Synthesis of chiral oxa- and azacycle-fused anthraquinone derivatives

Article abstract of DOI:10.1016/j.tetasy.2010.02.001

A convenient protocol for the synthesis of chiral pyran and piperidine ring-fused anthraquinone derivatives has been developed from (R)-2,3-O-cyclohexylidene-glyceraldehyde using sequential applications of enyne metathesis, Diels-Alder reaction and aromat

Full text of DOI:10.1016/j.tetasy.2010.02.001

Tetrahedron: Asymmetry 21 (2010) 232–236
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of chiral oxa- and azacycle-fused anthraquinone derivatives
*
Tanmoy Biswas, Titas Biswas, Shital K. Chattopadhyay
Department of Chemistry, University of Kalyani, Kalyani 741 235, West Bengal, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient protocol for the synthesis of chiral pyran and piperidine ring-fused anthraquinone deriva-
tives has been developed from (R)-2,3-O-cyclohexylidene-glyceraldehyde using sequential applications
of enyne metathesis, Diels–Alder reaction and aromatization as key steps.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 8 December 2009
Accepted 2 February 2010
Available online 26 February 2010
1. Introduction
thenium(IV) dichloride 8 in refluxing benzene. The reaction pro-
ceeded well to provide the desired diene 9 as only isolable
Anthraquinones embellished with a carbocyclic or heterocyclic
ring are important compounds due to their natural occurrence and
impressive levels of biological activities including antiproliferative
properties.1 Anthracyclines2 and anthrapyran antibiotics3 broadly
represent the two different classes of such compounds. Because
of their importance, extensive synthetic efforts have been ex-
pended over several decades towards their syntheses. Moreover,
a large number of simplified analogues of natural anthraquinones
have been synthesized and evaluated.4 A notable feature of some
important members belonging to these two classes is the presence
of a chiral side chain attached to the carbocyclic or heterocyclic
ring appended to the anthraquinone nucleus, for example, in
compounds such as doxorubicin5 1, espicofulin6 2 and pluraflavin
A7 3 (Fig. 1). In continuation of our work on the synthesis of ana-
logues of anthracyclines,8 herein we describe a synthetic route
to two oxa- and azacycle-fused chiral anthraquinone derivatives
of the type 4 which combines some of the structural features of
1–3.
product but in somewhat moderate yield (58%). The Diels–Alder
cycloaddition of vinylcycloalkenes has been extensively studied
both as a convenient means for assembling complex architectures
and a mechanistic probe for testing endo–exo selectivity.12 We ob-
served that cycloaddition of 9 with 1,4-naphthoquinone proceeded
smoothly in refluxing toluene to provide the cycloadduct 10 in
good yield but as an inseparable mixture of isomers, presumably
as exo- and endo-diastereoisomers.13 Moreover, compound 10 de-
graded considerably during attempted purification by silica gel
chromatography. However, this mixture of isomers could be effec-
tively aromatized by treatment with triethylamine in the presence
of silica gel under aerobic conditions. The desired anthraquinone
derivative 11 was obtained in a 47% yield over a two-step one-
pot conversion. Deprotection of the cyclohexylidene group in com-
pound 11 proceeded uneventfully under conventional conditions
and the diol 12 was obtained as a yellowish amorphous powder
in very good yield. The synthesis of the chiral anthrapyran deriva-
tive 12 proceeded in an overall yield of 10.1% over six steps starting
from 5.
We then concentrated on the preparation of an aza-analogue
of compound 12 from the common intermediate 6. Thus, the lat-
ter was converted to the corresponding mesylate 13 (Scheme 2)
and thence to the azide 14 under conventional conditions. Reduc-
tion of the azido group in 14 with LiAlH4 proceeded smoothly and
the intermediate crude amine was treated with p-toluenesulfonyl
chloride to prepare the corresponding p-toluenesulfonamide
derivative 15 which was obtained in a combined yield of 74% over
two steps. N-Alkylation of the latter with propargyl bromide
using NaH as a base then neatly provided the N-tethered enyne
derivative 16 in very good yield. The sequence of events de-
scribed for the preparation of the anthrapyran derivative 12 from
the enyne 7 was then repeated on compound 16. Thus, ring-clos-
ing metathesis of 16 with the catalyst 8 proceeded sluggishly in
refluxing benzene and the vinylcycloalkene derivative 17 was ob-
tained as the only isolable product in an acceptable yield (64%).
