A unified strategy for the syntheses of angucyclinone antibiotics: Total syntheses of tetrangulol, kanglemycin M, X-14881-E, and anhydrolandomycinone

Article abstract of DOI:10.1002/ejoc.201200049

A unified strategy for the syntheses of angucyclinone antibiotics was developed utilizing sequential intramolecular enyne metathesis, Diels-Alder/aromatization, photooxygenation, and one-pot elimination/ aromatization reactions. The diversity in this sequ

Full text of DOI:10.1002/ejoc.201200049

FULL PAPER
DOI: 10.1002/ejoc.201200049
A Unified Strategy for the Syntheses of Angucyclinone Antibiotics: Total
Syntheses of Tetrangulol, Kanglemycin M, X-14881-E, and
Anhydrolandomycinone
Devendar Goud Vanga[a] and Krishna P. Kaliappan*[a]
Keywords: Total synthesis / Synthesis design / Antibiotics / Enynes / Cycloaddition / Metathesis / Aromatization /
Photooxygenation
A unified strategy for the syntheses of angucyclinone anti-
biotics was developed utilizing sequential intramolecular en-
yne metathesis, Diels–Alder/aromatization, photooxygena-
tion, and one-pot elimination/aromatization reactions. The
diversity in this sequence was introduced in the Diels–Alder
reaction where a common diene was treated with various ap-
complish the total syntheses of tetrangulol, kanglemycin M,
X-14881-E, and anhydrolandomycinone in moderate to good
overall yields. The requisite diene was synthesized in excel-
lent yield from a known enyne through an intramolecular en-
yne metathesis. The scope of this flexible and divergent strat-
egy can be extended to the syntheses of similar scaffolds and
propriately functionalized quinones as the dienophiles to ac- unnatural aromatic angucyclinones.
Introduction
Angucyclines[1] belong to a relatively new and large
group of antibiotic natural products featuring an angularly
assembled carbotetracyclic skeleton. These natural products
are isolated from the culture broth of different microorga-
nisms. Besides their interesting structural features, they also
exhibit widespread biological activities such as antitumor,
antifungal, and antiviral properties.[2] This group of anti-
biotics includes naturally occurring quinones,[3] charac-
terized by an angular tetracyclic framework, which are be-
lieved to be biosynthesized from a decaketide derivative.[4]
In general, the angucyclines possess a benz[a]anthraquin-
one ring system as a common structural framework. Angu-
cyclines can be classified further into two subgroups de-
pending on the presence or absence of a C-glycoside moiety. Figure 1. Some examples of angucyclinones.
Angucyclines in the latter group, without a hydrolyzable
sugar moiety, are known as angucyclinones (Figures 1 and
2).
tively. Kanglemycin M was isolated from the fermentation
broth of Nocardia mediterranei kanglensis 1747-64 by
Cheng-Hang Sun in 1996.[8]
Tetrangomycin and tetrangulol were the first set of angu-
cyclinone antibiotics isolated by Kunstman and Mitscher
in 1965 from the species Streptomyces cyanogenus S-136.[5]
Anhydrolandomycinone and X-14881-E, which are struc-
turally similar to tetrangulol by having angular tetracyclic
planar frameworks but differerent C-11 and C-8 functional-
ities, were isolated from the species Streptomyces cyano-
genus S-136[6] and Streptomyces fradiae strain 34,[7] respec-
To date, several synthetic strategies to construct the
benzo[a]anthraquinone skeleton of angucyclinone have
been reported employing Diels–Alder[9,10–14] and Friedel–
Crafts reactions,[15] nucleophilic additions,[16] free radical
annulations,[17a–17d,17f,17g] rearrangements of cyclobut-
enones,[17e] and cobalt-mediated [2+2+2] cycloadditions[18]
(see Figure 3). Among all of these strategies, the Diels–
Alder approach has been widely used to assemble the
benzo[a]anthraquinone skeleton by using a chiral catalyst,
an enantiopure diene, or a chiral dienophile. In view of their
promising biological profiles and interesting structural
framework, we are interested in the syntheses of angucy-
clines and their analogues. As a part of our ongoing pro-
[a] Department of Chemistry, Indian Institute of Technology
Bombay,
Powai, Mumbai 400076, India
Fax: +91-22-2572-3480
E-mail: kpk@chem.iitb.ac.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200049.
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Total Synthesis of Angucyclinone Antibiotics
products. Earlier, we reported the enantioselective syntheses
of YM-181741, (+)-ochromycinone, (+)-rubiginone B2, (–)-
tetrangomycin, and MM-47755,[19] and, herein, we disclose
our unified strategy for the syntheses of tetrangulol, X-
14881-E, anhydrolandomycinone, and kanglemycin M.
Results and Discussion
Over the past few years, our group has been actively ex-
ploring the intra- and intermolecular enyne metathesis and
Diels–Alder reaction sequence, and it has culminated in the
syntheses of various sugar-quinone hybrids,[20] C-aryl gly-
cosides,[21] and some of angucyclinone natural products[19]
(vide supra). In this paper, we describe an application of
our strategy to construct the tetracyclic skeleton of angucy-
clinones by using sequential enyne metathesis, DAR, photo-
oxygenation, and aromatization reactions as the key steps.
According to our general retrosynthetic analysis as shown
in Scheme 1, we envisaged that the angular tetracyclic
planar framework of angucyclinones 20 could be derived
from ketone 21 through one-pot elimination and aromatiza-
tion reactions. We envisioned that the assembly of benzo-
[a]anthraquinone skeleton 21 required a Diels–Alder reac-
tion between common diene 23 and dienophile 22. Diene 23
originated from enyne 24 through an intramolecular enyne
metathesis. Enyne 24 could be traced back to ketone 25.
Figure 2. More examples of angucyclinone natural products.
Scheme 1. General retrosynthetic analysis.
Synthesis of Diene 28
The synthesis of requisite diene 28 commenced with the
nucleophilic addition of allenylmagnesium bromide to
ketone 25 to afford enyne 26.[22] The hydroxy group was
then protected to give MOM ether 27 in 91% yield. Upon
Figure 3. Earlier synthetic strategies to the tetracyclic framework
of angucyclinones.
gram to exploit the synthetic utility of sequential enyne me- the synthesis of 27, we executed an intramolecular enyne
tathesis and Diels–Alder reactions (DAR), we developed a metathesis using Grubbs’ first-generation catalyst (G-I)[23]
unified strategy for the syntheses of angucyclinone natural to furnish the desired diene 28 in 90% yield (Scheme 2).
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Total Synthesis of Tetrangulol
After synthesizing the required diene in good quantity,
the stage was set for investigating the Diels–Alder reaction
with an appropriate dienophile. Our first target was tet-
rangulol (6), for which juglone (29) was identified as the
appropriate dienophile. Accordingly, diene 28 was treated
with juglone (29) at 80 °C for 12 h to afford a mixture of
two regioisomers in a 1:2 ratio in favor of the undesired
isomer. When juglone was acetylated and the resultant 5-
acetoxynaphthoquinone (30) was used as the dienophile,
the Diels–Alder reaction led to similar results, and the ratio
of two regioisomers did not change significantly. Eventu-
ally, 5-acetoxy-2-bromo-1,4-naphthoquinone[24] (31) was
found to provide the desired regioisomer exclusively (see
Scheme 3). The resultant cycloadduct was subsequently
aromatized with K2CO3 and MeOH occurring with con-
comitant cleavage of the MOM ether to give compound 34
in 71% for the two steps. The cleavage of the MOM group
might be caused by the HBr generated in situ during the
reaction. This was supported further by evidence that the
MOM group remained intact when the reaction was per-
formed in the presence of an excess amount of K2CO3. Sub-
sequently, compound 34 was subjected to photooxygena-
tion[25] (Hg lamp, 125 W, and Philips India) to install the
oxygen functionality and afford ketone 36 in 65% yield.
Finally, ketone 36 was treated with a catalytic amount of
PTSA (p-toluenesulfonic acid) to provide tetrangulol (6) in
70% yield. The spectroscopic data of synthetic tetrangulol
was in good agreement with that of the natural product in
all aspects, thus completing the total synthesis of tetrangul-
ol (6)[26] in 22% overall yield starting from compound 25.
Scheme 2. Synthesis of diene 28. Reagents and conditions: (a) al-
lenylmagnesium bromide, THF (tetrahydrofuran), –78 °C, 3 h 85%;
(b) MOMCl (methoxymethyl chloride), DIPEA (diisopropylethyl-
amine), CH2Cl2, 91%; (c) G-I (Cy = cyclohexyl), CH2Cl2, reflux,
8 h, 90%.
Total Synthesis of Kanglemycin M
Kanglemycin M is structurally similar to tetrangulol and
varies only by having a C-3 hydroxy functionality, and,
therefore in principle, it could be derived from tetrangulol
by benzylic oxidation. However, all of our efforts to execute
this transformation were unsuccessful under several condi-
tions {such as SeO2, dioxane, reflux; NBS (N-bromosuc-
cinimide), AIBN [azobis(isobutyronitrile)], CCl4, reflux;
TBAP (tetrabutylammonium perchlorate), Py (pyridine)}.
