in
an overall yield of 9%.
late-stage chlorination of acetylated precursors failed.[5,11]
However, the Friedel–Crafts-like ipso substitution of a stan-
nylated naphthalene building block finally permitted the
clean introduction of this characteristic functionality and
ultimately the preparation of the natural product (Figure 1).
As a first attempt for the synthesis of 1, treatment of
dichloroacetylated 3-methoxytoluene 3 with citraconic an-
hydride in a double Friedel–Crafts acylation was envi-
sioned.[12,13] Apart from potential regioselectivity issues,
this procedure should allow straightforward assembly of
mollisin’s naphthoquinone core. Starting from 1-bromo-4-
methoxy-2-methylbenzene (2),[14] the corresponding Grig-
nard reagent was prepared and treated with dichloroacetyl
chloride to give desired ketone 3, albeit in a disappointing
yield of only 15%. The observed concomitant formation of
the symmetrical biaryl suggested that the reduction of the
activated dichloromethyl group had taken place. Reaction
of 3 with citraconic anhydride by using the AlCl3/NaCl sys-
tem of Laatsch[13] at 180 °C did not produce desired naph-
thoquinone 4 or its regioisomer or their O-demethylated
analogues (Scheme 1).
Introduction
Mollisin (1) is a fungal secondary metabolite produced
by several Mollisia species. It was first isolated by Gremmen
from Mollisia caesia and Mollisia fallens in 1956.[1,2] Molli-
sin has a naphthoquinone core and shows various antifun-
gal activities, for example, against the mold fungus Hetero-
basidion annosum, the poplar pests Dothichiza populea and
Pollaccia radiosa, as well as against the economically rel-
evant Sclerotinia trifoliorum, which can affect spruces.[2] The
structure of mollisin was elucidated in 1964 by Overeem
and van der Kerk,[3,4] who also pursued a first approach
towards its total synthesis.[5] Biosynthetically, mollisin is
produced through the polyketide pathway and the chlorine
atoms are introduced with the aid of chloroperoxidase.[6–10]
Despite its astonishingly simple structure (Figure 1), no
successful synthesis of 1 has been reported so far.[5,11]
Figure 1. Structure of mollisin.
Results and Discussion
As already described in the literature, the introduction of
the CH-acidic, electrophilic, and redox-active dichloro-
acetyl moiety proved to be particularly cumbersome. All
our attempts at direct electrophilic acylation of naphthalene
precursors with dichloroacetyl reagents and attempts at
Scheme 1. Attempted synthesis of mollisin by double Friedel–
Crafts acylation.
[a] Institute of Organic Chemistry, University of Mainz,
Duesbergweg 10–14, 55128 Mainz, Germany
E-mail: opatz@uni-mainz.de
Homepage: http://www.chemie.uni-mainz.de/OC/AK-Opatz/
[b] GVA-A30, BASF SE,
In a second strategy, 3,6-dimethylnaphthalene-1,8-diol
(8) was chosen as the key intermediate. This oxidation-sen-
sitive compound was synthesized according to the protocol
67056 Ludwigshafen, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301088.
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Schwolow, H. Kunz, J. Rheinheimer, T. Opatz
SHORT COMMUNICATION
by Overeem and van der Kerk,[5] which involved Ba(OH)2- chlorination of monoacetyl derivatives was unsuccessful.[11]
induced ring opening of 2,6-dimethyl-γ-pyrone (5). Hydrol- Therefore, it was decided to introduce the acyl group
ysis of the intermediate Ba2+-chelate complex with hydro- through a halogen substituent. After optimization, bromi-
chloric acid afforded diacetylacetone (6).[15] NMR spec- nation of the 4-position in 9 with Br2 in propionic acid pro-
troscopy revealed that this compound exists in three tauto- ceeded with a yield of 98%. Conversion of the bromide into
meric forms, 6b (69%), 6a (28%), and 6 (3%), in CDCl3 at the corresponding Grignard reagent and subsequent treat-
25 °C (Scheme 2).
ment with dichloroacetyl chloride did not produce desired
ketone 12.[20] To activate the 4-position for electrophilic at-
tack, stannane 11 was prepared by halogen–lithium ex-
change on bromide 10 with nBuLi and reaction with chlo-
rotrimethylstannane. A small amount of dehalogenated
product 9 was formed concomitantly, even under rigorous
exclusion of moisture, and was not separated from the stan-
nane.
