Synthesis of the AB-ring pyranolactone substructure of granaticin A

Article abstract of DOI:10.1002/ejoc.201201279

A synthesis of the AB-ring substructure of granaticin A was developed. The pyranolactone moiety was stereoselectively accessed by Sharpless asymmetric dihydroxylation and subsequent oxa-Pictet-Spengler cyclization. The use of BF₃·OEt₂ resulted in the formation of the cis pyranolactone, whereas the combination of BF₃·OEt₂ with trifluoroacetic acid led to the trans isomer. The resulting hydroquinones were cleaved selectively by ozonolysis to dicarboxylic acids. An aryl Grignard reagent could be regioselectively added to unsymmetrical anhydrides. As an alternative strategy for the construction of the B-ring, a benzyne-furan cycloaddition could be established. Synthesis of the AB-ring substructure of granaticin A was accomplished. The pyranolactone moiety was stereoselectively accessed by Sharpless asymmetric dihydroxylation and oxa-Pictet-Spengler cyclization. Ozonolysis of a hydroquinone led to pyranolactone anhydrides. Regioselective addition of a Grignard reagent to an unsymmetrical anhydride was observed. An alternative strategy was also investigated. Copyright

Full text of DOI:10.1002/ejoc.201201279

FULL PAPER
DOI: 10.1002/ejoc.201201279
Synthesis of the AB-Ring Pyranolactone Substructure of Granaticin A
Ruben Bartholomäus,[a,b] Janina Bachmann,[a,b] Christian Mang,[b] Lars Ole Haustedt,[b]
Klaus Harms,[a] and Ulrich Koert*[a]
Keywords: Natural products / Lactones / Ozonolysis / Fused-ring systems / Cyclization
A synthesis of the AB-ring substructure of granaticin A was
developed. The pyranolactone moiety was stereoselectively
accessed by Sharpless asymmetric dihydroxylation and sub-
sequent oxa-Pictet–Spengler cyclization. The use of BF3·OEt2
resulted in the formation of the cis pyranolactone, whereas
the combination of BF3·OEt2 with trifluoroacetic acid led to
the trans isomer. The resulting hydroquinones were cleaved
selectively by ozonolysis to dicarboxylic acids. An aryl Grig-
nard reagent could be regioselectively added to unsymmetri-
cal anhydrides. As an alternative strategy for the construc-
tion of the B-ring, a benzyne–furan cycloaddition could be
established.
Introduction
The natural product granaticin A was first isolated by
Keller-Schierlein et al. from Streptomyces olivaceus.[1] Its
structure was established by a combination of UV, IR, and
NMR spectroscopic analysis and ozonolytic degradation
and confirmed by X-ray crystallographic analysis of the tri-
acetylmonoiodoacetyl derivative.[2] Granaticin A showed an
interesting biological profile that includes antibiotic activity
against Gram-positive bacteria,[3] antitumor activity in mice
with P388 lymphatic leukemia, and cytotoxicity against KB
cells (ED50 = 1.6 μgml–1).[4] Structurally related natural
products are the rhodinoside of granaticin A called gra-
naticin B and dihydrogranaticin.[5,6]
The structure of granaticin A exhibits a central naphtho-
quinone moiety (rings B and C) flanked by an 2-oxabicyclo-
[2.2.2]oct-5-ene substructure (ring D) and a pyranolactone
(ring A). The rare 2-oxabicyclo[2.2.2]oct-5-ene moiety is
also found in the structure of sarubicin A.[7] The pyranolac-
tone substructure of granaticin A is present in several other
natural products such as nanaomycin D[8] and frenolicin B
(Figure 1).[9]
Stereoselective synthesis of the 2-oxabicyclo[2.2.2]oct-5-
ene substructure was accomplished by Yoshii, which led to
the total synthesis of racemic granaticin A,[10] followed by
the synthesis of the enantiopure natural product later.[11]
The BCD-ring substructure was synthesized stereoselec-
Figure 1. Structures of granaticin A, sarubicin A, nanaomycin D,
and frenolicin B.
tively by our group by Sharpless asymmetric dihydrox-
ylation and diastereoselective ketone reduction for the con-
struction of the 2-oxabicyclo[2.2.2]oct-5-ene and naphtho-
quinone moieties.[12] Here we present a novel route to the
AB-ring substructure of granaticin A containing the pyran-
olactone.
Results and Discussion
The synthetic strategies for the construction of the gra-
naticin skeleton used by Yoshii and in the present contri-
bution are compared in Scheme 1. Yoshii[10,11] focused on
benzannulation of cyanophthalide 2 and Michael acceptor
3 developed by Kraus.[13] The incompatibility of the pyran-
olactone with this key step shifted the introduction of the
lactone ring to the end of the synthesis. We intended a cou-
[a] Fachbereich Chemie, Philipps-Universität Marburg,
Hans-Meerwein-Straße, 35043 Marburg, Germany
Fax: +49-6421-2825677
E-mail: koert@chemie.uni-marburg.de
Homepage: http://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.201201279.
180
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Eur. J. Org. Chem. 2013, 180–190

Synthesis of the AB-Ring Pyranolactone Substructure of Granaticin A
pling of two nearly equally complex substructures with the
pyranolactone already installed.[12] The key step consists of
the addition of an organometallic intermediate generated
from bromide 4 to anhydride 5 and subsequent Friedel–
Crafts-type cyclization. A crucial point of this approach is
the regioselective attack at the anhydride. The stereoselec-
tive synthesis of anhydride 5 and studies concerning the re-
gioselective addition of aryl metal species are important
steps towards the realization of our strategy and content of
the present report.
Scheme 2. Stereoselective synthesis of alcohol 10 and X-ray crystal
structure of ester 11. Reagents and conditions: (a) Vinylmagnesium
bromide, THF, –60 °C, 95%; (b) Ac2O, py, 0 °C, 90%; (c) Pd2-
(dba)3, CO (30 bar), PPh3, EtN(iPr)2, NaBr, MeOH, 50 °C, 99%;
(d) AD-mix α, NaHCO3, MeSO2NH2, tBuOH/H2O = 1:1, 0 °C,
87%; (e) (S)-(+)-α-acetoxyphenylacetic acid, DMAP [4-(N,N-di-
methylamino)pyridine], DCC (N,NЈ-dicyclohexylcarbodiimide),
CH2Cl2, 20 °C, 97%.
Scheme 1. Different routes for the construction of the granaticin
skeleton.
cordance to Brückner’s work.[17] The absolute configuration
of compound 10 was secured by X-ray crystal structure
Different synthetic routes have been developed for the analysis of α-acetoxyphenyl acetate 11.[24]
stereoselective synthesis of the pyranolactone substructure.
Treatment of alcohol 10 with 1,1-dimethoxyethane and
For the synthesis of nanaomycin, Tatsuta used an intramo- BF3·OEt2 at 40 °C gave isochroman 12 in very good yield
lecular oxa-Michael reaction to close the dihydropyran (Scheme 3). Under these conditions, the oxa-Pictet–Speng-
ring.[13] An intramolecular palladium-catalyzed alkoxy ler cyclization gave exclusively the cis-pyranolactone. The
carbonylation of an allylic alcohol served as a key step in stereochemical assignment of compound 12 was possible by
the kalafungin synthesis of Kraus and in the crisamicin A X-ray crystal structure analysis.[24] The formation of the cis
synthesis of Yang.[14] The oxa-Pictet–Spengler reaction for product as the major stereoisomer can be explained, in ac-
the closure of the dihydropyran ring was pioneered by Mas- cordance to prior results, by an early transition state of the
quelin, Scalone, and Visnick in their approach to frenol- oxa-Pictet–Spengler cyclization that resembles (E)-oxa-
icin B.[15] Giles used a dioxolane as synthetic entry to the carbenium ion intermediate A.[16–18] Oxidation of 12 with
oxonium ion.[16] The acid-catalyzed isomerization of the cis cerium ammonium nitrate (CAN) led to p-benzoquinone
oxa-Pictet–Spengler product to the trans product was re- 13. Upon hydrogenation, hydroquinone 14 was obtained.
ported by Brückner.[17] Eid achieved the direct formation of Ozonolysis of the hydroquinone at –110 °C with subsequent
the trans oxa-Pictet–Spengler product in his synthesis of 7- oxidative workup resulted in the formation of dicarboxylic
deoxyfrenolicin B.[18]
acid 15 in very good yield.
Our synthetic plan was based on the assumption that
Selective ozonolytic conversion of the 2,3-dialkyl-substi-
pyranolactone anhydride 5 could be accessed by oxidative tuted hydroquinone derivative into a dialkyl-substituted
cleavage from an arenepyranolactone. An oxa-Pictet– maleic acid has no synthetic precedence. Degradation stud-
Spengler route to the latter requires alcohol intermediate 10 ies towards the elucidation of the structure of granaticin
(Scheme 2). The enantioselective synthesis of compound 10 relied on a related reaction for analytical purposes.[2a]
started with aldehyde 6.
Ozonolysis of benzoquinone 13 also gave dicarboxylic acid
Addition of vinylmagnesium bromide led to allylic 15; however, it was obtained in lower yield with the forma-
alcohol 7, which was converted into allylic acetate 8. Tsuji tion of byproducts. The presence of the phenolic OH groups
carbonylation under Murahashi conditions[19] gave β,γ-un- may lead to ozone precoordination and the observed selec-
saturated ester 9. Keeping the reaction time below 2 h mini- tivity in the oxidative cleavage.
mized the amount of α,β-unsaturated ester formed as a by-
product to less than 5%. Sharpless dihydroxylation of al- naticin key intermediate
kene 9 gave directly hydroxylactone 10 (Ͼ95%ee) in ac- Attempts to isomerize cis-hydroquinone ether 12 failed.
The synthesis of trans-diacid 19 as a precursor to gra-
5
was not straightforward.
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181

U. Koert et al.
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Scheme 3. Synthesis of cis-diacid 15 and X-ray crystal structure of
isochroman 12. Reagents and conditions: (a) 1,1-Dimethoxyethane,
BF3·OEt2, Et2O/THF = 4:1, 40 °C, 88%; (b) CAN, CH3CN,
–20 °C, 82%; (c) Pd/C, H2, EtOAc, 20 °C, 99%; (d) O3, CH2Cl2/
DMF = 4:1, –110 °C, 85%.
Scheme 4. Synthesis of trans-diacid 19 and X-ray crystal structure
of quinone 17. Reagents and conditions: (a) 1,1-Dimethoxyethane,
BF3·OEt2, TFA, 80 °C, 60 s, 41%, 14:1dr; (b) CAN, MeCN,
–20 °C, 59%; (c) Pd/C, H2, EtOAc, 20 °C, 99%; (d) O3, CH2Cl2/
DMF = 4:1, –110 °C, 82%.
ported by Braun.[20] The regioselectivity observed in the
present case will allow the use of anhydride 5 prepared from
diacid 19 as the key intermediate in the synthesis of gra-
naticin A.
