Synthetic Studies toward Actinorhodin and γ-Actinorhodin by using a Homo-coupling Strategy: Synthesis of Hemiactinorhodin and Hemi-γ-actinorhodin

Article abstract of DOI:10.1002/ejoc.201500510

A homo-coupling strategy toward the synthesis of actinorhodin and γ-actinorhodin has been explored. The monomeric unit was synthesized by employing an efficient combination of D?tz benzannulation and oxa-Pictet-Spengler reactions. Attempts towards oxidative homo-coupling of the pyranonaphthalene monomer intermediate to give dimer were unsuccessful. Later, monomer pyranonaphthalene was carried forward to complete the synthesis of hemiactinorhodin and hemi-γ-actinorhodin.

Full text of DOI:10.1002/ejoc.201500510

FULL PAPER
DOI: 10.1002/ejoc.201500510
Synthetic Studies toward Actinorhodin and γ-Actinorhodin by using a Homo-
coupling Strategy: Synthesis of Hemiactinorhodin and Hemi-γ-actinorhodin
[a]
[a]
[a]
Sandip V. Mulay, Amit Bhowmik, and Rodney A. Fernandes*
Keywords: Synthetic methods / Annulation / Oxygen heterocycles / Antibiotics / Actinorhodins
A homo-coupling strategy toward the synthesis of actinorho- aphthalene monomer intermediate to give dimer were un-
din and γ-actinorhodin has been explored. The monomeric
unit was synthesized by employing an efficient combination
of Dötz benzannulation and oxa-Pictet–Spengler reactions.
Attempts towards oxidative homo-coupling of the pyranon-
successful. Later, monomer pyranonaphthalene was carried
forward to complete the synthesis of hemiactinorhodin and
hemi-γ-actinorhodin.
Introduction
members of these dimeric pyranonaphthoquinones has
been relatively unexplored. In 1986, Nelson et al. isolated
Pyranonaphthoquinone antibiotics have attracted con-
siderable interest from synthetic chemists, because of their
wide range of biological activities against various Gram-
positive bacteria, pathogenic fungi, and yeasts as well as
their antiviral activity.[ Moore in 1977 proposed that this
class of antibiotics act as effective bis-alkylating agents
upon bioreduction in a mode similar to chemotherapeutic
drug mitomycin C.[ This class of antibiotics are isolated
from various strains of bacteria and fungi, the majority of
[14]
similar C -symmetric dimeric pyranonaphthoquinone crisa-
2
micin A (3) from microorganism Micromonospora purpureo-
chromogenes, which was obtained from a mud sample in
the Philippines. Crisamicin A (3) exhibited excellent activity
against Gram-positive bacteria and also showed in vitro ac-
tivity against B16 murine melanoma cells, Herpes simplex
1]
2]
[15]
virus, and vesicular stomatitis viruses.
The syntheses of monomeric pyranonaphthoquinones
[
3–5]
microbial origin.
elicolor produces a red pigment that shows litmus-type
Soil-dwelling bacteria Streptomyces co-
and monomers 4 and 5 of dimers 1–3 are well documen-
[16]
[17]
ted.
Wang and co-workers
reported the racemic syn-
properties, bright blue in alkaline and red in acid me-
thesis of crisamicin A (3), although the synthesis of dimeric
[
6–8]
dium.
mined by extensive chemical degradation and mass spec-
The structure of this pigment was later deter-
pyrano-naphthoquinones 1 and 2 is yet to be achieved.
[
9]
[18]
Laatsch
achieved the partial synthesis of an enantiomer
[
10]
trometry
to be dimeric pyranonaphthoquinone acti-
of actinorhodin (1) from a degradation product of the anti-
[
11]
norhodin (1; Figure 1). Later, Floss and co-workers
ambiguously established the point of connection of the two
molecular halves from biosynthetic studies. The other con-
un-
bacterial metabolite α-naphthocyclinone. Brimble and co-
[19]
workers
reported the synthesis of an analogue of acti-
norhodin (1) based on Suzuki–Miyaura coupling for the
C8–C8Ј linkage and a double furofuran annulation/oxidat-
ive rearrangement strategy. However they failed in the final
demethylation and to obtain the desired anti-stereochemis-
try of pyran substituents. In our efforts toward the stereo-
geners of actinorhodin (1), which includes γ-actinorhodin
2), have been isolated[
12,13]
from Streptomyces coelicolor
(
and all of them have an oxygen atom in the ortho position
1
13
of the biaryl axis. H and C NMR spectroscopic stud-
ies[
10,13]
showed that both actinorhodin (1) and γ-actinorho-
selective synthesis of pyranonaphthoquinones and related
din (2) consist of two halves with the same structure and
configuration, and joined in a symmetrical C8–C8Ј linkage.
Actinorhodin (1) shows activity against staphylococcus au-
reus bacteria, which are found in the human respiratory
tract and on the skin.[ The biological activity of other
[16g–16m,20]
compounds,
we observed that the sequence of
[21]
[22]
Dötz benzannulation
and oxa-Pictet–Spengler
reac-
tions enables the rapid construction of the pyranonaphtho-
quinone framework. Conceivably, these dimeric structures
7]
1
and 2 could be constructed by homo-coupling of their
monomeric precursors and give greater significance to rapid
assembly of these dimeric compounds. We have explored
the oxidative dimerization strategy by assembling monomer
compounds by employing Dötz benzannulation and oxa-
Pictet–Spengler reactions and we report our results in this
paper.
[
a] Department of Chemistry, Indian Institute of Technology –
Bombay,
Powai, Mumbai 400076, Maharashtra, India
E-mail: rfernand@chem.iitb.ac.in
http://www.chem.iitb.ac.in/~rfernand/default.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500510.
Eur. J. Org. Chem. 2015, 4931–4938
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4931

S. V. Mulay, A. Bhowmik, R. A. Fernandes
FULL PAPER
Figure 1. Structures of dimeric pyranonaphthoquinones and their monomers.
