Syntheses of C-ring modified dehydroabietylamides and their cytotoxic activity

Article abstract of DOI:10.1016/j.ejmech.2018.07.051

Due to their auspicious pharmacological efficacy as future drug candidates, natural products have been attracting scientific interest for centuries. An interesting field of research concerns the natural product class of terpenes. In this regard, a multitude of studies have already shown their promising biological potential. Therefore, a set of 27 derivatives of the diterpene dehydroabietylamine was synthesized, focusing on C-ring modifications and the derivatization of the amino moiety at C-18. Subsequent screening of the compounds in colorimetric sulforhodamine B-assays revealed an in vitro cytotoxicity especially towards malignant cell line MCF7. Particularly, 12-hydroxy-N-(isonicotinoyl)dehydroabietylamine and N-(4-methoxybenzoyl)dehydroabietylamine showed good cytotoxic activities (EC₅₀ (MCF7) = 4.3 ± 0.2 μM and EC₅₀ (MCF7) = 4.5 ± 1.5 μM, respectively) and significant selectivities (SI = 6.2 and SI = 8.8, respectively) towards malignant cell lines.

Full text of DOI:10.1016/j.ejmech.2018.07.051

Accepted Manuscript
Syntheses of C-ring modified dehydroabietylamides and their cytotoxic activity
Jana Wiemann, Lucie Fischer, Matthias Rohmer, René Csuk
PII:
S0223-5234(18)30607-X
10.1016/j.ejmech.2018.07.051
EJMECH 10586
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 30 May 2018
Revised Date: 15 July 2018
Accepted Date: 19 July 2018
Please cite this article as: J. Wiemann, L. Fischer, M. Rohmer, René. Csuk, Syntheses of C-ring
modified dehydroabietylamides and their cytotoxic activity, European Journal of Medicinal Chemistry
(2018), doi: 10.1016/j.ejmech.2018.07.051.
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ACCEPTED MANUSCRIPT
Syntheses of C-ring modified dehydroabietylamides and their cytotoxic activity
Jana Wiemann, Lucie Fischer (née Heller), Matthias Rohmer, René Csuk*
Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str. 2, D-
0
6120 Halle (Saale), Germany
Graphical abstract
Abstract
Due to their auspicious pharmacological efficacy as future drug candidates, natural products
have been attracting scientific interest for centuries. An interesting field of research concerns
the natural product class of terpenes. In this regard, a multitude of studies have already shown
their promising biological potential. Therefore, a set of 27 derivatives of the diterpene
dehydroabietylamine was synthesized, focusing on C-ring modifications and the
derivatization of the amino moiety at C-18. Subsequent screening of the compounds in
colorimetric sulforhodamine B-assays revealed an in vitro cytotoxicity especially towards
malignant cell line MCF7. Particularly, 12-hydroxy-N-(isonicotinoyl)dehydroabietylamine
and N-(4-methoxybenzoyl)dehydroabietylamine showed good cytotoxic activities (EC50
(
MCF7) = 4.3 ± 0.2 µM and EC (MCF7) = 4.5 ± 1.5 µM, respectively) and significant
50
selectivities (SI = 6.2 and SI = 8.8, respectively) towards malignant cell lines.
1
. Introduction
1

ACCEPTED MANUSCRIPT
Since ancient times, natural products have been used in traditional folk medicine for the
treatment of a wide spectrum of diseases and illnesses. References presumed that herbs and
1
th
flowers were already used as drugs 60,000 years ago. In the beginning of the 19 century, the
isolation of morphine as the first pharmacologically active pure compound marked the
2
revolution of modern medicine by natural products. Nowadays, approximately 50% of the
3
approved small molecule drugs are based on natural products and derivatives thereof.
Especially, the development of new potent anticancer agents is dominated by the use of
natural product leads. The potential of these substances was already demonstrated in the
1
950s with the discovery of the vinca alkaloids, vinblastine and vincristine. Today about 65%
of the anticancer agents in clinical use are of natural product origin (including plants, marine
3
, 4
organisms and microorganisms).
The ongoing scientific interest in the discovery and the
development of new anticancer agents is motivated by the limited use of common
chemotherapeutic agents due to their high toxicity towards healthy tissue and strong
associated side effects. Paclitaxel (Figure 1), for instance - one of the most prescript
chemotherapeutic agents worldwide - is approved for the treatment of metastatic breast cancer
5
6
and ovarian carcinomas , but is also leading to hypersensitivity as well as neurotoxic and
7
, 8
neuropathy side effects .
Based on their inherent biological activity and their great pharmacological potential, natural
substances continue to represent optimal lead structures for the discovery and the
development of future drug candidates. This potential is confirmed by the large number of
9
natural product derived compounds in the various phases of the clinical trials.
Figure 1. Structures of selected diterpenes.
In addition to Paclitaxel, other representatives of the natural product class of diterpenes are
showing a multitude of pharmacological properties as well, e.g. dehydroabietic aicd (Figure
1
0-15
1
). Dehydroabietic acid occurs widely in the natural resin of various pinus species.
As the most abundant component in resin acids, dehydroabietic acid provides a protection
against harmful microorganisms and covers mechanical damage. Ammonolysis and
2

ACCEPTED MANUSCRIPT
subsequent dehydration afforded dehydroabietylamine (Figure 1), another diterpene with a
1
6
broad spectrum of pharmacological properties. This tricyclic abietane-type diterpene is
modified with an amino moiety at C-18 and derivatives thereof are showing i.a. an
1
7
18
19
19
antimalarial , an antiinflammatory , an antibacterial , an antiviral and an anticancer
2
0-23
potential
. Several investigations on the cytotoxicity of dehydroabietylamides showed the
2
4-26
promising potential of these derivatizations.
Hence, we synthesized a set of 22
dehydroabietylamine derived amides and determined their in vitro anticancer potential in the
colorimetric sulforhodamine B-assay.
2
2
. Results and discussion
.1. Chemistry
We focused on three different groups of derivatizations starting from commercial available
dehydroabietylamine: (i) “simple” amide derivatives, (ii) C-ring-modified amides and (iii)
biotinylated conjugates.
A positive influence/promising potential of amide functionalities on the in vitro antitumor
2
4-28
activity of dehydroabietylamine derivatives was found in various investigations.
Therefore, we started with the derivatization of the amino moiety of dehydroabietylamine at
C-18. In view of structure-activity relationships to be carried out, a set of para-substituted
aromatic amides (1-6) was synthesized via EDC/HOBt coupling reactions in 51-77% isolated
yields (Scheme 1).
Scheme 1. Synthesis of dehydroabietylamides (1-6): (a) aromatic carboxylic acid, EDC, HOBt, DCM,
overnight, rt, 51-77%.
Moreover, we investigated the influence of additional C-ring modifications on the biological
activity of the dehydroabietylamides. Thus, dehydroabietylamine was modified in four steps
2
9
according to the procedure developed by González and Perez-Guaita (Scheme 2). Initially
the amino moiety at C-18 was protected by the reaction with phthalic anhydride to afford 7.
3

ACCEPTED MANUSCRIPT
Followed by an acylation under Friedel-Crafts conditions to provide 8. Compound 9 was
obtained by a Bayer-Villiger oxidation in the presence of meta-chloroperbenzoic acid.
Subsequent hydrazinolysis of 9 afforded target molecule 12-hydroxydehydroabietylamine
(10). First, 10 was modified by the reaction with benzoyl chloride to obtain the double
substituted product 11. Further amidations of 10 were carried out via EDC/HOBt coupling
reactions to preserve the hydroxy moiety at C-12 and to investigate its influence on the
biological activity and further possible structure-activity relationships. The syntheses of 12-17
were accomplished in 48-94% isolated yield. Moreover, the hydroxy moiety at C-12 was
acetylated to complete the set of the C-ring modified compounds. The acetylation of 12-16
was realized by the reaction with acetyl chloride and TEA to provide 18-22 in 61-97%
isolated yield. An optimization of the acetylation of 17 was realized by preceding the
acetylation of 10 in three steps to afford 23 and subsequent amidation to obtain 24.
4

ACCEPTED MANUSCRIPT
Scheme 2. Synthesis and derivatization of 12-hydroxydehydroabietylamine: (a) phthalic
anhydride, pyridine, reflux, 2.5h, 72%; (b) AcCl, AlCl , DCM, 0 °C to rt, 2h, 92%; (c)
3
.
mCPBA, TFA, DCM, 0 °C to rt, overnight, 86%; (d) N H H O, EtOH, 80 °C, 7h, 89%; (e)
2
4
2
benzoylchloride, TEA, DCM, 0 °C to rt, 0.5h, 54%; (f) aromatic carboxylic acid, EDC, HOBt,
DCM, 0 °C to rt, overnight, 48-94%; (g) AcCl, TEA, DCM, 0 °C, 0.5h, 61-97%; (h) Boc O,
2
NaOH, THF, 0 °C to rt, 2h, 74%; (i) AcCl, TEA, DCM, 0 °C to rt, 30 min, 88%; (j) TFA,
DCM, 0 °C to rt, 1.5h, 95%; (k) isonicotinic acid, EDC, HOBt, DCM, 0 °C to rt, overnight,
7
8%.
In general, a key aspect in the development of new chemotherapeutic drugs is the
optimization of the tumor specificity to avoid side effects that occur with the common
chemotherapeutic agents (e.g. with doxorubicin, epirubicin, cisplatin, paclitaxel). An often
discussed strategy to enhance drug uptake is the use of a vitamine-mediated targeting
3
0, 31
mechanism
. Based on the increased vitamin requirement for cellular functions, various
rapidly growing cancer cell lines show an over-expression of biotin-specific receptors at their
3
0, 31
cell surface allowing an efficient, targeted inclusion of biotin and biotinylated substances.
Thus, the third set of dehydroabietylamine derivatives consists of three biotinylated
conjugates to compare their cytotoxic activity and their tumor specificity with the
dehydroabietylamides. Starting from DA, 10 and 23, respectively, 25-27 were synthesized via
EDC/HOBt coupling reactions (Scheme 3).
Scheme 3. Synthesis of biotin conjugated dehydroabietylamine derivatives (25-27): (a) biotin,
EDC, HOBt, DMF, 0 °C to rt, overnight, 70-80%.
2
.2. Biological evaluation
The set of dehydroabietylamine derived compounds 1-6 and 10-27 was screened in
colorimetric SRB-assay to determine their in vitro cytotoxic activity; their EC values for
5
0
5

