Intra- And intermolecular oxa-pictet-spengler cyclization strategy for the enantioselective synthesis of deoxy analogues of (+)-nanomycin A methyl ester, (+)-eleutherin, (+)-allo-eleutherin, and (+)-thysanone

Article abstract of DOI:10.1002/ejoc.201000476

Enantioselective synthesis of deoxy analogues of pyranonaphthoquinone antibiotics (+)-nanomycin A methyl ester, (+)eleutherin, (+)-allo-eleutherin, and (+)-thysanone was achieved in good overall yield with high enantio- and diastereoselectivity from the common intermediate (R)-3-(2,5-dimethoxyph.enyl) propane-1,2-diol. The intramolecular oxaPictet-Spengler cyclization of 6-a:ryl-l.,3-dioxolone was de-veloped for the first time and utilized in the enantioselective synthesis of (H-)-deoxynanomycin A methyl ester, whereas the intermolecular oxa-Pictet-Spengler cycllzation strategy was applied to the enantioselective synthesis of deoxy analogues of (+)-eleutherm, (+)-allo-eleutherin, and. (+)-thysanone,

Full text of DOI:10.1002/ejoc.201000476

FULL PAPER
DOI: 10.1002/ejoc.201000476
Intra- and Intermolecular Oxa-Pictet–Spengler Cyclization Strategy for the
Enantioselective Synthesis of Deoxy Analogues of (+)-Nanomycin A Methyl
Ester, (+)-Eleutherin, (+)-Allo-Eleutherin, and (+)-Thysanone
Rajiv T. Sawant,[a] Satish G. Jadhav,[a] and Suresh B. Waghmode*[a]
Keywords: Quinones / Antibiotics / Organocatalysis / Cyclization / Enantioselectivity
Enantioselective synthesis of deoxy analogues of pyranon-
aphthoquinone antibiotics (+)-nanomycin A methyl ester, (+)-
eleutherin, (+)-allo-eleutherin, and (+)-thysanone was
achieved in good overall yield with high enantio- and dia-
stereoselectivity from the common intermediate (R)-3-(2,5-di-
methoxyphenyl)propane-1,2-diol. The intramolecular oxa-
Pictet–Spengler cyclization of 6-aryl-1,3-dioxolone was de-
veloped for the first time and utilized in the enantioselective
synthesis of (+)-deoxynanomycin A methyl ester, whereas
the intermolecular oxa-Pictet–Spengler cyclization strategy
was applied to the enantioselective synthesis of deoxy ana-
logues of (+)-eleutherin, (+)-allo-eleutherin, and (+)-thys-
anone.
Introduction
A pyran ring fused to a naphthoquinone nucleus is a
ubiquitous structural motif present in a number of natural
products (Figure 1) that exhibit a wide range of biological
activities, such as antibiotic, antiparasitic, antiviral, and
antitumor activities.[1] Nanomycin A (1) belongs to the
monomeric class of pyranonaphthoquinone antibiotics[1a]
and was isolated from the fungus Streptomyces rosa in
1974;[2] it exhibits inhibitory activity against mycoplasma,
fungi, and Gram-positive bacteria. It also shows inhibition
of the platelet-aggregation agent adenosine diphosphate
(ADP).[1,2] Due to the significant antitumor activity of 1,
several racemic syntheses of 1[3] as well as methyl ester 6a[3a]
and its deoxy analogue 6b[4] have been reported. Recently,
Brimble and co-workers reported the asymmetric synthesis
of (1R,3R)-deoxynanomycin A in 12 steps with 86%ee.[5]
However, the enantioselective syntheses of 1 and analogues
6a and 6b are not known.
Figure 1. Biologically active pyranonaphthoquinones.
Eleutherin (2) and isoeleutherin (3) were first isolated
from the bulbs of Eleutherin bulbosa (Iridaceae) in 1950[6]
and 1951,[7] respectively. (+)-Eleutherin (2) possess C-1–C-
3 cis stereochemistry on the pyran ring and is a reversible
inhibitor of topoisomerase II–a target for anticancer
agents.[8] (+)-Allo-eleutherin (4; Figure 1) is an enantiomer
of (+)-isoelutherin (3), and both were first synthesized from
(+)-eleutherin by treatment with H3PO4.[7] Several synthe-
ses of 2 and 3 and their analogues have been reported in
the literature.[4a,4b,9–11] However, existing methods are either
limited to racemic syntheses[4a,4b,9] or are based on chiral
pool synthesis[10] or enzymatic resolution,[11] whereas cata-
lytic asymmetric methods are rather rare. Very few enantio-
selective syntheses of 2,[10] 3,[10c] and deoxyeleutherin (6)[11]
have been reported. Recently, Fernandes and co-workers[10c]
used ethyl (S)-3-hydroxybutyrate as a chiral template in the
synthesis of (+)-2 and (+)-4.
Thysanone (5) was isolated from the fungus Thysano-
phora penicilloides in 1991[12] and is one of the effective in-
hibitors of human rhinovirus 3C-protease; therefore, it
should serve as a basis for the development of a chemo-
therapeutic agent for the common cold. Several racemic[13]
and enantiopure[11,14a,15] syntheses of (1R,3S)-thysanone (5)
and its analogues have been reported.
[a] Department of Chemistry, University of Pune,
Ganeshkhind, Pune 411007, Maharashtra, India
Fax: +91-20-25691728
E-mail: suresh@chem.unipune.ernet.in
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Intra- and Intermolecular Oxa-Pictet–Spengler Cyclization
Bromopyranobenzoquinone intermediates 10 and 18a
are valuable immediate precursors in the synthesis of nano-
mycin A, eleutherin, and many other pyranonaphthoquin-
one natural products.[3a,10a] Moreover, Diels–Alder reac-
tion[3a,4a,10a,15a,15b] of substituted 1,3-butadiene with bro-
mopyranobenzoquinones or pyranobenzoquinones and the
titanium tetrachloride promoted oxa-Pictet–Spengler re-
arrangement[16] of 5-aryl-1,3-dioxolanes have also been
used for the construction of the aromatic and pyran rings
of bioactive pyranonaphthoquinones, respectively. How-
ever, oxa-Pictet–Spengler rearrangement of 6-aryl-1,3-di-
oxolanes or an organocatalytic asymmetric approach has
not been reported for the synthesis of the pyranonaphtho-
quinone class of compounds apart from our earlier report
on the organocatalytic enantioselective formal synthesis of
(1R,3S)-thysanone.[14a] Towards this end, a convenient,
straightforward, and practical route to the synthesis of
enantiomerically pure bromopyranobenzoquinone or pyr-
anobenzoquinone intermediates and pyranonaphthoquin-
one antibiotics from easily available starting material is
highly desirable.
As part of our research program aimed towards the de-
velopment of new strategies for the organocatalytic enantio-
selective synthesis of biologically active compounds and
their chiral key intermediates[14] on the basis of proline-cat-
alyzed asymmetric α-aminooxylation of aldehydes,[17a] we
were encouraged to design a convenient and effective route
to the pyranonaphthoquinone antibiotic class of com-
pounds. Herein we report a general, short, and efficient
enantioselective synthesis of (+)-deoxynanomycin A methyl
ester (6b), (+)-demethoxyeleutherin (7), (+)-demethoxyallo-
eleutherin (8), and (+)-deoxythysanone (9) by employing -
proline-catalyzed-asymmetric α-aminooxylation[17a] and
oxa-Pictet–Spengler cyclization[16,18] as the key steps.
