Synthesis of the BCD-ring substructure of granaticin A

Article abstract of DOI:10.1002/ejoc.201201104

The BCD-ring substructure of granaticin A was synthesised following a new approach for the construction of the naphthoquinone moiety. The 2-oxabicyclo[2.2.2]oct-5-ene substructure was accessible stereoselectively using a Sharpless asymmetric dihydroxylation and a diastereoselective ketone reduction in combination with Yoshii's route. The naphthoquinone B-ring was prepared by addition of an aryllithium intermediate to an anhydride followed by a Friedel-Crafts cyclisation mediated by AlCl₃ and Mg(OTf) ₂. The success of the Friedel-Crafts cyclisation relied on the conversion of the ketone-carboxylic acid into a lactone acetal.

Full text of DOI:10.1002/ejoc.201201104

FULL PAPER
DOI: 10.1002/ejoc.201201104
Synthesis of the BCD-Ring Substructure of Granaticin A
Janina Bachmann,[a,b] Christian Mang,[b] Lars Ole Haustedt,[b] Klaus Harms,[a] and
Ulrich Koert*[a]
Keywords: Asymmetric synthesis / Natural products / Oxygen heterocycles / Quinones
The BCD-ring substructure of granaticin A was synthesised
following new approach for the construction of the
naphthoquinone moiety. The 2-oxabicyclo[2.2.2]oct-5-ene
substructure was accessible stereoselectively using
Sharpless asymmetric dihydroxylation and a diastereoselec-
tive ketone reduction in combination with Yoshii’s route. The
naphthoquinone B-ring was prepared by addition of an aryl-
lithium intermediate to an anhydride followed by a Friedel–
Crafts cyclisation mediated by AlCl3 and Mg(OTf)2. The suc-
cess of the Friedel–Crafts cyclisation relied on the conversion
of the ketone-carboxylic acid into a lactone acetal.
a
a
Introduction
The pyrano-naphthoquinone granaticin A (Figure 1) was
named after the red garnet-like crystals that were obtained
after isolation of the natural product from Streptomyces
olivaceus.[1] The structure of granaticin A was elucidated by
UV, IR, and NMR spectroscopic analysis in combination
with ozonolytic degradation, and was confirmed by X-ray
crystallography of the triacetyl-monoiodoacetyl deriva-
tive.[2,3] Some examples of structurally related natural prod-
ucts are known, such as the rhodinoside of granaticin A,
called granaticin B, and dihydro-granaticin.[4,5] Granaticin
A shows antibiotic activity against Gram positive bacte-
ria,[6] antitumor activity in mice with P388 lymphatic leuke-
mia, and cytotoxicity against KB cells (ED50 1.6 μg/mL).[7]
Granaticin A contains a rare 2-oxabicyclo[2.2.2]oct-5-ene
substructure. The only other natural product incorporating Figure 1. Structures of granaticin A, sarubicin A, and nanaomycin
this structural motif is sarubicin A (Figure 1) .[8] As shown
D.
by Floss et al., the biosynthetic origin of the 2-oxabicy-
clo[2.2.2]oct-5-ene structural feature is glucose, which is
converted into 2,6-dideoxy-4-keto-dTDP-glucose and then
attached to the hydroquinone precursor.[9] The pyrano-
lactone substructure of granaticin A is also present in many
other natural products such as nanaomycin D (Figure 1).[10]
Several stereoselective synthetic routes have been devel-
oped for the synthesis of the AB-ring substructure, with
most of them using an oxa-Pictet–Spengler reaction for the
construction of the pyranolactone.[11] The Yoshii group suc-
cessfully achieved the stereoselective synthesis of the 2-oxa-
bicyclo[2.2.2]oct-5-ene substructure that culminated in the
first and only total synthesis of racemic granaticin A,[12]
followed by the synthesis of the enantiomerically pure natu-
ral product.[13] A new stereoselective synthesis of the BCD-
ring substructure of granaticin A is presented in this paper.
Results and Discussion
A comparison between the key step used by Yoshii and
that used in this paper for the construction of the BCD-
ring substructure is shown in Scheme 1. Following Kraus’s
method, Yoshii used a benzannulation[14] of cyanophthalide
2 and Michael acceptor 3 to assemble the molecular skel-
eton of granaticin A (1).[12,13] The presence of the enone in
Michael acceptor 3 allowed the introduction of the lactone
ring to be postponed to the end of the synthesis. Our syn-
[a] Fachbereich Chemie, Philipps-Universität Marburg,
Hans-Meerwein-Straße, 35043 Marburg, Germany
Fax: +49-6421-2825677
E-mail: koert@chemie.uni-marburg.de
Homepage: www.uni-marburg.de/fb15/ag-koert
[b] AnalytiCon Discovery GmbH,
Hermannswerder Haus 17, 14473 Potsdam, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201104.
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Synthesis of the BCD-Ring Substructure of Granaticin A
thetic plan involved the addition of an organometallic inter- gave alcohol 12 with 97:3 diastereoselectivity.[19] The use of
mediate generated from bromide 4 to anhydride 5. A subse- L-Selectride or borane–THF complex gave similarly good
quent Friedel–Crafts type cyclisation would lead to the clo- selectivities in this reduction step, whereas the use of
sure of the B-ring. Regioselective attack on unsymmetrical NaBH4 in MeOH led to a ratio of only 86:14.
anhydrides has precedent in related systems.[15] The identifi-
cation of suitable conditions for the bromine–metal ex-
change and the investigation of the annulation with a sym-
metrical anhydride are important steps towards the realisa-
tion of our strategy, and the results are reported here.
Scheme 1. Different key steps for the construction of the granaticin
skeleton.
Enantiopure aryl bromide 4 was synthesised from
bromotetralone 6, which is available from p-dimethoxy-
benzene and succinic anhydride in 52% yield over six steps
(Scheme 2).[16] The reaction of ketone 6 with (1-ethoxyvi-
nyl)lithium,[12] which was transmetallated to the less basic
organocerium reagent, provided the corresponding tertiary
alcohol, which gave, after acid cleavage of the enol ether tBuLi, THF, –78 °C, CeCl3, 0 °C, 6 at –78 °C; 7: 87%, and 8: 10%;
and elimination of water, α,β-unsaturated ketone 7, together
with β,γ-unsaturated ketone 8. Compound 7 could be ob-
tained in pure form by crystallisation. The by-product (i.e.,
Scheme 2. Stereoselective synthesis of aryl bromide 15 and X-ray
structure of ester 10. Reagents and conditions: a) ethyl vinyl ether,
b) DBU, CH2Cl2, 40 °C; c) (DHQD)2Pyr, K3Fe(CN)6, NaHCO3,
methanesulfonamide, K2OsO4·2H2O, tBuOH/H2O, 0 °C, 3 d, 96%
(76% ee), after recrystallisation from EtOAc/n-heptane, 79%, (95%
ee); d) (S)-(+)-α-acetoxyphenylacetic acid, DMAP, DCC, CH2Cl2,
8) was converted into 7 by treatment with DBU (1,8-diaza-
bicycloundec-7-ene). Sharpless asymmetric dihydroxylation
of alkene 7 with commercially available AD-mix-β gave diol
9, with only 21% ee.[17] The enantioselectivity could be in-
creased to 76% ee by using (DHQD)2Pyr as a chiral ligand.
After recrystallisation of diol 9, enantiopure material (95%
ee) was obtained. The enantioselectivity of the dihydrox-
20 °C, 79%; e) acetone, cat. H2SO4, reflux, 97%; f) DIBAl-H (di-
isobutylaluminium hydride), THF, –78 °C, 93%; g) HCl (10% in
MeOH), 20 °C, 14 h, 86%; h) NBS, AIBN, CCl4, 45 min, reflux;
i) AgClO4, THF, 20 °C, 15 min, 87% over two steps; j) pTsOH, 2,2-
dimethoxypropane, THF, 20 °C, 91%.
