Total synthesis and antimicrobial activity of (±)- laurelliptinhexadecan-1-one and (±)-laurelliptinoctadecan-1-one

Article abstract of DOI:10.3390/molecules13122935

The structures previously assigned to (+)-laurelliptinhexadecan-1-one (1a) and (+)-laurelliptinoctadecan-1-one (1b) from Cocculus orbiculatus (L.) DC. (Menispermaceae) have been confirmed by total synthesis of the racemic alkaloids. The key step of the sy

Full text of DOI:10.3390/molecules13122935

Molecules 2008, 13, 2935-2947; DOI: 10.3390/molecules13122935
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Total Synthesis and Antimicrobial Activity of
(±)-Laurelliptinhexadecan-1-one and (±)-Laurelliptinoctadecan-
1-one
Surachai Nimgirawath1,*, Phansuang Udomputtimekakul 1, Samathi Pongphuttichai 1, Asawin
Wanbanjob 1 and Thongchai Taechowisan 2
1
Department of Chemistry, Faculty of Science, Silpakorn University, Nakorn Pathom 73000,
Thailand
2
Department of Microbiology, Faculty of Science, Silpakorn University, Nakorn Pathom 73000,
Thailand; E-mail: tthongch@su.ac.th (T. T.)
* Author to whom correspondence should be addressed; E-mail: surachai@su.ac.th.
Received: 8 November 2008; in revised form: 19 November 2008 / Accepted: 25 November 2008/
Published: 28 November 2008
Abstract: The structures previously assigned to (+)-laurelliptinhexadecan-1-one (1a) and
(+)-laurelliptinoctadecan-1-one (1b) from Cocculus orbiculatus (L.) DC. (Menispermaceae)
have been confirmed by total synthesis of the racemic alkaloids. The key step of the
synthesis involved formation of ring C of the aporphines by a radical-intiated cyclisation.
Both (±)-laurelliptinhexadecan-1-one (1a) and (±)-laurelliptinoctadecan-1-one (1b) were
inactive against Staphylococcus aureus ATCC25932, Escherichia coli ATCC10536 and
Candida albicans ATCC90028.
Keywords: Alkaloid; Amidic aporphine; Isoquinoline; Synthesis; Antimicrobial activity.
Introduction
Amidic aporphine alkaloids usually occur as N-formyl, N-acetyl and N-methoxycarbonyl
derivatives [1]. (+)-Laurelliptinhexadecan-1-one (1a) and (+)-laurelliptinoctadecan-1-one (1b) are two
unique amidic aporphine alkaloids in which a palmitoyl and a stearoyl functional group is attached to

Molecules 2008, 13
2936
the nitrogen of the aporphine nucleus, respectively (Figure 1)[2].
Figure 1. Structures of (+)-laurelliptinhexadecan-1-one (1a) and (+)-laurelliptinoctadecan-
1-one (1b).
1
4
C H O
1 a
C H O
3
3
5
2
2 '
3 b
3 a
N
( C H ) 1 2
2
1 '
N
( C H ) 1 4
2
6 a
C H
C H
3
3
3
H O
H O
3 '
H
H
1 1 a
O
O
7
1 1
1 0
7 a
8
C H O
C H O
3
3
9
O H
O H
( + ) - 1 b
( + ) - 1 a
These two unique alkaloids were isolated as an inseparable mixture from Cocculus orbiculatus
(Menispermaceae). Based on detailed spectroscopic analysis of the mixture, structures 1a and 1b were
assigned to (+)-laurelliptinhexadecan-1-one and (+)-laurelliptinoctadecan-1-one, respectively. The
mixture of 1a and 1b was found to exhibit weak activity toward the human hepatoma cell line HepG2
and breast cancer cell line MDA-MB-231. No antimicrobial activity has been reported. In view of the
fact that (+)-laurelliptinhexadecan-1-one (1a) and (+)-laurelliptinoctadecan-1-one (1b) occur as an
inseparable mixture, it is therefore desirable to carry out a total synthesis of these two alkaloids to
confirm their structures and to study the biological activities of the pure alkaloids.
Results and Discussion
The syntheses of both (±)-laurelliptinhexadecan-1-one (1a) and (±)-laurelliptinoctadecan-1-one (1b)
were based on the construction of ring C of the aporphine nucleus by a radical-initiated cyclisation [3].
It was initially anticipated that cyclisation of 2b and 2c would lead to the desired (±)-1a and (±)-1b
after removal of the benzyl protecting groups. Thus, condensation of 5-benzyloxy-2-bromo-4-
methoxyphenylacetyl chloride (3) [4] with 4-benzyloxy-3-methoxyphenethylamine (4) gave amide 5
which was converted to 6 in a Bischler-Napieralski reaction. Reduction of 6 with sodium borohydride
gave (2a) which was treated with palmitoyl chloride and stearoyl chloride to give 2b and 2c
respectively. Unfortunately, several attempts to effect cyclisation of both 2b and 2c by a radical-
initiated cyclisation were fruitless. Subsequently, isoquinoline 2a was reacted with trifluoroacetic
anhydride to give 2d, which was treated with tributyltin hydride and azobis(isobutyronitrile) to give 7a
in 22.7% yield and the hydrogenolysis product 2e in 29.1% yield. Due to steric hindrance, the
formation of 7a was accompanied by concurrent loss of the benzyl protecting group on the oxygen at
C-1. Furthermore, the loss of the benzyl radical from the radical intermediate formed after initial
cyclisation is also favoured electronically. The structure of 7a was supported by the presence of a
singlet at δH 8.14 due to the proton at C-11, characteristic of aporphines bearing a proton at that
position. Removal of the trifluoroacetyl protecting group was achieved using aqueous potassium
carbonate to give 7b which was treated with palmitoyl chloride and stearoyl chloride to give (±)-9-