2. Results and discussion
Our synthesis started from (R)-2,3-O-cyclohexylidene-glyceral-
dehyde 5 (Scheme 1) which on treatment with allylzinc bromide,
following literature precedent,9 provided the known homoallyl
alcohol 6 as the major product. The latter upon alkylation with
propargyl bromide led to smooth formation of the corresponding
ether 7. We surmised that a metathesis reaction10 of the oxygen-
tethered enyne 7 should provide access to the corresponding vinyl-
cycloalkene 9 onto which an anthraquinone moiety could possibly
be built upon through a Diels–Alder reaction with 1,4-naphthoqui-
none. Accordingly, compound 7 was treated with Grubbs’ first
generation catalyst11 benzylidene bistricyclohexylphosphinoru-
* Corresponding author. Tel.: +91 33 25828750; fax: +91 33 25828282.
E-mail address: skchatto@yahoo.com (S.K. Chattopadhyay).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.02.001

T. Biswas et al. / Tetrahedron: Asymmetry 21 (2010) 232–236
233
H
O
HO
Me
OH
Me
O
O
O
X
O
O
OH
O
OH
O
O
O
OH
O
O
O
OH
O
OH
OMe
OH OH
OH
OH
doxorubicin 1
espicufolin 2
pluraflavin A 3
4, X = O, NR
Figure 1.
i
ii
iii
O
O
O
O
O
O
O
O
OH
O
O
O
6
9
5
7
O
OH
O
O
HO
H
O
H
O
O
O
iv
O
v
vi
O
O
O
O
O
12
11
10
Scheme 1. Reagents and conditions: (i) allyl zincbromide, THF, 0 °C to rt, 12 h; (ii) NaH, propargyl bromide, THF + DMSO, 0 °C to rt, 18 h; (iii) Grubbs’ catalyst 8 (5 mol %),
benzene, reflux, 20 h; (iv) 1,4-naphthaquinone, benzene, reflux, 24 h; (v) Et3N, silica gel, O2 (air),CHCl3, rt, 7 h; (vi) HCl, THF, rt, 5 h.
Diels–Alder reaction of the latter with 1,4-naphthoquinone simi-
larly provided the cycloadduct 18 also as a mixture of inseparable
diastereomers. Subsequent aromatization of the latter using the
Et3N/silica gel protocol then neatly provided the corresponding
anthraquinone derivative 19. Acid-catalyzed deprotection of the
cyclohexylidene moiety in the latter then liberated the diol 20.
The synthesis of the piperidine ring-fused anthraquinone deriva-
tive 20 from the common intermediate 6 proceeded in an overall
yield of 9.5% over eight steps.
4. Experimental
4.1. General
Optical rotations were recorded in spectroscopic grade chloro-
form on a Jasco DIP-370 polarimeter, [a] values are recorded in
D
units of 10À1 deg cm2 gÀ1. Infrared spectra were recorded on a Per-
kin–Elmer Spectrum-1 spectrophotometer purchased through a
DST-FIST grant. Proton and carbon NMR spectra were recorded
on a Bruker DRX-300 spectrometer as a paid service from I.I.C.B.,
Kolkata. Chemical shifts are recorded relative to residual solvent
or TMS as a standard. Mass spectra were recorded on a JEOL-JMS
600 instrument from I. I. C. B., Kolkata or IACS, Kolkata. Petroleum
ether refers to the fraction boiling in the range 60–80 °C. Silica gel
(60–120 mesh) for column chromatography was purchased from
Spectrochem, India.
3. Conclusion
In brief, we have developed a concise synthetic route to chiral
pyran and piperidine ring-fused anthraquinone derivatives of
resemblance to some notable natural products. The methodology
involves use of easily available starting materials, less expensive
reagents and easy to perform experiments. The compounds
prepared may prove to be biologically relevant and the methodol-
ogy may prove to be adaptable for the synthesis of similar
compounds.