Results and Discussion
was transformed into 12 by regioselective bromination with
N-bromosuccinimide (NBS) followed by methylation with
As illustrated in Scheme 1, actinorhodin (1) could be ac- K CO and Me SO in 92% overall yield (two steps). The
2
3
2
4
cessed from γ-actinorhodin (2) through reductive opening synthesis of Fischer carbene 8 was achieved from 12 in a
of γ-lactone to acid by hydrogenolysis. γ-Actinorhodin (2) good yield of 71%. Dötz benzannulation reaction of 8 with
[
16l]
can be accessed from dimer 6, which in turn was anticipated alkyne 9
in benzene delivered single regioisomeric
by oxidative homo-coupling of monomer 7. The Dötz-type naphthol 13 in 52% yield. Methylation of 13 with NaH and
benzannulation of Fischer carbene 8 with alkyne 9 would MeI gave 14 (88%), and further one-pot acetonide depro-
produce the naphthalene unit with the β-hydroxy γ-lactone tection and in-situ lactonization with trifluoroacetic acid
moiety and an oxa-Pictet–Spengler reaction would install (TFA)/catalytic concd. aqueous HCl provided lactone 15 in
the pyran ring of monomer 7. Building block alkyne 9 84% yield. In our recent synthesis of arizonins C1 and
[
16m]
could be derived from chiral pool material d-glucono-δ- B1,
lactone 10.
we observed that the oxa-Pictet–Spengler reaction
[
16l]
of similar naphthyl hydroxylactone (four methoxy group on
The synthesis of monomeric precursor 7 is outlined in naphthalene ring) with acetaldehyde dimethyl acetal in pre-
Scheme 2. Commercially available 4-methoxy phenol 11 heated TFA (70 °C) as solvent and BF ·OEt as Lewis acid
3
2
Scheme 1. Retrosynthesis of actinorhodin 1 and γ-actinorhodin 2.
932
4
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4931–4938

Synthetic Studies toward Actinorhodin and γ-Actinorhodin
quickly provided the single anti-pyran diastereomer ive C–C coupling[24] by using FeCl in CH Cl and meth-
3
2
2
(
Scheme 2). When a similar reaction was performed on lact- anol was unsuccessful (Table 1, Entry 2). FeCl catalyzed
3
one 15, it gave only syn-pyran product 7 in low yield of oxidative homo-coupling reaction of 7 with m-CPBA[ as
5%. This reveals the influence of substituents position on oxidant was also disappointing (Table 1, Entry 3). In these
the naphthyl ring that play an important role in diastereo- two cases, decomposition of 7 was observed. In synthesis of
25]
3
[
26]
selectivity. Hence the oxa-Pictet–Spengler reaction of 15 ventiloquinone L, Brimble and co-workers observed that
with acetaldehyde dimethyl acetal catalyzed by BF ·OEt2 the treatment of a naphthopyran with ceric(IV) ammonium
3
was carried out in CH Cl at 0 °C to furnish selectively syn- nitrate (CAN) facilitated a tandem biaryl bond formation–
2
2
pyran diastereomer 7 in 76% yield.
oxidative demethylation to provide dimeric pyranonaphtho-
quinone. A similar reaction was observed by us in our
astropaquinones synthesis with phenyliodine-bis(trifluoro-
[
20e]
acetate) (PIFA).
When we subjected naphthopyran 7 to
CAN-mediated oxidative reaction conditions, demethylated
quinone regioisomers 16 (37%) and 17 (29%) were isolated
(Table 1, Entry 4). However, no homo-coupled product was
obtained. Similar results were obtained with PIFA (Table 1,
Entry 5), although with improved yields of 16 (49%) and
17 (38%). Our attempts to make biaryl linkage by oxidative
coupling of 7 by using oxidizing silver(I) oxide–triethyl-
[
18]
amine (Table 1, Entry 6) or CuCl(OH), tetramethylethyl-
[
27]
enediamine (TMEDA) in the presence of O2
(Table 1,
Entry 7) led to decomposition of 7. Under all the above
known conditions for oxidative homo-coupling reactions,
we could not obtain homo-coupled product 6. Hence we
continued with compound 7 for the synthesis of hemiacti-
norhodin (4) and hemi-γ-actinorhodin (5). The synthesis of
methyl ester of hemiactinorhodin and C-5 epimer of hemi-
γ-actinorhodin has been reported earlier by Brimble and
[
16a,16b]
co-workers.
The spectroscopic data ( H NMR, 13C NMR, and IR
spectroscopy) of separated quinone compound 17 was in
excellent agreement with that reported for ent-17 in the lit-
1
[
28]
erature.
The treatment of quinone 17 with excess BBr3
Scheme 2. Synthesis of monomeric precursor 7.
was expected to give demethylation of both methyl groups
[
16b]
and C-5 epimerization,
diastereomers 18 and 5 (28:72 determined by H NMR) in
however a mixture of syn/anti-
With monomeric precursor 7 in hand, our next task was
to oxidatively homo-couple it to get dimeric compound 6.
Naphthopyran 7 under Scholl reaction conditions
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
1
[
23]
65% yield was obtained (Scheme 3). By stirring this mixture
[2,3-
and
with concd. H SO in benzene C-5 epimerization resulted
2
4
1
to give 18/5 in 6:94 ratio (as determined by H NMR spec-
troscopy). A single recrystallization provided hemi-γ-aci-
norhodin (5) in 38% overall yield from 17. Alternatively,
CH SO H] in CH Cl at 0 °C failed to deliver expected
3
3
2
2
product 6, and instead starting material 7 was recovered
Table 1, Entry 1). The same reaction carried out for oxidat-
(
Table 1. Attempted oxidative homo-coupling reaction of 7 to 6.
Entry
Reaction conditions
Product/s
1
2
3
4
5
6
7
DDQ, CH
3
SO
3
H, CH
, MeOH, room temp., 6 h
Cl , room temp., 1.5 h
O (1:1), room temp., 30 min
O (1:1), 0 °C, 30 min
N, CHCl , 4 h
CuCl(OH),TMEDA/O , room temp., 8 h
2
Cl
2
, 0 °C, 30 min
7 recovered
FeCl
FeCl
CAN, CH
PIFA, CH
Ag O, Et
3
, CH
2
Cl
2
7 decomposed
3
, m-CPBA, CH
CN/H
CN/H
2
2
7 decomposed
3
2
16 (37%) and 17 (29%)
16 (49%) and 17 (38%)
complex mixture
complex mixture
3
2
2
3
3
2
Eur. J. Org. Chem. 2015, 4931–4938
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4933

S. V. Mulay, A. Bhowmik, R. A. Fernandes
FULL PAPER
quinone 17 on AlCl -mediated demethylation provided 5-
Undesired terminal quinone 16 (Table 1) was converted
3
epi-hemi-γ-acinorhodin (18) in 68% yield. H SO -mediated into 5-epi-hemi-γ-acinorhodin (18) as shown in Scheme 4.