Molecules 2008, 13
2937
benzyllaurelliptinhexadecan-1-one (7c) and (±)-9-benzyllaurelliptinoctadecan-1- one (7d), respectively.
Hydrogenolysis of 7c and 7d gave (±)-1a and (±)-1b respectively. Both (±)-1a and (±)-1b exist as the
1
Z and E conformers, the H-NMR spectral data of which are in good agreement with those of natural
(+)-1a and (+)-1b (Tables 1 and 3).
13
However, the C-NMR spectral data of synthetic (±)-1a and (±)-1b possess a number of signals
which are different from those assigned to the same carbons in natural (+)-1a and (+)-1b (Tables 2 and
4). These discrepancies may be due to the fact that in the original paper assignments of chemical shifts
to the carbon atoms involved were carried out on the spectra measured on the mixture of (+)-1a and
(+)-1b. Bearing this fact in mind, it can be concluded with good confidence that the structures
previously assigned to (+)-laurelliptinhexadecan-1-one (1a) and (+)-laurelliptinoctadecan-1-one (1b)
can be confirmed with our current syntheses of the racemic alkaloids. (±)-Laurelliptinhexadecan-1-one
(1a) and (±)-laurelliptinoctadecan-1-one (1b) at the concentration value 256 μg/mL were inactive
against Staphylococcus aureus ATCC25932, Escherichia coli ATCC10536 and Candida albicans
ATCC90028.
Scheme 1.
Synthetic routes to (±)-laurelliptinhexadecan-1-one (1a) and (±)-
laurelliptinoctadecan-1-one (1b).
B r
C H O
C H O
3
C H O
3
3
C l
+
B
A
N
N H
2
O
N H
B n O
B n O
B n O
O
B r
B r
C H O
3
4
O B n
3
C H O
3
C H O
5
6
3
O B n
O B n
C H O
C H O
C H O
3
3
3
D
E
2 a
2 a
2 a
2 d
2 b
N
R
1
N
N
H O
B n O
R
1
H O
R
1
C
7 c
7 d
1 a
1 b
I
2 c
R
2
O
F
2 d
C H O
C H O
3
G
3
7 a + 2 e
C H O
3
O H
O B n
O B n
H
7 a
7 b
7 c
1 a . R = C H
2 a : R = H , R = B r
1 b . R 1 = C 1 5
H
1 7 3 5
3 1
2 b : R 1 = C O C21 5 H 3 1 , R = B r
2 c : R = C O C 1 7 H 3 5 , R = B r
D
E
7 b
7 b
1
1
2
2 d : R 1 = C O C F 3 , R = 2B r
2 e : R = C O C F 3 , R = H
7 d
1
1
2
2
7 a : R = C O C F 3
7 b : R 1 = H
1
7 c : R = C O C H
7 d : R 1 = C O C 1 5
H
1 7 3 5
3 1
1
Reagents and conditions: A) 10% NaHCO3/ chloroform; B) POCl3/ benzene; C) NaBH4/ethanol; D)
palmitoyl chloride, 10 % NaHCO3/ chloroform; E) stearoyl chloride, 10 % NaHCO3/ chloroform;
F) (CF3CO)2O, Et3N/ chloroform; G) Bu3SnH, AIBN/ dry toluene; H) K2CO3/ methanol-water; I)
H2, Pd/C / ethanol.

Molecules 2008, 13
2938
Table 1. Comparison of 1H-NMR spectral data between (+)-laurelliptinhexadecan-1-one
(600 MHz, CDCl3) and (±)-laurelliptinhexadecan-1-one (300 MHz, CDCl3).
(+)-laurelliptin-
hexadecan-1-one
Z-form
(±)-laurelliptin-
hexadecan-1-one
Z-form
(+)-laurelliptin-
hexadecan-1-one
E-form
(±)-laurelliptin-
hexadecan-1-one
E-form
Position
1H
1H
1H
1H
Aporphine moiety
1
1a
2
6.55 (s)
6.56 (s)
6.59 (s)
6.60 (s)
3
3a
3b
4
2.66/2.83 (m)
2.52-2.91 (m)
2.66/2.83 (m)
2.52-2.91 (m)
2.75-2.82 (pseudo
ax., m)
5
3.23 (pseudo ax., br 3.24 (pseudo ax., br 2.75 (pseudo ax., br
t, 12.0) t, 12.11) t, 12.0)
4.02 (pseudo eq., br 4.00 (pseudo eq., br 4.95 (pseudo eq., br 4.96 (pseudo eq., br
d, 12.0)
5.11 (br d, 12.5)
2.61 (pseudo ax., br
t, 12.5)
d, 12.11)
5.12 (br d, 10.5)
2.58-2.75 (pseudo
ax., m)
d, 12.0)
4.60 (br d, 12.5)
2.99 (pseudo ax., br
t, 12.5)
d, 8.03)
4.61 (br d, 12.1)
2.91-3.10 (pseudo
ax., m)
6a
7
2.95 (pseudo eq., br
d, 12.5)
2.91-3.10 (pseudo
eq., m)
2.61 (pseudo eq., br
d, 12.5)
2.58-2.75 (pseudo
eq., m)
7a
8
6.82 (s)
6.83 (s)
6.82 (s)
6.83 (s)
9
10
11
8.06 (s)
8.07 (s)
3.92 (s)
8.09 (s)
8.10 (s)
3.92 (s)
11a
OCH3 x 2
ca. 3.90 (s)
ca. 3.90 (s)
Fatty acid moiety
1′
2′
2.44 (m)
1.65 (m)
2.51-2.40 (m)
1.78-1.60 (m)
1.15-1.40 (m)
2.34 (m)
1.65 (m)
2.40-2.30 (m)
1.78-1.60 (m)
1.15-1.40 (m)
3′
Aliphatic
CH2
1.18-1.30 (m)
1.18-1.30 (m)
Terminal
CH3
0.86 (t, 6.8)
0.88 (t, 6.8)
0.86 (t, 6.8)
0.88(t, 6.8)