The failure of this reaction is attributed to the presence of
free hydroxy groups in tetrangulol. Therefore, the hydroxy
groups of tetrangulol were protected as in diacetate 37 in
94% yield. This time, the sequence of bromination and hy-
drolysis leading to kanglemycin M was successful, but the
yield could not be improved to more than 40% (see
Scheme 4).
Because of the poor yield and difficulties encountered
in transforming tetrangulol into kanglemycin M through a
benzylic oxidation, we developed an alternative strategy
wherein the requisite hydroxymethyl group is introduced at
an early stage of the synthesis. Accordingly, we envisioned
that the total synthesis of kanglemycin M could be achieved
from diene 40 through a Diels–Alder reaction with quinone
31 (see Scheme 5).
Scheme 3. Reagents and conditions: (a) (i) toluene, 80 °C to 100 °C,
12 h; (ii) SiO2, NEt3, CHCl3, 4 h, 88% for two steps; (b) (i) toluene,
80 °C to 100 °C, 12 h; (ii) SiO2, NEt3, CHCl3, 4 h, 74% for two
steps; (c) toluene, 80 °C to 100 °C, 12 h; (d) K2CO3, MeOH, 71%
for two steps; (e) excess amount of K2CO3, MeOH, 72%; (f) hν,
O2, benzene, 2 d, 65%; (g) PTSA, benzene, reflux, 2 h, 70%.
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Total Synthesis of Angucyclinone Antibiotics
MeOH to afford compound 41 in 75% yield. The photo-
oxygenation of 41 (Hg lamp, 125 W, and Philips India) un-
der the positive pressure of oxygen afforded ketone 42 in
75% yield. The completion of the kanglemycin M synthesis
required the removal of the benzyl group and aromatiza-
tion. However, removing the benzyl group under hydro-
genolysis conditions led to the partial hydrogenation of the
phenolic ring with no reaction occurring at the benzyl
group to afford 43 in excellent yield. Though the exact
reasons for this unusual transformation are unknown, we
presume that it may be due to the presence of a phenolic
OH group. Nevertheless, this problem was circumvented by
carrying out the debenzylation with BCl3. When BCl3
(5 equiv.) was used at –78 °C, only aromatized compound
44 was obtained in 65% yield. However, when ketone 42
was treated with 15 equiv. of BCl3 at 0 °C and warmed to
room temp. for 36 h, it was smoothly converted into kangle-
mycin M (7) in 57% yield and 44 in 21% yield. Thus, the
total synthesis of kanglemycin M (7) was accomplished in
22% overall yield from compound 38. The spectroscopic
data of kanglemycin M were good in agreement with those
reported.[8]
Scheme 4. Reagents and conditions: (a) NaOAc, Ac2O, 100 °C, 7 h,
94%; (b) (i) NBS, (PhCO)2O2, CCl4, reflux, 8 h; (ii) dioxane/H2O,
24 h, reflux; (iii) NaOH (1 n), MeOH.
Total Synthesis of X-14881-E
After the successful syntheses of tetrangulol and kangle-
mycin M, we engaged in the synthesis of X-14881-E (8) by
utilizing the same strategy. The synthesis started with the
Diels–Alder reaction of diene 28 with 5-methoxy-2-bromo-
1,4-naphthoquinone (45) to provide the corresponding cy-
cloadduct which was further subjected to dehydrobromina-
tion/aromatization by using K2CO3 and MeOH to afford
compound 46 in 64% yield, resulting in concomitant re-
moval of the MOM group. Photooxygenation of compound
47 under the positive pressure of oxygen and subsequent
aromatization under acidic conditions completed the total
synthesis of X-14881-E (8) in 74% yield for the two steps
(see Scheme 6).[25d,26a,28] The spectroscopic data of the syn-
Scheme 5. Reagents and conditions: (a) Allenylmagnesium brom-
ide, THF, –78 °C, 3 h, 88%; (b) G-I, CH2Cl2, reflux, 8 h, 78%;
(c) (i) toluene, 80 °C to 100 °C, 12 h; (ii) K2CO3, MeOH, 75% for
two steps; (d) hν, O2, benzene, 2 d, 75%; (e) Pd/C, H2, EtOH, room
temp., 18 h, 85%; (f) BCl3 (5 equiv.), CH2Cl2, 78 °C to room temp.,
12 h, 65%; (g) BCl3 (15 equiv.), CH2Cl2, 0 °C to room temp., 36 h,
7 (57%) and 44 (21%).
Thus, the addition of allenylmagnesium bromide to
ketone 38[27] resulted in the requisite enyne 39, which upon
treatment with G-I, was smoothly transformed into diene
40 in good yield. With substantial quantities of diene 40 in
hand, we turned our attention to study the key Diels–Alder
reaction. As anticipated, this reaction proceeded smoothly
with dienophile 31 to furnish the corresponding cycload-
Scheme 6. Reagents and conditions: (a) (i) Toluene, 80 °C to
100 °C, 12 h; (ii) K2CO3, MeOH, 64% for two steps; (b) hν, O2,
duct which was subsequently aromatized with K2CO3 and benzene, 2 d, 73%; (c) PTSA, benzene, reflux, 2 h, 74%.
Eur. J. Org. Chem. 2012, 2250–2259
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D. G. Vanga, K. P. Kaliappan
FULL PAPER
thetic product matched with those of the natural product, by utilizing sequential intramolecular enyne metathesis and
and thus, a short total synthesis of X-14881-E (8) was ac- Diels–Alder reactions. Using this flexible strategy, we suc-
complished in 24% overall yield.
cessfully achieved the total syntheses of tetrangulol, kangle-
mycin M, X-14881-E, and anhydrolandomycinone.
Furthermore, our efforts are underway towards extending
the scope of this strategy for the syntheses of various natu-
ral products with a similar molecular framework such as
dehydrorabelomycine and analogues thereof.
Total Synthesis of Anhydrolandomycinone
Following the syntheses of tetrangulol, kanglemycin M,
and X-14881-E, we then focused our attention on the syn-
thesis of anhydrolandomycinone (9) using our general strat-
egy. Towards this end, we anticipated that the protected di-
hydroxynaphthoquinone 49 was a better dienophile to pro-
vide the cycloadduct in good yield. Accordingly, compound
48 was protected as its MOM ether using MOMCl and
DIPEA to afford 49 in 91% yield. Gratifyingly, protected
dienophile 49 smoothly underwent a Diels–Alder reaction
to furnish the corresponding cycloadduct. On the basis of
our earlier experience,[20] we immediately treated the cy-
cloadduct with triethylamine and silica gel to facilitate the
air oxidative aromatization without further purification to
provide 50 in 64% yield for the two steps. The introduction
of the oxygen functionality was achieved through photo-
oxygenation (Hg lamp, 125 W, and Philips India) under the
positive pressure of oxygen to afford ketone 51 in 66% yield
(see Scheme 7). Finally, aromatization of ketone 51 under
acidic conditions using PTSA provided anhydrolandomycin-
one (9) in 70% yield. The spectroscopic data of the syn-
thetic sample matched with those of the natural product,
and thus, we completed the total synthesis of anhydrolan-
domycinone (9)[29] in 20% overall yield.
Experimental Section
General Methods: Unless and otherwise noted, all starting materi-
als and reagents were obtained from commercial suppliers and used
after further purification. Tetrahydrofuran was distilled from so-
dium benzophenone ketyl, and toluene was distilled from sodium.
Dichloromethane, hexanes, and pyridine were freshly distilled from
calcium hydride. All solvents used for the routine isolation of prod-
ucts and for chromatography were reagent grade and glass distilled.
Reaction flasks were dried in an oven at 100 °C for 12 h. Air- and
moisture-sensitive reactions were performed under an argon/nitro-
gen atmosphere. Chromatography was performed using silica gel
(100–200 mesh) with the indicated solvents. All reactions were
monitored by thin layer chromatography which was performed on
0.25 mm E. Merck silica plates (60F-254) using UV light as the
visualizing agent and aqueous phosphomolybdic acid, containing
concentrated H2SO4, and heat as the developing agents. IR spectra
were recorded with Thermo Nicolet Avater 320 FTIR and Nicolete
Impact 400 machines. Mass spectra were obtained with a Waters
Micromass-Q-Tof microTM (YA105) spectrometer. 1H and 13C
NMR spectroscopic data were recorded with either Bruker AV
400 MHz or Varian AS 400 MHz spectrometers. The NMR spec-
troscopic data is presented in the order of chemical shift, multi-
plicity (s, singlet; br. s, broad singlet; d, doublet; t, triplet; q, quar-
tet; m, multiplet), coupling constant in Hertz (Hz), and number of
protons.
General Procedure for DAR Followed by Aromatization: A solution
of the dienophile (1.1 mmol) in toluene (15 mL) was treated with
a solution of 1,3-diene (1.0 mmol) in toluene (3 mL) at room tem-
perature, and then the mixture was heated at 80 °C for 12 h fol-
lowed by 100 °C for 2 h. After removing the solvent in vacuo, the
crude Diels–Alder adduct was dissolved in MeOH (10 mL), and
the resulting solution was treated with solid K2CO3 (3 mmol) and
stirred in the dark for 12 h. The solvent was removed in vacuo, and
the residue was treated with water. The mixture was extracted with
CHCl3. The organic layer was washed with brine, dried with anhy-
drous Na2SO4, and concentrated. Purification by silica gel column
chromatography afforded the tetracycle.