Scheme 1. Retrosynthetic analysis of 6a and 6b.
We began the synthesis of 6a and 6b with the preparation
of 6-aryl-1,3-dioxolanes 13a/b. (R)-Diols 12a[14a] and
12b[14b] were prepared in 98%ee by following our reported
organocatalytic approach[14a,14b] that is based on -proline-
catalyzed asymmetric α-aminooxylation of aldehyde[17a] fol-
lowed by treatment with 1,1Ј-diethoxyethane in the pres-
ence of p-TsA in CH2Cl2 to give 1,3-dioloxolanes 13a and
13b in excellent yield. The mixture of 13a was subjected to
intramolecular oxa-Pictet–Spengler cyclization[16] with
TiCl4 (2 equiv.) in dry CH2Cl2 at –30 °C to give trans-con-
figured pyran 14b in poor yield (7%) along with hydrolyzed
product diol 12a in 89% yield, whereas oxa-Pictet–Spengler
rearrangement of 13b proceeded smoothly to give exclu-
sively trans-pyran 15b in very good yield (87%) along with
hydrolyzed product diol 12b in 11% yield. The TiCl4-pro-
moted intramolecular oxa-Pictet–Spengler cyclization was
found to be highly diastereoselective to give trans-pyran 14b
and 15b as single diastereomers (Scheme 2).
Results and Discussion
Synthesis of (1S,3R)-Nanomycin A Methyl Ester (6a) and
(+)-Deoxynanomycin A Methyl Ester (6b)
The retrosynthetic strategy for the synthesis of 6a and 6b
is outlined in Scheme 1. We envisage that 6a and 6b could
be obtained from quinone intermediates 10 and 11, as their
racemic form has been synthesized by Kraus and Shi[3a] and
Yoshii and Kometani,[4a] respectively. The synthetic chal-
lenge of this retrosynthetic pathway is to establish the two
stereogenic center at C-1 and C-3 of quinones 10 and 11.
We realize that (R)-diol 12a/b[14a,14b] would serve as a suit-
able precursor with the required C-3 stereocenter of 10 and
11, which can be easily prepared by using -proline-cata-
lyzed asymmetric α-aminooxylation of the aldehyde.[14] Our
plan was to generate the C-1 stereocenter by using intramo-
Scheme 2. Reagents and conditions: (i) CH3CH(OEt)2, p-TsA,
CH2Cl2, 0 °C – r.t., 7 h; (ii) TiCl4, CH2Cl2, –30 °C, 3.5 h.
The trans stereochemical relationship between H1 and H3
lecular oxa-Pictet–Spengler cyclization[16] of 6-aryl-1,3-di- on the pyran ring in 14b and 15b was assigned on the basis
oxolanes 13a/b derived from (R)-diol 12a/b to give pyrans of NOESY proton NMR experiments. The H3 proton
14a/b and 15a/b, which can be further transformed into showed strong NOE correlation to the methyl protons and
quinones 10 and 11 by simple functional group interconver- very weak correlation to H1, indicating that H1 and H3 are
sion (Scheme 1).
trans to each other (Figure 2).
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FULL PAPER
Donner and co-workers[10a] and Yoshii and Kometani[4a] re-
ported the enantiopure and racemic syntheses of quinone
18a and 19a as key intermediates for the total synthesis of
(+)-eleutherin (2) and (Ϯ)-demethoxyeleutherin (7), respec-
tively. We envisaged a new and short synthesis of important
intermediate (+)-18a, (+)-19a/b, and (+)-23 from (S)-
alcohols 20a[14a] and 20b[14b] (98%ee) through oxa-Pictet–
Spengler cyclization followed by oxidation of pyrans 21a/b
and 22a/b (Scheme 5).
Figure 2. NOE observed in trans-14b and trans-15b.
The poor yield in the oxa-Pictet–Spengler rearrangement
of bromo-1,3-dioxolane 13a into pyran 14b may be due to
the electron-withdrawing effect of the bromide substituent
at C-4 of the aryl ring, which deactivates the aryl ring
towards Friedel–Crafts electrophilic cyclization to give
14b.[19] Due to the poor yield of pyran 14b, our plan to
prepare important intermediate 10 for the eventual synthe-
sis of 6a was unsuccessful. Thus, it was decided to complete
the synthesis of (+)-6b from pyran 15b. For one carbon ho-
mologation of alcohol 14b, we adopted a two-step reaction
sequence to convert alcohol 15b into nitrile 16, which in-
volved tosylation of 15b with p-toluenesulfonyl chloride by
using Et3N and DMAP in CH2Cl2, followed by nucleophilic
displacement of the tosylate with NaCN and NaI in DMF
at 80 °C to furnish nitrile 16 in 85% yield over the two
steps. Compound 16 was hydrolyzed with aqueous 50%
NaOH in MeOH to afford the carboxylic acid, which was
treated with MeI by using anhydrous K2CO3 in DMF at
room temperature to give ester 17 in 92% yield over two
steps. Oxidative demethylation of pyran 17 with cerium(IV)
ammonium nitrate (CAN) in aqueous CH3CN gave quin-
one 11 in 82% yield. Quinone 11 was converted into 6b in
78% yield by following a two-step (Diels–Alder followed
by aromatization) literature procedure[4a] (Scheme 3). The
physical and spectroscopic data of quinone (+)-6b are in
accordance with the reported data of racemic 6b.[4a]
Scheme 4. Retrosynthetic analysis of 2 and 7–9.
We focused initially on the synthesis of intermediate 18a
for the synthesis of (+)-eleutherin (2). Thus, alcohol (S)-
20a was prepared by following our reported organocatalytic
approach[14a,14b] and subjected to oxa-Pictet–Spengler cycli-
zation with acetaldehyde or 1,1Ј-diethoxyethane under dif-
ferent reaction conditions by using different acids such as
BF3·Et2O, H3PO4, and HCl; unfortunately, all attempts
were failed to give desire cyclized product 21a/b required
for the synthesis of intermediate 18a to prepare 2. The low
reactivity of alcohol (S)-20a towards oxa-Pictet–Spengler
cyclization is similar to our earlier observation in the cycli-
zation of bromo-1,3-dioxolane 13a into pyran 14a/b
(Scheme 5). This may be due to the electron-withdrawing
effect of the bromide substituent at C-4 of the aryl ring,
which deactivates the aryl ring towards Friedel–Crafts cycli-
zation.[19]
Scheme 3. Reagents and conditions: (i) (a) p-TsCl, Et3N, CH2Cl2,
0 °C to r.t., 30 h, (b) NaCN, NaI, DMF, 70 °C, 12 h, 85% (over
two steps); (ii) (a) 50% NaOH, MeOH, 80 °C, 8 h, (b) MeI,
K2CO3, DMF, r.t., 4.5 h, 92% (over two steps); (iii) CAN (3 equiv.),
CH3CN/H2O (4:1), 0 °C to r.t., 20 min, 82%; (iv) see ref.[4a]: (a) 1-
acetoxy-1,3-butadiene, toluene, r.t., 48 h; (b) 1% aq. Na2CO3,
EtOH, r.t., 5 h;78% (over two steps).
Scheme 5. Attempted oxa-Pictet–Spengler cyclization on (S)-20a.