Upon cleavage of the acetonide under acidic conditions,
ylation was determined by NMR analysis of the (S)-O-acet- triol 13 was obtained. Benzylic bromination of 13 according
ylmandelic ester (i.e., 10) derived from compound 9. The to Yoshii[12] and subsequent AgI-initiated intramolecular
absolute configuration of compound 10 was determined by Williamson reaction resulted in the formation of the desired
X-ray crystallography (Scheme 2).[18] After conversion of 2-oxabicyclo[2.2.2]oct-5-ene derivative (i.e., 14). After acet-
diol 9 into acetonide 11, a substrate-controlled reduction of onide-protection of the diol, aryl bromide 15 was available
the ketone group was achieved. DIBAl-H in THF at –78 °C for the intended bromine–metal exchange reaction.
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FULL PAPER
Cyclohexyl maleic anhydride 16 was chosen as substrate
The formation of compound 22 indicates the instability
for the coupling studies (Scheme 3).[20] Bromine–lithium ex- of the 2-oxabicyclo[2.2.2]oct-5-ene substructure under
change of aryl bromide 15 was not straightforward, since acidic conditions. Both aryl methyl ethers were cleaved un-
the high reactivity of the aryllithium species led to a con- der the cyclisation conditions. If the cyclisation occurs after
siderable amount of the protonated by-product. The opti- the ether cleavage, an intramolecular acyl shift followed by
mal reaction conditions for the bromine–lithium exchange a Fries rearrangement could also give a mechanistic expla-
were found to be a reaction time of 10 min at –60 °C. After nation for the formation of 21. Attempts to conduct the
addition of anhydride 15, a mixture of hemiacetal 17 and Friedel–Crafts cyclisation under protic conditions (HF,
ketocarbocylic acid 18 was obtained in 64% yield. Transme- H2SO4, H3PO4, TFA, Nafion-H) were unsuccessful, and led
tallation of the aryllithium intermediate to give a magne- to elimination side-reactions in the cyclohexyl ring.[22]
sium species did not improve the yield (55%). Treatment of
The mixture of hemiacetal 17 and ketocarbocylic acid 18
the 17/18 mixture with oxalyl chloride followed by the ad- could be converted into acetate 23, which proved to be a
dition of methanol gave, via the keto-acid chloride, mixed suitable precursor for the Friedel–Crafts reaction
acetal 19 (as a 1:1 epimeric mixture). The acetonide was (Scheme 4). The use of 5 equiv. AlCl3 in combination with
cleaved to reveal the diol in this step. Attempts to close 2 equiv. Mg(OTf)2 in 1,3-dichlorobenzene was found to give
the B-ring to form the naphthoquinone by a Friedel–Crafts optimal results for the formation of naphthoquinone 21.
reaction were unsuccessful in the presence of the free diol.
Therefore, monoacetate 20 was prepared and used for the
cyclisation studies. The Friedel–Crafts cyclisation[21] of
mixed acetal 20 with AlCl3 in nitromethane at 60 °C pro-
duced the desired naphthoquinone (i.e., 21) together with
anthraquinone 22.
Scheme 4. Synthesis of naphthoquinone 21. Reagents and condi-
tions: a) p-TsOH, CH2Cl2, 20 °C, 3 h, then Ac2O, pyridine, DMAP,
20 °C, 99%; b) AlCl3, Mg(OTf)2, 1,3-dichlorobenzene, 60 °C,
30 min, 31%.
Conclusions
In summary, the synthesis of the BCD-ring substructure
of granaticin A was accomplished. The 2-oxabicyclo[2.2.2]-
oct-5-ene substructure was stereoselectively accessible using
a Sharpless asymmetric dihydroxylation, a diastereoselec-
tive ketone reduction, and a benzylic bromination/William-
son reaction, as implemented by Yoshii. The naphthoquin-
one moiety was formed by reaction of an aryllithium inter-
mediate prepared by bromine–lithium exchange and a sym-
metrical anhydride, followed by a Friedel–Crafts cyclisation
mediated by AlCl3 and Mg(OTf)2. To achieve a successful
Friedel–Crafts cyclisation, it was ncessary to convert the
ketone-carboxylic acid into a lactone acetal. This new route
should be applicable to the synthesis of granaticin A as well
as its derivatives, which would enable structure–activity re-
lationship studies and allow the exploration of this intri-
guing natural product scaffold.
Experimental Section
General Methods: All air-sensitive reactions were carried out under
argon with anhydrous solvents in dried glassware. All solvents were
dried according to standard procedures, or were bought dry
(Sigma–Aldrich). Reagents were used as purchased. Flash
chromatography was performed on silica gel (0.04–0.063 mm/Fluka
Analytical). Analytical TLC was carried out on aluminium-coated
silica gel 60 F254. Optical rotations were measured at the sodium
D line with a 1 dm path length and 1 mL cell. NMR spectra were
Scheme 3. Synthesis of naphthoquinone 21. Reagents and condi-
tions: a) nBuLi, THF, –60 °C, 10 min, then 16, –78 °C, 20 min,
64%; b) oxalyl chloride, 20 °C, then MeOH, 0 °C, 74%; c) Ac2O,
DMAP, 20 °C, 91%; d) AlCl3, MeNO2, 60 °C, 30 min; 21: 21%,
and 22: 18%.
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Synthesis of the BCD-Ring Substructure of Granaticin A
recorded with Bruker DPX-400 or DRX-500 spectrometers using
partially deuterated solvents as internal standards. Coupling con-
stants (J) are given in Hz, and chemical shifts (δ) in ppm. Multi-
plicities are denoted as follows: s = singlet, d = doublet, t = triplet,
m = multiplet. IR spectra were recorded with a Bruker IFS 200
spectrometer. Mass spectra were recorded with a Qstar pulstar I
instrument from Applied Biosystems, or on a Finnigan LTQ-FT
instrument from Thermo Fisher Science.
28.40 mmol), K2CO3 (3.93 g, 28.40 mmol), methanesulfonamide
(900 mg, 9.46 mmol), and K2OsO4·2H2O (35 mg, 0.10 mmol) were
added to a stirred solution of enone 7 (2.94 g, 9.46 mmol) in H2O
(90 mL) and tBuOH (90 mL) at 0 °C. The reaction mixture was
stirred for 3 d at a constant temperature. After completion of the
reaction, NaHSO4 (10 mg) and H2O (50 mL) were added. The
aqueous layer was extracted with EtOAc (5ϫ 100 mL), and the
combined organic layers were washed with an aq. NaHCO3 solu-
tion and dried with Na2SO4, and the solvents were removed under
reduced pressure. The crude residue was purified by column
chromatography on silica gel (EtOAc/n-hexane, 0:1 to 1:1) to give
diol 9 (13.14 g, 9.08 mmol, 96%, 76% ee) as a colourless solid.
Diol 9 was crystallised from EtOAc/n-heptane to give the racemic
compound as colourless crystals (628.4 mg, 1.82 mmol, 19%, m.p.
rac-9: 159–160 °C), and the enantiomerically pure compound in the
filtrate (2.47 g, 7.16 mmol, 79%, 95% ee). Data for 9: m.p. 67–
69 °C. Rf = 0.31 (EtOAc/n-hexane, 1:1). [α]2D4 = +0.24 (c = 1.03,
1-(7-Bromo-5,8-dimethoxy-3,4-dihydronaphthalen-1-yl)ethanone (7)
and 1-(7-Bromo-5,8-dimethoxy-1,4-dihydronaphthalen-1-yl)ethanone
(8): Ethyl vinyl ether (29.26 g, 405.6 mmol) was dissolved in dry
THF (100 mL) under an atmosphere of argon. The solution was
cooled to –78 °C, and tBuLi (179 mL, 304.4 mmol) was added. The
yellow mixture was stirred for 1 h at 0 °C until a colourless solution
was observed. This solution was poured into a suspension of CeCl3
(50.00 g, 202.8 mmol) in dry THF (150 mL) at –78 °C, which had
been stirred for 12 h under an atmosphere of argon beforehand.