Although Stille-type coupling of 11 with acyl chlor-
ide[21,22] did not provide 12, the dichloroacetyl group could
be introduced by Friedel–Crafts-like acylation.[23] Substitu-
tion at the ipso position is favored because of the weak C–
Sn bond, which makes the trimethylstannyl cation a good
leaving group. Upon screening the reaction conditions, we
found that the formation of naphthoquinone 4 was best
achieved by oxidation of acyl naphthalene 12 with the
H2O2/K3[Fe(CN)6] system.[24] In contrast, Frémy’s salt did
not effect the oxidation of 12. Finally, O-demethylation
with AlCl3 and chromatographic purification provided mol-
lisin (1) as yellow crystals in an overall yield of 9% from
commercially available 2,6-dimethyl-γ-pyrone (Scheme 3).
Scheme 2. Tautomeric equilibrium of diacetylacetone (6) in CDCl3
at 298 K.
Crystallization from light petroleum ether gave tautomer
6a, which was analyzed by X-ray crystallography (Figure 2).
Figure 2. ORTEP plot of diacetylacetone tautomer 6a at 173 K (el-
lipsoids drawn at the 50% probability level).
The naphthalene core was established by triple intermo-
lecular Knoevenagel condensation[16] of two molecules of
diacetylacetone (6). While Overeem[5] used pure piperidine
as the catalyst for this reaction, we found a combination of
piperidine (0.3 equiv.) and acetic acid (0.03 equiv.) to be
more effective. Deacetylation of dimerization product 7 by
a retro-Friedel–Crafts reaction[17,18] with hydrobromic acid
and acetic acid in pyridine provided symmetrical key inter-
mediate 8.
For the subsequent transformations, the judicious choice
of the O-protecting group was crucial. Whereas diisoprop-
ylsilylene protection was too labile under the conditions re-
quired for electrophilic aromatic substitution, O-allylation
led to Claisen rearrangement,[19] even at ambient tempera-
ture. Double benzylation was sluggish, and reactions of 8
with p-methoxybenzyl chloride (PMBCl)/Bu4NI as well as
with tert-butyldimethylsilyl chloride/4-(dimethylamino)pyr-
idine (TBDMSCl/DMAP) did not go to completion. In
contrast, double methylation with dimethyl sulfate accord-
ing to Overeem provided highly stable dimethyl derivative 9
in quantitative yield.[5]
Scheme 3. Total synthesis of mollisin (1).
As already described by Matthes,[11] the introduction of
the dichloroacetyl group by Friedel–Crafts acylation with
The target molecule proved to be identical to natural
dichloroacetyl chloride and various Lewis acids failed, and, mollisin in all respects. Furthermore, the structures of mol-
for instance, the action of acetyl chloride/TiCl4 even gave lisin and intermediates 4 and 12 were proven by X-ray crys-
the 4,5-diacetylated product. We also found that late-stage tallography (Figure 3, see also the Supporting Information).
6520
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Total Synthesis of the Antifungal Natural Product Mollisin
structure: SIR97;[28] program used to refine the structure:
SHELXL97;[29] molecular graphics and software used to prepare
material for publication: PLATON.[30]
2,2-Dichloro-1-(4-methoxy-2-methylphenyl)ethanone (3): According
to a modified synthesis of Tishchenko,[31] a portion (100 µL) of 1-
bromo-4-methoxy-2-methylbenzene
(2;
1.01 g,
5.02 mmol,
1.0 equiv.) in dry THF (2 mL) was added to a suspension of magne-
sium turnings (122 mg, 5.02 mmol, 1.0 equiv., stored several hours
over iodine before use) in dry THF (2 mL). After the suspension
turned cloudy, the residual amount (1.9 mL) of the solution of the
aryl bromide was added slowly. The reaction mixture was cooled to
–78 °C, and a solution of dichloroacetyl chloride (460 μL, 704 mg,
4.77 mmol, 0.95 equiv.) in dry THF (2 mL) was added dropwise.
After stirring for 30 min at –78 °C, the reaction mixture was
warmed to 0 °C. For hydrolysis, 1 n hydrochloric acid (15 mL) was
added, and the mixture was extracted with Et2O (2ϫ 15 mL). The
combined organic layer was washed with saturated aqueous
NaHCO3 (1ϫ 20 mL) and water (1ϫ 20 mL) and then dried with
MgSO4. The solvent was removed in vacuo. After purification by
column chromatography on silica gel (cyclohexane/EtOAc, 20:1),
the title compound (180 mg, 770 μmol, 15%) was obtained as a
yellow oil. Rf = 0.20 (cyclohexane/EtOAc, 20:1). 1H NMR
(300 MHz, CDCl3): δ = 7.83 (d, J = 8.6 Hz, 1 H, H-6Ј), 6.84–6.77
(m, 2 H, H-3Ј, H-4Ј), 6.68 (s, 1 H, CHCl2), 3.87 (s, 3 H, OCH3),
2.58 (s, 3 H, CH3) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 186.4
(CO), 163.2 (C-4Ј), 145.2 (C-2Ј), 132.2 (C-6Ј), 123.9 (C-1Ј), 118.3
(C-3Ј), 111.0 (C-5Ј), 69.0 (CHCl2), 55.6 (OCH3), 22.7 (CH3) ppm.