Isomerization at the benzoquinone stage with 13 by using
sulfuric acid gave only decomposition of the starting mate-
rial. This isomerization worked well for a related naphtho-
quinone case,[17] which indicates the importance of struc-
tural details in the oxa-Pictet–Spengler cyclization. In the
present case, it was found that the use of trifluoroacetic acid
(TFA) as solvent and BF3·OEt2 as additive at 80 °C gave
trans-product 16 as the major stereoisomer (14:1dr) by re-
stricting the reaction time to 60 s (Scheme 4). Longer reac-
tion times resulted in decomposition of the starting mate-
rial. A mechanistic rationale[18] for the observed trans-selec-
tivity in the oxa-Pictet–Spengler reaction by using TFA as
solvent is difficult. The decreased nucleophilicity of the pro-
tonated hydroquinone ether could shift the transition state
from the oxacarbenium ion towards the (more stable) trans
pyranolactone. After CAN oxidation of 16, benzoquinone
17 was obtained. The stereochemical assignment in the
trans-series was confirmed by X-ray crystal structure analy-
sis of compound 17.[24] Hydrogenation of benzoquinone 17
led to hydroquinone 18. Subsequent ozonolysis to trans-di-
carboxylic acid 19 showed the same high chemoselectivity
as that for the cis case.
Scheme 5. Grignard addition to cis-anhydride 21. Reagents and
conditions: (a) TFAA, CH2Cl2, 20 °C, 97%; (b) 1. 1-bromo-2,5-di-
methoxybenzene (20), Mg, 1,2-dibromoethane, THF, reflux; 2. 21,
THF, –80 °C, 53%; (c) MeI, Cs2CO3, DMF, 20 °C, 50%.
With diacids 15 and 19 in hand, anhydride formation
and subsequent addition of aryl metal reagents was investi-
Benzannulation of benzoquinones 13 and 17 has the po-
gated next. cis-Diacid 15 could be transformed into cis-an- tential to open a synthetic entry to naphthoquinone natural
hydride 21 by treatment with trifluoroacetic anhydride products such as nanaomycin D and frenolicin B.[14a] To
(TFAA). As a result of problems with the chromatographic this end, [4+2] cycloaddition of benzoquinone 13 was inves-
purification of the anhydride, it was coevaporated with tolu- tigated. Diels–Alder reaction of benzoquinone 13 with 1-
ene a few times to remove the excess amounts of TFAA/ acetoxy-1,3-butadiene (26) led to the corresponding cy-
TFA and used directly in the next step. Reaction of anhy- cloadduct, which aromatized to naphthoquinone 27 upon
dride 21 with 2,5-dimethoxyphenylmagnesium bromide addition of silica gel (Scheme 6).
gave the desired acylation product as a 10:1 mixture of iso-
Alternatively, a cycloaddition strategy making use of a
mers 22/23. The NMR spectroscopic structural assignment benzyne–furan
cycloaddition was investigated
(HMBC) of the major isomer was possible at the stage of (Scheme 7).[21–23] Suitable benzyne precursors are arylli-
the corresponding methyl esters 24 and 25 (Scheme 5). In a thium reagents derived from substituted 1-bromo-2,5-di-
related example, the regioselective addition of an organo- methoxybenzenes of type 4. The furans required for this
metallic reagent to an unsymmetrical anhydride was re- approach could be derived from the ozonolysis products of
182
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Synthesis of the AB-Ring Pyranolactone Substructure of Granaticin A
The application of the benzyne–furan strategy to the
coupling of aryl bromide 4 with trans-furan 33 will require
a regioselective cycloaddition. Regioselectivity in benzyne–
furan cycloadditions has precedence for related systems.[21]
Scheme 6. Synthesis of pyranonaphthoquinone lactone 27. Rea-
gents and conditions: (a) SiO2, MeOH, 20 °C, 50%.
Conclusions
In summary, synthesis of the AB-ring substructure of
granaticin A was developed. The pyranolactone substruc-
ture was stereoselectively accessed with Sharpless asymmet-
ric dihydroxylation and oxa-Pictet–Spengler cyclization.
Conditions for the selective synthesis of the cis and the trans
oxa-Pictet–Spengler product have been identified. Cleavage
of the hydroquinone moiety by ozonolysis led selectively to
a substituted maleic anhydride. A 10:1 regioselectivity was
found for the addition of an aryl Grignard reagent to the
unsymmetrical anhydride. The anhydride could also be con-
verted into a furan and subsequently used in a benzyne–
furan cycloaddition as a coupling strategy. The two comple-
mentary anhydride routes should be applicable for the syn-
thesis of granaticin A as well as its derivatives, which would
allow structure–activity relationship studies and the explo-
ration of this intriguing natural product scaffold.
hydroquinones 14 and 18. In the cis-series, anhydride 21
was reduced with Li(OtBu)3AlH to a mixture of lactones
28 and 29. Further reduction of the lactone mixture with
DIBAL-H to the corresponding lactols and subsequent
water elimination during acidic workup led to the cis-furan,
which was converted into methyl acetal 30. In the trans-
series, ozonolysis of hydroquinone 18 and subsequent re-
duction of the corresponding anhydride gave a mixture of
lactones 31 and 32. Analogously to the cis-route, the trans-
furan was obtained by DIBAL-H reduction followed by
treatment with aqueous HCl. Treatment with BF3·OEt2 in
MeOH gave methyl acetal 33. The X-ray crystal structure
of 33 proved that no stereoscrambling had occurred during
the reaction sequence from 18.[24]
For the benzyne–furan cycloaddition, 1-bromo-2,5-di-
methoxy-benzene (20) was added at –78 °C to a preformed
mixture of furan 30 and LDA in THF. Cycloadduct 34 was
obtained in quantitative yield. Treatment of 34 with
BF3·OEt2 in MeOH at 65 °C resulted in aromatization,
which led to an inseparable mixture of the regioisomeric
phenols. Acid-catalyzed acetal cleavage followed by one-pot
Jones oxidation gave naphthoquinone 35.
Experimental Section
General: All air-sensitive reactions were carried out under an atmo-
sphere of argon with anhydrous solvents in dried glassware. All
solvents were dried according to standard procedures or were
Scheme 7. Benzyne–furan cycloaddition route and X-ray structure of furan 33. Reagents and conditions: (a) Li(OtBu)3AlH, THF, 0 °C,
50%; (b) 1. DIBAL-H, CH2Cl2, –78 °C; 2. aq. HCl, 0 °C; 3. BF3·OEt2, MeOH, 40 °C, 48%; (c) 1. O3, CH2Cl2/DMF = 4:1, –110 °C;
2. TFAA, CHCl3, 20 °C; 3. Li(OtBu)3AlH, THF, 0 °C, 42%; (d) 1. DIBAL-H, CH2Cl2, –78 °C; 2. aq. HCl, 0 °C; 3. BF3·OEt2, MeOH,
40 °C, 55%; (e) LDA, 1-bromo-2,5-dimethoxybenzene (20), THF, –78 °C, 100%; (f) 1. BF3·OEt2, MeOH, 65 °C; 2. aq. H2SO4, acetone,
reflux; 3. Jones’ reagent, acetone, 20 °C, 26%.
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U. Koert et al.
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bought dry (Sigma–Aldrich). Reagents were used as purchased.
Flash chromatography was performed on silica gel (0.04–
0.063 mm/Fluka Analytical). Analytical TLCs were carried out on
aluminum-coated silica gel 60 F254. Optical rotation was measured
at the sodium D line with a 1-dm path length and 1-mL cell. NMR
spectra were recorded with a Bruker DPX-400 or DRX-500 spec-
trometer by using partially deuterated solvents as internal stan-
dards; rr = regioisomer ratio. Multiplicities are denoted as follows:
s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. IR
spectra were recorded with a Bruker IFS 200 spectrometer. Mass
spectra were recorded with a Qstar pulstar I from Applied Biosys-
tems and with a Finnigan LTQ-FT from Thermo Fisher Science.
(5.25 mL, 30.69 mmol), Pd2(dba)3 (584 mg, 0.64 mmol), and NaBr
(790 mg, 7.68 mmol) were dissolved in methanol (160 mL). The
mixture was stirred under an atmosphere of carbon monoxide
(30 bars) in an autoclave at 50 °C for 2 h. The reaction mixture was
cooled to room temperature and brine (50 mL) was added. The
aqueous layer was extracted with EtOAc (4ϫ 100 mL). The com-
bined organic layer was washed with brine, dried with Na2SO4,
filtered, and concentrated under reduced pressure to give ester 9
(9.92 g, 29.52 mmol, 99%) as a yellow oil in sufficient purity for
the next step. An analytically pure sample was obtained by column
chromatography on silica gel (pentane/EtOAc, 5:1), which gave the
product as a yellow oil in 76% yield. Rf = 0.25 (EtOAc/n-hexane,
1
1:6). H NMR (400 MHz, CDCl3): δ = 3.28 (d, J = 6.1 Hz, 2 H,
1-(2Ј,5Ј-Dimethoxyphenyl)prop-2-en-1-ol (7): 2,5-Dimethoxybenzal-
dehyde (6; 50.00 g, 301 mmol) was dissolved in dry THF (150 mL).
The solution was cooled to –60 °C and a solution of vinylmagne-
sium bromide (1 m in THF, 331 mL, 331 mmol) was added drop-
wise. After stirring for 30 min, the solution was warmed to room
temperature and was quenched with satd. aq. NH4Cl (50 mL). Af-
ter adding 1 m HCl to pH 6, the resulting mixture was extracted
with EtOAc (4ϫ 50 mL). The combined organic layer was washed
with brine, dried with Na2SO4, filtered, and concentrated under
reduced pressure to give allylic alcohol 7 (57.9 g, 298 mmol, 99%)
as colorless oil in sufficient purity for the next step. An analytically
pure sample was obtained by column chromatography on silica gel
(EtOAc/n-heptane, 1:4), which gave the product in the form of a
colorless oil in 95% yield. Rf = 0.43 (EtOAc/n-hexane, 1:2). 1H
NMR (400 MHz, CDCl3): δ = 2.80 (s, 1 H, OH), 3.77 (s, 3 H,
OMe), 3.82 (s, 3 H, OMe), 5.17 (d, J = 10.6 Hz, 1 H, 3-H), 5.32
(d, J = 17.2 Hz, 1 H, 3-H), 5.37 (d, J = 5.1 Hz, 1 H, 1-H), 6.11
2-H), 3.71 (s, 3 H,COOCH3), 3.78 (s, 3 H, OMe), 3.80 (s, 3 H,
OMe), 6.29 (t, J = 7.1 Hz, 1 H, 3-H), 6.76 (t, J = 7.3 Hz, 1 H, 4-
H), 6.77–6.81 (m, 2 H, 3Ј-HAr, 4Ј-HAr), 7.00 (d, J = 3.0 Hz, 1 H,
6Ј-HAr) ppm. 13C NMR (125 MHz, CDCl3): δ = 38.7 (C-2), 52.0
(COOCH3), 55.9 (OMe), 56.3 (OMe), 112.2 (CAr-3Ј), 112.3 (CAr
-
1Ј), 113.9 (CAr-4Ј), 122.7 (C-3), 126.8 (CAr-1Ј), 128.2 (C-4), 151.1
(CAr-2Ј), 153.8 (CAr-5Ј), 172.3 (COO) ppm. IR (film): ν = 2999,
˜
2951, 2834, 1734, 1494, 1463, 1433, 1217, 1159, 1044, 971, 754,
714 cm–1. HRMS (ESI): calcd. for C13H16O4 [M + Na]+ 259.0941;
found 259.0941.