Then, we turned our attention to complete the synthesis
of quinones 19a/b in optically pure form (Scheme 6). Thus,
(S)-alcohol 20b was prepared by following our reported or-
ganocatalytic approach[14a,14b] and subjected to oxa-Pictet–
Spengler cyclization with 1,1Ј-diethoxyethane in the pres-
ence of BF3·Et2O to give a mixture of pyrans 22a/b (25:75
ratio) in 86% yield. The 22a/b mixture was easily separated
Synthesis of (+)-Eleutherin (2), (+)-Deoxyeleutherin (7),
(+)-Deoxyallo-eleutherin (8), and (+)-Deoxythysanone (9)
The retrosynthetic strategy for the synthesis of pyrano- by column chromatography to give cis-22a[4a] (21%) and
naphthoquinones 2 and 7–9 is depicted in Scheme 4. trans-22b[4a] (65%) from (S)-20b. The 1,3-relationship of the
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Intra- and Intermolecular Oxa-Pictet–Spengler Cyclization
newly generated stereocenter in pyrans 22a/b was confirmed annulated pyran 25 in 85% yield. Finally, (+)-deoxy-
1
by comparing the H NMR spectroscopic values with the thysanone (9) was prepared in 77% yield from pyran 25
those reported in the literature[4a] and converting nonpolar over
a two-step reaction sequence involving radical
diastereomer 22a into (+)-demethoxyeleutherin (7).[11] Oxi- bromination of pyran 25 and hydrolysis of the bromide
dative demethylation of pyran 22a with CAN in aqueous intermediate in aqueous THF (Scheme 7). The physical and
CH3CN gave quinone 19a in 84% yield. Quinone 19a was spectroscopic data of (+)-9 are in good agreement with the
converted into (+)-7[11] in 80% yield by following a two- reported data.[11,15c]
step (Diels–Alder followed by aromatization) literature pro-
cedure.[4a] The physical and spectroscopic data of (+)-19a
and (+)-7 are in accordance with the literature data of race-
mic 19a[4a] and (+)-7.[11] Similarly, (+)-demethoxyallo-eleu-
therin (8) was synthesized from trans-22b in 63% yield.
Conclusions
In conclusion, we have accomplished the first concise
enantioselective synthesis of (+)-deoxynanomycin A methyl
ester (6b) in nine steps by employing a novel intramolecular
oxa-Pictet–Spengler cyclization of 6-aryl-1,3-dioxolone 13b.
We have also demonstrated the enantioselective four-step
syntheses of (+)-demethoxyeleutherin (7) and (+)-demeth-
oxyallo-eleutherin (8) and the six-step synthesis of (+)-de-
oxythysanone 9 by using an intermolecular oxa-Pictet–
Spengler cyclization of (S)-1-(2,5-dimethoxyphenyl)propan-
2-ol (20b). Good yields, ready availability of the starting
materials, and high enantio- and diastereoselectivity are
some of the salient features of our synthetic approach,
which represents a good alternative to the known methods.
Although, the present strategy failed to synthesize bromo-
pyranobenzoquinone intermediates 10 and 18a for the
preparation of nanomycin A methyl ester (6a) and eleu-
therin (2), we believe that the present synthetic strategy
could serve as a potential route for the synthesis of related
pyranonaphthoquinone natural products. Efforts are in
Scheme 6. Reagents and conditions: (i) CH3CH(OEt)2, BF3·Et2O,
CH2Cl2, 0 °C to r.t., 3.5 h, 21% (22a), 65% (22b); (ii) CAN
(3 equiv.), CH3CN/H2O (4:1), 0 °C to r.t., 0.5 h; 84% (19a), 78%
(19b); (iii) see ref.[4a]: (a) 1-acetoxy-1,3-butadiene, toluene, r.t., 48 h;
(b) 1% aq. Na2CO3, EtOH, r.t., 5 h; 80% (7), 82% (8) (over two progress in this direction.
steps).
To demonstrate the further utility of (S)-alcohol 20b for
Experimental Section
the synthesis of (+)-deoxythysanone (9), we subjected (S)-
20b to oxa-Pictet–Spengler cyclization with methoxymethyl General Methods: Melting points were recorded with a Thomas
Hoover Capillary melting point apparatus. Thin-layer chromatog-
raphy was performed on Merck 60F254 silica gel plates, and visual-
ization was accomplished by irradiation with UV light and/or by
treatment with a solution of phosphomolybdic acid (1.25 g) and
Ce(SO4)2·H2O (0.5 g) in concentrated H2SO4/H2O (3.47 mL) fol-
lowed by heating. Crude products were purified by column
chromatography on silica gel of 100–200 mesh. IR spectra were re-
corded with a Shimadzu FTIR 8400 in CHCl3 or as KBr pellets.
Optical rotations were obtained with Jasco P-1020 digital polarime-
ter. 1H and 13C NMR spectra were recorded with a Varian Mercury
spectrometer at 300 and 75 MHz, respectively, by using CDCl3 as
a solvent. Chemical shifts are reported in δ units (ppm) with refer-
ence to TMS as an internal standard. GC mass spectra were ob-
tained with a Shimadzu GC–MS-QP5050A spectrometer. Elemen-
tal analyses were carried out with a Thermo-Electron Corporation
CHNS Analyzer, FLASH-EA 1112. Analytical HPLC was per-
formed on a chiral AD-H column (250 mmϫ4.6 mmϫ5 µ). Enan-
tiomeric excesses were measured by using either chiral HPLC or by
comparison with specific rotation. All solvents were purified and
dried by standard procedures prior to use.
chloride in the presence of ZnCl2 (30 mol-%) in dry Et2O
to afford pyran 23 in 80% yield. The oxidation of 23 with
CAN in aqueous CH3CN furnished quinone 24 in 81%
yield. Diels–Alder reaction[4a] of quinone 24 with 1-ace-
toxy-1,3-butadiene in toluene followed by aromatization
with 1% aqueous Na2CO3 solution in EtOH gave benz-
Scheme 7. Reagents and conditions: (i) MeOCH2Cl (2.1 equiv.),
ZnCl2 (30 mol-%), Et2O, 0 °C to r.t., 7 h, 83%; (ii) CAN (3 equiv.),
CH3CN/H2O (4:1), 0 °C to r.t., 25 min, 81%; (iii) (a) 1-acetoxy-1,3-
butadiene, toluene, r.t., 48 h; (b) 1% aq. Na2CO3, EtOH, r.t., 5 h;
85%, (over two steps); (iv) Br2 (1 equiv.), CCl4, hν, 0.5 h; then THF/
H2O (3:1), r.t., 1 h, 77% (over two steps).