Finally, bromotetralone 6 (6.20 g, 21.74 mmol) in dry THF (50 mL)
was added to the suspension, and the resulting mixture was stirred
for 2 h at –78 °C. The reaction was stopped by the addition of H2O
(50 mL), and the mixture was stirred for 10 min at room tempera-
ture, filtered, and washed with EtOAc (3ϫ 200 mL). The organic
phase was washed with HCl (5% aq.) and dried with Na2SO4, and
the solvents were removed under reduced pressure. The resulting
oil was dissolved in EtOAc (10 mL), and HCl (10% aq.; 180 mL)
was added. The mixture was heated at reflux for 36 h, and was
then allowed to cool to room temperature. The aqueous phase was
extracted with EtOAc (5ϫ 100 mL), and the combined organic ex-
tracts were washed with NaHCO3 solution and dried with Na2SO4,
and the solvents were removed under reduced pressure. The crude
residue was purified by column chromatography on silica gel
(EtOAc/n-hexane, 1:9) to give an isomeric mixture, which could
then be separated by crystallisation (EtOAc/n-heptane) to give en-
one 7 (5.89 g, 18.92 mmol, 87%) as colourless crystals (m.p. 128–
129 °C), and a mixture of 7 and 8 (9:1, 0.68 g, 2.17 mmol, 10%) as
colourless oil. Data for 7: Rf = 0.76 (EtOAc/n-hexane, 1:1). IR
CHCl ). IR (film): ν = 3411, 2940, 2839, 1710, 1577, 1466, 1229,
˜
3
1056, 1017, 952, 907, 768, 704 (m) cm–1 1H NMR (500 MHz,
.
CDCl3): δ = 1.93–2.08 (m, 2 H, 3-H), 2.13 (s, 3 H, COCH3), 2.53
(ddd, J = 6.6, 12.4, 18.4 Hz, 1 H, 4-H), 2.99 (ddd, J = 1.5, 5.6,
18.2 Hz, 1 H, 4-H), 3.68 (s, 3 H, 8-OMe), 3.81 (s, 3 H, 5-OMe),
3.89 (dd, J = 3.0, 12.1 Hz, 1 H, 2-H), 4.95 (s, 1 H, OH), 6.99 (s, 1
H, 6Ar-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 23.1 (C-4), 23.4
(COCH3), 26.2 (C-3), 56.0 (5-OMe), 61.6 (8-OMe), 71.2 (C-2), 78.8
(C-1), 114.4 (CAr-7), 115.0 (CAr-6), 127.5 (CAr-4a), 132.2 (CAr-8a),
148.5 (CAr-8), 154.0 (CAr-5), 206.8 (COCH3) ppm. HRMS (ESI):
calcd. for C14H18BrO5 [M + Na]+ 367.0157; found 367.0152.
(1S,2R)-1-Acetyl-7-bromo-1-hydroxy-5,8-dimethoxy-1,2,3,4-tetra-
hydronaphthalen-2-yl (2ЈS)-(Acetyloxy)(phenyl)acetate (10): Diol 9
(25.3 mg, 0.07 mmol) was dissolved in CH2Cl2 (5 mL), and (S)-(+)-
α-acetoxyphenylacetic acid (17.1 mg, 0.09 mmol) and a catalytic
amount of DMAP (ca. 1 mg, 0.12 mmol) were added. The solution
was cooled to 0 °C in an ice-bath, and DCC (18.2 mg, 0.09 mmol)
was added portionwise. The reaction mixture was warmed to room
temp. and was stirred for 14 h. The solid urea was removed by
filtration through silica and washed with EtOAc (2ϫ 10 mL), and
the solvent was removed from the filtrate under reduced pressure.
The crude product was crystallised from EtOAc/n-heptane at –4 °C
to give ester 10 (35.4 mg, 0.07 mmol, 79%) as a colourless solid
(m.p. 186 °C). Rf = 0.56 (EtOAc/n-hexane, 1:1). [α]2D3 = +73.7 (c =
(film): ν = 2959, 2937, 2894, 2826, 1682, 1612, 1458, 1403, 1212,
˜
1
977, 824, 761, 657 cm–1. H NMR (400 MHz, CDCl3): δ = 2.23 (s,
3 H, COCH3), 2.26 (dd, J = 4.9, 7.8 Hz, 2 H, 3-H), 2.67 (t, J =
7.8 Hz, 2 H, 4-H), 3.54 (s, 3 H, 8-OMe), 3.81 (s, 3 H, 5-OMe), 6.43
(t, J = 4.9 Hz, 1 H, 2-H), 7.01 (s, 1 H, 6Ar-H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 20.6 (C-4), 22.1 (COCH3), 28.8 (C-3), 56.2
1.00, CHCl ). IR (film): ν = 3492, 2940, 1754, 1736, 1720, 1216,
˜
3
1040, 739 cm–1. H NMR (500 MHz, CDCl3): δ = 1.81–1.86 (m, 1
1
(5-OMe), 61.8 (8-OMe), 114.5 (CAr-7), 115.4 (CAr-6), 126.0 (CAr
-
H, 3-H), 2.07 (s, 3 H, COCH3), 2.10 (dd, J = 6.1, 12.8 Hz, 1 H, 3-
H) 2.18 (s, 3 H, COOCH3), 2.56 (ddd, J = 6.4, 12.2, 18.6 Hz, 1 H,
4-H), 2.95 (dd, J = 4.9, 18.3 Hz, 1 H, 4-H), 3.66 (s, 3 H, 8-OMe),
3.78 (s, 3 H, 5-OMe), 4.71 (s, 1 H, OH), 5.17 (dd, J = 3.7, 12.2 Hz,
1 H, 2-H), 5.81 (s, 1 H, 2Ј-H), 6.99 (s, 1 H, 6Ar-H), 7.40–7.46 (m,
5 H, 2ЈAr-H, 3ЈAr-H, 4ЈAr-H, 5ЈAr-H, 6ЈAr-H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 20.7 (COOCH3), 21.9 (C-3), 22.7 (C-4),
23.4 (COCH3), 56.0 (5-OMe), 61.7 (8-OMe), 74.1 (C-2Ј), 74.7 (C-
2), 77.7 (C-1), 114.7 (CAr-7), 115.1 (CAr-6), 126.8 (CAr-4a), 127.7
(CAr-4ЈЈ), 129.0 (CAr-3ЈЈ, CAr-5Ј), 129.5 (CAr-2ЈЈ, CAr-6ЈЈ), 131.8
(CAr-8a), 133.4 (C-1ЈЈ), 148.2 (CAr-8), 154.0 (CAr-5), 168.4 (COO),
170.4 (COOCH3), 204.9 (CO) ppm. HRMS (ESI): calcd. for
C24H25BrO8 [M + Na]+ 543.0631; found 543.0629.
4a), 128.2 (CAr-8a), 133.3 (C-2), 140.3 (C-1), 146.8 (CAr-8), 153.2
(CAr-5), 202.7 (COCH3) ppm. HRMS (ESI): calcd. for C14H15BrO3
[M + Na]+ 333.0102; found 333.0097.
1
Data for 8: Rf 0.76 (EtOAc/n-heptane, 1:1). H NMR (400 MHz,
CDCl3): δ = 2.02 (s, 3 H, COCH3), 3.15–3.38 (m, 2 H, 4-H), 3.37
(s, 3 H, OMe), 3.80 (s, 3 H, OMe), 4.47–4.48 (m, 1 H, 1-H), 5.78–
5.81 (m, 1 H, 3-H), 6.07–6.11 (m, 1 H, 2-H), 6.94 (s, 1 H, 6Ar-H)
ppm.