4.1.1. (1S)-1-[(2R)-1,4-Dioxaspiro[4.5]dec-2-yl]-3-butenyl (2-
propynyl) ether 7
A solution of 6 (0.40 g, 1.88 mmol) in dry THF (5 ml) was added
dropwise to a stirred suspension of NaH (0.14 g, 5.83 mmol) in a

234
T. Biswas et al. / Tetrahedron: Asymmetry 21 (2010) 232–236
i
v
iii
iv
ii
O
O
O
O
6
O
O
O
O
NHTs
OMs
N3
14
TsN
13
16
15
O
O
H
O
O
NTs
viii
O
vi
vii
O
O
O
O
O
TsN
TsN
19
17
18
OH
HO
H
O
O
NTs
ix
20
Scheme 2. Reagents and conditions: (i) MsCl, Et3N, CH2Cl2, 0 °C to rt, 24 h; (ii) NaN3, DMF, 80 °C, 36 h; (iii) LiAlH4, Et2O, 0 °C to rt, 8 h; (iv) TsCl, pyridine, CH2Cl2, rt, 18 h; (v)
NaH, propargyl bromide, THF + DMSO, 0 °C to rt, 18 h; (vi) Grubbs’ catalyst 8 (5 mol %), benzene, reflux, 24 h; (vii) 1,4-naphthaquinone, benzene, reflux, 24 h; (viii) Et3N, silica
gel, O2 (air), CHCl3, rt, 7 h; (ix) HCl, THF, rt, 9 h.
mixture of anhydrous THF + DMSO (20 ml, 10:1) at 0 °C under
nitrogen atmosphere. The reaction mixture was allowed to come
to room temperature and stirred for 40 min. A solution of propar-
gyl bromide (0.34 g, 2.9 mmol) in anhydrous THF (2 ml) was then
added dropwise to the reaction mixture at 0 °C and stirring was
continued for 18 h at room temperature. The reaction was
quenched with saturated aqueous NH4Cl solution at 0 °C and then
the reaction mixture was extracted with ethyl acetate (2 Â 25 ml).
The combined organic layer was washed with water (2 Â 20 ml)
and brine (20 ml). It was then dried (Na2SO4), filtered and the
filtrate was concentrated in vacuo to leave the crude product
which on chromatography (silica gel, ethyl acetate–petroleum
4.1.2. (2R)-2-[(2S)-5-Vinyl-3,6-dihydro-2H-2-pyranyl]-1,4-
dioxaspiro[4.5]decane 9
Grubbs, catalyst 8 (16 mg, 5 mol %) was added to a stirred solu-
tion of the propargyl ether 7 (0.10 g, 0.4 mmol) in dry degassed ben-
zene (10 ml), under an argon atmosphere and the homogeneous
mixture was heated at reflux for 20 h. It was then concentrated in
vacuo to leave a crude product which on chromatography (silica
gel, ethyl acetate–petroleum ether, 1:9) provided the product 9 as
a colourless liquid (0.058 g, 58%). [
a]
D = +12 (c 0.09, CHCl3). IR
(neat): 2935, 1651, 1606, 1101 cmÀ1
.
1H NMR (300 MHz, CDCl3): d
6.25 (1H, dd, J = 11.0, 18.0), 5.85 (1H, br s), 4.94 (1H, d, J = 11.0),
4.89 (1H, d, J = 18.0), 4.45–4.26 (2H, m), 4.10–4.02 (3H, m), 3.95–
3.93 (2H, m), 3.46–3.39 (1H, m), 1.59–1.40 (10H, m). 13C NMR
(75 MHz, CDCl3): d 135.7, 134.7, 125.2, 110.8, 109.9, 77.5, 74.9,
66.9, 65.4, 36.4, 34.8, 28.0, 25.1, 24.0, 23.8. MS (TOF MS ES+): m/z
(%) = 273 (M++Na, 100). Anal. Calcd for C15H22O3: C, 71.97; H, 8.86.
Found: C, 72.26; H, 9.02.
ether, 1:19) provided the product
(0.367 g, 78%). [ D = +24 (c 0.13, CHCl3). IR (neat): 3302, 2936,
2117, 1641, 1099 cmÀ1 1H NMR (300 MHz, CDCl3): d 5.92–5.83
7 as a colourless liquid
a]
.