(R)-4-(4-Bromo-2,5-dimethoxybenzyl)-2-methyl-1,3-dioxolane (13a):
To a stirred solution of (R)-diol 12a (500 mg, 1.72 mmol) and 1,1Ј-
diethoxyethane (1.23 mL, 8.62 mmol) in dry CH2Cl2 (20 mL) was
added p-toluenesulfonic acid (32 mg, 0.17 mmol) at 0 °C, and the
mixture was stirred at room temperature for 4 h. The reaction was
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R. T. Sawant, S. G. Jadhav, S. B. Waghmode
FULL PAPER
quenched with saturated aqueous NaHCO3 solution and extracted
with CH2Cl2 (3ϫ5 mL). The combined organic layer was washed
with brine, dried with anhydrous Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (EtOAc/hexane, 0.7:9.3) to give a 1:3 mixture of 13a (529 mg,
97%) as a colorless oil. Rf = 0.35 (EtOAc/hexane, 1.5:8.5). 1H
NMR (300 MHz, CDCl3): δ = 1.33 (d, J = 5.1 Hz, 0.75 H, CH3),
1.38 (d, J = 4.8 Hz, 2.25 H, CH3), 2.74–2.93 (m, 2 H, CH2), 3.54
(dd, J = 8.1, 6.9 Hz, 0.25 H, CH), 3.65 (dd, J = 8.1, 6.0 Hz, 0.75
H, CH), 3.76 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 3.79–3.85 (m,
0.75 H, CH), 4.01–4.06 (m, 0.25 H, CH), 4.24–4.39 (m, 0.75 H,
CH), 5.05 (q, J = 4.8 Hz, 0.75, CH), 5.14 (q, J = 4.8 Hz, 0.25, CH),
6.79 (s, 1 H, ArH), 7.01 (s, 1 H, ArH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 20.0, 33.8, 34.6, 55.9, 56.8, 69.2, 69.9, 75.0, 75.6, 100.8,
101.6, 109.4, 115.2, 115.4, 115.6, 125.9, 149.7, 151.7 ppm. IR
CH3), 2.40 (dd, J = 17.1, 11.4 Hz, 1 H, CH), 2.65 (dd, J = 17.1,
3.3 Hz, 1 H, CH), 3.65 (dd, J = 11.4, 7.2 Hz, 1 H, CH), 3.33 (s, 6
H, OCH3), 3.81–3.82 (m, 1 H, CH), 4.04–4.10 (m, 1 H, CH), 5.13
(q, J = 6.6 Hz, 1 H, CH), 6.66 (s, 2 H, ArH), ppm. 13C NMR
(75 MHz, CDCl3): δ = 19.3, 24.1, 55.3, 55.4, 65.9, 66.9, 68.0, 107.1,
107.4, 122.3, 128.9, 149.2, 150.9 ppm. IR (KBr): ν = 3376, 2939,
˜
1447, 1253, 1082, 1043 cm–1. MS: m/z = 238 [M]+. C13H18O4
(238.28): calcd. C 65.53, H 5.31; found C 65.62, H 5.39.
(+)-2-[(1S,3R)-5,8-Dimethoxy-1-methyl-3,4-dihydro-1H-benzo-
pyran-3-yl]acetonitrile (16): To as stirred solution of alcohol 15b
(255 mg, 1.07 mmol) in dry CH2Cl2 (15 mL) under an atmosphere
of nitrogen was added Et3N (195 µL, 1.39 mmol), DMAP (15 mg),
and p-toluenesulfonyl chloride (223 mg, 1.17 mmol) at 0 °C, and
the mixture was stirred at room temperature for 30 h. After comple-
tion of the reaction (monitored by TLC), saturated aqueous solu-
tion of NH4Cl was added, and the solution was extracted with
CH2Cl2 (3ϫ15 mL). The combined organic layer was washed with
brine, dried with anhydrous Na2SO4, and concentrated under re-
duced pressure, and the residue was purified by column chromatog-
raphy (EtOAc/hexane, 1.1 8:9) to afford the tosylate (94%, 395 mg)
as a white solid. Rf = 0.30 (EtOAc/hexane, 2:8). [α]2D6 = +25.4 (c =
(CHCl ): ν = 2999, 2935, 1487, 1213 cm–1. MS (EI): m/z = 317
˜
3
[M]+. C13H17BrO4 (317.18): calcd. C 49.23, H 5.40; found C 49.32,
H 5.47.
(R)-4-(2,5-Dimethoxybenzyl)-2-methyl-1,3-dioxolane (13b): The
1:1.5 mixture of 13b (550 mg, 98%) was prepared as a colorless
oil from 12b (500 mg, 2.10 mmol) by using the same experimental
procedure as that described for 13a. Rf = 0.35 (EtOAc/hexane,
1
0.5, CHCl3). M.p. 119–121 °C. H NMR (300 MHz, CDCl3): δ =
1
1.41 (d, J = 6.6 Hz, 1 H, CH3), 2.22–2.35 (m, 3 H, CH), 2.44 (s, 3
H, CH3), 2.59 (dd, J = 16.8, 2.7 Hz, 1 H, CH), 3.74 (s, 3 H, OCH3),
3.75 (s, 3 H, OCH3), 4.12–4.17 (m, 3 H, CH and CH2), 5.03 (q, J
= 6.6 Hz, 1 H, CH), 6.63 (s, 2 H, ArH), 7.33 (d, J = 8.4 Hz, 2 H,
ArH), 7.82 (d, J = 8.1 Hz, 2 H, ArH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 19.1, 21.6, 24.5, 55.4, 55.5, 64.5, 68.3, 72.3, 107.5,
107.6, 121.5, 128.0, 128.6, 129.7, 133.1, 144.7, 149.2, 150.9 ppm.
1.5:8.5). H NMR (300 MHz, CDCl3): δ = 1.35 (d, J = 4.8 Hz, 1.2
H, CH3), 1.40 (d, J = 5.1 Hz, 1.8 H, CH3), 2.81 (dd, J = 12.6,
7.2 Hz, 1 H, CH), 2.96 (dd, J = 13.5, 6.3 Hz, 1 H, CH), 3.57 (dd,
J = 8.4, 6.9 Hz, 0.4 H, CH), 3.68 (dd, J = 8.1, 6.0 Hz, 0.6 H, CH),
3.75 (s, 3 H, OCH3), 3.76 (s, 3 H, OCH3), 3.81 (dd, J = 7.8, 6.6 Hz,
0.6 H, CH), 4.02 (dd, J = 8.1, 6.0 Hz, 0.4 H, CH), 4.31–4.42 (m, 1
H, CH), 5.01 (q, J = 4.8 Hz, 0.6 H, CH), 5.17 (q, J = 4.8 Hz, 0.4 H,
CH), 6.70–6.78 (m, 3 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ
= 20.0, 34.0, 34.8, 55.5, 55.6, 69.3, 70.0, 75.2, 75.9, 100.7, 101.5,
111.0, 111.6, 111.7, 117.2, 126.7, 126.9, 151.6, 153.2 ppm. IR
IR (CHCl ): ν = 2937, 1483, 1217, 1072 cm–1. MS: m/z = 392
˜
3
[M]+. C20H24O6S (392.47): calcd. C 61.21, H 6.16; found C 61.30,
H 6.22. To a solution of tosylate (456 mg, 1.16 mmol) in anhydrous
DMF (15 mL) under an atmosphere of nitrogen was added NaI
(225 mg, 1.51 mmol) and NaCN (74 mg, 1.51 mmol), and the mix-
ture was stirred at 80 °C for 12 h. The reaction mixture was cooled
to room temperature, diluted with water, and extracted with EtOAc
(3ϫ25 mL). The combined organic layer was washed with brine,
dried with anhydrous Na2SO4, and concentrated under reduced
pressure, and the residue was purified by column chromatography
(EtOAc/hexane, 0.8:9.2) to give nitrile 16 (264 mg, 91%) as a color-
less solid. Rf = 0.4 (EtOAc/hexane, 2:8). [α]2D6 = +41.8 (c = 0.50,
CHCl3). M.p. 63–65 °C. 1H NMR (300 MHz, CDCl3): δ = 1.51 (d,
J = 6.6 Hz, 3 H, CH3), 2.45 (dd, J = 17.1, 10.8 Hz, 1 H, CH), 2.67
(d, J = 6.0 Hz, 2 H, CH2), 2.91 (dd, J = 17.1, 3.6 Hz, 1 H, CH),
3.77 (s, 3 H, OCH3), 3.78 (s, 3 H, OCH3), 4.18–4.24 (m, 1 H, CH),
5.13 (q, J = 6.6 Hz, 1 H, CH), 6.66 (s, 2 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 19.2, 24.7, 27.9, 55.3, 55.5, 62.8, 68.8, 107.7,
(CHCl ): ν = 2939, 1502, 1220, 1043 cm–1. MS: m/z = 238 [M]+.