Figure 3. ORTEP plot of the crystal structures of intermediate 12
(left) and mollisin (1, right) at 173 K (ellipsoids drawn at the 50%
probability level).
Conclusions
In summary, the first total synthesis of the fungal fungi-
cide mollisin was achieved in nine steps starting from 2,6-
dimethyl-γ-pyrone, which was ring opened and subjected to
self-condensation to give 3,6-dimethylnaphthalene-1,8-diol.
The introduction of the characteristic dichloroacetyl group
was accomplished by bromination at the 4-position, halo-
gen–tin exchange, and Friedel–Crafts-like acylation. This
reaction sequence circumvented chemoselectivity problems
originating from the reactivity of the dichloroacetyl moiety.
Final oxidation followed by Lewis-acidic deprotection fur-
nished the naphthoquinone structure of the natural prod-
uct.
MS (FD+): m/z (%) = 232.0 (100.0) [M (235Cl)]+, 234.0 (65.3) [M
˙
(35Cl,37Cl)]+. MS (ESI+): m/z (%) = 233.2 (100.0) [M (235Cl) +
˙
H]+, 235.1 (68.2) [M (35Cl,37Cl) + H]+. IR (ATR): ν = 2931, 2843,
˜
1693, 1602, 1565, 1454, 1327, 1251, 1128, 1052, 1041, 824,
755 cm–1.
Diacetylacetone (6):[32]
Experimental Section
General Methods: All reactions under anhydrous conditions were
performed in dried glassware under an argon atmosphere. Solvents
were dried by standard procedures.[25] Reactions at a temperature
of 0 °C were performed in a water/ice bath. Elemental analyses
were performed in the microanalytical laboratory of the Institute
of Organic Chemistry, Johannes Gutenberg University Mainz, with
a Vario EL cube (Elementar, Hanau). Flash chromatography was
performed on silica gel 60 (0.035–0.070 mm, Acros). Chromatog-
raphy solvents (petroleum ether, cyclohexane, EtOAc) were distilled
prior to use. For analytical TLC, silica gel aluminum sheets (60
Ba(OH)2·8H2O (100.0 g, 317.0 mmol, 2.0 equiv.) was dissolved al-
most completely in boiling water (1.3 L) under an argon atmo-
sphere. The resulting suspension was added directly to a 50 °C
warm solution of 2,6-dimethyl-γ-pyrone (19.67 g, 158.5 mmol,
1.0 equiv.) in aqueous NaOH (8 wt.-%, 40 mL). A yellow precipi-
tate formed immediately. The solution was cooled slowly to 0 °C.
The crystals were filtered off, washed with aqueous NaOH (4 wt.-
%), and then dissolved under ice cooling in aqueous HCl (15 wt.-
F254, Merck) were used. Visualization was accomplished by illumi-
nating with UV light (254 nm) or treatment with Seebach’s reagent
[Ce(SO4)2·4H2O (1.0 g), H3PMo12O40 (2.5 g), H2O (94 mL), conc. %, 200 mL). The solution was stirred for 1 h, extracted with Et2O
H2SO4 (6 mL)]. NMR spectra were recorded with AC 300, (3ϫ 200 mL), and dried with MgSO4. The solvent was removed by
AM 400, and AV 400 instruments (Bruker) by using the residual
solvent peak as an internal reference (CDCl3: δH = 7.26 ppm, δC
distillation in vacuo. The product was recrystallized from petro-
leum ether to afford the title compound (14.16 g, 99.61 mmol,
63%) as a colorless, crystalline solid. Rf = 0.50 (cyclohexane/
EtOAc, 3:5), m.p. (petroleum ether): 48.0–49.0 °C (ref.[32] 49 °C).
Tautomeric equilibrium of 3 in CDCl3: 6b: 69%, 6a: 28%, 6: 3%.
