A concise total synthesis of arizonins B1 and C1

Article abstract of DOI:10.1016/j.tetasy.2013.10.011

A concise and efficient total synthesis of arizonins B1 and C1 is reported. A key building block alkyne is synthesized from d-glucono-δ-lactone and used in the Doetz benzannulation reaction to construct the naphthalene unit. An oxa-Pictet-Spengler reactio

Full text of DOI:10.1016/j.tetasy.2013.10.011

Tetrahedron: Asymmetry 24 (2013) 1548–1555
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Tetrahedron: Asymmetry
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A concise total synthesis of arizonins B1 and C1
⇑
Rodney A. Fernandes , Sandip V. Mulay, Vijay P. Chavan
Department of Chemistry, Indian Institute of Technology Bombay, Powai 400076, Mumbai, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 July 2013
Accepted 16 October 2013
A concise and efficient total synthesis of arizonins B1 and C1 is reported. A key building block alkyne is
synthesized from D-glucono-d-lactone and used in the Dötz benzannulation reaction to construct the
naphthalene unit. An oxa-Pictet–Spengler reaction gave the pyran ring while an H2SO4 mediated isomer-
ization set the correct stereochemistry of the target molecules. Alternatively, a direct anti-pyran stereo-
chemistry was prepared in a TFA solvent. The synthesis is competitive to previous reports and marks the
first enantioselective synthesis of arizonin B1.
Ó 2013 Elsevier Ltd. All rights reserved.
Me
5
Me
1. Introduction
OH
O
OR
O
O
R'O
O
Hochlowski et al.1 isolated six new anti-Gram-positive antibiot-
ics from the fermentation broth of Actinoplanes arizonaensis sp.
nov. strain AB660D-122. These are known as arizonins A1, A2,
B1, B2, C1, and C3 1–6 (Fig. 1). Their structures were elucidated
by spectroscopic and analytical techniques including the X-ray
studies of arizonin A1 3. The absolute stereochemistry for arizonin
B1 1 was ascertained by comparing the ORD curves with that of
nanaomycin D 7 and kalafungin 8 (Fig. 1).2 Based on this study
and a comparison of spectroscopic data, the stereochemistry of
other members was determined.1 Karwowski et al.3 carried out
bioactivity studies of the above strain of antibiotics and found
arizonins A1 and B1 to exhibit moderate to potent in vitro antimi-
crobial activity against Gram-positive bacteria. The first synthetic
attempt to prepare these molecules was by Brimble et al.4a who
reported on a racemic synthesis of 5-epi-arizonin B1 and 5-epi-ari-
zonin C1 involving a furo-furan to furo-pyran rearrangement. Later
the same group reported4b on the racemic synthesis of arizonin C1
2 involving an earlier strategy and a late stage BBr3 mediated C-5
epimerization. However, this led to the complete demethylation
of the C-7,8 methoxy groups. Remethylation completed the syn-
thesis of ( )-arizonin C1. Recently, Brückner et al.5 reported on
the first enantioselective synthesis of (ꢀ)-arizonin C1 2 by employ-
ing a Dötz benzannulation and asymmetric dihydroxylation. As
part of our research program involving the stereoselective synthe-
sis of various pyranonaphthoquinones and related molecules,6 we
herein report a concise enantioselective total synthesis of arizonins
B1 1 and C1 2. Our strategy relies on the synthesis of a key building
O
3
O
O
O
1
O
O
7 (-)-nanaomycin D
1 R = H, R' = Me, arizonin B1
2 R = R' = Me, arizonin C1
3
R = Me, R' = H, arizonin A1
Me
Me
O
OH
O
O
OR
O
R'O
O
O
CO2Me
O
OR''
O
8 (+)-kalafungin
4
R = Me, R' = R'' = H, arizonin A2
R = R'' = H, R' = Me, arizonin B2
R = R' = R'' = Me, arizonin C3
5
6
Figure 1. Structures of arizonins 1–6 and related molecules.
Dötz benzannulation, oxa-Pictet–Spengler reaction, and H2SO4
mediated epimerization/demethylation.
2. Results and discussion
Our retrosynthetic approach to arizonins B1 1 and C1 2 is
shown in Scheme 1. The key building block alkyne 11 could be
derived from the chiral pool material
through the intermediate diol 12 by the usual functional group
manipulations.6j The Dötz benzannulation of Fischer carbene 10
with alkyne 11 would produce the naphthalene unit of 9 with
D-glucono-d-lactone 13
block alkyne from a chiral pool material (D-glucono-d-lactone),
the b-hydroxy-
c-lactone moiety installed. The oxa-Pictet–Spengler
⇑
Corresponding author. Tel.: +91 (22)25767174; fax: +91 (22)25767152.
E-mail address: rfernand@chem.iitb.ac.in (R.A. Fernandes).
reaction of 9 would install the pyran ring of the target molecules.
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.10.011

R. A. Fernandes et al. / Tetrahedron: Asymmetry 24 (2013) 1548–1555
1549
Table 1
oxa-Pictet-Spengler
MeO
Me
O
Bestmann–Ohira’s reaction for the synthesis of alkyne 11 using reagent 14 and an
aldehyde from 12
OR
O
O
OMe OMe
OR'
OH
O
Entry Reaction conditions
11 (yield)a
1
2
3
4
5
6
7
14 (1.5 equiv), K2CO3 (2.5 equiv), MeOH, rt, 12 h
14 (1.5 equiv), Cs2CO3 (2.5 equiv), i-PrOH, rt, 12 h
14 (1.5 equiv), K2CO3 (2.5 equiv), MeOH, rt, 2 h
14 (1.5 equiv), K2CO3 (2.5 equiv), MeOH, 0 °C, 1 h, rt, 2 h 24%
14 (1.5 equiv), K2CO3 (1.5 equiv), MeOH, 0 °C, 1 h, rt, 2 h 38%
14 (1.5 equiv), K2CO3 (1.2 equiv), MeOH, 0 °C, 1 h, rt, 8 h 51%
Decomp.
Decomp.
18%
OMe
O
O
O
9
1
2
R = H, R' = Me, arizonin B1
R = R' = Me, arizonin C1
OMe
OMe
Cr(CO)5
Dötz
benzannulation
MeO
14 (1.5 equiv), NaOMe (1.5 equiv), THF, 0 °C, 2 h
30%
a
Yields are from compound 12 including aldehyde formation.