(4S,5S)-4-Hydroxy-5-(2Ј,5Ј-dimethoxyphenyl)-4,5-dihydrofuran-
2(3H)-one (10): AD-mix-α (58.00 g), NaHCO3 (10.66 g,
127.00 mmol), and methanesulfonamide (4.02 g, 42.32 mmol) were
dissolved in tert-butyl alcohol (200 mL) and water (200 mL). After
the mixture was cooled to 0 °C, methyl ester 9 (10.00 g,
42.32 mmol) was added. The mixture was stirred for 12 h at 0 °C
followed by 12 h at room temperature, at which point a satd. aq.
sodium sulfite solution (50 mL) was added. The mixture was stirred
for 1 h at room temperature and extracted with EtOAc (5 ϫ
100 mL). The combined organic layer was dried with Na2SO4, fil-
tered, and concentrated under reduced pressure. The crude product
was purified by flash column chromatography on silica gel (n-hept-
ane/EtOAc, 1:1 to 1:4) to afford lactone 10 (8.78 g, 36.85 mmol,
87%) as a yellow solid (m.p. 60 °C). Rf = 0.25 (EtOAc/n-hexane,
(ddd, J = 5.6, 10.6, 17.2 Hz, 1 H, 2-H), 6.76–6.90 (m, 2 H, 3Ј-HAr
,
4Ј-HAr), 6.89 (d, J = 3.0 Hz, 1 H, 1Ј-HAr) ppm. 13C NMR
(125 MHz, CDCl3): δ = 55.9 (OMe), 56.1 (OMe), 71.8 (C-1), 112.0
(CAr4Ј), 113.2 (CAr3Ј), 113.7 (C-3), 114.8 (CAr-6Ј), 132.0 (CAr-1Ј),
139.4 (C-2), 151.1 (CAr-2Ј), 154.0 (CAr-5Ј) ppm. IR (film): ν = 3418,
˜
2941, 2834, 1610, 1494, 1464, 1212, 1042, 921, 806, 710, 479 cm–1.
HRMS (ESI): calcd. for C11H14O3 [M + Na]+ 217.0835; found
217.0838.
1
1:1). H NMR (500 MHz, CDCl3): δ = 2.66 (d, J = 17.6 Hz, 1 H,
1-(2Ј,5Ј-Dimethoxyphenyl)allyl Acetate (8): Alcohol
7 (9.00 g,
3-H), 2.86 (dd, J = 5.4, 17.7 Hz, 1 H, 3-H), 3.05 (s, 1 H, OH), 3.76
(s, 3 H, OMe), 3.80 (s, 3 H, OMe), 4.77–4.78 (m, 1 H, 4-H), 5.71
(d, J = 3.4 Hz, 1 H, 5-H), 6.78–6.91 (m, 2 H, 3Ј-HAr, 4Ј-HAr), 7.04
(d, J = 2.0 Hz, 1 H, 1Ј-HAr) ppm. 13C NMR (125 MHz, CDCl3):
δ = 38.3 (C-3), 56.0 (OMe, OMe), 68.9 (C-4), 82.0 (C-5), 111.5
46.34 mmol) was dissolved in dry pyridine (25 mL). The solution
was cooled to 0 °C and acetic anhydride (21.9 mL, 231.68 mmol)
was added dropwise. The cooling bath was removed, and the mix-
ture was stirred at room temperature overnight. The solution was
poured into ice water and extracted with EtOAc (3ϫ 100 mL). The
combined organic layer was washed with brine, dried with Na2SO4,
filtered, and concentrated under reduced pressure to give acetate 8
(10.16 g, 43.00 mmol, 93%) as a yellow oil in sufficient purity for
the next step. An analytically pure sample was obtained by column
chromatography on silica gel (EtOAc/n-hexane, 1:6), which gave the
product as a yellow oil in 90% yield. Rf = 0.28 (EtOAc/n-hexane,
(CAr-3Ј), 113.1 (CAr-6Ј), 115.0 (CAr-4Ј), 122.4 (CAr-1Ј), 149.8 (CAr
-
2Ј), 154.1 (CAr-5Ј), 175.6 (COO) ppm. IR (film): ν = 3535, 2969,
˜
2942, 2839, 1763, 1743, 1497, 1215, 1160, 1036, 1015, 885, 815,
699 cm–1. HRMS (ESI): calcd. for C12H14O5 [M + Na]+ 261.0733;
found 261.0735. [α]D = +47.3 (c = 1.05, CHCl3, 18 °C).
(2ЈS,3ЈS)-2-(2ЈЈ,5ЈЈ-Dimethoxyphenyl)-5Ј-oxotetrahydrofuran-3Ј-yl
(2S)-2-(Acetyloxy)(phenyl)acetate (11): Hydroxyacetone 10
(78.0 mg, 0.33 mmol) was dissolved in toluene/CH2Cl2 (5:1, 6 mL).
(S)-(+)-α-acetoxyphenylacetic acid (95 mg, 0.49 mmol) and a cata-
lytic amount of DMAP were added. The solution was cooled to
0 °C with an ice bath and DCC (101 mg, 0.49 mmol) was added
portionwise. The reaction mixture was warmed to room tempera-
ture and stirred for 1 h. The solvent was removed under reduced
pressure, and the crude product was purified by flash column
chromatography on silica gel (n-heptane/EtOAc, 5:1 to 2:3) to af-
ford ester 11 (132 mg, 0.32 mmol, 97%, Ͼ95%de) as a colorless
crystalline solid (m.p. 158 °C). Rf = 0.67 (n-heptane/EtOAc, 1:2).
1H NMR (500 MHz, CDCl3): δ = 7.28 (dd, J = 7.7, 7.4 Hz, 1 H,
Ph), 7.20 (dd, J = 7.6, 7.3 Hz, 2 H, Ph), 7.00 (d, J = 7.3 Hz, 2 H,
1
1:6). H NMR (400 MHz, CDCl3): δ = 2.12 (s, 3 H, CH3), 3.77 (s,
3 H, OMe), 3.80 (s, 3 H, OMe), 5.18 (d, J = 10.4 Hz, 1 H, 3-H),
5.24 (d, J = 17.2 Hz, 1 H, 3-H), 5.99 (ddd, J = 5.6, 10.6, 17.1 Hz,
1 H, 2-H), 6.62 (d, J = 5.5 Hz, 1 H, 1-H), 6.80–8.82 (m, 2 H, 3Ј-
HAr, 6Ј-HAr), 6.92 (d, J = 2.4 Hz, 1 H, 4Ј-HAr) ppm. 13C NMR
(125 MHz, CDCl3): δ = 21.3 (CH3), 55.9 (OMe), 56.4 (OMe), 70.7
(C-1), 112.1 (CAr-6Ј), 113.4 (CAr-3Ј), 113.7 (CAr-4Ј), 116.2 (C-3),
128.8 (CAr-1Ј), 135.9 (C-2), 150.9 (CAr-2Ј), 153.8 (CAr-5Ј), 169.9
(COO) ppm. IR (film): ν = 2998, 2942, 2835, 1737, 1498, 1463,
˜
1370, 1278, 1213, 1178, 1091, 1044, 1021, 976, 806, 714, 609,
482 cm–1. HRMS (ESI): calcd. for C13H16O4 [M + Na]+ 259.0946;
found 259.0941.
Methyl (E)-4-(2Ј,5Ј-Dimethoxyphenyl)but-3-enoate (9): Allylic acet-
ate 8 (10.00 g, 29.74 mmol), PPh3 (652 mg, 2.49 mmol), DIPEA Ph), 6.92 (d, J = 2.8 Hz, 1 H, 6ЈЈ-H), 6.72 (dd, J = 8.9, 3.0 Hz, 1
184
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 180–190

Synthesis of the AB-Ring Pyranolactone Substructure of Granaticin A
H, 4ЈЈ-H), 6.53 (d, J = 8.9 Hz, 1 H, 3ЈЈ-H), 5.85 (dd, J = 4.7, 5.4 Hz, (3aS,5R,9bS)-6,9-Dihydroxy-5-methyl-3,3a,5,9b-tetrahydro-2H-
1 H, 3Ј-H), 5.73 (d, J = 4.2 Hz, 1 H, 2Ј-H), 5.55 (s, 1 H, 2-H), 3.73 furo[3,2-c]isochromen-2-one (14): Quinone 13 (1.20 g, 5.12 mmol)
(s, 3 H, 5ЈЈ-OMe), 3.52 (s, 3 H, 2ЈЈ-OMe), 3.02 (dd, J = 18.4, 6.0 Hz,
1 H, 4Ј-H), 2.72 (d, J = 18.4 Hz, 1 H, 4Ј-H), 2.03 (s, 3 H, OAc)
was dissolved in EtOAc (150 mL). The solution was stirred under
an argon atmosphere and Pd/C (600 mg) was added. Under an at-
ppm. 13C NMR (126 MHz, CDCl3): δ = 173.9 (C-5Ј), 170.2 (C-1), mosphere of hydrogen, the mixture was stirred for 10 min, and
167.9 (OAc), 153.5 (C-5ЈЈ), 149.5 (C-2ЈЈ), 132.8 (Ph), 129.0 (Ph), upon completion of the reaction, it was filtered through a plug of
128.8 (Ph), 127.1 (Ph), 122.2 (C-1ЈЈ), 114.6 (C-4ЈЈ), 112.0 (C-6ЈЈ), Celite. The solvent was removed under reduced pressure to afford
111.0 (C-3ЈЈ), 80.1 (C-2Ј), 74.4 (C-2), 71.6 (C-3Ј), 55.8 (5ЈЈ-OMe), hydroquinone 14 (1.19 g, 5.05 mmol, 99%) as a yellow solid (m.p.
55.5 (2ЈЈ-OMe), 36.8 (C-4Ј), 20.5 (OAc) ppm. IR (film): ν = 2931, 192–194 °C). Rf = 0.21 (EtOAc/n-hexane, 2:1). 1H NMR
˜
2848, 1783, 1748, 1498, 1429, 1276, 1220, 1176, 1150, 1027, 813,
(400 MHz, [D4]MeOH): δ = 1.60 (d, J = 6.2 Hz, 3 H, 5-CH3), 2.55
(d, J = 17.2 Hz, 1 H, 3-H), 3.02 (dd, J = 4.5, 17.2 Hz, 1 H, 3-H),
730, 694, 594, 510 cm–1. HRMS (ESI): calcd. for C22H22O8 [M +
Na]+ 437.1207; found 437.1216. [α]D = +87.4 (c = 1.10, CHCl3, 4.32 (dd, J = 2.3, 4.3 Hz, 1 H, 3a-H), 4.82 (q, J = 6.3 Hz, 1 H, 5-
18 °C).
H), 5.40 (d, J = 2.1 Hz, 1 H, 9b-H), 6.62 (d, J = 8.6 Hz, 1 H, 8-
H), 6.69 (d, J = 8.7 Hz, 1 H, 7-H) ppm. 13C NMR (125 MHz, [D4]
MeOH): δ = 21.3 (5-CH3), 39.1 (C-3), 71.2 (C-3a), 72.8 (C-5), 75.3
(C-9b), 114.6 (C-7), 117.2 (C-8), 118.4 (C-9a), 129.0 (C-5a), 147.4
(3aS,5R,9bS)-6,9-Dimethoxy-5-methyl-3,3a,5,9b–tetrahydro-2H-
furo-[3,2-c]isochromen-2-one (12): Hydroxyacetone 10 (3.00 g,
12.61 mmol) was dissolved in a mixture of Et2O/THF (4:1,
140 mL). After cooling to 0 °C, acetaldehyde dimethyl acetal
(5.33 mL, 50.4 mmol) and BF3·OEt2 (9.53 mL, 75.6 mmol) were
added successively. The ice bath was removed, and the mixture was
stirred at 40 °C for 6 h. After completion, the reaction mixture was
cooled to 0 °C and a satd. aq. NaHCO3 solution was added slowly
for neutralization (pH = 7). The aqueous layer was extracted with
EtOAc (4ϫ 100 mL), and the combined organic layer was dried
with Na2SO4, filtered, and concentrated under reduced pressure.