1H NMR, NOESY (400 MHz, CDCl3): δ = 15.20 (s, 1 H, OH-4),
14.17 (s, 2 H, OH-b), 5.55 (s, 1 H, H-5), 5.12 (s, 1 H, H-c), 3.69 (s,
=
77.16 ppm; [D6]DMSO: δH = 2.50 ppm, δC = 39.52 ppm).[26] IR
spectra were recorded with a Tensor 27 FTIR spectrometer
(Bruker) by using a diamond ATR unit. FD mass spectra were
recorded with a MAT 95 spectrometer (Finnigan). ESI mass spec-
trometry was performed with a LC–MSD Trap ion trap (Bruker/
Agilent) by using a C8 core shell column with 2.7 μm particle size 4 H, H-III), 3.40 (s, 2 H, H-3), 2.24 (s, 3 H, H-1), 2.23 (s, 6 H, H-
(Ascentis Express, 2.1 mmϫ30 mm, Agilent). The samples were
dissolved in MeCN (c 0.1 mg/mL) and filtered. Melting points were
determined with a KSP 1 N (Krüss Optronic) at a heating rate of
I), 2.06 (s, 3 H, H-7), 1.96 (s, 3 H, H-a) ppm. 13C NMR, 13C-DEPT,
HSQC, HMBC (100.6 MHz, CDCl3): δ = 202.4 (C-II), 202.1 (C-
2), 198.4 (C-IV), 193.9 (C-d), 191.2 (C-6), 187.0 (C-4), 178.6 (C-b),
1 °Cmin–1. X-Ray structure determination was performed with a 101.2 (C-5), 98.7 (C-c), 57.8 (C-III), 54.0 (C-3), 31.1 (C-1), 24.7 (C-
Siemens/Bruker Smart CCD diffractometer. Data collection: 7), 21.9 (C-a) ppm. MS (FD+): m/z (%) = 142.07 (100.0) [M]+.
˙
APEX2;[27] cell refinement: SAINT;[27] program used to solve the
C7H10O3 (142.15): calcd. C 59.14, H 7.09; found C 58.80, H 7.16.
Eur. J. Org. Chem. 2013, 6519–6524
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S. Schwolow, H. Kunz, J. Rheinheimer, T. Opatz
SHORT COMMUNICATION
IR (ATR): ν = 3726, 2963, 2922, 1647, 1596, 1542, 1389, 1354,
dried with Na2SO4, and the solvent was removed in vacuo. The
product was recrystallized from ethanol to afford the title com-
pound (391 mg, 1.81 mmol, quant.) as a yellow, crystalline solid.
Rf = 0.23 (cyclohexane/EtOAc, 8:1), m.p. (ethanol): 134.0–135.5 °C
(ref.[5] 135–137 °C). 1H NMR (300 MHz, CDCl3): δ = 7.08 (s, 2 H,
H-4, H-5), 6.60 (s, 1 H, H-2, H-7), 3.95 (s, 6 H, CH3-1, CH3-8),
2.44 (s, 6 H, CH3-6, CH3-3) ppm. 13C NMR (100.6 MHz, CDCl3):
δ = 156.9 (C-1, C-8), 137.8 (C-4a), 136.3 (C-3, C-6), 119.6 (C-4, C-
5), 114.0 (C-8a), 107.6 (C-2, C-7), 56.4 (OCH3-1, OCH3-8), 21.9
˜
1238, 1183, 1141, 1034, 896, 821, 754 cm–1.
1-(1,8-Dihydroxy-3,6-dimethylnaphthalen-2-yl)ethanone (7): Ac-
cording to a modified synthesis of Overeem,[5] a mixture of AcOH
(170 μL, 2.97 μmol, 0.03 equiv.) and piperidine (2.29 mL, 2.51 g,
29.5 mmol, 0.30 equiv.) was added to molten diacetylacetone (6;
14.0 g, 98.4 mmol, 1.00 equiv.) under an argon atmosphere, and the
mixture was stirred for 2–4 h at 90 °C (TLC control). The reaction
mixture was concentrated in vacuo, coevaporated with toluene, and
recrystallized from EtOAc. The product was washed with 1 n HCl,
half-saturated aqueous NaHCO3, water, and EtOAc, and the title
compound (7.14 g, 31.0 mmol, 63%) was obtained as a yellow,
(CH -3, CH -6) ppm. MS (FD+): m/z (%) = 216.1 (100.0) [M]+. IR
˙
3
3
(ATR): ν = 2964, 2848, 1627, 1577, 1466, 1382, 1367, 1355, 1272,
˜
1173, 1123, 1102, 822, 737 cm–1.
crystalline solid. Rf
= 0.40 (cyclohexane/EtOAc, 3:1), m.p.