General Procedure for Photooxygenation: A solution of the tetra-
cyclic quinone (1 mmol) in benzene (315 mL) was irradiated with
a mercury lamp (125 W, Philips India) under a positive pressure of
oxygen for 24 to 36 h. The solvent was removed in vacuo, and the
residue was then purified by silica gel flash column chromatog-
raphy.
Scheme 7. Reagents and conditions: (a) MOMCl, DIPEA, CH2Cl2,
0 °C to room temp. 6 h, 91%; (b) (i) toluene, 80 °C to 100 °C, 12 h;
(ii) silica gel, NEt3, CHCl3, 4 h, 64% for two steps; (c) hν, O2, benz-
ene, 2 d, 66%; (d) PTSA, benzene, reflux, 2 h, 70%.
General Procedure for A-Ring Aromatization: A solution of the
quinone (0.1 mmol) in benzene (5 mL) was treated with a catalytic
amount of PTSA, and the reaction mixture was heated to reflux
for 2 h. The reaction mixture was cooled to room temp. and
quenched with an aqueous NaHCO3 solution. The resulting mix-
ture was extracted with ethyl acetate (3ϫ20 mL). The combined
organic layers were washed with a brine solution, dried with
Conclusions
In summary, we presented a unified strategy for the syn-
theses of angular all-aromatic tetracyclic planar molecules Na2SO4, and evaporated in vacuo. The crude compound was puri-
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Total Synthesis of Angucyclinone Antibiotics
fied by silica gel flash column chromatography to afford the tet-
racycle.
0.30 mmol) and diene 28 (50 mg, 0.27 mmol) in toluene was heated
at 80 °C for 12 h and then at 100 °C for 2 h. After the solvent was
removed in vacuo, the crude Diels–Alder adduct was dissolved in
CHCl3 (2 mL), and the resulting solution was treated with NEt3
(1 mL) and silica gel (1 g). The mixture was stirred for 4 h to afford
tetracycle 32 (85 mg, 88%) in 1:2 ratio as a yellow semisolid; Rf =
4-Methyloct-7-en-1-yn-4-ol (26): A solution of allenylmagnesium
bromide (prepared from 6.85 mL, 61.2 mmol of propargyl brom-
ide) in diethyl ether (20 mL) was added to a solution of ketone 25
(2 g, 20.4 mmol) in THF (50 mL) at –78 °C. After stirring for 3 h,
the reaction mixture was warmed to room temp. and diluted with
an aqueous NH4Cl solution. The aqueous layer was extracted with
diethyl ether (3ϫ30 mL). The combined organic layers were
washed with brine and dried with anhydrous Na2SO4, and then the
solvent was evaporated in vacuo. The crude compound was purified
by flash column chromatography to afford 26 as colorless liquid
0.40 (ethyl acetate/hexanes, 1:2). IR (CHCl ): ν = 3410, 3016, 2929,
˜
3
2857, 1669, 1635, 1584, 1369, 1275, 1153, 1079, 759 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 12.9 (s, 1 H, major isomer), 12.54 (s, 1 H,
minor isomer), 8.18 (d, J = 8.0 Hz, 1 H, minor isomer), 8.17 (d, J
= 8.0 Hz, 1 H, major isomer), 7.77 (dd, J = 7.8, 1.2 Hz, 1 H, major
isomer), 7.74 (dd, J = 7.8, 1.2 Hz, 1 H, minor isomer), 7.67–7.60
(m, 1 H), 7.49 (d, J = 8.0 Hz, 1 H), 7.28 (dd, J = 7.8, 1.2 Hz, 1 H,
major isomer), 7.25 (dd, J = 7.8, 1.2 Hz, 1 H, minor isomer), 4.85
(d, J = 7.2 Hz, 1 H), 4.67 (d, J = 7.2 Hz, 1 H), 3.55–3.48 (m, 2 H),
3.19 (s, 3 H), 3.18 (d, J = 17.2 Hz, 1 H), 2.92 (d, J = 17.2 Hz, 1
H), 2.20–2.12 (m, 1 H), 1.86–1.78 (m, 1 H), 1.40 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 191.9, 189.0, 185.0, 183.2, 162.5,
161.2, 144.8, 144.2, 140.9, 136.8, 136.2, 135.9, 135.2, 133.7, 133.2,
133.0, 131.0, 130.5, 125.8, 125.2, 124.6, 123.3, 119.5, 118.8, 117.5,
91.2, 72.9, 72.8, 55.4, 43.4, 43.2, 34.1, 34.0, 29.9, 27.0, 26.7,
25.2 ppm. HRMS (ESI): calcd. for C21H21O5 [M + H]+ 353.1389;
found 353.1387.
(2.4 g, 85%); R = 0.4 (ethyl acetate/hexanes, 1:9). IR (CHCl ): ν =
˜
f
3
3307, 3019, 2978, 2400, 1377, 1215, 1112, 916, 759, 669 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 5.90–5.80 (m, 1 H), 5.06 (dd, J =
17.2, 1.7 Hz, 1 H), 4.98 (dd, J = 11.1, 1.7 Hz, 1 H), 2.38 (t, J =
2.4 Hz, 2 H), 2.19–2.12 (m, 2 H), 2.09 (t, J = 2.4 Hz, 1 H), 1.82 (s,
1 H), 1.75–1.62 (m, 2 H), 1.29 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 138.7, 114.7, 80.9, 71.7, 71.4, 40.1, 32.6, 28.1,
26.4 ppm. HRMS (ESI): calcd. for C9H16O [M + H]+ 139.1123;
found 139.1120.
5-(Methoxymethoxy)-5-methyloct-1-en-7-yne (27): To a stirred solu-
tion of alcohol 26 (2.5 g, 18.0 mmol) and DIPEA (19 mL,
108.5 mmol) in CH2Cl2 (30 mL) at 0 °C was added dropwise
MOMCl (3 m in toluene, 30 mL, 90 mmol), and the reaction mix-
ture was stirred for 6 h at room temp. The reaction mixture was
quenched with water, and the resulting mixture was extracted with
CH2Cl2 (3ϫ50 mL). The organic layer was washed with brine,
dried with Na2SO4, and concentrated in vacuo. The crude com-
pound was purified by flash column chromatography to afford 27
(3 g, 91%) as a colorless liquid; Rf = 0.5 (ethyl acetate/hexanes,
3-(Methoxymethoxy)-3-methyl-7,12-dioxo-1,2,3,4,7,12-hexahydro-
tetraphenyl Acetate (33): Following the general procedure for the
Diels–Alder reaction, a solution of compound 30 (65 mg,
0.30 mmol) and diene 28 (52 mg, 0.27 mmol) afforded a mixture of
tetracycle 33 (80 mg, 74%) as a yellow, viscous solid. Rf = 0.30
(ethyl acetate/hexanes, 1:2). IR (CHCl ): ν = 3016, 2929, 2857,
˜
3
1772, 1669, 1625, 1594, 1530, 1369, 1275, 1193, 1039, 759 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 8.0 Hz, 1 H), 8.06 (d,
J = 7.9 Hz, 1 H), 7.75 (t, J = 7.9 Hz, 1 H), 7.44 (d, J = 8.0 Hz, 1
H), 7.37 (d, J = 7.9 Hz, 1 H), 4.84 (d, J = 7.5 Hz, 1 H), 4.66 (d, J
= 7.5 Hz, 2 H), 3.50–3.46 (m, 2 H), 3.18 (s, 3 H), 3.15 (d, J =
17.2 Hz, 1 H), 2.88 (d, J = 17.2 Hz, 1 H), 2.48 (s, 3 H), 2.16–2.10
(m, 1 H), 1.84–1.76 (m, 1 H), 1.39 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 185.2, 184.9, 183.3, 182.5, 169.9, 169.8,
149.6, 144.1, 143.6, 139.9, 139.4, 137.1, 135.3, 134.8, 134.7, 134.6,
134.3, 134.0, 132.6, 132.3, 130.2, 129.7, 129.0, 127.0, 125.9, 125.5,
125.1, 125.0, 124.3, 91.1, 73.1, 73.0, 55.4, 43.2, 43.1, 34.1, 34.0,
29.8, 26.5, 26.2, 25.1, 21.5, 21.4 ppm. HRMS (ESI): calcd. for
C23H23O6 [M + H]+ 395.1495; found 395.1497.
1:9). IR (CHCl ): ν = 3088, 2929, 1947, 1677, 1643, 1606, 1449,
˜
3
1375, 1261, 1216, 1119, 1039, 917, 758 cm–1. H NMR (400 MHz,
1
CDCl3): δ = 5.91–5.77 (m, 1 H), 5.04 (dd, J = 17.0, 1.8 Hz, 1 H),
4.95 (dd, J = 9.6, 1.8 Hz, 1 H), 4.77–4.69 (m, 2 H), 3.39 (s, 3 H),
2.46 (dd, J = 2.6, 0.9 Hz, 2 H), 2.20–2.09 (m, 2 H), 2.01 (t, J =
2.6 Hz, 1 H), 1.88–1.61 (m, 2 H), 1.33 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 138.7, 114.5, 91.3, 81.2, 76.9, 70.5, 55.7,
38.1, 30.3, 28.0, 23.5 ppm. HRMS (ESI): calcd. for C11H18O2 [M
+ Na]+ 205.1204; found 205.1198.