ACCEPTED MANUSCRIPT
five human tumor cell lines and one nonmalignant mouse fibroblasts were measured. The
results are compiled in Table 1.
Table 1. Cytotoxicity of compounds 1-6 and 10-27, dehydroabietylamine (DA, for
comparison) and betulinic acid (BA, as a standard); EC values in µM from SRB assay after
5
0
9
6 h of treatment; the values are averaged from three independent experiments performed
each in triplicate; confidence interval CI = 95%. Human cancer cell lines: FaDu
hypopharyngeal carcinoma), A2780 (ovarian carcinoma), HT29 (colorectal carcinoma),
MCF7 (breast carcinoma), SW1736 (thyroid carcinoma) and nonmalignant mouse fibroblasts
NIH 3T3).
EC50
(
(
FaDu
A2780
HT29
MCF7
SW1736
NIH 3T3
[
µM]
DA
1
3.9 ± 0.1
>30
3.8 ± 0.1
>30
2.1 ± 0.1
>30
3.0 ± 0.2
>30
4.2 ± 0.3
>30
2.4 ± 0.0
>30
2
14.1 ± 0.2
17.3 ± 6.2
18.9 ± 3.4
>30
8.7 ± 3.5
9.1 ± 2.4
12.5 ± 3.6
>30
8.5 ± 1.4
10.4 ± 3.5
22.8 ± 3.5
>30
8.0 ± 1.1
4.5 ± 1.5
10.4 ± 3.7
>30
13.0 ± 2.1
11.2 ± 4.2
14.2 ± 2.1
>30
6.9 ± 1.0
22.8 ± 3.6
13.5 ± 2.6
>30
3
4
5
6
14.4 ± 1.4
11.5 ± 0.4
>30
9.8 ± 3.1
17.3 ± 0.2
>30
10.7 ± 1.3
9.5 ± 0.2
>30
7.9 ± 1.9
8.9 ± 0.3
>30
14.2 ± 2.7
13.6 ± 0.5
>30
16.9 ± 1.5
22.0 ± 3.2
>30
10
11
12
13
14
15
16
17
18
19
14.8 ± 0.3
>30
12.5 ± 0.5
>30
16.2 ± 0.7
>30
4.8 ± 0.3
>30
11.5 ± 0.9
>30
18.1 ± 1.0
>30
20.0 ± 1.8
12.2 ± 2.4
21.9 ± 2.1
18.8 ± 1.1
13.4 ± 0.9
20.2 ± 0.8
--
13.2 ± 1.9
10.0 ± 0.7
6.6 ± 0.4
12.9 ± 2.4
8.1 ± 0.9
17.9 ± 1.2
--
13.5 ± 3.6
17.2 ± 1.9
10.5 ± 1.1
19.0 ± 2.6
9.0 ± 0.9
11.2 ± 0.5
--
11.7 ± 1.5
8.5 ± 1.1
5.0 ± 0.5
4.3 ± 0.2
4.5 ± 0.3
10.5 ± 0.8
--
16.1 ± 0.3
7.0 ± 0.3
10.2 ± 0.4
27.3 ± 5.5
13.5 ± 1.8
17.2 ± 1.2
--
23.2 ± 6.1
16.8 ± 3.0
16.0 ± 3.7
24.2 ± 1.2
17.3 ± 1.8
21.4 ± 1.3
--
a
2
0
21
22
23
24
12.8 ± 2.7
14.4 ± 2.4
13.1 ± 0.9
12.4 ± 1.2
19.4 ± 2.2
5.0 ± 0.2
20.0 ± 0.7
14.4 ± 1.9
26.7 ± 2.6
11.7 ± 2.1
10.1 ± 0.3
15.3 ± 1.9
11.5 ± 2.4
6.1 ± 1.9
10.7 ± 0.6
5.7 ± 0.8
10.7 ±2.6
15.3 ± 0.9
18.3 ± 1.3
12.8 ± 1.4
>30
>30
>30
29.5 ± 2.5
6

ACCEPTED MANUSCRIPT
25
26
27
24.5 ± 2.6
>30
18.6 ± 1.3
>30
15.5 ± 1.7
>30
11.6 ± 3.8
>30
>30
>30
15.7 ± 6.4
>30
>30
>30
>30
>30
>30
>30
BA 10.7 ± 2.1
9.7 ± 2.0
16.0 ± 2.1
10.6 ± 0.8
14.8 ± 1.4
12.9 ± 1.5
a
Compound 20 is not soluble under the conditions of the SRB-Assay.
In general, the dehydroabietylamine derivatives showed a moderate to good cytotoxic activity.
In this context, the distinct influence of almost all compounds on the proliferation of the
breast cancer cell line MCF7 is particularly noteworthy. The lowest EC values of this study
5
0
can be observed for this cell line. Thus, the following discussion of possible structure-activity
relationships is concentrated on the impact on the malignant cell line MCF7 and the
nonmalignant mouse fibroblasts NIH 3T3. The cytotoxicity for the nonmalignant cell line is
relevant in order to obtain an idea of the selectivity [characterized by the selectivity index
(
SI); e.g. SI = EC (NIH 3T3)/EC (MCF7)] of the compounds which is an important aspect
50 50
for prospective pharmacological applications.
The pharmacological promise of DA, which has intensively been investigated in various
20, 23
studies
, is confirmed by the low EC values for all examined human cancer cell lines but
50
the results are spoiled by a distinct low selectivity (SI = 0.8). Therefore, we investigated the
influence of an amidation of the amino moiety at C-18 on the in vitro cytotoxic activity at
first. Whereas N-benzoyldehydroabietylamine (1) showed a total loss of a cytotoxic activity
(
EC > 30 µM), the introduction of a substituent in para position of the aromatic moiety can
50
affect the cytotoxicity significantly. In addition to N-(4-hydroxybenzoyl)dehydroabietylamine
(2), N-(4-methylbenzoyl)dehydroabietylamine (4) and N-(isonicotinoyl)dehydroabietylamine
(6) that showed a good (to moderate) cytotoxicity (EC50 (MCF7) = 8.0 ± 1.1 µM, EC50
(MCF7) = 10.4 ± 3.7 µM and EC50 (MCF7) = 7.9 ± 1.9 µM, respectively), N-(4-
methoxybenzoyl)dehydroabietylamine (3) is particularly noteworthy. In this first group of
compounds, 3 is characterized by the highest cytotoxic activity (EC (MCF7) = 4.5 ± 1.5
5
0
µM) - comparable to DA (EC (MCF7) = 3.0 ± 0.2 µM) - and an increased selectivity (SI =
50
8
.8) - ten times higher than DA. The effect of C-ring modification on the cytotoxic activity of
the dehydroabietylamides is inconclusive with regard to the elucidation of structure-activity
relationships. Whereas a C-ring modification of DA led to a general decrease in cytotoxicity
(
from EC (MCF7) = 3.0 ± 0.2 µM to EC (MCF7) = 10.1 ± 0.3 µM) and a slight increase in
50 50
selectivity (from SI = 0.9 to SI > 3.0), this trend cannot be observed after the derivatization of
its amine moiety by substituted benzoic acids. Their cytotoxicity and selectivity are still
7

ACCEPTED MANUSCRIPT
strongly influenced by the substituents of the aromatic residue. For example, no distinct
cytotoxic activity can be determined for 1 and 5 (EC > 30 µM), while - in contrast to DA -
5
0
C-ring modifications introduce a definitive improvement of their in vitro cytotoxicity (e.g. 12-
hydroxy-N-benzoyldehydroabietylamine (12): EC (MCF7) = 4.8 ± 0.3 µM or 12-hydroxy-
50
N-(4-chlorobenzoyl)dehydroabietylamine (16): EC (MCF7) = 5.0 ± 0.5 µM). Furthermore,
50
1
2-hydroxy-N-(isonicotinoyl)dehydroabietylamine (17), which showed the highest cytotoxic
activity (EC (MCF7) = 4.3 ± 0.2 µM) combined with a high selectivity (SI = 6.2) in this
5
0
study, should be mentioned. The acetylated dehydroabietylamides 18-24 show no further
significant increase of their cytotoxicity or of their selectivity.
The results of the SRB assay concerning the biotinylated derivatives 25-27 do not indicate
any positive effect on the cytotoxic activity; in addition to the distinct decrease in the
cytotoxic activity, no significant selectivity can be observed. Accordingly, the biotinylation of
dehydroabietylamine is not an appropriate method to increase its tumor specificity.
3
. Conclusion
In summary, a set of 27 dehydroabietylamine derivatives was synthesized by simple
derivatization of the amino moiety at C-18 and by modifications of the C-ring of the abietane-
framework. Subsequent screening in the colorimetric SRB-assays determined their in vitro
cytotoxicity for several human tumor cell lines and a nonmalignant mouse fibroblast. The
suitable combination of modifications lead to cytotoxic activities comparable to those of
dehydroabietylamine, and additionally, to an increased selectivity towards malignant cell
lines. In addition, Swisstargetprediction (http://www.swisstargetprediction.ch) shows
compounds of this kind as inhibitors of 17β-hydroxysteroid dehydrogenase I. Inhibitors of
this enzyme might be ideal candidates for treating cancer patients who developed aromatase
3
2
inhibitor resistance.
4
4
. Experimental part
.1 General
Dehydroabietylamine (purity > 90 %) was obtained from TCI; further reagents were bought
from commercial suppliers without any further purification. The solvents were dried
according to usual procedures. TLC was performed on silica gel (Macherey-Nagel, detection
with ceriummolybdate spray reagent and UV absorption). Melting points are uncorrected
(
LEICA hot stage microscope). Microanalysis were performed with a Foss-Heraeus Vario EL
CHNS) instrument. NMR spectra were recorded using the VARIAN spectrometers Gemini
(
8

ACCEPTED MANUSCRIPT
13
2
000 or Unity 500 at 27 °C (δ given in ppm; J in Hz, typical experiments: C APT, DQF-
COSY, HMBC, HSQC). ESI-MS spectra were taken on a Finnigan MAT LCQ 7000
electrospray, voltage 4.1 kV, sheath gas nitrogen) instrument. The optical rotations were
(
measured on a Perkin-Elmer polarimeter 341 at 20 °C; IR spectra were recorded on a Perkin-
Elmer FT-IR spectrometer Spectrum 1000; UV-vis spectra were recorded on Perkin-Elmer
Lambda 14 spectrometer.
4
.2 General procedures
4
.2.2 General procedures A
The carboxylic acid (1.2 eq.) was suspended in DCM (dry, 10 mL/100 mg carboxylic acid)
and cooled to 0 °C. HOBt (1.4 eq.) and EDC (1.4 eq.) were added. After 30 min of stirring at
0
°C, the amine (1 eq.) was added. After completion of the reaction (as indicated by TLC) and
usual aqueous work-up the residue was subjected to column chromatography.
4
.2.3 General procedures B
Acetylation was achieved by reaction with AcCl (1.2 eq.) and TEA (cat.) in dry DCM (dry, 10
mL/100 mg carboxylic acid). After completion of the reaction (as indicated by TLC) and
usual aqueous work-up the residue was subjected to column chromatography.
4
.3 Syntheses
The syntheses of the compounds 1-9 were performed according to previously reported
3
3
procedures.
4
.3.1 12-Hydroxydehydroabietylamine (10)
Compound 9 (1.25 g, 2.64 mmol) was dissolved in boiling ethanol (25 mL) and hydrazine
monohydrate (0.78 mL, 15.91 mmol) was added. After completion of the reaction (as
indicated by TLC) the suspension was filtered and the residue was washed with fresh ethanol
(
2 x 5 mL). The filtrate was concentrated under diminished pressure and suspended in NaOH
, 30 mL). After 1 hour, the aqueous mixture was neutralized with HCl (2 ) and extracted
(2
M
M
with DCM (6 x 40 mL). The organic phase was washed with brine (50 mL), dried and
concentrated under diminished pressure. Compound 10 (0.71 g, 89%) was obtained without
any further purification as a colorless solid; R = 0.38 (silica gel, chloroform/methanol, 9:1);
F
mp = 193-198 °C; [α] = +50.9° (c = 0.36, CHCl ); IR (KBr): v = 3442br, 2956s, 2926s,
D
3
2
862s, 2366w, 2344w, 1636m, 1612m, 1586w, 1510w, 1460w, 1422m, 1386w, 1324w, 1242w,
9