˜
3
C13H18O4 (238.28): calcd. C 65.53, H 5.31; found C 65.56, H 5.36.
(+)-(1S,3R)-7-Bromo-5,8-dimethoxy-1-methyl-3-hydroxymethy-l-
3,4-dihydro-1H-benzo[c]pyran (14b): To a stirred solution of 1,3-di-
oxoalane 13a (200 mg, 0.63 mmol) in CH2Cl2 (15 mL) under an
atmosphere of nitrogen was added TiCl4 (138 µL, 1.26 mmol) in
dry CH2Cl2 (1 mL) dropwise over 5 min, and the mixture was
stirred at the same temperature for 3.5 h. The reaction was
quenched with saturated aqueous NH4Cl solution and extracted
with CH2Cl2 of (3 ϫ 15 mL). The combined organic layer was
washed with brine, dried with anhydrous Na2SO4, and concen-
trated under reduced pressure, and the residue was purified by col-
umn chromatography (EtOAc/hexane, 1.8:8.2) to give trans-14b
(14 mg, 7%) as a colorless oil. Rf = 0.4 (EtOAc/hexane, 4:6). [α]2D6
1
= +35.9 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ = 1.55
117.3, 121.3, 128.2, 149.2, 150.7 ppm. IR (CHCl ): ν = 2935, 2252,
˜
3
1483, 1259, 1074 cm–1. MS: m/z = 247 [M]+. C14H17NO3 (247.19):
(d, J = 6.6 Hz, 3 H, CH3), 2.34 (dd, J = 17.4, 11.4 Hz, 1 H, CH),
2.58 (dd, J = 17.1, 3.6 Hz, 1 H, CH), 3.69 (dd, J = 11.4, 4.5 Hz, 1
H, CH), 3.75–3.83 (m, 1 H, CH), 3.77 (s, 3 H, OCH3), 3.80 (s, 3
H, OCH3), 4.01–4.07 (m, 1 H, CH), 5.13 (q, J = 6.6 Hz, 1 H, CH),
6.80 (s, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.3,
23.8, 55.6, 60.7, 65.9, 66.7, 68.6, 112.5, 113.6, 121.9, 134.8, 146.5,
calcd. C 68.0, H 6.93, N 5.66; found C 68.09, H 6.96, N 5.72.
(+)-Methyl 2-[(1S,3R)-5,8-Dimethoxy-1-methyl-3,4-dihydro-1H-
benzopyran-3-yl]acetate (17): To a solution of nitrile 16 (228 mg,
0.92 mmol) in MeOH (3 mL) was added 50% NaOH (3 mL), and
the mixture was stirred for 8 h at 100 °C. The reaction mixture was
cooled to room temperature and acidified with cold 5% HCl and
extracted with EtOAc (3ϫ20 mL). The combined organic layer was
washed with brine, dried with anhydrous Na2SO4, and concen-
153.7 ppm. IR (CHCl ): ν = 3450, 2931, 1469, 1265 cm–1. MS (EI):
˜
3
m/z = 317 [M]+. C13H17BrO4 (317.18): calcd. C 49.23, H 5.40;
found C 49.31, H 5.46.
(+)-(1S,3R)-5,8-Dimethoxy-1-methyl-3-hydroxymethyl-3,4-dihydro- trated under reduced pressure to give the carboxylic acid, which
1H-benzo[c]pyran (15b): Product trans-15b (175 mg, 87%) was ob-
tained as a colorless solid from 13a (200 mg, 0.84 mmol) by using
the same experimental procedure as that described for 14b. Rf =
was used in the next step without purification. To a stirred solution
of the crude acid in anhydrous DMF was added K2CO3 (165 mg,
1.19 mmol) and MeI (69 µL, 1.11 mmol) at room temperature, and
the mixture was stirred for 3.5 h. The reaction mixture was diluted
0.4 (EtOAc/hexane, 4:6). [α]2D6 = +23.2 (c = 1.0, CHCl3). M.p. 67–
1
69 °C. H NMR (300 MHz, CDCl3): δ = 1.51 (d, J = 6.6 Hz, 3 H, with water and extracted with EtOAc (3ϫ15 mL). The combined
4446
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4442–4449

Intra- and Intermolecular Oxa-Pictet–Spengler Cyclization
organic layer was washed with brine, dried with anhydrous Na2SO4,
and concentrated under reduced pressure, and the residue was puri-
fied by column chromatography (EtOAc/hexane, 0.7:9.3) to give
ester 17 (238 mg, 98%) as a colorless oil. Rf = 0.5 (EtOAc/hexane,
2:8). [α]2D6 = –17.1 (c = 0.90, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 1.51 (d, J = 6.6 Hz, 3 H, CH3), 2.37 (dd, J = 17.1, 11.4 Hz, 1
H, CH), 2.62–2.66 (m, 2 H, CH2), 2.81 (dd, J = 17.1, 3.3 Hz, 1 H,
1.36 (d, J = 6.0 Hz, 3 H, CH3), 1.55 (d, J = 6.6 Hz, 3 H, CH3),
2.37 (dd, J = 16.8, 10.7 Hz, 1 H, CH), 2.86 (d, J = 6.0 Hz, 1 H,
CH), 3.58–3.66 (m, 1 H, CH), 3.78 (s, 3 H, OCH3), 3.82 (s, 3 H,
OCH3), 5.02 (q, J = 6.7 Hz, 1 H, CH), 6.69 (s, 2 H, ArH) ppm.
13C NMR (75 MHz, CDCl3): δ = 21.6, 21.7, 31.1, 55.3, 55.6, 69.0,
70.8, 107.6, 107.7, 125.2, 129.3, 150.2, 150.5 ppm. IR (CHCl ): ν =
˜
3
2970, 2931, 2835, 1491, 1437, 1257, 1074 cm–1. MS: m/z = 222
CH), 3.73 (s, OCH3), 3.76 (s, 3 H, OCH3), 3.77 (s, 3 H, OCH3), [M]+. C13H18O3 (222.28): calcd. C 70.24, H 8.16; found C 70.30, H
4.34–4.43 (m, 1 H, CH), 5.07 (q, J = 6.6 Hz, 1 H, CH), 6.64 (s, 2 8.23. Further elution (EtOAc/hexane, 0.2:9.8) gave polar trans-iso-
H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.0, 28.0, 40.9,
mer 22b (87 mg, 65%) as a colorless oil. Rf = 0.5 (EtOAc/hexane,
0.5:9.5). [α]2D6 = +32.8 (c = 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 1.28 (d, J = 6.3 Hz, 3 H, CH3), 1.50 (d, J = 6.6 Hz, 3
H, CH3), 2.30 (dd, J = 17.4, 10.8 Hz, 1 H, CH), 2.76 (dd, J = 17.4,
3.6 Hz, 1 H, CH), 3.76 (s, 3 H, OCH3), 3.77 (s, 3 H, OCH3), 4.05–
4.07 (m, 1 H, CH), 5.08 (q, J = 6.6 Hz, 1 H, CH), 6.64 (s, 2 H,
ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.5, 21.9, 30.3, 55.3,
55.5, 62.1, 68.2, 107.1, 107.4, 123.4, 129.0, 149.4, 150.8 ppm. IR
51.5, 55.2, 55.3, 63.2, 68.3, 107.2, 107.3, 122.4, 128.7, 149.2, 150.7,
171.5 ppm. IR (CHCl ): ν = 2941, 1737, 1600, 1479, 1255 cm–1.
