Diastereoselective synthesis of substituted hexahydrobenzo[de]isochromanes and evaluation of their antileishmanial activity

Article abstract of DOI:10.1039/c5ob02038g

Hexahydrobenzo[de]isochromanes and hexahydropyrano[3,4,5-ij]isoquinolines can be efficiently synthesized via Friedel Crafts and oxa Pictet-Spengler reaction of acrylyl enol ethers mediated by triflic acid in good yields. The reaction is highly stereoselective. Two of the hexahydrobenzo[de]isochromanes are found to have moderate antileishmanial activity.

Full text of DOI:10.1039/c5ob02038g

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DOI: 10.1039/C5OB02038G
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ARTICLE TYPE
Diastereoselective Synthesis of Substituted Hexahydrobenzo[de]iso-
chromans and their Evaluation as Antileishmanial activity
Anil K. Saikia,*a Sabera Sultana,a Ngangbam Renubala Devi,a Manash J. Deka,a Kartikeya Tiwarib
Vikash K. Dubeyb*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Hexahydrobenzo[de]isochromanes and hexahydropyrano[3,4,5-ij]isoquinolines can be efficiently synthesized via Friedel Crafts and oxa
Pictet-Spengler reaction of acrylyl enol ethers mediated by triflic acid in good yields. The reaction is highly stereoselective. Two of the
10 hexahydrobenzo[de]isochromanes are found to have moderate antileishmanial activity.
46
47 envisioned that treatment of enol ether 1 with triflic acid would
11 Introduction
48 provide carbocation A, which after Friedel Crafts reaction will
12
49 give enol ether B. The enol ether B will generate oxonium ion
13 Heterocyclic structures are considered as prominent features in
14 synthetic chemistry because of their existence in many natural
15 products and biologically active molecules. Particularly, oxygen
16 heterocyclic compounds fused with aromatic ring systems such as
17 chromane1 and isochromane2 derivatives are reported to be
18 biologically active. As for example excentricine, N-methyl
19 excentricine isolated from Stephania excentrica and
20 stephalooxocanine isolated from Stephania cepharantha are
21 acetylcholesterase inhibitors.3 Owing to their wide range of
22 biological activities, synthesis of substituted isochromans have
23 attracted the attention of the synthetic community and various
24 methods have been developed for the functionalization of
25 isochromane core in recent years.4 Therefore, development of
26 suitable methodology for the synthesis of substituted
27 isochromans, in a single step, is most desirable. Friedel crafts5
28 and Pictet-Spengler6 reactions are two important C-C bond
29 forming reactions and are demonstrated in the synthesis of
30 structurally diverse molecules. Herein, we wish to disclose a
50 under acidic condition to facilitate the oxa Pictet-Spengler type
51 reaction to give the tricyclic compound 2 (Scheme 1).
52
53 Scheme 1. Strategy for isochromane synthesis
54
55
H
R2
R3
56
R2
R3
R2
R3
R1
Friedel-Crafts
R
R1
O
R1
O
H
R
R
O
EtO
B
EtO2C
EtO2C
A
1
O
oxa Pictet-
Spengler
57
58
59
60
61
R2
R2
R3
R3
R1
R
R1
R
O
O
EtO
EtO
31 methodology
for
the
synthesis
of
C
2
O
OH
32 hexahydrobenzo[de]isochromane from aryl and alkene
33 substituted acrylyl enol ethers catalyzed by triflic acid. We
34
35
MeO
36
MeO
62 Results and discussion
A
B
N
A
B
R
37
38
39
40
41
42
43
MeO
N
C
O
63
MeO
C
O
OH
64 The reaction of (E)-ethyl 3-((5-methyl-2-phenylhex-4-en-1-
65 yl)oxy)acrylate 1b with triflic acid gave ethyl 2-((1S*,3aS*)-
66 3a,6,6-trimethyl-1,3,3a,4,5,6- hexahydrobenzo[de]isochroman-1-
67 yl)acetate 2b in 75% yield. The reaction was also performed with
68 different Bronsted and Lewis acids and the results are shown in
69 Table 1. The reaction with 1.0 equivalent of BF3.OEt2, In(OTf)3,
70 Sc(OTf)2, and InCl3 produced no products, but starting material
OH
OH
OH
stephaoxocanine
R = H , excentricine
R = Me, N-methyl excentricine
44 Fig.
1
Biologically important hexahydropyrano[3,4,5-
45 ij]isoquinoline derivatives
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recovered in all the cases. On the other hand, TMSOTf, FeCl3 and 53 and C-3a positions. It was confirmed by NOE experiment of the
TsOH gave inseparable mixture of products (Table 1). The scope 54 compound 2b. On the other hand, stereochemistry of the products
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of the reaction is investigated by employing different types of 55 having substitutions at 1, 3, 3a and 6 positions is determined by
DOI: 10.1039/C5OB02038G
substrates having aliphatic and aromatic substituents at different 56 NOE experiments of 2d. In case of mono substitution at 6-
positions of the acrylyl enol ethers. It was observed from the 57 position of the products, diastereomeric mixture with different
Table 1 that, substrates having electron donating groups on the 58 ratios were obtained (entries 11-13, 15). The reaction is mild and
aromatic ring gave products in good yield. The reaction is highly 59 substituents such as ester, ether, and halides are not affected in
diastereoselective and produced exclusively single diastereomers 60 these reaction conditions.
in most of the cases, and the stereochemistry of compounds is 61 After successful study of this methodology to the synthesis of
10 determined by 2-D nuclear Overhauser effect (NOESY). The 62 hexahydrobenzo[de]isochromane, its application to the synthesis
11 products 2a, 2h-j, and 2m where there is no bridgehead methyl 63 of hexahydropyrano[3,4,5-ij]isoquinoline was explored. The
12 group, the hydrogen at 3Ca-H and hydrogen at C1-H are in cis 64 starting material enol ethers 1p-q (Scheme 2) when treated with
65
13 configuration, which is determined from the DEPT, HMQC and
14 NOESY experiments of 2i. It showed a clear characteristic NOE
66 Table 2. Synthesis of Hexahydrobenzo[de]isochromane
15
R3
R3
R4
R4
16 Table 1 Optimization of the reaction condition
67
68
R2
O
R2
O
17
R1
R1
TfOH (10 mol%)
18
R
69
CH2Cl2/ 0 o
10 min
C
19
R
reagent
70
EtO2C
CO2Et
20
2
O
CH2Cl2/ 0 oC
O
1
71
Yield (%) a
21
Sl.No.
d. r.b
Product 2
Substrate 1
time/min
72
EtO2C
2b
22
CO2Et
1b
73
H
entry
reagent (equiv)
yield(%)b
time/min
30
76
1
74
2a
1a
--c
O
1
BF3.OEt2 (1.0)
75
O
23
H
76
--c24
EtO2C
In(OTf)3 (1.0)
Sc(OTf)2 1.0)
CO2Et
30
30
2
3
77
--c
25
78
--c 26
75
InCl3 (1.0)
1b
2b
30
2
79
4
5
O
O
O
O
27
--d
28
30
80
TMSOTf (1.0)
FeCl3 (1.0)
EtO2C
CO2Et
81
30
30
--d
29
6
7
82
--d
30
65
p-TsOH (1.0)
83
3
31
O
84
2c
75
1c
TfOH (1.0)
10
10
32
8
9
EtO2C
85
CO2Et
7533
Cl
TfOH (10 mol%)
86
Cl
aReaction conditions: enol ether (1.0 mmol), solvent (2 mL) bYield refers
to isolated yield. cNo reaction, starting material was recovered. dcomplex
mixture.
87
76
4
88
O
1d
2d
89
EtO2C
CO2Et
90
34 correlation between the hydrogens 3Ca-H and C1-H (see SI).
35 Similarly, compounds 2b, 2k and 2o having bridgehead
36 substituents show cis relationship between the substituents at C-1
37
91
68
92
5
6
7
O
O
O
O
93
1e
2e
94
EtO2C
CO2Et
38
Cl
95
OMe
OMe
39
96
NOE
40
H
NOE
O
O
NOE
H
COOCH2CH3
75
97
41
42
43
44
45
46
47
48
49
50
51
O
1f
2f
98
CO2Et
EtO2C
CO2Et
99
2b
2d
100
101
102
103
104
105
106
107
108
109
NOE
OMe
OMe
H
O
55
O
NTs
NOE
1g
2g
H
EtO2C
CO2Et
H
NOE
O
CO2Et
H
O
H
COOEt
1h
2h
O
8
2i
2q
Br
71
Br
H
EtO2C
CO2Et
52 Figure 2. NOE of compounds 2b, 2d, 2i and 2q
2
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48 The mechanism of formation of hexahydrobenzo[de]isochromans
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a
Sl.No.
2
Product
Yield (%)
d. r.b
1
Substrate
49 can be explained as follows. The enol ether 1 reacts with acid to
DOI: 10.1039/C5OB02038G
2
50 form carbocation A, which after Friedel-Crafts reaction and
51 subsequent elimination and addition of protons give
52 oxocarbenium ion C. The oxocarbenium ion C is then attacked
53 by aromatic ring via Pictet-Spengler type reaction to form
54 hexahydrobenzo[de]isochromane 2 (Scheme 3).
55
H
9
1i
62
2i
O
O
3
4
5
H
EtO2C
CO2Et
H
O
74
O
1j
10
11
MeO
2j
6
56 Scheme 3 Plausible mechanism of the reaction
57
MeO
H
EtO2C
7
8
CO2Et
H
R1
R1
R1
R2
R1
R2
R2
H
R
O
R2
R
O
R
O
R
O
H
- H
9
3:1
70
O
EtO
EtO
O
EtO
2k
1
A
B
A'
10
11
12
EtO
1k
O
O
O
EtO2C
CO2Et
O
58
+H
Cl
Cl
59
H
R1
R2
R1
R2
R1
R2
R1
R2
60
61
4:1
75
R
O
R
12
R
R
H
O
O
13
H
2l
O
O
1l
O
14
15
16
62
CO2Et
EtO2C
EtO
EtO
C'
EtO
EtO
C
63
2
OH
OH
O
H
O
OH
D
64
71
8:1
65
13
2m
O
Br
Br
1m
17
18
19
20
66 Evaluation of antileishmanial activity of 2f, 2j and 2p
H
CO2Et
EtO2C
67
68 Leishmania is
a dimorphic protozoan parasite, which is
69 responsible for self healing cutaneous leishmaniasis (CL) and life
70 claiming visceral leishmaniasis (VL), commonly known as kala-
O
14
1n
O
2n
73
21
22
EtO2C
CO2Et
120
A
100
23
15
80
60
40
20
O
O
2o
57
1o
8:5
24
CO2Et
EtO2C
aYields refer to isolated yield. The compounds were characterized by IR, NMR and Mass
spectrometry. bRatio is determined by 1H NMR.