The β,γ-enone (i.e., 8) could be isomerised into enone 7 by adding
CH2Cl2 and DBU (4 equiv.) under an atmosphere of argon. The
solution was stirred at 40 °C overnight. H2O was added to the solu-
tion, and the aqueous phase was extracted with EtOAc (3ϫ
50 mL). The combined organic extracts were washed with brine
and dried with Na2SO4, and the solvents were removed under re-
duced pressure. The crude product was dissolved in a mixture of
EtOAc/n-heptane and cooled to 0 °C to give solid enone 7.
1-[(3aR,9bS)-8-Bromo-6,9-dimethoxy-2,2-dimethyl-4,5-dihydro-
naphtho[1,2-d][1,3]dioxol-9b(3aH)-yl]ethanone (11): Diol 9 (1.04 g,
3.01 mmol) was dissolved in dry acetone (15 mL), and a catalytic
amount of conc. sulfuric acid (0.02 mL, 0.38 μmol) was added
dropwise. The solution was heated under reflux (80 °C) for 3 h.
1Ј-[(1S,2R)-7-Bromo-1,2-dihydroxy-5,8-dimethoxy-1,2,3,4-tetra-
hydro-naphthalen-1-yl]ethanone (9): (DHQD)2Pyr (837 mg, After cooling to room temperature, NaHCO3 (saturated aq.;
0.95 mmol), K3Fe(CN)6 (9.35 g, 28.40 mmol), NaHCO3 (2.39 g, 50 mL) was added. The aqueous phase was extracted with EtOAc
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J. Bachmann, C. Mang, L. O. Haustedt, K. Harms, U. Koert
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(5 ϫ 30 mL). The combined organic extracts were washed with
brine and dried with Na2SO4, and the solvents were removed under
reduced pressure. The crude residue was purified by column
chromatography on silica gel (EtOAc/n-hexane, 1:4) to give pro-
tected diol 11 (1.12 g, 2.91 mmol, 97%) as a colourless solid (m.p.
122 °C). Rf = 0.81 (EtOAc/n-hexane, 1:1). [α]2D4 = –136.2 (c = 1.00,
4.19 (dd, J = 3.5, 8.6 Hz, 1 H, 2-H), 4.78 (q, J = 6.6 Hz, 1 H, 1Ј-
H), 6.95 (s, 1 H, 6Ar-H) ppm. 13C NMR (125 MHz, CDCl3): δ =
18.5 (CH3), 21.2 (C-4), 25.0 (C-3), 55.9 (5-OMe), 62.5 (8-OMe),
69.2 (C-2), 73.8 (C-1Ј), 76.8 (C-1), 114.1 (CAr-6), 115.2 (CAr-7),
127.6 (CAr-4a), 133.5 (CAr-8a), 150.5 (CAr-8), 153.4 (CAr-5) ppm.
HRMS (ESI): calcd. for C14H19BrO5 [M + Na]+ 369.0314; found
369.0314.
CHCl ). IR (film): ν = 2979, 2940, 1713, 1579, 1463, 1225, 1080,
˜
3
1018, 653 cm–1. H NMR (500 MHz, CDCl3): δ = 1.13 (s, 3 H, 2-
1
(1R,3R,4S,9R)-6-Bromo-5,8-dimethoxy-9-methyl-2,3-dihydro-1,4-
(epoxymethano)naphthalene-3,4(1H)-diol (14): Triol 13 (828 mg,
2.39 mmol) was dissolved in dry CCl4 (30 mL), and NBS (510 mg,
2.87 mmol) and a catalytic amount of AIBN (5 mg, 0.03 mmol)
were added. The solution was heated under reflux for 45 min. The
solution was cooled to 0 °C, and was washed with NaHSO3 (1%
aq.; 20 mL) and brine (20 mL). The aqueous phases were extracted
with CH2Cl2 (2ϫ 20 mL). The combined organic phases were dried
with Na2SO4, and the solvents were removed under reduced pres-
sure. The crude product was dissolved in dry THF (10 mL), and
dry AgClO4 (495 mg, 2.39 mmol) was added at room temperature
under an atmosphere of nitrogen. The reaction was quenched after
15 min by the addition of brine (20 mL), and the aqueous phase
was extracted with EtOAc (4 ϫ 20 mL). The combined organic
phases were dried with Na2SO4, and the solvents were removed
under reduced pressure. The crude residue was purified by column
chromatography on silica gel (EtOAc/n-heptane, 1:2) to give oxa-
bicyclic diol 14 (722 mg, 2.09 mmol, 87 %) as a colourless solid
(m.p. 62 °C). Rf = 0.37 (EtOAc/n-heptane, 1:1). [α]2D4 = –168.4 (c =
CH3), 1.55 (s, 3 H, 2-CH3), 1.79–1.86 (m, 1 H, 4-H), 2.23 (d, J =
14.0 Hz, 1 H, 4-H), 2.46 (s, 3 H, COCH3), 2.51–2.58 (m, 1 H, 5-
H), 2.80 (dd, J = 3.7, 17.1 Hz, 1 H, 5-H), 3.78 (s, 3 H, 9-OMe),
3.86 (s, 3 H, 6-OMe), 4.20 (d, J = 1.8 Hz, 1 H, 3a-H), 6.91 (s, 1 H,
7Ar-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 16.7 (C-5), 23.2
(C-4), 25.6 (COCH3), 27.1 (2-CH3), 27.7 (2-CH3), 56.0 (6-OMe),
61.6 (9-OMe), 74.7 (C-3a), 85.6 (C-9b), 110.3 (C-2), 113.5 (CAr-8),
114.3 (CAr-7), 127.3 (CAr-5a), 133.7 (CAr-9a), 149.2 (CAr-9), 153.0
(CAr-6), 209.5 (COCH3) ppm. HRMS (ESI): calcd. for C17H21BrO5
[M + Na]+ 407.0470; found 407.0473.
(1ЈR)-1-[(3aR,9bR)-8-Bromo-6,9-dimethoxy-2,2-dimethyl-4,5-di-
hydronaphtho[1,2-d][1,3]dioxol-9b(3aH)-yl]ethanol (12): Ketone 11
(1.40 g, 3.63 mmol) was dissolved in dry THF (80 mL). The solu-
tion was cooled to –78 °C, and DIBAl-H (54.40 mL, 54.40 mmol)
was added by syringe, keeping the temperature below –70 °C. The
mixture was stirred for 1 h at constant temperature. The reaction
was stopped by the addition of H2O (5 mL) with vigorous stirring
at 0 °C. The ice-bath was removed, and the reaction mixture was
warmed to room temperature. The solid was removed by filtration,
and washed with EtOAc (5ϫ 20 mL). The solvent of the filtrate
was removed under reduced pressure to give alcohol 12 (1.36 g,
3.52 mmol, 97%) as a colourless solid in sufficient purity for the
next step. An analytically pure sample was obtained by column
chromatography on silica gel (EtOAc/n-hexane, 1:4) to give the
product as a yellow solid in 93% yield (m.p. 92–93 °C). Rf = 0.36
(EtOAc/n-hexane, 1:4). [α]2D4 = +49.8 (c = 1.09, CHCl3). IR (film):
0.95, CHCl ). IR (film): ν = 3448, 2970, 2933, 2887, 1582, 1474,
˜
3
1220, 1039, 813, 749 cm–1. H NMR (400 MHz, CDCl3): δ = 0.85
1
(d, J = 6.1 Hz, 3 H, 9-CH3), 1.43 (dt, J = 1.8, 1.9, 14.5 Hz, 1 H,
2endo-H), 2.69 (ddd, J = 3.8, 8.7, 14.3 Hz, 1 H, 2exo-H), 3.76 (q, J
= 6.01 Hz, 1 H, 9-H), 3.79 (s, 3 H, 8-OMe), 3.93 (s, 3 H, 5-OMe),
4.00 (dd, J = 2.3, 8.8 Hz, 1 H, 3-H), 5.12 (dd, J = 1.8, 3.8 Hz, 1
H, 1-H), 7.03 (s, 1 H, 7Ar-H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 16.7 (9-CH3), 37.1 (C-2), 56.1 (8-OMe), 62.7 (C-1), 63.3 (5-
ν = 3482, 2983, 2938, 1574, 1463, 1394, 1253, 1226, 1207, 857 cm–1.