ACCEPTED MANUSCRIPT
-
1
1
1
6
168w cm ; UV-vis (CHCl ): λ (log ε) = 302 nm (3.50); H NMR (400 MHz, CDCl ): δ =
3
max
3
.82 (s, 1H,14-H), 6.62 (s, 1H, 11-H), 3.19 - 3.09 (m, 1H, 15-H), 2.90 - 2.71 (m, 2H, 7-H + 7-
a
H ), 2.62 (d, J = 13.3 Hz, 1H, 18-H ), 2.44 (dd, J = 13.4, 2.6 Hz, 1H, 18-H ), 2.20 - 2.14 (m,
b
a
b
1
H, 1-H ), 1.84 - 1.61 (m, 4H, 2-H + 2-H + 6-H + 6-H ), 1.47 (dd, J = 11.1, 3.6 Hz, 1H, 5-
a a b a b
H), 1.43 - 1.27 (m, 3H, 3-H + 3-H + 1-H ), 1.25 - 1.19 (m, 9H, 16-H + 17-H + 20-H), 0.89
a
b
b
1
3
(
s, 3H, 19-H) ppm; C NMR (100 MHz, CDCl ): δ = 151.3 (C-13), 148.4 (C-9), 132.1 (C-
3
1
1
1
2), 126.7 (C-14), 126.7 (C-8), 111.1 (C-11), 53.83 (C-18), 45.1 (C-5), 38.8 (C-1), 37.5 (C-
0), 37.3 (C-4), 35.4 (C-3), 29.6 (C-7), 26.9 (C-15), 25.3 (C-20), 22.9 (C-16), 22.7 (C-17),
+
9.0 (C-6), 18.9 (C-2), 18.9 (C-19) ppm; MS (ESI, MeOH): m/z (%) = 302.2 ([M+H] , 100);
analysis calculated for C H NO (301.47): C 79.68, H 10.36, N 4.65; found: C 79.51, H
20
31
1
0.45, N 4.43.
4
.3.2 12-Benzoyloxy-N-benzoyldehydroabietylamine (11)
Compound 10 (0.10 g, 0.33 mmol) was dissolved in DCM (10 mL), TEA (0.20 mL, 1.44
mmol) and benzoyl chloride (0.12 mL; 1.04 mmol) were added. After 30 min stirring at 0 °C
followed by usual aqueous work-up, the residue was subjected to column chromatography
(silica gel, n-hexane/ethyl acetate, 7:3). Compound 11 (0.09 g, 54%) was obtained as a
colorless solid; R = 0.44 (silica gel, n-hexane/ethyl acetate, 7:3); mp = 105 °C; [α] = +43.2°
F
D
(
c = 0.33, CHCl ); IR (KBr): v = 3424br, 2962m, 2928m, 2868m, 1736s, 1646s, 1602m,
3
1
1
578w, 1540m, 1490m, 1450m, 1384w, 1312w, 1266s, 1244s, 1176m, 1164m, 1114w, 1086m,
-1
1
064m, 1024w, 708s cm ; UV-vis (CHCl ): λ (log ε) = 240 nm (4.35), 278 nm (3.83); H
3
max
NMR (400 MHz, CDCl3): δ = 8.24 - 8.19 (m, 2H, 28-H), 7.78 - 7.72 (m, 2H, 23-H), 7.67 -
7
.61 (m, 1H, 30-H), 7.55 - 7.47 (m, 3H, 29-H + 25-H), 7.46 - 7.40 (m, 2H, 24-H), 6.99 (s, 1H,
4-H), 6.97 (s, 1H, 11-H), 6.17 - 6.11 (dd, J = 6.2, 6.2 Hz, 1H, NH), 3.46 (dd, J = 13.6, 6.3
1
Hz, 1H, 18-H ), 3.33 (dd, J = 13.6, 6.4 Hz, 1H, 18-H ), 3.05 - 2.91 (m, 2H, 15-H + 7-H ),
a
b
a
2
2
2
1
2
.89 - 2.78 (K, 1H, 7-H ), 2.25 - 2.18 (m, 1H, 1-H ), 2.07 - 1.98 (m, 1H, 6-H ), 1.86 - 1.73 (m,
b a a
H, 6-H + 2-H ), 1.72 - 1.58 (m, 1H, 2-H ) 1.56 - 1.49 (m, 2H, 5-H + 3-H ), 1.48 - 1.32 (m,
b
a
b
a
H, 3-H + 1-H )), 1.26 (s, 3H, 20-H), 1.21 (d, J = 7.0 Hz, 3H, 16-H), 1.18 (d, J= 7.0 Hz, 3H,
b
b
13
7-H), 1.02 (s, 3H, 19-H) ppm; C NMR (100 MHz, CDCl3): δ = 167.8 (C-21), 165.6 (C-
6), 148.4 (C-9), 146.6 (C-13), 137.2 (C-12), 135.0 (C-22), 133.6 (C-30), 133.0 (C-8), 131.5
(
C-25), 130.3 (C-28), 129.9 (C-27), 128.8 (C-24), 128.7 (C-29), 127.3 (C-14), 127.0 (C-23),
18.2 (C-11), 50.4 (C-18), 45.6 (C-5), 38.5 (C-1), 37.8 (C-4), 37.8 (C-10), 36.5 (C-3), 30.1
C-7), 27.4 (C-15), 25.5 (C-20), 23.2 (C-16), 23.1 (C-17), 19.2 (C-6), 19.0 (C-19), 18.7 (C-2)
1
(
+
+
ppm; MS (ESI, MeOH): m/z (%) = 510.3 ([M+H] , 32), 527.1 ([M+NH4] , 5), 532.5
10

ACCEPTED MANUSCRIPT
+
+
+
+
(
[M+Na] , 15), 564.1 ([M+Na+MeOH] , 10), 1019.2 ([2M+H] , 100), 1041.1 ([2M+Na] ,
7
0); analysis calculated for C H NO (509.68): C 80.12, H 7.71, N 2.75; found: C 79.87, H
34 49 3
2
.94, N 2.56.
4
.3.3 12-Hydroxy-N-benzoyldehydroabietylamine (12)
Compound 12 was prepared according to general procedure A from benzoic acid (0.05 g, 0.40
mmol) and compound 10 (0.10 g, 0.33 mmol) followed by column chromatography (silica
gel, n-hexane/ethyl acetate, 7:3). Compound 12 (0.07 g, 53%) was obtained as a colorless
solid; R = 0.32 (silica gel, n-hexane/ethyl acetate, 7:3); mp = 194-196 °C; [α] = +6.6° (c =
F
D
0
.34, CHCl ); IR (KBr): v = 3432br, 2958s, 2928s, 2868m, 1646s, 1578w, 1542m, 1534m,
3
-1
1
490w, 1420w, 1306m, 1292m, 1270m, 1242m, 1180w, 710m cm ; UV-vis (CHCl ): λ (log
3
max
1
ε) = 240 nm (4.10), 298 nm (3.53); H NMR (400 MHz, CDCl ): δ = 7.76 - 7.70 (m, 2H, 23-
3
H), 7.52 - 7.45 (m, 1H, 25-H), 7.45 - 7.38 (m, 2H, 24-H), 6.82 (s, 1H, 14-H), 6.64 (s, 1H, 11-
H), 6.17 - 6.09 (dd, J = 6.2, 6.2 Hz, 1H, NH), 4.94 (s, 1H, OH), 3.45 - 3.30 (m, 2H, 18-H +
a
1
1
1
8-H ), 3.12 (hept, J = 6.8 Hz, 1H, 15-H), 2.91 - 2.68 (m, 2H, 7-H + 7-H ), 2.22 - 2.14 (m,
b
a
b
H, 1-H ), 1.98 - 1.90 (m, 1H, 6-H ), 1.84 - 1.59 (m, 3H, 2-H + 2-H + 6-H ), 1.55 - 1.49 (m,
a
a
a
b
b
H, 3-H ), 1.45 (dd, J = 12.3, 1.9 Hz, 1H, 5-H), 1.42 - 1.29 (m, 2H, 1-H + 3-H ), 1.25 - 1.19
a
b
b
13
(
m, 9H, 16-H + 17-H + 20-H), 1.00 (s, 3H, 19-H) ppm; C NMR (100 MHz, CDCl ): δ =
3
1
2
1
67.9 (C-21), 151.1 (C-13), 148.1 (C-9), 135.0 (C-22), 131.9 (C-12), 131.6 (C-25), 128.8 (C-
4), 127.0 (C-8), 127.0 (C-23), 126.9 (C-14), 111.1 (C-11), 50.6 (C-18), 46.1 (C-5), 38.5 (C-
), 37.8 (C-4), 37.7 (C-10), 36.5 (C-3), 29.8 (C-7), 27.0 (C-15), 25.5 (C-20), 22.8 (C-16), 22.7
(C-17), 19.4 (C-6), 18.9 (C-19), 18.8 (C-2) ppm; MS (ESI, MeOH): m/z (%) = 406.3
+
+
+
(
[M+H] , 100), 428.3 ([M+Na] , 52), 460.3 ([M+Na+MeOH] , 8); analysis calculated for
C H NO (405.57): C 79.96, H 8.70, N 3.45; found: C 79.77, H 8.95, N 3.21.
27
35
2
4
.3.4 12-Hydroxy-N-(4-hydroxy)benzoyldehydroabietylamine (13)
Compound 13 was prepared according to general procedure A from 4-hydroxybenzoic acid
0.08 g, 0.60 mmol) and compound 10 (0.20 g, 0.66 mmol). Column chromatography (silica
(
gel, n-hexane/ethyl acetate/chloroform, 1:1:2) gave compound 13 (0.18 g, 65%) as a colorless
solid; R = 0.47 (silica gel, n-hexane/ethyl acetate/chloroform, 1:1:2); mp = 261-263 °C; [α]
F
D
=
+30.7° (c = 0.34, DMSO); IR (KBr): v = 3422vs, 3266s, 2940m, 2930m, 2868w, 1636m,
1
1
606s, 1578w, 1558s, 1510s, 1466w, 1436m, 1418m; 1388w, 1310m, 1288m, 1232m, 1202w,
-1
1
180m cm ; UV-vis (DMSO): λ (log ε) = 269 nm (4.32); H NMR (400 MHz, DMSO-d ):
max
6
δ = 9.87 (s, 1H, OH), 8.71 (s, 1H, OH), 7.92 (dd, J = 6.4 Hz, 1H, NH), 7.71 - 7.66 (m, 2H, 23-
11