5-(Methoxymethoxy)-5-methyl-1-vinylcyclohex-1-ene (28): A solu-
tion of enyne 27 (500 mg, 2.74 mmol) in CH2Cl2 (60 mL) was
treated with G-I (7 mmol-%), and the resulting mixture was then
heated to reflux for 8 h. The reaction mixture was cooled to room
temp., and DMSO was added (50 equiv. with respect to the catalyst,
5.0 mmol). The mixture was stirred for 6 h to remove the metal
impurities. Evaporation of the solvent followed by purification the
residue by silica gel flash column chromatography provided 1,3-
diene 28 (450 mg, 90%); Rf = 0.5 (ethyl acetate/hexanes, 1:9). IR
3,8-Dihydroxy-3-methyl-1,2,3,4-tetrahydrotetraphene-7,12-dione
(34): Using the general procedure for the Diels–Alder reaction fol-
lowed by aromatization, 5-acetoxy-2-bromo-1,4-naphthoquinone
(31, 355 mg, 1.20 mmol), diene 28 (200 mg, 1.0 mmol), and K2CO3
(451 mg, 3.27 mmol) afforded tetracycle 34 which was purified by
silica gel flash column chromatography to give a yellow solid
(250 mg, 71 %). Rf = 0.5 (ethyl acetate/hexanes, 1:1); m.p. 205–
206.6 °C. IR (CHCl ): ν = 3348, 2957, 2926, 2852, 1663, 1630,
˜
(CHCl ): ν = 3079, 3016, 2979, 2932, 2119, 1640, 1452, 1378, 1216,
3
˜
3
1454, 1371, 1273, 1249, 1160, 1073, 909, 824, 774, 712 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 12.52 (s, 1 H), 8.19 (d, J = 8.0 Hz,
1 H), 7.74 (dd, J = 8.3, 1.2 Hz, 1 H), 7.65 (t, J = 8.3 Hz, 1 H), 7.49
(d, J = 8.0 Hz, 1 H), 7.25 (dd, J = 8.3, 1.2 Hz, 1 H), 3.54 (t, J =
6.8 Hz, 1 H), 2.99 (s, 2 H), 2.07–1.93 (m, 1 H), 1.89–1.82 (m, 1 H),
1.41 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 188.9, 185.0,
162.0, 144.4, 140.3, 136.8, 135.4, 135.2, 133.3, 131.3, 125.3, 123.3,
119.5, 115.7, 68.1, 45.0, 35.9, 28.9, 26.7 ppm. HRMS (ESI): calcd.
for C19H17O4 [M + H]+ 309.1127; found 309.1131.
1144, 1036, 915, 758, 668 cm–1. H NMR (400 MHz, CDCl3): δ =
1
6.38 (dd, J = 17.6, 10.5 Hz, 1 H), 5.73 (s, 1 H), 5.08 (d, J = 17.6 Hz,
1 H), 4.91 (d, J = 10.5 Hz, 1 H), 4.78 (d, J = 7.4 Hz, 1 H), 4.72 (d,
J = 7.4 Hz, 1 H), 3.35 (s, 3 H), 2.45 (d, J = 17.6 Hz, 1 H), 2.36–
2.28 (m, 1 H), 2.17 (d, J = 17.6 Hz, 1 H), 2.13–2.10 (m, 1 H), 1.84–
1.78 (m, 1 H), 1.65–1.57 (m, 1 H), 1.30 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 139.7, 134.1, 128.4, 110.2, 91.0, 74.5, 55.3,
36.1, 33.5, 25.2, 23.8 ppm. HRMS (ESI): calcd. for C11H18O2Na
[M + Na]+ 205.1204; found 205.1208.
Hydroxy-Substituted 3-(Methoxymethoxy)-3-methyl-1,2,3,4-tetra-
hydrotetraphene-7,12-dione (32): Following the general procedure
for the Diels–Alder reaction, a solution of juglone (29) (52 mg,
8-Hydroxy-3-(methoxymethoxy)-3-methyl-1,2,3,4-tetrahydrotetra-
phene-7,12-dione (35): Using the general procedure for the Diels–
Alder reaction followed by aromatization, 5-acetoxy-2-bromo-1,4-
Eur. J. Org. Chem. 2012, 2250–2259
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2255

D. G. Vanga, K. P. Kaliappan
FULL PAPER
naphthoquinone (31) (355 mg, 1.2 mmol), diene 28 (200 mg, Kanglemycin M (7): To a solution of diacetate 37 (90 mg,
1.0 mmol), and K2CO3 (1.35 g, 9.81 mmol), afforded tetracycle 35 0.23 mmol) dissolved in dry CCl4 (10 mL) were added NBS (33 mg,
which was purified by silica gel flash column chromatography (30% 0.18 mmol) and (PhCO2)O2 (5 mg, 0.02 mmol) at room temp. un-
ethyl acetate in hexanes) to give a yellow solid (280 mg, 72%). Rf
= 0.4 (ethyl acetate/hexanes, 1:2); m.p. 205–206.6 °C. IR (CHCl3):
der a nitrogen atomosphere. The reaction mixture was heated to
reflux for 5 h and then cooled to room temp., and the solvent was
removed in vacuo. For hydrolysis, the crude residue was dissolved,
ν = 3390, 3018, 2925, 2852, 1667, 1634, 1581, 1454, 1364, 1290,
˜
1238, 1156, 1072, 1039, 918, 756 cm–1
CDCl3): δ = 12.49 (s, 1 H), 8.12 (d, J = 8.0 Hz, 1 H), 7.69 (dd, J
= 7.8, 1.2 Hz, 1 H), 7.61 (t, J = 7.8 Hz, 1 H), 7.49 (d, J = 8.0 Hz, tion was cooled to room temp. and extracted with EtOAc
1 H), 7.21 (dd, J = 7.8, 1.2 Hz, 1 H), 4.84 (d, J = 7.5 Hz, 1 H), (3ϫ20 mL). The combined organic layers were was dried with an-
.
1H NMR (400 MHz, in dioxane (10 mL)/H2O (10 mL) and CaCO3 (250 mg), and the
mixture was heated at 100 °C for 24 h. The resulting alcohol solu-
4.66 (d, J = 7.5 Hz, 1 H), 3.46 (t, J = 6.8 Hz, 1 H), 3.19 (s, 3 H), hydrous Na2SO4, and the solvent was evaporated in vacuo. The
3.17 (d, J = 17.3 Hz, 1 H), 2.89 (d, J = 17.3 Hz, 1 H), 2.17–2.10 crude compound was immediately treated with NaOH (1 n solu-
(m, 1 H), 1.83–1.76 (m, 1 H), 1.39 (s, 3 H) ppm. 13C NMR tion, 10 mL) in MeOH (20 mL) for 5 h, and the mixture was neu-
(100 MHz, CDCl3): δ = 188.9, 184.9, 161.9, 144.7, 140.6, 136.7, tralized with a dilute solution of HCl. The reaction mixture was
135.2, 135.1, 133.31, 130.9, 125.1, 123.2, 119.4, 115.7, 91.1, 72.9,
55.4, 43.3, 33.9, 26.6, 25.1 ppm. HRMS (ESI): calcd. for C21H21O5
[M + H]+ 353.1389; found 353.1385.
extracted with CH2Cl2 (3ϫ20 mL), and the solvent was removed
in vacuo. The crude residue was purified by silica gel column
chromatography to give kanglemycin M (7, 30 mg, 40 %) as a
brown solid. Rf = 0.4 (ethyl acetate/hexanes, 1:1); m.p. 143–145 °C.
3,8-Dihydroxy-3-methyl-3,4-dihydrotetraphene-1,7,12(2H)-trione
(36): Following the general procedure for photooxygenation, a
solution of tetracycle 34 (100 mg, 0.32 mmol) in benzene (300 mL)
was irradiated for 40 h to afford compound 36 (70 mg, 65%) as an
orange solid. Rf = 0.3 (ethyl acetate/hexanes, 1:1); m.p. 183–
IR (CHCl ): ν = 3455, 3016, 2924, 2853, 1662, 1634, 1454, 1412,
˜
3
1363, 1289, 1261, 1042, 758 cm–1 1H NMR (400 MHz, [D6]-
.
DMSO): δ = 11.98 (s, 1 H), 10.70 (s, 1 H), 8.24 (d, J = 8.5 Hz, 1
H), 8.12 (d, J = 8.5 Hz, 1 H), 7.77 (t, J = 7.9 Hz, 1 H), 7.57 (d, J
= 7.9 Hz, 1 H), 7.46 (s, 1 H), 7.33 (d, J = 7.9 Hz, 1 H), 7.08 (s, 1
H), 5.46 (t, J = 5.4 Hz, 1 H, OH), 4.64 (d, J = 5.4 Hz, 2 H) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 187.3, 186.1, 160.4, 155.1,
146.1, 138.1, 137.2, 136.0, 135.1, 134.9, 133.1, 123.2, 121.2, 119.2,
119.0, 116.4, 114.9, 113.3, 62.4 ppm. HRMS (ESI): calcd. for
C19H13O5 [M + H]+ 321.0763; found 321.0763.