0
l
o
M
M
M
M
0
0
2
M
µ
r
t
µ
µ
µ
µ
n
5
0
5
0
o
C
2
5
7
0
1
Concentration of 2f
25 triflic acid under the same reaction conditions gave ethyl 2-
120
100
80
60
40
20
0
26 ((7R*,9aS*)-3,3-dimethyl-1-tosyl-1,2,3,7,9,9a
27 pyrano[3,4,5-ij]isoquinolin-7-yl)acetate
hexahydro-
B
2p and ethyl2-
28 ((3S*,7R,9aS*)-3-methyl-3-phenyl-1-tosyl-1,2,3,7,9,9a-
29 hexahydropyrano[3,4,5- ij]isoquinolin-7-yl)acetate 2q in 90%
30 and 85% yields, respectively (Scheme 2). The stereochemistry of
31 2p and 2q is determined by NOE experiment of 2q (see SI).
32
l
o
M
M
M
M
0
0
2
M
µ
r
t
µ
µ
µ
µ
n
5
0
0
0
o
C
2
5
0
5
1
1
33 Scheme 2. Synthesis of hexahydropyrano[3,4,5-ij]isoquinoline
34
Concentration of 2j
120
100
80
60
40
20
0
C
35
NTs
NTs
H36
TfOH
37
O
O
CH2Cl2
0 oC, 10 min
2p38
39
1p
H
EtO2C
EtO2C
90%
40
l
o
M
µ
M
M
µ
r
t
µ
n
0
0
0
0
5
o
5
0
C
1
41
Concentration of 2p
71
72
NTs42
H43
NTs
73 Figure 3. Antileishmanial effect of compounds (A), 2f (B), 2j
74 and (C), 2p on Leishmania donovani promastigote cells. The IC50
75 values were found out to be 72.5 µM, 98.75 µM and 440 µM,
76 respectively.
TfOH
44
45
46
CH2Cl2
0 oC /10 min
O
H
O
1q
EtO2C
85%
2q
EtO2C
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azar in India.7 Due to the high toxicity, high cost and drug 59 Pale yellow oil; Rf (hexane/ EtOAc 24:1) 0.50; yield 225 mg,
1
resistance of available drugs, there is a need of synthesizing and 60 78%; H NMR (400 MHz, CDCl3) δ 1.25 (t, J = 7.2 Hz, 3 H),
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evaluation of antileishmanial activity of new compounds.8 We 61 1.54 ( s, 3 H ), 1.64 (s, 3 H), 2.26-2.33 (m,D1OHI: 1)0, .210.4349-/C25.5O2B0(2m03, 8G
have already studied the antileishmanial activity of few 62 1 H), 3.01 (quintet, J = 6.8 Hz, 1 H), 3.96 (d, J = 6.8 Hz, 2 H),
oxabicyclo[3.3.1]nonanones and found promising result for one 63 4.14 (q, J = 7.2 Hz, 2 H), 5.03 (t, J = 7.6 Hz, 1 H), 5.17 (d, J
of the compounds.9 Encouraged by these results we have 64 =12.4 Hz, 1 H), 7.18-7.21 (m, 2 H), 7.22-7.25 ( m, 1 H ) 7.28-
undertaken to screen some tricyclic oxygen and nitrogen 65 7.32 (m, 2 H), 7.54 (d, J = 13.2 Hz, 1 H); 13C NMR (100 MHz,
heterocycles fused with aromatic ring as these ring systems such 66 CDCl3) δ 14.5, 17.9, 25.9, 31.1, 45.5, 59.9, 74.2, 96.6, 121.3,
as chromane1 and isochromane2 derivatives are reported to be 67 126.9, 128.0, 128.6, 134.0, 141.8, 162.5, 168.0; IR (KBr, neat)
10 biologically active. The three compounds were experimentally 68 2980, 2928, 1712, 1632, 1454, 1319, 1220, 1136, 1041, 770, 692
11 assessed for their anti- leishmanial activities. IC50 values for 2f, 69 cm-1; HRMS (ESI) calcd. for C18H25O3 (M + H)+ 289.1798 found
12 2j and 2p were found out to be 72.5 µM, 98.75 µM and 440 µM 70 289.1799.
13 respectively. The compounds 2f and 2h were found to be most
71
14 effective against Leishmania donovani promastigotes with 72 (E)-Ethyl 3-((2,5-dimethyl-2-phenylhex-4-en-1-yl)oxy)acrylate
15 moderate IC50 values, while compound 2p was found to be least 73 (1b)
16 effective with a high IC50 value (Figure 3). This signifies that
74
17 Leishmania donovani promastigotes are more sensitive to 75 Pale yellow oil; Rf (hexane/ EtOAc, 24:1) 0.50; yield 242 mg,
1
18 compounds 2f and 2h as compared to 2p. However, the known 76 80%; H NMR (600 MHz, CDCl3) δ 1.25 (t, J = 7.2 Hz, 3 H),
19 potential antileishmanials like mliltefosine has an IC50 value of 77 1.35 (s, 3 H), 1.56 ( s, 3 H ), 1.63 ( s, 3 H), 2.42 (d, J = 7.2 Hz, 2
20 25 µM. Thus there is need for further improvement in the efficacy 78 H), 3.86 (d, J = 9.6 Hz, 1 H), 3.92 (d, J = 9.6 Hz, 1 H), 4.15 (q, J
21 of these compounds. This provides a novel chemical space for 79 = 7.2 Hz, 2 H), 4.89 (t, J = 7.2 Hz, 1 H), 5.19 (d, J = 12.6 Hz, 1
22 further modification for development of highly effective 80 H), 7.22 (t, J = 8.4 Hz, 1 H), 7.25-7.33 (m, 4 H), 7.57 (d, J = 12.6
23 antileishmanial compounds.
81 Hz, 1 H); 13C NMR (150 MHz, CDCl3) δ 14.6, 18.2, 22.9, 26.1,
82 37.2, 42.4, 60.0, 78.3, 96.5, 119.5, 126.4, 126.5, 128.5, 134.6,
83 144.9, 162.8, 168.0; IR (KBr, neat) 2977, 1709, 1625, 1444,
84 1326, 1220, 1133, 1048, 760, 685 cm-1; HRMS (ESI) calcd. for
24
25 Conclusions
26
27 In conclusion, we have developed a mild and efficient method for 85 C19H27O3 (M + H)+ 303.1955 found 303.1956.
28 the synthesis of hexahydrobenzo[de]isochromane via Friedel
29 Crafts and oxa Pictet-Spengler type reaction of enol ether in good 87 (E)-Ethyl
30 yields. The same methodology can be used for the synthesis of 88 yl)oxy)acrylate (diastereomeric mixture, 4:3, 1c)
31 hexahydropyrano[3,4,5-ij]isoquinoline. The reaction is highly
86
3-((2,5-dimethyl-1,2-diphenylhex-4-en-1-
89
32 diastereoselective and compatible to functional groups such as 90 Pale yellow oil; Rf (hexane/ EtOAc, 24:1) 0.50; yield 306 mg,
1
33 ester, halides and ether. This methodology would provide a tool 91 81%; H NMR (600 MHz, CDCl3) δ 1.18 (t, J = 7.2 Hz, 3 H,
34 to synthesize tricyclic heterocyclic compounds having
a
92 major), 1.98 (t, J = 7.2 Hz, 3 H, minor), 1.27 (s, 3 H, major),
35 functional group at the bridgehead position. Two of the 93 1.29 (s, 3 H, minor), 1.56 ( s, 3 H, major), 1.57 (s, 3 H, minor),
36 hexahydrobenzo[de]isochromanes 2f, 2h are found to have 94 1.60 (s, 3 H), 2.45 (dd, J = 14.4 and 8.4 Hz, 2 H, minor), 2.61
37 antileishmanial activity with IC50 values 72.5 µM and 98.75 µM, 95 (dd, J = 14.4 and 7.2 Hz, 2 H, major), 4.01-4.11 (m, 2 H), 4.81 (t,
38 respectively.
96 J = 7.2 Hz, 1 H, major), 4.87 (t, J = 7.2 Hz, 1 H, minor), 4.88 (s,
97 1 H, major), 4.95 (s, 1 H, minor), 5.11 (d, J = 12.6 Hz, 1 H,
98 major), 5.15 (d, J = 12.0 Hz, 1 H, minor), 6.70 (d, J = 7.8 Hz, 2
99 H, minor), 6.81 (d, J = 7.2 Hz, 2 H, major), 7.08-7.26 (m, 8 H),
39
40 Experimental section
41
42 General Information: General Information: All the reagents 100 7.39 (d, J = 12.0 Hz, 1 H, major), 7.49 ( d, J = 12.0 Hz, 1 H,
43 were of reagent grade (AR grade) and were used as purchased 101 minor); 13C NMR ( 150 MHz, CDCl3) δ 14.3, 14.5, 18.3, 18.4,
44 without further purification. Silica gel (60-120 mesh size) was 102 18.8, 20.9, 26.0, 26.1, 36.3, 36.4, 46.5, 47.0, 59.8, 59.9, 91.0,
45 used for column chromatography. Reactions were monitored by 103 91.6, 98.4, 98.6, 119.8, 120.2, 126.5, 126.5, 127.6, 127.7, 127.8,
46 TLC on silica gel GF254 (0.25 mm). Melting points were 104 127.9, 128.0, 128.1, 128.18, 128.2, 128.4, 133.8, 134.3, 135.6,
47 recorded in an open capillary tube and are uncorrected. Fourier 105 136.8, 142.8, 161.8, 162.0, 168.0; IR (KBr, neat) 2981, 2929,
48 transform-infra red (FT-IR) spectra were recorded as neat liquid 106 1712, 1642, 1446, 1368, 1220, 1130, 1045, 779 cm-1; HRMS
49 or KBr pellets. NMR spectra were recorded in CDCl3 with 107 (ESI) calcd. for C25H31O3 (M + H)+ 379.2268 found 379.2265.
1
50 tetramethylsilane as the internal standard for H (600 MHz, 400 108
51 MHz) or 13C (150 MHz, 100 MHz) NMR. Chemical shifts (δ) are 109 (E)-Ethyl 3-((1-(4-chlorophenyl)-2,5-dimethyl-2-phenylhex-4-
52 reported in ppm and spin-spin coupling constants (J) are given in 110 en-1-yl)oxy)acrylate ( diastereomeric mixture, 3:2, 1d)
53 Hz. HRMS spectra were recorded using Q-TOF mass 111
54 spectrometer. The starting material enol ethers 1a-q is prepared 112 Pale yellow oil; Rf (hexane/ EtOAc 24:1) 0.50; yield 293 mg,
1
55 as per literature procedure (see SI).