ACCEPTED MANUSCRIPT
H), 6.78 - 6.74 (m, 2H, 24-H), 6.66 (s, 1H, 11-H), 6.60 (s, 1H, 14-H), 3.38 (dd, J = 13.4, 7.1
Hz, 1H, 18-H ), 3.07 (hept, J = 6.8 Hz, 1H, 15-H), 2.94 (dd, J = 13.4, 5.8 Hz, 1H, 18-H ),
a
b
2
1
2
7
.73 - 2.57 (m, 2H, 7-H + 7-H ), 2.13 - 2.05 (m, 1H, 1-H ), 1.99 - 1.91 (m, 1H, 6-H ), 1.76 -
a b a a
.50 (m, 3H, 2-H + 2-H + 6-H ), 1.45 (ddd, J = 13.4, 13.4, 3.8 Hz, 1H, 3-H ), 1.36 - 1.29 (m,
a
b
b
a
H, 5-H + 3-H ), 1.20 (ddd, J = 12.6, 12.6, 3.3 Hz, 1H, 1-H ), 1.12 (s, 3H, 20-H), 1.10 (d, J =
b
a
1
3
.2 Hz, 3H, 16-H), 1.09 (d, J = 7.2 Hz, 3H, 17-H), 0.89 (s, 3H, 19-H) ppm; C NMR (100
MHz, DMSO-d ): δ = 166.4 (C-21), 159.9 (C-25), 152.0 (C-13), 147.4 (C-9), 131.3 (C-12),
6
1
1
29.2 (C-23), 125.9 (C-24), 125.5 (C-22), 124.7 (C-8), 114.6 (C-11), 110.2 (C-14), 49.2 (C-
8), 44.6 (C-5), 38.2 (C-1), 37.8 (C-4), 36.9 (C-10), 35.8 (C-3), 29.2 (C-7), 26.1 (C-15), 25.3
(C-20), 22.6 (C-16), 22.5 (C-17), 18.9 (C-19), 18.9 (C-6), 18.3 (C-2) ppm; MS (ESI, MeOH):
+
+
+
+
m/z (%) = 422.2 ([M+H] , 20), 444.3 ([M+Na] , 30), 843.3 ([2M+H] , 10), 865.2 ([2M+Na] ,
1
00); analysis calculated for C H NO (421.57): C 76.92, H 8.37, N 3.32; found: C 76.71, H
27 35 3
8
.55, N 3.17.
4
.3.5 12-Hydroxy-N-(4-methoxy)benzoyldehydroabietylamine (14)
Compound 14 was prepared according to general procedure A from 4-methoxybenzoic acid
0.12 g, 0.79 mmol) and compound 10 (0.20 g, 0.66 mmol), followed by column
chromatography (silica gel, n-hexane/ethyl acetate/chloroform, 1:1:2) to yield compound 14
0.22 g, 77%) as a colorless solid; R = 0.56 (silica gel, n-hexane/ethyl acetate, 6:4); mp =
(
(
F
2
1
1
27-229 °C; [α] = +5.3° (c = 0.36, CHCl ); IR (KBr): v = 3422br, 2958s, 2928s, 2868w,
D 3
638s, 1608s, 1572m, 1546m, 1504s, 1460m, 1440m, 1418m, 1384w, 1378w, 1308m, 1256s,
-1
178s, 1112w, 1032m, 844m, 766m cm ; UV-vis (CHCl ): λ (log ε) = 242 nm (4.16), 264
3
max
1
nm (4.21); H NMR (400 MHz, CDCl ): δ = 7.74 - 7.67 (m, 2H, 23-H), 6.94 - 6.88 (m, 2H,
3
2
4-H), 6.81 (s, 1H, 14-H), 6.65 (s, 1H, 11-H), 6.07 (dd, J = 6.0, 6.0 Hz, 1H, NH), 5.28 (s, 1H,
OH), 3.83 (s, 3H, 26-H), 3.41 - 3.31 (m, 2H, 18-H + 18-H ), 3.17 - 3.08 (hept, J = 6.8 Hz,
a
b
1
1
1
H, 15-H), 2.88 - 2.81 (m, 1H, 7-H ), 2.76 - 2.68 (m, 1H, 7-H ), 2.19 - 2.12 (m, 1H, 1-H ),
a b a
.95 - 1.89 (m, 1H, 6-H ), 1.81 - 1.60 (m, 3H, 6-H + 2-H + 2-H ), 1.54 - 1.47 (m, 1H, 3-H ),
a
b
a
b
a
.43 (dd, J = 12.3, 1.7 Hz, 1H, 5-H), 1.39 - 1.29 (m, 2H, 3-H + 1-H ), 1.25 - 1.20 (m, 6H, 17-
b
b
1
3
H + 16-H), 1.20 (s, 3H, 20-H), 0.98 (s, 3H, 19-H) ppm; C NMR (100 MHz, CDCl ): δ =
3
167.5 (C-21), 162.3 (C-25), 151.2 (C-13), 148.1 (C-9), 131.9 (C-12), 128.8 (C-23), 127.2 (C-
22), 126.9 (C-8), 126.8 (C-14), 114.0 (C-24), 111.1 (C-11), 55.6 (C-26), 50.5 (C-18), 46.1 (C-
5), 38.5 (C-1), 37.8 (C-4), 37.7 (C-10), 36.5 (C-3), 29.8 (C-7), 27.0 (C-15), 25.4 (C-20), 22.8
(C-16), 22.7 (C-17), 19.4 (C-6), 18.9 (C-19), 18.8 (C-2) ppm; MS (ESI, MeOH): m/z (%) =
+
+
+
+
4
36.3 ([M+H] , 21), 458.3 ([M+Na] , 20), 871.2 ([2M+H] , 25), 893.3 ([2M+Na] , 100);
12

ACCEPTED MANUSCRIPT
analysis calculated for C H NO (435.60): C 77.20, H 8.56, N 3.22; found: C 76.99, H 8.69,
2
8
37
3
N 3.10.
4
.3.6 12-Hydroxy-N-(4-methyl)benzoyldehydroabietylamine (15)
Compound 15 was prepared according to general procedure A from 4-methylbenzoic acid
0.08 g, 0.60 mmol) and compound 10 (0.15 g, 0.50 mmol). Column chromatography (silica
(
gel, n-hexane/ethyl acetate/chloroform, 8:2:10) gave compound 15 (0.10 g, 48%) as a
colorless solid;
R = 0.36 (silica gel, n-hexane/ethyl acetate/chloroform, 8:2:10); mp = 243-245 °C; [α] =
F
D
+
11.3° (c = 0.30, CHCl ); IR (KBr): v = 3384br, 2954s, 2936s, 2924s, 2866m, 1626s, 1614s,
3
1
7
550s, 1506s, 1466m, 1438m, 1418s, 1386m, 1376m, 1316m, 1302s, 1238m, 1188m, 1118w,
-1
1
52m cm ; UV-vis (CHCl ): λ
(log ε) = 244 nm (4.20), 300 nm (3.61); H NMR (400
3
max
MHz, CDCl ): δ = 7.63 (d, J = 8.2 Hz, 2H, 23-H), 7.21 (d, J = 7.9 Hz, 2H, 24-H), 6.81 (s, 1H,
3
1
4-H), 6.64 (s, 1H, 11-H), 6.12 (dd, J = 6.1, 6.1 Hz, 1H, NH), 5.26 (s, 1H, OH), 3.44 - 3.30
(
m, 2H, 18-H + 18-H ), 3.13 (hept, J = 6.7 Hz, 1H, 15-H), 2.89 - 2.80 (m, 1H, 7-H ), 2.78 -
a
b
a
2
1
1
.66 (m, 1H, 7-H ), 2.38 (s, 3H, 26-H), 2.19 - 2.12 (m, 1H, 1-H ), 1.97 - 1.88 (m, 1H, 6-H ),
b a a
.82 - 1.60 (m, 3H, 6-H + 2-H + 2-H ), 1.55 - 1.47 (m, 1H, 3-H ), 1.43 (dd, J = 12.3, 1.9 Hz,
b
a
b
a
H, 5-H), 1.40 - 1.29 (m, 2H, 3-H + 1-H ), 1.23 (d, J = 5.3 Hz, 3H, 16-H), 1.21 (d, J = 5.3
b
b
1
3
Hz, 3H, 17-H), 1.20 (s, 3H, 20-H), 0.99 (s, 3H, 19-H) ppm; C NMR (100 MHz, CDCl ): δ =
3
1
2
1
67.9 (C-21), 151.2 (C-13), 148.0 (C-9), 142.0 (C-25), 132.1 (C-22), 131.9 (C-12), 129.4 (C-
4), 127.0 (C-23), 126.9 (C-8), 126.8 (C-14), 111.1 (C-11), 50.5 (C-18), 46.1 (C-5), 38.5 (C-
), 37.8 (C-4), 37.7 (C-10), 36.5 (C-3), 29.8 (C-7), 26.9 (C-15), 25.4 (C-20), 22.8 (C-16), 22.7
(C-17), 21.6 (C-26), 19.4 (C-6), 18.9 (C-19), 18.8 (C-2) ppm; MS (ESI, MeOH): m/z (%) =
+
+
+
+
4
20.3 ([M+H] , 18), 442.3 ([M+Na] , 12), 839.3 ([2M+H] , 48), 861.3 ([2M+Na] , 100);
analysis calculated for C H NO (419.60): C 80.15, H 8.89, N 3.34; found: C 79.88, H 9.02,
2
8
37
2
N 3.16.
4
.3.7 12-Hydroxy-N-(4-chloro)benzoyldehydroabietylamine (16)
Compound 16 was prepared according to general procedure A from 4-chlorobenzoic acid
0.09 g, 0.60 mmol) and compound 10 (0.15 g, 0.50 mmol) followed by column
chromatography (silica gel, n-hexane/ethyl acetate/chloroform, 8:2:10) to yield compound
(
1
8
2
6 (0.13 g, 60%) as a colorless solid; R = 0.45 (silica gel, n-hexane/ethyl acetate/chloroform,
F
:2:10); mp = 246-248 °C; [α] = +9.8° (c = 0.33, DMSO), IR (KBr): v = 3420br, 2956s,
D
926s, 2866m, 1642s, 1630s, 1596s, 1548s, 1510m, 1486s, 1438w, 1418m, 1388w, 1308m,
13

ACCEPTED MANUSCRIPT
-
1
1
2
6
6
2
1
1
238m, 1182m, 1094m, 1048w, 1014m, 846m, 758m cm ; UV-vis (DMSO): λ
(log ε) =
max
1
65 nm (6.77); H NMR (400 MHz, DMSO-d ): δ = 8.72 (s, 1H, OH), 8.31 - 8.24 (dd, J = 6.3,
6
.3 Hz, 1H, NH), 7.86 - 7.79 (m, 2H, 23-H), 7.52 - 7.46 (m, 2H, 24-H), 6.67 (s, 1H, 14-H),
.61 (s, 1H, 11-H), 3.40 (dd, J = 13.4, 7.0 Hz, 1H,18-H ) 3.07 (hept, J = 6.8 Hz, 1H, 15-H),
a
.99 (dd, J = 13.5, 5.8 Hz, 1H, 18-H ), 2.75 - 2.57 (m, 2H, 7-H + 7-H ), 2.14 - 2.05 (m, 1H,
b
a
b
-H ), 1.99 - 1.88 (m, 1H, 6-H ), 1.76 - 1.63 (m, 1H, 2-H ), 1.63 - 1.50 (m, 2H, 6-H + 2-H ),
a
a
a
b
b
.50 - 1.40 (m, 1H, 3-H ), 1.39 - 1.29 (m, 2H, 5-H + 3H ), 1.22 (m, 1H, 1-H ), 1.12 (s, 3H, 20-
a
b
b
H), 1.10 (d, J = 7.0 Hz, 3H, 16-H), 1.08 (d, J = 7.0 Hz, 3H, 17-H), 0.90 (s, 3H, 19-H) ppm;
1
3
C NMR (100 MHz, DMSO-d ): δ = 165.8 (C-21), 152.0 (C-13), 147.3 (C-9), 135.7 (C-25),
6
1
1
33.6 (C-22), 131.3 (C-12), 129.2 (C-23), 128.2 (C-24), 125.9 (C-14), 124.7 (C-8), 110.2 (C-
1), 49.5 (C-18), 44.7 (C-5), 38.1 (C-1), 37.8 (C-4), 37.0 (C-10), 35.8 (C-3), 29.1 (C-7), 26.1
(C-15), 25.3 (C-20), 22.6 (C-17), 22.5 (C-16), 18.9 (C-19), 18.9 (C-6), 18.3 (C-2) ppm; MS
+
+
+
(
ESI, MeOH): m/z (%) = 440.2 ([M+H] , 56), 462.3 ([M+Na] , 35), 901.2 ([2M+Na] , 100);
analysis calculated for C H ClNO (440.02): C 73.70, H 7.79, N 3.18; found: C 73.50,
27
34
2
H7.93, N 3.00.
4
.3.8 12-Hydroxy-N-(isonicotinoyl)dehydroabietylamine (17)
Compound 17 was prepared according to general procedure A from isonicotinic acid (0.07 g,
.57 mmol) and compound 10 (0.15 g, 0.50 mmol). Column chromatography (silica gel, ethyl
acetate/chloroform, 1:1) afforded compound 17 (0.16 g, 78%) as a colorless solid; R = 0.27
0
F
(
silica gel, ethyl acetate/chloroform, 1:1); mp = 120-125 °C; [α] = +8.8° (c = 0.38, CHCl );
D 3
IR (KBr): v = 3422br, 2958s, 2928s, 2868m, 1652s, 1618m, 1552s, 1510m, 1418m, 1306m,
-
1
1
2
5
3
2
3
-
240m, 1184m, 1066w, 1000w, 756m cm ; UV-vis (CHCl ): λ
(log ε) = 242 nm (3.96),
3
max
1
97 nm (3.66); H NMR (400 MHz, CDCl ): δ = 8.70 (d, J = 4.9 Hz, 2H, 24-H), 7.58 (d, J =
3
.2 Hz, 2H, 23-H), 6.82 (s, 1H, 14-H), 6.65 (s, 1H, 11-H), 6.32 (t, J = 5.8 Hz, 1H, NH), 3.47 -
.30 (m, 2H, 18-H + 18-H ), 3.15 (hept, J = 6.7 Hz, 1H, 15-H), 2.92 - 2.82 (m, 1H, 7-H ),
a
b
a
.78 - 2.67 (m, 1H, 7-H ), 2.21 - 2.08 (m, 1H, 1-H ), 1.95 - 1.88 (m, 1H, 6-H ), 1.83 - 1.57 (m,
b
a
a
H, 6-H + 2-H + 2-H ), 1.55 - 1.46 (m, 1H, 3-H ), 1.42 (dd, J = 10.5, 1.8 Hz, 1H, 5-H), 1.39
b
a
b
a
1.26 (m, 2H, 3-H + 1-H ), 1.25 - 1.18 (m, 9H, 16-H + 17-H + 20-H), 0.99 (s, 3H, 19-H)
b
b
13
ppm; C NMR (100 MHz, CDCl ): δ = 165.9 (C-21), 151.5 (C-13), 150.4 (C-24), 147.9 (C-
3
9
), 142.2 (C-22), 132.2 (C-12), 126.8 (C-14), 126.6 (C-8), 121.1 (C-23), 111.0 (C-11), 50.7
C-18), 46.0 (C-5), 38.4 (C-1), 37.9 (C-4), 37.6 (C-10), 36.5 (C-3), 29.7 (C-7), 26.9 (C-15),
5.4 (C-20), 22.8 (C-16), 22.7 (C-17), 19.4 (C-6), 18.9 (C-19), 18.7 (C-2) ppm; MS (ESI,
(
2
14