OMe), 70.7 (C-3), 72.5 (C-9), 79.5 (C-4), 114.9 (CAr-7), 116.3 (CAr-
˜
1H NMR (400 MHz, CDCl3): δ = 0.91 (d, J = 7.1 Hz, 3 H, CHOH-
6), 127.5 (CAr-8a), 128.4 (CAr-4a), 149.3 (CAr-5), 149.9 (CAr-8)
CH3), 1.12 (s, 3 H, 2-CH3), 1.47 (s, 3 H, 2-CH3), 1.83–1.91 (m, 1
ppm. HRMS (ESI): calcd. for C14H17BrO5 [M + Na]+ 367.0157;
H, 4-H), 2.26–1.31 (m, 1 H, 4-H), 2.55 (m, 1 H, 5-H), 2.84 (dd, J found 367.0153.
= 4.6, 17.2 Hz, 1 H, 5-H), 3.78 (s, 3 H, 9-OMe), 3.82 (s, 3 H, 6-
(3aR,5S,9bR,10R)-8-Bromo-6,9-dimethoxy-2,2,10-trimethyl-4,5-di-
OMe), 4.64 (s, 1 H, 3a-H), 4.97 (q, J = 7.1 Hz, 1 H, 1Ј-H), 6.95 (s,
1 H, 7Ar-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 17.4 (CHOH-
CH3, C-5), 24.1 (C-4), 27.4 (2-CH3), 28.2 (2-CH3), 55.9 (6-OMe),
62.0 (9-OMe), 66.8 (C-1Ј), 71.5 (C-3a), 84.3 (C-9b), 108.0 (C-2),
114.2 (CAr-8), 115.6 (CAr-7), 127.4 (CAr-5a), 132.4 (CAr-9a), 150.7
(CAr-9), 153.0 (CAr-6) ppm. HRMS (ESI): calcd. for C17H23BrO5
[M + Na]+ 409.0627; found 409.0623.
hydro-3aH-5,9b-(epoxymethano)naphtho[1,2-d][1,3]dioxole (15):
Diol 14 (474 mg, 1.37 mmol) and pTsOH (7.10 mg, 0.04 mmol)
were dissolved in dry THF (20 mL). The solution was cooled to
0 °C, and 2-methoxypropane (347 mg, 4.81 mmol) was added. The
reaction mixture was stirred at room temperature for 12 h, and then
the solution was treated with NaHCO3 (saturated aq.; 50 mL). The
aqueous phase was extracted with EtOAc (4ϫ 20 mL), and the
combined organic extracts were washed with brine, and dried with
(1R,2R)-7-Bromo-1[(1ЈR)-1-hydroxyethyl]-5,8-dimethoxy-1,2,3,4-
tetrahydronaphthalene-1,2-diol (13): Alcohol 12 (679 mg, Na2SO4. The solvents were removed under reduced pressure. The
1.97 mmol) was dissolved in HCl (10% in MeOH; 15 mL), and crude residue was purified by chromatography on silica gel (EtOAc/
was stirred for 14 h at room temperature. NaHCO3 (saturated aq.; n-heptane, 1:9) to give bromide 15 (477 mg, 1.24 mmol, 91%) as a
50 mL) was added slowly to the reaction mixture at 0 °C. The aque-
ous phase was extracted with EtOAc (5ϫ 50 mL). The combined
organic extracts were washed with brine (50 mL) and dried with
Na2SO4, and the solvents were removed under reduced pressure.
The remaining crude product was purified by column chromatog-
raphy on silica gel (EtOAc/n-heptane, 0:1 to 1:1) to give triol 13
(565 mg, 1.69 mmol, 86%) as a colourless solid (m.p. 124–125 °C).
Rf = 0.30 (EtOAc/n-heptane, 1:1). [α]2D4 = +373.9 (c = 1.06, CHCl3).
colourless solid (m.p. 50–52 °C). Rf = 0.69 (EtOAc/n-heptane, 1:1).
[α]2D3 = +5.8 (c = 1.38, CHCl ). IR (film): ν = 2987, 2934, 2901,
˜
3
2887, 1473, 1291, 219, 1115, 1045, 991, 839, 757 cm–1. 1H NMR
(400 MHz, [D4]methanol): δ = 0.74 (d, J = 6.6 Hz, 3 H, 10-CH3),
1.38 (dd, J = 6.3, 12.9 Hz, 1 H, 4endo-H), 1.52 (s, 3 H, 2-CH3), 1.56
(s, 3 H, 2-CH3), 2.69 (ddd, J = 5.1, 9.1, 14.2 Hz, 1 H, 4exo-H), 3.73
(s, 3 H, 6-OMe), 3.81 (s, 3 H, 9-OMe), 4.00 (q, J = 6.4 Hz, 1 H,
10-H), 4.30 (dd, J = 6.1, 9.1 Hz, 1 H, 3a-H), 5.19 (d, J = 5.1 Hz,
1 H, 5-H), 7.20 (s, 1 H, 7Ar-H) ppm. 13C NMR (125 MHz, [D4]-
methanol): δ = 18.9 (10-CH3), 27.0 (2-CH3), 27.0 (2-CH3), 34.2
IR (film): ν = 3364, 2936, 2837, 1573, 1461, 1422, 1223, 959, 890,
˜
1
819, 711 (m) cm–1. H NMR (400 MHz, CDCl3): δ = 0.99 (d, J =
6.6 Hz, 3 H, CH3), 1.25 (br. s, 1 H, OH), 1.81–1.95 (m, 2 H, 3-H), (C-4), 56.7 (6-OMe), 62.0 (9-OMe), 65.4 (C-5), 78.2 (C-3a), 78.6
2.43 (ddd, J = 6.3, 8.3, 18.2 Hz, 1 H, 4-H), 2.87 (dt, J = 6.1,
18.2 Hz, 1 H, 4-H), 3.78 (s, 3 H, 5-OMe), 3.94 (s, 3 H, 8-OMe),
(C-10), 83.6 (C-9b), 115.3 (C-2), 115.9 (CAr-7), 119.9 (CAr-8),
129.3 (CAr-5a), 130.6 (CAr-9a), 149.8 (CAr-6), 150.3 (CAr-9) ppm.
6566
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6562–6569

Synthesis of the BCD-Ring Substructure of Granaticin A
HRMS (ESI): calcd. for C17H21BrO5 [M + Na]+ 407.0470; found
407.0464.
7), 128.3 (CAr-4a), 128.6 (CAr-6), 129.3 (CAr-8a), 129.4 (C-7aЈ),
149.7 (CAr-8), 150.6 (CAr-5), 160.5 (C-3aЈ), 171.4 (C-1Ј) ppm. Rf
(diastereomer 2) = 0.09 (EtOAc/n-hexane, 1:1). 1H NMR
(500 MHz, CDCl3, diastereomer 2): δ = 0.88 (d, J = 6.1 Hz, 3 H,
9-CH3), 1.39 (d, J = 14.15 Hz, 1 H, 2-H), 1.60–1.72 (m, 5 H, 4Ј-H,
5Ј-H, 6Ј-H), 2.16–2.19 (m, 1 H, 7Ј-H) 2.33 (m, 2 H, 6Ј-H), 2.67–
2.74 (m, 1 H, 2-H), 3.33 (s, 3 H, OMe), 3.78–3.80 (m, 1 H, 9-H),
3.77 (s, 3 H, OMe), 3.82 (s, 3 H, OMe), 3.97 (m, 1 H, 3-H), 5.16
(br. s, 1 H, 1-H), 5.44 (s, 1 H, OH), 7.18 (s, 1 H, 7Ar-H) ppm. 13C
NMR (125 MHz, CDCl3, diastereomer 2): δ = 17.0 (9-CH3), 20.0
(C-6Ј), 21.5 (C-5Ј), 21.6 (C-4Ј) 22.6 (C-7Ј), 37.2 (C-2), 50.6 (OMe),
56.0 (OMe), 62.7 (C-1), 66.0 (OMe), 71.3 (C-3), 72.5 (C-9), 79.6
(C-4), 106.9 (C-3Ј), 109.7 (C-7), 128.3 (CAr-4a), 128.9 (CAr-6), 129.3
(CAr-8a), 129.7 (C-7aЈ), 149.5 (CAr-8), 150.9 (CAr-5), 161.3 (C-3aЈ),
171.3 (C-1Ј) ppm. HRMS (ESI): calcd. for C23H28O8 [M + Na]+
455.1682; found 455.1682.