1-Bromo-4,5-dimethoxy-2,7-dimethylnaphthalene (10): 1,8-Dimeth-
oxy-3,6-dimethylnaphthalene (9; 200 mg, 925 μmol, 1.0 equiv.) was
dissolved in propionic acid (10 mL) under an argon atmosphere
and cooled to 0 °C. Portions (0.2–0.5 mL) of a stock solution of
Br2 (500 μL) in propionic acid (31.4 mL) were added at 0 °C (stir-
ring) under TLC monitoring until the starting material was con-
sumed (ca. 2.5 h). Careful addition was required to prevent dibro-
mination. After addition of ice (20 g) and saturated aqueous
NaHCO3 (5 mL), the mixture was extracted with CH2Cl2 (3ϫ
20 mL). The combined organic extract was washed with saturated
aqueous NaHCO3 (2ϫ 20 mL) and water (1ϫ 20 mL) and then
dried with MgSO4. The solvent was removed in vacuo. After purifi-
cation by column chromatography on silica gel (cyclohexane/
EtOAc, 10:1), the title compound (267 mg, 905 μmol, 98%) was
obtained as a yellow, amorphous solid. Rf = 0.20 (cyclohexane/
(EtOAc): 180.2–181.6 °C [ref.[5] 183–184 °C (AcOH)]. 1H NMR
(400 MHz, [D6]DMSO): δ = 6.99, 6.98 (2 s, 2 H, H-4Ј, H-5Ј), 6.60
(s, 1 H, H-7Ј), 2.53 (s, 3 H, CH3CO), 2.33 (s, 3 H, CH3-3Ј), 2.24
(s, 3 H, CH3-6Ј) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ =
204.2 (CO), 153.8, 153.3 (C-1Ј, C-8Ј), 138.0, 136.4 (C-3Ј, C-6Ј),
133.3 (C-2Ј), 122.1 (C-4aЈ), 118.6, 117.9 (C-4Ј, C-5Ј), 110.8 (C-8aЈ),
110.3 (C-7Ј), 32.2 (CH3CO), 21.4, 19.9 (CH3-6Ј, CH3-3Ј) ppm. MS
(FD+): m/z (%) = 460.1 (100.0) [2M]+, 297.0 (51.5) [M + 3Na –
˙
2H]+, 230.0 (23.5) [M]+. C H O (230.26): calcd. C 73.03, H 6.13;
˙
˙
14 14
3
found C 72.93, H 6.18. IR (ATR): ν = 3726, 3709, 3628, 1637,
˜
1541, 1404, 1374, 985, 874, 846, 669, 650 cm–1.
3,6-Dimethylnaphthalene-1,8-diol (8):[5] Ac2O (15 mL), aqueous
HBr (48 wt.-%, 7.5 mL), and pyridine (0.45 mL) were added to 7
(1.48 g, 6.43 mmol, 1.0 equiv.) under an argon atmosphere. The
brown suspension dissolved upon heating to 105 °C. After 1 h, the
solution was slowly cooled to room temperature and then cooled
by using an ice bath. After the addition of water (150 mL), the
resulting black precipitate was absorbed with cotton wool and dis-
solved in Et2O (300 mL). The organic phase was washed with aque-
ous HCl (1 n, 1ϫ 100 mL) and dried with MgSO4. The solvent
was removed by distillation in vacuo. The product was recrys-
tallized from benzene/petroleum ether to obtain the title compound
(997 mg, 5.29 mmol, 82%) as a colorless, crystalline solid. Rf = 0.36
(cyclohexane/EtOAc, 2:1), m.p. (benzene/petroleum ether): 125.0–
127.2 °C (ref.[5] 127–128 °C). 1H NMR (400 MHz, CDCl3): δ =
10.65 (s, 2 H, OH-1, OH-8), 6.94 (s, 2 H, H-4, H-5), 6.48 (s, 1 H,
1
EtOAc, 10:1), m.p. 114.0–115.0 °C. H NMR (300 MHz, CDCl3):
δ = 7.71 (s, 1 H, H-8), 6.70 (s, 1 H, H-3), 6.67 (s, 1 H, H-6), 3.96
(s, 3 H, OCH3-4), 3.94 (s, 3 H, OCH3-5), 2.57 (s, 3 H, CH3-2), 2.50
(s, 3 H, CH3-7) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 157.2 (C-
4), 156.4 (C-5), 137.9 (C-2), 136.8 (C-7), 135.5 (C-8a), 119.3 (C-8),
115.2 (C-4a), 114.9 (C-1), 108.5 (C-3), 108.4 (C-6), 56.7 (OCH3-4),
56.6 (OCH3-5), 24.8 (CH3-2), 22.4 (CH3-7) ppm. MS (FD+): m/z
(%) = 294.3 (100.0) [M (79Br)]+, 296.3 (94.0) [M (81Br)]+. IR (ATR):
˙
˙
ν = 3004, 2914, 2841, 1623, 1601, 1566, 1380, 1259, 1176, 1102,
˜
823 cm–1. C14H15BrO2 (295.18): calcd. C 56.97, H 5.12; found C
56.83, H 5.01.