The crude product was purified by flash column chromatography
on silica gel (n-heptane/EtOAc, 2:1 to 1:2) to afford isochroman 12
(2.94 g, 11.1 mmol, 88%) as a yellow solid (m.p. 131 °C). Rf = 0.20
(C-6), 151.1 (C-9), 179.1 (COO) ppm. IR (film): ν = 3333, 2945,
˜
2850, 1778, 1491, 1448, 1329, 1286, 1205, 1156, 1032, 916, 827,
696, 461 cm–1. HRMS (ESI): calcd. for C12H12O5 [M + Na]+
259.0577; found 259.0580. [α]D = –46.7 (c = 1.01, MeOH, 18 °C).
(3aS,5R,7aS)-3,3a,5,7a-Tetrahydro-5-methyl-2-oxo-2H-furo[3,2-b]-
pyran-6,7-dicarboxylic Acid (15): Hydroquinone 14 (3.54 g,
15.13 mmol) was dissolved in CH2Cl2/DMF (4:1, 250 mL) and
ozone/oxygen was bubbled through the solution until a pale blue
color was observed. The generation of ozone was stopped and oxy-
gen was bubbled through the solution for a further 15 min. H2O2
(30%, 3 mL) and glacial acetic acid (3 mL) were then added slowly.
The cooling bath was removed, and the reaction mixture was
warmed to room temperature slowly. The solvents were removed
under reduced pressure. The remaining crude product was dis-
solved in H2O (1 mL) and purified by solid-phase extraction
1
(EtOAc/n-hexane, 1:2). H NMR (400 MHz, CDCl3): δ = 1.57 (d,
J = Hz, 3 H, 5-CH3), 2.69 (d, J = 17.2 Hz, 1 H, 3-H), 2.83 (dd, J
= 4.4, 17.2 Hz, 1 H, 3-H), 3.77 (s, 3 H, OMe), 3.83 (s, 3 H, OMe),
4.28 (dd, J = 2.4, 4.2 Hz, 1 H, 3-Ha), 4.84 (q, J = 6.2 Hz, 1 H, 5-
H), 5.32 (d, J = 1.9 Hz, 1 H, 9b-H), 6.77 (d, J = 9.0 Hz, 1 H, 8- (Waters Sep-Pak® Vac 6cc, C18–1 g, H2O/CH3CN, 1:0 to 9:1). Af-
H
Ar), 6.87 (d, J = 9.0 Hz, 1 H, 7-HAr) ppm. 13C NMR (125 MHz,
CDCl3): δ = 21.3 (5-CH3), 38.3 (C-3), 55.7 (OMe), 56.2 (OMe),
ter intensive drying under high vacuum, the remaining oil was
evaporated in CH2Cl2 to afford diacid 15 (3.11 g, 12.86 mmol,
69.8 (C-5), 71.1 (C-3a), 72.7 (C-9b), 109.1 (CAr-8), 112.5 (CAr-7), 85%) as a white solid (m.p. 141–143 °C). Rf = 0.23 (EtOAc/MeOH/
118.0 (CAr-9a), 130.5 (CAr-5a), 149.9 (CAr-6), 152.9 (CAr-9), 175.9 H2O/CH3CN, 4.5:1:1:1). 1H NMR (400 MHz, [D4]MeOH): δ =
(COO) ppm. IR (film): ν = 2942, 2842, 1769, 1597, 1597, 1486,
1.37 (d, J = 6.7 Hz, 3 H, 5-CH3), 2.54 (d, J = 17.6 Hz, 1 H, 3-H),
3.06 (dd, J = 5.0, 17.7 Hz, 1 H, 3-H), 4.41 (dd, J = 2.8, 4.6 Hz, 1
H, 3a-H), 4.50 (q, J = 6.4 Hz, 1 H, 5-H), 5.10 (s, 1 H, 7a-H) ppm.
13C NMR (125 MHz, [D4]MeOH): δ = 18.9 (5-CH3), 38.0 (C-3),
71.4 (C-5), 73.7 (C-3a), 73.9 (C-7a), 122.5 (C-7), 153.1 (C-6), 166.6
˜
1257, 1155, 1081, 1064, 981, 967, 898, 826, 716, 501, 566 cm–1
.
HRMS (ESI): calcd. for C14H16O5 [M + Na]+ 287.0890; found
287.0894. [α]D = –17.6 (c = 1.02, CHCl3, 18 °C).
(3aS,5R,9bS)-5-Methyl-3,3a-dihydro-5H-furo[3,2-c]isochromene-
2,6,9-(9bH)-trione (13): Isochroman 12 (500 mg, 1.89 mmol) was
dissolved in H2O/MeCN (1:1, 30 mL), and the solution was cooled
to –10 °C. CAN (2.07 g, 3.78 mmol) was added, which resulted in
darkening of the mixture. After ca. 3 min, the reaction mixture be-
came bright yellow again and it was stirred for 10 min at –10 °C.
Brine (10 mL) was added, and the mixture was extracted with
EtOAc (3ϫ30 mL). The combined organic layer was dried with
Na2SO4 and filtered. The solvent was removed under reduced pres-
sure. Silica gel chromatography (n-heptane/EtOAc, 2:1–1:3) gave
quinone 13 (364 mg, 1.55 mmol, 82%) as a yellow solid (m.p. 136–
140 °C, decomposition). Rf = 0.41 (n-heptane/EtOAc, 1:1). 1H
NMR (500 MHz, CDCl3): δ = 6.86 (d, J = 10.2 Hz, 1 H, 8-H), 6.81
(d, J = 10.2 Hz, 1 H, 7-H), 5.13–5.07 (m, 1 H, 9b-H), 4.63 (dq, J
= 6.6, 1.5 Hz, 1 H, 5-H), 4.32 (dd, J = 4.6, 2.6 Hz, 1 H, 3a-H),
2.87 (dd, J = 17.5, 4.7 Hz, 1 H, 2-H), 2.71 (d, J = 17.5 Hz, 1 H, 3-
(COOH), 170.3 (COOH), 177.4 (COO) ppm. IR (film): ν = 2920,
˜
1774, 1702, 1633, 1397, 1250, 1205, 1157, 1076, 1044, 993, 908,
869, 690, 636 cm–1. HRMS (ESI): calcd. for C10H10O7 [M + Na]+
265.0319; found 265.0328. [α]D = –0.6 (c = 1.06, MeOH, 22 °C).
(3aS,5S,9bS)-6,9-Dimethoxy-5-methyl-3,3a,5,9b-tetrahydro-2H-
furo[3,2-c]isochromen-2-one (16): Hydroxyacetone 10 (2.00 g,
8.40 mmol) and acetaldehyde dimethyl acetal (3.40 mL,
32.11 mmol) were dissolved in THF (10 mL). The mixture was can-
nulated into a solution of BF3·OEt2 (12.66 mL, 100.9 mmol) in
TFA (100 mL) at 80 °C. After stirring for 1 min, the mixture was
cooled to 0 °C and satd. aq. NaHCO3 was added slowly for neu-
tralization (pH = 7). The aqueous layer was extracted with EtOAc
(3 ϫ 100 mL), and the combined organic layer was dried with
Na2SO4, filtered, and concentrated under reduced pressure. The
crude product was purified by flash column chromatography on
H), 1.52 (d, J = 6.7 Hz, 3 H, 5-Me) ppm. 13C NMR (126 MHz, silica (n-heptane/EtOAc, 2:1 to 1:2) to afford isochroman 16
CDCl3): δ = 185.9 (C-6), 184.3 (C-9), 174.4 (C-2), 148.1 (C-5a),
137.3 (C-7), 136.2 (C-8), 132.9 (C-9a), 71.3 (C-3a), 69.4 (C-9b),
(912 mg, 3.45 mmol, 14:1dr, 41%) as a yellow solid (m.p. 127 °C).
Rf = 0.20 (EtOAc/n-hexane, 1:2). H NMR (400 MHz, CDCl3): δ
1
68.5 (C-5), 37.3 (C-3), 20.1 (5-Me) ppm. IR (film): ν = 2940, 1775, = 1.46 (d, J = 6.7 Hz, 3 H, 5-CH3), 2.65 (d, J = 17.5 Hz, 1 H, 3-
˜
1654, 1319, 1298, 1145, 1110, 1036, 1006, 989, 904, 841, 484 cm–1. H), 2.92 (dd, J = 5.0, 17.5 Hz, 1 H, 3-H), 3.79 (s, 3 H, OMe), 3.84
HRMS (ESI): calcd. for C12H10O5 [M + Na]+ 257.0420; found
257.0422. [α]D = 28.9 (c = 1.02, CHCl3, 18 °C).
(s, 3 H, OMe), 4.69 (dd, J = 2.9, 4.9 Hz, 1 H, 3a-H), 5.15 (q, J =
6.7 Hz, 1 H, 5-H), 5.33 (d, J = 2.8 Hz, 1 H, 9b-H), 6.77 (d, J =
Eur. J. Org. Chem. 2013, 180–190
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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185

U. Koert et al.
FULL PAPER
8.9 Hz, 1 H, 8-HAr), 6.84 (d, J = 8.9 Hz, 1 H, 7-HAr) ppm. 13C
and purified by solid-phase extraction (Waters Sep-Pak® Vac 6cc,
NMR (125 MHz, CDCl3): δ = 18.6 (5-CH3), 37.8 (C-3), 55.8 C18–1 g, H2O/CH3CN, 1:0 to 9:1). After intensive drying under
(OMe), 56.3 (OMe), 66.1 (C-5), 67.5 (C-3a), 71.6 (C-9b), 109.2
(CAr-8), 111.6 (CAr-7), 117.1 (CAr-9a), 130.3 (CAr-5a), 148.8 (CAr
6), 152.8 (CAr-9), 175.6 (COO) ppm. IR (film): ν = 2988, 2937,
high vacuum, the remaining oil was evaporated with CH2Cl2 to
afford diacid 19 (405 mg, 1.67 mmol, 82%) as a colorless solid
(m.p. 111–113 °C). Rf = 0.14 (EtOAc/MeOH/H2O/CH3CN,
-
˜
1772, 1605, 1288, 1258, 1197, 1152, 1072, 983, 968, 905, 799, 4.5:1:1:1). 1H NMR (500 MHz, [D4]MeOH): δ = 1.39 (d, J =
713 cm–1. HRMS (ESI): calcd. for C14H16O5 [M + Na]+ 287.0890;
found 287.0889. [α]D = –135.9 (c = 1.05, CHCl3, 18 °C).