10
O
OH
O
CO2Me
HO
CO2Me
sequence from D-glucono-d-lactone 13 to alkyne 11 required six
steps and resulted in 33% overall yield.
chiron
O
approach
O
We continued our synthesis with further steps as shown in
Scheme 3. The Dötz benzannulation9 of alkyne 11 with the Fischer
carbene 105,10 in benzene solvent gave single regioisomeric naph-
thol 15 isolated in 48% yield. The methylation of 15 to 16 (85%
yield) and a further one-pot acetonide deprotection and lactoniza-
tion with trifluroacetic acid/catalytic conc. HCl furnished lactone 9
12
11
O
O
HO
HO
OH
in 87% yield, ½a 2D5
ꢁ
¼ ꢀ4:6 (c 0.5, CHCl3), lit.5
½
a 2D5
ꢁ
¼ ꢀ3:5 (c 0.46,
OH
D-glucono-δ-lactone 13
CHCl3). The oxa-Pictet–Spengler11 reaction of 9 with acetaldehyde
dimethylacetal catalyzed by TMSOTf provided the syn/anti diaste-
reomers 17a and 17b (65:35 by 1H NMR, 68%) as an inseparable
mixture (reaction conditions not shown in Scheme 3, see Section 4).
However, the same reaction when catalyzed by BF3ꢂOEt2, reversed
the stereoselectivity to give syn/anti diastereomers 17a and 17b
(27:73 by 1H NMR, 72%) as an inseparable mixture (Scheme 3). Fur-
ther cerium ammonium nitrate (CAN) oxidation provided syn/anti-
quinones, 5-epi-arizonin C1 18, and arizonin C1 2 (27:73, 84%).
Regioselective AlCl3 mediated demethylation of the mixture gave
a 19/1 mixture in 80% yield. Stirring this mixture with conc.
H2SO4 over 30 min resulted in C-5 epimerization to give 19/1 in
a 6:94 ratio. A single recrystallization provided arizonin B1 1 in
52% yield from the mixture. Alternatively, when the mixture of
18/2 was stirred with conc. H2SO4 over 45 min a remarkable regio-
selective C-7 demethylation occurred in addition to the C-5 epi-
merization directly providing arizonin B1 1 in 51% isolated yield,
Scheme 1. Retrosynthesis of arizonins B1 1 and C1 2.
The key building block alkyne 11 for the anticipated Dötz benz-
annulation was synthesized from chiral pool material -glucono-d-
D
lactone 13 as shown in Scheme 2. Compound 13 was processed
through four steps to give diol 12 (overall 65% yield).6j For the
installation of the desired alkyne moiety, the well known Corey–
Fuchs7 procedure resulted in the decomposition of the aldehyde
derived from the cleavage of diol 12. Hence we opted for an alter-
native procedure using the Bestmann–Ohira reagent 14.8 The opti-
6j
mization of this reaction is given in Table 1.
O
O
O
OH
ref. 6j
HO
a 2D5
ꢁ
¼ þ137 (c 0.108, MeOH), lit.1
½
a 2D5
ꢁ
¼ ꢀ53 (c 0.112, MeOH). A
four steps
CO2Me
½
HO
HO
OH
65% overall
slight charring of the material was observed which accounts for
the lower yield. Methylation of the C-7 phenolic OH group using
Ag2O/MeI provided arizonin C1 2 in 77% yield. If conc. H2SO4 treat-
ment of the 18/2 mixture was carried over 25 min, it gave only the
C-5 epimerized product (18/2 = 6:94 ratio). A single recrystalliza-
O
OH
13
12
O
i) NaIO4, acetone
tion then provided arizonin C1 2 in 48% yield, ½a D25
ꢁ
¼ þ75:3 (c
CO2Me
sat. aq. NaHCO3, rt, 4 h
O
0.7, MeOH), lit.1
½
a 2D5
ꢁ
¼ ꢀ84:3 (c 1.017, MeOH), lit.5
½ ꢁ ¼ ꢀ86:5
a 2D5
O
ii) Table 1,
O
(c 0.7, MeOH). The spectroscopic data (1H NMR, 13C NMR, HRMS,
IR) were in excellent agreement with those reported in the
literature.1,5
OEt
OEt
P
11
N2
14
33% overall yield
In an oxa-Pictet–Spengler reaction of hydroxylactone 9 in triflu-
oroacetic acid (TFA) as the solvent and BF3ꢂOEt2 as the Lewis acid in
less than 1 min (55 s) we isolated the single anti-pyran diastereo-
mer 17b in 45% yield (Scheme 4). The lower yield was attributed
to the considerable charring of the material. We believe lowering
the electron density on the naphthalene ring through protonation
with TFA would lead to a ring closure through the oxocarbenium
ion intermediate to give the more stable anti-pyran ring product
17b.12 Further quinone formation with CAN gave arizonin C1 2 in
from 13 (6 steps)
Scheme 2. Synthesis of alkyne 11.
The cleavage of diol 12 to the corresponding aldehyde and sub-
sequent reaction under standard Bestmann–Ohira’s conditions
over a 12 h reaction led to the decomposition of the intermediate
aldehyde (Table 1, entry 1). Changing the base to Cs2CO3 gave sim-
ilar results (entry 2). Reduction in reaction time to 2 h, it furnished
alkyne 11 in 18% yield (entry 3). Lowering the reaction tempera-
ture to 0 °C resulted in an improved yield of 11 (24%, entry 4). Low-
ering of base concentration from 2.5 to 1.5 equiv and then to
1.2 equiv furnished alkyne 11 in improved yields of 38% and 51%,
respectively (entries 5 and 6). Changing the base to NaOMe did
not give better results (30%, entry 7). The overall synthetic
85% yield, ½a 2D5
¼ þ73:9 (c 0.15, MeOH). This represents a direct
ꢁ
synthesis of anti-pyran products without the need for C-5
epimerizations.
We noted a discrepancy in the specific rotations of the com-
pounds synthesized by us in comparison to the natural materials
and also those synthesized by Brückner et al.5of the same absolute

1550
R. A. Fernandes et al. / Tetrahedron: Asymmetry 24 (2013) 1548–1555
OMe OMe
OMe OMe
OMe OMe
Cr(CO)5
MeO
benzene
MeO
O
O
OH
O
MeO
45 oC, 12 h
TFA/H2O, HCl (cat)
CO2Me
CO2Me
+
48%
CH2Cl2, rt, 24 h
87%
O
OR
O
OMe
O
11
10
9
15, R = H
16
NaH, MeI
DMF, 0 oC
, R = Me
CH3CH(OMe)2,
to rt, 3 h, 85%
BF3·OEt2, CH2Cl2
0 oC to rt, 12 h, 72%
OMe Me
O
OMe
Me
O
OMe OMe
MeO
MeO
O
+
OMe
O
OMe
O
O
17a
(27 : 73)
17b
CAN, MeCN/H2O
rt, 15 min, 84%
O
O
Me
O
Me
O
O
OH
O
O
Me
O
Me
O
OH
OMe
OMe
MeO
O
MeO
MeO
MeO
AlCl3, CH2Cl2
0 oC, 10 min
O
O
O
O
+
+
rt, 45 min, 80%
O
O
O
O
O
O
1
19
5-epi-arizonin B1
2
5-epi-arizonin C1 18
i. conc. H2SO4
30 min
19/1 = 6:94
ii. single recrystallization
52% overall
i. conc. H2SO4, 25 min
ii. single recrystallization
48% overall
conc. H2SO4
45 min, 51%
Me
Me
O
OH
O
O
OMe
O
O
MeO
MeO
O
Ag2O, MeI
CH2Cl2, rt
30 min, 77%
O
O
O
O
arizonin C1 2
arizonin B1 1
Scheme 3. Synthesis of arizonins B1 1 and C1 2.