2
4
C-5 epimerization of 18 in benzene gave a mixture of 18 BBr -mediated demethylation resulted also in C-5 epimeriz-
3
and 5 in a 7:93 ratio and a single crystallization provided 5 ation and quinone tautomerization to provide a mixture of
1
in 62% overall yield from 18. Hydrogenation of hemi-γ- 18 and 5 (38:62, determined by H NMR spectroscopy) in
acinorhodin (5) with H /Pd-C resulted in the opening of the 45% yield. Alternatively, based on Couladouros report,[
30]
2
lactone ring to give hemiactinorhodin 4 in a good yield of the conversion of terminal quinone 16 into 5-epi-hemi-γ-
[
29]
83%
(Scheme 3). Compounds 4 and 5 are monomeric acinorhodin (18) was efficiently achieved by the sequence
units of dimeric pyranonaphthoquinones 1 and 2, respec- of reductive acetylation, oxidation, and hydrolysis. Thus,
tively.
the one-pot reduction of quinone 16 to hydroquinone with
Zn and in-situ acetylation with Ac O and Et N/4-(dimeth-
2
3
ylamino)pyridine (DMAP) afforded 19 in an excellent yield
of 90%. CAN-mediated oxidation of 19 provided quinone
2
0 in good yield of 78%. Mild hydrolysis of 20 with K CO3
2
in MeOH gave 18 in 75% yield.
Conclusions
In conclusion, we efficiently synthesized a pyran ring
containing monomeric precursor 7 by Dötz benzannulation
and oxa-Pictet–Spengler reaction for oxidative homo-cou-
pling to get dimeric pyranonaphthoquinones actinorhodin
and γ-actinorhodin. Attempts for oxidative homo-coupling
of 7 failed to give the anticipated dimer molecules. How-
ever, the monomers were carried forward to complete the
synthesis of hemiactinorhodin and hemi-γ-actinorhodin.
The oxidation of 7 gave two regioisomeric, separable quin-
ones 16 and 17. Undesired terminal quinone 16 was ef-
ficiently converted into desired 5-epi-hemi-γ-acinorhodin
(18) by using Couladouros protocol.
Experimental Section
General: Flasks were oven or flame dried and cooled in a desicca-
tor. Dry reactions were carried out under an atmosphere of Ar or
N
2
. Solvents and reagents were purified by standard methods. Thin
layer chromatography was performed on EM 250 Kieselgel 60 F254
silica gel plates. The spots were visualized by staining with KMnO
4
1
13
Scheme 3. Synthesis of hemi-γ-actinorhodin (5) and hemi-
actinorhodin (4).
or by UV lamp. H and C NMR spectroscopic data were re-
corded at 400 or 500, and 100 or 125 MHz, respectively. Chemical
Scheme 4. Synthesis of 5-epi-hemi-γ-actinorhodin (18) from 16.
4934
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4931–4938

Synthetic Studies toward Actinorhodin and γ-Actinorhodin
–1
shifts are reported relative to tetramethylsilane δ = 0.00 ppm for
1173, 1068, 1002, 909, 843, 802, 735, 710 cm . 1H NMR
1
13
H, and CDCl
samples were prepared by evaporation from CHCl
3
δ = 77.00 ppm (t) for C NMR spectroscopy. IR
on CsBr plates.
(400 MHz, CDCl /TMS): δ = 1.56 (s, 3 H), 1.63 (s, 3 H), 2.73 (dd,
3
3
J = 16.3, 9.1 Hz, 1 H), 2.99 (dd, J = 16.3, 2.8 Hz, 1 H), 3.64 (s, 3
H), 3.90 (s, 3 H), 3.91 (s, 3 H), 3.99 (s, 3 H), 4.26 (td, J = 8.8,
2.7 Hz, 1 H), 5.35 (d, J = 8.4 Hz, 1 H), 6.74 (s, 2 H), 7.15 (s, 1 H),
High-resolution mass spectra were obtained by using positive elec-
trospray ionization. Optical rotations were measured with a Jasco
P-2000 digital polarimeter.
1
3
9.74 (s, 1 H, OH) ppm; C NMR (100 MHz, CDCl
3
): δ = 27.1,
7.2, 37.4, 51.6, 56.6, 57.3, 57.9, 76.1, 78.9, 105.4, 106.8, 108.2,
09.2, 117.1, 118.5, 119.8, 145.8, 149.6, 150.2, 151.8, 171.5 ppm.
+ Na]+ 429.1520; found
2
1
2-Bromo-1,4-dimethoxybenzene (12): NBS (2.87 g, 16.12 mmol,
1.0 equiv.) was added portion wise to a stirred solution of 4-meth-
HRMS: m/z calcd. for [C21
26 8
H O
3
oxyphenol (11) (2.0 g, 16.11 mmol) in CH CN (40 mL) at 0 °C. The
429.1523.
reaction mixture was slowly warmed to room temperature and
stirred for 3 h. The solvent was evaporated at reduced pressure and
the residue dissolved in EtOAc/water (1:1, 50 mL). The separated
aqueous layer was extracted with EtOAc (2ϫ 20 mL). The com-
Methyl (3R,4R)-4-(1,4,5,8-Tetramethoxynaphthalen-2-yl)-3,4-(iso-
propylidenedioxy)butanoate (14): NaH (77 mg, 1.92 mmol, 60% in
mineral oil, 1.2 equiv.) was added to a solution of naphthol 13
2 4
bined organic layers were washed with brine, dried (Na SO ), and
(
0.65 g, 1.60 mmol) in dry dimethylformamide (10 mL) at 0 °C. The
concentrated. The residue was purified by silica gel column
chromatography with petroleum ether/EtOAc (9:1 to 4:1) as eluent
to give 2-bromo-4-methoxyphenol (3.11 g, 95%) as a colorless so-
lid; m.p. 43–44 °C (ref.[ m.p. 42–43 °C).
reaction mixture was stirred at room temperature for 20 min, then
cooled to 0 °C and MeI (0.2 mL, 3.20 mmol, 2.0 equiv.) was added.