ACCEPTED MANUSCRIPT
+
+
+
MeOH): m/z (%) = 407.4 ([M+H] , 100), 813.2 ([2M+H] , 26), 835.2 ([2M+Na] , 6); analysis
calculated for C H N O (406.56): C 76.81, H 8.43, N 6.89; found: C 76.62, H 8.69; N 6.59.
2
6
34
2
2
4
.3.9 12-Acetoxy-N-benzoyldehydroabietylamine (18)
Compound 18 was prepared according to general procedure B from compound 12 (0.14 g,
0
.35 mmol). Column chromatography (silica gel, n-hexane/ethyl acetate/chloroform,
8
.5:1.5:10) afforded compound 18 (0.15 g, 96%) as a colorless solid; R = 0.5 (silica gel, n-
F
hexane/ethyl acetate/chloroform, 8.5:1.5:10); mp = 87-92 °C; [α] = +29.9° (c = 0.33,
D
CHCl ); IR (KBr): v = 3422s, 2962s, 2928s, 2868m, 1758s, 1644s, 1580m, 1540s, 1492m,
3
-
1
1
2
7
1
458m, 1368m, 1304m, 1290m, 1208vs, 1176m, 1018m cm ; UV-vis (CHCl ): λ (log ε) =
3 max
1
86 nm (3.11); H NMR (400 MHz, CDCl ): δ = 7.74 (d, J = 7.3 Hz, 2H, 23-H), 7.48 (dd, J =
3
.2, 7.2 Hz, 1H, 25-H), 7.42 (dd, J = 7.3, 7.3 Hz, 2H, 24-H), 6.93 (s, 1H, 14-H), 6.82 (s, 1H,
1-H), 6.19 - 6.12 (m, 1H, NH), 3.45 (dd, J = 13.6, 6.1 Hz, 1H, 18-H ), 3.31 (dd, J = 13.5, 6.2
a
Hz, 1H, 18-H ), 2.96 - 2.85 (m, 2H, 7-H + 15-H), 2.85 - 2.74 (m, 1H, 7-H ), 2.30 (s, 3H, 27-
b
a
b
H) 2.22 - 2.16 (m, 1H, 1-H ), 2.02 - 1.95 (m, 1H, 6-H ), 1.82 - 1.64 (m, 3H, 2-H + 2-H + 6-
a
a
a
b
H ), 1.55 - 1.45 (m, 1H, 3-H ), 1.45 - 1.31 (m, 2H, 1-H + 3-H ), 1.23 (s, 3H, 20-H), 1.18 (d, J
b
a
b
b
13
=
6.9 Hz, 3H, 16-H), 1.16 (d, J = 6.9 Hz, 3H, 17-H), 1.00 (s, 3H, 19-H) ppm; C NMR (100
MHz, CDCl ): δ = 170.1 (C-26), 167.8 (C-21), 148.3 (C-13), 146.3 (C-9), 137.0 (C-12), 135.0
3
(C-22), 133.0 (C-8), 131.5 (C-25), 128.7 (C-24), 127.2 (C-14), 127.0 (C-23), 118.0 (C-11),
5
0.4 (C-18), 45.5 (C-5), 38.4 (C-1), 37.8 (C-4), 37.8 (C-10), 36.5 (C-3), 30.1 (C-7), 27.3 (C-
5), 25.5 (C-20), 23.1 (C-16), 23.1 (C-17), 21.1 (C-27), 19.2 (C-6), 18.9 (C-19), 18.7 (C-2)
1
+
+
ppm; MS (ESI, MeOH): m/z (%) = 448.2 ([M+H] , 64), 465.0 ([M+NH ] , 10), 467.3
4
2+
+
(
[2M+Ca] , 20), 470.3 ([M+Na] , 100); analysis calculated for C H NO (447.61): C 77.82,
31 39 5
H 8.33, N 3.13; found: C 77.49, H 8.57, N 2.96.
4
.3.10 12-Acetoxy-N-(4-acetoxy)benzoyldehydroabietylamine (19)
Compound 19 was prepared according to general procedure B from compound 13 (0.08 g,
.19 mmol). Column chromatography (silica gel, n-hexane/ethyl acetate/chloroform, 6:4:10)
0
gave compound 19 (0.09 g, 94%) as a colorless solid; R = 0.47 (silica gel, n-hexane/ethyl
F
acetate/chloroform, 6:4:10); mp = 95-98 °C; [α] = +24.2° (c = 0.33, CHCl ); IR (KBr): v =
D
3
3
1
422m, 2962m, 2928m, 2868w, 1758s, 1648m, 1606m, 1542m, 1498s, 1466w, 1458w, 1438w,
-1
370w, 1306w, 1288w, 1204vs, 1166s, 1104w, 1016m, 914m cm ; UV-vis (CHCl ): λ (log
3
max
1
ε) = 246 nm (4.11); H NMR (400 MHz, CDCl ): δ = 7.76 (d, J = 8.4 Hz, 1H, 23-H), 7.14 (d,
3
J = 8.4 Hz, 1H, 24-H), 6.93 (s, 1H, 14-H), 6.82 (s, 1H, 11-H), 6.12 (dd, J = 5.6, 5.6 Hz, 1H,
15

ACCEPTED MANUSCRIPT
NH), 3.42 (dd, J = 13.6, 6.1 Hz, 1H, 18-H ), 3.30 (dd, J = 13.6, 6.2 Hz, 1H, 18-H ), 2.98 -
a
b
2
1
5
.72 (m, 3H, 15-H + 7-H + 7-H ), 2.30 (s, 3H, 27-H), 2.29 (s, 3H, 29-H), 2.23 - 2.16 (m, 1H,
a b
-H ), 2.01 - 1.93 (m, 1H, 6-H ), 1.84 - 1.62 (m, 3H, 2-H + 2-H + 6-H ), 1.54 - 1.44 (m, 2H,
a
a
a
b
b
-H + 3-H ), 1.44 - 1.28 (m, 2H, 3-H + 1-H ), 1.23 (s, 3H, 20-H), 1.18 (d, J = 6.9 Hz, 3H, 16-
a
b
a
1
3
H), 1.16 (d, J = 7.0 Hz, 3H, 17-H), 0.99 (s, 3H, 19-H) ppm; C NMR (100 MHz, CDCl ): δ =
3
1
1
70.1 (C-28), 169.1 (C-26), 167.0 (C-21), 153.1 (C-25), 148.3 (C-13), 146.3 (C-9), 137.0 (C-
2), 133.0 (C-8), 132.6 (C-22), 128.4 (C-23), 127.2 (C-14), 121.9 (C-24), 118.0 (C-11), 50.5
(C-18), 45.6 (C-5), 38.4 (C-1), 37.8 (C-4), 37.7 (C-10), 36.5 (C-3), 30.0 (C-7), 27.3 (C-15),
2
5.5 (C-20), 23.1 (C-16), 23.1 (C-17), 21.3 (C-29), 21.1 (C-27), 19.2 (C-6), 18.9 (C-19), 18.7
+
+
(
C-2) ppm; MS (ESI, MeOH): m/z (%) = 506.2 ([M+H] , 45), 522.9 ([M+NH ] , 10), 528.3
4
+
+
+
(
[M+Na] , 30), 1011.3 ([2M+H] , 95), 1033.1 ([2M+Na] , 100); analysis calculated for
C H NO (505.65): C 73.63, H 7.77, N 2.77; found: C 73.41, H, N.
31
39
5
4
.3.11 12-Acetoxy-N-(4-methoxy)benzoyldehydroabietylamine (20)
Compound 20 was prepared according to general procedure B from compound 14 (0.08 g,
.18 mmol). Column chromatography (silica gel, n-hexane/ethyl acetate/chloroform, 8:2:10)
0
yielded compound 20 (0.08 g, 93%) as a colorless solid; R = 0.30 (silica gel, n-hexane/ethyl
F
acetate/chloroform, 8:2:10); mp = 94-96 °C; [α] = +28.2° (c = 0.35, CHCl ); IR (KBr): v =
D
3
3
1
424s, 2962m, 2928m, 2868m, 1758s, 1640s, 1608s, 1576w, 1542m, 1504vs, 1462m, 1368m,
-1
310m, 1300m, 1292m, 1254vs, 1210s, 1176s, 1110w, 1018m cm ; UV-vis (CHCl ): λ (log
3
max
1
ε) = 265 nm (4.19); H NMR (400 MHz, CDCl ): δ = 7.71 (d, J = 8.7 Hz, 2H, 23-H), 6.93 (s,
3
1
H, 14-H), 6.90 (d, J = 8.7 Hz, 1H, 24-H), 6.82 (s, 1H, 11-H), 6.06 (dd, J = 5.7, 5.7 Hz, 1H,
NH), 3.83 (s, 3H, 26-H), 3.43 (dd, J = 13.7, 6.2 Hz, 1H, 18-H ), 3.29 (dd, J = 13.6, 6.3 Hz,
a
1
2
1
H, 18-H ), 2.95 - 2.85 (m, 2H, 15-H + 7-H ), 2.85 - 2.73 (m, 1H, 7-H ), 2.30 (s, 3H, 28-H),
b a b
.22 - 2.15 (m, 1H, 1-H ), 2.02 - 1.94 (m, 1H, 6-H ), 1.85 - 1.63 (m, 3H, 2-H + 2-H + 6-H ),
a
a
a
b
b
.53 - 1.45 (m, 2H, 5-H + 3-H ), 1.45 - 1.30 (m, 2H, 3-H + 1-H ), 1.23 (s, 3H, 20-H), 1.18 (d,
a
b
b
1
3
J = 6.9 Hz, 3H, 16-H), 1.16 (d, J = 6.9 Hz, 3H, 17-H), 0.99 (s, 3H, 19-H) ppm; C NMR (100
MHz, CDCl ): δ = 170.1 (C-27), 167.3 (C-21), 162.2 (C-25), 148.4 (C-13), 146.3 (C-9), 137.0
3
(C-12), 133.1 (C-12), 128.8 (C-23), 127.2 (C-22), 127.2 (C-14), 118.0 (C-11), 113.9 (C-24),
5
7
1
5
5.5 (C-26), 50.3 (C-18), 45.5 (C-5), 38.4 (C-1), 37.8 (C-4), 37.8 (C-10), 36.5 (C-3), 30.1 (C-
), 27.3 (C-15), 25.5 (C-20), 23.1 (C-16), 23.1 (C-17), 21.1 (C-28), 19.2 (C-6), 19.0 (C-19),
+
2+
8.7 (C-2) ppm; MS (ESI, MeOH): m/z (%) = 478.3 ([M+H] , 50), 497.5 ([2M+Ca] , 5),
+
+
+
00.3 ([M+Na] , 30), 955.2 ([2M+H] , 85), 977.1 ([2M+Na] , 100); analysis calculated for
C H NO (477.64): C 75.44, H 8.23, N 2.93; found: C 75.33, H 8.46, N 2.77.
30
39
4
16