(4,5-Dimethoxy-2,7-dimethylnaphthalen-1-yl)trimethylstannane (11):
1-Bromo-4,5-dimethoxy-2,7-dimethylnaphthalene (10; 292 mg,
990 μmol, 1.0 equiv.) was dissolved in dry THF (6 mL), cooled to
–78 °C, and nBuLi (1.6 m in hexane, 0.74 mL, 1.19 mmol,
1.2 equiv.) was added dropwise. After 15 min, Me3SnCl (1 m in
THF, 1.09 mL, 1.09 mmol, 1.1 equiv.) was added, and the reaction
solution was warmed to 25 °C within 16 h. Et2O (7 mL) was added
to the mixture, and the organic layer was washed with saturated
aqueous NaHCO3 (2ϫ 10 mL) and water (1ϫ 10 mL) and then
dried with Na2SO4. The solvent was removed in vacuo. The crude
product was obtained as a mixture with 1,8-dimethoxy-3,6-dimeth-
ylnaphthalene (9) (11/9 = 9:1) as a yellow, amorphous solid and
used without further purification. The analytical data derives from
measurements on the mixture. Rf = 0.36 (cyclohexane/EtOAc, 2:1),
1H NMR (400 MHz, CDCl3): δ = 7.29 (s, 1 H, H-8Ј), 6.65 (s, 2 H,
H-3Ј, H-6Ј), 3.96 (s, 6 H, 2 OCH3Ј), 2.56 (s, 3 H, CH3-2Ј), 2.54 (s,
3 H, CH3-7Ј), 0.46 [s, 9 H, Sn(CH3)3] ppm. 13C NMR (75.5 MHz,
CDCl3): δ = [ppm] = 157.6, 157.5 (C-4Ј, C-5Ј), 144.7 (C-2Ј), 143.2
(C-7Ј), 138.2 (C-4aЈ), 135.7 (C-8Ј), 130.7 (C-1Ј), 122.3 (C-3Ј), 110.7
(C-8aЈ), 108.6 (C-6Ј), 56.7 (OCH3-4Ј), 56.3 (OCH3-5Ј), 28.3 (CH3-
2Ј), 26.2 (CH3-7Ј) ppm. MS (FD+): m/z (%) = 380.4 (100.0) [M
H-2, H-7), 2.31 (s,
(100.6 MHz, [D6]DMSO): δ = 153.8 (C-1, C-8), 136.8 (C-4a), 136.4
6
H, CH3-6, CH3-3) ppm. 13C NMR
(C-3, C-6), 117.5 (C-4, C-5), 111.1 (C-8a), 109.5 (C-2, C-7), 21.4
(CH -3, CH -6) ppm. MS (FD+): m/z (%) = 188.0 (100.0) [M]+.
˙
3
3
C12H12O2 (188.23): calcd. C 76.57, H 6.43; found C 76.34, H 6.65.
IR (ATR): ν = 3734, 3250, 1646, 1626, 1578, 1368, 1340, 1283,
˜
1153, 1081, 1010, 842, 669 cm–1.
1,8-Dimethoxy-3,6-dimethylnaphthalene (9):[5] A suspension of 8
(340 mg, 1.81 mmol, 1.0 equiv.), K2CO3 (1.50 g, 10.9 mmol,
6.0 equiv.), and dimethyl sulfate (210 μL, 2.17 mmol, 1.2 equiv.) in
dry acetone (5 mL) was heated under reflux for 16 h. After cooling
to room temperature, the reaction was stopped by adding a few
milliliters of dilute aqueous NH3, and the mixture was stirred for
15 min. The reaction mixture was neutralized with dilute aqueous
HCl and extracted with Et2O (3ϫ 30 mL). The organic layer was
dried with Na2SO4, and the solvent was removed in vacuo. The
residue was again treated with K2CO3 (1.50 g, 10.9 mmol,
6.0 equiv.) and dimethyl sulfate (210 μL, 2.17 mmol, 1.2 equiv.) in
dry acetone (5 mL) for 16 h under reflux. After cooling to room
temperature, the reaction was stopped by adding a few milliliters
of dilute aqueous NH3, and the mixture was stirred for 15 min.