The reaction mixture was stirred at 0 °C to room temperature for
31]
3
h. It was then quenched with ice-cold water (5 mL) and the solu-
tion extracted with EtOAc (3ϫ 20 mL). The combined organic lay-
ers were washed with water, brine, dried (Na SO ), and concen-
Anhydrous K
stirred solution of above 2-bromo-4-methoxyphenol (3.1 g,
5.27 mmol) in acetone (50 mL) and stirred at room temperature
2 3
CO (3.17 g, 22.93 mmol, 1.5 equiv.) was added to a
2
4
trated. The residue was purified by silica gel column chromatog-
1
raphy with petroleum ether/EtOAc (9:1 to 4:1) as eluent to give 14
for 10 min. Dimethylsulfate (1.74 mL, 18.32 mmol, 1.2 equiv.) was
added and the reaction mixture stirred for 12 h at room tempera-
ture. The reaction was quenched with water (20 mL) and acetone
was evaporated. EtOAc (40 mL) was added and the organic layer
separated. The aqueous layer was extracted with EtOAc (2ϫ
2
5
(
0.591 g, 88%) as a yellow solid; m.p. 53–55 °C. [α]
.9, CHCl ). IR (CHCl
3 3
D
= +29.8 (c =
): ν˜ = 2986, 2934, 2837, 1742, 1602, 1519,
462, 1434, 1366, 1333, 1258, 1194, 1173, 1071, 1014, 993, 909,
0
1
8
–
1 1
3
33, 804, 698 cm . H NMR (500 MHz, CDCl /TMS): δ = 1.57
(
=
(
s, 3 H), 1.64 (s, 3 H), 2.72 (dd, J = 16.2, 8.9 Hz, 1 H), 2.88 (dd, J
16.2, 2.9 Hz, 1 H), 3.63 (s, 3 H), 3.76 (s, 3 H), 3.89 (s, 3 H), 3.92
s, 3 H), 3.96 (s, 3 H), 4.27 (td, J = 8.7, 2.9 Hz, 1 H), 5.29 (d, J =
2
0 mL). The combined organic layers were washed with water,
brine, dried (Na SO ), and concentrated. The residue was purified
by silica gel column chromatography with petroleum ether/EtOAc
2
4
1
3
8
.5 Hz, 1 H), 6.84 (s, 2 H), 7.07 (s, 1 H) ppm; CNMR (125 MHz,
): δ = 27.1, 27.2, 36.9, 51.5, 56.8, 56.9, 57.8, 62.5, 76.5, 78.9,
105.3, 108.0, 108.9, 109.3, 120.6, 122.5, 126.8, 148.0, 150.1, 151.4,
(
(
1
(
(
9:1) as eluent to afford 12 (3.21 g, 97%) as a colorless oil. IR
CHCl ): ν˜ = 3001, 2941, 2906, 2835, 1607, 1576, 1497, 1460, 1438,
359, 1273, 1222, 1151, 1041, 864, 800, 732 cm . H NMR
400 MHz, CDCl /TMS): δ = 3.76 (s, 3 H), 3.84 (s, 3 H), 6.80–6.85
m, 2 H), 7.10–7.13 (m, 1 H) ppm; 13C NMR (100 MHz, CDCl
):
CDCl
3
3
–1
1
+
1
53.6, 171.2 ppm. HRMS: m/z calcd. for [C22
28 8
H O + Na]
3
443.1676; found 443.1678.
3
δ = 55.9, 56.8, 111.9, 112.9, 113.6, 119.0, 150.3, 154.0 ppm. HRMS:
m/z calcd. for [C H O Br + Na] 238.9678; found 238.9674.
8 9 2
(
4R,5R)-4-Hydroxy-5-(1,4,5,8-tetramethoxynaphthalen-2-yl)di-
hydrofuran-2(3H)-one (15): Trifluoroacetic acid/H O (9:1, 1 mL)
and concd. HCl (2 drops) were added to a solution of 14 (0.55 g,
.31 mmol) in CH Cl (15 mL). The resulting solution was stirred
at room temperature for 18 h and then quenched with saturated
aq. NaHCO (5 mL). The solution was extracted with CH Cl (3ϫ
0 mL) and the combined organic layers were washed with brine,
+
2
Fischer Carbene 8: nBuLi (3.0 mL, 4.84 mmol, 1.05 equiv., 1.6 m
solution in hexane) was added to a solution of 12 (1.0 g,
1
2
2
4
.61 mmol) in dry Et
stirred for 20 min. The reaction mixture was then transferred into
a suspension of Cr(CO) (1.12 g, 5.09 mmol, 1.1 equiv.) in dry Et
25 mL) at 0 °C. The reaction mixture was stirred for 1 h at 0 °C
and then at room temperature for 2 h. Et O was evaporated and
the residue dissolved in dry CH Cl (30 mL). To this solution was
added Me OBF (1.02 g, 6.90 mmol, 1.5 equiv.) in one portion at
°C and the reaction mixture stirred for 1 h, then warmed to room
2
O (25 mL) at –60 °C and the reaction mixture
3
2
2
1
6
2
O
(
2 4
dried (Na SO ), and concentrated. The residue was purified by sil-
ica gel column chromatography with petroleum ether/EtOAc (4:1
to 1:1) as eluent to give 15 (0.382 g, 84%) as a yellow solid; m.p.
1
3
1
TMS): δ = 1.87 (s, 1 H, OH), 2.75 (d, J = 17.7 Hz, 1 H), 2.96 (ddd,
J = 17.7, 5.4, 1.2 Hz, 1 H), 3.77 (s, 3 H), 3.90 (s, 3 H), 3.93 (s, 3
H), 3.96 (s, 3 H), 4.89–4.91 (m, 1 H), 5.89 (d, J = 3.5 Hz, 1 H),
6
(
2
2
2
2
5
25–127 °C. [α]
D 3 3
= –5.43 (c = 0.7, CHCl ). IR (CHCl ): ν˜ = 3460,
3
4
000, 2935, 2838, 1776, 1603, 1519, 1465, 1370, 1262, 1223, 1157,
0
–
1 1
temperature and stirred for 2 h. The red colored reaction mixture
was concentrated and the residue purified by silica gel column
chromatography with petroleum ether/CH Cl (9:1 to 4:1) as eluent
2 2
to give 8 (1.22 g, 71%) as a red amorphous solid. This product was
used immediately in the next step.