configurations as shown herein. The natural arizonin B1 has
½
a 2D5
ꢁ
¼ ꢀ53 (c 0.112, MeOH) and arizonin C1 ½a D25
¼ ꢀ84:3 (c
ꢁ
1.017, MeOH).1 Synthesized arizonin C1 has ½a 2D0
ꢁ
¼ ꢀ86:5 (c 0.7,
OMe OMe
Me
O
OMe OMe
MeO
MeO
CH3CH(OMe)2,
BF3·OEt2, TFA
70 oC, 55 s, 45%
MeOH).5 Our specific rotation values at different concentrations
are given in Table 2. We were surprised with these differences,
especially when the intermediate compound 9 synthesized by us
had matching specific rotation and spectroscopic data with that
reported.5 The synthetic sequence from this lactone to the target
molecules is similar.13 The discrepancy was observed for both ari-
zonins B1 and C1. We synthesized the enantiomer of arizonin C1
ent-2 following the literature method (using asymmetric dihydr-
oxylation to induce chiral elements, Scheme 5).5 This showed a
O
OH
O
O
OMe
OMe
O
9
17b
Me
O
OMe
O
O
CAN, MeCN/H2O
rt, 15 min, 85%
MeO
O
specific rotation of ½a D25
¼ ꢀ72:4 (c 0.84, MeOH); see Table 2 for
ꢁ
values at different concentrations.14 This matches that of the natu-
ral isolate. We also recorded CD spectra of a series of compounds
(Figs. 2 and 3). By analogy, the arizonins B1 and C1 CD spectra
match with those of kalafungin and they should have the same
absolute stereochemistry (Fig. 2). However the compounds
O
arizonin C1 2
Scheme 4. Alternative synthesis of arizonin C1 2.

R. A. Fernandes et al. / Tetrahedron: Asymmetry 24 (2013) 1548–1555
1551
Table 2
Optical rotations of arizonins B1, C1, and ent-C1 at different concentrations
Arizonin
B1
Natural1
Brückner5
—
This work
ꢀ53 (c 0.112, MeOH)
+137.0 (c 0.108, MeOH)
+168.0 (c 0.024, MeOH)
+88.9 (c 0.011, MeOH)
+166.6 (c 0.024, CHCl3)
+75.3 (c 0.7, MeOH)
+88.2 (c 0.25, MeOH)
+93.9 (c 0.04, MeOH)
+112.0 (c 0.01, MeOH)
ꢀ72.4 (c 0.84, MeOH)
ꢀ79.2 (c 0.7, MeOH)
ꢀ76.6 (c 0.35, MeOH)
ꢀ77.2 (c 0.1, MeOH)
ꢀ68.0 (c 0.01, MeOH)
C1
ꢀ84.3 (c 1.017, MeOH)
ꢀ86.5 (c 0.7, MeOH)
C1 (enantiomer)
—
—
12
8
OMe OMe
OMe OMe
Cr(CO)5
MeO
MeO
ref. 5
CO2Me
(+)-kalafungin
arizonin C1
arizonin B1
OMe
10
20
4
OMe OMe
(DHQ)2PHAL, K3Fe(CN)6
K2CO3, MeSO2NH2
MeO
0
OH
K2OsO4·2H2O, t-BuOH/H2O
0 oC, 24 h, rt, 12 h, 81%
OMe
O
-4
ent-9
O
[α]D25 = +5.2 (c 0.4, CHCl3)
-8
250
300
350
400
450
500
CH3CH(OMe)2,
Wavelength (nm)
BF3·OEt2, CH2Cl2
0 oC to rt, 12 h, 71%
Figure 2. Circular dichroism spectra (MeOH) of (+)-kalafungin 8, arizonin C1 2, and
arizonin B1 1.
CAN, MeCN/H2O
rt, 15 min, 83%
4
O
O
Me
Me
OMe
OMe
O
MeO
MeO
O
O
(+)-kalafungin
arizonin C1
+
ent-arizonin C1
2
O
O
O
O
O
ent-2
ent-18
27:73
i. conc. H2SO4, 25 min
ii. single recrystallization
47% overall
0
Me
O
OMe
O
O
-2
300
350
400
450
500
MeO
Wavelength (nm)
Figure 3. Circular dichroism spectra (MeOH) of (+)-kalafungin 8, arizonin C1 2, and
ent-arizonin C1.
O
O
[α]D25 = -72.4 (c 0.84, MeOH)
ent-2
{½a 2D5
¼ þ166:6 (c 0.024, CHCl3) see Table 2} differ by only one
ꢁ
Scheme 5. Synthesis of ent-2 (naturally configured arizonin C1) on the route, which
the literature5 describes for the (supposedly) enantiomeric series.
methoxy group and it is possible that they may have the same sign
of the specific rotation since the stereochemistry of chiral elements
is the same although this is not a general rule. Recently, we have
adopted a similar strategy6j from alkyne 11 toward the synthesis
of kalafungin and frenolicin B where such discrepancies were not
observed. This validates the correctness of this strategy. However,
we were unable to explain this discrepancy. We believe a future
synthesized with this absolute stereochemistry have a specific
rotation opposite to that reported.1,5 The synthesized ent-arizonin
C1 shows an opposite CD curve to that of (+)-kalafungin 8 (Fig. 3).
Kalafungin, {½a D20
ꢁ
¼ þ160:6 (c 0.3, CHCl3}2h and arizonin B1,

1552
R. A. Fernandes et al. / Tetrahedron: Asymmetry 24 (2013) 1548–1555
report on the synthesis of these molecules through different
approach may resolve these differences.15
27.0, 37.2, 51.9, 69.6, 75.0, 77.7, 79.9, 110.8, 170.4; HRMS m/z calcd
for [C10H14O4+H]+ 199.097, found 199.0988.