3-[(3aR,5R,9bS,10R)-6,9-Dimethoxy-2,2,10-trimethyl-4,5-dihydro-
3aH-5,9b-(epoxymethano)naphtho[1,2-d][1,3]dioxol-8-yl]-3Ј-hydroxy-
4Ј,5Ј,6Ј,7Ј-tetrahydro-2Ј-benzofuran-1(3H)-one (17) and
(3aR,5R,9bS,10R)-2[[6,9-Dimethoxy-2,2,10-trimethyl-4,5-dihydro-
3aH-5,9b-(epoxymethano)naphtho[1,2-d][1,3]dioxol-8-yl]carbonyl]-
cyclohex-1Ј-ene-1Ј-carboxylic Acid (18): Bromide 15 (1.31 g,
3.40 mmol) was dissolved in dry THF (50 mL) under an atmo-
sphere of argon. The solution was cooled to –78 °C, and nBuLi
(1.63 mL, 4.08 mmol) was added. After 4 min, the solution was
warmed to –60 °C for 4 min, and was then cooled back down to
–78 °C. A solution of anhydride 16 (621 mg, 4.08 mmol) in dry
THF (10 mL) was added quickly. After stirring for 30 min, the
solution was warmed to room temperature and was poured into a
sat. aq. NH4Cl solution. The aqueous phase was extracted with
EtOAc (5ϫ 20 mL). The combined organic extracts were washed
with brine, dried with Na2SO4, and filtered, and the solvents were
evaporated under reduced pressure. The crude residue was purified
by chromatography on silica gel (EtOAc/n-heptane, 0:1 to 1:1) to
give a mixture acid 17 and lactone 18 (1.01 g, 2.19 mmol, 64%) as
a colourless oil. Rf = 0.41 (EtOAc/n-hexane, 1:1). [α]2D3 = –17.5 (c
(1R,3R,4S,9R)-4-Hydroxy-5,8-dimethoxy-6-(1Ј-methoxy-3-oxo-
1Ј,3Ј,4Ј,5Ј,6Ј,7Ј-hexahydro-2Ј-benzofuran-1Ј-yl)-9-methyl-1,2,3,4-
tetrahydro-1,4-(epoxymethano)naphthalen-3-yl Acetate (rac-20):
Diol rac-19 (229 mg, 0.50 mmol) was dissolved in Ac2O (3.00 mL)
and pyridine (6.00 mL) at room temperature. A catalytic amount
of DMAP was added, and the solution was stirred overnight. The
solvent was removed under reduced pressure after addition of n-
hexane and the crude product was dissolved in EtOAc (20 mL),
and H2O (30 mL) was added. The organic phase was separated,
and the aqueous phase was extracted with EtOAc (3ϫ 50 mL). The
combined organic extracts were dried with Na2SO4. The solvents
were removed under reduced pressure. The crude residue was puri-
fied by chromatography on silica gel (EtOAc/n-heptane, 1:4) to give
acetate rac-20 (99.7 mg, 0.21 mmol, 91%) as a colourless solid, as
a separable 1:1 mixture of two diastereomers (m.p. 91–93 °C). Rf =
= 1.27, CHCl ). IR (film): ν = 2973, 2933, 1734, 1474, 1383, 1221,
˜
3
1116, 1044, 988, 741, 509 cm–1. 1H NMR (400 MHz, [D4]meth-
anol): δ = 0.81 (d, J = 6.1 Hz, 3 H, CH3), 1.33 (dd, J = 6.4, 13.1 Hz,
1 H, 4-H), 1.47 (s, 3 H, CH3), 1.51 (s, 3 H, CH3), 1.66–2.25 (m, 8
H, 3Ј-H, 4Ј-H, 5Ј-H, 6-H), 2.69 (ddd, J = 4.9, 9.2, 13.1 Hz, 1 H, 4-
H), 3.56 (s, 3 H, OMe), 3.87 (s, 3 H, OMe), 4.01 (q, J = 6.5 Hz, 1
H, 10-H), 4.28 (dd, J = 6.1, 9.2 Hz, 1 H, 3a-H), 5.23 (d, J = 4.9 Hz,
1 H, 5-H), 7.49 (s, 1 H, 7Ar-H) ppm. The acid/lactone mixture
showed a complex 13C NMR spectrum, which was not assigned.
Complete 13C NMR characterisation was possible for the subse-
quent compound 19. HRMS (ESI): calcd. for C25H30O8 [M +
Na]+ 481.1838; found 481.1836.
0.36 (EtOAc/n-heptane, 1:9). IR (film): ν = 3493, 2936, 2860, 1765,
˜
1738, 1473, 1377, 1335, 1235, 1130, 1073, 1046, 1006, 964, 734 (m)
1
cm–1. H NMR (400 MHz, CDCl3, diastereomer 1): δ = 0.70 (d, J
= 6.1 Hz, 3 H, 9-CH3), 1.45 (dd, J = 2.0, 14.7 Hz, 1 H, 2-H), 1.62–
1.74 (m, 5 H, 4Ј-H, 5Ј-H, 6Ј-H), 1.91 (s, 3 H, Ac), 2.08–2.09 (m, 1
H, 4Ј-H), 2.35 (m, 2 H, 7Ј-H), 2.86 (ddd, J = 3.5, 8.8, 14.9 Hz, 1
H, 2-H), 3.35 (s, 3 H, OMe), 3.82 (s, 3 H, OMe), 3.82–3.85 (m, 1
H, 9-H), 3.86 (s, 3 H, OMe), 5.04 (dd, J = 2.0, 8.6 Hz, 1 H, 3-H),
(1R,3R,4S,9R)-3Ј-[3,4-Dihydroxy-5,8-dimethoxy-9-methyl-1,2,3,4-
tetrahydro-1,4-(epoxymethano)naphthalen-6-yl]-3Ј-methoxy-
4Ј,5Ј,6Ј,7Ј-tetrahydro-2Ј-benzofuran-1Ј(3H)-one (rac-19): The mix-
ture of rac-17 and rac-18 (150 mg, 0.33 mmol) was dissolved in
oxalyl chloride (5 mL) at room temperature, and the solution was
stirred for 30 min. The solvent was then removed under reduced
pressure. The crude residue was dissolved in MeOH (5 mL) at 0 °C.