ACCEPTED MANUSCRIPT
4
.3.12 12-Acetoxy-N-(4-methyl)benzoyldehydroabietylamine (21)
Compound 21 was prepared according to general procedure B from compound 15 (0.06 g,
.14 mmol). Column chromatography (silica gel, n-hexane/ethyl acetate/chloroform, 8:2:10)
0
afforded compound 21 (0.04 g, 62%) as a colorless solid; R = 0.56 (silica gel, n-hexane/ethyl
F
acetate/chloroform, 8:2:10); mp = 92-95 °C; [α] = +28.3° (c = 0.31, CHCl ); IR (KBr): v =
D
3
3
424br, 2962s, 2928s, 2868m, 1758s, 1642s, 1614m, 1542s, 1500s, 1458m, 1368m, 1302m,
-1
1
1
208s, 1176m, 1018m, 752m cm ; UV-vis (CHCl ): λ (log ε) = 242 nm (4.15); H NMR
3
max
(
400 MHz, CDCl ): δ = 7.63 (d, J = 8.1 Hz, 2H, 24-H), 7.22 (d, J = 7.9 Hz, 2H, 23-H), 6.93
3
(s, 1H, 14-H), 6.82 (s, 1H, 11-H), 6.10 (dd, J = 5.9, 5.9 Hz, 1H, NH), 3.43 (dd, J = 13.7, 6.3
Hz, 1H, 18-H ), 3.30 (dd, J = 13.7, 6.4 Hz, 1H, 18-H ), 2.97 - 2.85 (m, 2H, 7-H + 15-H), 2.84
a
b
a
-
2.73 (m, 1H, 7-H ), 2.38 (s, 3H, 26-H), 2.30 (s, 3H, 28-H), 2.23 - 2.15 (m, 1H, 1-H ), 2.03 -
b a
1
1
=
.94 (m, 1H, 6-H ), 1.83 - 1.62 (m, 3H, 2-H + 2-H + 6-H ), 1.55 - 1.44 (m, 2H, 5-H + 3-H ),
a a b b a
.44 - 1.28 (m, 2H, 3-H + 1-H ), 1.23 (s, 3H, 20-H), 1.18 (d, J = 7.0 Hz, 3H, 16-H), 1.16 (d, J
b
b
13
6.9 Hz, 3H, 17-H), 0.99 (s, 3H, 19-H) ppm; C NMR (100 MHz, CDCl ): δ = 170.1 (C-27),
3
167.7 (C-21), 148.4(C-9), 146.3 (C-12), 141.9 (C-25), 137.0 (C-13), 133.1 (C-8), 132.1 (C-
22), 129.4 (C-23), 127.2 (C-14), 127.0 (C-24), 118.0 (C-11), 50.3 (C-18), 45.5 (C-5), 38.4 (C-
1), 37.8 (C-4), 37.8 (C-10), 36.5 (C-3), 30.1 (C-7), 27.3 (C-15), 25.5 (C-20), 23.1 (C-16), 23.1
(C-17), 21.6(C-26), 21.1 (C-28), 19.2 (C-6), 18.9 (C-19), 18.7 (C-2) ppm; MS (ESI, MeOH):
+
+
+
+
m/z (%) = 462.3 ([M+H] , 42), 479.1 ([M+NH ] , 4), 484.4 ([M+Na] , 38), 923.3 ([2M+H] ,
4
+
7
2), 945.2 ([2M+Na] , 100); analysis calculated for C H NO (461.64): C 78.05, H 8.52, N
30
39
3
3
.03; found: C 77.78, H 8.76, N 2.81.
4
.3.13 12-Acetoxy-N-(4-chloro)benzoyldehydroabietylamine (22)
Compound 22 was prepared according to general procedure B from compound 16 (0.06 g,
.14 mmol). Column chromatography (silica gel, n-hexane/ethyl acetate/chloroform, 8:2:10)
0
afforded compound 22 (0.06 g, 89%) as a colorless solid; R = 0.36 (silica gel, n-hexane/ethyl
F
acetate/chloroform, 8:2:10); mp = 94-98 °C; [α] = +25.3° (c = 0.33, CHCl ); IR (KBr): v =
D
3
3
420br, 2962s, 2928s, 2868m, 1758s, 1646s, 1596m, 1542m, 1486s, 1368m, 1306m, 1210s,
-1
1
1
176m, 1092m, 1016m, 758m cm ; UV-vis (CHCl ): λ (log ε) = 242 nm (4.26); H NMR
3
max
(
400 MHz, CDCl ): δ = 7.71 - 7.63 (m, 2H, 23-H), 7.42 - 7.36 (m, 2H, 24-H), 6.93 (s, 1H, 14-
3
H), 6.82 (s, 1H, 11-H), 6.09 (dd, J = 6.4, 6.4Hz, 1H, NH), 3.44 (dd, J = 13.7, 6.5 Hz, 1H, 18-
H ), 3.28 (dd, J = 13.7, 6.4 Hz, 1H, 18-H ), 2.97 - 2.85 (m, 2H, 7-H + 15-H), 2.84 - 2.72 (m,
a
b
a
1
H, 7-H ), 2.30 (s, 3H, 27-H), 2.23 - 2.15 (m, 1H, 1-H ), 2.01 - 1.92 (m, 1H, 6-H ), 1.85 - 1.59
b a a
17

ACCEPTED MANUSCRIPT
(
m, 3H, 2-H + 2-H + 6-H ), 1.54 - 1.44 (m, 2H, 3-H + 5-H), 1.43 - 1.31 (m, 2H, 1-H + 3-
a
b
b
a
b
H ), 1.23 (s, 3H, 20-H), 1.18 (d, J = 6.9 Hz, 3H, 16-H), 1.16 (d, J = 6.9 Hz, 3H, 17-H), 0.99
b
1
3
(
s, 3H, 19-H) ppm; C NMR (100 MHz, CDCl ): δ = 170.1 (C-26), 166.7 (C-21), 148.3 (C-
3
9
), 146.3 (C-13), 137.8 (C-25), 137.0 (C-12), 133.3 (C-22), 133.0 (C-8), 129.0 (C-24), 128.4
(C-23), 127.2 (C-14), 118.0 (C-11), 50.4 (C-18), 45.5 (C-5), 38.4 (C-1), 37.8 (C-4), 37.8 (C-
1
1
4
0), 36.5 (C-3), 30.0 (C-7), 27.3 (C-15), 25.5 (C-20), 23.1 (C-16), 23.1 (C-17), 21.1 (C-27),
+
9.2 (C-6), 19.0 (C-19), 18.7 (C-2) ppm; MS (ESI, MeOH): m/z (%) = 482.3 ([M+H] , 34),
+
+
+
+
99.1 ([M+NH ] , 12), 504.3 ([M+Na] , 42). 965.1 ([2M+H] , 58), 984.9 ([2M+Na] , 100);
4
analysis calculated for C H ClNO (482.05): C 72.26, H 7.53, N 2.91; found: C 71.94, H
2
9
36
3
7
.75, N 2.71.
4
.3.14 12-Acetoxydehydroabietylamine (23)
Compound 10 (0.45 g, 1.59 mmol) was dissolved in THF (30 mL) and the solution was
cooled to 0 °C. Sodium hydroxide (1 , 7 mL) and di-tert-butyl dicarbonate (0.35 mg, 1.61
mmol) were added. After 2h of stirring at room temperature the solvent was removed under
vacuum and sodium dihydrogen phosphate (1 , 20 mL) was added. The aqueous phase was
N
N
extracted with DCM (4 x, 40 mL). The combined organic phases were washed with brine (30
mL), dried and concentrated in vacuum. For analysis a sample was purified by column
chromatography (silica gel, n-hexane/ethyl acetate/chloroform, 8:2:10); R = 0.43 (silica gel,
F
n-hexane/ethyl acetate/chloroform, 8:2:10); mp = 96-98 °C; [α] = +27.4° (c = 0.33, CHCl );
D
3
IR (KBr): v = 3422vs, 2962m, 2928m, 2868m, 1690s, 1618m, 1510s, 1472w, 1458m,
-
1
1
3
418m¸1368m, 1324w, 1308w, 1246m, 1166s, 1052w cm ; UV-vis (CHCl ): λ
(log ε) =
3
max
1
07 nm (3.24); H NMR (400 MHz, CDCl ): δ = 6.83 (s, 1H, 14-H), 6.64 (s, 1H, 11-H), 4.53
3
(
dd, J = 6.0, 6.0 Hz, 1H, NH), 3.17 - 3.04 (m, 2H, 15-H + 18-H ), 2.96 (dd, J = 13.9, 7.0 Hz,
a
1
H, 18-H ), 2.84 (dd, J = 16.1, 6.0 Hz, 1H, 7-H ), 2.74 (ddd, J = 17.1, 11.4, 7.3 Hz, 1H, 7-
b a
H ), 2.21 - 2.14 (m, 1H, 1-H ), 1.87 - 1.78 (m, 1H, 6-H ), 1.79 - 1.71 (m, 1H, 2-H ), 1.71 -
b
a
a
a
1
.61 (m, 2H, 6-H + 2-H ), 1.43 (s, 9H, 23-H), 1.44 - 1.32 (m, 2H, 1-H + 3-H ), 1.28 - 1.24
b b b a
(
m, 1H, 3-H ), 1.24 (d, J = 4.1 Hz, 3H, 16-H), 1.23 (d, J = 4.1 Hz, 3H, 17-H), 1.20 (s, 3H, 20-
b
1
3
H), 0.90 (s, 3H, 19-H) ppm; C NMR (100 MHz, CDCl ): δ = 156.4 (C-21), 151.0 (C-9),
3
1
1
48.4 (C-13), 131.8 (C-12), 127.2 (C-8), 126.8 (C-14), 111.1 (C-11), 79.3 (C-22), 51.3 (C-
8), 45.1 (C-5), 38.5 (C-1), 37.6 (C-4), 37.5 (C-10), 36.1 (C-3), 29.7 (C-7), 28.6 (C-23), 27.0
(C-15), 25.4 (C-20), 22.9 (C-16), 22.7 (C-17), 19.1 (C-6), 18.8 (C-2), 18.8 (C-19) ppm; MS
+
+
(
ESI, MeOH): m/z (%) = 424.2 ([M+Na] , 100), 456.2 ([M+Na+MeOH] , 15); analysis
calculated for C H NO (401.58): C 74.77, H 9.79, N 3.49; found: C 74.55, H 9.93, N 3.21.
2
5
39
3
18