113 75%; H NMR (600 MHz, CDCl3) δ 1.19 (t, J = 7.2 Hz, 3 H,
114 major), 1.21 (t, J = 7.2 Hz, 3 H, minor), 1.26 (s, 3 H, major), 1.27
56
57 (E)-Ethyl
58 (1a)
3-((5-methyl-2-phenylhex-4-en-1-yl)oxy)acrylate 115 (s, 3 H, minor), 1.57 ( s, 3 H, minor), 1.58 (s, 3 H, major), 1.60 (s,
116 3 H, minor), 1.61 (s, 3 H, major), 2.49 (dd, J = 14.4 and 8.4 Hz, 2
4
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H, minor), 2.60 (dd, J = 14.4 and 7.8 Hz, 2 H, major), 4.02-4.12 59 128.8, 129.1, 129.2, 129.6, 133.7, 134.2, 142.7, 142.8, 159.1,
(m, 2 H), 4.79 (t, J = 7.2 Hz, 1 H, minor), 4.84 (s, 1 H, major), 60 159.4, 161.9, 162.1, 168.0; IR (KBr, neat) 2980, 2930, 1708,
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4.89 (t, J = 7.2 Hz, 1 H, major), 4.92 (s, 1 H, minor), 5.09 (d, J = 61 1641, 1622, 1514, 1445, 1376, 1220, 1176, 1037, 830, 763, 685
12.6 Hz, 1 H, major), 5.13 (d, J = 12.6 Hz, 1 H, minor ), 6.59 (d, 62 cm-1; HRMS (ESI) calcd. for C17H18NaO5 (M + Na)+ 431.2193
DOI: 10.1039/C5OB02038G
J = 8.4 Hz, 2 H, minor), 6.70 (d, J = 8.4 Hz, 2 H, major), 7.06 (d, 63 found 431.2180.
J = 8.4 Hz, 1 H), 7.10-7.14 (m, 2 H), 7.19-7.27 (m, 1 H), 7.37 (d, 64
J = 12.6 Hz, 1 H, major), 7.48 (d, J = 12.6 Hz, 1 H, minor); 13C 65 (E)-Ethyl 3-((1-(3-methoxyphenyl)-2,5-dimethyl-2-phenylhex-
NMR (150 MHz, CDCl3) δ 14.5, 18.4, 18.5, 21.1, 26.0, 26.1, 66 4-en-1-yl)oxy)acrylate (diasteromeric mixture, 3:2, 1g)
36.1, 36.5, 46.5, 47.0, 59.9, 60.1, 90.2, 90.8, 98.8, 98.9, 119.6,
67
10 119.9, 126.7, 126.8, 127.8, 127.9, 127.9, 128.0, 128.1, 128.3, 68 Colourless oil; Rf (hexane/ EtOAc 24:1) 0.48; yield 199 mg, 49
1
11 129.2, 129.7, 133.8, 134.0, 134.6, 135.4, 142.2, 142.3, 161.5, 69 %; H NMR (400 MHz, CDCl3) δ 1.18-1.35 (m, 6 H), 1.57 (s, 6
12 161.7, 167.8; IR (KBr, neat) 2980, 2927, 1709, 1628, 1624, 1445, 70 H, major), 1.63 (s, 6 H, minor), 2.47 (dd, J =16.0 and 9.6 Hz, 1
13 1377, 1220, 1130, 1046, 760, 699 cm-1; HRMS (ESI) calcd. for 71 H), 2.61 (d, J = 4.0 Hz, 1 H), 3.53 (s, 3 H, major), 3.56 (s, 3 H,
14 C25H30ClO3 (M + H)+ 413.1878 found 413.1861.
72 minor), 4.04-4.17 (m, 2 H), 4.81 (t, J = 7.2 Hz, 1 H, major), 4.84
73 (s, 1 H, minor), 4.90 (t, J = 7.2 Hz, 1 H, minor), 4.92 (s, 1 H,
15
16 (E)-Ethyl
3-((2,5-dimethyl-2-phenyl-1-(p-tolyl)hex-4-en-1- 74 major), 5.15 (d, J = 12.6 Hz, 1 H, minor), 5.16 (d, J = 12.0 Hz, 1
17 yl)oxy)acrylate (diasteromeric mixture, 4:3, 1e)
75 H, major), 6.10 (s, 1 H, major), 6.17 (s, 1 H, minor), 6.38 (d, J =
76 8.0 Hz, 1 H, major), 6.51 (d, J = 8.0 Hz, 1 H, minor), 6.69 (d, J =
18
19 Colourless oil; Rf (hexane/ EtOAc 24:1) 0.48; yield 294 mg, 77 8.0 Hz, 1 H), 6.75 (d, J = 8.0, 1 H), 7.03 (t, J = 8.0 Hz, 1 H), 7.10
1
20 75%; H NMR (600 MHz, CDCl3) δ 1.19 (t, J = 7.2 Hz, 3 H, 78 (t, J = 8.0 Hz, 1 H, minor), 7.15 ( d, J = 8.0 Hz, 1 H, major), 7.16-
21 minor), 1.21 (t, J = 7.2 Hz, 3 H, major), 1.28 (s, 3 H, minor), 79 7.31(m, 3 H), 7.41 (d, J = 12 Hz, 1 H, minor), 7.50 (d, J = 12 Hz,
22 1.30 (s, 3 H, major), 1.57 (s, 3 H, minor), 1.58 (s, 3 H, major), 80 1 H, major); 13C NMR (150 MHz, CDCl3) δ 14.4, 14.5, 18.3,
23 1.61 (s, 3 H), 2.25 (s, 3 H, major), 2.29 (s, 3 H, minor), 2.46 (dd, 81 18.4, 18.9, 21.2, 26.1, 26.2, 30.0, 36.5, 47.0, 58.2, 59.9, 60.0,
24 J = 14.4 and 8.4 Hz, 2 H, minor), 2.61-2.63 (m, 2 H, major), 82 91.0, 91.4, 98.5, 98.6, 113.1, 113.4, 114.0, 114.3, 120.1, 120.4,
25 4.04-4.10 (m, 2 H), 4.82 (t, J = 7.2 Hz, 1 H, major), 4.87 (s, 1 H, 83 128.0, 128.2, 128.4, 133.9, 134.4, 138.3, 142.8, 142.8, 158.8,
26 minor), 4.89 (t, J = 7.2 Hz, 1 H, minor), 4.93 (s, 1 H, major ), 84 159.0, 161.8, 162.1, 168.0. IR (KBr, neat) 2975, 2948, 1706,
27 5.12 (d, J = 12.0 Hz, 1 H, minor), 5.16 (d, J = 12.6 Hz, 1 H, 85 1650, 1620, 1511, 1425, 1370, 1210, 1100, 1031, 755, 690 cm-1;
28 major), 6.61 (d, J = 7.8 Hz, 2 H, major), 6.71 (d, J = 7.8 Hz, 2 H, 86 HRMS (ESI) calcd. for C26H32NaO4 (M + Na)+ 431.2193 found
29 minor), 6.91 (d, J = 7.8 Hz, 2 H, minor), 6.98 (d, J = 7.8 Hz, 2 H, 87 431.2195.
30 major), 7.15 (d, J = 7.8 Hz, 2 H), 7.20-7.36 (m, 1 H), 7.38 (d, J = 88
31 12.6 Hz, 1 H, major), 7.49 ( d, J = 12.6 Hz, 1 H, minor); 13C 89 (E)-Ethyl
3-((2-(4-bromophenyl)-5-methylhex-4-en-1-
32 NMR (150 MHz, CDCl3) δ 14.5, 18.3, 18.4, 20.9, 21.2, 21.3, 90 yl)oxy)acrylate (1h)
33 26.0, 26.1, 36.3, 36.4, 46.5, 47.0, 59.8, 59.8, 91.0, 91.6, 98.3,
91
34 98.4, 119.9, 120.2, 126.4, 126.5, 127.8, 127.9, 128.0, 128.1, 92 Pale yellow oil; Rf (hexane/ EtOAc 24:1) 0.48; yield 275 mg,
1
35 128.2, 128.25, 128.3, 128.4, 128.5, 133.7, 133.8, 134.2, 137.5, 93 71%; H NMR (600 MHz, CDCl3) δ 1.25 (t, J = 7.2 Hz, 3 H),
36 137.9, 142.8, 142.9, 161.9, 162.2, 168.0; IR (KBr, neat) 2978, 94 1.54 ( s, 3 H ), 1.65 ( s, 3 H), 2.26 (quint, J = 7.2 Hz, 1 H), 2.45
37 1707, 1622, 1444, 1220, 1130, 1038, 854, 758 cm-1; HRMS (ESI) 95 (quint, J = 7.2 Hz, 1 H), 2.95 (quint, J = 7.2 Hz, 1 H), 3.92-3.94
38 calcd. for C26H33O3 (M + H)+ 393.2424 found 393.2425.
96 (m, 2 H), 4.14 (q, J = 7.2 Hz, 2 H), 4.98 (t, J = 7.8 Hz, 1 H), 5.16
39 97 (d, J = 12.6 Hz, 1 H), 7.06 (d, J = 7.8 Hz, 2 H), 7.42 (d, J = 8.4
40 (E)-Ethyl 3-((1-(4-methoxyphenyl)-2,5-dimethyl-2-phenylhex- 98 Hz, 2 H), 7.52 (d, J = 13.2 Hz, 1 H); 13C NMR ( 150 MHz,
41 4-en-1-yl)oxy)acrylate (diasteromeric mixture, 3:2, 1f)
99 CDCl3) δ 14.5,18.0, 25.9, 31.0, 45.1, 60.0, 73.9, 96.9, 120.8,
100 120.9, 129.8, 131.7, 134.4, 140.8, 162.3, 167.9; IR (KBr, neat)
42
43 Colourless oil; Rf (hexane/ EtOAc 24:1) 0.48; yield 238 mg, 101 2977, 2929, 1709, 1625, 1489, 1327, 1220, 1137, 1048, 821, 758,
1
44 70%; H NMR (600 MHz, CDCl3) δ 1.19 (t, J = 7.2 Hz, 3 H, 102 685 cm-1; HRMS (ESI) calcd. for C18H23BrO3 (M + Na)+
45 major), 1.20 (t, J = 7.2 Hz, 3 H, minor), 1.26 (s, 3 H, minor), 1.29 103 389.0723 found 389.0726.