4.1.2. Fischer carbene 105,10
3. Conclusions
To a stirred solution of TMEDA (5.43 mL, 36.19 mmol, 1.0 equiv)
in dry Et2O (100 mL) at room temperature was added n-BuLi
(22.6 mL, 36.19 mmol, 1.0 equiv, 1.6 M solution in hexane). The
mixture was stirred for 10 min after which 1,2-dimethoxybenzene
(5.0 g, 36.19 mmol) was added. The reaction mixture was stirred at
room temperature for 2.5 h, then cooled to ꢀ78 °C and a solution of
bromine (1.85 mL, 36.19 mmol, 1.0 equiv) in dry hexane (10 mL)
was added. The reaction was maintained at ꢀ78 °C for 30 min
and then allowed to warm to room temperature. It was then
quenched with satd aq Na2SO3 (20 mL). The solution was extracted
with EtOAc (3 ꢃ 30 mL) and the combined organic layers were
washed with water, brine, dried (Na2SO4), and concentrated. The
residue was purified by silica gel column chromatography using
petroleum ether/EtOAc (9.5:0.5 to 9:1) as eluent to give 1-bro-
mo-2,3-dimethoxybenzene (6.68 g, 85%) as a colorless oil: IR
In conclusion we have performed a concise and efficient total
synthesis of arizonin B1 and arizonin C1. The key building block
alkyne 11 was prepared from chiral pool material D-glucono-d-lac-
tone in six steps and 33% overall yield. Dötz benzannulation and
oxa-Pictet–Spengler reaction provided the desired pyranonaphtho-
quinone structure while H2SO4 mediated epimerization led to the
desired stereochemistry of the target molecules. A remarkable
H2SO4 mediated regioselective demethylation in addition to C-5
epimerization was also observed. Secondly, a direct anti-pyran ring
formation was also observed in TFA solvent catalyzed by BF3ꢂOEt2.
Herein we have reported on the first asymmetric synthesis of ari-
zonin B1. The use of alkyne 11, which possesses the required ste-
reoelements for the Dötz benzannulation constitutes as a new
strategy that can be readily adopted for the synthesis of related
pyranonaphthoquinones.
(CHCl3):
1289, 1264, 1237, 1173, 1150, 1080, 1039, 1004, 910, 837, 769,
649 cmꢀ1 1H NMR (400 MHz, CDCl3/TMS): d = 3.86 (s, 3H), 3.87
m = 3007, 2940, 2838, 1585, 1572, 1480, 1460, 1435,
4. Experimental
4.1. General
;
(s, 3H), 6.85 (dd, J = 8.3, 1.5 Hz, 1H), 6.93 (t, J = 8.1 Hz, 1H), 7.13
(dd, J = 8.0, 1.5 Hz, 1H); 13C NMR (100 MHz, CDCl3): d = 55.8, 60.3,
111.4, 117.5, 124.5, 124.8, 146.2, 153.7; HRMS m/z calcd for [C8H9-
O2Br+H]+ 216.9864, found 216.9873.
To a solution of the above 1-bromo-2,3-dimethoxybenzene
(2.0 g, 9.21 mmol, 1.0 equiv) in dry Et2O (35 mL) at ꢀ78 °C was
added n-BuLi (6.0 mL 9.67 mmol, 1.05 equiv, 1.6 M solution in hex-
ane) and the reaction mixture was stirred for 15 min. It was then
Flasks were oven or flame dried and cooled in a desiccator. Dry
reactions were carried out under an atmosphere of Ar or N2. Sol-
vents 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 KMnO4 or by
UV lamp. 1H NMR and 13C NMR were recorded at 400 and
100 MHz, respectively, and chemical shifts are based on TMS peak
at d = 0.00 ppm for proton NMR and CDCl3 peak at d = 77.00 ppm (t)
for carbon NMR. IR samples were prepared by evaporation from
CHCl3 on CsBr plates. High-resolution mass spectra were obtained
using positive electrospray ionization. Compound 12 was prepared
from 13 following literature procedures.6j
transferred to
a suspension of Cr(CO)6 (2.23 g, 10.13 mmol,
1.1 equiv) in dry Et2O (35 mL) at 0 °C. The reaction mixture was
stirred for 1 h at 0 °C and then at room temperature for 2 h. Next,
Et2O was evaporated and the residue was dissolved in dry CH2Cl2
(30 mL). To this solution was added Me3OBF4 (2.04 g, 13.82 mmol,
1.5 equiv) in portions at 0 °C and the reaction mixture was stirred
for 1 h. It was then warmed to room temperature and stirred for
2 h. The red colored reaction mixture was concentrated and puri-
fied by silica gel column chromatography using petroleum ether/
CH2Cl2 (9:1 to 4:1) as eluent to give 10 (2.23 g, 65%) as a red solid:
mp 81–83 °C. This was immediately used in the next step. Charac-
terization data are the same as reported earlier.5
4.1.1. Methyl (3R,4R)-3,4-isopropylidenedioxyhex-5-ynoate 11
To a solution of 12 (1.80 g, 7.68 mmol, 1.0 equiv) in acetone
(28 mL) were added satd aq NaHCO3 (0.6 mL) and solid NaIO4
(3.28 g, 15.36 mmol, 2.0 equiv). The resulting mixture was stirred
at room temperature for 4 h. Acetone was then removed under
reduced pressure and the residue was filtered through a small
pad of silica gel, and washed with petroleum ether/EtOAc (7:3)
to give a crude aldehyde (1.55 g). This was virtually pure and used
for the next step.
4.1.3. Methyl-(3R,4R)-4-(1-hydroxy-4,5,6-trimethoxynaphth-
alen-2-yl)-3,4-isopropylidenedioxybutanoate 15
To a freshly prepared Fischer carbene complex 10 (0.5 g,
1.343 mmol, 1.0 equiv) in dry and degassed benzene (10 mL) was
added chiral alkyne 11 (0.320 g, 1.61 mmol, 1.2 equiv). The reac-
tion mixture was then stirred at 45 °C for 12 h. It was then cooled
to room temperature, exposed to air, and stirred for a further
30 min. The reaction mixture was concentrated and the residue
purified by silica gel column chromatography using petroleum
ether/EtOAc (9:1 to 4:1) as an eluent to give 15 (0.26 g, 48%) as a
To a solution of above crude aldehyde (1.55 g, 7.66 mmol,
1.0 equiv) in MeOH (25 mL) were added freshly prepared Best-
mann–Ohira’s reagent 14 (2.53 g, 11.5 mmol, 1.5 equiv) and
K2CO3 (1.27 g, 9.2 mmol, 1.2 equiv) sequentially. The resulting
solution was stirred at 0 °C for 1 h and then at room temperature
for 8 h. It was then quenched with satd aq NH4Cl (12 mL) and
MeOH was removed under reduced pressure. The solution was ex-
tracted with EtOAc (3 ꢃ 35 mL) and the combined organic layers
were washed with water, brine, dried (Na2SO4), and concentrated.