Molecules 2008, 13
2939
13
Table 2. Comparison of C-NMR spectral data between (+)-laurelliptinhexadecan-1-one
(150 MHz, CDCl3) and (±)-laurelliptinhexadecan-1-one (75 MHz, CDCl3).
(+)-laurelliptin-
hexadecan-1-one
Z-form
(±)-laurelliptin-
hexadecan-1-one
Z-form
(+)-laurelliptin-
hexadecan-1-one
E-form
(±)-laurelliptin-
hexadecan-1-one
E-form
position
13C
13C
13C
13C
Aporphine moiety
1
108.3 (d)
111.9 (s)
108.5 (d)
108.8 (d)
112.0 (s)
108.9 (d)
125.3 (s)
1a
124.2 (s)
2
144.98-145.2 (s)a
144.8-145.9 (s)a
141.1 (s)
144.98-145.2 (s)a
144.8-145.9 (s)a
3
141.0 (s)
140.9 (s)
141.1 (s)
3a
125.86 (s)
120.6 (s)
124.0 (s)
120.1 (s)
3b
120.5 (s)
125.6 (s)
120.0 (s)
126.2 (s)
4
34.5 (t)
30.7 (t)
30.6 (t)
29.7 (t)
5
41.4 (t)
41.4 (t)
36.8 (t)
36.7 (t)
6a
50.8 (d)
50.8 (d)
53.4 (d)
53.4 (d)
7
33.2 (t)
33.3 (t)
35.9 (t)
36.1 (t)
7a
123.5 (s)
123.7 (s)
128.8 (s)
123.9 (s)
8
114.5 (d)
114.6 (d)
113.9 (d)
113.9 (d)
9
10
144.98-145.2 (s)a
144.98-145.2 (s)a
118.8 (d)
144.8-145.9 (s)a
144.8-145.9 (s)a
111.9 (d)
144.98-145.2 (s)a
144.98-145.2 (s)a
111.9 (d)
144.8-145.9 (s)a
144.8-145.9 (s)a
112.0 (d)
11
11a
125.4 (s)
130.3 (s)
125.0 (s)
129.6 (s)
OCH3 x 2
56.0 (q) and 56.2 (q)
56.1 (q) and 56.3 (q)
Fatty acid moiety
171.8 (s)
56.0 (q) and 56.2 (q)
56.1 (q) and 56.3 (q)
1′
2′
172.1 (s)
33.2 (t)
172.6 (s)
34.2 (t)
172.5 (s)
34.6 (t)
33.3 (t)
3′
25.3 (t)
25.3 (t)
25.5 (t)
25.6 (t)
Aliphatic
CH2
29-32 (t)
29-32 (t)
29-32 (t)
29-32 (t)
Terminal
CH3
14.1 (q)
14.1 (q)
14.1 (q)
14.1 (q)
a assignments may be interchangeable

Molecules 2008, 13
2940
Table 3. Comparison of 1H-NMR spectral data between (+)-laurelliptinoctadecan-1-one
(600 MHz, CDCl3) and (±)-laurelliptinoctadecan-1-one (300 MHz, CDCl3).
(+)-laurelliptin-
octadecan-1-one
Z-form
(±)-laurelliptin-
octadecan-1-one
Z-form
(+)-laurelliptin-
octadecan-1-one
E-form
(±)-laurelliptin-
octadecan-1-one
E-form
position
1H
1H
1H
1H
Aporphine moiety
1
1a
2
6.55 (s)
6.53 (s)
6.59 (s)
6.57 (s)
3
3a
3b
4
2.66/2.83 (m)
3.23 (pseudo ax., br
t, 12.0)
2.52-2.88 (m)
3.21 (pseudo ax., br
t, 12.0)
2.66/2.83 (m)
2.75 (pseudo ax., br
t, 12.0)
2.52-2.88 (m)
2.66-2.78 (pseudo
ax., m)
5
4.02 (pseudo eq., br
d, 12.0)
4.00 (pseudo eq., br
d, 12.0)
4.95 (pseudo eq., br
d, 12.0)
4.95 (pseudo eq., br
d, 7.95)
6a
7
5.11 (br d, 12.5)
2.61 (pseudo ax., br
t, 12.5)
5.12 (br d, 13.8)
2.54-2.72 (pseudo
ax., m)
4.60 (br d, 12.5)
2.99 (pseudo ax., br
t, 12.5)
4.61 (br d, 12.1)
2.88-3.50 (pseudo
ax., m)
2.95 (pseudo eq., br
d, 12.5)
2.88-3.50 (pseudo
eq., m)
2.61 (pseudo eq., br
d, 12.5)
2.54-2.72 (pseudo
eq., m)
7a
8
6.82 (s)
6.82 (s)
8.06 (s)
6.82 (s)
6.82 (s)
9
10
11
8.06 (s)
8.09 (s)
8.10 (s)
3.89 (s)
11a
OCH3 x 2
ca. 3.90 (s)
3.89 (s)
ca. 3.90 (s)
Fatty acid moiety
1′
2′
2.44 (m)
1.65 (m)
2.50-2.39 (m)
1.73-1.60 (m)
1.15-1.40 (m)
2.34 (m)
1.65 (m)
2.39-2.29 (m)
1.73-1.60 (m)
1.15-1.40 (m)
3′
Aliphatic
CH2
1.18-1.30 (m)
1.18-1.30 (m)
Terminal
CH3
0.86 (t, 6.8)
0.87 (t, 6.9)
0.86 (t, 6.8)
0.87(t, 6.9)