185.8 °C. IR (CHCl ): ν = 3459, 2961, 2923, 2846, 1697, 1666,
˜
3
1633, 1589, 1454, 1365, 1281, 1219, 1156, 1075, 915, 770 cm–1. H
1
NMR (400 MHz, CDCl3): δ = 12.18 (s, 1 H), 8.24 (d, J = 8.1 Hz,
1 H), 7.61–7.57 (m, 2 H), 7.49 (d, J = 8.1 Hz, 1 H), 7.23–7.20 (m,
1 H), 3.10 (s, 2 H), 3.05 (d, J = 15.0 Hz, 1 H), 2.94 (d, J = 15.0 Hz,
1 H), 1.55 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 197.3,
187.9, 183.3, 162.2, 147.8, 137.3, 136.3, 135.4, 133.9, 133.8, 129.5,
123.8, 119.8, 115.5, 72.7, 54.0, 44.2, 30.0 ppm. HRMS (ESI): calcd.
for C19H15O5 [M + H]+ 323.0919; found 323.0920.
4-(Benzyloxymethyl)oct-7-en-1-yn-4-ol (39): A solution of allenyl-
magnesium bromide (prepared from 4.1 mL, 36.70 mmol of prop-
argyl bromide) in diethyl ether (20 mL) was added to a solution of
ketone 38 (2.5 g, 12.20 mmol) in THF (50 mL) at –78 °C. After
stirring for 3 h, the reaction mixture was warmed to room temp.
and then diluted with an aqueous NH4Cl solution. The aqueous
layer was extracted with diethyl ether (3ϫ30 mL). The combined
organic layers were washed with brine and dried with anhydrous
Na2SO4, and the solvent was evaporated in vacuo. The crude com-
pound was purified by flash column chromatography to afford 39
(2.65 g, 88%) as a colorless liquid; Rf = 0.6 (ethyl acetate/hexanes,
Tetrangulol (6): Following the general procedure for the A-ring aro-
matization, a solution of quinone 36 (100 mg, 0.31 mmol) in benz-
ene (20 mL) was treated with a catalytic amount of PTSA, and the
reaction mixture was heated to reflux for 2 h to afford compound
6 (66 mg, 70%) as a brown solid. Rf = 0.7 (ethyl acetate/hexanes,
1:10); m.p. 189–191.2 °C. IR (KBr): ν = 3408, 2924, 2832, 2716,
˜
1599, 1362, 1308, 1296, 1270, 1154, 778 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 12.25 (s, 1 H), 11.27 (s, 1 H), 8.31 (d, J = 8.6 Hz, 1
H), 8.13 (d, J = 8.6 Hz, 1 H), 7.85 (d, J = 7.6 Hz, 1 H), 7.69 (t, J
= 7.6 Hz, 1 H), 7.33 (d, J = 7.6 Hz, 1 H), 7.26 (s, 1 H), 7.14 (d, J
= 1.8 Hz, 1 H), 2.49 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 189.9, 188.0, 161.8, 155.4, 142.2, 139.3, 137.9, 137.0, 135.0,
132.6, 124.9, 122.0, 121.5, 121.4, 120.4, 114.8, 21.4 ppm. HRMS
(ESI): calcd. for C19H13O4 [M + H]+ 305.0814; found 305.0819.
2:8). IR (CHCl ): ν = 3547, 3302, 3066, 3031, 2920, 2860, 2117,
˜
3
1640, 1453, 1205, 1098, 997, 914, 740 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.38–7.27 (m, 5 H), 5.88–5.76 (m, 1 H), 5.03 (d, J =
17.2 Hz, 1 H), 4.95 (d, J = 10.2 Hz, 1 H), 4.57 (s, 2 H), 3.52 (d, J
= 9.0 Hz, 1 H), 3.41 (d, J = 9.0 Hz, 1 H), 2.49 (d, J = 2.6 Hz, 2
H), 2.41 (s, 1 H), 2.17–2.11 (m, 2 H), 2.01 (t, J = 2.6 Hz, 1 H),
1.74–1.69 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.7,
138.0, 128.6, 128.5, 127.9, 127.8, 114.6, 80.6, 74.4, 73.6, 73.3, 70.9,
35.4, 27.6, 27.5 ppm. HRMS (ESI): calcd. for C16H20O2Na [M +
Na]+ 267.1360; found 267.1361.
3-Methyl-7,12-dioxo-7,12-dihydrotetraphene-1,8-diyl Diacetate (37):
NaOAc (65 mg, 0.78 mmol) was added to a solution of tetrangulol
(6) (80 mg, 0.26 mmol) in Ac2O (10 mL) at room temp. The reac-
tion mixture was heated to 100 °C for 8 h, cooled to room temp.,
and then diluted with water. The mixture was extracted with diethyl
ether (3ϫ30 mL), and the solvent was removed in vacuo to give a
yellow solid which was purified by silica gel column chromatog-
raphy to afford compound 37 as a yellow solid (96 mg, 94%). Rf =
1-(Benzyloxymethyl)-3-vinylcyclohex-3-enol (40): A solution of en-
yne 39 (500 mg, 2.04 mmol) in CH2Cl2 (60 mL) was treated with
G-I (7 mmol-%), and then the reaction mixture was heated to re-
flux for 8 h. The mixture was cooled to room temperature, and
DMSO (50 equiv. with respect to the catalyst, 5.00 mmol) was
added. The mixture was stirred for 6 h to remove the metal impuri-
0.5 (ethyl acetate/hexanes, 1:1); m.p. 188–190.5 °C. IR (CHCl ): ν
˜
3
= 3012, 2928, 2857, 1772, 1670, 1596, 1450, 1367, 1281, 1195, 1104,
1
758 cm–1. H NMR (400 MHz, CDCl3): δ = 8.19 (d, J = 8.6 Hz, 1 ties. Evaporation of the solvent and purification of the residue by
H), 8.02 (d, J = 8.6 Hz, 1 H), 7.96 (d, J = 7.7 Hz, 1 H), 7.78 (t, J
silica gel flash column chromatography provided 1,3-diene 40
= 7.7 Hz, 1 H), 7.56 (s, 1 H), 7.38 (d, J = 7.7 Hz, 1 H), 7.32 (s, 1 (390 mg, 78%). Rf = 0.5 (ethyl acetate/hexanes, 2:8). IR (CHCl3):
H), 2.55 (s, 3 H), 2.50 (s, 3 H), 2.37 (s, 3 H) ppm. 13C NMR ν = 3271, 2924, 2854, 1643, 1453, 1217, 1097, 1027, 989, 899,
˜
(100 MHz, CDCl3): δ = 185.1, 181.5, 169.7, 169.1, 149.7, 147.3, 762 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.37–7.28 (m, 5 H),
140.3, 138.1, 137.9, 135.2, 134.4, 134.0, 133.4, 128.9, 126.1, 125.9,
124.6, 123.9, 122.5, 121.1, 21.7, 21.35, 21.27 ppm. HRMS (ESI):
calcd. for C23H17O6 [M + H]+ 389.1025; found 389.1031.
6.37 (dd, J = 17.5, 10.7 Hz, 1 H), 5.74 (s, 1 H), 5.06 (d, J = 17.5 Hz,
1 H), 4.91 (d, J = 10.7 Hz, 1 H), 4.58 (s, 2 H), 3.40 (s, 2 H), 2.46
(s, 1 H), 2.37–2.29 (m, 1 H), 2.24 (s, 2 H), 2.20–2.08 (m, 1 H), 1.78–
2256
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2250–2259

Total Synthesis of Angucyclinone Antibiotics
1.62 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 139.5, 138.2, to room temp., stirred for 36 h, and then diluted with water. The
133.5, 128.5, 128.4, 127.8, 127.7, 110.7, 76.63, 73.5, 70.4, 33.7, 30.5,
22.9 ppm. HRMS (ESI): calcd. for C16H21O2 [M + H]+ 245.1542;
found 245.1548.
resulting mixture was extracted with CH2Cl2 (3ϫ20 mL), and the
solvent was removed in vacuo. The crude residue was purified by
silica gel column chromatography to give kanglemycin M (7)
(21 mg, 57%) as a brown solid along with compound 44 (10 mg,
21%). Data for compound 44: Rf = 0.7 (ethyl acetate/hexanes, 2:8);
3-(Benzyloxymethyl)-3,8-dihydroxy-1,2,3,4-tetrahydrotetraphene-
7,12-dione (41): Using the general procedure for the Diels–Alder
reaction followed by aromatization, 5-acetoxy-2-bromo-1,4-naph-
thoquinone (31) (355 mg, 1.00 mmol), diene 40 (220 mg,
0.9 mmol), and K2CO3 (372 mg, 2.70 mmol) afforded tetracycle
compound 41 which was purified by silica gel flash column
chromatography to give a yellow solid (280 mg, 75%). Rf = 0.6
m.p. 167–169.5 °C. IR (CHCl ): ν = 3400, 2923, 2852, 1637, 1456,
˜
3
1418, 1369, 1306, 1259, 1171, 1102, 1017, 750 cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 12.24 (s, 1 H), 11.33 (s, 1 H), 8.30 (d, J =
8.6 Hz, 1 H), 8.23 (d, J = 8.6 Hz, 1 H), 7.87 (d, J = 7.8 Hz, 1 H),
7.70 (t, J = 7.8 Hz, 1 H), 7.50 (s, 1 H), 7.43–7.32 (m, 5 H), 7.29 (s,
1 H), 4.71 (s, 2 H), 4.66 (s, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 189.6, 187.7, 161.6, 155.6, 142.1, 139.0, 138.2, 137.8,
136.9, 135.3, 134.7, 132.3, 128.5, 127.8, 124.8, 122.0, 121.3, 121.2,
119.5, 117.3, 114.5, 72.6, 70.9 ppm. HRMS (ESI): calcd. for
C26H19O5 [M + H]+ 411.1232; found 411.1233.