The residue was purified by silica gel column chromatography
using petroleum ether/EtOAc (9:1) as eluent to afford alkyne 11
yellow oil: ½a 2D5
ꢁ
¼ þ9:1 (c 0.6, CHCl3); IR (CHCl3):
m = 3367, 2989,
2928, 2854, 1743, 1661, 1603, 1464, 1384, 1277, 1172, 1065,
926, 853, 762 cmꢀ1 1H NMR (400 MHz, CDCl3/TMS): d = 1.54 (s,
;
3H), 1.68 (s, 3H), 2.66 (dd, J = 15.3, 7.1 Hz, 1H), 2.75 (dd,
J = 15.3,4.0 Hz, 1H), 3.66 (s, 3H), 3.87 (s, 3H), 3.91 (s, 3H), 3.99 (s,
3H), 4.35ꢀ4.40 (m, 1H), 4.94 (d, J = 8.9 Hz, 1H), 6.48 (s, 1H), 7.30
(d, J = 9.2 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H), 8.31 (s, 1H, OH); 13C
NMR (100 MHz, CDCl3): d = 26.8, 27.0, 36.1, 52.0, 56.9, 57.7, 61.7,
77.2, 82.1, 107.1, 109.0, 109.7, 114.5, 119.0, 122.4, 123.3, 143.6,
145.6, 149.0, 151.0, 170.7; HRMS m/z calcd for [C21H26O8+Na]+
429.1525, found 429.1526.
(0.777 g, 51% over two steps) as a colorless oil: ½a D25
¼ þ1:65 (c
ꢁ
0.9, CHCl3); IR (CHCl3):
m = 3273, 2991, 2955, 2123, 1743, 1439,
1383, 1372, 1333, 1240, 1193, 1176, 1067, 995, 906, 846, 758,
668 cmꢀ1 1H NMR (400 MHz, CDCl3/TMS): d = 1.40 (s, 3H), 1.53
;
(s, 3H), 2.54 (d, J = 2.0 Hz, 1H), 2.63 (dd, J = 15.5, 7.0 Hz, 1H), 2.69
(dd, J = 15.6, 5.1 Hz, 1H), 3.72 (s, 3H), 4.38 (dt, J = 7.4, 2.0 Hz, 1H),
4.40 (dd, J = 7.3, 5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): d = 26.2,

R. A. Fernandes et al. / Tetrahedron: Asymmetry 24 (2013) 1548–1555
1553
4.1.4. Methyl-(3R,4R)-4-(1,4,5,6-tetramethoxynaphthalen-2-yl)-
3,4-isopropylidenedioxybutanoate 16
(s, 3H), 4.37 (dd, J = 4.2, 2.4 Hz, 1H), 5.09 (q, J = 6.3 Hz, 1H), 5.59
(d, J = 2.5 Hz, 1H), 7.36 (d, J = 9.3 Hz, 1H), 7.93 (d, J = 9.3 Hz, 1H);
HRMS m/z calcd for [C20H22O7+H]+ 375.1444, found 375.1441.
To a solution of naphthol 15 (0.24 g, 0.59 mmol, 1.0 equiv) in
dry DMF (7 mL) at 0 °C was added NaH (28.3 mg, 0.7086 mmol,
60% in mineral oil, 1.2 equiv). The reaction mixture was stirred at
room temperature for 20 min, then cooled to 0 °C and MeI
(0.074 mL, 1.18 mmol, 2.0 equiv) was added. The reaction mixture
was stirred at 0 °C to room temperature for 3 h. It was then
quenched with ice cold water (5 mL) and the solution was
extracted with EtOAc (3 ꢃ 20 mL). The combined organic layers
were washed with water, brine, dried (Na2SO4), and concentrated.
The residue was purified by silica gel column chromatography
using petroleum ether/EtOAc (9:1 to 4:1) as eluent to give 16
4.1.7. (3aR,5S,11bR)-6,7,8,11-Tetramethoxy-5-methyl-3,3a,5,
11b-tetrahydro-2H-benzo[g]furo[3,2-c]isochromen-2-one 17a
and (3aR,5R,11bR)-6,7,8,11-tetramethoxy-5-methyl-3,3a,5,
11b-tetrahydro-2H-benzo[g]furo[3,2-c]isochromen-2-one 17b
To a solution of lactone 9 (0.1 g, 0.29 mmol, 1.0 equiv) in CH2Cl2
(15 mL) at 0 °C were added acetaldehyde dimethylacetal
(0.061 mL, 0.58 mmol, 2.0 equiv) and BF3ꢂOEt2 (0.073 mL,
0.58 mmol, 2.0 equiv). The reaction mixture was stirred at 0 °C to
room temperature for 12 h. It was then quenched with satd aq
NaHCO3 (5 mL) and the solution extracted with CH2Cl2
(3 ꢃ 20 mL). The combined organic layers were washed with brine,
dried (Na2SO4), and concentrated. The residue was purified by sil-
ica gel column chromatography using petroleum ether/EtOAc (9:1
to 1:1) as eluent to afford an inseparable mixture of syn/anti diaste-
reomers 17a and 17b (0.0774 g, 72%, syn/anti = 27/73, 1H NMR) as
colorless gummy solid: 1H NMR (400 MHz, CDCl3/TMS) for major
diastereomer: d = 1.57 (d, J = 6.8 Hz, 3H), 2.71 (d, J = 17.5, Hz, 1H),
2.96 (dd, J = 17.5, 4.9 Hz, 1H), 3.86 (s, 6H), 4.02 (s, 3H), 4.07 (s,
3H), 4.75 (dd, J = 4.8, 2.8 Hz, 1H), 5.39 (q, J = 6.7 Hz, 1H), 5.58 (d,
J = 2.8 Hz, 1H), 7.34 (d, J = 9.3 Hz, 1H), 7.91 (d, J = 9.3 Hz, 1H);
HRMS m/z calcd for [C20H22O7+H]+ 375.1444, found 375.1448.
(0.211 g, 85%) as a yellow solid: mp 67–69 °C; ½a D25
¼ þ26:1 (c
ꢁ
0.6, CHCl3); IR (CHCl3):
m = 3018, 2935, 2844, 1739, 1603, 1580,
1463, 1381, 1361, 1278, 1175, 1070, 852, 819, 668 cmꢀ1 1H
;
NMR (400 MHz, CDCl3/TMS): d = 1.57 (s, 3H), 1.64 (s, 3H), 2.69
(dd, J = 16.1, 8.4 Hz, 1H), 2.78 (dd, J = 16.1, 3.4 Hz, 1H), 3.62 (s,
3H), 3.87 (s, 3H), 3.88 (s, 3H), 3.99 (s, 6H), 4.28 (td, J = 8.5, 3.4 Hz,
1H), 5.21 (d, J = 8.6 Hz, 1H), 6.91 (s, 1H), 7.32 (d, J = 9.2 Hz, 1H),
7.80 (d, J = 9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): d = 27.1, 27.2,
36.6, 51.7, 56.6, 57.1, 61.8, 62.4, 76.5, 78.5, 103.8, 109.5, 115.5,
118.8, 122.2, 122.6, 125.5, 144.7, 148.0, 150.8, 152.7, 171.1; HRMS
m/z calcd for [C22H28O8+H]+ 421.1862 found 421.1861.