Molecules 2008, 13
2941
Table 4. Comparison of 13C-NMR spectral data between (+)-laurelliptinoctadecan-1-one
(150 MHz, CDCl3) and (±)-laurelliptinoctadecan-1-one (75 MHz, CDCl3).
(+)-laurelliptin-
octadecan-1-one
Z-form
(±)-laurelliptin-
octadecan-1-one
Z-form
(+)-laurelliptin-
octadecan-1-one
E-form
(±)-laurelliptin-
octadecan-1-one
E-form
position
13C
13C
13C
13C
Aporphine moiety
1
108.3 (d)
111.9 (s)
108.5 (d)
108.8 (d)
112.0 (s)
109.0 (d)
125.6 (s)
1a
124.2 (s)
2
144.98-145.2 (s)a
145.1-145.9 (s)a
141.2 (s)
144.98-145.2 (s)a
145.1-145.9 (s)a
3
141.0 (s)
140.9 (s)
141.1 (s)
3a
125.86 (s)
120.7 (s)
124.0 (s)
120.1 (s)
3b
120.5 (s)
126.0 (s)
120.0 (s)
125.2 (s)
4
34.5 (t)
30.7 (t)
30.6 (t)
29.7 (t)
5
41.4 (t)
41.5 (t)
36.8 (t)
36.8 (t)
6a
50.8 (d)
50.9 (d)
53.4 (d)
53.5 (d)
7
33.2 (t)
33.3 (t)
35.9 (t)
36.1 (t)
7a
123.5 (s)
123.6 (s)
128.8 (s)
123.9 (s)
8
114.5 (d)
114.7 (d)
113.9 (d)
114.1 (d)
9
10
144.98-145.2 (s)a
144.98-145.2 (s)a
118.8 (d)
145.1-145.9 (s)a
145.1-145.9 (s)a
112.1 (d)
144.98-145.2 (s)a
144.98-145.2 (s)a
111.9 (d)
145.1-145.9 (s)a
145.1-145.9 (s)a
112.1 (d)
11
11a
125.4 (s)
130.1 (s)
125.0 (s)
129.5 (s)
OCH3 x 2
56.0 (q) and 56.2 (q)
56.1 (q) and 56.3 (q)
Fatty acid moiety
172.1 (s)
56.0 (q) and 56.2 (q)
56.1 (q) and 56.3 (q)
1′
2′
172.1 (s)
33.2 (t)
172.6 (s)
34.2 (t)
172.6 (s)
34.5 (t)
33.3 (t)
3′
25.3 (t)
25.4 (t)
25.5 (t)
25.5 (t)
Aliphatic
CH2
29-32 (t)
29-32 (t)
29-32 (t)
29-32 (t)
Terminal
CH3
14.1 (q)
14.1 (q)
14.1 (q)
14.1 (q)
a assignments may be interchangeable
Experimental
General
Melting points were determined on a Stuart Scientific SMP 2 melting point apparatus and are
uncorrected. Infrared spectra were recorded on CH2Cl2-films with a Perkin Elmer Spectrum GX FT-IR

Molecules 2008, 13
2942
spectrophotometer. Ultraviolet spectra were recorded on methanol solutions with a Perkin Elmer
1
Lambda 35 UV-VIS spectrophotometer. H- and 13C-NMR spectra were recorded for deutero-
1
13
chloroform solutions, unless otherwise stated, at 300 MHz for H and 75 MHz for C with a Bruker
AVANCE 300 spectrometer. Tetramethylsilane was used as the internal standard. Mass spectra were
recorded on a POLARIS Q mass spectrometer. Elemental analysis was performed on a Perkin Elmer
2400 Elemental Analyser.
2-(2-Bromo-5-benzyloxy-4-methoxyphenyl)-N-(4-benzyloxy-3-methoxyphenethyl)acetamide (5).
A
mixture of 5-benzyloxy-4-methoxy-2-bromophenylacetic acid (26.0 g, 0.07 mol) and thionyl chloride
(22.0 g, 0.19 mol) in benzene (150 mL) was refluxed for 1 h. Removal of the solvent under vacuum
gave 5-benzyloxy-2-bromo-4-methoxyphenylacetyl chloride (3) [4] which was dissolved in ethanol-
free chloroform (150 mL) and added to a mixture of 4-benzyloxy-3-methoxyphenethylamine (4) (18.1
g, 0.07 mol) in chloroform (150 mL) and 10% sodium hydrogen carbonate (120 mL). The mixture was
then stirred for 4 h and the chloroform layer was washed with water (100 mL), 10% hydrochloric acid
(100 mL), water (100 mL), then dried over anhydrous sodium sulfate. Removal of the solvent under
vacuum gave a residue which was triturated with ethanol to give 2-(2-bromo-5-benzyloxy-4-
methoxyphenyl)-N-(4-benzyloxy-3-methoxyphenethyl)acetamide (5) as white prisms (38.7 g, 93.3%);
1
m.p. 133-134 °C (lit. [5] m.p. 135 °C); H-NMR: δ 7.45-7.29 (10H, m, Ph-H); 6.99 (1H, s, Ar-H);
6.81 (1H, s, Ar-H); 6.72 (1H, d, J = 8.1 Hz, Ar-H); 6.64 (1H, d, J = 1.8 Hz, Ar-H); 6.48 (1H, dd, J =
8.1, 1.8 Hz, Ar-H); 5.40 (1H, br s, NH); 5.10 (2H, s, CH2Ph); 5.08 (2H, s, CH2Ph); 3.85 (3H, s, OCH3);
3.84 (3H, s, OCH3); 3.54 (2H, s, CH2CON); 3.42 (2H, apparent q, J = 6.6 Hz, CH2N); 2.65 (2H, t, J =
6.9 Hz, CH2); 13C-NMR: δ 170.0 (C), 149. (C), 147.8 (C), 146.9 (C), 137.3 (C), 136.4 (C), 131.6 (C),
128.6 (CH), 128.5 (CH), 128.1 (CH), 127.8 (CH), 127.5 (CH), 127.3 (CH), 126.3 (C), 120.6 (CH),
116.4 (CH), 116.1 (CH), 115.4 (C), 114.2 (CH), 112.4 (CH), 109.5 (C), 71.1 (CH2), 56.3 (OCH3), 56.0
(OCH3), 43.5 (CH2), 40.7 (CH2), 35.0 (CH2).
1-(5-Benzyloxy-2-bromo-4-methoxybenzyl)-7-benzyloxy-6-methoxy-3,4-dihydroisoquinoline
(6).
Phosphorus oxychloride (75.0 g, 0.49 mol) was added to a solution of 2-(2-bromo-5-benzyloxy-4-
methoxyphenyl)-N-(4-benzyloxy-3-methoxyphenethyl)acetamide (5) (25.0 g, 0.04 mol) in benzene
(150 mL) and the solution was refluxed with stirring for 3 h. The reaction mixture was then evaporated
under vacuum to yield a brown liquid which was shaken with water (150 mL) and chloroform (150
mL). The mixture was then basified with concentrated ammonia and the chloroform layer was dried
over anhydrous sodium sulfate. Removal of the solvent under vacuum gave a dark orange solid which
was triturated with ethanol to yield dihydroisoquinoline (6) as a pale yellow solid (21.8 g, 90.1%); m.p.
108-110 °C (lit. [6] m.p. 105-106 °C); UV (MeOH) λmax nm (log ε): 207 (4.76), 230 (4.49), 283 (4.00),
311 (3.85); IR νmax (film): 3063, 3032, 3005, 2933, 2838, 1621, 1603, 1568, 1506, 1455, 1439, 1378,
1
1357, 1322, 1256, 1214, 1160, 1142, 1073, 1026, 981, cm-1; H-NMR: δ 7.45-7.20 (10H, m, Ph-H);
7.02 (1H, s, Ar-H); 6.99 (1H, s, Ar-H); 6.78 (1H, s, Ar-H); 6.64 (1H, s, Ar-H); 5.04 (2H, s, CH2Ph);
5.03 (2H, s, CH2Ph); 4.08 (2H, s, CH2); 3.90 (3H, s, OCH3); 3.84 (3H, s, OCH3); 3.65 (2H, t, J = 7.8
13
Hz, CH2N); 2.55 (2H, t, J = 7.8 Hz, CH2); C-NMR: δ 167.0 (C), 149.1 (C), 147.7 (C), 146.7 (C),
136.7 (C), 136.6 (C), 132.4 (C), 128.5 (CH), 128.4 (CH), 128.0 (CH), 127.7 (CH), 127.5 (CH), 127.1