After neutralization with dilute aqueous HCl, the mixture was ex-
tracted with Et2O (3ϫ 30 mL). The combined organic layers were
(
120Sn)]+, 378.4 (68.7) [M (118Sn)]+, 376.4 (40.9) [M (116Sn)]+. IR
˙ ˙ ˙
(ATR): ν = 2916, 2839, 1587, 1454, 1364, 1347, 1330, 1257, 1124,
˜
1105, 827, 771 cm–1.
6522
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6519–6524

Total Synthesis of the Antifungal Natural Product Mollisin
2,2-Dichloro-1-(4,5-dimethoxy-2,7-dimethylnaphthalen-1-yl)-
ethanone (12): On the basis of a procedure outlined by Neu-
mann,[33] a solution of crude 11, synthesized from 10 (2.33 g,
7.91 mmol, 1.0 equiv.), in dry CH2Cl2 (30 mL) was added to AlCl3
(1.58 g, 11.9 mmol, 1.5 equiv.). The reaction mixture was cooled to
–30 °C, and a solution of dichloroacetyl chloride (1.14 mL,
11.9 mmol, 1.5 equiv.) in dry CH2Cl2 (30 mL) was added dropwise.
The reaction mixture was warmed to 25 °C within 16 h and ice
(50 g) was added. The aqueous layer was extracted with CH2Cl2
(2ϫ 50 mL), and the combined organic extract was washed with
ether/EtOAc, 4:1) the title compound (178 mg, 568 μmol, 71%) was
obtained as a yellow, crystalline solid. Rf = 0.35 (petroleum ether/
EtOAc, 4:1), m.p. (petroleum ether/EtOAc, 5:1, decomp.): 198.3–
199.7 °C. 1H NMR, NOESY (400 MHz, CDCl3): δ = 12.08 (s, 1
4
H, OH), 7.18 (s, 1 H, H-6), 6.84 (q, J = 1.6 Hz, 1 H, H-3), 6.31
4
(s, 1 H, CHCl2), 2.42 (s, 3 H, CH3-7), 2.17 (d, J = 1.6 Hz, 3 H,
CH3-2) ppm. 13C NMR, HMBC, HMQC (100.6 MHz, CDCl3): δ
= 192.0 (COCHCl2), 189.4 (C-4), 186.2 (C-1), 162.3 (C-5), 148.8
(C-2), 146.5 (C-7), 136.2 (C-3), 130.4 (C-8), 130.2 (C-8a), 126.2 (C-
6), 112.9 (C-4a), 71.0 (CHCl2), 20.7 (CH3-7), 16.6 (CH3-2) ppm.
half-saturated aqueous NaHCO3 (2 ϫ 40 mL) and water (1 ϫ MS (FD+): m/z (%) = 312.4 (100.0) [M]+. C H Cl O (313.14):
˙
14 10
2
4
50 mL) and then dried with Na2SO4. The solvent was removed
in vacuo. After purification by column chromatography on silica
gel (petroleum ether/EtOAc, 20:1), the title compound (2.12 g,
6.50 mmol, 73% over two steps from 7) was obtained as a yellow,
crystalline solid. Rf = 0.35 (cyclohexane/EtOAc, 2:1), m.p. 109.0–
111.0 °C. 1H NMR (400 MHz, CDCl3): δ = 6.76 (s, 1 H, H-8Ј),
6.67 (s, 1 H, H-6Ј), 6.61 (s, 1 H, H-3Ј), 6.46 (s, 1 H, CHCl2), 3.99
(s, 3 H, OCH3-4Ј), 3.96 (s, 3 H, OCH3-5Ј), 2.45 (s, 3 H, CH3-2Ј),
2.45 (s, 3 H, CH3-7Ј) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
193.0 (CO), 159.3 (C-4Ј), 157.8 (C-5Ј), 139.0 (C-2Ј), 137.3 (C-7Ј),
134.3 (C-8aЈ), 124.3 (C-1Ј), 116.0 (C-8Ј), 114.0 (C-4aЈ), 108.3 (C-
6Ј), 107.4 (C-3Ј), 70.7 (CHCl2), 56.4 (OCH3), 56.3 (OCH3), 22.3
(CH3-7Ј), 20.6 (CH3-2Ј) ppm. MS (FD+): m/z (%) = 326.3 (100.0)
[M (2 35Cl)]+ , 328.3 (65.1) [M (35Cl,37Cl)]+ , 330.3 (9.4) [M
calcd. C 53.70, H 3.22; found C 53.41, H 3.35. IR (ATR): ν = 3330,
˜
2925, 1723, 1644, 1613, 1460, 1371, 1287, 1123, 668 cm–1.