˜
3
MS: m/z = 280 [M]+. C15H20O5 (280.32): calcd. C 64.27, H 7.19;
found C 64.35, H 7.23.
(+)-Methyl 2-(1S,3R)-(5,8-Dioxo-1-methyl-3,4-dihydro-lH-benzopy-
ran-3-yl)acetate (11): To a precooled (0 °C) solution of (+)-pyran
17 (100 mg, 0.35 mmol) in CH3CN (8 mL) was added dropwise a
solution of CAN (587 mg, 1.07 mmol) in water (2 mL). The mix-
ture was stirred for 20 min, then diluted with water, and extracted
with ethyl acetate (3ϫ15 mL). The combined organic layer were
dried with Na2SO4 and concentrated under reduced pressure. The
crude product was purified by column chromatography (EtOAc/
hexane, 1:9) to afford (+)-11 as a pale-yellow solid (60 mg, 82%).
Rf = 0.4 (EtOAc/hexane, 2:8). [α]2D5 = +61.2 (c = 1.0, CHCl3). M.p.
(CHCl ): ν = 2935, 1493, 1263, 1066 cm–1. MS: m/z = 222 [M]+.
˜
3
C13H18O3 (222.28): calcd. C 70.24, H 8.16; found C 70.32, H 8.25.
(+)-(1R,3S)-1,3-Dimethyl-3,4-dihydro-1H-benzo[c]pyran-5,8-dione
(19a): To a precooled (0 °C) solution of (+)-pyran 22a (29 mg,
0.13 mmol) in CH3CN (4 mL) was added dropwise a solution of
CAN (214 mg, 0.39 mmol) in water (1 mL). The mixture was
stirred for 20 min at the same temperature, then diluted with water
77–79 °C (ref.[4a] 99–105.5 °C). 1H NMR (300 MHz, CDCl3): δ = (5 mL), and extracted with ethyl acetate (3 ϫ12 mL). The com-
1.48 (d, J = 6.6 Hz, 3 H, CH3), 2.22 (dddd, J = 18.9, 12.6, 10.5, bined organic layer was dried with Na2SO4 and concentrated under
2.1 Hz, 1 H, CH), 2.68–2.69 (m, 3 H, CH2 and CH), 3.73 (s, 3 H, reduced pressure. The crude product was purified by column
OCH3), 4.24–4.31 (m, 1 H, CH), 4.82 (q, J = 6.4 Hz, 1 H, CH) chromatography (EtOAc/hexane, 0.4:9.6) to afford (+)-19a (21 mg,
6.70 (d, J = 10.2 Hz, 1 H, olefinic CH), 6.75 (d, J = 10.2 Hz, 1 H, 84%) as a pale-yellow liquid. Rf = 0.45 (EtOAc/hexane, 1:9). [α]2D5
olefinic CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.1, 27.1,
40.3, 51.8, 63.3, 67.0, 136.0, 136.4, 138.6, 144.1, 170.9, 185.4,
= +178.1 (c = 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.34
(d, J = 6.3 Hz, 3 H, CH3), 1.48 (d, J = 6.6 Hz, 3 H, CH3), 2.1
(dddd, J = 18.6, 14.4, 10.2, 4.2 Hz, 1 H, CH), 2.60 (dt, J = 18.6,
2.7 Hz, 1 H, CH), 3.52–3.59 (m, 1 H, CH), 4.66–4.70 (m, 1 H, CH),
6.67 (d, J = 9.9 Hz, 1 H, olefinic CH), 6.73 (d, J = 10.2 Hz, 1 H,
olefinic CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.6, 21.1,
29.8, 68.6, 69.5, 135.7, 136.9, 140.3, 144.2, 186.2, 186.3 ppm. IR
186.0 ppm. IR (CHCl ): ν = 2931, 1739, 1656, 1438, 1213,
˜
3
1159 cm–1. MS: m/z = 250 [M]+. C13H14O5 (250.25): calcd. C 62.39,
H 5.64; found C 62.44, H 5.71.
(+)-Methyl 2-[(1R,3R)-1-Methyl-5,10-dioxo-3,4,5,10-tetrahydro-
1H-naphtho[2,3-c]pyran-3-yl]acetate (6b): Compound (+)-6b
(49 mg, 78%) was prepared from quinone 11 (53 mg, 0.21 mmol)
as a pale-yellow solid by using a known procedure.[4a] Rf = 0.5
(EtOAc/hexane, 2:8). [α]2D5 = +37.0 (c = 0.30, CHCl3). M.p. 184–
(CHCl ): ν = 2926, 1654, 1600, 1462, 1386, 1170 cm–1. MS: m/z =
˜
3
192 [M]+. C11H12O3 (192.21): calcd. C 68.74, H 6.29; found C
68.82, H 6.34.
186 °C (ref.[4a] 185–187 °C). 1H NMR (300 MHz, CDCl3): δ = 1.56 (+)-(1R,3R)-1,3-Dimethyl-3,4-dihydro-1H-benzo[c]pyran-5,8-d-ione
(d, J = 6.9 Hz, 3 H, CH3), 2.35 (dddd, J = 19.2, 12.6, 10.8, 2.1 Hz,
1 H, CH), 2.65–2.68 (m, 2 H, CH2), 2.82 (dd, J = 18.9, 3.6 Hz, 1
(19b): Compound 19b (57 mg, 78%) was prepared as a yellow crys-
talline solid from 22b (85 mg, 0.38 mmol) by using the same pro-
H, CH), 3.75 (s, 3 H), 4.29–4.38 (m, 1 H, CH), 5.02 (q, J = 6.6 Hz, cedure as that described for 19a. Rf = 0.4 (EtOAc/hexane, 1.0:9.0).
1 H, CH), 7.71–7.74 (m, 2 H, ArH), 8.05–8.09 (m, 2 H, ArH) ppm.
[α]2D6 = +145.9 (c = 1.0, CHCl3). M.p. 123–125 °C (ref.[4a] 100–
105 °C). H NMR (300 MHz, CDCl3): δ = 1.32 (d, J = 6.0 Hz, 3
1
13C NMR (75 MHz, CDCl3): δ = 19.3, 27.1, 40.4, 51.8, 63.4, 67.4,
126.2, 131.7, 131.9, 133.6, 133.7, 140.9, 146.3, 171.0, 183.0, H, CH3), 1.46 (d, J = 6.9 Hz, 3 H, CH3), 2.11 (d, J = 19.2, 12.3,
183.7 ppm. IR (CHCl ): ν = 3020, 2928, 1734, 1662, 1438, 1215, 10.2, 2.4 Hz, 1 H, CH), 3.89–3.99 (m, 1 H, CH), 4.83 (q, J =
˜
3
1074 cm–1. MS: m/z = 300 [M]+. C17H16O5 (300.31): calcd. C 67.99,
H 5.37; found C 68.06, H 5.42.