Molecules 2008, 13
2943
(CH), 115.8 (CH), 114.9 (CH), 114.5 (C), 112.9 (C), 112.3 (CH), 110.7 (CH), 106.0 (C), 105.4 (C),
71.2 (CH2), 70.9 (CH2), 56.2 (OCH3), 56.1 (OCH3), 46.1 (CH2), 41.2 (CH2), 25.7 (CH2).
1-(5-Benzyloxy-2-bromo-4-methoxybenzyl)-7-benzyloxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline (2a).
Sodium borohydride (11.1 g, 0.29 mol) was added portionwise to a stirred solution of
dihydroisoquinoline (6) (15.0 g, 0.03 mol) in ethanol (150 mL) and the mixture was stirred for 3 h.
Removal of the ethanol under vacuum gave a residue which was shaken with water (100 mL) and
chloroform (100 mL) and the chloroform layer was dried. Removal of the solvent gave a crude white
solid which was triturated with ethanol to give tetrahydroisoquinoline 2a as a yellow solid (14.0 g,
93.0%); m.p. 91-93 °C (Lit. [7] m.p. 90-90.5 °C); UV (MeOH) λmax nm (log ε): 211 (4.48), 236sh
(4.26), 290sh (3.79), 324 (3.70); IR νmax (film): 3585, 3063, 3032, 3007, 2936, 2839, 1592, 1567, 1506,
1
1456, 1438, 1410, 1383, 1356, 1334, 1320, 1267, 1217, 1173, 1143, 1081, 1053, 1024, 958 cm-1; H-
NMR: δ 7.46-7.20 (10H, m, Ph-H); 7.06 (1H, s, Ar-H); 6.74 (1H, s, Ar-H); 6.71(1H, s, Ar-H); 6.59
(1H, s, Ar-H); 5.11(4H, s, 2 x CH2Ph); 4.05-3.97 (1H, m, H-1); 3.85 (6H, s, 2 x OCH3); 3.13-3.01 (2H,
m, CH2); 2.87-2.64 (4H, m, 2 x CH2); 13C-NMR: δ 149.1 (C), 148.3 (C), 147.1 (C), 146.2 (C), 137.4
(C), 136.7 (C), 130.5 (C), 130.3 (C), 128.6 (CH), 128.0 (CH), 127.9 (C), 127.8 (CH), 127.4 (CH),
127.3 (CH), 117.3 (CH), 116.3 (CH), 115.4 (C), 112.9 (CH), 112.2 (CH), 71.4 (CH2), 71.1 (CH2), 56.3
(OCH3), 56.0 (OCH3), 55.1 (CH), 42.3 (CH2), 40.1 (CH2), 29.4 (CH2).
1-(5-Benzyloxy-2-bromo-4-methoxybenzyl)-7-benzyloxy-6-methoxy-2-trifluoroacetyl-1,2,3,4-tetra-
hydroisoquinoline (2d). Trifluoroacetic anhydride (54.0 g, 0.26 mol) was added to a stirred solution of
tetrahydroisoquinoline 2a (23.2 g, 0.04 mol) and triethylamine (36.0 g) in chloroform (300 mL) at 0-
10 °C. Stirring was continued at room temperature for 3 h. Chloroform (200 mL) was added and the
chloroform layer was washed with 10% NaHCO3 (4 x 300 mL), water (300 mL), 10% HCl (6 x 300
mL) and water (300 mL), then dried. Removal of the solvent under vacuum gave a brown solid which
was triturated with ethanol to yield trifluoroacetyltetrahydroisoquinoline 2d as a pale yellow solid
(17.3 g, 63.9%); m.p. 157-158 °C; UV (MeOH) λmax nm (log ε): 208 (4.75), 232sh (4.12), 287 (3.65);
IR νmax (film): 3033, 2919, 2849, 1689, 1609, 1509, 1456, 1440, 1381, 1258, 1197, 1165, 1141, 1116,
1027, 912 cm-1; Anal. Calc. for C34H31NO5BrF3: C 60.90, H 4.66, N 2.09%. Found: C 60.72, H 4.81, N
2.25%. 1H-NMR: δ 7.45-7.30 (10H, m, Ph-H); 7.01 (1H, s, Ar-H); 6.61 (1H, s, Ar-H); 6.60 (1H, s, Ar-
H); 6.45 (1H, s, Ar-H); 5.65-5.57 (1H, m, H-1); 5.00 (2H, s, CH2Ph); 4.98 (2H, s, CH2Ph); 4.02-3.91
(1H, m, H-3α); 3.88 (3H, s, OCH3); 3.85 (3H, s, OCH3); 3.64-3.53 (1H, m, H-3β); 3.28-2.68 (4H, m,
13
2 x CH2); C-NMR: δ (both conformers) 155.8 (C), 149.3 (C), 148.9 (C), 147.4 (C), 146.8 (C),
136.9(C), 136.7 (C), 128.7 (CH), 128.6 (CH), 128.3 (C), 128.1 (CH), 128.0 (CH), 127.4 (CH), 127.3
(CH), 127.2 (CH), 126.4 (C), 125.5 (C), 118.4 (C), 116.7 (CH), 116.5 (CH), 116.0 (C), 115.8 (CH),
114.6 (C), 112.9 (CH), 112.7 (CH), 111.8 (CH), 111.4 (CH), 71.4 (CH2), 71.3 (CH2), 71.2 (CH2), 56.6
(OCH3), 56.2 (OCH3), 56.1 (OCH3), 56.0 (OCH3), 54.1 (CH), 42.3 (CH2), 41.8 (CH2), 40.8 (CH2),
40.2 (CH2), 40.1 (CH2), 37.5 (CH2), 28.7 (CH2), 27.2 (CH2).
9-Benzyloxy-2,10-dimethoxy-1-hydroxy-6-trifluoroacetylnoraporphine
(7a).
A
solution
of
azobis(isobutyronitrile) (3.7 g, 0.02 mol) and tributyltin hydride (25.2 g, 0.09 mol) in toluene (160 mL)