3
075, 1013, 978, 908, 835, 803 cm . H NMR (500 MHz, CDCl /
1
3
.83 (ABq, J = 8.7 Hz, 2 H), 6.98 (s, 1 H) ppm; C NMR
100 MHz, CDCl ): δ = 38.3, 55.9, 56.8, 57.7, 62.2, 69.6, 82.1,
05.7, 106.6, 108.7, 120.3, 121.3, 123.7, 145.9, 149.2, 150.9, 153.2,
+ Na]+ 371.1101;
75.9 ppm. HRMS: m/z calcd. for [C18
3
Methyl
(3R,4R)-4-(1-Hydroxy-4,5,8-trimethoxynaphthalen-2-yl)-
1
1
[16l]
3,4-(isopropylidenedioxy)butanoate (13): Alkyne
9
(0.957 g,
20 7
H O
4.83 mmol, 1.5 equiv.) was added to freshly prepared Fischer carb-
found 371.1103.
ene complex 8 (1.22 g, 3.28 mmol) in dry and degassed benzene
15 mL). The reaction mixture was stirred at 45 °C for 15 h, then (3aR,5S,11bR)-3,3a,5,11b-Tetrahydro-6,7,10,11-tetramethoxy-5-
(
cooled to room temperature, exposed to air, and stirred further
for 30 min. The reaction mixture was concentrated and the residue
purified by silica gel column chromatography with petroleum ether/
methyl-1,4-dioxacyclopenta[a]anthracen-2-one (7): Acetaldehyde di-
methyl acetal (77.5 mg, 0.86 mmol, 2.0 equiv.) and BF ·OEt
(0.140 mL, 0.86 mmol, 2.0 equiv.) were added to a solution of lact-
one 15 (0.150 g, 0.43 mmol) in CH Cl (15 mL) at 0 °C. The reac-
tion mixture was stirred at 0 °C to room temperature for 5 h, then
quenched with saturated aq. NaHCO (5 mL), and the solution
3
2
EtOAc (9:1 to 4:1) as eluent to give 13 (0.692 g, 52%) as a yellow
2
2
oil. [α]2
5
= –54.9 (c = 1.1, CHCl
D
3
). IR (CHCl
3
): ν˜ = 3351, 2985,
2937, 2840, 1741, 1605, 1519, 1497, 1454, 1383, 1331, 1251, 1190,
3
Eur. J. Org. Chem. 2015, 4931–4938
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4935

S. V. Mulay, A. Bhowmik, R. A. Fernandes
FULL PAPER
extracted with CH
were washed with brine, dried (Na
residue was purified by silica gel column chromatography with pe-
2
Cl
2
(3ϫ 20 mL). The combined organic layers
SO ), and concentrated. The
chromatography with petroleum ether/EtOAc (3:1 to 3:2) as eluent
2
4
to afford a mixture of 5 and 18 (9.6 mg, 65%, anti/syn = 72:28,
1
determined by H NMR spectroscopy) as a red solid.
troleum ether/EtOAc (9:1 to 3:1) as eluent to give 7 (0.122 g, 76%)
2 4
Concd. H SO (0.5 mL) was added to a stirred solution of the mix-
as a colorless solid; m.p. 135–137 °C. [α]2
5
= +231.3 (c = 0.56,
D
ture of 5 and 18 in benzene (3 mL) at 5 °C. The reaction mixture
was slowly warmed to room temperature, stirred for 30 min, then
diluted with ice-cold water (15 mL), and extracted with EtOAc (5ϫ
CHCl
3
). IR (CHCl
3
): ν˜ = 3000, 2936, 2838, 1780, 1610, 1588, 1504,
1
9
1
=
(
458, 1430, 1356, 1288, 1256, 1204, 1152, 1112, 1061, 1035, 986,
–
1 1
06, 882, 806, 669 cm . H NMR (500 MHz, CDCl
.73 (d, J = 6.3 Hz, 3 H), 2.76 (d, J = 17.3, Hz, 1 H), 2.92 (dd, J
17.3, 4.4 Hz, 1 H), 3.71 (s, 3 H), 3.94 (s, 3 H), 3.97 (s, 3 H), 3.98
s, 3 H), 4.35 (dd, J = 4.2, 2.4 Hz, 1 H), 5.06 (q, J = 6.3 Hz, 1 H),
.60 (d, J = 2.3 Hz, 1 H), 6.84 (ABq, J = 8.6 Hz, 2 H) ppm;
3
/TMS): δ =
1
0 mL). The combined organic layers were washed with water,
brine, dried (Na SO ), and concentrated. The residue was purified
by silica gel column chromatography with petroleum ether/EtOAc
3:1 to 3:2) as eluent to give a mixture of 5 and 18 (in 94:6 ratio),
which upon recrystallization provided 5 (5.6 mg, 38% from 17) as
2
4
(
5
1
3
CNMR (100 MHz, CDCl
0.0, 71.5, 73.2, 106.5, 108.1, 120.3, 121.8, 123.3, 130.3, 149.0,
22 7
49.8, 150.3, 153.4, 175.8 ppm. HRMS: m/z calcd. for [C20H O
3
): δ = 22.2, 38.4, 56.7, 57.0, 61.5, 64.7,
2
5
a red solid; m.p. 205–206 °C. [α]
D
3
= +226 (c = 0.06, CHCl ). IR
7
1
(
1
CHCl
3
): ν˜ = 3430, 2925, 2853, 1788, 1614, 1574, 1455, 1411, 1341,
–
1
1
250, 1199, 1154, 1036, 904 cm . H NMR (400 MHz, CDCl
3
/
+
+
H] 375.1438; found 375.1437.
TMS): δ = 1.57 (d, J = 6.9 Hz, 3 H), 2.71 (d, J = 17.7, Hz, 1 H),
3aR,5S,11bR)-3,3a,5,11b-Tetrahydro-6,11-dimethoxy-5-methyl-1,4- 2.99 (dd, J = 17.7, 5.2 Hz, 1 H), 4.72 (dd, J = 5.2, 3.0 Hz, 1 H),
dioxacyclopenta[a]anthracene-2,7,10-trione (16) and (3aR,5S,11bR)- 5.16 (q, J = 6.8 Hz, 1 H), 5.30 (d, J = 2.9 Hz, 1 H), 7.24 (ABq, J
,3a,5,11b-Tetrahydro-7,10-dimethoxy-5-methyl-1,4-dioxacyclo-
penta[a]anthracene-2,6,11-trione (17): PIFA (241 mg, 0.561 mmol,
(
1
3
3
= 9.6, 2 H), 12.49 (s, 1 H, OH), 12.53 (s, 1 H, OH) ppm; C NMR
(125 MHz, CDCl ): δ = 18.3, 36.9, 66.3, 66.6, 68.6, 111.0, 111.7,
.5 equiv.) was added to a stirred solution of 7 (140 mg, 132.5, 132.97, 133.0, 148.7, 165.8, 166.3, 174.0, 176.8, 177.5 ppm.
.374 mmol) in CH CN/water (1:1, 14 mL). The reaction mixture HRMS: m/z calcd. for [C16
+ Na]+ 339.0475; found
3
1
0
3
12 7
H O
was stirred at 0 °C for 30 min, then diluted with EtOAc (10 mL)
and the organic layer separated. The aqueous layer was extracted
with EtOAc (3ϫ 10 mL) and the combined organic extracts were
washed with water, brine, dried (Na SO ), and concentrated. The
2 4
residue was purified by silica gel column chromatography with pe-
339.0463.