(1H, m), 5.15–5.07 (2H, m), 4.27 (2H, s), 4.07–3.99 (2H, m),
3.96–3.88 (1H, m), 3.70–3.59 (1H, m), 2.42 (1H, t, J = 2.5),
2.38–2.33 (2H, m), 1.61–1.56 (10H, m). 13C NMR (75 MHz, CDCl3):
d 134.0, 117.6, 109.7, 80.0, 78.2, 76.6, 74.3, 65.9, 57.6, 36.2, 35.4,
34.9, 25.2, 24.0, 23.8. MS (TOF MS ES+): m/z (%) = 273
(M++Na, 100). Anal. Calcd for C15H22O3: C, 71.97; H, 8.86. Found:
C, 72.19; H, 8.99.
4.1.3. (2S)-2-[(2R)-1,4-Dioxaspiro[4.5]dec-2-yl]-1,4,7,12-
tetrahydro-2Hnaphtho[2,3-f]isochromene-7,12-dione 11
A solution of the diene 9 (0.054 g, 0.22 mmol) and 1,4-naphtha-
quinone (0.041 g, 0.26 mmol) in anhydrous benzene (4 ml) was

T. Biswas et al. / Tetrahedron: Asymmetry 21 (2010) 232–236
235
heated at reflux for 24 h. It was then concentrated in vacuo to leave
a crude product which was taken in anhydrous CHCl3 (2 ml). The
resulting solution was then stirred with silica gel (60–120 mesh,
1.5 g) and Et3N (0.44 g, 4.3 mmol) under aerobic conditions for
7 h. It was then filtered and the filtrate was concentrated in vacuo
to leave a crude product which on chromatography (silica gel, ethyl
acetate–petroleum ether, 1:9) provided the product 11 as a pale
combined organic layer was washed successively with H2O
(2 Â 25 ml) and brine (25 ml). It was then dried (Na2SO4), filtered
and the filtrate was concentrated in vacuo to leave a crude product
which was purified by column chromatography on silica gel (ethyl
acetate–petroleum ether, 1:49) to provide the product 14 as a col-
ourless liquid (0.29 g, 71%). [
a]
D = À25 (c 0.1, CHCl3). IR (neat):
2937, 2112, 1102, 927 cmÀ1 1H NMR (300 MHz, CDCl3): d 5.88–
.
yellow solid (0.041 g, 47%), mp 182–183 °C. [
a
]
D = À19 (c 0.12,
5.79 (1H, m), 5.22–5.14 (2H, m), 4.13 (1H, q, J = 6.5), 4.04 (1H,
dd, J = 6.5, 8.5), 3.77 (1H, dd, J = 6.5, 8.0), 3.3 (1H, q, J = 6.5), 2.35–
2.30 (2H, m), 1.72–1.57 (10H, m). 13C NMR (75 MHz, CDCl3): d
133.3, 118.4, 110.5, 77.5, 66.0, 62.7, 36.0, 35.2, 34.7, 25.1, 23.9,
23.8. MS (TOF MS ES+): m/z (%) = 260 (M++Na, 100).
CHCl3). IR (KBr): 2932, 1670, 1286 cmÀ1 1H NMR (500 MHz,
.
DMSO-d6): d 8.13 (2H, dd, J = 5.5, 8.5), 8.07 (1H, d, J = 8.0), 7.90–
7.87 (2H, m), 7.56 (1H, d, J = 8.0), 4.93 (1H, d, J = 16.0) 4.86 (1H,
d, J = 16.0), 4.13–4.09 (2H, m), 3.91 (1H, dd, J = 4.5, 7.5), 3.58–
3.55 (2H, m), 3.07 (1H, dd, J = 11.5, 18.5), 1.61–1.51 (8H, m),
1.09–1.06 (2H, m). 13C NMR (125 MHz, DMSO-d6): d 186.0, 184.1,
144.2, 137.4, 136.1, 135.8, 135.5, 134.5, 133.6, 132.1, 131.8,
128.4, 127.6, 126.4, 110.8, 78.7, 76.5, 69.3, 67.5, 37.4, 36.0, 32.4,
26.2, 25.2, 25.0. HRMS (FAB): m/z calcd for C25H24O5 (M+):