46 (s, 3 H, major), 1.55 (s, 3 H, minor), 1.56 (s, 3 H, major), 1.60 (s, 104
47 3 H, major), 1.61 (s, 3 H, minor), 2.44 (dd, J = 15.0 and 8.4 Hz, 2 105 (E)-Ethyl 3-((5-methyl-2-(p-tolyl)hex-4-en-1-yl)oxy)acrylate
48 H, minor), 2.56-2.66 (m, 2 H, major), 3.73 (s, 3 H, major), 3.76 106 (1i)
49 (s, 3 H, minor), 4.03-4.10 (m, 2 H), 4.82 (t, J = 7.2 Hz, 1 H, 107 Pale yellow oil; Rf (hexane/ EtOAc 24:1) 0.48; yield 211 mg,
1
50 major), 4.83 (s, 1 H, minor), 4.88 (t, J = 7.2 Hz, 1 H, minor), 108 70%; H NMR (600 MHz, CDCl3) δ 1.26 (t, J = 7.2 Hz, 3 H),
51 4.90 (s, 1 H, major), 5.10 (d, J = 12.6 Hz, 1 H, minor), 5.15 (d, J 109 1.57 (s, 3 H ), 1.66 ( s, 3 H), 2.29 (quint, J = 7.2 Hz, 1 H), 2.33 (s,
52 = 12.6 Hz, 1 H, major), 6.61 (d, J = 7.2 Hz, 4 H, major), 6.71 (d, 110 3 H), 2.48 (quint, J = 7.2 Hz, 1 H), 2.96 (quint, J = 7.2 Hz, 1 H),
53 J = 7.8 Hz, 4 H, minor), 6.13 (d, J = 7.8 Hz, 1 H), 7.19-7.26 (m, 111 3.95 (d, J = 6.0 Hz, 2 H), 4.15 (q, J = 7.2 Hz, 2 H), 5.04 (t, J =
54 3 H), 7.35-7.40 (m, 1 H), 7.38 (d, J = 12.6 Hz, 1 H, minor), 7.48 112 7.2 Hz, 1 H), 5.18 (d, J = 12.6 Hz, 1 H), 7.08 (d, J =7.8 Hz, 2 H),
55 ( d, J = 12.6 Hz, 1 H, major); 13C NMR (150 MHz, CDCl3) δ 113 7.12 (d, J = 7.8 Hz, 2 H), 7.56 (d, J = 12.6 Hz, 1 H); 13C NMR (
56 14.5, 18.2, 18.3, 18.4, 18.9, 20.9, 26.0, 26.1, 36.3, 36.3, 46.6, 114 150 MHz, CDCl3) δ 14.5, 18.0, 21.2, 25.9, 31.1, 45.1, 59.9, 74.4,
57 47.0, 55.1, 55.2, 59.7, 59.8, 90.7, 91.3, 98.3, 98.4, 112.9, 113.1, 115 96.6, 121.4, 127.8, 129.3, 133.8, 136.5, 138.7, 162.6, 168.0; IR
58 119.8, 120.2, 126.4, 126.5, 127.8, 127.9, 128.0, 128.1, 128.3, 116 (KBr, neat) 2977, 2928, 1710, 1625, 1447, 1325, 1219, , 1136,
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Journal Name, [year], [vol], 00–00 | 5

Organic & Biomolecular Chemistry
Page 6 of 10
1
2
3
4
5
6
7
8
9
1048, 816, 768 cm-1; HRMS (ESI) calcd. for C19H27O3 (M + H)+
303.1955 found 303.1952.
59
60 (E)-Ethyl
3-(((E)-2-(4-bromophenyl)-5-phenylpent-4-en-1-
View Article Online
61 yl)oxy)acrylate (1m)
DOI: 10.1039/C5OB02038G
(E)-Ethyl
3-((2-(4-methoxyphenyl)-5-methylhex-4-en-1-
62
yl)oxy)acrylate (1j)
63 Pale yellow oil; Rf (hexane/ EtOAc 24:1) 0.48; yield 298 mg,
1
64 72%; H NMR (400 MHz, CDCl3) δ 1.25 (t, J = 7.2 Hz, 3 H),
Pale yellow oil; Rf (hexane/ EtOAc 24:1) 0.48; yield 239 mg, 65 2.54 (quint, J = 7.2 Hz, 1 H), 2.67 (quint, J = 7.6 Hz, 1 H), 3.11
1
75%; H NMR (600 MHz, CDCl3) δ 1.25 (t, J = 7.2 Hz, 3 H), 66 (quint, J = 7.2 Hz, 1 H), 3.98 (d, J = 6.0 Hz, 2 H), 4.14 (q, J =
1.55 ( s, 3 H ), 1.65 (s, 3 H), 2.26 (quint, J = 7.2 Hz, 1 H), 2.46 67 7.2 Hz, 2 H), 5.18 (d, J = 12.8 Hz, 1 H), 6.02 (quint, J = 7.6 Hz,
10 (quint, J = 7.2 Hz, 1 H), 2.95 (quint, J = 7.2 Hz, 1 H), 3.79 (s, 3 68 1 H), 6.38 (d, J = 15.6 Hz, 1 H), 7.10 (d, J = 8.4 Hz, 2 H), 7.18-
11 H), 3.92 (d, J = 6.0 Hz, 2 H), 4.14 (q, J = 7.2 Hz, 2 H), 5.02 (t, J 69 7.21 (m, 1 H), 7.25-7.27 (m, 4 H), 7.45 (d, J = 8.0 Hz, 2 H), 7.54
12 = 7.2 Hz, 1 H), 5.17 (d, J = 12.6 Hz, 1 H), 6.85 (d, J = 8.4 Hz, 2 70 (d, J = 12.4 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 14.5, 35.9,
13 H), 7.10 (d, J = 8.4 Hz, 2 H), 7.55 (d, J = 12.6 Hz, 1 H); 13C 71 45.0, 60.0, 73.8, 97.1, 121.1, 126.3, 126.7, 127.5, 128.7, 129.8,
14 NMR (150 MHz, CDCl3) δ 14.5, 18.0, 25.9, 31.2, 44.7, 55.4, 72 131.9, 132.8, 137.3, 140.1, 162.2, 167.8; IR (KBr, neat) 2979,
15 59.9, 74.5, 96.6, 114.1, 121.4, 128.9, 133.7, 133.8, 158.6, 162.6, 73 2933, 1706, 1631, 1485, 1325, 1219, 1136, 1043, 963, 771, 683
16 168.0; IR (KBr, neat) 2928, 1710, 1625, 1463, 1325, 1220, 1136, 74 cm-1; HRMS (ESI) calcd. for C22H24BrO3 (M + H)+ 415.0903
17 1040, 829, 772 cm-1; HRMS (ESI) calcd. for C19H27O4 (M + H)+ 75 found 415.0900.
18 319.1904 found 319.1907.
76
19
77 (E)-Ethyl 3-((4,7-dimethyl-4-phenyloct-6-en-3-yl)oxy)acrylate
20 (E)-Ethyl
3-(((E)-2-methyl-2,5-diphenylpent-4-en-1- 78 (diaestereomeric ratio 3:1, 1n)
21 yl)oxy)acrylate (1k)
79
22
80 Pale yellow oil; Rf (hexane/ EtOAc 24:1) 0.48; yield 270 mg,
1
23 Colourless oil; Rf (hexane/ EtOAc 24:1) 0.48; yield 245 mg, 81 82%; H NMR (600 MHz, CDCl3) δ 0.80 (t, J = 7.2 Hz, 3 H,
24 70%; H NMR (400 MHz, CDCl3) δ 1.25 (t, J = 7.2 Hz, 3 H), 82 major), 0.97 (t, J = 7.2 Hz, 3 H, minor), 1.24-1.30 (m, 6 H),
1
25 1.42 (s, 3 H), 2.59 (dd, J = 14.0 and 14.0 Hz, 1 H), 2.70 (dd, J = 83 1.31-1.41 (m, 2 H), 1.51 (s, 3 H), 1.59 (s, 3 H), 2.41 (d, J = 7.2
26 14.0 and 6.8 Hz, 1 H), 3.93 (dd, J = 12.8 and 9.6 Hz, 2 H), 4.15 84 Hz, 2 H, major), 2.53 (d, J = 7.2 Hz, 2 H, minor), 3.52 (d, J = 9.6
27 (q, J = 7.2 Hz, 2 H), 5.20 (d, J = 12.8 Hz, 1 H), 5.91 (quint, J = 85 Hz, 1 H, minor), 3.90 (d, J = 9.6 Hz, 1 H, major), 4.16 (q, J = 7.2
28 7.6 Hz, 1 H), 6.38 (d, J = 15.6 Hz, 1 H), 7.16-7.20 (m, 1 H), 7.20- 86 Hz, 2 H), 4.71 (t, J = 6.6 Hz, 1 H, major), 4.85 (t, J = 6.6 Hz, 1
29 7.25 (m, 5 H), 7.27-7.36 (m, 4 H), 7.59 (d, J = 13.2 Hz, 1 H); 13
C
87 H, minor), 5.33 (d, J = 12.0 Hz, 1 H), 7.19-7.38 (m, 5 H, major,
30 NMR (100 MHz, CDCl3) δ 14.5, 22.9, 42.3, 42.5, 60.0, 78.4, 88 minor), 7.37 (d, J = 7.8 Hz, 1 H, minor) 7.55 (d, J = 8.0 Hz, 1 H,
31 96.7, 125.7, 126.3, 126.5, 126.8, 127.4, 128.7, 133.5, 137.5, 89 major); 13C NMR (100 MHz, CDCl3) δ 11.4, 11.9, 14.6, 18.25,
32 144.3, 162.7, 168.0; IR (KBr, neat) 2975, 2928, 1707, 1629, 90 18.3, 19.5, 23.8, 24.7, 26.0, 26.1, 36.6, 37.8, 46.8, 59.8, 81.3,
33 1455, 1399, 1210, 1132, 1040, 964, 770, 680 cm-1; HRMS (ESI) 91 95.5, 96.5, 119.8, 120.8, 126.2, 126.4, 127.2, 127.6, 128.3, 128.4,
34 calcd. for C23H27O3 (M + H)+ 351.1955 found 351.1950.
92 134.1, 144.2, 165.3, 168.7; IR (KBr, neat) 2974, 2926, 1706,
93 1635, 1455, 1378, 1233, 1133, 1045, 814, 701 cm-1; HRMS (ESI)
35
36 (E)-Ethyl
3-(((E)-1-(4-chlorophenyl)-2-methyl-2,5- 94 calcd. for C21H31O3 (M + H)+ 331.2268 found 331.2257.