CCDC-945345 (for 1), -945346 (for 4), -945347 (for 6a), and
-945348 (for 12) contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1D and 2D NMR spectra for all new com-
pounds.
Acknowledgments
˙
˙
(237Cl)]+. C H Cl O (327.21): calcd. C 58.73, H 4.93; found C
˙
16 16
2
3
The authors thank the Rhineland-Palatinate Center for Integrated
Natural Product Research for financial support and the Institute
for Biotechnology and Drug Research (IBWF, Kaiserslautern) for
an authentic sample of mollisin. The crystallographic analyses per-
formed by Dr. D. Schollmeyer (Mainz) are gratefully acknowl-
edged.
58.92, H 5.01, IR (ATR): ν = 3425, 3001, 2933, 2849, 1713, 1625,
˜
1594, 1466, 1390, 1344, 1270, 1201, 1114, 1086, 1042, 829, 801,
738 cm–1.
8-(2,2-Dichloroacetyl)-5-methoxy-2,7-dimethylnaphthalene-1,4-di-
one (4): On the basis of a procedure outlined by Shinnaka,[24]
a
solution of 12 (380 mg, 1.17 mmol) and potassium ferricyanide
(800 μg, 23.0 μmol, 2 mol-%) in a mixture of AcOH/water (10:1,
5 mL) was heated to 45 °C. H2O2 (35 wt.-% in water, 380 μL,
4.43 mmol, 3.8 equiv.) was added to the solution over a period of
1 h. After stirring for 1 h, the reaction was quenched with water
(20 mL) and extracted with Et2O (2ϫ 20 mL). The combined or-
ganic phase was washed with saturated aqueous NaHCO3 (2ϫ
20 mL) and water (1ϫ 20 mL) and dried with Na2SO4. The solvent
was removed in vacuo. After recrystallization from MeOH, the title
compound (202 mg, 617 μmol, 53%) was obtained as an orange,
crystalline solid. Rf = 0.30 (cyclohexane/EtOAc, 1:1), m.p. (MeOH,
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1
decomp.): 162.8–164.2 °C. H NMR (400 MHz, CDCl3): δ = 7.18
(s, 1 H, H-6), 6.73 (s, 1 H, H-3), 6.30 (s, 1 H, CHCl2), 4.01 (s, 3 H,
OCH3), 2.46 (s, 3 H, CH3-7), 1.96 (s, 3 H, CH3-2) ppm. 13C NMR,
HMBC, HMQC (100.6 MHz, CDCl3): δ = 191.9 (Cl2HCCO), 187.1
(C-1), 183.3 (C-4), 160.4 (C-5), 144.8 (C-7), 144.6 (C-2), 138.5 (C-
3), 133.0 (C-8a), 129.4 (C-8), 120.0 (C-6), 117.7 (C-4a), 71.3
(CHCl2), 56.8 (OCH3), 20.9 (CH3-7), 15.8 (CH3-2) ppm. MS
(ESI+): m/z (%) = 348.9 (100.0) [M – 235Cl + Na]+, 351.0 (52.8)
[M – 35Cl,37Cl + Na]+. C15H12Cl2O4 (327.16): C 55.07, H 3.70;
found C 54.71, H 4.04, IR (ATR): ν = 1719, 1655, 1587, 1307,
˜
1260, 1218, 1077, 731 cm–1.
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AlCl3 (530 mg, 3.97 mmol, 5.0 equiv.) was suspended in dry
CH2Cl2 (10 mL). The suspension was stirred for 5 min. A mixture
of ice water/NaCl/conc. HCl (1:1, 10 mL) was added at 0 °C, and
the reaction mixture was extracted with Et2O (3ϫ 25 mL). The
combined organic layer was washed with saturated aqueous
NaHCO3 (1ϫ 20 mL) and water (1ϫ 20 mL) and then dried with
MgSO4. The solvent was removed by distillation in vacuo. After
purification by column chromatography on silica gel (petroleum
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Eur. J. Org. Chem. 2013, 6519–6524
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6523

S. Schwolow, H. Kunz, J. Rheinheimer, T. Opatz
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Received: July 22, 2013
Published Online: August 23, 2013
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Eur. J. Org. Chem. 2013, 6519–6524