4.1.5. (4R,5R)-4-Hydroxy-5-(1,4,5,6-tetramethoxynaphth-2-yl)-
dihydrofuran-2(3H)-one 9
4.1.8. Arizonin B1 1
To a solution of compound 16 (0.2 g, 0.475 mmol. 1.0 equiv) in
CH2Cl2 (5 mL) were added TFA/H2O (9:1, 0.5 mL) and 2 drops of
conc. HCl. The resulting solution was stirred at room temperature
for 24 h. It was then quenched with satd aq NaHCO3 (5 mL) and ex-
tracted with CH2Cl2 (3 ꢃ 30 mL). The combined organic layers were
washed with brine, dried (Na2SO4), and concentrated. The residue
was purified by silica gel column chromatography using petroleum
ether/EtOAc (9:1 to 4:1) as eluent to give 9 (0.144 g, 87%) as a pale
yellow solid: mp 148–150 °C, lit.5 mp 155–160 °C (decomp.);
To a stirred solution of a 17a and 17b mixture (27:73, 50 mg,
0.133 mmol, 1.0 equiv) in CH3CN (5 mL) was added a solution of
cerium(IV) ammonium nitrate (146 mg, 0.267 mmol, 2.0 equiv) in
water (5 mL). The reaction mixture was stirred at room tempera-
ture for 15 min. It was then diluted with CH2Cl2 (15 mL) and the
organic layer separated. The aqueous layer was extracted with CH2-
Cl2 (3 ꢃ 15 mL). The combined organic extracts were washed with
water, brine, dried (Na2SO4), and concentrated. The residue was
purified by silica gel column chromatography using petroleum
ether/EtOAc (9:1 to 7:3) as eluent to afford an inseparable mixture
of syn/anti diastereomers 18 and 2 (38.6 mg, 84%) as a yellow solid.
½
a 2D5
(CHCl3):
ꢁ
¼ ꢀ4:6 (c 0.5, CHCl3), lit5
½
a 2D0
ꢁ
¼ ꢀ3:5 (c 0.46, CHCl3); IR
m = 3449, 3002, 2936, 2843, 1776, 1624, 1603, 1580,
1475, 1464, 1383, 1362, 1278, 1233, 1158, 1077, 1058, 1025,
To
a solution of the above 18 and 2 mixture (38.6 mg,
1010, 973, 918, 898, 866, 819, 801, 670 cmꢀ1 1H NMR (400 MHz,
;
0.112 mmol, 1.0 equiv) in dry CH2Cl2 (15 mL) at 0 °C was added
AlCl3 (29.9 mg, 0.224 mmol, 2.0 equiv) in portions and the reaction
mixture stirred for 15 min. The ice bath was removed and stirring
was continued at room temperature for 45 min. It was then
quenched with water (5 mL) and the solution extracted with CH2-
Cl2 (5 ꢃ 15 mL). The combined organic layers were washed with
brine, dried (Na2SO4), and concentrated. The residue was purified
by silica gel flash column chromatography using petroleum
ether/EtOAc (9:1 to 7:3) as eluent to provide a mixture of 19 and
1 (29.6 mg, 80%) as an orange gummy solid. The mixture was trea-
ted with conc. H2SO4 (2 mL). The resulting mixture was stirred at
room temperature for 30 min. Brine solution (5 mL) was added
and reaction mixture extracted with EtOAc (3 ꢃ 10 mL). The com-
bined organic layers were washed with satd aq NaHCO3, brine,
dried (Na2SO4), and concentrated. The residue was purified by sil-
ica gel column chromatography using petroleum ether/EtOAc (9:1
to 1:1) as eluent to give a mixture of 1 and 19 (94:6, 1H NMR). A
single recrystallization (CH2Cl2/hexane) gave pure arizonin B1 1
CDCl3/TMS): d = 2.77 (d, J = 17.6 Hz, 1H), 2.97 (dd, J = 17.6, 5.4 Hz,
1H), 3.84 (s, 3H), 3.88 (s, 3H), 3.96 (s, 3H), 3.99 (s, 3H), 4.83 (dd,
J = 4.9, 3.7 Hz, 1H), 5.85 (d, J = 3.5 Hz, 1H), 6.84 (s, 1H), 7.29 (d,
J = 9.2 Hz, 1H), 7.71 (d, J = 9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d = 38.5, 56.0, 56.6, 61.4, 62.1, 69.9, 81.3, 104.3, 114.5, 118.7, 119.4,
121.8, 124.3, 143.5, 146.5, 150.2, 151.4, 176.2; HRMS m/z calcd for
[C18H20O7+H]+ 349.1289, found 349.1296.
4.1.6. (3aR,5S,11bR)-6,7,8,11-Tetramethoxy-5-methyl-3,3a,5,
11b-tetrahydro-2H-benzo[g]furo[3,2-c]isochromen-2-one 17a
and (3aR,5R,11bR)-6,7,8,11-tetramethoxy-5-methyl-3,3a,5,11b-
tetrahydro-2H-benzo[g]furo[3,2-c]isochromen-2-one 17b
To a solution of lactone 9 (50 mg, 0.144 mmol, 1.0 equiv) in CH2-
Cl2 (10 mL) at 0 °C were added acetaldehyde dimethylacetal
(0.030 mL, 0.288 mmol, 2.0 equiv) and TMSOTf (0.039 mL,
0.216 mmol, 1.5 equiv). The reaction mixture was stirred at 0 °C
for 2 h. It was then quenched with satd aq NaHCO3 (5 mL) and
the solution extracted with CH2Cl2 (3 ꢃ 20 mL). The combined
organic layers were washed with brine, dried (Na2SO4), and con-
centrated. The residue was purified by silica gel column chroma-
tography using petroleum ether/EtOAc (9:1 to 1:1) as eluent to
afford an inseparable mixture of syn/anti diastereomers 17a and
17b (36.5 mg, 68%, syn/anti = 65/35, 1H NMR) as a colorless gummy
solid: 1H NMR (400 MHz, CDCl3/TMS) for major diastereomer:
d = 1.75 (d, J = 6.3 Hz, 3H), 2.78 (d, J = 17.2, Hz, 1H), 2.92 (dd,
J = 17.2, 4.4 Hz, 1H), 3.75 (s, 3H), 3.87 (s, 3H), 4.03 (s, 3H), 4.10
(15.4 mg, 52%) as an orange semi solid: ½a D25
ꢁ
¼ þ137 (c 0.108,
MeOH), lit.1
½
a 2D5
ꢁ
¼ ꢀ53 (c 0.112, MeOH); IR (CHCl3):
m
= 3461,
3020, 2928, 2855, 1791, 1650, 1621, 1458, 1434, 1366, 1336,
1319, 1269, 1240, 1154, 1072, 1035, 995, 957, 921, 843,
670 cmꢀ1 1H NMR (400 MHz, CDCl3/TMS): d = 1.56 (d, J = 6.9 Hz,
;
3H), 2.68 (d, J = 17.7 Hz, 1H), 2.96 (dd, J = 17.7, 5.2 Hz, 1H), 4.00
(s, 3H), 4.68 (dd, J = 5.1, 3.0 Hz, 1H), 5.07 (q, J = 6.9 Hz, 1H), 5.25
(d, J = 2.9 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H),

1554
R. A. Fernandes et al. / Tetrahedron: Asymmetry 24 (2013) 1548–1555
12.27 (s, 1H, OH); 13C NMR (100 MHz, CDCl3): d = 18.5, 36.9, 56.5,
66.2, 66.4, 68.7, 114.8, 115.7, 121.4, 123.3, 135.8, 149.4, 152.4,
154.3, 174.0, 180.4, 188.5; HRMS m/z calcd for [C17H14O7+H]+
331.0818, found 331.0827.
layer was extracted with EtOAc (3 ꢃ 10 mL). The combined organic
layers were washed with brine, dried (Na2SO4), and concentrated.