(ethyl acetate/hexanes, 1:1); m.p. 113–115.5 °C. IR (CHCl ): ν =
˜
3
3435, 2923, 2855, 1665, 1635, 1583, 1455, 1368, 1270, 1160, 1093,
1
1073, 773 cm–1. H NMR (400 MHz, CDCl3): δ = 12.54 (s, 1 H),
8.18 (d, J = 8.0 Hz, 1 H), 7.74 (dd, J = 7.6, 1.2 Hz, 1 H),7.64 (t, J
= 7.6 Hz, 1 H), 7.49 (d, J = 8.0 Hz, 1 H), 7.39–7.29 (m, 5 H), 7.25
(dd, J = 8.0, 1.1 Hz, 1 H), 4.61 (s, 2 H), 3.54–3.50 (m, 2 H), 3.48
(s, 2 H), 3.01 (s, 2 H), 2.53 (s, 1 H), 2.07–2.01 (m, 1 H), 1.87–1.82
(m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 188.9, 184.9,
161.9, 144.0, 140.7, 138.0, 136.7, 135.3, 133.2, 131.2, 128.7, 128.1,
127.9, 125.2, 123.3, 119.5, 115.7, 76.7, 73.8, 69.6, 40.5, 31.2,
25.9 ppm. HRMS (ESI): calcd. for C26H23O5 [M + H]+ 415.1545;
found 415.1542.
3-Hydroxy-8-methoxy-3-methyl-1,2,3,4-tetrahydrotetraphene-
7,12-dione (46): Using the general procedure for the Diels–Alder
reaction followed by aromatization, 5-methoxy-2-bromo-1,4-
naphthoquinone (45) (80 mg, 0.30 mmol), diene 28 (50 mg,
0.27 mmol), and K2CO3 (111 mg, 0.81 mmol) afforded tetracycle
46 which was purified by silica gel flash column chromatography
to give a yellow semisolid (250 mg, 64%); Rf = 0.4 (ethyl acetate/
hexanes, 1:1). IR (CHCl ): ν = 3460, 2923, 2851, 1659, 1587, 1467,
˜
3
3-(Benzyloxymethyl)-3,8-dihydroxy-3,4-dihydrotetraphene-
1,7,12(2H)-trione (42): Following the general procedure for photo-
oxygenation, a solution of tetracycle compound 41 (250 mg,
0.60 mmol) in benzene (300 mL) was irradiated for 40 h to afford
compound 42 (110 mg, 75%) as an orange semisolid; Rf = 0.3 (ethyl
1353, 1268, 1107, 1025, 991, 823, 749, 719 cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 8.10 (d, J = 8.0 Hz, 1 H), 7.84 (dd, J =
7.7, 1.1 Hz, 1 H), 7.68 (t, J = 7.7 Hz, 1 H), 7.43 (d, J = 7.7 Hz, 1
H), 7.27 (d, J = 8.0 Hz, 1 H), 4.03 (s, 3 H), 3.49 (t, J = 6.2 Hz, 2
H), 2.95 (s, 2 H), 2.00–1.94 (m, 1 H), 1.87–1.80 (m, 1 H), 1.65 (br.
s, 1 H), 1.38 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 185.9,
183.2, 159.8, 142.4, 138.7, 137.7, 135.4, 135.0, 130.3, 125.6, 121.0,
119.9, 117.0, 68.2, 56.7, 44.9, 35.9, 28.8, 26.6 ppm. HRMS (ESI):
calcd. for C20H19O4 [M + H]+ 323.1283; found 323.1287.
acetate/hexanes, 1:1). IR (CHCl ): ν = 3459, 2925, 2855, 1703,
˜
3
1673, 1636, 1592, 1455, 1361, 1276, 1217, 1159, 1097, 913,
754 cm–1. 1H NMR (400 MHz, CDCl3): δ = 12.26 (s, 1 H), 8.30 (d,
J = 8.0 Hz, 1 H), 7.67–7.63 (m, 2 H), 7.54 (d, J = 8.0 Hz, 1 H),
7.39–7.29 (m, 6 H), 4.60 (s, 2 H), 3.52, 3.48 (ABq, JA,B = 3.5 Hz,
2 H), 3.16 (s, 2 H), 3.11, 3.02 (ABq, JA,B = 15.3 Hz, 2 H), 2.82 (br.
s, 1 H, OH) ppm. 13C NMR (100 MHz, CDCl3): δ = 197.0, 187.6,
183.1, 162.2, 147.3, 137.5, 137.2, 136.2, 135.9, 135.2, 134.0, 133.7,
129.5, 128.8, 128.3, 128.0, 123.8, 119.8, 115.5, 73.9, 73.8, 49.6,
39.7 ppm. HRMS (ESI): calcd. for C26H21O6 [M + H]+ 429.1338;
found 429.1342.
3-Hydroxy-8-methoxy-3-methyl-3,4-dihydrotetraphene-1,7,12(2H)-
trione (47): Following the general procedure for photooxygenation,
a solution of tetracycle compound 46 (40 mg, 0.12 mmol) in benz-
ene (300 mL) was irradiated for 40 h to afford compound 47
(30 mg, 73%) as an orange solid. Rf = 0.3 (ethyl acetate/hexanes,
1:1); m.p. 144–146.5 °C. IR (CHCl ): ν = 3512, 2928, 1696, 1655,
˜
3
1590, 1440, 1346, 1304, 1268, 1225, 1116, 1022, 820, 798, 722 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.28 (d, J = 8.0 Hz, 1 H), 7.76
(dd, J = 8.1, 1.3 Hz, 1 H), 7.70 (t, J = 8.1 Hz, 1 H), 7.52 (d, J =
8.0 Hz, 1 H), 7.30 (dd, J = 8.1, 1.3 Hz, 1 H), 4.03 (s, 3 H), 3.16 (s,
2 H), 3.09 (d, J = 14.8 Hz, 1 H), 2.99 (d, J = 14.8 Hz, 1 H), 1.50
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 197.4, 184.7,
181.5, 159.7, 147.1, 137.7, 135.4, 135.1, 134.9, 134.4, 133.8, 129.8,
120.6, 119.5, 117.2, 72.1, 56.5, 53.8, 44.1, 29.8 ppm. HRMS (ESI):
calcd. for C20H17O5 [M + H]+ 337.1076; found 337.1074.
3-(Benzyloxymethyl)-3,7,12-trihydroxy-3,4,10,11-tetrahydrotetra-
phene-1,8(2H,9H)-dione (43): To a solution of quinone 42 (80 mg,
0.18 mmol) dissolved in EtOH (10 mL) under a H2 atomosphere
was added a catalytic amount of 10% Pd/C. The reaction mixture
was stirred for 18 h. The solid in the reaction mixture was filtered
through Celite, and the filtrate was subjected to silica gel column
chromatography to afford compound 43 (70 mg, 85%) as a dark
red semisolid; R = 0.4 (ethyl acetate/hexanes, 1:1). IR (CHCl ): ν
˜
f
3
= 3436, 2927, 2252, 1725, 1637, 1495, 1455, 1389, 1354, 1328, 1090,
910, 735 cm–1. 1H NMR (400 MHz, CDCl3): δ = 13.46 (s, 1 H),
9.43 (s, 1 H), 8.67 (d, J = 8.5 Hz, 1 H), 7.38–7.31 (m, 5 H), 7.24
(d, J = 8.5 Hz, 1 H), 4.59 (s, 2 H), 3.51 (s, 2 H), 3.44, 3.24 (ABq,
JA,B = 17.1 Hz, 2 H), 3.11 (t, J = 6.0 Hz, 2 H), 3.08 (s, 2 H), 2.79
(br. s, 1 H), 2.73 (t, J = 6.0 Hz, 2 H), 2.12 (quint, J = 6.0 Hz, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 205.9, 203.3, 155.7,
149.8, 141.1, 137.5, 132.7, 128.7, 128.6, 128.2, 127.9, 127.6, 127.5,
126.2, 124.0, 112.7, 75.8, 73.8, 72.5, 50.1, 41.9, 38.8, 29.9, 24.5,
22.2 ppm. HRMS (ESI): calcd. for C26H25O6 [M + H]+ 433.1651;
found 433.1650.