3aR,5S,11bR)-3,3a,5,11b-Tetrahydro-7,10-dihydroxy-5-methyl-1,4-
dioxacyclopenta[a]anthracene-2,6,11-trione (18): AlCl (62 mg,
.465 mmol, 4.0 equiv.) was added in portions to a stirred solution
of 17 (40 mg, 0.116 mmol) in dry CH Cl (10 mL) at 0 °C and the
reaction mixture stirred for 15 min. The ice bath was removed and
stirring continued at room temperature for 1.5 h. The mixture was
then quenched with an aqueous solution of oxalic acid (10 %,
(
3
0
2
2
troleum ether/EtOAc (3:1 to 1:1) as eluent to afford 16 (63 mg,
4
9 %) as a yellow solid. Further elution with petroleum ether/
EtOAc (2:3) as eluent gave 17 (49 mg, 38%) as a dark yellow solid.
Data for 16: M.p. 190–192 °C. [α]2
IR (CHCl
5
= +280.7 (c = 0.32, CHCl
).
D
3
2 2
10 mL) and the solution extracted with CH Cl (5ϫ 15 mL). The
3
): ν˜ = 3021, 2941, 2853, 1783, 1664, 1621, 1562, 1462, combined organic extracts were washed with water, brine, dried
410, 1343, 1303, 1259, 1236, 1205, 1153, 1107, 1071, 1011, 991, (Na SO ), and concentrated. The residue was purified by silica gel
/TMS): δ = flash column chromatography with petroleum ether/EtOAc (3:1 to
.67 (d, J = 6.4 Hz, 3 H), 2.78 (d, J = 17.4, Hz, 1 H), 2.93 (dd, J 3:2) as eluent to provide 18 (25 mg, 68%) as a red solid; m.p. 196–
17.4, 4.4 Hz, 1 H), 3.81 (s, 3 H), 4.02 (s, 3 H), 4.34 (dd, J = 4.3, 198 °C. [α]
.4 Hz, 1 H), 4.95 (qd, J = 6.2, 0.7 Hz, 1 H), 5.40 (dd, J = 2.5, 2925, 2857, 1791, 1610, 1570, 1456, 1407, 1349, 1323, 1252, 1202,
.7 Hz, 1 H), 6.86 (s, 2 H) ppm; 13CNMR (100 MHz, CDCl
): δ = 1150, 1115, 1038, 996, 906, 879 cm . H NMR (500 MHz, CDCl /
3
1
9
1
2
4
–
1 1
58, 908, 883, 853 cm . H NMR (400 MHz, CDCl
3
2
5
=
D 3 3
= –240 (c = 0.07, CHCl ). IR (CHCl ): ν˜ = 3431,
2
0
2
1
–1
1
3
1.4, 37.8, 62.0, 64.0, 70.0, 71.1, 71.5, 124.0, 125.2, 131.7, 138.5,
38.6, 144.2 153.9, 156.4, 174.9, 183.6, 184.1 ppm. HRMS: m/z
TMS): δ = 1.66 (d, J = 6.6 Hz, 3 H), 2.76 (d, J = 17.5, Hz, 1 H),
2.92 (dd, J = 17.5, 4.6 Hz, 1 H), 4.37 (dd, J = 4.5, 2.5 Hz, 1 H),
4.83 (qd, J = 6.6, 1.5 Hz, 1 H), 5.28 (dd, J = 2.2, 1.7 Hz, 1 H), 7.26
+
calcd. for [C18
H
16
O
7
+ Na] 367.0788; found 367.0790.
(
ABq, J = 9.6, 2 H), 12.45 (s, 1 H, OH), 12.50 (s, 1 H, OH) ppm;
Data for 17:[28] M.p. 207–209 °C. [α]
25
D 3
= –93.0 (c = 0.2, CHCl ).
1
3
CNMR (125 MHz, CDCl
11.9, 131.8, 132.0, 134.5, 149.7, 163.4, 163.8, 174.3, 179.7,
80.3 ppm. HRMS: m/z calcd. for [C16
+ Na]+ 339.0475;
3
): δ = 20.5, 37.3, 69.0, 69.4, 71.0, 111.0,
IR (CHCl
3
): ν˜ = 3013, 2925, 2853, 1790, 1658, 1585, 1568, 1479,
408, 1334, 1287, 1262, 1238, 1195, 1153, 1115, 1081, 1055, 1008,
1
1
1
9
12 7
H O
–
1 1
3
92, 961, 920, 892, 820, 678 cm . H NMR (400 MHz, CDCl /
found 339.0475.
Synthesis of Hemi-γ-actinorhodin (5) from 18: Concd. H
(1 mL) was added to a stirred solution of 18 (14 mg, 0.044 mmol)
3
): δ in benzene (4 mL) at 5 °C. The reaction mixture was slowly warmed
TMS): δ = 1.52 (d, J = 6.7 Hz, 3 H), 2.72 (d, J = 17.5, Hz, 1 H),
.91 (dd, J = 17.5, 4.8 Hz, 1 H), 3.95 (s, 6 H), 4.32 (dd, J = 4.7,
2
2
1
2 4
SO
.7 Hz, 1 H), 4.75 (qd, J = 6.7, 1.5 Hz, 1 H), 5.37 (dd, J = 2.6,
.7 Hz, 1 H), 7.32 (s, 2 H) ppm; 13C NMR (125 MHz, CDCl
=
19.4, 37.2, 56.8, 56.84, 68.6, 69.3, 71.4, 120.15, 120.2, 120.6,
to room temperature over 45 min, then diluted with ice-cold water
1
21.5, 133.4, 150.6, 153.0, 153.5, 174.5, 181.5, 183.9 ppm. HRMS:
(15 mL), and extracted with EtOAc (5ϫ 10 mL). The combined
organic layers were washed with water, brine, dried (Na SO ), and
2 4
+
m/z calcd. for [C18
3aR,5R,11bR)-3,3a,5,11b-Tetrahydro-7,10-dihydroxy-5-methyl-1,4-
dioxacyclopenta[a]anthracene-2,6,11-trione, Hemi-γ-actinorhodin
5): BBr (0.46 mL, 0.46 mmol, 10 equiv., 1 m solution in CH Cl
was added slowly over 10 min to a stirred solution of 17 (16 mg,
.0465 mmol) in dry CH Cl (7 mL) at –78 °C. The reaction mix-
ture was stirred at –78 °C for 15 min and then slowly warmed to
°C and stirred for 1 h, then quenched with saturated aq. NaHCO
15 mL) and the solution extracted with CH Cl (3ϫ 20 mL). The
combined organic layers were washed with brine, dried (Na SO ),
and concentrated. The residue was purified by silica gel column
H
16
O
7
+ H] 345.0969; found 345.0967.
concentrated. The residue was purified by silica gel column
chromatography with petroleum ether/EtOAc (3:1 to 3:2) as eluent
to give a mixture of 5 and 18 (in 93:7 ratio) that on recrystallization
provided 5 (8.7 mg, 62%) as a red solid. The analytical and spectro-
scopic data is as before.