404.1624. Found: 404.1622.
4.1.7. (1R)-1-[(2S)-1,4-Dioxaspiro[4.5]dec-2-yl]-3-butenyl-4-
methyl-1-benzene-sulfonamide 15
A solution of the azide 14 (2.37 g, 10.0 mmol) in dry ether
(12 ml) was added dropwise over 25 min to a suspension of lith-
ium aluminium hydride (0.76 g, 20 mmol) in dry ether (12 ml) at
0 °C under nitrogen atmosphere. The reaction mixture was allowed
to come to room temperature and stirred for 8 h. It was cooled to
0 °C and then slowly quenched with aqueous NaOH solution
(2.5 M, 10 ml). The ether layer was separated and the thick aque-
ous layer was triturated with ether (25 ml). The combined organic
extract was washed successively with H2O (2 Â 25 ml) and brine
(25 ml). It was then dried (Na2SO4), filtered and the filtrate was
concentrated in vacuo to leave a crude product. The latter was dis-
solved in dichloromethane (50 ml) and then treated with p-tolu-
enesulfonyl chloride (2.28 g, 12 mmol) and dry pyridine (1.5 ml,
18.5 mmol) at room temperature for 18 h. The reaction mixture
was then washed successively with HCl (1 M, 2 Â 25 ml), H2O
(2 Â 25 ml) and brine (25 ml). It was then dried (Na2SO4), filtered
and the filtrate was concentrated in vacuo to leave a crude product
which was purified by column chromatography on silica gel (ethyl
acetate–petroleum ether, 1:9) to provide the product 15 as a vis-
4.1.4. (2S)-2-[(1R)-1,2-Dihydroxyethyl]-1,4,7,12-tetrahydro-2H-
naphtho[2,3-f]isochromene-7,12-dione 12
A solution of the acetal derivative 11 (0.05 g, 0.12 mmol) in tet-
rahydrofuran (3 ml) was stirred with HCl (6 N, 3 ml) for 5 h at
room temperature. It was then diluted with water (10 ml) and
the precipitated solid was filtered, washed with H2O (10 ml) and
dried in vacuo. It was then recrystallized from methanol to provide
the product 12 as a pale yellow solid (0.028 g, 71%), mp 235–
237 °C. [
a
]
D = À6 (c 0.75, DMF). IR (KBr): 3357, 1668, 1587, 1326,
1288 cmÀ1
.
1H NMR (400 MHz, DMSO-d6): d 8.14 (2H, d, J = 2.0),
8.08 (1H, d, J = 8.0), 7.92–7.90 (2H, m), 7.58 (1H, d, J = 8.0), 4.98–
4.92 (2H, m), 4.86–4.80 (1H, m), 4.59 (1H, t, J = 5.5), 3.62–3.57
(5H, m), 3.19 (1H, dd, J = 10.0, 19.0). 13C NMR (100 MHz, DMSO-
d6): d 184.5, 182.7, 142.9, 137.0, 134.5, 134.4, 133.9, 133.0, 132.1,
130.6, 130.1, 126.8, 126.1, 124.7, 74.6, 73.6, 67.9, 62.8, 29.4. MS
(TOF MS ES+): m/z (%) = 347 (M++Na, 100). Anal. Calcd for
C19H16O5: C, 70.36; H, 4.97. Found: C, 70.49; H, 5.12.
cous liquid (2.70 g, 74% over two steps). [
a
]
D = +3.3 (c 0.5, CHCl3).
.
IR (neat): 3286, 2934, 1642, 1330, 1162 cmÀ1
1H NMR (300 MHz,
CDCl3): d 7.74 (2H, d, J = 8.0), 7.30 (2H, d, J = 8.0), 5.60–5.54 (1H,
m), 5.00–4.94 (2H, m), 4.70 (1H, d, J = 7.5), 4.14 (1H, dt, J = 3.0,
6.5), 3.89 (1H, dd, J = 6.5, 8.5), 3.59 (1H, dd, J = 7.0, 8.5), 3.31–
3.24 (1H, m), 2.43 (3H, s), 2.36–2.31 (1H, m), 2.19–2.17 (1H, m),
1.57–1.38 (10H, m). 13C NMR (75 MHz, CDCl3): d 143.4, 137.7,
133.3, 129.6, 127.0, 118.6, 109.8, 75.3, 65.5, 53.8, 37.2, 35.8, 34.4,
25.0, 23.9, 23.6, 21.5. MS (TOF MS ES+): m/z (%) = 388 (M++Na,
100). Anal. Calcd for C19H27NO4S: C, 62.44; H, 7.44; N, 3.83. Found:
C, 62.59; H, 7.60; N, 4.01.