37 diphenylpent-4-en-1-yl)oxy)acrylate (diastereomerc ratio 2:1,
95
38 1l)
96 (E)-Ethyl
3-(((E)-2-methyl-2-phenylhex-4-en-1-
39
97 yl)oxy)acrylate (1o)
40 Pale yellow oil; Rf (hexane/ EtOAc 24:1) 0.48; yield 313 mg,
98
41 68%; 1H NMR (400 MHz) δ 1.18-2.26 (m, 3 H, major & minor), 99 Pale yellow oil; Rf (hexane/ EtOAc 24:1) 0.48; yield 196 mg,
42 1.32 (s, 3 H, major), 1.34 (s, 3 H, minor), 2.56 (dd, J = 14.0 and 100 68%; 1H NMR (400 MHz, CDCl3) δ 1.28 (t, J = 7.6 Hz, 3 H),
43 9.2 Hz, 1 H, minor), 2.71 (dd, J = 14.4 and 9.2 Hz, 1 H, major), 101 1.33 ( s, 3 H ), 1.59 (d, J = 6.8 Hz, 3 H), 2.37 (dd, J = 13.6 and
44 2.95 (ddd, J = 13.6, 5.6 and 4.8 Hz, 1 H, major & minor), 4.02- 102 Hz, 1 H), 2.47 (dd, J = 13.6 and 7.6 Hz, 1 H), 3.84 (d, J = 10.0
45 4.13 (m, 2 H, major & minor), 4.87 (s, 1 H, minor), 4.98 (s, 1 H, 103 Hz, 1 H), 3.90 (d, J = 9.6 Hz, 1 H), 4.14 (q, J =7.2 Hz, 2 H), 5.11-
46 major), 5.12 (d, J = 12.4 Hz, 1 H, minor), 5.16 (d, J = 12.4 Hz, 1 104 5.16 (m, 1 H), 5.19 (d, J = 12.4 Hz, 1 H), 5.37-5.55 (m , 1 H),
47 H, major), 5.78-5.87 (m, 1 H, major), 5.89-5.95 (m, 1 H, minor), 105 7.18-7.24 (m, 1 H), 7.25 -7.39 (m, 4 H), 7.56 (d, J = 12.4 Hz, 1
48 6.40 (d, J =15.6 Hz, 1 H, major & minor), 6.63 (d, J = 8.8 Hz, 2 106 H) ; 13C NMR (100 MHz, CDCl3) δ 14.6, 18.2, 22.8, 41.9, 42.1,
49 H, major), 6.73 (d, J = 8.8 Hz, 2 H, minor), 7.07-7.19 (m, 12 H, 107 59.9, 78.4, 96.5, 126.2, 126.5, 126.5, 128.5, 128.9, 144.7, 162.8,
50 major & minor), 7.39 (d, J = 12.8 Hz, 1 H, minor), 7.49 (d, J = 108 168.1; IR (KBr, neat) 2926, 1708, 1630, 1454, 1323, 1205, 1131,
51 12.4 Hz, 1 H, major); 13C NMR (100 MHz, CDCl3) δ 14.5, 18.6, 109 1042, 964, 749, 701 cm-1; HRMS (ESI) calcd. for C18H25O3 (M +
52 21.3, 41.3, 42.1, 46.4, 46.9, 59.9, 60.0, 90.4, 90.7, 98.9, 99.1, 110 H)+ 289.1798 found 289.1790.
53 125.8, 126.1, 126.2, 126.3, 126.9, 127.0, 127.2, 127.3, 127.9, 111
54 128.0, 128.1, 128.4, 128.5, 128.6, 129.2, 129.7, 133.3, 133.7, 112 (E)-Ethyl
3-(2-(4-methyl-N-(2-
55 133.9, 135.1, 137.6, 141.8, 142.0, 161.3, 161.6, 167.7; IR (KBr, 113 methylallyl)phenylsulfonamido)-2-phenylethoxy)acrylate (1p)
56 neat) 2979, 1707, 1642, 1492, 1321, 1220, 1131, 1048, 761, 686 114
57 cm-1; HRMS (ESI) calcd. for C29H30ClO3 (M + H)+ 461.1878 115 Pale yellow oil; Rf (hexane/ EtOAc 17:3) 0.40; yield 244 mg,
1
58 found 461.1885.
116 55%; H NMR (400 MHz, CDCl3) δ 1.28 (t, J = 7.2 Hz, 3 H),
6
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 7 of 10
Organic & Biomolecular Chemistry
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2
1.56 ( s, 3 H), 2.45 ( s, 3 H), 3.35 (d, J = 16.0 Hz, 1 H), 3.84 (d, J 59 Ethyl
2-((1S*,3aS*)-3a,6,6-trimethyl-1,3,3a,4,5,6-
= 16.0 Hz, 1 H), 4.14-4.19 (m, 3 H), 4.32-4.41 (m, 2 H), 4.77 (s, 60 hexahydrobenzo[de]isochroman-1-yl)acetate (2b)
View Article Online
DOI: 10.1039/C5OB02038G
3
1 H), 4.85 (s, 1 H), 5.20 (d, J = 12.8 Hz, 1 H), 7.02-7.04 (m, 2 H),
61
4
7.24-7.29 (m, 5 H), 7.45 (d, J = 12.8 Hz, 1 H), 7.68 (d, J = 8.4 62 Pale yellow oil; Rf (hexane/ EtOAc 24:1) 0.48; yield 227 mg,
Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 14.5, 20.0, 21.7, 51.5, 63 75%; 1H NMR (600 MHz, CDCl3) δ 1.19 (s, 3 H), 1.29 (t, J = 7.2
59.4, 60.1, 69.6, 97.4, 114.7, 127.7, 128.6, 128.7, 128.8, 129.7, 64 Hz, 3 H), 1.33 ( s, 3 H), 1.38 (dt, J = 12.6 and 3.6 Hz, 1 H), 1.40
134.7, 137.9, 142.3, 143.7, 161.4, 167.7; IR (KBr, neat) 2920, 65 (s, 3 H), 1.50 (dt, J = 13.2 and 3.0 Hz, 1 H), 1.63 (dt, J = 13.8
1725, 1632, 1443, 1219, 1039, 928, 772, 680 cm-1; HRMS (ESI) 66 and 3.0 Hz, 1 H), 2.11 (dt, J = 14.4 and 3.6 Hz, 1 H), 2.82 (dd, J
5
6
7
8
9
calcd. for C24H30NO5S (M + H)+ 444.1839 found 444.1839.
67 = 15.0 and 9.6 Hz, 1 H), 2.94 (dd, J = 15.0 and 3.0 Hz, 1 H), 3.49
68 (d, J = 10.8, 1 H), 3.67 (d, J = 10.8, 1 H), 4.20-4.24 ( m, 2 H),
10
11 (E)-Ethyl
3-(2-(4-methyl-N-(2- 69 5.32 (dd, J = 9.6 and 3.0 Hz, 1 H), 6.84 (d, J = 7.2 Hz, 1 H), 7.15
70 (t, J = 7.8 Hz, 1 H), 7.21 (d, J = 7.8 Hz, 1 H); 13C NMR (150
12 phenylallyl)phenylsulfonamido)-2-phenylethoxy)acrylate (1q)
13 71 MHz, CDCl3) δ 14.4, 27.1, 28.9, 32.4, 33.9, 34.0, 34.1, 34.6,
14 Pale yellow oil; Rf (hexane/ EtOAc 17:3) 0.40; yield 288 mg, 72 43.7, 60.8, 74.1, 75.3, 122.2, 125.9, 126.4, 134.6, 138.0, 144.3,
1
15 57%; H NMR (600 MHz, CDCl3) δ 1.27 (t, J = 7.2 Hz, 3 H), 73 171.7; IR (KBr, neat) 2961, 2866, 1737, 1472, 1286, 1220, 1159,
16 2.44 (s, 3 H), 3.92 (d, J = 16.2 Hz, 1 H), 4.06 (dd, J = 10.2 and 74 1097, 1032, 765 cm-1; HRMS (ESI) calcd. for C19H27O3 (M + H)+
17 3.6 Hz, 1 H), 4.15 (q, J = 7.2 Hz, 2 H), 4.28 (dd, J = 10.2 and 1.8 75 303.1955 found 303.1955.
18 Hz, 1 H), 4.39 (d, J = 16.2 Hz, 1 H), 5.05 (d, J = 12.6 Hz, 1 H),
19 5.11 (s, 1 H), 5.18 (t, J = 7.2 Hz, 1 H), 5.34 (s, 1 H), 6.99 (d, J = 77 Ethyl
20 7.8 Hz, 2 H), 7.20-7.32 (m, 12 H), 7.60 (d, J = 8.4 Hz, 1 H); 13C 78 1,3,3a,4,5,6-hexahydrobenzo[de]iso-chroman-1-yl)acetate (2c)
21 NMR (150 MHz, CDCl3) δ 14.6, 21.7, 49.6, 59.2, 60.1, 69.9,
76
2-((1S*,3R*,3aS*)-3a,6,6-trimethyl-3-phenyl-
79
22 97.4, 116.8, 126.8, 127.8, 128.3, 128.6 (2C), 128.7 (2C), 129.7, 80 Pale yellow oil; Rf (hexane/ EtOAc 24:1) 0.48; yield 246 mg,
23 134.6, 137.6, 138.7, 143.7, 144.5, 161.3, 167.7; IR (KBr, neat) 81 65%; 1H NMR (600 MHz, CDCl3) δ 1.15 (s, 3 H), 1.24 (s, 3 H),
24 2931, 1707, 1632, 1332, 1145, 1042, 732 cm-1; HRMS (ESI) 82 1.28 (t, J = 7.2 Hz, 3 H), 1.31 (dt, J = 15.0 and 7.2 Hz, 1 H), 1.37
25 calcd. for C29H32NO5S (M + H)+ 506.1996 found 506.2000.
83 (s, 3 H), 1.55 (dt, J = 13.8 and 3.0 Hz, 1 H), 1.68 (dt, J = 13.8 and
84 2.4 Hz, 1 H), 1.92 (dt, J = 14.4 and 2.4 Hz, 1 H), 2.93 (dd, J =
26
27 General Procedure for the Synthesis of cyclized product 2a-q: 85 14.4 and 9.0 Hz, 1 H), 2.98 (dd, J = 14.4 and 3.6 Hz, 1 H ), 4.16-
86 4.20 ( m, 1 H), 4.22-4.30 ( m, 1 H), 4.52 ( s, 1 H), 5.50 ( dd, J =
28
29 To a solution of enol ether (1.0 mmol) in dry dichloromethane (1 87 9.6 and 4.2 Hz, 1 H), 6.91 (d, J = 7.2 Hz, 1 H), 7.20 (t, J = 7.8
30 mL) at 0 °C was added trifluoromethanesulfonic acid (10 mol%) 88 Hz, 1 H), 7.26-7.29 (m, 2 H), 7.31 (t, J = 7.8 Hz, 2 H), 7.38 (d, J
31 under a N2 atmosphere.. The reaction mixture was stirred for 10 89 = 7.2 Hz, 2 H); 13C NMR (150 MHz, CDCl3) δ 14.2, 22.4, 29.7,
32 minutes. The progress of the reaction was monitored by TLC 90 32.4. 33.8, 34.1, 34.3, 37.7, 44.3, 60.8, 74.7, 87.2, 122.4, 126.2,
33 with ethyl acetate and hexane (EtOAc/hexane 24:1) as eluents. 91 126.5, 127.5, 128.2, 134.7, 135.6, 138.8, 139.0, 144.7, 171.6; IR
34 After the completion of the reaction, the solvent was removed on 92 (KBr, neat) 2960, 1717, 1622, 1447, 1369, 1220, 1123, 1094,
35 a rotary evaporator and quenched with a saturated solution of 93 1029, 854, 165, 703 cm-1; HRMS (ESI) calcd. for C25H31O3 (M +
36 NaHCO3 (2 mL). The product was extracted with ethyl acetate 94 H)+ 379.2268 found 379.2267.
37 (10 mL) and then washed with brine solution (3 mL). The organic
95
38 layer was dried (Na2SO4) and evaporated to give the crude 96 Ethyl 2-((1S*,3R*,3aS*)-3-(4-chlorophenyl)-3a,6,6-trimethyl-
39 product, which was purified by column chromatography over 97 1,3,3a,4,5,6-hexahydro-benzo[de]isochroman-1-yl)acetate (2d)
40 silica gel giving corresponding products 2a-q.