X-14881-E (8): Following the general procedure for the A-ring aro-
matization, a solution of quinone 47 (50 mg, 0.14 mmol) in benzene
(10 mL) was treated with a catalytic amount of PTSA, and the
reaction mixture was heated to reflux for 2 h to afford compound
8 (30 mg, 74%) as a brown solid. Rf = 0.7 (ethyl acetate/hexanes,
1:10); m.p. 185–187.4 °C. IR (KBr): ν = 3428, 2923, 2851, 2716,
˜
1660, 1586, 1468, 1354, 1316, 1269, 1171, 1035, 1010, 958, 791,
698 cm–1. 1H NMR (400 MHz, CDCl3): δ = 11.15 (s, 1 H), 8.28 (d,
J = 8.5 Hz, 1 H), 7.93 (dd, J = 7.7, 0.9 Hz, 1 H), 7.73 (t, J = 7.7 Hz,
1 H), 7.35 (d, J = 8.5 Hz, 1 H), 7.24 (br. s, 1 H), 7.12 (d, J =
1.7 Hz, 1 H), 4.07 (s, 3 H), 2.48 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 190.7, 182.2, 159.6, 155.1, 141.2, 138.4, 137.6, 137.3,
136.8, 135.4, 130.7, 122.8, 121.3, 121.0, 119.9, 119.8, 119.2, 118.2,
56.7, 21.3 ppm. HRMS (ESI): calcd. for C20H15O4 [M + H]+
Kanglemycin M (7): To a solution of quinone 42 (50 mg,
0.12 mmol) dissolved in CH2Cl2 (10 mL) under a nitrogen atmo-
sphere at 0 °C was added dropwise a solution of BCl3 (1 m in
CH2Cl2, 1.76 mL, 1.76 mmol). The reaction mixture was warmed 319.0970; found 319.0963.
Eur. J. Org. Chem. 2012, 2250–2259
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2257

D. G. Vanga, K. P. Kaliappan
FULL PAPER
5,8-Bis(methoxymethoxy)naphthalene-1,4-dione (49): To a stirred
solution of dihydroxyquinone 48 (500 g, 2.63 mmol) and DIPEA
(2.75 mL, 15.78 mmol) in CH2Cl2 (20 mL) at 0 °C under a nitrogen
atmosphere was added dropwise MOMCl (3 m in toluene, 4.38 mL,
786 cm–1. H NMR (400 MHz, CDCl3): δ = 13.02 (s, 1 H), 12.52
(s, 1 H), 11.13 (s, 1 H), 8.36 (d, J = 8.5 Hz, 1 H), 8.17 (d, J =
8.5 Hz, 1 H), 7.36 (d, J = 2.7 Hz, 2 H), 7.31 (s, 1 H), 7.19 (s, 1 H),
2.51 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 191.1, 186.3,
1
13.15 mmol), and the reaction mixture was stirred for 6 h at room 159.1, 158.3, 155.2, 142.1, 139.3, 138.4, 135.8, 131.7, 130.7, 130.5,
temp. The reaction mixture was quenched with water, and the re-
sulting mixture was extracted with CH2Cl2 (3ϫ50 mL). The com-
bined organic layers were washed with brine, dried with anhydrous
Na2SO4, and evaporated in vacuo. The crude compound was puri-
fied by flash column chromatography to afford 49 as a purple semi-
solid (670 mg, 91 %). Rf = 0.5 (ethyl acetate/hexanes, 1:9). IR
122.0, 121.8, 120.9, 120.2, 113.8, 111.4, 21.4 ppm. HRMS (ESI):
calcd. for C19H13O5 [M + H]+ 321.0763; found 321.0753.
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data including 1H and 13C NMR spectra for
all the compounds.
(CHCl ): ν = 2985, 2853, 1663, 1448, 1374, 1242, 1047, 847, 787,
˜
3
634 cm–1. H NMR (400 MHz, CDCl3): δ = 7.49 (s, 2 H), 6.78 (s,
1
Acknowledgments
2 H), 5.27 (s, 4 H), 3.54 (s, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 184.7, 152.3, 138.6, 125.3, 122.3, 96.1, 56.7 ppm.
HRMS (ESI): calcd. for C14H14O6Na [M + Na]+ 301.0688; found
301.0685.
We thank the Department of Science and Technology (DST), New
Delhi for the financial support. K. P. K. thanks the DST for the
award of Swarnajayanti Fellowship, and D. G. V. thanks the Uni-
versity Grants Commission (UGC), New Delhi for a fellowship.
We acknowledge Prof. I. N. N. Namboothiri for allowing us to use
their photochemical apparatus.
3,8,11-Tris(methoxymethoxy)-3-methyl-1,2,3,4-tetrahydrotetra-
phene-7,12-dione (50): Following the general procedure for the
Diels–Alder reaction, a solution of 5,8-bis(methoxymethoxy)naph-
thalene-1,4-dione (49) (168 mg, 0.60 mmol) and diene 28 (100 mg,
0.5 mmol) in toluene was heated at 80 °C for 12 h and then at
100 °C for 2 h. After the solvent was removed in vacuo, the crude
Diels–Alder adduct was dissolved in CHCl3 (2 mL), and the re-
sulting solution was treated with NEt3 (1 mL) and silica gel (1 g).
The reaction mixture was stirred for 4 h to afford tetracycle 50
(160 mg, 64%) as a yellow, viscous liquid; Rf = 0.45 (ethyl acetate/
[1] a) J. Rohr, R. Thiericke, Nat. Prod. Rep. 1992, 9, 103–137; b)
K. Krohn, J. Rohr, Top. Curr. Chem. 1997, 188, 127–195; c)
M. C. Carreño, A. Urbano, Synlett 2005, 1–25.
[2] P. W. Schindler, Biotechnol. Forum 1989, 2, 142.
[3] R. H. Thomson, Naturally Occurring Quinones IV, 4th ed.,
Blackie Academic & Professional, London, 1997.
[4] a) T. J. Simpson, Nat. Prod. Rep. 1987, 4, 339–376; b) D.
O’Hagan, The Polyketide Metabolites, Ellis Horwood, Chiches-
ter, 1991; c) S. J. Gould, X. C. Cheng, C. Melville, J. Am. Chem.
Soc. 1994, 116, 1800–1804; d) D. O’Hagan, Nat. Prod. Rep.
1995, 12, 1–32.
[5] a) M. Dann, D. V. Lefemine, F. Barbatschi, M. P. Kunstmann,
L. Mitscher, Antimicrob. Agents Chemother. 1965, 832–835; b)
M. P. Kunstmann, L. A. Mitscher, J. Org. Chem. 1966, 31,
2920–2925.
hexanes, 1:1). IR (CHCl ): ν = 3021, 2928, 1645, 1586, 1454, 1316,
˜
3
1261, 1217, 1025, 759, 668 cm–1. 1H NMR (400 MHz, CDCl3): δ
= 7.93 (d, J = 8.0 Hz, 1 H), 7.47–7.40 (m, 3 H), 7.36 (d, J = 8.0 Hz,
1 H), 5.30 (s, 2 H), 5.29 (s, 2 H), 4.84 (d, J = 7.5 Hz, 1 H), 4.68 (d,
J = 7.5 Hz, 2 H), 3.57 (s, 3 H), 3.56 (s, 3 H), 3.22 (s, 3 H), 3.15 (d,
J = 17.0 Hz, 1 H), 2.86 (d, J = 17.0 Hz, 1 H), 2.11–2.04 (m, 1 H),
1.82–1.75 (m, 1 H), 1.38 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 186.5, 184.0, 151.8, 151.5, 142.6, 137.3, 134.3, 134.2,
132.9, 127.4, 125.2, 124.5, 123.8, 96.6, 96.4, 91.2, 73.5, 56.7, 56.6,
55.4, 43.0, 34.0, 25.6, 25.2 ppm. HRMS (ESI): calcd. for
C25H28O8Na [M + Na]+ 479.1682; found 479.1680.
[6] T. Henkel, J. Rohr, J. M. Beale, L. Schwenen, J. Antibiot. 1990,
43, 492–503.
[7] H. Maehr, C. Liu, M. Liu, A. Perrotta, J. M. Smallheer, T. H.
Williams, J. F. Blount, J. Antibiot. 1982, 35, 1627–1631.
[8] C. H. Sun, N. J. Wang, B. L. Han, Chin. J. Antibiot. 1996, 21,
81–83.
3,8,11-Tris(methoxymethoxy)-3-methyl-3,4-dihydrotetraphene-
1,7,12(2H)-trione (51): Following the general procedure for photo-
oxygenation, a solution of quinone 50 (150 mg, 0.32 mmol) in
benzene (300 mL) was irradiated for 30 h to afford compound 51
(105 mg, 66%) as an orange, viscous liquid; Rf = 0.25 (ethyl acetate/
[9] a) A. Guingant, M. M. Barreto, Tetrahedron Lett. 1987, 28,
1307–1310; b) D. S. Larsen, M. D. O’Shea, Tetrahedron Lett.
1993, 34, 1373–1376; c) K. Krohn, F. Ballwanz, W. Baltus, Lie-
bigs Ann. Chem. 1993, 911–913; d) D. S. Larsen, M. D. O’Shea,
J. Chem. Soc. Perkin Trans. 1 1995, 1, 1019–1028; e) T. Matsu-
moto, T. Sohma, H. Yamaguchi, S. Murata, K. Suzuki, Tetra-
hedron 1995, 51, 7347–7360; f) K. Krohn, J. Micheel, Tetrahe-
dron 1998, 54, 4827–4838; g) G. Matsuo, Y. Miki, M. Nakata,
S. Matsumura, K. J. Toshima, J. Org. Chem. 1999, 64, 7101–
7106; h) K. Krohn, J. Michael, M. Zukowski, Tetrahedron
2000, 56, 4753–4758; i) G. B. Caygill, D. S. Larsen, S. Broker,
J. Org. Chem. 2001, 66, 7427–7431; j) T. Rozek, J. H. Bowie,
S. M. Pyke, B. W. Skelton, A. J. White, J. Chem. Soc. Perkin
Trans. 1 2001, 1, 1826–1830; k) G. A. Kraus, N. Zhang, A.