6.9 Hz, 3 H, 5-CH3), 2.50 (d, J = 17.8 Hz, 1 H, C-3), 3.08 (dd, J
= 5.3, 17.8 Hz, 1 H, 3-H), 4.64 (dd, J = 3.2, 5.1 Hz, 1 H, C-3a),
4.74 (q, J = 6.8 Hz, 1 H, 5-H), 5.12 (d, J = 3.0 Hz, 1 H, 7a-H)
ppm. 13C NMR (125 MHz, [D4]MeOH): δ = 17.0 (5-CH3), 37.7 (C-
3), 67.9 (C-3a), 70.9 (C-5), 73.7 (C-7a), 125.1 (C-7), 150.2 (C-6),
(3aS,5S,9bS)-5-Methyl-3,3a-dihydro-5H-furo[3,2-c]isochromene-
2,6,9-(9bH)-trione (17): Isochroman 16 (285 mg, 1.08 mmol) was
dissolved in MeCN/water (1:1, 10 mL), and the mixture was cooled
to –20 °C. CAN (1.18 g, 2.16 mmol) was added in one portion. The
reaction mixture was stirred at –20 °C for 10 min. Upon complete
conversion of the starting material, brine (20 mL) was added, and
the mixture was extracted with EtOAc (3ϫ25 mL). The combined
organic layer was dried with Na2SO4, and the solvent was removed
under reduced pressure. Silica gel chromatography (n-heptane/
EtOAc, 4:1–1:2) gave quinone 17 (149 mg, 0.64 mmol, 59%) as a
yellow solid (m.p. 125–130 °C, decomposition). Rf = 0.49 (n-hept-
ane/EtOAc, 1:2). 1H NMR (400 MHz, CDCl3): δ = 6.87 (d, J =
10.2 Hz, 1 H, 8-H), 6.82 (d, J = 10.2 Hz, 1 H, 7-H), 5.09 (d, J =
2.9 Hz, 1 H, 9b-H), 4.90 (q, J = 6.9 Hz, 1 H, 5-H), 4.64 (dd, J =
4.9, 3.0 Hz, 1 H, 3a-H), 2.94 (dd, J = 17.8, 5.2 Hz, 1 H, 3-H), 2.66
(d, J = 17.8 Hz, 1 H, 3-H), 1.47 (d, J = 6.9 Hz, 3 H, 5-Me) ppm.
13C NMR (126 MHz, CDCl3): δ = 185.3 (C-6), 184.5 (C-9), 174.1
(C-2), 147.5 (C-5a), 136.72/136.68 (C-7/C-8), 132.3 (C-9a), 68.5 (C-
9b), 66.5/66.3 (C-3a/C-5), 37.0 (C-3), 18.5 (5-Me) ppm. IR (film):
167.4 (COOH), 169.8 (COOH), 177.2 (COO) ppm. IR (film): ν =
˜
3180 (br. m), 2940 (br. m), 1709 (s), 1205 (m), 1155 (m), 1084 (w),
1065 (w), 991 (w), 731 (w), 688 (w) cm–1. HRMS (ESI): calcd. for
C10H10O7 [M + Na]+ 265.0319; found 265.0319. [α]D = +0.7 (c =
1.68, MeOH, 22 °C).
(3aS,5R,8bS)-5-Methyl-3a,8b-dihydro-5H-difuro[3,2-b:3Ј,4Ј-d]pyr-
an-2,6,8-(3H)-trione (21): Dicarboxylic acid 19 (71 mg, 0.29 mmol)
was suspended in DCM (5 mL). TFAA (1 mL) was added, which
resulted in a clear solution within 10 min. After stirring for 15 min,
the solvent and the excess amount of TFAA were removed under
reduced pressure. Silica gel chromatography (15 g dried silica gel;
n-heptane/EtOAc/TFAA, 50:25:1.5–25:25:1) afforded anhydride 21
(64 mg, 0.29 mmol, 97%) as a colorless hygroscopic solid. Rf = 0.37
1
(n-heptane/EtOAc/TFAA, 25:25:1). H NMR (400 MHz, CDCl3):
δ = 5.03 (s, 1 H, 8b-H), 4.64 (dq, J = 6.7, 1.5 Hz, 1 H, 5-H), 4.48
(dd, J = 5.0, 3.0 Hz, 1 H, 3a-H), 2.97 (dd, J = 18.0, 5.3 Hz, 1 H,
3-H), 2.81 (d, J = 18.0 Hz, 1 H, 3-H), 1.62 (d, J = 6.9 Hz, 3 H, 5-
Me) ppm. 13C NMR (126 MHz, CDCl3): δ = 173.1 (C-2), 161.22/
161.15 (C-6/C-8), 151.8 (C-5a), 136.9 (C-8a), 72.6 (C-3a), 68.2 (C-
5), 67.7 (C-8b), 36.3 (C-3), 17.5 (5-Me) ppm. HRMS (APCI): calcd.
for C10H9O6 [M + H]+ 225.0394; found 225.0392.
ν = 2937, 1773, 1655, 1604, 1306, 1199, 1147, 1004, 990, 904, 841,
˜
462 cm–1. HRMS (ESI): calcd. for C12H10O5 [M + Na]+ 257.0420;
found 257.0419. [α]D = +5.4 (c = 1.03, CHCl3, 18 °C).
(3aS,5S,9bS)-6,9-Dihydroxy-5-methyl-3,3a,5,9b-tetrahydro-2H-
furo[3,2-c]isochromen-2-one (18): Quinone 17 (136 mg, 0.58 mmol)
was dissolved in EtOAc (25 mL). The solution was stirred under
an argon atmosphere and Pd/C (10 mg) was added. Under an at-
mosphere of hydrogen, the mixture was stirred for 5 min, and upon
completion of the reaction, it was filtered through a plug of Celite.
The solvent was removed under reduced pressure to afford hydro-
quinone 18 (136 mg, 0.58 mmol, 99%) as a yellow solid (m.p. 181–
(3aS,5R,7aS)-6-(2Ј,5Ј-Dimethoxybenzoyl)-5-methyl-2-oxo-
3,3a,5,7a-tetrahydro-2H-furo[3,2-b]pyran-7-carboxylic Acid (22) and
(3aS,5R,7aS)-7-(2Ј,5Ј-Dimethoxybenzoyl)-5-methyl-2-oxo-
3,3a,5,7a-tetrahydro-2H-furo[3,2-b]pyran-6-carboxylic (23): Mg
turnings (70 mg, 3.25 mmol) were stirred in THF (5 mL) at 70 °C
for 10 min. After the addition of 1,2-dibromoethane (1 drop), the
mixture was heated at reflux for 5 min. Subsequently, 1-bromo-2,5-
dimethoxybenzene (20; 565 mg, 2.60 mmol) was added, and the
mixture was stirred at 70 °C for 1 h. Anhydride 21 (139 mg,
0.62 mmol) was dissolved in THF (10 mL), and the solution was
cooled to –80 °C. The Grignard solution was cooled to room tem-
perature and partially (1.31 mL, 0.68 mmol) added to the anhy-
dride solution at –80 °C over 5 min. The reaction mixture was
warmed up to –50 °C over 1 h. The reaction was quenched by ad-
dition of satd. NH4Cl (10 mL). After addition of 1 m HCl (1 mL)
and brine (5 mL), the mixture was extracted with EtOAc
(3ϫ20 mL). The combined organic layer was dried with Na2SO4,
and the solvent was removed under reduced pressure. Silica gel
chromatography (n-hexane/EtOAc, 1:1; EtOAc/H2O/MeOH/
MeCN 6:1:1:1) afforded ketocarboxylic acids 22 and 23 (120 mg,
0.33 mmol, 53%) as an inseparable mixture of regioisomers as a
pale brown solid. Data for 22: Rf = 0.41 (DCM/MeOH, 9:1). 1H
NMR (400 MHz, MeOD): δ = 7.44 (d, J = 2.7 Hz, 1 H, 6Ј-H),
7.15–6.89 (m, 2 H, 3Ј-H, 4Ј-H), 5.11 (s, 1 H, 7-H), 4.54 (q, J =
6.6 Hz, 1 H, 5-H), 4.45 (br. s, 1 H, 3a-H), 3.79 (s, 3 H, OMe), 3.72
(s, 3 H, OMe), 3.09 (dd, J = 17.6, 5.0 Hz, 1 H, 3-H), 2.57 (d, J =
17.6 Hz, 1 H, 3-H), 1.15 (br. s, 3 H, 5-Me) ppm. 13C NMR: As a
result of the equilibrium between the keto acid and the dia-
stereomeric hemiacetals, it was not possible to characterize com-
pounds 22 and 23 by 13C NMR spectroscopy properly. However,
full characterization could be achieved at the following methyl ester
1
193 °C). Rf = 0.21 (EtOAc/n-hexane, 2:1). H NMR (400 MHz,
d4MeOH): δ = 1.48 (d, J = 6.7 Hz, 3 H, 5-CH3), 2.49 (d, J =
17.5 Hz, 1 H, 3-H), 3.09 (dd, J = 5.0, 17.5 Hz, 1 H, 3-H), 4.75 (dd,
J = 2.7, 4.6 Hz, 1 H, 3a-H), 5.07 (q, J = 6.6 Hz, 1 H, 5-H), 5.40
(d, J = 2.5 Hz, 1 H, 9b-H), 6.61 (d, J = 8.6 Hz, 1 H, 8-HAr), 6.66
(d, J = 8.6 Hz, 1 H, 7-HAr) ppm. 13C NMR (125 MHz, d4MeOH):
δ = 18.6 (5-CH3), 38.6 (C-3), 67.6 (C-3a), 69.0 (C-5), 74.2 (C-9b),
114.6 (C-7), 116.2 (C-9a), 117.4 (C-8), 128.9 (C-5a), 146.3 (C-6),
150.8 (C-9), 178.8 (COO) ppm. IR (film): ν = 3349 (br. m), 2978
˜
(w), 2931 (w), 1744 (s), 1492 (s), 1278 (s), 1256 (s), 1206 (s), 1154
(s), 1088 (s), 1029 (s), 976 (m), 913 (s), 816 (m), 715 (m) cm–1.
HRMS (ESI): calcd. for C12H12O5 [M + Na]+ 259.0577; found
259.0587. [α]D = 160.8 (c = 1.03, MeOH, 18 °C).
(3aS,5S,7aS)-3,3a,5,7a-Tetrahydro-5-methyl-2-oxo-2H-furo[3,2-b]-
pyran-6,7-dicarboxylic Acid (19): Hydroquinone 18 (481 mg,
2.04 mmol) was dissolved in CH2Cl2/DMF (4:1, 25 mL). The solu-
tion was cooled to –110 °C, and freshly generated O3 (200 L/h,
0.75 A) was bubbled through the solution until the mixture was
green. To remove the remaining O3, oxygen was bubbled through
the reaction mixture until the color turned yellow, and then H2O2
(30%, 0.4 mL) and glacial acetic acid (0.4 mL, 7.00 mmol) were
added. After the addition, the reaction was warmed to room tem-
perature slowly, and the solvent was removed under reduced pres-
sure. The remaining crude material was dissolved in H2O (0.5 mL)
186
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 180–190

Synthesis of the AB-Ring Pyranolactone Substructure of Granaticin A
stage (compounds 24 and 25). IR (film): ν = 2917, 2837, 1766, 20.4 (5-Me) ppm. IR (film): ν = 39, 1782, 1671, 1660, 1592, 1287,
˜
˜
1645, 1496, 1464, 1415, 1278, 1223, 1153, 1036, 988, 895, 816, 728, 1147, 1108, 1037, 992, 880, 729, 682, 479 cm–1. HRMS (ESI): calcd.