(
(
3
2
2
)
0
2
2
Synthesis of Hemiactinorhodin (4) from 5: Pd/C (10%, 4 mg) was
added to a solution of 5 (12 mg, 0.038 mmol) in EtOAc (5 mL) and
the resulting mixture was stirred at room temperature under an H
2
atmosphere (balloon pressure) for 3 h. Then EtOAc was removed
under reduced pressure and the residue was purified by silica gel
0
(
3
2
2
2
4
4936
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4931–4938

Synthetic Studies toward Actinorhodin and γ-Actinorhodin
column chromatography with CH
ford 4 (10 mg, 83%) as an orange solid; m.p. 197–198 °C. [α]
40.8 (c = 0.025, CHCl ). IR (CHCl
705, 1600, 1563, 1455, 1409, 1334, 1251, 1159, 1112, 1073, 1034,
2
Cl
2
/EtOAc (4:1) as eluent to af-
2.40 (s, 3 H), 2.44 (s, 3 H), 2.69 (d, J = 17.6, Hz, 1 H), 2.87 (dd, J
= 17.6, 4.8 Hz, 1 H), 4.29 (dd, J = 4.6, 2.6 Hz, 1 H), 4.69 (qd, J =
2
5
D
=
+
1
9
3
3
): ν˜ = 3469, 2923, 2852, 1736, 6.7, 1.6 Hz, 1 H), 5.21 (dd, J = 2.4, 1.8 Hz, 1 H), 7.41 (ABq, J =
1
3
3
8.8 Hz, 2 H) ppm; CNMR (100 MHz, CDCl ): δ = 19.5, 20.9 (2
–1 1
61, 909 cm . H NMR (500 MHz, CDCl
3
/TMS): δ = 1.60 (d, J
C), 37.0, 68.5, 69.2, 71.3, 123.9, 125.0, 130.9, 131.2, 134.1, 147.0,
=
6.7 Hz, 3 H), 2.39 (dd, J = 18.9, 10.6 Hz, 1 H), 2.74 (d, J =
147.5, 150.9, 169.1, 169.3, 174.2, 180.0, 182.7 ppm. HRMS: m/z
16 9
H O
+ Na]+ 423.0687; found 423.0691.
6
5
.3 Hz, 2 H), 2.90 (dd, J = 18.9, 2.9 Hz, 1 H), 4.32–4.37 (m, 1 H), calcd. for [C20
.07 (q, J = 6.6 Hz, 1 H), 7.23 (s, 2 H), 12.50 (s, 1 H, OH), 12.53
Conversion of 20 into 18: Anhydrous K
.0 equiv.) was added to a stirred solution of diacetate-quinone 20
25 mg, 0.062 mmol) in MeOH (5 mL) at room temperature. The
2 3
CO (26 mg, 0.186 mmol,
(
s, 1 H, OH) ppm; 13C NMR (125 MHz, CDCl
3
): δ = 19.3, 27.4,
0.3, 63.1, 67.6, 111.3, 111.34, 130.2, 130.4, 141.4, 146.9, 160.1,
14 7
60.2, 175.4, 183.3, 183.9 ppm. HRMS: m/z calcd. for [C16H O
3
(
4
1
reaction mixture was stirred for 4 h and then slowly neutralized
with HCl (1 n). The mixture was diluted with EtOAc (20 mL) and
the organic layer separated. The aqueous layer was extracted with
EtOAc (3ϫ 15 mL). The combined organic extracts were washed
+
+
Na] 341.0632; found 341.0634.
Conversion of 16 into a Mixture of 18 and 5: BBr
3
(0.58 mL,
0
.58 mmol, 10 equiv., 1m solution in CH Cl ) was slowly added
over 10 min to a stirred solution of 16 (20 mg, 0.058 mmol) in dry
CH Cl (7 mL) at –78 °C. The reaction mixture was stirred at
78 °C for 15 min and then slowly warmed to 0 °C and stirred for
h, then quenched with saturated aq. NaHCO (15 mL), and the
Cl (3ϫ 20 mL). The combined or-
ganic layers were washed with brine, dried (Na SO ), and concen-
2
2
2 4
with water, brine, dried (Na SO ), and concentrated. The residue
was purified by silica gel column chromatography with petroleum
ether/EtOAc (3:1 to 3:2) as eluent to afford 18 (14.8 mg, 75%) as
a red solid. The analytical and spectroscopic data is as before.
2
2
–
1
3
solution extracted with CH
2
2
2
4
Acknowledgments
trated. The residue was purified by silica gel column chromatog-
raphy with petroleum ether/EtOAc (3:1 to 3:2) as eluent to afford
a mixture of 5 and 18 (8.3 mg, 45%, anti/syni = 68:32, determined
This work was financially supported by the Department of Science
and Technology (DST), New Delhi (grant number SB/S1/OC-42/
1
by H NMR spectroscopy) as a red solid.
2013). S. V. M. and A. B. thank the Council of Scientific and Indus-
(
3aR,5S,11bR)-3,3a,5,11b-Tetrahydro-6,11-dimethoxy-7,10-diacet- trial Research (CSIR), New Delhi and the Indian Institute of Tech-
oxy-5-methyl-1,4-dioxacyclopenta[a]anthracen-2-one (19): DMAP
nology (IIT), Bombay for research fellowships, respectively.
(
1
1.8 mg, 0.0146 mmol, 0.1 equiv.) and Zn powder (95 mg,
.45 mmol, 10.0 equiv.) were sequentially added to a stirred solu-
tion of quinone 16 (50 mg, 0.145 mmol) in Ac O (5 mL) and Et
1 mL) at 0 °C. The reaction mixture was stirred for 2 h at room
[
2
3
N
(
aran, Tetrahedron 2000, 56, 1937–1992; c) J. Sperry, P. Bachu,
M. A. Brimble, Nat. Prod. Rep. 2008, 25, 376–400.
[2] a) H. W. Moore, Science 1977, 197, 527–532; b) H. W. Moore,
R. Czerniak, Med. Res. Rev. 1981, 1, 249–280.
3] R. H. Thomson, Naturally Occurring Quinones, 2nd ed., Aca-
demic Press, London, 1971, p. 282.