98
41
99 Colourless oil; Rf (hexane/ EtOAc 24:1) 0.48; yield 313 mg,
2-((1S*,3aR*)-6,6-dimethyl-1,3,3a,4,5,6- 100 76%; 1H NMR (600 MHz, CDCl3) δ 1.11 ( s, 3 H), 1.23 (s, 3 H),
42 Ethyl
43 hexahydrobenzo[de]isochroman-1-yl)acetate (2a)
101 1.26-1.29 (m, 4 H), 1.37 (s, 3 H), 1.55 (dt, J = 13.8 and 3.0 Hz, 1
44
102 H), 1.65 (dt, J = 13.8 and 2.4 Hz, 1 H), 1.92 (dt, J = 13.8 and 2.4
45 Pale yellow oil; Rf (hexane/ EtOAc 24:1) 0.48; yield 219 mg, 103 Hz, 1 H), 2.91 (dd, J = 14.4 and 9.0 Hz, 1 H), 2.98 (dd, J = 14.4
46 76%; 1H NMR (400 MHz, CDCl3) δ 1.23 (s, 3 H), 1.26 (t, J = 7.2 104 and 3.6 Hz, 1 H), 4.16-4.20 (m, 1 H), 4.22-4.26 (m, 1 H), 4.49 (s,
47 Hz, 3 H), 1.36 ( s, 3 H), 1.65-1.71 (m, 2 H), 1.74- 1.77 (m, 2 H), 105 1 H), 5.49 (dd, J = 9.6 and 3.6 Hz, 1 H), 6.91 ( d, J = 7.8 Hz, 1
48 2.72 (dd, J = 15.2 and 9.2 Hz, 1 H), 2.88 (dd, J = 15.2 and 8.0 Hz, 106 H), 7.20 (t, J = 7.8 Hz, 1 H) , 7.26-7.31 ( m, 5 H); 13C NMR (150
49 1 H), 2.92 (dd, J = 12.0 and 7.2 Hz, 1 H), 3.36 (dd, J = 11.2 and 107 MHz, CDCl3) δ 14.5, 22.3, 29.7, 32.4. 33.8, 34.0, 34.3, 37.6,
50 10.4 Hz, 1 H ), 4.03 ( dd, J = 10.4 and 4.8 Hz, 1 H), 4.19 (q, J = 108 44.2, 60.9, 74.8, 82.9, 122.4, 126.3, 126.6, 127.7, 129.5, 133.3,
51 7.2 Hz, 2 H), 5.31 (d, J = 6.8 Hz, 1 H), 6.87 ( d, J = 7.2 Hz, 1 H), 109 134.5, 137.3, 138.7, 144.7, 171.5; IR (KBr, neat) 2929, 1734,
52 6.17 (t, J = 7.6 Hz, 1 H), 7.24 (d, J = 7.6 Hz, 1 H); 13C NMR (100 110 1448, 1375, 1220, 1168, 1088, 1028, 930, 771, 680 cm-1; HRMS
53 MHz, CDCl3) δ 14.4, 21.6, 31.9. 32.8, 34.5, 36.6, 38.3, 43.3, 111 (ESI) calcd. for C25H30ClO3 (M + H)+ 413.1878 found 413.1884.
54 60.5, 69.6, 74.1, 122.8, 125.2, 126.2, 133.8, 135.1, 145.8, 171.3; 112
55 IR (KBr, neat) 2926, 2858, 1735, 1445, 1373, 1220, 1180, 1029, 113 Ethyl
2-((1S*,3R*,3aS*)-3a,6,6-trimethyl-3-(p-tolyl)-
56 855, 761 cm-1; HRMS (ESI) calcd. for C18H25O3 (M + H)+ 114 1,3,3a,4,5,6-hexahydro-benzo[de]iso-chroman-1-yl)acetate
57 289.1798 found 289.1799.
115 (2e)
58
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Pale yellow oil; Rf (hexane/ EtOAc 24:1) 0.48; yield 267 mg, 59 Pale yellow oil; Rf (hexane/ EtOAc 24:1) 0.48; yield 260 mg,
1
68%; 1H NMR (600 MHz, CDCl3) δ 1.15 (s, 3 H), 1.23 (s, 3 H), 60 71%; H NMR (600 MHz, CDCl3) δ 1.20 (s, 3 H), 1.23-1.29 (m,
1.25-1.29 (m, 4 H), 1.37 (s, 3 H), 1.54 (dt, J = 10.8 and 3.0 Hz, 1 61 4 H), 1.33 (s, 3 H), 1.66-1.69 (m, 1 H), 1.71D-O1I.:7160.(1m03,9V2i/eCwH5A)O,rtBic20le.27O013nl8inGe
H), 1.66 (dt, J = 12.0 and 2.4 Hz, 1 H), 1.91 (dt, J = 13.8 and 1.8 62 (dd, J = 15.6 and 9.0 Hz, 1 H), 2.80-2.85 (m, 2 H), 3.31 (t, J =
Hz, 1 H), 2.35 (s, 3 H), 2.92 (dd, J = 14.4 and 9.0 Hz, 1 H), 2.97 63 10.8 Hz, 1 H), 4.02 (dd, J = 10.8 and 4.8 Hz, 1 H), 4.17-4.20 (m,
(dd, J = 14.4 and 3.6 Hz, 1 H), 4.15-4.18 ( m, 1 H), 4.19-4.25 (m, 64 2 H), 5.23 (dd, J = 9.0 and 3.0 Hz, 1 H), 7.0 (s, 1 H), 7.32 ( d, J =
1 H), 4.48 (s, 1 H), 5.49 (dd, J = 9.0 and 3.6 Hz , 1 H), 6.91 (d, J 65 1.8 Hz, 1 H); 13C NMR (150 MHz, CDCl3) δ 14.4, 21.7, 32.1,
= 7.8 Hz, 1 H), 7.12 ( d, J = 7.2 Hz, 2 H), 7.19 (t, J = 7.8 Hz, 1 66 33.0, 35.1, 36.7, 38.4, 43.3, 60.9, 69.8, 73.9, 120.5, 125.1, 128.7,
H), 7.25-7.26 ( m, 3 H); 13C NMR (150 MHz, CDCl3) δ 14.5, 67 133.2, 137.9, 147.8, 171.2; IR (KBr, neat) 2961, 1736, 1445,
10 21.3, 22.4, 29.7, 32.4. 33.9, 34.1, 34.3, 37.7, 44.3, 60.8, 74.7, 68 1371, 1220, 1108, 1028, 931, 855, 761, 685 cm-1; HRMS (ESI)
11 83.3, 122.4, 126.2, 126.5, 128.1, 128.2, 134.7, 135.9, 137.1, 69 calcd. for C18H23NaBrO3 (M + Na)+ 389..0723 found 389.0722.
12 139.1, 144.7, 171.6; IR (KBr, neat) 2980, 2924, 1709, 1623, 70
13 1445, 1376, 1220, 1130, 1046, 944, 760, 699 cm- 1; HRMS (ESI) 71 Ethyl
2-((1S*,3aR*)-6,6,8-trimethyl-1,3,3a,4,5,6-
72 hexahydrobenzo[de]isochroman-1-yl)acetate (2i)
14 calcd. for C26H33O3 (M + H)+ 393.2424 found 393.2427.
15
73
16 Ethyl
2-((1S*,3R*,3aS*)-3-(4-methoxyphenyl)-3a,6,6- 74 Colourless oil; Rf (hexane/ EtOAc 24:1) 0.48; yield 187 mg,
17 trimethyl-1,3,3a,4,5,6-hexahydro-benzo[de]isochroman-1-
75 62%; 1H NMR (600 MHz, CDCl3) δ 1.22 (s, 3 H), 1.23-1.28 (m,
76 4 H), 1.35 ( s, 3 H), 1.65-1.70 (m, 1 H), 1.72-1.75 (m, 2 H), 2.30
77 (s, 3 H), 2.71 (dd, J = 15.0 and 9.6 Hz, 1 H), 2.85-2.88 (m, 2 H),
18 yl)acetate (2f)
19
20 Pale yellow oil; Rf (hexane/ EtOAc 24:1) 0.48; yield 306 mg, 78 3.32 (t, J = 10.8 Hz, 1 H), 4.02 (dd, J = 10.8 and 4.2 Hz, 1 H),
21 75%; 1H NMR (600 MHz, CDCl3) δ 1.14 (s, 3 H), 1.23 (s, 3 H), 79 4.20 (q, J = 7.2 Hz 2 H), 5.28 (dd, J = 10.2 and 7.2 Hz, 1 H), 6.70
22 1.23-1.29 (m, 4 H), 1.37 (s, 3 H), 1.54 (dt, J = 13.8 and 3.6 Hz, 1 80 (s, 1 H), 7.04 (s, 1 H); 13C NMR (150 MHz, CDCl3) δ 14.4, 21.6,
23 H), 1.64 (dt, J = 13.8 and 3.0 Hz, 1 H), 1.92 (dt, J = 13.8 and 3.6 81 22.0, 32.3, 33.1, 34.7, 36.7, 38.7, 43.7, 60.8, 70.0, 74.4, 122.9,
24 Hz, 1 H), 2.92 (dd, J = 14.4 and 9.0 Hz, 1 H), 2.97 (dd, J = 14.4 82 126.3, 131.2, 135.4, 135.8, 145.0, 171.7; IR (KBr, neat) 2925,
25 and 3.6 Hz, 1 H), 3.81 (s, 3 H), 4.17 (dd, J = 10.8 and 7.2 Hz, 1 83 2858, 1736, 1612, 1465, 1374, 1220, 1168, 1109, 1031, 856, 772
26 H), 4.24 (dd, J = 10.8 and 7.2 Hz, 1 H), 4.47 (s, 1 H), 5.49 (dd, J 84 cm-1; HRMS (ESI) calcd. for C19H27O3 (M + H)+ 303.1955 found
27 = 9.0 and 3.6 Hz, 1 H), 6.86 (d, J = 6.6 Hz, 2 H), 6.90 (d, J = 7.8 85 303.1955.