The reaction mixture was allowed to warm to room temperature,
and was stirred for 15 min. The solvent was removed under reduced
pressure. The crude product was dissolved in EtOAc (20 mL), and
H2O (30 mL) was added. The organic phase was separated, and
the aqueous phase was extracted with EtOAc (3ϫ 50 mL). The
combined organic extracts were dried with Na2SO4. The solvents
were removed under reduced pressure. The crude residue was puri-
fied by chromatography on silica gel (CH2Cl2/MeOH, 99:1) to give
mixed acetal rac-19 (103 mg, 0.24 mmol, 74%) as a colourless solid,
as a separable 1:1 mixture of two diastereomers. Rf (diastereomer
5.17 (s, 1 H, 1-H), 5.20 (s, 1 H, OH), 7.28 (s, 1 H, 7Ar-H) ppm. 13
C
NMR (125 MHz, CDCl3, diastereomer 1): δ = 16.3 (9-CH3), 20.0
(C-5Ј), 21.2 (Ac), 21.6 (C-6Ј, C-7Ј), 22.3 (C-4Ј), 37.3 (C-2), 50.4
(OMe), 55.9 (OMe), 62.4 (C-1), 66.0 (OMe), 72.7 (C-3), 72.9 (C-
9), 77.0 (C-4, overlapping solvent signal), 106.8 (C-1Ј), 109.8 (CAr
-
7), 128.4 (CAr-4a), 128.9 (CAr-6), 129.1 (CAr-8a), 129.5 (C-3aЈ),
149.7 (CAr-8), 149.9 (CAr-5), 160.5 (C-7aЈ), 170.5 (COOCH3), 171.4
(C-3Ј) ppm. 1H NMR (400 MHz, CDCl3, diastereomer 2): δ = 0.92
(d, J = 6.1 Hz, 3 H, 9-CH3), 1.36 (dd, J = 2.0, 14.8 Hz, 1 H, 2-H),
1.62–1.75 (m, 5 H, 4Ј-H, 5Ј-H, 6Ј-H), 1.85 (s, 3 H, Ac), 2.08–2.09
(m, 1 H, 4Ј-H), 2.35 (m, 2 H, 7Ј-H), 2.78–2.86 (m, 1 H, 2-H), 3.35
(s, 3 H, OMe), 3.78 (s, 3 H, OMe), 3.82–3.85 (m, 1 H, 9-H), 3.84
(s, 3 H, OMe), 5.00 (dd, J = 2.0, 8.6 Hz, 1 H, 3-H), 5.14 (s, 1 H,
OH), 5.18 (s, 1 H, 1-H), 7.20 (s, 1 H, 7Ar-H) ppm. 13C NMR
(125 MHz, CDCl3, diastereomer 2): δ = 17.1 (9-CH3), 20.1 (C-5Ј),
21.2 (Ac), 21.6 (C-6Ј, C-7Ј), 22.6 (C-4Ј), 37.1 (C-2), 50.4 (OMe),
56.0 (OMe), 62.5 (C-1), 65.8 (OMe), 72.3 (C-3), 74.0 (C-9), 77.1
(C-4, overlapping solvent signal) 107.3 (C-1Ј), 109.6 (CAr-7), 128.6
(CAr-4a), 129.1 (CAr-6), 129.5 (CAr-8a, C-3aЈ), 149.4 (CAr-8), 150.4
(CAr-5), 160.8 (C-7aЈ), 170.4 (COOCH3), 171.2 (C-3Ј) ppm. HRMS
(ESI): calcd. for C25H30O9 [M + Na]+ 497.1788; found 497.1784.
1) = 0.11 (EtOAc/n-hexane, 1:1). IR (film): ν = 3479, 2929, 2851,
˜
1
1765, 1452, 1390, 1217, 1076, 1042, 1007, 917, 869 cm–1. H NMR
(500 MHz, CDCl3, diastereomer 1): δ = 0.68 (d, J = 6.1 Hz, 3 H,
9-CH3), 1.48 (dd, J = 2.0, 14.2 Hz, 1 H, 2-H), 1.63–1.72 (m, 5 H,
4Ј-H, 5Ј-H, 6Ј-H), 2.06–2.10 (m, 1 H, 7Ј-H) 2.33 (m, 2 H, 6Ј-H),
2.73 (ddd, J = 4.0, 8.8, 14.4 Hz, 1 H, 2-H), 3.35 (s, 3 H, OMe),
3.72 (q, J = 6.1 Hz, 1 H, 9-H), 3.83 (s, 3 H, OMe), 3.85 (s, 3 H,
OMe), 4.02–4.04 (m, 1 H, 3-H), 5.16 (br. s, 1 H, 1-H), 5.44 (s, 1
H, OH), 7.21 (s, 1 H, 7Ar-H) ppm. 13C NMR (125 MHz, CDCl3,
diastereomer 1): δ = 16.2 (9-CH3), 20.1 (C-6Ј), 21.6 (C-4Ј, C-5Ј), (1R,3R,4S,13R)-4,5,12-Trihydroxy-13-methyl-6,11-dioxo-
22.2 (C-7Ј), 37.2 (C-2), 50.6 (OMe), 55.9 (OMe), 62.7 (C-1), 66.6
(OMe), 70.5 (C-3), 72.7 (C-9), 79.6 (C-4), 107.0 (C-3Ј), 109.8 (CAr
1,2,3,4,6,7,8,9,10,11-decahydro-1,4-(epoxymethano)tetracen-3-yl
Acetate (rac-21) and 1,6,11-Trihydroxy-7,8,9,10-tetrahydrotetra-
-
Eur. J. Org. Chem. 2012, 6562–6569
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6567

J. Bachmann, C. Mang, L. O. Haustedt, K. Harms, U. Koert
FULL PAPER
cene-5,12-dione (22): Acetate rac-20 (30.0 mg, 0.06 mmol) was dis-
solved in dry nitromethane (1 mL) under an atmosphere of argon,
and this solution was added by syringe to a tube containing dry
AlCl3 (42.2 mg, 0.32 mmol), which was sealed with a Teflon® cap.
The reaction mixture was heated under microwave irradiation at
60 °C for 30 min. After cooling to room temperature, the reaction
1 H, OH), 6.88 (s,1 H, 7-H) ppm. 13C NMR (125 MHz, CDCl3,
diastereomer 1): δ = 16.3 (CH3), 20.0 (C-7Ј), 21.0 (Ac), 21.2 (C-6Ј),
21.5 (C-5Ј), 21.8 (Ac), 22.2 (C-4Ј), 37.0 (C-2), 55.7 (OMe), 62.2 (C-
1), 65.9 (OMe), 72.6 (C-9), 72.9 (C-3), 77.4 (C-4), 104.9 (C-1Ј),
108.2 (C-7), 127.8 (C-6), 128.2 (C-4a), 129.1 (C-8a), 129.3 (C-3aЈ),
149.5 (C-8), 149.5 (C-5), 160.4 (C-7aЈ), 167.6 (COOCH3), 170.3 (C-
mixture was decomposed with oxalic acid solution (5% (w/w) aq.; 3Ј), 170.4 (COOCH3) ppm. 1H NMR (500 MHz, CDCl3, dia-
20 mL). The aqueous phase was extracted with EtOAc (5 ϫ
20 mL). The combined organic extracts were dried with Na2SO4.
The solvents were removed under reduced pressure. The remaining
crude product was purified by chromatography on silica gel
(CH2Cl2/CH3CN = 1:0 to 9:1) to give the cyclised product rac-21
(5.30 mg, 0.013 mmol, 21%) as a red solid (m.p. Ͼ 300 °C) and 22
(3.35 mg, 0.011 mmol, 18%) as a red solid (m.p. Ͼ 300 °C).
stereomer 2): δ = 0.82 (d, J = 6.1 Hz, 3 H, CH3), 1.39 (d, J =
12.2 Hz, 1 H, 2-H), 1.52–1.77 (m, 5 H, 5Ј-H, 6Ј-H, 7Ј-H), 1.85 (s,
3 H, OAc), 2.16 (s, 3 H, OAc), 2.22–2.32 (m, 3 H, 4Ј-H, 7Ј-H),
2.77–2.83 (m, 1 H, 2-H), 3.78 (s, 3 H, OMe), 3.80–3.84 (m, 1 H, 9-
H), 3.87 (s, 3 H, OMe), 5.00 (t, J = 7.0 Hz, 1 H, 3-H), 5.08 (s, 1
H, OH), 5.12 (s, 1 H, 1-H), 6.88 (s, 1 H, 7-H) ppm. 13C NMR
(125 MHz, CDCl3, diastereomer 2): δ = 16.6 (CH3), 20.1 (C-7Ј),
21.0 (Ac), 21.2 (C-6Ј), 21.6 (C-5Ј), 21.9 (Ac), 22.9 (C-4Ј), 36.9 (C-
2), 55.8 (OMe), 62.3 (C-1), 65.6 (OMe), 72.4 (C-9), 73.3 (C-3), 77.0
(C-4), 105.3 (C-1Ј), 108.1 (C-7), 128.1 (C-6), 128.4 (C-4a), 129.1
(C-8a), 129.5 (C-3aЈ), 149.4 (C-8), 149.9 (C-5), 161.1 (C-7a), 167.6
(COOCH3), 170.4 (C-3Ј), 170.5 (COOCH3) ppm. HRMS (ESI):
calcd. for C26H30O10 [M + Na]+ 525.1737; found 525.1735.