4.1.5. (1S)-1-[(2R)-1,4-Dioxaspiro[4.5]dec-2-yl]-3-butenyl
methanesulfonate 13
Methanesulfonyl chloride (0.6 ml, 7.75 mmol) was added drop-
wise to a stirred solution of the alcohol 6 (0.81 g, 3.82 mmol) and
triethylamine (1.1 ml, 7.89 mmol) in dry dichloromethane (4 ml)
under nitrogen at 0 °C. The reaction mixture was allowed to come
to room temperature and stirred for 24 h. It was then diluted with
H2O (25 ml) and extracted with dichloromethane (2 Â 50 ml). The
combined organic layer was washed successively with HCl (1 M,
2 Â 50 ml), H2O (2 Â 50 ml) and brine (50 ml). It was then dried
(Na2SO4), filtered and the filtrate was concentrated in vacuo to
leave a crude product which on chromatography (silica gel, ethyl
acetate–petroleum ether, 1:19) provided the product 13 as a col-
4.1.8. N1-{(1R)-1-[(2S)-1,4-Dioxaspiro[4.5]dec-2-yl]-3-butenyl-
N1-(2-propynyl)-4-methyl-1-benzenesulfonamide 16
A solution of 15 (0.2 g, 0.55 mmol) in dry THF (1 ml) was added
to a stirred suspension of NaH (0.02 g, 0.82 mmol) in a mixture of
dry THF + DMSO (5 ml, 10:1), dropwise at 0 °C under nitrogen
atmosphere. The reaction mixture was allowed to come to room
temperature and stirred for 45 min. A solution of propargyl bro-
mide (0.42 g, 3.5 mmol) in dry THF (1 ml) was then added drop-
wise at 0 °C and the reaction mixture was stirred for 18 h at
room temperature. It was then slowly quenched with saturated
aqueous NH4Cl solution (5 ml) at 0 °C, diluted with H2O (20 ml)
and extracted with ethyl acetate (2 Â 25 ml). The combined organ-
ic layer was washed with H2O (2 Â 20 ml) and brine (20 ml). It was
then dried (Na2SO4), filtered and the filtrate was concentrated un-
der reduced pressure to leave a crude product which was purified
by column chromatography on silica gel (ethyl acetate–petroleum
ether, 1:19) to provide the product 16 as a colourless liquid
ourless liquid (0.964 g, 87%). [
a]D = +19 (c 0.12, CHCl3). IR (neat):
2938, 1364, 1177, 929 cmÀ1 1H NMR (300 MHz, CDCl3): d 5.91–
.
5.77 (1H, m), 5.23–5.17 (2H, m), 4.79 (1H, q, J = 6.0), 4.19 (1H, q,
J = 6.5), 4.05 (1H, t, J = 8.5), 3.91 (1H, dd, J = 7.0, 8.0), 3.05 (3H, s),
2.52 (2H, t, J = 7.0), 1.59–1.40 (10H, m). 13C NMR (75 MHz, CDCl3):
d 132.0, 119.4, 110.4, 80.7, 75.3, 64.9, 38.8, 36.3, 36.0, 34.7, 25.0,
23.9, 23.7. MS (TOF MS ES+): m/z (%) = 313 (M++Na, 100). Anal.
Calcd for C13H22O5S: C, 53.77; H, 7.64. Found: C, 53.91; H, 7.78.
4.1.6. (1R)-1-[(2S)-1,4-Dioxaspiro[4.5]dec-2-yl]-3-butenyl azide
14
Sodium azide (0.23 g, 3.54 mmol) was added to a stirred solu-
tion of the mesylate 13 (0.50 g, 1.72 mmol) in dry DMF (5 ml), un-
der nitrogen and the reaction mixture was stirred at 80 °C for 36 h.
It was allowed to come to room temperature, diluted with water
(25 ml) and then extracted with diethyl ether (3 Â 25 ml). The
(0.196 g, 89%). [
2121, 1642, 1340, 1161 cmÀ1
(2H , d, J = 8.0), 7.26 (2H, d, J = 8.0 Hz), 5.71–5.60 (1H, m), 5.08–
a]
D = +27 (c 0.1, CHCl3). IR (neat): 3290, 2936,
.