28 Hz, 1 H), 7.18 ( t, J =7.8 Hz, 1 H), 7.25 (d, J = 7.8 Hz, 1 H), 7.28
29 (d, J = 9.0 Hz, 2 H); 13C NMR (150 MHz, CDCl3) δ 14.5, 22.3, 87 Ethyl
30 29.7, 32.4. 33.9, 34.0, 34.3, 37.7, 44.32, 55.42, 60.8, 74.7, 83.1, 88 hexahydro-benzo[de]isochroman-1-yl)acetate (2j)
31 113.0, 122.4, 126.2, 126.5, 129.2, 131.1, 134.7, 139.1, 144.7,
86
2-((1S*,3aR*)-8-methoxy-6,6-dimethyl-1,3,3a,4,5,6-
89
32 159.1, 171.6; IR (KBr, neat) 2960, 1735, 1613, 1514, 1370, 1220, 90 Pale yellow oil; Rf (hexane/ EtOAc 24:1) 0.48; yield 235 mg,
33 1123, 1035, 930, 759, 685 cm-1; HRMS (ESI) calcd. for 91 74%; 1H NMR (600 MHz, CDCl3) δ 1.22 ( s, 3 H), 1.22-1.29 (m,
34 C26H32NaO4(M + Na)+ 431.2193 found 431.2186.
92 4 H), 1.34 (s, 3 H), 1.62-1.67 (m, 1 H), 1.72- 1.75 (m, 2 H), 2.72
35
93 (t, J = 15.0 and 9.6 Hz, 1 H), 2.81-2.86 (m, 2 H), 3.31 (t, J = 10.2
36 Ethyl
2-((1S*,3R*,3aS*)-3-(3-methoxyphenyl)-3a,6,6- 94 Hz, 1 H), 3.77 (s, 3 H), 4.00 (dd, J = 10.8 and 4.8 Hz, 1 H), 4.20
37 trimethyl-1,3,3a,4,5,6-hexahydrobenzo[de]isochromen-1-
95 (q, J = 7.2 Hz 2 H), 5.26 (dd, J = 9.0 and 3.0 Hz, 1 H), 6.41 (d, J
96 = 2.4 Hz, 1 H), 6.77 ( d, J = 2.4 Hz, 1 H); 13C NMR (150 MHz,
97 CDCl3) δ 14.4, 22.0, 32.3, 33.0, 35.1, 36.4, 38.7, 43.6, 55.4, 60.9,
38 yl)acetate (2g)
39
40 Pale yellow oil; Rf (hexane/ EtOAc 24:1) 0.48; yield 224 mg, 98 70.2, 74.4, 107.4, 111.6, 126.7, 136.8, 146.8, 158.2, 171.6; IR
1
41 55%; H NMR (600 MHz, CDCl3) ) δ 1.14 (s, 3 H), 1.23 (s, 3 99 (KBr, neat) 2959, 2858, 1736, 1605, 1471, 1372, 1220, 1174,
42 H), 1.23-1.29 (m, 4 H), 1.37 (s, 3 H), 1.54 (dt, J = 14.0 and 4.0 100 1112, 1063, 854, 765 cm-1; HRMS (ESI) calcd. for C19H27O4(M
43 Hz, 1 H), 1.64 (dt, J = 14.0 and 4.0 Hz, 1 H), 1.92 (dt, J = 14.0 101 + H)+ 319.1904 found 319.1906.
44 and 4.0 Hz, 1 H), 2.92 (dd, J = 18.0 and 6.0 Hz, 1 H), 2.97 (dd, J 102
45 = 12.0 and 6.0 Hz, 1 H), 3.81 (s, 3 H), 4.16-4.27 (m, 2 H), 4.47 103 Ethyl
2-((1S*,3aS*)-3a-methyl-6-phenyl-1,3,3a,4,5,6-
46 (s, 1 H), 5.49 (dd, J = 12.0 and 6.0 Hz, 1 H), 6.86 (d, J = 7.2 Hz, 104 hexahydrobenzo[de]isochroman-1-yl)acetate (diastereomeric
47 1 H), 6.91 (d, J = 7.2 Hz, 1 H), 6.95-6.96 (m, 2 H), 7.19 (t, J = 105 mixture, 3:1, 2k)
48 7.2 Hz, 1 H), 7.23 (t, J = 8.0 Hz, 1 H), 7.27-7.29 (m, 1 H). 13C 106
49 NMR (150 MHz, CDCl3) δ 14.3, 22.9, 29.9, 32.2, 33.9, 34.0, 107 Pale yellow oil; Rf (hexane/ EtOAc 24:1) 0.48; yield 245 mg,
1
50 34.1, 37.7, 44.3, 55.5, 60.8, 74.8, 83.4, 112.7, 114.3, 120.9, 108 70%; H NMR (400 MHz, CDCl3) δ 1.22-1.32 (m, 4 H), 1.40 (s,
51 122.4, 126.2, 126.5, 128.4, 134.5, 139.5, 140.5, 144.7, 159.1, 109 3 H, minor), 1.49 (s, 3 H, major), 1.52-1.59 (m, 2 H), 1.81-1.86
52 171.6. IR (KBr, neat) 2952, 1729, 1610, 1530, 1365, 1218, 1120, 110 (m, 1 H, minor), 2.13-2.20 (m, 1 H, major), 2.56-2.61 (m, 1 H,
53 1030, 925, 765, 690 cm-1; HRMS (ESI) calcd. for C26H32NaO4 (M 111 minor), 2.81-2.89 (m, 1 H, major), 2.94-3.00 (m, 1 H), 3.55 (d, J
54 + Na)+ 431.2193 found 431.2197.
112 = 10.4 Hz, 1 H, major), 3.59 (d, J = 10.8 Hz, 1 H, minor), 3.72 (
113 d, J = 10.8 Hz, 1 H, major), 3.74 (d, J = 11.2 Hz, 1 H, minor),
55
56 Ethyl
2-((1S*,3aR*)-8-bromo-6,6-dimethyl-1,3,3a,4,5,6- 114 4.06 ( t, J = 9.2 Hz, 1 H), 4.20-4.26 (m, 2 H), 5.35 (dd, J = 9.0
57 hexahydrobenzo[de]isochroman-1-yl)acetate (2h)
115 and 3.0 Hz, 1 H, major), 5.37 (dd, J = 9.6 and 6.6 Hz, 1 H,
116 minor), 6.69-6.73 (m, 1 H), 6.88 ( m, 1 H), 6.95 (d, J = 6.8 Hz, 1
58
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H), 6.97-7.04 (m, 1 H), 7.15-7.25 (m, 3 H), 7.29-7.33 (m, 1 H); 59 9.6 Hz, 1 H), 2.93 (dd, J = 15.6 and 3.0 Hz, 1 H), 3.56 (dd, J =
13C NMR (150 MHz, CDCl3) δ 14.4, 14.7, 26.9, 27.5, 27.6, 27.8, 60 12.0 and 3.6 Hz, 1 H), 4.16-4.30 (m, 2 H), 5.19 (dd, J = 9.6 and
29.0, 32.0, 33.7, 43.3, 43.4, 43.5, 46.7, 59.5, 60.9, 74.2, 75.3, 61 3.0 Hz, 1 H), 6.82 (d, J = 7.8 Hz, 1 H), 7.12 (t, J =V7ie.w8 AHrtzic,le1OHnli)n,e
DOI: 10.1039/C5OB02038G
75.6, 122.5, 122.6, 126.1, 126.3, 126.4, 128.5, 128.7, 128.7, 62 7.20 (d, J = 7.8 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 10.7,
128.8, 128.9, 134.7, 137.9, 138.1, 139.5, 148.0, 148.6, 171.7; IR 63 14.3, 20.6, 28.5, 32.2, 33.9, 34.3, 34.6, 37.3, 43.5, 60.8, 61.5,
(KBr, neat) 2926, 1736, 1449, 1220, 1096, 772, 702 cm-1; 64 68.4, 82.3, 121.8, 125.8, 125.9, 134.7, 136.2, 145.1, 171.8; IR
HRMS (ESI) calcd. for C23H27O3 (M + H)+ 351.1955 found 65 (KBr, neat) 2927, 1738, 1637, 1372, 1220, 1127, 1038, 772 cm-1;
351.1953.
66 HRMS (ESI) calcd. for C21H31O3 (M + H)+ 331.2268 found
67 331.2261.
10 Ethyl
2-((1S*,3R*,3aS*)-3-(4-chlorophenyl)-3a-methyl-6-
68
11 phenyl-1,3,3a,4,5,6-hexahydro-benzo[de]isochroman-1-
69 Ethyl
2-((1S*,3aS*)-3a,6-dimethyl-1,3,3a,4,5,6-
12 yl)acetate (diastereomerc mixture, 4:1, 2l)
70 hexahydrobenzo[de]isochroman-1-yl)acetate (diastereomerc
13
71 ratio 8:5, 2o)
14 Colourless oil; Rf (hexane/ EtOAc 24:1) 0.48; yield 345 mg,
1
72
15 75%; H NMR (600 MHz, CDCl3) δ 1.20-1.30 (m, 6 H), 1.32- 73 Colourless oil; Rf (hexane/ EtOAc, 24:1) 0.48; yield 164 mg,
1
16 1.36 (m, 1 H), 1.64-1.80 (m, 1 H), 1.93-2.05 (m, 1 H), 2.08-2.12 74 57%; H NMR (600 MHz, CDCl3) δ 1.23 (d, J = 6.6 Hz, 3 H,
17 (m, 1 H), 2.93-2.96 (m, 1 H), 3.00-3.06 (m, 1 H), 4.06-4.26 (m, 3 75 major), 1.24 (d, J = 6.6 Hz, 3 H, minor), 1.27-39 (m, 6 H), 1.41-
18 H), 4.55 (s, 1 H, major), 4.60 (s, 1 H, minor), 5.53 (dd, J = 9.6 76 1.45 (m, 1 H), 1.47-1.55 (m, 1 H), 1.58-1.652 (m, 1 H, major),
19 and 3.6 Hz, 1 H, major), 5.57 (dd, J = 9.0 and 3.6 Hz, 1 H, 77 1.77-1.84 (m 1 H, minor), 1.98-2.05 (m, 1 H, major), 2.25-2.33
20 minor), 6.77 (d, J = 7.8 Hz, 1 H, major), 6.82 (d, J = 7.2 Hz, 1 H, 78 (m, 1 H, minor), 2.65 (dt, J = 15.0 and 3.0 Hz, 1 H, major), 2.80-
21 minor), 6.93 (d, J = 7.8 Hz, 1 H, major), 6.97 (d, J = 7.8 Hz, 1 H, 79 3.00 (m, 2 H), 3.02-3.05 (m, 1 H, minor), 3.45-3.70 (2 H), 4.17-
22 minor), 7.04-7.10 (m, 1 H), 7.18-7.33 (m, 9 H); 13C NMR (100 80 4.26 (m, 2 H), 5.28-5.32 (m, 1 H, minor), 5.47-5.51 (m, 1 H,
23 MHz, CDCl3) δ 14.5, 22.2, 22.9, 27.1, 28.0, 29.0, 29.9, 32.1, 81 major), 6.81-6.86 (m, 1 H), 7.04-7.14 (m, 2 H); 13C NMR (100
24 32.8, 37.4, 44.1, 46.6, 60.9, 74.8, 74,9, 82.9, 83.1, 122.8, 122.9, 82 MHz, CDCl3) δ 14.4, 19.7, 25.1, 30.9, 33.6, 35.4, 36.2, 41.7,
25 126.4, 126.5, 127.7, 127.8, 128.5, 128.7, 128.8, 129.3, 129.5, 83 42.1, 43.1, 43.8, 47.1, 61.0, 69.7, 69.8, 72.7, 73.8, 73.9, 120.3,
26 129.9, 133.4, 134.6, 137.2, 138.6, 140.1, 147.9, 171.5; IR (KBr, 84 120.5, 126.4, 126.7, 128.6, 128.7, 134.5, 134.8, 137.8, 137.9,
27 neat) 2979, 1733, 1444, 1371, 1220, 1036, 931, 854, 761, 685 cm- 85 146.6, 147.2, 171.1; IR (KBr, neat) 2927, 2855, 1734, 1621,
28 1; HRMS (ESI) calcd. for C29H30ClO3 (M + H)+ 461.1878 found 86 1451, 1372, 1286, 1163, 1095, 1028, 805, 848, 702 cm-1; HRMS
29 461.1883.