552 cm–1. HRMS (ESI): calcd. for C18H18O8 [M + Na]+ 385.0894;
found 385.0899. Data for 23: Rf = 0.41 (DCM/MeOH, 9:1).
for C16H12O5 [M + Na]+ 307.0577; found 307.0576. [α]D = +72.1
(c = 1.07, CHCl3, 18 °C).
Methyl (3aS,5R,7aS)-6-(2,5-Dimethoxybenzoyl)-5-methyl-2-oxo- (3aS,5R,8bS)-5-Methyl-3a,8b-dihydro-5H-difuro[3,2-b:3Ј,4Ј-d]pyr-
3,3a,5,7a-tetrahydro-2H-furo[3,2-b]pyran-7-carboxylate (24) and an-2,6-(3H,8H)-dione (28) and (3aS,5R,8bS)-5-Methyl-3,3a,6,8b-
Methyl (3aS,5R,7aS)-7-(2,5-Dimethoxybenzoyl)-5-methyl-2-oxo- tetrahydro-5H-difuro[3,2-b:3Ј,4Ј-d]pyran-2,8-dione (29): Anhydride
3,3a,5,7a-tetra-hydro-2H-furo[3,2-b]pyran-6-carboxylate (25): The
mixture of keto acids 22 and 23 (35 mg, 0.10 mmol) was dissolved
in dry DMF (2 mL). Subsequently, MeI (6.64 μL, 0.11 mmol) and
Cs2CO3 (35 mg, 0.11 mmol) were added. The reaction mixture was
stirred at room temperature for 4 h. The reaction was stopped by
the addition of satd. NH4Cl (5 mL) and 1 m HCl (1 mL). The mix-
21 (65 mg, 0.29 mmol) was dissolved in dry THF (5 mL), and the
solution was cooled to 0 °C. Li(OtBu)3AlH (LTBA) (1.0 m in THF,
0.61 mL, 0.61 mmol) was added slowly, and the reaction mixture
was stirred at 0 °C for 2 h. The reaction was stopped by addition
of 1 m HCl (3 mL) and brine (3 mL), and the mixture was extracted
with EtOAc (3ϫ10 mL). The combined organic layer was dried
ture was extracted with EtOAc (3ϫ10 mL), the combined organic with Na2SO4, and the solvent was removed under reduced pressure.
layer was dried with Na2SO4, and the solvent was removed under
reduced pressure. Silica gel chromatography (n-heptane/EtOAc,
2:1–1:2) afforded methyl esters 24 and 25 (18 mg, 0.05 mmol, 50%,
rr = 10:1) as an inseparable mixture as a colorless solid. Data for
Silica gel chromatography (10 g, n-heptane/EtOAc, 2:3–0:1) af-
forded regioisomeric bislactones 28 (15 mg, 0.071 mmol, 25%) and
29 (15 mg, 0.071 mmol, 25%) as pale brown solids. Data for 28:
1
M.p. 110 °C. Rf = 0.54 (EtOAc). H NMR (500 MHz, CDCl3): δ
24: Rf = 0.23 (n-heptane/EtOAc, 1:1). 1H NMR (500 MHz, = 5.01 (dd, J = 17.6, 2.6 Hz, 1 H, 8-H), 4.88 (dd, J = 17.9, 2.8 Hz,
CDCl3): δ = 7.56 (d, J = 3.2 Hz, 1 H, 6Ј-H), 7.12 (dd, J = 9.0,
1 H, 8-H), 4.84 (s, 1 H, 8b-H), 4.44 (dd, J = 5.5, 3.3 Hz, 2 H, 5-H,
3.2 Hz, 1 H, 4Ј-H), 6.90 (d, J = 9.0 Hz, 1 H, 3Ј-H), 5.04 (d, J = 3a-H), 2.93 (dd, J = 18.1, 5.6 Hz, 1 H, 3-H), 2.76 (d, J = 18.0 Hz, 1
1.3 Hz, 1 H, 7a-H), 4.55 (q, J = 6.8 Hz, 1 H, 5-H), 4.42 (dd, J = H, 3-H), 1.54 (d, J = 6.8 Hz, 3 H, 5-Me) ppm. 13C NMR
4.7, 3.0 Hz, 1 H, 3a-H), 3.83 (s, 3 H, 5Ј-OMe), 3.74 (s, 3 H, 2Ј- (126 MHz, CDCl3): δ = 174.0 (C-2), 169.7 (C-6), 151.6 (C-8a),
OMe), 3.62 (s, 3 H, CO2Me), 2.90 (dd, J = 17.6, 4.9 Hz, 1 H, 3-
H), 2.72 (d, J = 17.5 Hz, 1 H, 3-H), 1.23 (d, J = 6.8 Hz, 3 H, 5-Me)
134.8 (C-5a), 72.1 (C-3a), 70.9 (C-8b), 70.3 (C-8), 68.3 (C-5), 36.5
(C-3), 17.3 (5-Me) ppm. IR (film): ν = 2936, 2854, 1754, 1678,
˜
ppm. 13C NMR (126 MHz, CDCl3): δ = 193.4 (6-CO-1Ј), 174.7 (C- 1162, 1144, 1101, 1040, 1013, 993, 903, 692 cm–1. HRMS (ESI):
2), 164.7 (CO2Me), 162.3 (C-6), 154.6 (C-2Ј), 154.0 (C-5Ј), 125.6
(C-1Ј), 123.3 (C-4Ј), 117.4 (C-7), 114.2 (C-3Ј), 112.3 (C-6Ј), 72.5 –5.4 (c = 0.65, CHCl3, 19 °C). Data for 29: M.p. 95 °C. Rf = 0.38
(C-3a), 72.3 (C-7a), 71.9 (C-5), 55.95/55.89 (2Ј-OMe/5Ј-OMe), 52.4
calcd. for C10H10O5 [M + Na]+ 233.0420, found 233.0422. [α]D
=
1
(EtOAc). H NMR (500 MHz, CDCl3): δ = 4.91 (d, J = 3.6 Hz, 2
(CO Me), 37.7 (C-3), 17.4 (5-Me) ppm. IR (film): ν = 2925, 2840, H, 6-H), 4.87 (d, J = 1.7 Hz, 1 H, 8b-H), 4.57 (q, J = 6.8 Hz, 1 H,
˜
2
1781, 1717, 1644, 1495, 1414, 1255, 1220, 1151, 1033, 989, 958,
876, 728, 549 cm–1. HRMS (ESI): calcd. for C19H20O8 [M + Na]+
399.1050, found 399.1055. Data for 25: Rf = 0.23 (n-heptane/
EtOAc, 1:1). 1H NMR (500 MHz, CDCl3): δ = 7.31 (d, J = 3.2 Hz,
1 H, 6Ј-H), 7.07 (dd, J = 9.0, 3.1 Hz, 1 H, 4Ј-H), 6.90 (d, J =
9.0 Hz, 1 H, 3Ј-H), 4.92 (dd, J = 2.3, 2.2 Hz, 1 H, 7a-H), 4.49 (dq,
J = 6.6, 1.6 Hz, 1 H, 5-H), 4.32 (dd, J = 5.0, 3.0 Hz, 1 H, 3a-H),
5-H), 4.41 (dd, J = 5.2, 2.9 Hz, 1 H, 3a-H), 2.92 (dd, J = 17.8,
5.3 Hz, 1 H, 3-H), 2.71 (d, J = 17.8 Hz, 1 H, 3-H), 1.42 (d, J =
6.9 Hz, 3 H, 5-Me) ppm. 13C NMR (126 MHz, CDCl3): δ = 174.4
(C-2), 170.7 (C-8), 169.4 (C-5a), 121.6 (C-8a), 72.8 (C-3a), 69.5 (C-
6), 68.83 (C-5), 68.76 (C-8b), 36.8 (C-3), 18.3 (5-Me) ppm. IR
(film): ν = 2924, 2853, 1779, 1742, 1204, 1151, 1112, 1071, 1040,
˜
1021, 996, 973, 896 cm–1. HRMS (ESI): calcd. for C10H10O5 [M +
3.80 (s, 3 H, OMe), 3.78 (s, 3 H, OMe), 3.50 (s, 3 H, CO2Me), 2.83 Na]+ 233.0420; found 233.0424. [α]D = –81.7 (c = 0.35, CHCl3,
(dd, J = 17.7, 5.2 Hz, 1 H, 3-H), 2.70 (d, J = 17.7 Hz, 1 H, 3-H),
1.44 (d, J = 6.6 Hz, 3 H, 5-Me) ppm. 13C NMR (126 MHz,
CDCl3): δ = 193.5 (6-CO-1Ј), 174.3 (C-2), 165.6 (CO2Me), 138.9
(C-7), 137.9 (C-6), 73.7 (C-7a), 71.8 (C-3a), 70.0 (C-5), 56.4 (OMe),
56.0 (OMe), 52.1 (CO2Me), 37.1 (C-3), 19.6 (5-Me) ppm; CAr were
excluded because of weak and overlapping signals.
19 °C).
(2R,3aS,5R,8bS)-2-Methoxy-5-methyl-3,3a,5,8b-tetrahydro-2H-di-
furo[3,2-b:3Ј,4Ј-d]pyran (30): Bislactones 28/29 (1:1, 340 mg,
1.62 mmol) were dissolved in dry DCM (20 mL), and the solution
was cooled to –78 °C. DIBAL-H (1.0 m in cyclohexane, 6.48 mL,
6.48 mmol) was added, and the reaction mixture was stirred at –60
to –78 °C for 1 h. Upon complete consumption of the starting ma-
terial, EtOAc (1 mL) was added. After 5 min, the mixture was
poured onto ice water. Then, 1 m HCl (15 mL) was added, and the
mixture was stirred for 3 min. Brine (20 mL) was added, and the
mixture was extracted with CHCl3 (3ϫ20 mL). The combined or-
ganic layer was dried with Na2SO4, and the solvent was removed
under reduced pressure. The hemiacetals (153 mg, 0.73 mmol, 48%,
3:2dr) were obtained as colorless solids in good purity. Without
(3aS,5R,11bS)-5-Methyl-3,3a-dihydro-2H-benzo[g]furo[3,2-c]iso-
chrom-ene-2,6,11-(5H,11bH)-trione (27): To a solution of quinone
13 (2.27 mmol, 532 mg) dissolved in MeOH (10 mL) was added
diene 26 (0.40 mL, 3.41 mmol). After the reaction mixture had
been stirred for 6 h at room temperature, a further portion of the
diene (0.20 mL, 1.71 mmol) was added. The mixture was stirred for
2 h and silica gel (2 g) was added. The solvent was removed under
reduced pressure. Silica gel chromatography (40 g, n-heptane/
EtOAc, 3:1–1:5) afforded naphthoquinone 27 (324 mg, 1.14 mmol, further purification they were dissolved in MeOH (25 mL).