ACCEPTED MANUSCRIPT
N-Boc-dehydroabietylamine was acetylated according to general procedure B to yield 12-
acetoxy-N-Boc-dehydroabietylamine. Column chromatography (silica gel, n-hexane/ethyl
acetate/chloroform, 8.5:1.5:10) afforded 12-acetoxy-N-Boc-dehydroabietylamine (0.45 g,
6
4% over two steps) as a colorless solid; RF = 0.48 (silica gel, n-hexane/ethyl
acetate/chloroform, 8.5:1.5:10; mp = 65-66 °C; [α] = +31.3° (c = 0.34, CHCl ); IR (KBr): v
D
3
=
3442vs, 2966m, 2930m, 2868w, 1758m, 1718m, 1702m, 1636m, 1508m, 1498m, 1458w,
-1
1
384w¸1366m, 1246m, 1208m, 1170s, 1016w cm ; UV-vis (CHCl ): λ (log ε) = 296 nm
3 max
1
(
3.00); H NMR (500 MHz, CDCl ): δ = 6.94 (s, 1H, 14-H), 6.83 (s, 1H, 11-H), 4.52 (dd, J =
3
6
.0, 6.0 Hz, 1H, NH), 3.11 (dd, J = 13.8, 6.5 Hz, 1H, 18-H ), 2.95 - 2.86 (m, 2H, 15-H + 7-
a
H ), 2.79 (ddd, J = 17.4, 11.2, 7.5 Hz, 1H, 7-H ), 2.30 (s, 3H, 25-H), 2.20 - 2.14 (m, 1H, 1-
a
b
H ), 1.90 - 1.83 (m, 1H, 6-H ), 1.79 - 1.60 (m, 3H, 6-H + 2-H + 2-H ), 1.46 (dd, J = 12.5, 2.2
a
a
b
a
b
Hz, 1H, 5-H), 1.43 (s, 9H, 23-H), 1.42 - 1.34 (m, 2H, 1-H + 3-H ), 1.27 - 1.21 (m, 1H, 3-H ),
b
a
b
1
1
.20 (s, 3H, 20-H), 1.19 (d, J = 7.3 Hz, 3H, 16-H), 1.17 (d, J = 7.3 Hz, 3H, 17-H), 0.90 (s, 3H,
1
3
9-H) ppm; C NMR (125 MHz, CDCl ): δ = 170.1 (C-24), 156.3 (C-21), 148.6 (C-9), 146.3
3
(
C-13), 137.0 (C-12), 133.2 (C-8), 127.1 (C-14), 118.1 (C-11), 79.3 (C-22), 51.2 (C-18), 44.6
C-5), 38.4 (C-1), 37.7 (C-4), 37.5 (C-10), 36.1 (C-3), 29.9 (C-7), 28.5 (C-23), 27.3 (C-15),
(
2
5.4 (C-20), 23.2 (C-16), 23.1 (C-17), 21.1 (C-25), 19.0 (C-6), 18.8 (C-19), 18.7 (C-2) ppm;
+
+
MS (ESI, MeOH): m/z (%) = 466.2 ([M+Na] , 100), 909.1 ([2M+Na] , 10); analysis
calculated for C H NO (443.62): C 73.10, H 9.32, N 3.16; found: C 72.97, H 9.52, N 2.87.
2
7
41
4
1
2-Acetoxy-N-Boc-dehydroabietylamine was dissolved in DCM (20 mL), cooled to 0 °C and
TFA (5 mL) was added. After 2.5 h of stirring at room temperature, the solution was diluted
with DCM (30 mL) and was washed with aqueous sodium hydrogen carbonate solution
(saturated, 3 x, 20 mL). The organic phase was washed with brine (20 mL), dried and
concentrated in vacuo. Compound 23 (0.32 g, 92 %) was obtained as a colorless solid; R =
F
0
.29 (silica gel, chloroform/methanol, 9:1); mp = 103-104 °C; [α] = +18.4 (c = 0.32, CHCl );
D 3
IR(KBr): v = 3181w, 2970w, 2925w, 1790w, 1749m, 1620w, 1514m, 1464w, 1378w, 1220m,
-
1
1
;
195s, 1143vs, 1020m, 809m, 784s, 707vs cm ; UV-vis (CHCl ): λ (log ε) = 296 nm (2.75)
3 max
1
H NMR (500 MHz, CDCl ): δ = 7.22 (br s, 2H, NH ), 6.94 (s, 1H, 14-H), 6.78 (s, 1H, 11-
3
2
H), 2.97 - 2.74 (m, 5H, 18-H + 18-H + 15-H + 7-H + 7-H ), 2.28 (s, 3H, 22-H), 2.22 - 2.17
a
b
a
b
(
m, 1H, 1-H ), 1.84 - 1.64 (m, 4H, 6-H + 6-H + 2-H + 2-H ), 1.55 - 1.49 (m, 1H, 3-H ), 1.42
a a b a b a
-
1.34 (m, 2H, 1-H + 5-H), 1.31 - 1.21 (m, 1H, 3-H ), 1.20 (s, 3H, 20-H), 1.18 (d, J = 6.9 Hz,
b b
1
3
3
H, 16-H), 1.15 (d, J = 6.9 Hz, 3H, 17-H), 1.02 (s, 3H, 19-H) ppm; C NMR (125 MHz,
CDCl ): δ = 170.8 (C-21), 147.8 (C-9), 146.3 (C-13), 137.4 (C-12), 132.6 (C-8), 127.2 (C-
3
1
4), 117.7 (C-11), 51.6 (C-18), 45.6 (C-5), 37.8 (C-1), 37.5 (C-10), 35.8 (C-4), 35.1 (C-3),
19

ACCEPTED MANUSCRIPT
2
8.6 (C-7), 27.3 (C-15), 24.8 (C-20), 23.1 (C-16), 23.0 (C-17), 21.1 (C-22), 18.8 (C-6), 18.1
+
+
(
C-2), 17.6 (C-19) ppm; MS (ESI, MeOH): m/z (%) = 344.1 ([M+H] , 100), 687.2 ([2M+H] ,
5
9
); analysis calculated for C H NO (343.50): C 76.92, H 9.68, N 4.08; found: C 76.84, H
22 33 2
.51, N3.85.
4
.3.15 12-Acetoxy-N-(isonicotinoyl)dehydroabietylamine (24)
Compound 24 was prepared according to general procedure A from compound 23 (0.10 g,
.29 mmol) and isonicotinic acid (0.05 g, 0.4 mmol). Column chromatography (silica gel, n-
hexane/ethyl acetate 3:7) gave compound 24 (0.10 g, 77%) as a colorless solid; R = 0.3
0
F
(
silica gel, n-hexane/ethyl acetate, 3:7); mp = 85-89 °C; [α] = +29.6° (c = 0.34, CHCl ); IR
D 3
(KBr): v = 3406s, 2962s, 2930s, 2868m, 1758s, 1654s, 1542s, 1496m, 1458m, 1438m, 1408m,
-1
1
370m, 1300m, 1210vs, 1176m, 1162m, 1066w, 1018m, 756m cm ; UV-vis (CHCl ): λ
3
max
1
(
log ε) = 298 nm (3.21); H NMR (500 MHz, CDCl ): δ = 8.71 (d, J = 4.8 Hz, 2H, 26-H),
3
7
.58 (d, J = 5.0 Hz, 2H, 25-H), 6.93 (s, 1H, 14-H), 6.81 (s, 1H, 11-H), 6.26 (dd, J = 5.0, 5.0
Hz, 1H, NH), 3.46 (dd, J = 13.7, 6.4 Hz, 1H, 18-H ), 3.29 (dd, J = 13.7, 6.3 Hz, 1H, 18-H ),
a
b
2
2
1
-
.96 - 2.85 (m, 2H, 7-H + 15-H), 2.78 (ddd, J = 17.7, 11.2, 7.5 Hz, 1H, 7-H ), 2.29 (s, 3H,
a
b
2-H), 2.22 - 2.16 (m, 1H, 1-H ), 1.99 - 1.93 (m, 1H, 6-H ), 1.82 - 1.71 (m, 2H, 6-H + 2-H ),
a
a
b
a
.71 - 1.64 (m, 1H, 2-H ), 1.53 - 1.47 (m, 1H, 3-H ), 1.45 (dd, J = 12.3, 1.9 Hz, 1H, 5-H), 1.42
b
a
1.30 (m, 2H, 1-H + 3-H ), 1.22 (s, 3H, 20-H), 1.18 (d, J = 6.9 Hz, 3H, 16-H), 1.15 (d, J =
b
b
1
3
6
1
8
3
.9 Hz, 3H, 17-H), 1.00 (s, 3H, 19-H) ppm; C NMR (125 MHz, CDCl ): δ = 170.2 (C-21),
3
65.8 (C-23), 150.6 (C-26), 148.2 (C-9), 146.3 (C-13), 142.1 (C-24), 137.1 (C-12), 132.9 (C-
), 127.2 (C-14), 121.1 (C-25), 118.0 (C-11), 50.5 (C-18), 45.4 (C-5), 38.3 (C-1), 37.9 (C-4),
7.7 (C-10), 36.5 (C-3), 29.9 (C-7), 27.3 (C-15), 25.4 (C-20), 23.1 (C-16), 23.1 (C-17), 21.1
(C-22), 19.2 (C-6), 19.0 (C-19), 18.6 (C-2) ppm; MS (ESI, MeOH): m/z (%) = 449.3
+
+
+
+
(
[M+H] , 100), 471.3 ([M+Na] , 5), 897.1 ([2M+H] , 30), 918.9 ([2M+Na] , 10); analysis
calculated for C H N O (448.60): C 74.97, H 8.09, N 6.24; found: C 74.81, H 8.23, N 5.87.
2
8
36
2
3
4
.3.16 N-Biotinyldehydroabietylamine (25)
Compound 25 was prepared according to general procedure
A
from
dehydroabietylamine (0.15 g, 0.52 mmol) and biotin (0.13 g, 0.53 mmol) using DMF as
solvent. Column chromatography (silica gel, chloroform/methanol, 9:1) afforded compound
2
1
2
5 (0.22 g, 81%) as a colorless solid; R = 0.36 (silica gel, chloroform/methanol, 9:1); mp =
F
28-130 °C; [α] = +41.3° (c = 0.32, CHCl ); IR (KBr): v = 3406m, 3312s, 3076m, 2956s,
D
3
926s, 2866m, 1704vs, 1654s, 1648s, 1550m, 1508w, 1498m, 1458m, 1382m, 1326w, 1266m,
20