30
87 (ESI) calcd. for C18H25O3 (M + H)+ 289.1798 found 289.1795.
88
31 Ethyl
2-((1S*,3aR*)-8-bromo-6-phenyl-1,3,3a,4,5,6- 89 Ethyl
2-((7R*,9aS*)-3,3-dimethyl-1-tosyl-1,2,3,7,9,9a-
32 hexahydrobenzo[de]isochroman-1-yl)acetate (diastereomeric 90 hexahydropyrano[3,4,5-ij]isoquinolin-7-yl)acetate (2p)
33 mixture, 8:1, 2m)
91
34
92 Pale yellow oil; Rf (hexane/ EtOAc 17:3) 0.48; yield 399 mg,
35 Pale yellow oil; Rf (hexane/ EtOAc 24:1) 0.48; yield 294 mg, 93 90%; 1H NMR (400 MHz, CDCl3) δ 1.18 (s, 3 H), 1.22 (t, J = 7.2
36 71%; 1H NMR (400 MHz, CDCl3) δ 1.22-1.30 (m, 4 H), 1.59- 94 Hz, 3 H), 1.35 (s, 3 H), 2.41 (s, 3 H), 2.66 (dd, J = 15.6 and 8.8
37 1.63 (m, 1 H), 1.82-1.97 (m, 1 H), 2.21- 2.31 (m, 1 H), 2.62-2.83 95 Hz, 1 H), 2.80 (dd, J = 15.2 and 3.2 Hz, 1 H), 3.16 (d, J = 12.4
38 (m, 1 H), 2.87-3.06 (m, 2 H), 3.40 (dt, J = 11.2 and 10.4 Hz, 1 96 Hz, 1 H), 3.41 (d, J = 12.0 Hz, 1 H), 3.54 (t, J = 10.4 Hz, 1 H),
39 H), 4.00-4.06 (m, 1 H), 4.08- 4.13 (m, 1 H), 4.19-4.24 (m, 2 H), 97 4.15 (q, J = 7.2 Hz, 2 H), 4.34 (dd, J = 9.6 and 4.4 Hz, 1 H), 4.61
40 5.18-5.20 (m, 1 H, minor), 5.26-5.33 (m, 1 H, major), 6.87-6.96 98 (dd, J = 10.4 and 4.0 Hz, 1 H), 5.22 (dd, J = 8.8 and 3.2 Hz, 1 H),
41 (m, 2 H), 7.03-7.08 (s, 1 H), 7.15-7.22 (m, 2 H), 7.24-7.34 (m, 2 99 6.87-6.89 (m, 1 H), 7.18-7.22 (m, 2 H), 7.30 (d, J = 7.6 Hz, 2 H),
42 H); 13C NMR (150 MHz, CDCl3) δ 14.3, 14.4, 22.9, 25.1, 32.2, 100 7.71 (d, J = 8.0 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 14.4,
43 33.6, 34.0, 35.4, 43.2, 43.8, 61.0, 69.8, 69.9, 73.8, 73.9, 120.3, 101 21.7, 27.3, 28.6, 36.0, 43.1, 53.9, 57.0, 61.0, 67.5, 74.0, 122.9,
44 120.5, 125.6, 125.64, 126.5, 126.8, 128.6, 128.7, 128.9, 129.0, 102 123.9, 127.4, 127.6, 130.1, 135.5, 136.7, 143.4, 143.8, 171.1; IR
45 131.0, 131.3, 131.6, 134.4, 137.8, 137.9, 139.5, 140.7, 146.6, 103 (KBr, neat) 2971, 1734, 1447, 1337, 1220, 1160, 1103, 1036,
46 147.2, 171.1, 171.2; IR (KBr, neat) 2929, 1736, 1619, 1447, 104 927, 771, 679 cm-1; HRMS (ESI) calcd. for C24H30NO5S (M +
47 1372, 1220, 1163, 1094, 768, 685 cm-1; HRMS (ESI) calcd. for 105 H)+ 444.1839 found 444.1839.
48 C22H24BrO3 (M + H)+ 415.0903 found 415.0894.
106
49
107 Ethyl
2-((3S*,7R*,9aS*)-3-methyl-3-phenyl-1-tosyl-
50 Ethyl 2-((1S*,3R*,3aS*)-3-ethyl-3a,6,6-trimethyl-1,3,3a,4,5,6- 108 1,2,3,7,9,9a-hexahydropyrano[3,4,5-ij]isoquinolin-7-yl)acetate
51 hexahydro-benzo[de]isochroman-1-yl)acetate (2n)
109 (2q)
52
110
53 Colourless oil, Rf (hexane/ EtOAc 24:1) 0.48; yield 241 mg, 111 Pale yellow oil; Rf (hexane/ EtOAc 17:3) 0.48; yield 429 mg,
1
54 73%; H NMR (600 MHz, CDCl3) δ 1.04 (t, J = 7.2 Hz, 3 H), 112 85%; 1H NMR (400 MHz, CDCl3) δ 1.27 (s, 3 H), 1.66 (s, 3 H),
55 1.17 (s, 3 H), 1.22-1.26 (m, 1 H), 1.29 (t, J = 7.2 Hz, 3 H), 1.31- 113 2.40 (s, 3 H), 2.77 (dd, J = 15.6 and 8.4 Hz, 1 H), 2.86 (dd, J =
56 1.35 (m, 1 H), 1.37 ( s, 3 H ), 1.41 (s, 3 H), 1.50-1.55 (m, 1 H), 114 15.6 and 3.6 Hz, 1 H), 3.46 (d, J = 13.2 Hz, 1 H), 3.50 (d, J =
57 1.58 (dt, J = 13.8 and 3.0 Hz, 1 H), 1.71 (dt, J = 13.8 and 3.0 Hz, 115 10.2 Hz, 1 H), 3.72 (d, J = 12.6 Hz, 1 H), 4.19 (q, J = 7.2 Hz, 2
58 1 H), 2.06 (dt, J = 13.8 and 3.0 Hz, 1 H), 2.78 (dd, J = 15.0 and 116 H), 4.57 (dd, J = 10.2 and 4.2 Hz, 1 H), 4.69 (dd, J = 10.2 and 4.2
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Journal Name, [year], [vol], 00–00 | 9

Organic & Biomolecular Chemistry
Page 10 of 10
59 2 (a) E. C. Taylor and A. Weissberger, The Chemistry of Heterocyclic
1
2
Hz, 1 H), 5.32 (dd, J = 8.4 and 3.6 Hz, 1 H), 6.80 (d, J = 7.8 Hz,
60
61
62
63
64
65
66
67
Compounds: John Wiley & Sons: New Work, 1981, 1990, 1995, Vol.
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DOI: 10.1039/C5OB02038G
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1 H), 6.94 (d, J = 7.8 Hz, 1 H), 7.11-7.15 (m, 3 H), 7.23 (d, J =
8.4 Hz, 2 H), 7.25 (d, J = 7.2 Hz, 1 H), 7.30 (t, J = 7.2 Hz, 2 H),
7.56 (d, J = 8.4 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 14.4,
21.7, 25.4, 43.2, 44.2, 53.2, 56.7, 61.0, 67.2, 74.0, 123.2, 126.8,
126.9, 127.3, 127.4, 127.8, 128.4, 129.9, 130.8, 135.5, 137.7,
142.6, 143.7, 145.8, 171.1; IR (KBr, neat) 2925, 2854, 1735.
1624, 1468, 1332, 1158, 1090, 1026, 830, 767 cm-1; HRMS (ESI)
calcd. for C29H32NO5S (M + H)+ 506.1996 found 506.1994.
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14 Leishmania donovani (MHOM/IN/2010/BHU 1081) strain was
15 obtained from Dr. Shyam Sundar, Banaras Hindu University,
16 Varanasi and cultivated in M199 liquid media supplemented with
17 15% heat-inactivated fetal bovine serum (FBS), 100 U penicillin
18 and 100 µg ml-1 streptomycin was used for assessing the anti-
19 leishmanial activity of 2f, 2j and 2p. The anti-leishmanial effect
20 was checked using methods reported earlier.9a,10,11 MTT [ 3-(4,5-
21 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay
22 was employed to check the antileishmanial efficacy of the
23 compounds. Exponential phase promastigote cells (2.5 x 106)
24 were seeded in a 96 well plate and treated with varying
25 concentrations of compounds and incubated at 25°C for 24 hours.
26 Cells were centrifuged and resuspended in MTT (0.5mg/ml) and
27 again incubated at 25°C for 4 hours. Cells were again centrifuged
28 and DMSO was added to dissolve the formazon pellet and
29 absorbance taken at 570 nm. Miltefosine (IC50-25 µM), a potent
30 antileishmanial compound was used as a positive control.
31
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33 Acknowledgements
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35 Authors are grateful to Council of Scientific and Industrial
36 Research (CSIR), New Delhi, (Grant No. 02/0159/13/EMR-II)
37 and Centre of Excellence (CoE), MHRD, New Delhi, for
38 financial support. Authors are also thankful to Central Instrument
39 Facility (CIF) of IIT Guwahati for NMR and HRMS facilities. SS
40 and NRD are grateful to MHRD, New Delhi for their fellowship,
41 respectively.
104 10 A. K. Shukla, S. Patra and V. K. Dubey, Mol Cell Biochem. 2011,
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42 Notes and references
43 a Department of Chemistry, Indian Institute of Technology Guwaqhati,
44 Guwahati 781039, Assam, India. Fax: +91 361 269 0762; Tel: +91 361
45 258 2316; E-mail: asaikia@iitg.ernet.in
46 bDepartment of Bioscience and Bioengineering, Indian Institute of
47 Technology Guwaqhati, Guwahati 781039, Assam, India. Tel: +91 361
48 258 2203; E-mail: vdubey@iitg.ernet.in
49 † Electronic Supplementary Information (ESI) available: [details of any
50 supplementary information available should be included here]. See
51 DOI: 10.1039/b000000x/
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