1H NMR (300 MHz, CDCl3): d 7.81

236
T. Biswas et al. / Tetrahedron: Asymmetry 21 (2010) 232–236
4.99 (2H, m), 4.31 (2H, dd, J = 2.5, 6.0), 4.26–4.19 (1H, m), 3.98–
3.87 (2H, m), 3.76 (1H, t, J = 8.0), 2.45–2.42 (5H, m), 2.12 (1H, t,
J = 2.5), 1.61–1.36 (10H, m). 13C NMR (75 MHz, CDCl3): d 143.3,
137.4, 134.0, 129.1, 127.8, 118.0, 109.4, 79.5, 75.6, 72.8, 66.2,
58.3, 35.9, 34.6, 34.5, 34.1, 25.0, 23.8, 23.7, 21.4. MS (TOF MS
ES+): m/z (%) = 426 (M++Na, 100). Anal. Calcd for C22H29NO4S: C,
65.48; H, 7.24; N, 3.47. Found: C, 65.64; H, 7.37; N, 3.54.
It was then diluted with H2O (10 ml) and extracted with ethyl ace-
tate (2 Â 25 ml). The combined organic extract was washed
sequentially with aqueous NaHCO3 solution (10%, 2 Â 20 ml),
H2O (20 ml) and brine (20 ml). It was then dried (Na2SO4), filtered
and the filtrate was concentrated in vacuo to leave a crude product
which was purified by column chromatography on silica gel (ethyl
acetate–petroleum ether, 3:7) to provide the product 20 as a yel-
lowish solid (0.033 g, 76%), mp 131–132 °C. [
a]
D = +22 (c 0.1,
4.1.9. (2R)-2-[(2S)-1,4-Dioxaspiro[4.5]dec-2-yl]-1-[(4-methyl-
phenyl)sulfonyl]-5-vinyl-1,2,3,6-tetrahydropyridine 17
CHCl3). IR (KBr): 3425, 1670, 1592, 1327, 1284, 1159 cmÀ1
.
1H
NMR (300 MHz, CDCl3): d 8.25–8.22 (1H, m), 8.19–8.16 (2H, m),
7.82–7.75 (2H, m), 7.56 (2H, d, J = 8.0), 7.45 (1H, d, J = 8.0), 7.10
(2H, d, J = 8.0), 4.79 (1H, d, J = 17.0), 4.66 (1H, d, J = 17.0), 4.31–
4.25 (1H, m), 3.84–3.81 (1H, m), 3.69–3.59 (2H, m), 3.54 (1H, dd,
J = 4.0, 18.0), 3.38 (1H, dd, J = 7.0, 18.0), 2.19 (3H, s), 1.83 (2H, br
s). 13C NMR (75 MHz, CDCl3): d 185.2, 182.8, 143.9, 140.3, 136.3,
135.7, 134.6, 134.3, 134.0, 133.9, 132.5, 131.5, 130.8, 130.0,
129.7, 127.2, 126.7, 125.9, 72.6, 63.3, 53.3, 46.0, 27.3, 21.3. MS
(TOF MS ES+): m/z (%) = 477 (27), 499 (M+À1+Na, 100), 500
(M++Na, 47). Anal. Calcd for C26H23NO6S: C, 65.39; H, 4.85; N,
2.93. Found: C, 65.56; H, 4.97; N, 3.14.
Catalyst 8 (15 mg, 5 mol %) was added to a stirred solution of
the enyne 16 (0.15 g, 0.37 mmol) in dry and degassed benzene
(10 ml) under an argon atmosphere and the homogeneous mixture
was heated at reflux for 24 h. It was then concentrated in vacuo to
leave a crude product which was purified by column chromatogra-
phy on silica gel (ethyl acetate–petroleum ether, 1:19) to provide
the product 17 as a colourless liquid (0.096 g, 64%). [
a
]
.