The residue was purified by silica gel column chromatography
using petroleum ether/EtOAc (9:1 to 1:1) as eluent to afford 17b
(12.1 mg, 45%) as
þ120:8 (c 0.25, CHCl3); IR (CHCl3):
1613, 1599, 1507, 1464, 1361, 1336, 1276, 1215, 1199, 1155,
1132, 1067, 1049, 1011, 981, 905, 668 cmꢀ1 1H NMR (400 MHz,
a
colorless solid: mp 176–178 °C;
½
a 2D5
ꢁ
¼
4.1.9. Synthesis of arizonin B1 1 from a mixture of 18 and 2
through direct epimerization of C-5 and regioselective demeth-
ylation
m
= 2931, 2852, 1786, 1740,
;
A mixture of 18 and 2 (16.7 mg, 0.049 mmol) was treated with
conc. H2SO4 (2 mL). The resulting mixture was then stirred at room
temperature for 45 min. Partial charring of the material was ob-
served. Brine solution (5 mL) was then added and the reaction mix-
ture extracted with EtOAc (3 ꢃ 10 mL). The combined organic
layers were washed with satd aq NaHCO3, brine, dried (Na2SO4),
and concentrated. The residue was purified by silica gel column
chromatography using petroleum ether/EtOAc (9:1 to 1:1) as elu-
ent to give arizonin B1 1 (7.7 mg, 48%) as an orange semi solid:
CDCl3/TMS): d = 1.57 (d, J = 6.8 Hz, 3H), 2.72 (d, J = 17.6, Hz, 1H),
2.99 (dd, J = 17.6, 4.9 Hz, 1H), 3.87 (s, 6H), 4.03 (s, 3H), 4.07 (s,
3H), 4.76 (dd, J = 4.7, 2.8 Hz, 1H), 5.40 (q, J = 6.7 Hz, 1H), 5.58 (d,
J = 2.8 Hz, 1H), 7.35 (d, J = 9.2 Hz, 1H), 7.92 (d, J = 9.2 Hz, 1H); 13C
NMR (100 MHz, CDCl3): d = 19.7, 37.9, 56.6, 61.9, 62.5, 64.2, 66.1,
67.9, 72.2, 114.4, 115.5, 119.8, 124.6, 125.1, 129.2, 142.7, 146.1,
151.2, 153.5, 175.4; HRMS m/z calcd for [C20H22O7+H]+ 375.1444,
found 375.1445.
½
a 2D5
ꢁ
¼ þ135 (c 0.11, MeOH). The spectroscopic data were the same
4.1.13. Arizonin C1 2
as before.
The title compound was prepared from 17b (12 mg,
0.032 mmol, 1 equiv) by a similar procedure as described for the
conversion of mixture of 17a and 17b to 18 and 2 to give 2
4.1.10. Arizonin C1 2 from arizonin B1 1
To a stirred solution of 1 (4 mg, 0.012 mmol) in CH2Cl2 (5 mL)
was added silver(I) oxide (39.3 mg, 0.169 mmol, 14 equiv) and
methyl iodide (0.015 mL, 0.24 mmol, 20 equiv) at room tempera-
ture and the reaction mixture stirred for 30 min at room tempera-
ture. The reaction mixture was filtered through a small pad of silica
gel and the filtrate evaporated under reduced pressure. The residue
was purified by silica gel column chromatography using petroleum
ether/EtOAc (9:1 to 1:1) as eluent to afford arizonin C1 2 (3.2 mg,
77%) as an orange solid: mp 115ꢀ130 °C (decomp.), lit.5 mp
(9.4 mg, 85%) as a yellow solid: ½a D25
¼ þ73:9 (c 0.15, MeOH). The
ꢁ
spectroscopic data were the same as before.
Acknowledgements
This work was financially supported by the Department of Sci-
ence and Technology, New Delhi (Grant No. SR/S1/OC-25/2008)
and Board of Research in Nuclear sciences (BRNS), Government of
India (Grant No. 2009/37/25 BRNS). S.V.M. and V.P.C. thank the
Council of Scientific and Industrial Research (CSIR) New Delhi for
research fellowships.
110ꢀ135 °C (decomp.);
½
a 2D5
ꢁ
¼ þ75:3 (c 0.7, MeOH), lit.5
½
a 2D0
ꢁ
¼ ꢀ86:5 (c 0.7, MeOH); IR (CHCl3):
m = 3011, 2926, 2853,
1789, 1663, 1575, 1486, 1456, 1403, 1368, 1337, 1274, 1234,
References
1201, 1156, 1125, 1069, 1036, 993, 947, 905, 845, 820, 711,
669 cmꢀ1 1H NMR (400 MHz, CDCl3/TMS): d = 1.55 (d, J = 6.9 Hz,
;
1. Hochlowski, J. E.; Brill, G. M.; Anders, W. W.; Spanton, S. G.; McAlpine, J. B. J.
Antibiot. 1987, 40, 401–407.
3H), 2.69 (d, J = 17.7 Hz, 1H), 2.96 (dd, J = 17.7, 5.2 Hz, 1H), 3.93,
(s, 3H), 3.99 (s, 3H), 4.67 (dd, J = 5.1, 3.1 Hz, 1H), 5.07 (q,
J = 6.9 Hz, 1H), 5.26 (d, J = 3.0 Hz, 1H), 7.24 (d, J = 8.6 Hz, 1H),
8.00 (d, J = 8.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): d = 18.6, 37.0,
56.3, 61.2, 66.3, 66.7, 68.9, 116.1, 124.9 (2C), 125.2, 133.1, 149.5,
150.5, 159.2, 174.2, 181.3, 182.4; HRMS m/z calcd for
[C18H16O7+H]+ 345.0974, found 345.0979.
2. For nanaomycin D, isolation (a) Omura, S.; Tanaka, H.; Okada, Y.; Marumo, H. J.
Chem. Soc., Chem. Commun. 1976, 320–321; Synthesis (b) Tatsuta, K.; Akimoto,
K.; Annaka, M.; Ohno, Y.; Kinoshita, M. J. Antibiot. 1985, 38, 680–682; (c)
Tatsuta, K.; Akimoto, K.; Annaka, M.; Ohno, Y.; Kinoshita, M. Bull. Chem. Soc. Jpn.