6.9 Hz, 1 H, CH), 6.69 (d, J = 10.2 Hz, 1 H, olefinic CH), 6.74 (d,
J = 10.2 Hz, 1 H, olefinic CH) ppm. 13C NMR (75 MHz, CDCl3):
δ = 19.5, 21.3, 29.2, 62.4, 66.8, 136.0, 136.4, 139.3, 144.1, 185.7,
(+)-(1R,3S)- and (+)-(1S,3S)-5,8-Dimethoxy-1,3-dimethyl-3,4-dihy-
dro-1H-benzo[c]pyran (22a and 22b): To a stirred solution of (S)-
20b[14b] (122 mg, 0.62 mmol) and 1,1Ј-diethoxyethane (267 µL,
1.86 mmol) in CH2Cl2 (5 mL) was slowly added BF3·Et2O (118 µL,
0.93 mmol) at 0 °C, and the mixture was stirred at room tempera-
ture for 3.5 h. Saturated aqueous NaHCO3 was added, and mixture
was extracted with CH2Cl2 (3ϫ15 mL). The combined organic ex-
tract was washed with brine, dried with anhydrous Na2SO4, and
concentrated under reduced pressure to afford a mixture of 22a
and 22b, which was purified by column chromatography (EtOAc/
hexane, 0.1:9.9) to give nonpolar cis-isomer 22a (30 mg, 21%) as a
white solid. Rf = 0.52 (EtOAc/hexane, 0.5:9.5). M.p. 64–66 °C.
[α]2D6 = +224.0 (c = 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ =
186.3 ppm. IR (CHCl ): ν = 2983, 2935, 2854, 1660, 1597, 1311,
˜
3
1138, 985, 844 cm–1. MS: m/z = 192 [M]+. C11H12O3 (192.21):
calcd. C 68.74, H 6.29; found C 68.85, H 6.36.
(+)-(1R,3S)-1,3-Dimethyl-3,4-dihydro-1H-naphtho-[2,3-c]pyran-
5,10-dione (7):[11] Compound (+)-7 (20 mg, 80 %) was prepared
from 19a (20 mg, 0.10 mmol) as a yellow solid by using a known
procedure,[4a] Rf = 0.52 (EtOAc/hexane, 1.5:8.5). [α]2D6 = +248.1 (c
= 0.10, CHCl3) {ref.[11] [α]2D0 = +227.2 (c = 0.10, CHCl3)}. M.p.
121–123 °C (ref.[4a] 122–125 °C). 1H NMR (300 MHz, CDCl3): δ =
1.38 (d, J = 6.6 Hz, 3 H, CH3), 1.55 (d, J = 6.3 Hz, 3 H, CH3),
2.27 (dddd, J = 18.0, 14.4, 9.9, 3.6 Hz, 1 H, CH), 2.79 (dd, J =
19.2, 2.7 Hz, 1 H, CH), 3.55–3.66 (m, 1 H, CH), 4.07–4.90 (m, 1
Eur. J. Org. Chem. 2010, 4442–4449
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4447

R. T. Sawant, S. G. Jadhav, S. B. Waghmode
FULL PAPER
H, CH), 7.26–7.75 (m, 2 H, ArH), 8.02–8.10 (m, 2 H, ArH) ppm.
(+)-(S)-3-Methyl-3,4-dihydro-1H-naphtho[2,3-c]pyran-5,10-dione
(25): A solution of quinone 24 (115 mg, 0.64 mmol) and -acet-
oxybutadiene (361 mg, 3.23 mmol) in toluene (1.2 mL) was kept at
room temperature for 48 h. The mixture was evaporated to dryness
under reduced pressure, and the obtained oil was dissolved in
EtOH (7 mL). To this solution was added 1% aqueous Na2CO3
solution (1.5 mL), and the mixture was stirred at room temperature
for 5 h, diluted with water, and extracted with EtOAc (3ϫ15 mL).
The combined organic layer was washed with brine, dried with an-
hydrous Na2SO4, and concentrated under reduced pressure, and the
residue was purified by column chromatography (EtOAc/hexane,
0.7:9.3) to afford (+)-25 (126 mg, 85%) as a yellow solid. Rf = 0.5
(EtOAc/hexane, 2:8). [α]2D6 = +251.7 (c = 0.2, CHCl3). M.p. 168–
170 °C. 1H NMR (300 MHz, CDCl3): δ = 1.38 (d, J = 6.6 Hz, 3
H, CH3), 2.24–2.36 (m, 1 H), 2.75 (dt, J = 19.2, 2.7 Hz, 1 H, CH),
3.64–3.74 (m, 1 H, CH), 4.52 (dt, J = 19.2, 3.9 Hz, 1 H, CH), 4.84
(dd, J = 18.3, 1.8 Hz, 1 H, CH), 7.68–7.75 (m, 2 H, ArH), 8.03–
8.09 (m, 2 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.2,
29.4, 63.2, 69.5, 126.0, 126.2, 126.3, 131.7, 131.8, 133.7, 141.8,
13C NMR (75 MHz, CDCl3): δ = 20.8, 21.2, 30.3, 68.7, 70.0, 126.2,
131.7, 132.4, 133.7, 142.5, 146.7, 183.9, 184.0 ppm. IR (CHCl ): ν
˜
3
= 2931, 1662, 1593, 1458, 1292, 1128 cm–1. MS: m/z = 242 [M]+.
C15H14O3 (242.27): calcd. C 74.36, H 5.82; found C 74.45, H 5.87.
The physical and spectroscopic data of 7 are in accordance with
the literature data.[11]
(+)-(1R,3R)-1,3-Dimethyl-3,4-dihydro-1H-naphtho[2,3-c]pyran-
5,10-dione (8): Compound (+)-8 (25 mg, 82%) was prepared as a
yellow solid from 19b (24 mg, 0.12 mmol) by using a known pro-
cedure.[4a] Rf = 0.60 (EtOAc/hexane, 2:8). [α]2D6 = +66.3 (c = 0.12,
CHCl3). M.p. 147–149 °C (ref.[4a] 146–148 °C). 1H NMR
(300 MHz, CDCl3): δ = 1.36 (d, J = 6.0 Hz, 3 H, CH3), 1.54 (d, J
= 7.2 Hz, 3 H, CH3), 2.26 (dddd, J = 19.5, 12.3, 9.9, 2.4 Hz, 1 H,
CH), 2.76 (dd, J = 19.5, 3.6 Hz, 1 H, CH), 3.99–4.03 (m, 1 H, CH),
5.02 (q, J = 6.8 Hz, 1 H, CH), 7.27–7.73 (m, 2 H, ArH), 8.05–8.09
(m, 2 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.6, 21.4,
29.8, 62.4, 67.1, 126.2, 131.7, 132.0, 133.6, 133.7, 141.6, 146.3,
183.2, 184.0 ppm. IR (CHCl ): ν = 2929, 1658, 1593, 1460, 1327,
˜
3
1180 cm–1. MS: m/z = 242 [M]+. C15H14O3 (242.27): calcd. C 74.36,
142.3, 183.3, 183.6 ppm. IR (CHCl ): ν = 2924, 2854, 1658, 1591,
˜
3
1452, 1296, 1074 cm–1. MS: m/z = 228 [M]+. C14H12O3 (228.24):
H 5.82; found C 74.46, H 5.89.
calcd. C 73.67, H 5.30; found C 73.73, H 5.35.