Molecules 2008, 13
2944
was added dropwise in four equal portions over 3 h to a refluxing solution of
trifluoroacetyltetrahydroisoquinoline 2d (16.0 g, 0.02 mol) in toluene (250 mL) and the resulting
mixture was then refluxed for another 24 h. The solvent was then removed under vacuum and the
residue was dissolved in acetonitrile (200 mL) and washed with hexane (3 x 200 mL), then dried.
Removal of the solvent gave a brown solid which was triturated with ethanol to give crude
noraporphine 7a (6.92 g), which was separated on a silica gel column using benzene-chloroform as
eluent. The earlier fractions gave the hydrogenolysis product 2e as a white solid (4.1 g, 29.1%); m.p.
85-86 °C; 1H-NMR: δ 7.48-7.25 (10H, m, Ph-H of both conformers); 6.79 and 6.74 (total 1H, 2 d, J =
8.6 and 8.2 Hz, Ar-H of both conformers); 6.61-6.55 (total 2H, m, Ar-H of both conformers); 6.53-
6.46 (total 1H, m, Ar-H of both conformers); 6.27 and 6.25 (total 1H, 2 s, Ar-H of both conformers);
5.44 (1H, apparent t, J = 6.2 Hz, H-6a of both conformers); 5.17, 4.90 (total 2H, 2 AB q, J = 12.2 and
12.4 Hz, CH2Ph of both conformers); 5.08, 4.98 (total 2H, 2 s, CH2Ph of both conformers); 3.93, 3.90,
3.84 and 3.82 (total 6H, 4 s, 2 x OCH3 of both conformers); 3.33-3.20 (1H, m, CH2 of both
conformers); 3.00-2.50 (5H, m, CH2 of both conformers); 13C-NMR: δ (both conformers) 155.8 (C),
148.9 (C), 148.7 (C), 148.0 (C), 146.5 (C), 137.0 (C), 136.9 (C), 129.3 (C), 128.6 (CH), 128.5 (CH),
127.9 (CH), 127.8 (CH), 127.4 (CH), 127.2 (CH), 126.4 (C), 125.7 (C), 122.6 (CH), 118.5 (C), 115.4
(CH), 113.1 (CH), 111.6 (CH), 111.5 (CH), 70.9 (CH2), 70.9 (CH2), 56.3 (OCH3), 56.2 (OCH3), 56.0
(OCH3), 55.2 (CH), 41.0 (CH2), 40.6 (CH2), 28.5 (CH2). The later fractions gave pure noraporphine 7a
as a yellow-white solid (2.7 g, 22.7%); m.p. 232-234 °C; UV (MeOH) λmax nm (log ε): 213 (4.57),
272sh (3.99), 281 (4.08), 306 (4.12); IR νmax (film): 3373, 2920, 2850, 1682, 1605, 1513, 1463, 1401,
1383, 1371, 1337, 1310, 1281, 1255, 1202, 1169, 1139, 1099, 1049, 1025, 928 cm-1; Anal. Calc. for
C27H24NO5F3: C 64.93, H 4.84, N 2.80%. Found: C 65.09, H 4.68, N 2.65%. 1H-NMR: δ 8.14 (1H, s,
H-11), 7.60-7.30 (5H, m, Ph-H); 6.80 (1H, s, H-8), 6.57 (1H, s, H-3), 6.23 (1H, s, OH), 5.18 (2H, AB
q, J = 12.3 Hz, CH2Ph), 5.09-5.00 (1H, m, H-6a), 4.25-4.14 (1H, m, H-5α), 3.94 (3H, s, OCH3), 3.93
13
(3H, s, OCH3), 3.38-3.26 (1H, m, H-5β), 3.04-2.66 (4H, m, 2 x CH2); C-NMR: δ 155.9 (C), 148.0
(C), 147.5 (C), 146.0 (C), 141.6 (C), 137.1 (C), 128.6 (CH), 128.3 (C), 127.9 (CH), 127.3 (CH), 124.6
(C), 124.1 (C), 123.7 (C), 120.2 (C), 118.3 (C), 113.8 (CH), 113.1 (CH), 108.7 (CH), 70.9 (CH2), 56.3
(OCH3), 56.2 (OCH3), 52.6 (CH), 41.4 (CH2), 32.9 (CH2), 30.2 (CH2).
9-Benzyloxy-2,10-dimethoxy-1-hydroxynoraporphine (7b). A mixture of the noraporphine 7a (1.6 g,
3.21 mmol), potassium carbonate (3.0 g), methanol (150 mL) and water (9 mL) was refluxed for 4 h.
The solvent was then removed under vacuum and 5% sodium bicarbonate (100 mL) was added to the
residue, which was extracted with chloroform (3 x 30 mL), then dried over anhydrous sodium sulfate.
Removal of the solvent gave a dark-brown solid which was triturated with ethanol to give
noraporphine 7b as a brown solid (996.7 mg, 77.3%); m.p. 197-198 °C; UV (MeOH) λmax nm (log ε):
217 (4.62), 270sh (4.12), 280 (4.22), 305 (4.23); IR νmax (film): 3583, 3292, 2919, 2849, 1603, 1509,
1463, 1455, 1398, 1373, 1284, 1252, 1213, 1124, 1102, 1038, 1025, 992 cm-1; MS (EI) m/z (%): 403
(M+, 32), 312 (100), 91 (7); Anal. Calc. for C25H25NO4: C 74.42, H 6.24, N 3.47%. Found: C 74.26, H
6.38, N 3.66%. 1H-NMR: δ 8.09 (1H, s, H-11); 7.50-7.28 (5H, m, Ph-H); 6.76 (1H, s, H-8); 6.54 (1H, s,
H-3); 5.17 (2H, s, CH2Ph); 3.91 (3H, s, OCH3); 3.89 (3H, s, OCH3); 3.40-3.31 (1H, m, H-5α); 3.05-
2.58 (6H, m, H-5β, CH, 2 x CH2); 13C-NMR: δ 147.9 (C), 146.9 (C), 145.9 (C), 140.8 (C), 137.3 (C),