Melekhov, J. H. Jensen, Synlett 2001, 521–522; l) K. Krohn, A.
Agocs, C. Bäuerlein, J. Carbohydr. Chem. 2003, 22, 579–592.
[10] a) V. A. Boyd, B. E. Drake, G. A. Sulikowski, J. Org. Chem.
1993, 58, 3191–3193; b) V. A. Boyd, G. A. Sulikowski, J. Am.
Chem. Soc. 1995, 117, 8472–8473; c) K. Kim, G. A. Sulikowski,
Angew. Chem. 1995, 107, 2587; Angew. Chem. Int. Ed. Engl.
1995, 34, 2396–2398; d) K. Kim, V. A. Boyd, A. Sobti, G. A.
Sulikowski, Isr. J. Chem. 1997, 37, 3–22.
hexanes, 1:1). IR (CHCl ): ν = 2929, 2857, 1673, 1636, 1572, 1471,
˜
3
1409, 1321, 1246, 1154, 1082, 1001, 920, 757 cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 8.16 (d, J = 8.4 Hz, 1 H), 7.73 (d, J =
7.8 Hz, 1 H), 7.48, 7.40 (ABq, JA,B = 9.2 Hz, 2 H), 5.36, 5.33 (ABq,
JA,B = 7.0 Hz, 2 H), 5.30 (s, 2 H), 4.87, 4.48 (ABq, JA,B = 7.8 Hz,
2 H), 3.60 (s, 3 H), 3.55 (s, 3 H), 3.38 (d, J = 15.2 Hz, 1 H), 3.14
(d, J = 2.2 Hz, 1 H), 3.10 (d, J = 2.2 Hz, 1 H), 3.07 (s, 3 H), 2.93
(d, J = 15.2 Hz, 1 H), 1.48 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 195.7, 185.7, 182.0, 152.0, 150.6, 147.2, 138.7, 134.2,
133.0, 132.9, 129.7, 127.5, 125.1, 123.6, 123.3, 96.3, 96.1, 91.2, 56.7,
55.7, 51.9, 42.6, 25.6 ppm. HRMS (ESI): calcd. for C25H26O9Na
[M + Na]+ 493.1475; found 493.1467.
Anhydrolandomycinone (9): Following the general procedure for
aromatization, a solution of compound 51 (100 mg, 0.31 mmol) in
benzene (20 mL) was treated with a catalytic amount of PTSA, and
the resulting mixture was heated to reflux for 2 h to afford com-
pound 9 (66 mg, 70%) as a purple solid. Rf = 0.7 (ethyl acetate/
[11] K. Krohn, M. H. Sohrab, U. Flörke, Tetrahedron: Asymmetry
2004, 15, 713–718.
[12] J. Motoyoshiya, Y. Masue, G. Iwayama, S. Yoshioka, Y. Nishii,
H. Aoyama, Synthesis 2004, 2099–2102.
hexanes, 1:10); m.p. 204–206.5 °C. IR (CHCl ): ν = 3447, 2921,
˜
3
2851, 1731, 1608, 1585, 1498, 1449, 1414, 1317, 258, 1181, 1143,
2258
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2250–2259

Total Synthesis of Angucyclinone Antibiotics
[13] a) M. C. Carreño, A. Urbano, J. Fischer, Angew. Chem. 1997,
109, 1695; Angew. Chem. Int. Ed. Engl. 1997, 36, 1621–1623;
b) M. C. Carreño, A. Urbano, C. Di Vitta, J. Org. Chem. 1998,
63, 8320–8330; c) M. C. Carreño, A. Urbano, C. Di Vitta,
Chem. Commun. 1999, 817–818; d) M. C. Carreño, A. Urbano,
[20] K. P. Kaliappan, V. Ravikumar, Org. Biomol. Chem. 2005, 3,
848–851.
[21] a) K. P. Kaliappan, A. V. Subrahmanyam, Org. Lett. 2007, 9,
1121–1124; b) A. V. Subrahmanyam, K. Palanichamy, K. P.
Kaliappan, Chem. Eur. J. 2010, 16, 8545–8556.
C. Di Vitta, Chem. Eur. J. 2000, 6, 906–913; e) M. C. Carreño, [22] B. M. Trost, A. B. Pinkerton, J. Am. Chem. Soc. 2002, 124,
A. Somoza, M. Ribagorda, A. Urbano, Chem. Eur. J. 2007, 13,
879–890.
[14] a) D. S. Larsen, M. D. O’Shea, S. Broker, Chem. Commun.
1996, 203–204; b) D. S. Larsen, M. D. O’Shea, J. Org. Chem.
1996, 61, 5681–5683; c) J. S. Landells, D. S. Larsen, J. Simpson,
Tetrahedron Lett. 2003, 44, 5193–5196.
7376–7389.
[23] M. Rosillo, L. Casarrubios, G. Domínguez, J. Pérez-Castells,
Tetrahedron Lett. 2001, 42, 7029–7031.
[24] a) S. W. Heinzman, J. R. Grunwell, Tetrahedron Lett. 1980, 21,
4305–4308; b) M. E. Jung, J. A. Hagenah, J. Org. Chem. 1983,
48, 5359–5361.
[15] a) T. Rozek, W. Janowski, J. M. Hevko, E. R. T. Tieknink, S.
Dua, D. J. M. Stone, J. H. Bowie, Aust. J. Chem. 1998, 51, 515–
523; b) M. L. Patil, H. B. Borate, D. E. Ponde, V. H.
Deshpande, Tetrahedron 2002, 58, 6615–6620.
[25] a) K. R. Huffman, M. Loy, E. F. Ullman, J. Am. Chem. Soc.
1965, 87, 5417–5423; b) R. B. Blankespoor, R. L. De Jong, R.
Dystra, D. A. Hamstra, D. B. Rozema, D. P. VanMeurs, P.
Vink, J. Am. Chem. Soc. 1991, 113, 3507–3513; c) M. A. Gar-
cia-Garibay, A. Gamarnik, L. Pang, W. S. Jenks, J. Am. Chem.
Soc. 1994, 116, 12095–12096; d) K. Krohn, K. Khanbabaee, J.
Micheel, Liebigs Ann. 1995, 1529–1537.
[16] D. Mal, H. N. Roy, J. Chem. Soc. Perkin Trans. 1 1999, 3167–
3171.
[17] a) W. S. Murphy, D. Neville, G. Ferguson, Tetrahedron Lett.
1996, 37, 7615–7618; b) G. A. Kraus, W. Zhiwen, Tetrahedron [26] a) P. M. Brown, R. H. Thomson, J. Chem. Soc. Perkin Trans.
Lett. 1997, 38, 6509–6512; c) C.-P. Chuang, S.-F. Wang, Tetra-
hedron 1998, 54, 10043–10052; d) T. Matsumoto, H. Yamagu-
chi, M. Tanabe, Y. Yasui, K. Suzuki, Tetrahedron Lett. 2000,
41, 8393–8396; e) A. R. Hergueta, H. W. Moore, J. Org. Chem.
2002, 67, 1388–1391; f) F. M. Hauser, W. A. Dorsch, D. Mal,
Org. Lett. 2002, 4, 2237–2239; g) K. Sato, N. Asao, Y. Yamam-
oto, J. Org. Chem. 2005, 70, 8977–8981.
1 1976, 997–1000; b) M. Yamaguchi, T. Okuma, A. Horiguchi,
C. Ikeura, T. Minami, J. Org. Chem. 1992, 57, 1647–1649; c)
K. Krohn, U. Flörke, C. Fround, N. Hayat, Eur. J. Org. Chem.
2000, 1627–1632; d) K. A. Parker, Q.-J. Ding, Tetrahedron
2000, 56, 10249–10254; e) K. A. George, Z. Ning, M. Alex,
J. H. Jan, Synlett 2001, 521–522.
[27] K. Thai, L. Wang, T. Dudding, F. Bilodeau, M. Gravel, Org.
Lett. 2010, 12, 5708–5711.
[28] S. Grabley, P. Hammann, K. Hutter, H. Kluge, R. Thiericke, J.
Wink, J. Antibiot. 1991, 44, 670–673.
[18] a) A. Kalogerakis, U. Groth, Org. Lett. 2003, 5, 843–844; b)
A. Kalogerakis, U. Groth, Synlett 2003, 1886–1888; c) C. Ka-
senheimer, U. Groth, Org. Lett. 2006, 8, 2507–2510.
[19] a) K. P. Kaliappan, V. Ravikumar, Synlett 2007, 977–979; b) [29] W. R. Roush, R. J. Neitz, J. Org. Chem. 2004, 69, 4906–4911.
K. P. Kaliappan, V. Ravikumar, J. Org. Chem. 2007, 72, 6116–
6126.
Received: January 13, 2012
Published Online: February 24, 2012
Eur. J. Org. Chem. 2012, 2250–2259
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2259