D = À41 (c
0.15, CHCl3). IR (neat): 2935, 1652, 1334, 1161 cmÀ1
1H NMR
(300 MHz, CDCl3): d 7.72 (2H, d, J = 8.0), 7.23 (2H, d, J = 8.0), 6.20
(1H, dd, J = 11.0, 18.0), 5.61 (1H, d, J = 3.5), 5.08–4.94 (2H, m),
4.37 (1H, d, J = 18.0), 4.21–4.05 (2H, m), 3.97 (1H, dd, J = 6.0, 8.0),
3.87–3.79 (1H, m), 3.69 (1H, dd, J = 6.0, 8.0), 2.42–2.31 (4H, m),
1.85 (1H, dd, J = 3.5, 19.0), 1.59–1.52 (10H, m). 13C NMR (75 MHz,
CDCl3): d 143.0, 136.1, 132.3, 129.6, 129.4, 127.0, 124.5, 118.6,
111.6, 74.5, 66.5, 52.4, 40.5, 36.0, 34.7, 25.7, 25.1, 23.9, 23.8,
21.4. MS (TOF MS ES+): m/z (%) = 426 (M++Na, 100). Anal. Calcd
for C22H29NO4S: C, 65.48; H, 7.24; N, 3.47. Found: C, 65.59; H,
7.39; N, 3.58.
Acknowledgements
We are thankful to DST, New Delhi, for funds (Grant No. SR/S1/
OC-51/2005), and CSIR, New Delhi, for fellowships.
References
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A solution of the diene 17 (0.075 g, 0.186 mmol) and 1,4-naph-
thaquinone (0.032 g, 0.20 mmol) in dry benzene (4 ml) was heated
at reflux for 24 h. It was then cooled and concentrated in vacuo to
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(2 ml). The resulting solution was stirred with silica gel (60–120
mesh, 1.4 g) and Et3N (0.50 ml, 3.6 mmol) under aerobic conditions
for 7 h. It was then concentrated in vacuo to leave a crude product
which was purified by column chromatography on silica gel (ethyl
acetate–petroleum ether, 1:9) to provide the product 19 as a yel-
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lowish solid (0.049 g, 48%), mp 105–106 °C. [a]D = +1 (c 0.1, CHCl3).
IR (KBr): 2934, 1668, 1360, 1161 cmÀ1. 1H NMR (400 MHz, CDCl3):
d 8.18–8.12 (2H, m), 8.08 (1H, d, J = 8.0), 7.74–7.68 (2H, m), 7.55
(2H, d, J = 8.0), 7.32 (1H, d, J = 8.0), 7.03 (2H, d, J = 8.0), 4.70 (1H,
d, J = 17.0), 4.55 (1H, d, J = 17.0), 4.27–4.23 (1H, m), 4.11–4.02
(1H, m), 3.95–3.89 (1H, m), 3.86–3.84 (1H, m), 3.55 (1H, dd,
J = 7.0, 18.5), 3.37 (1H, dd, J = 3.0, 18.5), 2.16 (3H, s), 1.59–1.48
(4H, m), 1.42–1.33 (6H, m). 13C NMR (100 MHz, CDCl3): d 185.3
(s), 183.0 (s), 143.4 (s), 140.6 (s), 136.8 (s), 136.5 (s), 134.7 (s),
134.3 (d), 134.0 (s), 133.8 (d), 132.5 (s), 131.3 (d), 131.0 (s),
129.5 (d), 127.4 (d), 127.3 (d), 126.7 (d), 125.7 (d), 110.3 (s), 76.7
(d), 66.3 (t), 52.8 (d), 45.7 (t), 35.9 (t), 34.7 (t), 28.4 (t), 25.1 (t),
23.9 (t), 23.8 (t), 21.3 (q). MS (TOF MS ES+): m/z (%) = 580
(M++Na, 100). Anal. Calcd for C32H31NO6S: C, 68.92; H, 5.60; N,
2.51. Found: C, 69.09; H, 5.71; N, 2.67.
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4.1.11. (2R)-2-[(1S)-1,2-Dihydroxyethyl]-3-[(4-methylphenyl)-
sulfonyl]-1,2,3,4,7,12-hexahydro-naphtho[2,3-f]isoquinolin-7,
12-dione 20
A solution of the acetal derivative 19 (0.05 g, 0.09 mmol) in THF
(3 ml) was stirred with HCl (6 N, 3 ml) for 9 h at room temperature.