Molecules 2008, 13
2945
128.7 (C), 128.5 (CH), 128.4 (C), 127.8 (CH), 127.3 (CH), 125.5 (C), 124.1 (C), 119.1 (C), 113.6
(CH), 113.0 (CH), 109.4 (CH), 71.0 (CH2), 56.2 (OCH3), 56.1 (OCH3), 53.8 (CH), 43.3 (CH2), 36.9
(CH2), 29.0 (CH2).
9-Benzyloxy-2,10-dimethoxy-1-hydroxy-6-palmitoylnoraporphine (7c). A solution of palmitoyl
chloride (389.0 mg, 1.42 mmol) in chloroform (80 mL) was added to a stirred mixture of noraporphine
7b (400.0 mg, 0.99 mmol) in chloroform (80 mL) and 10% sodium bicarbonate (120 mL). Stirring was
continued overnight. The chloroform layer was separated, then dried. Removal of the solvent gave a
brown solid which was recrystallized with ethanol to give palmitoylnoraporphine 7c as a yellow-white
solid (530.0 mg, 83.3%); m.p. 85-86°C; UV (MeOH) λmax nm (log ε): 218 (4.45), 273sh (3.98),
281(4.04), 306 (4.10), 314sh (4.07); IR νmax (film): 3503, 2923, 2852, 1635, 1605, 1515, 1463, 1456,
1428, 1398, 1338, 1277, 1249, 1215, 1192, 1165, 1123, 1098, 1027 cm-1; MS (EI) m/z (%): 641(M+,
63), 550(10), 386(100), 295(79), 91 (15); Anal. Calc. for C41H55NO5: C 76.72, H 8.64, N 2.18%.
1
Found: C 76.62, H 8.80, N 2.35%. H-NMR: δ (both conformers) 8.15, 8.13 (total 1H, 2 s, H-11);
7.50-7.28 (total 5H, m, Ph-H); 6.81, 6.79 (total 1H, 2 s, H-8); 6.59, 6.55 (total 1H, 2 s, H-3); 6.23 (1H,
br s, OH); 5.26-5.15 (total 2H, m, CH2Ph); 5.13, 4.60 (total 1H, 2 br d, J = 3.8 and 13.2 Hz, H-6a);
4.94, 4.01 (total 1H, 2 br d, J = 8.1 and 10.1 Hz, H-5); 3.92 (3H, s, OCH3); 3.89 (3H, s, OCH3); 3.21
and 2.78-2.68 (total 1H, br t, J = 12.1 Hz, and m, H-5); 3.03-2.87 and 2.74-2.54 (total 2H, m, CH2-7);
2.97-2.59 (total 2H, m, CH2-4); 2.43-2.31 ( total 2H, m, CH2-2′); 1.75-1.55 (2H, m, CH2-3′); 1.45-1.15
(24H, m, aliphatic CH2); 0.88 (3H, t, J = 6.6 Hz, terminal CH3); 13C-NMR: δ (both conformers) 172.6
(C), 172.0 (C), 148.2 (C), 147.7 (C), 147.3 (C), 145.9 (C), 145.7 (C), 141.4 (C), 141.3 (C), 137.2 (C),
137.0 (C), 129.5 (C), 128.5 (CH), 127.8 (CH), 127.3 (CH), 126.1 (C), 125.6 (C), 125.1 (C), 124.8 (C),
124.2 (C), 120.4 (C), 119.9 (C), 113.8 (CH), 113.3 (CH), 113.1 (CH), 109.1 (CH), 108.7 (CH), 71.1
(CH2), 70.8 (CH2), 56.3 (OCH3), 56.2 (OCH3), 53.4 (CH), 50.9 (OCH3), 41.4 (CH2), 36.8 (CH2), 36.2
(CH2), 34.5 (CH2), 34.0 (CH2), 33.4 (CH2), 31.9 (CH2), 30.7 (CH2), 29.7 (CH2), 29.5 (CH2), 29.4
(CH2), 29.3 (CH2), 29.2 (CH2), 25.6 (CH2), 25.3 (CH2), 24.9 (CH2), 22.7 (CH2), 14.1 (CH3).
9-Benzyloxy-2,10-dimethoxy-1-hydroxy-6-stearoylnoraporphine (7d). In
a
similar manner,
stearoylnoraporphine 7d was obtained in 88.4% yield as a yellow-white solid from ethanol; m.p. 83-84
°C; UV (MeOH) λmax nm (log ε): 218 (4.37), 272sh (3.69), 281 (3.79), 305 (3.87), 314sh (3.82); IR
ν
max (film): 3393, 2923, 2852, 1641, 1603, 1513, 1464, 1428, 1399, 1337, 1255, 1214, 1115, 1100,
1026 cm-1; MS (EI) m/z (%): 669 (M+, 6), 578 (1), 386 (10), 296 (100), 91 (3); Anal. Calc. for
1
C43H59NO5: C 77.09, H 8.88, N 2.09%. Found: C 77.26, H 8.65, N 2.23%. H-NMR: δ (both
conformers) 8.15, 8.13 (total 1H, 2 s, H-11); 7.50- 7.28 (total 5H, m, Ph-H); 6.82, 6.79 (total 1H, 2 s,
H-8); 6.60, 6.56 (total 1H, 2 s, H-3); 6.19 (1H, br s, OH); 5.20-5.11 (total 2H, m, CH2Ph); 5.10, 4.60
(total 1H, 2 br d, J = 9.7 and 12.6 Hz, H-6a); 4.95, 4.03 (total 1H, 2 br d, J = 7.7 and 13.6 Hz, H-5);
3.92 (3H, s, OCH3); 3.89 (3H, s, OCH3); 3.22 and 2.76-2.68 (total 1H, br t, J = 12.1 Hz and m, H-5);
3.07-2.89 and 2.71-2.55 (total 2H, m, CH2-7); 2.90-2.55 (total 2H, m, CH2-4); 2.43-2.33 (total 2H, m,
CH2-2′); 1.75-1.55 (2H, m, CH2-3′); 1.40-1.15 (28H, m, aliphatic CH2); 0.88(3H, t, J = 6.7 Hz,
terminal CH3); 13C-NMR: δ (both conformers) 172.5 (C), 171.9 (C), 148.3 (C), 147.8 (C), 147.3 (C),
145.9 (C), 145.7 (C), 141.4 (C), 137.2 (C), 137.1 (C), 129.5 (C), 128.5 (CH), 127.8 (CH), 127.3 (CH),