ACCEPTED MANUSCRIPT
-1
1
1
216w, 1172w cm ; UV-vis (CHCl ): λ
(log ε) = 285 nm (3.21); H NMR (500 MHz,
3
max
CDCl ): δ = 7.16 (d, J = 8.2 Hz, 1H, 11-H), 6.99 (dd, J = 8.2, 1.6 Hz, 1H, 12-H), 6.90 (d, J =
3
1
.4 Hz, 1H, 14-H), 6.28 (br s, 1H, NH), 6.00 (br s, 1H, NH), 4.43 (dd, J = 4.9, 4.9 Hz, 1H,
2
9-H), 4.19 (dd, J = 4.8, 4.8 Hz, 1H, 27-H), 3.22 (dd, J = 13.6, 5.3 Hz, 1H, 18-H ), 3.11 (dd, J
a
=
+
13.6, 5.8 Hz, 1H, 18-H ), 3.07 - 3.01 (m, 1H, H-26), 2.94 - 2.78 (m, 4H, 7-H + 7-H + 15-H
b a b
30-H ), 2.69 (d, J = 12.8 Hz, 1H, 30-H ), 2.32 - 2.26 (m, 1H, 1-H ), 2.21 (t, J = 7.3 Hz, 2H,
a
b
a
2
2
1
0
2-H + 22-H ), 1.93 - 1.87 (m, 1H, 6-H ), 1.81 - 1.57 (m, 8H, 2-H + 2-H + 6-H + 25-H +
a b a a b b a
5-H + 24-H + 24-H + 23-H ), 1.45 - 1.37 (m, 3H, 23-H + 3-H + 5-H), 1.37 - 1.32 (m, 1H,
b
a
b
a
b
a
-H ), 1.32 - 1.24 (m, 1H, 3-H ), 1.23 (d, J = 6.9 Hz, 6H, 16-H + 17-H), 1.21 (s, 3H, 20-H),
b
b
1
3
.93 (s, 3H, 19-H) ppm; C NMR (125 MHz, CDCl ): δ = 173.6 (C-21), 163.9 (C-28), 147.3
3
(
C-13), 145.7 (C-9), 135.0 (C-8), 127.1 (C-14), 124.3 (C-11), 123.9 (C-12), 61.9 (C-27), 60.4
C-28), 55.6 (C-26), 49.9 (C-18), 45.4 (C-5), 40.5 (C-30), 38.5 (C-1), 37.6 (C-4), 37.6 (C-10),
(
3
6.3 (C-3), 36.3 (C-22), 33.5 (C-15), 30.3 (C-7), 28.3 (C-23), 28.2 (C-24), 26.0 (C-25), 25.5
(C-20), 24.1 (C-16), 24.1 (C-17), 19.1 (C-6), 19.0 (C-19), 18.8 (C-2) ppm; MS (ESI, MeOH):
+
+
+
m/z (%) = 512.3 ([M+H] , 10), 534.4 ([M+Na] , 10), 1023.3 ([2M+H] , 15), 1045.3
+
(
[2M+Na] , 100); analysis calculated for C H N O S (511.76): C 70.41, H 8.86, N 8.21, S
3
0
45
3
2
6
.27; found: C 70.13, H 8.96, N 8.65, S 6.03.
4
.3.17 N-Biotinyl-12-hydroxydehydroabietylamine (26)
Compound 26 was prepared according to general procedure A from compound 10 (0.15 g,
.50 mmol) and biotin (0.17 g, 0.70 mmol) using DMF as solvent. Column chromatography
silica gel, chloroform/methanol, 9:1) afforded compound 26 (0.19 g, 72%) as a colorless
solid; R = 0.39 (silica gel, chloroform/methanol, 9:1); mp = 154-156 °C; [α] = +55.4° (c =
0
(
F
D
0
.35, MeOH); IR (KBr): v = 3404s, 2928s, 2866m, 1696vs, 1654s, 1550m, 1510m, 1458m,
-1
1
380m, 1308m, 1268m, 1242m, 1184m, 1164m, 1088w, 1048w cm ; UV-vis (MeOH): λ
max
1
(
log ε) = 303 nm (3.47); H NMR (500 MHz, CD OD): δ = 6.75 (s, 1H, 14-H), 6.61 (s, 1H,
3
1
1-H), 4.38 (dd, J = 7.8, 4.5 Hz, 1H, 29-H), 3.83 (dd, J = 7.8, 4.4 Hz, 1H, 27-H), 3.63 – 3.56
(
m, 1H, 18-H ), 3.15 (hept, J = 6.9 Hz, 1H, 15-H), 2.81 (dd, J = 12.7, 5.0 Hz, 1H, 30-H ), 2.73
a
a
(
dd, J = 10.2, 5.2 Hz, 2H, 7-H + 7-H ), 2.63 – 2.59 (m, 2H, 18-H + 30-H ), 2.51 (ddd, J =
a b b b
7
1
1
4
.3, 4.5 Hz, 1H, 26-H), 2.24 – 2.18 (m, 3H, 1-H + 22-H + 22-H ), 2.04 – 1.97 (m, 1H, 6-H ),
a a b a
.80 (dddd, J = 16.3, 13.1, 8.2, 3.0 Hz, 1H, 2-H ), 1.72 – 1.62 (m, 3H, 2-H + 6-H + 25-H ),
a
b
b
a
.61 – 1.51 (m, 1H, 25-H ), 1.50 – 1.40 (m, 4H, 24-H + 24-H + 3-H + 5-H), 1.40 – 1.23 (m,
b
a
b
a
H, 1-H + 3-H + 23-H + 23-H ), 1.19 (s, 3H, 20-H), 1.19 (d, J = 6.9 Hz, 3H, 16-H), 1.16 (d,
b
b
a
b
13
J = 6.9 Hz, 3H, 17-H), 0.92 (s, 3H, 19-H) ppm; C NMR (125 MHz, CD OD): δ = 176.0 (C-
3
21

ACCEPTED MANUSCRIPT
2
1), 166.1 (C-28), 153.3(C-13), 149.2 (C-9), 133.2 (C-12), 127.4 (C-14), 127.1 (C-8), 111.5
(
C-11), 63.2 (C-27), 61.5 (C-29), 57.0 (C-26), 50.5 (C-18), 45.4 (C-5), 40.9 (C-30), 39.7 (C-
), 39.0 (C-4), 38.6 (C-10), 37.2 (C-3), 36.8 (C-22), 30.7 (C-7), 29.8 (C-23), 29.4 (C-24), 27.8
C-15), 27.0 (C-25), 25.9 (C-20), 23.6 (C-16), 22.8 (C-17), 20.5 (C-6), 19.8 (C-2), 19.7 (C-
1
(
+
+
1
9) ppm; MS (ESI, MeOH): m/z (%) = 528.4 ([M+H] , 74), 550.5 ([M+Na] , 100); analysis
calculated for C H N O S (527.76): C 68.27, H 8.59, N 7.96, S 6.08; found: C 67.96, H
3
0
45
3
3
8
4
.73, N 7.75, S 5.86.
.3.18 12-Acetoxy-N-biotinyldehydroabietylamine (27)
Compound 27 was prepared according to general procedure A from compound 23 (0.10 g,
.29 mmol) and biotin (0.09 g, 0.37 mmol) using DMF as solvent. Column chromatography
silica gel, chloroform/methanol, 9:1) afforded compound 27 (0.09 g, 55%) as a colorless
solid; R = 0.27 (silica gel, chloroform/methanol, 9:1); mp = 130-132 °C; [α] = +53.4° (c =
0
(
F
D
0
1
2
.31, CHCl ); IR (KBr): v = 3284w, 2958w, 2926m, 2866w, 1754m, 1697s, 1648s, 1539m,
3
-1
496m, 1455m, 1368m, 1207vs, 1016m, 912m, 729m cm ; UV-vis (CHCl ): λ
(log ε) =
3
max
1
96 nm (3.03); H NMR (400 MHz, CDCl ): δ = 6.94 (s, 1H, 14-H), 6.80 (s, 1H, 11-H), 6.13
3
(s, 1H, NH), 5.99 (dd, J = 6.3, 6.3 Hz, 1H, NH), 4.41 (dd, J = 7.5, 4.7 Hz, 1H, 31-H), 4.18
(
dd, J = 7.5, 4.7 Hz, 1H, 29-H), 3.24 (dd, J = 13.7, 5.9 Hz, 1H, 18-H ), 3.09 - 3.00 (m, 2H, 18-
a
H + 28-H), 2.95 - 2.85 (m, 2H, 15-H + 7-H ), 2.85 - 2.74 (m, 2H, 7-H + 32-H ), 2.62 (d, J =
b
a
b
a
1
1
1
3
2.8 Hz, 1H, 32-H ), 2.29 (s, 3H, 22-H), 2.23 - 2.12 (m, 3H, 24-H + 24-H + 1-H ), 1.94 -
b a b a
.85 (m, 1H, 6-H ), 1.80 - 1.54 (m, 7H, 6-H + 2-H + 2-H + 25-H + 25-H +27-H + 27-H ),
a
b
a
b
a
b
a
b
.46 - 1.34 (m, 5H, 26-H + 26-H + 3-H + 1-H + 5-H), 1.34 - 1.22 (m, 1H, 3-H ), 1.19 (s,
a
b
a
b
b
H, 20-H), 1.18 (d, J = 6.7 Hz, 3H, 16-H) 1.16 (d, J = 6.7 Hz, 3H, 17-H), 0.91 (s, 3H, 19-H)
13
ppm; C NMR (100 MHz, CDCl ): δ = 173.5 (C-23), 170.2 (C-21), 163.8 (C-30), 148.5 (C-
3
13), 146.3 (C-9), 137.0 (C-12), 133.2 (C-8), 127.2 (C-14), 118.0 (C-11), 62.0 (C-29), 60.3 (C-
31), 55.6 (C-28), 49.7 (C-18), 44.8 (C-5), 40.5 (C-32), 38.4 (C-1), 37.7 (C-4), 37.6 (C-10),
36.2 (C-3), 36.2 (C-24), 29.8 (C-7), 28.3 (C-25), 28.2 (C-26), 27.3 (C-15), 25.9 (C-27), 25.4
(C-20), 23.2 (C-16), 23.1 (C-17), 21.1 (C-22), 19.0 (C-19), 19.0 (C-6), 18.7 (C-2) ppm; MS
2
+
+
2+
(
ESI, MeOH): m/z (%) = 304.8 ([M+Ca] , 10), 570.5 ([M+H] , 50), 589.5 ([2M+Ca] , 5),
+
+
+
5
92.5 ([M+Na] , 10), 1139.2 ([2M+H] , 80), 1161.3 ([2M+Na] , 100); analysis calculated for
C H N O S (569.80): C 67.45, H 8.31, N 7.37, S 5.63; found: C 67.31, H 8.60, N 7.52, S
30
45
3
3
5
.52.
22

ACCEPTED MANUSCRIPT
Acknowledgments
We like to thank Dr. R. Kluge for the measurement of the ESI-MS spectra, Dr. D. Ströhl and
his team for the NMR spectra and Ms. V. Simon, BSc, for measuring optical rotations, IR and
UV-vis spectra. The cell lines were kindly provided by Dr. Th. Müller (Dept. of
Haematology/Oncology, Martin-Luther Universität Halle-Wittenberg). Financial support by
“ScienceCampus Halle WCH” (W13004216) is gratefully recognized.
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Highlights
*
*
*
*
Dehydroabietylamine shows a broad spectrum of biological activities
“Simple” amides, C-ring-modified and biotinylated amides were prepared
These compounds were screened in SRB assays for cytotoxic activity
Several compounds showed high cytotoxicity and good selectivity for human tumor cells