(+)-(S)-5,8-Dimethoxy-3-methyl-3,4-dihydro-1H-benzo[c]pyran (23):
To a precooled (0 °C) solution of (+)-alcohol 20b (200 mg,
1.02 mmol) and methoxymethyl chloride (232 µL, 3.06 mmol) in
dry diethyl ether (15 mL) was added anhydrous ZnCl2 (41 mg,
0.30 mmol) under an atmosphere of nitrogen, and the mixture was
stirred at room temperature for 4 h. To this reaction mixture was
added water, and the mixture was stirred for 10 min and then ex-
tracted with EtOAc (3ϫ25 mL). The combined extract was washed
with aqueous NaHCO3 solution, water, and brine, dried with
Na2SO4, and concentrated under reduced pressure. The crude
product was purified by column chromatography (EtOAc/hexane,
0.6:9.4) to give (+)-23 (175 mg, 82%) as a colorless solid. Rf = 0.5
(EtOAc/hexane, 1.5:8.5). [α]2D6 = +149.9 (c = 1.0, CHCl3). M.p. 49–
51 °C (ref.[20] 68–69 °C). 1H NMR (300 MHz, CDCl3): δ = 1.35 (d,
J = 6.0 Hz, 3 H, CH3), 2.39 (dd, J = 16.5, 10.8 Hz, 1 H, CH), 2.75
(dd, J = 17.1, 3.3 Hz, 1 H, CH), 3.65–3.72 (m, 1 H, CH) 3.74 (s, 3
H, OCH3), 3.76 (s, 3 H, OCH3), 4.59 (d, J = 15.9 Hz, 1 H, CH),
4.92 (d, J = 15.9 Hz, 1 H, CH), 6.58 (d, J = 8.7 Hz, 1 H, ArH),
6.63 (d, J = 8.7 Hz, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3):
δ = 21.6, 30.2, 55.3, 55.4, 64.4, 69.9, 106.6, 107.3, 123.8, 124.5,
(+)-(1R,3S)-1-Hydroxy-3-methyl-3,4,5,10-tetrahydro-1H-naphtho-
[2,3-c]pyran-5,10-dione (9):[11,15c] To a solution of pyran 25 (55 mg,
0.21 mmol) in CCl4 (35 mL) was added bromine (11.3 µL,
0.21 mmol) in CCl4 (1 mL) at room temperature, and the mixture
was irradiated with 300 W tungsten lamp for 30 min. The reaction
mixture was cooled to room temperature and concentrated under
reduced pressure. To this obtained residue was added THF (10 mL)
and water (2 mL), and the mixture was stirred for 1 h at room tem-
perature, diluted with water, and extracted with EtOAc
(3ϫ20 mL). The combined organic layer was washed with brine,
dried with anhydrous Na2SO4, and concentrated, and the residue
was purified by column chromatography (EtOAc/hexane, 1.6:8.4)
to give (+)-9 (42 mg, 77%) as a yellow solid. Rf = 0.3 (EtOAc/
hexane, 2.5:7.5). [α]2D6 = +138.8 (c = 0.80, CH2Cl2) {ref.[15c] [α]2D0
=
+29.5 (c = 0.80, CH2Cl2); ref.[11] [α]2D0 = +139.3 (c = 0.76, CH2Cl2)}.
M.p. 160–162 °C (ref.[11,15c] 161–162 °C). 1H NMR (300 MHz,
CDCl3): δ = 1.40 (d, J = 6.7 Hz, 3 H, CH3), 2.27 (dd, J = 19.2,
10.8 Hz, 1 H, CH), 2.78 (dd, J = 19.5, 3.3 Hz, 1 H, CH), 3.63 (br.
s, 1 H, OH), 4.30–4.39 (m, 1 H, CH), 6.07 (br. s, 1 H, CH), 7.74–
7.78 (m, 2 H, ArH), 8.09–8.13 (m, 2 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 20.9, 29.3, 62.6, 86.8, 126.3, 131.8, 133.8,
149.3, 150.7 ppm. IR (CHCl ): ν = 2935, 1604, 1485, 1257,
˜
3
1072 cm–1. MS: m/z = 208 [M]+. C12H16O3 (208.25): calcd. C 69.21,
134.0, 140.2, 143.5, 183.2, 184.3 ppm. IR (CHCl ): ν = 3421, 2980,
˜
3
H 7.74; found C 69.25, H 7.78.
2928, 1668, 1591, 1446, 1290, 1076 cm–1. MS: m/z = 244 [M]+.
C14H12O4 (244.24): calcd. C 68.85, H 4.95; found C 68.89, H 5.01.
The physical and spectroscopic data of 9 are in accordance with
the literature data.[11,15c]
(+)-(S)-3-Methyl-3,4-dihydro-1H-benzo[c]pyran-5,8-dione (24): To a
precooled (0 °C) solution of (+)-23 (152 mg, 0.73 mmol) in CH3CN
(9 mL) was added dropwise a solution of CAN (1.2 g, 2.19 mmol)
in water (3 mL). The mixture was stirred at the same temperature
for 20 min and then diluted with water and extracted with ethyl
acetate (3ϫ10 mL). The combined layer was dried with Na2SO4
and concentrated under reduced pressure. The crude product was
purified by column chromatography (EtOAc/hexane, 0.7:9.3) to af-
ford (+)-24 (120 mg, 92%) as a yellow solid. Rf = 0.5 (EtOAc/hex-
ane, 2:8). [α]2D6 = +270.8 (c = 0.5, CHCl3). M.p. 101–103 °C (ref.[20]
Acknowledgments
R.T.S. is thankful to the Council of Scientific and Industrial Re-
search (CSIR), New Delhi, for a senior research fellowship. We
are grateful to the Board of College and University Development
(BCUD) and the Shimadzu Analytical Centre, University of Pune
for financial support and spectroscopic data, respectively.
1
89–91 °C). H NMR (300 MHz, CDCl3): δ = 1.36 (d, J = 6.0 Hz,
3 H, CH3), 2.12–2.24 (m, 1 H, CH), 2.58 (d, 19.2, 2.7 Hz, 1 H,
CH), 3.60–3.69 (m, 1 H, CH), 4.38 (dt, J = 18.3, 2.7 Hz, 1 H, CH),
4.68 (dt, J = 18.3, 2.7 Hz, 1 H, CH), 6.68 (d, J = 10.2 Hz, 1 H,
olefinic CH), 6.73 (d, J = 10.2 Hz, 1 H, olefinic CH) ppm. 13C
NMR (75 MHz, CDCl3): δ = 21.1, 28.8, 62.7, 69.4, 136.0, 136.3,
[1] For a reviews on isolation, structure, and synthesis of pyrano-
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139.5, 140.2, 185.7, 186.0 ppm. IR (CHCl ): ν = 2945, 1658, 1597,
˜
3
1402, 1143 cm–1. MS (EI): m/z = 179 [M + 1]+. C10H10O3 (178.18):
calcd. C 67.41, H 5.66; found C 67.50, H 5.73.
4448
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Eur. J. Org. Chem. 2010, 4442–4449

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Received: April 8, 2010
Published Online: June 23, 2010
Eur. J. Org. Chem. 2010, 4442–4449
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4449