50%) as a yellow solid (m.p. 185 °C, decomposition). Rf = 0.45 (n- BF3·OEt2 (0.1 mL, 0.81 mmol) was added, and the mixture was
1
heptane/EtOAc, 1:1). H NMR (500 MHz, CDCl3): δ = 8.18–8.12 stirred at 40 °C for 1 h. Upon complete consumption of the starting
(m, 1 H, 10-H), 8.10–8.04 (m, 1 H, 7-H), 7.83–7.74 (m, 2 H, 8-H, material, the mixture was poured into 0.5 m NaHCO3 (50 mL) and
9-H), 5.30 (dd, J = 2.1, 2.0 Hz, 1 H, 11b-H), 4.79 (dq, J = 6.6,
extracted with CHCl3. The combined organic layer was dried with
1.6 Hz, 1 H, 5-H), 4.36 (dd, J = 4.6, 2.5 Hz, 1 H, 3a-H), 2.90 (dd, Na2SO4, and the solvent was removed under reduced pressure.
J = 17.5, 4.7 Hz, 1 H, 3-H), 2.75 (d, J = 17.5 Hz, 1 H, 3-H), 1.60
(d, J = 6.7 Hz, 3 H, 5-Me) ppm. 13C NMR (126 MHz, CDCl3): δ
= 184.2 (C-6), 182.4 (C-11), 174.4 (C-2), 150.6 (C-5a), 134.7 (C-
11a), 134.5/134.3 (C-8/C-9), 132.5/131.7 (C-6a/C-10a), 126.8 (C-
Furan 30 (164 mg, 0.73 mmol, 100%, 48% over two steps, 15:1dr)
was obtained as a colorless solid in sufficient purity (Ͼ95%). Ana-
lytically pure samples were obtained by silica gel chromatography
(n-pentane/Et2O, 9:1–2:1). Data for 30: M.p. 59 °C. Rf = 0.52 (n-
10), 126.6 (C-7), 71.3 (C-3a), 70.0 (C-11b), 68.9 (C-5), 37.4 (C-3), pentane/Et2O, 4:1). 1H NMR (500 MHz, CDCl3): δ = 7.58 (s, 1 H,
Eur. J. Org. Chem. 2013, 180–190
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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187

U. Koert et al.
FULL PAPER
8-H), 7.20 (t, J = 1.2 Hz, 1 H, 6-H), 5.24 (dd, J = 5.9, 3.2 Hz, 1
H, 2-H), 4.81 (d, J = 2.8 Hz, 1 H, 8b-H), 4.49 (qd, J = 6.3, 1.5 Hz,
1 H, 5-H), 4.21 (ddd, J = 6.2, 3.3, 0.7 Hz, 1 H, 3a-H), 3.42 (s, 3 H,
(C-3), 17.2 (5-Me) ppm. IR (film): ν = 2940, 2360, 1774, 1738,
˜
1349, 1256, 1207, 1151, 1061, 1023, 1002, 972, 899, 860, 760, 672,
597, 547, 446 cm–1. HRMS (ESI): calcd. for C10H10O5 [M + Na]+
OMe), 2.40 (ddd, J = 14.8, 5.9, 1.0 Hz, 1 H, 3-H), 2.27 (ddd, J = 233.0420, found 233.0420. [α]D = –0.96 (c = 1.25, CHCl3, 21 °C).
1
14.8, 6.2, 3.2 Hz, 1 H, 3-H), 1.49 (d, J = 6.4 Hz, 3 H, 5-Me) ppm.
Data for 32: M.p. 69 °C. Rf = 0.45 (EtOAc). H NMR (500 MHz,
13C NMR (126 MHz, CDCl3): δ = 141.4 (C-8), 135.3 (C-6), 124.9 CDCl3): δ = 4.95 (d, J = 18.1 Hz, 1 H, 6-H), 4.86 (dd, J = 18.0,
(C-5a), 117.8 (C-8a), 105.4 (C-2), 77.6 (C-3a), 68.8 (C-8b), 68.2 (C-
2.0 Hz, 1 H, 6-H), 4.86 (m, 1 H, 8b-H), 4.81 (q, J = 7.1 Hz, 1 H,
5-H), 4.56 (dd, J = 5.3, 3.0 Hz, 1 H, 3a-H), 2.92 (dd, J = 17.8,
5.3 Hz, 1 H, 3-H), 2.65 (d, J = 17.8 Hz, 1 H, 3-H), 1.46 (d, J =
7.1 Hz, 3 H, 5-Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 174.5
5), 55.6 (OMe), 41.0 (C-3), 20.6 (5-Me) ppm. IR (film): ν = 3109,
˜
2908, 2835, 1557, 1442, 1341, 1307, 1252, 1216, 1184, 1091, 1028,
945, 897, 863, 835, 797, 645, 597, 537 cm–1. HRMS (ESI): calcd.
for C11H14O4 [M + Na]+ 233.0784; found 233.0783. [α]D = –234.4 (C-2), 170.6 (C-8), 169.6 (C-5a), 120.4 (C-8a), 70.0 (C-6), 68.3 (C-
(c = 0.50, CHCl3, 21 °C). Minor anomer: Rf = 0.30 (n-pentane/
8b), 67.8 (C-5), 66.9 (C-3a), 36.5 (C-3), 18.2 (5-Me) ppm. IR (film):
Et2O, 2:1). 1H NMR (500 MHz, CDCl3): δ = 7.56 (“t”, J = 1.1 Hz, ν = 2938, 2360, 1751, 1682, 1440, 1350, 1198, 1152, 1123, 1100,
˜
1 H, 8-H), 7.18 (“t”, J = 1.2 Hz, 1 H, 6-H), 5.13 (dd, J = 6.2,
1.6 Hz, 1 H, 2-H), 4.73 (d, J = 3.6 Hz, 1 H, 8b-H), 4.45 (qd, J =
6.3, 1.5 Hz, 1 H, 5-H), 4.15 (dd, J = 5.7, 3.7 Hz, 1 H, 3a-H), 3.32
(s, 3 H, OMe), 2.40 (“dt”, J = 14.6, 6.2 Hz, 1 H, 3-H), 2.23 (dd, J
= 14.6, 1.0 Hz, 1 H, 3-H), 1.52 (d, J = 6.4 Hz, 3 H, 5-Me) ppm.
13C NMR (126 MHz, CDCl3): δ = 141.1 (C-8), 135.0 (C-6), 125.0
(C-5a), 119.2 (C-8a), 105.7 (C-2), 76.5 (C-3a), 70.8 (C-8b), 68.2 (C-
5), 55.5 (OMe), 39.9 (C-3), 20.6 (5-Me) ppm.
1036, 991, 919, 900, 806, 766, 706, 677, 564, 526, 443 cm–1. HRMS
(ESI): calcd. for C10H10O5 [M + Na]+ 233.0420; found 233.0419.
[α]D = –39.0 (c = 1.05, CHCl3, 23 °C).
(2R,3aS,5S,8bS)-2-Methoxy-5-methyl-3,3a,5,8b-tetrahydro-2H-di-
furo-[3,2-b:3Ј,4Ј-d]pyran (33): Bislactones 31 (219 mg, 1.04 mmol)
and 32 (424 mg, 2.02 mmol) were dissolved in CH2Cl2 (30 mL), and
the solution was cooled to –80 °C. DIBAL-H (1.0 m in cyclohexane,
12.3 mL, 12.3 mmol) was added. The mixture was stirred at –80 °C
for 1 h. The reaction was quenched by addition of EtOAc (5 mL),
and the mixture was stirred for 5 min at –65 °C. Then, the mixture
was poured onto ice, HCl (3.0 m, 10 mL) was added, and it was
vigorously stirred for 5 min. The mixture was extracted with CHCl3
(3ϫ25 mL), and the combined organic layer was dried with anhy-
drous Na2SO4. The solvent was removed under reduced pressure.
The crude hemiacetal (366 mg, 1.87 mmol, 61%, 3:2dr) was ob-
tained in good purity as a pale yellow solid. It was used in the next
step without purification. The hemiacetal (350 mg, 1.79 mmol) was
dissolved in MeOH (10 mL) and BF3·OEt2 (22 μL, 0.18 mmol) was
added. The mixture was stirred at 45 °C for 15 min. Upon complete
conversion of the starting material, the mixture was poured into
NaHCO3 (1.0 m, 20 mL) and extracted with CHCl3 (3ϫ30 mL).
The combined organic layer was dried with anhydrous Na2SO4,
and the solvent was removed under reduced pressure. Crude furan
33 (339 mg, 1.61 mmol, 90%, 55% over 2 steps, 8:1dr) was ob-
tained as a colorless solid (m.p. 95 °C). Rf = 0.61 (major epimer,
n-pentane/Et2O, 2:1). Rf = 0.46 (minor epimer, n-pentane/Et2O,
(3aS,5S,8bS)-5-Methyl-3,3a,8,8b-tetrahydro-2H-difuro[3,2-b:3Ј,4Ј-d]-
pyran-2,6-(5H)-dione (31) and (3aS,5S,8bS)-5-Methyl-3,3a,6,8b-
tetrahydro-2H-difuro[3,2-b:3Ј,4Ј-d]pyran-2,8-(5H)-dione (32): Hy-
droquinone 18 (1.73 g, 7.31 mmol) was dissolved in DCM/DMF
(4:1, 125 mL), and the solution was cooled to –110 °C. A mixture
of ozone and oxygen was passed through the solution. After
25 min, the color of the mixture turned from pale yellow to green.
Then, ozone generation was stopped and oxygen was passed
through the solution to remove the excess amount of ozone. After
the mixture had turned yellow again, H2O2 (30%, 3 mL) and glacial
acetic acid (3 mL) were added. The mixture was warmed up to
room temperature and all volatiles were removed under reduced
pressure. After 4 h under high vacuum, the crude dicarboxylic acid
(2.32 g) was obtained as a pale brown gum that still contained
minor amounts of DMF. This material was used in the next step
without purification. The crude dicarboxylic acid (2.32 g) was sus-
pended in CHCl3 at room temperature and TFAA (1.55 mL,
11.0 mmol) was added. The mixture was stirred at room tempera-
ture for 1 h. When the mixture became a clear solution, all volatiles
were removed under reduced pressure. After 1 h under high vac-
uum, the crude anhydride (3.20 g) was obtained. This material was
used in the next step without purification. The crude anhydride
(3.20 g) was dissolved in dry THF (40 mL), and the solution was
cooled to –50 °C. LTBA (1.0 m in THF, 18.3 mL, 18.3 mmol) was
added at –50 °C, and the mixture was stirred for 10 min at that
temperature. Subsequently, the mixture was stirred at 0 °C for 1.5 h.
The reaction was stopped by addition of HCl (3.0 m, 5 mL). Water
(25 mL) and brine (10 mL) were added, and the mixture was ex-
tracted with CHCl3 (3ϫ20 mL). The combined organic layer was
dried with anhydrous Na2SO4, and the solvent was removed under
reduced pressure. Silica gel chromatography (80 g, n-pentane/
EtOAc, 1:1–0:1) afforded bislactone 31 (243 mg, 1.16 mmol, 16%
over three steps, 80 % purity) as a pale yellow solid and its re-
gioisomer 32 (403 mg, 1.92 mmol, 26% over three steps) as a color-
2:1). IR (film): ν = 3114, 2973, 2928, 2360, 1738, 1551, 1434, 1372,
˜
1340, 1212, 1133, 1093, 1072, 1017, 955, 892, 865, 797, 760, 601,
583, 557, 503 cm–1. HRMS (ESI): calcd. for C11H14O4 [M + Na]+
233.0784, found 233.0784. [α]D = –123.5 (c = 1.10, CHCl3, 20 °C,
dr = 8:1). Data for the major epimer: 1H NMR (500 MHz, CDCl3):
δ = 7.56 (d, J = 1.1 Hz, 1 H, 8-H), 7.22 (s, 1 H, 6-H), 5.20 (dd, J
= 5.7, 2.8 Hz, 1 H, 2-H), 4.99 (q, J = 6.6 Hz, 1 H, 5-H), 4.89 (d, J
= 3.8 Hz, 1 H, 8b-H), 4.52 (ddd, J = 6.3, 3.5, 2.7 Hz, 1 H, 3a-H),
3.41 (s, 3 H, OMe), 2.35 (ddd, J = 14.5, 5.7, 2.5 Hz, 1 H, 3-H),
2.26 (ddd, J = 14.5, 6.4, 2.8 Hz, 1 H, 3-H), 1.44 (d, J = 6.7 Hz, 3
H, 5-Me) ppm. 13C NMR (126 MHz, CDCl3): δ = 141.2 (C-8),
135.6 (C-6), 124.2 (C-5a), 116.9 (C-8a), 105.0 (C-2), 71.0 (C-3a),
67.9 (C-8b), 64.8 (C-5), 55.6 (OMe), 40.0 (C-3), 21.4 (5-Me) ppm.