1985, 58, 1699–1706; (d) Winters, M. P.; Stranberg, M.; Moore, H. W. J. Org.
Chem. 1994, 59, 7572–7574; (e) Fernandes, R. A.; Brückner, R. Synlett 2005,
1281–1285; For kalafungin, isolation (f) Bergy, M. E. J. Antibiot. 1968, 21, 454–
457; Synthesis (g) Kraus, G. A.; Cho, H.; Crowley, S.; Roth, B.; Sugimoto, H.;
Prugh, S. J. Org. Chem. 1983, 48, 3439–3444; (h) Donner, C. D. Tetrahedron Lett.
2007, 48, 8888–8890; (j) See Ref. 2e.
4.1.11. Synthesis of arizonin C1 through H2SO4 mediated epi-
merization of a mixture of 18 and 2
3. Karwowski, J. P.; Jackson, M.; Theriault, R. J.; Prokop, J. F.; Maus, M. L.; Hansen,
C. F.; Hensey, D. M. J. Antibiot. 1988, 41, 1205–1211.
A mixture of 18 and 2 (18.4 mg, 0.053 mmol) was treated with
conc. H2SO4 (2 mL). The resulting mixture was then stirred at room
temperature for 25 min. Brine solution (5 mL) was then added and
the reaction mixture extracted with EtOAc (3 ꢃ 10 mL). The com-
bined organic layers were washed with satd aq NaHCO3, brine,
dried (Na2SO4), and concentrated. The residue was purified by sil-
ica gel column chromatography using petroleum ether/EtOAc (9:1
to 1:1) as eluent to give a mixture of 18 and 2 (6:94, 1H NMR). A
single recrystallization (CH2Cl2/hexane) gave pure arizonin C1 2
4. (a) Brimble, M. A.; Phythian, S. J. Tetrahedron Lett. 1993, 34, 5813–5814; (b)
Brimble, M. A.; Phythian, S. J.; Prabaharan, H. J. Chem. Soc., Perkin Trans. 1 1995,
2855–2860.
5. Mahlau, M.; Fernandes, R. A.; Brückner, R. Eur. J. Org. Chem. 2011, 4765–4772.
6. (a) Fernandes, R. A.; Chavan, V. P. Tetrahedron Lett. 2008, 49, 3899–3901; (b)
Fernandes, R. A.; Chavan, V. P.; Ingle, A. B. Tetrahedron Lett. 2008, 49,
6341–6343; (c) Fernandes, R. A.; Chavan, V. P. Eur. J. Org. Chem. 2010, 4306–
4311; (d) Fernandes, R. A.; Mulay, S. V. Synlett 2010, 2667–2671; (e) Fernandes,
R. A.; Mulay, S. V. J. Org. Chem. 2010, 75, 7029–7032; (f) Fernandes, R. A.;
Chavan, V. P.; Mulay, S. V. Tetrahedron: Asymmetry 2011, 22, 487–492; (g)
Fernandes, R. A.; Chavan, V. P. Tetrahedron: Asymmetry 2011, 22, 1312–1319;
(h) Fernandes, R. A.; Ingle, A. B. Eur. J. Org. Chem. 2011, 6624–6627; (i)
Fernandes, R. A.; Ingle, A. B.; Chavan, V. P. Org. Biomol. Chem. 2012, 10, 4462–
4466; (j) Fernandes, R. A.; Chavan, V. P.; Mulay, S. V.; Manchoju, A. J. Org. Chem.
2012, 77, 10455–10460.
(8.8 mg, 48%) as an orange solid: ½a D25
¼ þ75:4 (c 0.65, MeOH).
ꢁ
The spectroscopic data were the same as before.
7. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 18, 3769–3772.
8. Roth, G. J.; Liepold, B.; Müller, S. G.; Bestmann, H. J. Synthesis 2004, 1, 59–62.
9. (a) Dötz, K. H. Angew. Chem., Int. Ed. Engl. 1975, 14, 644–645; (b) Dötz, K. H.;
Tomuschat, P. Chem. Soc. Rev. 1999, 28, 187–198.
10. Bos, M. E.; Wulff, W. D.; Miller, R. A.; Chamberlin, S.; Brandvold, T. A. J. Am.
Chem. Soc. 1991, 113, 9293–9319.
11. (a) Masquelin, T.; Hengartner, U.; Streith, J. Synthesis 1995, 780–786; (b) Larghi,
E. L.; Kaufman, T. S. Eur. J. Org. Chem. 2011, 5195–5231.
12. For a similar direct anti-pyran ring formation in oxa-Pictet–Spengler reaction
with a lower electron density on the naphthalene ring (no methoxy groups)
see: Eid, C. N.; Shim, J.; Bikker, J.; Lin, M. J. Org. Chem. 2009, 74, 423–426.
4.1.12. (3aR,5R,11bR)-6,7,8,11-Tetramethoxy-5-methyl-3,3a,5,
11b-tetrahydro-2H-benzo[g]furo[3,2-c]isochromen-2-one 17b
To a preheated solution of BF3ꢂOEt2 (0.091 mL, 0.72 mmol,
10.0 equiv) in TFA (2 mL) was added a solution of lactone 9
(25 mg, 0.072 mmol, 1.0 equiv) and acetaldehyde dimethylacetal
(0.031 mL 0.29 mmol, 4.0 equiv) in THF (0.5 mL) at 70 °C and stir-
red for 55 s. The reaction mixture was cooled to 0 °C and satd aq
NaHCO3 was slowly added for neutralization (pH 7). The aqueous

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13. Isomerization of the C-5 centre is known in the literature to the more stable
anti-pyran products either mediated by BBr3 or H2SO4. However under the
conditions employed and our own previous work,6j we ruled out epimerization
at all stereogenic centres so as to reverse the sign of specific rotations. Also any
other stereogenic centre epimerization should give a different diastereomer.
The matching spectroscopic data of the final compounds also rule out this
possibility.
15. Discrepancies in specific rotations is a known phenomenon, see for similar
discrepancies in the case of a related pyranonaphthoquinone, thysanone (a)
Singh, S. B.; Cordingley, M. G.; Ball, R. G.; Smith, J. L.; Dombrowski, A. W.; Goetz,
M. A. Tetrahedron Lett. 1991, 32, 5279–5282; (b) Donner, C. D.; Gill, M.
Tetrahedron Lett. 1999, 40, 3921–3924; (c) Donner, C. D.; Gill, M. J. Chem. Soc.,
Perkin Trans. 1 2002, 938–948; (d) Sperry, J.; Brimble, M. A. Synlett 2008,
1910–1912; (e) Sperry, J.; Tuen, T. Y.; Brimble, M. A. Synthesis 2009, 2561–
2569.
14. These results are contradictory to previous report.5