4] H. G. Floss, in: Antibiotics (Ed.: J. W. Corcoran), Springer,
Berlin, 1981, vol. 4, p. 215, and references cited therein.
5] a) H. G. Floss, P. J. Keller, J. M. Beale, J. Nat. Prod. 1986, 49,
temperature, then diluted with water (10 mL), and the resulting
solution was extracted with EtOAc (3ϫ 10 mL). The combined
organic layers were washed with water, brine, dried (Na SO ), and
2 4
[
[
[
concentrated. The residue was purified by silica gel column
chromatography with petroleum ether/EtOAc (3:1 to 1:1) as eluent
to give 19 (56 mg, 90 %) as a colorless solid; m.p. 213–215 °C.
2
5
[
α]
D
= +343.6 (c = 0.2, CHCl
3 3
). IR (CHCl ): ν˜ = 3020, 2938, 2850,
1
1
767, 1622, 1596, 1526, 1453, 1354, 1328, 1289, 1180, 1154, 1110,
068, 1034, 1017, 924, 905, 707 cm . H NMR (400 MHz, CDCl /
3
9
57–970; b) H. G. Floss, J. M. Beale, Angew. Chem. Int. Ed.
–1 1
Engl. 1989, 28, 146–177; Angew. Chem. 1989, 101, 147–179.
TMS): δ = 1.67 (d, J = 6.2 Hz, 3 H), 2.36 (s, 3 H), 2.40 (s, 3 H), [6] H. Brockmann, H. Pini, Naturwissenschaften 1947, 34, 190.
2
(
6
.74 (d, J = 17.3, Hz, 1 H), 2.88 (dd, J = 17.3, 4.2 Hz, 1 H), 3.69
s, 3 H), 4.03 (s, 3 H), 4.30 (dd, J = 3.8, 2.2 Hz, 1 H), 5.00 (q, J =
.2, Hz, 1 H), 5.55 (d, J = 2.0 Hz, 1 H), 7.14 (ABq, J = 8.1, 2
[7] H. Brockmann, H. Pini, O. von Plotho, Chem. Ber. 1950, 83,
161–167.
[
8] H. Brockmann, V. Loeschcke, Chem. Ber. 1955, 88, 778–788.
[9] a) H. Brockmann, E. Hieronymus, Chem. Ber. 1955, 88, 1379–
390; b) H. Brockmann, W. Müller, K. van der Merwe, Natur-
13
H) ppm; C NMR (125 MHz, CDCl
6
1
3
): δ = 20.6, 20.7, 21.7, 38.2,
1.7, 65.6, 69.8, 71.4, 72.7, 120.0, 120.9, 121.7, 122.8, 124.2, 131.4,
43.7, 144.0, 148.0, 152.6, 169.2, 170.0, 175.4 ppm. HRMS: m/z
1
wissenschaften 1962, 49, 131.
[
[
[
[
10] H. Brockmann, A. Zeeck, K. van der Merwe, W. Müller, Justus
+
calcd. for [C22
22 9
H O + Na] 453.1156; found 453.1152.
Liebigs Ann. Chem. 1966, 698, 209–229.
11] C. P. Gorst-Allman, B. A. M. Rudd, C.-J. Chang, H. G. Floss,
J. Org. Chem. 1981, 46, 455–456.
12] P. Christiansen, Ph. D. Thesis, University of Göttingen, Ger-
many, 1970.
13] B. Krone, A. Zeeck, Liebigs Ann. Chem. 1987, 751–758.
(
3aR,5S,11bR)-3,3a,5,11b-Tetrahydro-7,10-diacetoxy-5-methyl-1,4-
dioxacyclopenta[a]anthracen-2,6,11-trione (20): A solution of CAN
114 mg, 0.208 mmol, 2.0 equiv.) in water (5 mL) was added to a
stirred solution of 19 (45 mg, 0.104 mmol) in CH CN (5 mL). The
(
3
reaction mixture was stirred at room temperature for 45 min, then
diluted with EtOAc (15 mL), and the organic layer separated. The
aqueous layer was extracted with EtOAc (2ϫ 15 mL) and the com-
bined organic extracts were washed with water, brine, dried
[14] R. A. Nelson, J. A. Pope Jr., G. M. Luedemann, L. E. McDan-
iel, C. P. Schaffner, J. Antibiot. 1986, 39, 335–344.
[15] D. Ling, L. S. Shield, K. L. Rinehart Jr., J. Antibiot. 1986, 39,
345–353.
[
16] a) M. A. Brimble, L. J. Duncalf, S. J. Phythian, Tetrahedron
Lett. 1995, 36, 9209–9210; b) M. A. Brimble, L. J. Duncalf, S. J.
Phythian, J. Chem. Soc. Perkin Trans. 1 1997, 1399–1404; c)
M. A. Brimble, M. R. Nairn, H. Prabaharan, Tetrahedron
2 4
(Na SO ), and concentrated. The residue was purified by silica gel
column chromatography with petroleum ether/EtOAc (3:1 to 1:1)
as eluent to afford 20 (32.6 mg, 78%) as a yellow solid; m.p. 165–
5
1
3
66 °C. [α]2
D
= +24.8 (c = 0.46, CHCl
3
). IR (CHCl
3
): ν˜ = 3082,
2
000, 56, 1937–1992; d) R. A. Fernandes, R. Brückner, Synlett
021, 2940, 2852, 1774, 1671, 1588, 1467, 1416, 1370, 1322, 1292,
258, 1182, 1152, 1115, 1080, 1039, 1014, 996, 946, 900, 669 cm .
H NMR (400 MHz, CDCl /TMS): δ = 1.50 (d, J = 6.7 Hz, 3 H),
3
2
005, 1281–1285; e) C. D. Donner, Tetrahedron Lett. 2007, 48,
–
1
1
8888–8890; f) P. Bachu, J. Sperry, M. A. Brimble, Tetrahedron
2008, 64, 3343–3350; g) R. A. Fernandes, V. P. Chavan, A. B.
1
Eur. J. Org. Chem. 2015, 4931–4938
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4937

S. V. Mulay, A. Bhowmik, R. A. Fernandes
FULL PAPER
Ingle, Tetrahedron Lett. 2008, 49, 6341–6343; h) R. A. Fer-
nandes, V. P. Chavan, Eur. J. Org. Chem. 2010, 4306–4311; i)
R. A. Fernandes, V. P. Chavan, S. V. Mulay, Tetrahedron:
Asymmetry 2011, 22, 487–492; j) R. A. Fernandes, A. B. Ingle,
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