Data for the minor epimer: 1H NMR (500 MHz, CDCl3): δ = 7.53
(s, 1 H, 8-H), 7.18 (s, 1 H, 6-H), 5.07 (q, J = 6.3 Hz, 1 H, 5-H),
5.04 (dd, J = 5.9, 1.3 Hz, 1 H, 2-H), 4.97 (d, J = 5.5 Hz, 1 H, 8b-
H), 4.61 (ddd, J = 7.8, 5.6, 2.0 Hz, 1 H, 3a-H), 3.21 (s, 3 H, OMe),
2.44–2.38 (m, 1 H, 3-H), 2.23–2.19 (m, 1 H, 3-H), 1.44 (d, J =
6.7 Hz, 3 H, 5-Me) ppm. 13C NMR (126 MHz, CDCl3): δ = 140.9
(C-8), 135.2 (C-6), 124.7 (C-5a), 119.0 (C-8a), 104.9 (C-2), 71.6 (C-
3a), 69.2 (C-8b), 63.6 (C-5), 55.1 (OMe), 39.0 (C-3), 20.9 (5-Me)
ppm.
1
less foam. Data for 31: M.p. 90 °C. Rf = 0.53 (EtOAc). H NMR
(500 MHz, CDCl3): δ = 5.02 (dd, J = 17.5, 3.0 Hz, 1 H, 8-H), 4.90
(d, J = 17.3 Hz, 1 H, 8-H), 4.87 (d, J = 3.6 Hz, 1 H, 8b-H), 4.71
(ddq, J = 6.8, 2.8, 1.6 Hz, 1 H, 5-H), 4.65 (dd, J = 5.3, 3.6 Hz, 1 H,
3a-H), 2.93 (dd, J = 18.0, 5.8 Hz, 1 H, 3-H), 2.67 (d, J = 17.5 Hz, 1
H, 3-H), 1.41 (d, J = 6.9 Hz, 3 H, 5-Me) ppm. 13C NMR
(126 MHz, CDCl3): δ = 174.3 (C-2), 170.3 (C-6), 150.5 (C-8a), (2R,3aS,5R,11bS)-2,7,10-Trimethoxy-5-methyl-6,11-epoxy-
135.3 (C-5a), 71.0 (C-8), 70.1 (C-8b), 66.51/66.49 (C-5/C-8b), 35.8 3,3a,5,11b-tetrahydro-2H-benzo[g]furo[3,2-c]isochromene (34): Di-
188
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Eur. J. Org. Chem. 2013, 180–190

Synthesis of the AB-Ring Pyranolactone Substructure of Granaticin A
isopropylamine (0.27 mL, 1.90 mmol) was dissolved in THF, and
the solution was cooled to –20 °C. nBuLi (2.5 m in hexane,
0.76 mL, 1.90 mmol) was added, and the mixture was stirred for
10 min at room temperature. Then, the mixture was cooled to
–78 °C and a solution of furan 30 (93 mg, 0.38 mmol, Ͼ99:1dr) in
THF (5 mL) was added. Bromoarene 20 (205 mg, 1.90 mmol) was
dissolved in THF (2 mL), and the solution was added dropwise to
the LDA/furan mixture at –78 °C. The color changed from pale
yellow to dark orange. The mixture was stirred for 20 min at
–78 °C. The reaction was stopped by addition of H2O (2 mL). Brine
(10 mL) and H2O (20 mL) were added, and the mixture was ex-
tracted with CHCl3 (3ϫ25 mL). The combined organic layer was
dried with Na2SO4, and the solvent was removed under reduced
pressure. Silica gel chromatography (10 g, n-pentane/Et2O, 4:1–1:1)
afforded Diels–Alder adduct 34 (153 mg, 0.38 mmol, 100%, 8:1dr)
(5-Me) ppm. IR (film): ν = 2939, 2841, 2360, 2342, 1776, 1654,
˜
1585, 1479, 1407, 1261, 1236, 1150, 1054, 1036, 990, 960, 920, 815,
748, 678, 554, 503, 470 cm–1. HRMS (ESI): calcd. for C18H16O7
[M + Na]+ 367.0788, found 367.0789.
Supporting Information (see footnote on the first page of this arti-
1
cle): H NMR and 13C NMR spectra of all new compounds.
Acknowledgments
Financial support by the Deutsche Forschungsgemeinschaft, the
Innowatt program of the Bundesministerium für Wirtschaft und
Technologie, Brandenburg, and the Fonds der Chemischen Indus-
1
as a pale brown foam. Rf = 0.27 (n-pentane/Et2O, 2:1). H NMR
(500 MHz, CDCl3): δ = 6.58–6.53 (m, 2 H, 8-H, 9-H), 6.01 (s, 1 H, trie is gratefully acknowledged.
11-H), 5.81 (s, 1 H, 6-H), 5.26 (dd, J = 5.8, 3.0 Hz, 1 H, 2-H),
4.09–4.07 (m, 1 H, 11b-H), 4.01 (qd, J = 6.7, 2.2 Hz, 1 H, 5-H),
3.80 (s, 3 H, 10-OMe), 3.77 (s, 3 H, 7-OMe), 3.42 (s, 3 H, 2-OMe),
[1] R. Corbaz, L. Ettlinger, E. Gäumann, J. Kalvado, W. Keller-
2.29 (ddd, J = 14.8, 5.8, 1.2 Hz, 1 H, 3-H), 2.14 (ddd, J = 14.8,
6.5, 3.0 Hz, 1 H, 3-H), 1.48 (d, J = 6.7 Hz, 3 H, 5-Me) ppm. 13C
NMR (75 MHz, CDCl3): δ = 158.2 (C-5a), 148.3 (C-10), 148.0 (C-
7), 143.9 (C-11a), 137.3/137.1 (C-6a/C-10a), 112.5 (C-9), 112.1 (C-
8), 105.6 (C-2), 81.5 (C-11), 80.0 (C-6), 76.2 (C-3a), 71.1 (C-11b),
Schierlein, F. Kradolfer, B. K. Manukian, L. Neipp, V. Prelog,
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69.6 (C-5), 56.6 (10-OMe), 56.5 (7-OMe), 55.6 (2-OMe), 40.4 (C-3), [3] P. Soong, Y. Y. Jen, Y. S. Hsu, A. A. Au, Res. Rep. Taiwan
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19.5 (5-Me) ppm. The relative configuration of the newly formed
stereocenters could not be assigned by NOE spectroscopy. IR
(film): ν = 2935, 2834, 2361, 2342, 1494, 1463, 1439, 1254, 1224,
˜
1178, 1071, 1026, 955, 843, 790, 754, 712, 575 cm–1. HRMS (ESI):
calcd. for C19H22O6 [M + Na]+ 369.1309; found 369.1303. [α]D
–99.9 (c = 1.40, CHCl3, 23 °C).
=
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(3aS,5R,11bS)-7,10-Dimethoxy-5-methyl-3,3a-dihydro-2H-benzo[g]-
furo-[3,2-c]isochromene-2,6,11-(5H,11bH)-trione (35): To a solution
of Diels–Alder adduct 34 (150 mg, 0.42 mmol) in MeOH (20 mL)
was added BF3·OEt2 (2 mL). The mixture was stirred at 65 °C for
1 h. Upon complete conversion of the starting material, the mixture
was poured onto ice-cold 1.0 m NaHCO3 (50 mL) and extracted
with CHCl3 (3ϫ30 mL). The combined organic layer was dried
with Na2SO4, and the solvent was removed under reduced pressure.
The crude regioisomeric phenols were obtained as a pale brown
foam (147 mg, 0.42 mmol, 98%, rr = 1:1, Rf = 0.36 (n-pentane/
Et2O, 2:1). To a solution of this material dissolved in acetone
(15 mL) was added H2SO4 (1.0 m, 2 mL). The mixture was stirred
at 60 °C for 1 h. Then, the mixture was cooled to 0 °C and Jones
reagent[1] (1.01 g, 1.80 mmol) was added. The mixture was stirred
for 15 min at room temperature. Water (10 mL) and brine (10 mL)
were added, and the mixture was extracted with CHCl3
(3ϫ15 mL). The combined organic layer was dried with anhydrous
Na2SO4, and the solvent was removed under reduced pressure. Sil-
ica gel chromatography (10 g, n-pentane/EtOAc, 1:1–1:3) afforded
naphthoquinone 35 (39 mg, 0.11 mmol, 26%) as a dark yellow so-
lid. Jones reagent was prepared from CrO3 (1.03 g, 10.3 mmol) and
conc. H2SO4 (0.87 mL, 16.3 mmol) in H2O (3.00 mL). Rf = 0.27
(n-pentane/Et2O, 2:1). 1H NMR (300 MHz, CDCl3): δ = 7.31 (“s”,
2 H, 8-H, 9-H), 5.37 (dd, J = 2.6, 1.7 Hz, 1 H, 11b-H), 4.74 (qd, J
= 6.7, 1.5 Hz, 1 H, 5-H), 4.32 (dd, J = 4.7, 2.7 Hz, 1 H, 3a-H),
3.95 (s, 6 H, 2ϫ OMe), 2.91 (dd, J = 17.6, 4.8 Hz, 1 H, 3-H), 2.72
(d, J = 17.5 Hz, 1 H, 3-H), 1.52 (d, J = 6.7 Hz, 3 H, 5-Me) ppm.
13C NMR (126 MHz, CDCl3): δ = 184.0 (C-6), 181.6 (C-11), 174.6
(C-2), 153.7/153.2 (7-OMe/10-OMe), 150.7 (C-5a), 133.6 (C-11a),
121.7/120.8 (C-6a/C-10a), 120.5/120.4 (C-8/C-9), 71.6 (C-3a), 69.4
(C-11b), 68.8 (C-5), 57.02/56.97 (7-OMe/10-OMe), 37.4 (C-3), 19.6
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Eur. J. Org. Chem. 2013, 180–190
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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U. Koert et al.
FULL PAPER
[23] G. E. Morton, A. G. M. Barrett, J. Org. Chem. 2005, 70, 3525–
3529.
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[24] CCDC-8999155 (for 11), -899154 (for 12), -899156 (for 17),
and -8999157 (for 33) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
Received: September 25, 2012
Published Online: October 30, 2012
190
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Eur. J. Org. Chem. 2013, 180–190