Data for rac-21: R 0.42 (CH Cl /CH CN, 95:5). IR (film): ν =
˜
f
2
2
3
3526, 2927, 2855, 1742, 1644, 1596, 1455, 1407, 1354, 1229, 1137,
1
1058, 1022, 777 cm–1. H NMR (500 MHz, CDCl3): δ = 0.97 (d, J
= 6.1 Hz, 3 H, 13-CH3), 1.47 (d, J = 15.0 Hz, 1 H, 2-H), 1.78 (m,
4 H, 7-H, 10-H), 1.95 (s, 3 H, Ac), 2.65 (m, 4 H, 8-H, 9-H), 2.88
(ddd, J = 3.4, 8.6, 15.0 Hz, 1 H, 2-H), 3.93 (q, J = 6.1 Hz, 1 H,
13-H), 5.10 (d, J = 6.7 Hz, 1 H, 3-H), 5.26 (s, 1 H, 1-H), 5.77 (s, 1
H, OH), 12.79 (s, 1 H, OH), 13.43 (s, 1 H, OH) ppm. 13C NMR
(125 MHz, CDCl3): δ = 16.8 (13-CH3), 21.1 (C-7, C-10, Ac), 23.1
(C-8, C-9), 36.6 (C-2), 62.0 (C-1), 73.0 (C-3, C-13), 77.9 (C-4),
110.8 (CAr-11a), 111.0 (CAr-5a), 134.6 (CAr-4a), 140.0 (CAr-12a),
145.0 (CAr-6a), 145.9 (CAr-10a), 156.1 (CAr-12), 160.8 (CAr-5),
170.6 (COO), 183.3 (CAr-11), 184.1 (CAr-6) ppm. HRMS (ESI):
calcd. for C22H22O8 [M + Na]+ 437.1212; found 437.1211.
(1R,3R,4S,13R)-4,5,12-Trihydroxy-13-methyl-6,11-dioxo-
1,2,3,4,6,7,8,9,10,11-decahydro-1,4-(epoxymethano)tetracen-3-yl
Acetate (21): Acetate 23 (18.8 mg, 0.04 mmol) was dissolved in dry
1,3-dichlorobenzene (1 mL) under an atmosphere of argon, and
was transferred by syringe to a tube, which was sealed with a Tef-
lon® cap, containing dry AlCl3 (25.0 mg, 0.19 mmol) and Mg-
(OTf)2 (24.2 mg, 0.08 mmol). The reaction mixture was heated un-
der microwave irradiation at 75 °C for 15 min. After cooling to
room temperature, the reaction mixture was treated with oxalic acid
solution (5% (w/w) aq.; 20 mL). The aqueous phase was extracted
with EtOAc (5ϫ 20 mL). The combined organic extracts were
dried with Na2SO4. The solvents were removed under reduced pres-
sure. The crude residue was purified by chromatography on silica
gel (CH2Cl2/CH3CN = 1:0 to 9:1) to give cyclised product 21
Data for 22: R 0.91 (CH Cl /MeOH, 9:1). IR (film): ν = 3357,
˜
f
2
2
2922, 2853, 1659, 1445, 1393, 1289, 1237, 1194, 1162, 827, 775, 705
1
(m) cm–1. H NMR (500 MHz, CDCl3): δ = 1.83 (m, 4 H, 8-H, 9-
H), 2.78 (m, 4 H, 7-H, 10-H), 7.27 (d, 1 H, 2Ar-H), 7.67 (dd, J =
7.9 Hz, 1 H, 3Ar-H), 7.86 (d, J = 7.4 Hz, 1 H, 4Ar-H), 12.32 (s, 1
H, OH), 12.85 (s, 1 H, OH), 13.67 (s, 1 H, OH) ppm. 13C NMR
(125 MHz, CDCl3): δ = 21.6 (C-8, C-9), 23.9 (C-7, C-10), 108.9
(CAr-5a, C-11a), 116.1 (CAr-12a), 119.0 (CAr-4), 124.01 (CAr-2),
133.6 (CAr-4a), 136.4 (CAr-3), 139.5 (CAr-10a), 140.0 (CAr-6a),
156.7 (CAr-11, CAr-6) 162.3 (CAr-1), 185.7 (C-5, C-12) ppm. HRMS
(ESI): calcd. for C18H14O5 [M + Na]+ 333.0739; found 333.0733.
(4.7 mg, 0.012 mmol, 31%) as a red solid (m.p. Ͼ 300 °C). [α]2D2
–0.9 (c = 1.00, CHCl3).
=
The analytical data matched the data found for the same com-
pound prepared from 20.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of all new compounds.
(1R,3R,4S,9R)-1Ј-[3-Acetoxy-4-hydroxy-5,8-dimethoxy-9-methyl-
1,2,3,4-tetrahydro-1,4-(epoxymethano)naphthalen-6-yl]-3Ј-oxo-
1Ј,3Ј,4Ј,5Ј,6Ј,7Ј-hexahydro-2-benzofuran-1Ј-yl Acetate (23): A mix-
ture of 17 and 18 (242 mg, 0.53 mmol) was dissolved in CH2Cl2
(10 mL), and pTsOH (7.0 mg, 0.04 mmol) was added. The solution
was stirred at room temperature. After 3 h, a mixture of pyridine
(6 mL) and Ac2O (2 mL) was added, together with a catalytic
amount of DMAP, and the mixture was stirred at room tempera-
ture overnight. The solution was poured into ice-water, and ex-
tracted with EtOAc (4ϫ 20 mL). The combined organic extracts
were washed with brine, dried with Na2SO4, filtered, and evapo-
rated under reduced pressure with n-heptane (3 ϫ 50 mL). The
crude product was purified by chromatography on silica gel
Acknowledgments
Financial support from the Deutsche Forschungsgemeinschaft
(DFG), the Bundesministerium für Wirtschaft und Technologie/
Brandenburg (Innowatt program) and the Fonds der Chemischen
Industrie is gratefully acknowledged.
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˜
f
3502, 2925, 2855, 1772, 1739, 1463, 1372, 1233, 1206, 1044, 1008,
910, 867, 731, 447 cm–1. 1H NMR (500 MHz, CDCl3, diastereomer
1): δ = 0.71 (d, J = 6.1 Hz, 3 H, CH3), 1.39 (d, J = 14.7 Hz, 1 H,
2-H), 1.52–1.77 (m, 5 H, 5Ј-H, 6Ј-H, 7Ј-H), 1.88 (s, 3 H, OAc), 2.18
(s, 3 H, OAc), 2.22–2.32 (m, 3 H, 4Ј-H, 7Ј-H), 2.77–2.83 (m, 1 H,
2-H), 3.80 (s, 3 H, OMe), 3.80–3.84 (m, 1 H, 9-H), 3.88 (s, 3 H,
OMe), 5.00 (t, J = 7.02 Hz, 1 H, 3-H), 5.12 (s, 1 H, 1-H), 5.17 (s,
6568
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6562–6569

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Received: August 14, 2012
Published Online: October 19, 2012
Eur. J. Org. Chem. 2012, 6562–6569
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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