Molecules 2008, 13
2946
126.2 (C), 125.6 (C), 125.2 (C), 124.8 (C), 124.2 (C), 120.4 (C), 120.0 (C), 113.8 (CH), 113.3 (CH),
113.1 (CH), 109.1 (CH), 108.7 (CH), 71.1 (CH2), 70.9 (CH2), 56.3 (OCH3), 56.2 (OCH3), 53.4 (CH),
50.9 (CH), 41.4 (CH2), 36.8 (CH2), 36.3 (CH2), 34.5 (CH2), 33.4 (CH2), 31.9 (CH2), 30.7 (CH2), 29.7
(CH2), 29.5 (CH2), 29.4 (CH2), 25.6 (CH2), 25.3 (CH2), 22.7 (CH2), 14.1 (CH3).
(±)-Laurelliptinhexadecan-1-one (1a). A solution of noraporphine 7c (300.5 mg, 0.47 mmol) in
ethanol (70 mL), was hydrogenolysed over Pd/C (31.1 mg) at atmospheric pressure for 48 h. The
catalyst was filtered off and the solvent removed under vacuum. The resulting white residue was
recrystallized from ethanol to give (±)-laurelliptinhexadecan-1-one (1a) as a gray-white solid (182.0
mg, 70.5%); m.p. 147-148 °C; UV (MeOH) λmax nm (log ε): 221 (4.57), 272sh (4.13), 282 (4.20), 305
(4.27), 315sh (4.24); IR νmax (film): 3370, 2923, 2852, 1622, 1602, 1513, 1464, 1431, 1413, 1366,
1330, 1279, 1246, 1193, 1122, 1096, 1035, 960 cm-1; MS (EI) m/z (%): 551 (M+, 26), 296 (100); Anal.
Calc. for C34H49NO5: C 74.01, H 8.95, N 2.54%. Found: C 74.19, H 9.07, N 2.68%. 1H-NMR and 13C-
NMR see Tables 1 and 2.
(±)-Laurelliptinoctadecan-1-one (1b). In a similar manner, (±)-laurelliptinoctadecan-1-one (1b) was
obtained in 79.2% yield as a gray-white solid from ethanol; m.p. 146-147 °C; UV (MeOH) λmax nm
(log ε): 221 (4.61), 271sh (4.11), 282 (4.20), 305 (4.28), 313sh (4.25); IR νmax (film): 3383, 2923, 2852,
1625, 1600, 1509, 1463, 1413, 1366, 1330, 1279, 1246, 1193, 1122, 1096, 1034, 960 cm-1; MS (EI)
m/z (%): 579 (M+, 17), 296 (100); Anal. Calc. for C36H53NO5: C 74.57, H 9.21, N 2.42%. Found: C
74.7, H 9.12, N 2.36%.1H-NMR and 13C-NMR see Tables 3 and 4.
Minimum inhibitory concentration (MIC)
The MICs of (±)-laurelliptinhexadecan-1-one and (±)-laurelliptinoctadecan-1-one were determined
by the NCCLS microbroth dilution method [8]. (±)-Laurelliptinhexadecan-1-one and (±)-
laurelliptinoctadecan-1-one were weighed and dissolved in DMSO to make a solution of concentration
2.56 mg/mL. From this stock solution two-fold serial dilution was carried out with culture medium in
96-well microplates (100 μl of total volume) to give a series of solutions ranging from 256 μg/mL to
0.50 μg/mL. Three different microorganisms were selected viz. Staphytolcoccus aureus ATCC25932,
Escherichia coli ATCC10536 and Candida albicans ATCC90028. They were subcultured on nutrient
broth supplemented with 10% glucose (NBG) (for bacteria) or Sabouraud glucose broth (for yeast) and
incubated at 37 oC for 24 h. A final concentration of 1 x 105 cfu/mL of test bacteria or yeast was added
o
to each dilution. The plates were incubated at 37 C for 48 h. MIC was defined as the lowest
concentration of test agent that inhibited bacterial or yeast growth, as indicated by the absence of
turbidity. Test agent-free broth containing 5% DMSO was incubated as growth control.
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Molecules 2008, 13
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Sample Availability: All products reported in this paper are available from the authors.
© 2008 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.
This article is an open-access article distributed under the terms and conditions of the Creative
Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).