Synthetic transformations of higher terpenoids. XXI.* preparation of phlomisoic acid and its N-containing derivatives

Article abstract of DOI:10.1007/s10600-010-9577-6

A method for preparing 15,16-epoxylabda-8(9),13(16),14-trien-18-oic (phlomisoic) acid was proposed. Its structure was confirmed by an XSA. N-containing derivatives of phlomisoic acid that contained amines, hydrazides, and methyl esters of amino acids on the C-18 atom in addition to (2-oxo-2-aminoacetyl)-substituted derivatives of the C-16 methyl ester of phlomisoic acid were prepared.

Full text of DOI:10.1007/s10600-010-9577-6

Chemistry of Natural Compounds, Vol. 46, No. 2, 2010
SYNTHETIC TRANSFORMATIONS OF HIGHER TERPENOIDS.
XXI.* PREPARATION OF PHLOMISOIC ACID
AND ITS N-CONTAINING DERIVATIVES
1,2
1
1*
M. E. Mironov, Yu. V. Kharitonov, E. E. Shulꢀts,
UDC 547.913.6
1
1
1
M. M. Shakirov, I. Yu. Bagryanskaya, and G. A. Tolstikov
A method for preparing 15,16-epoxylabda-8(9),13(16),14-trien-18-oic (phlomisoic) acid was proposed. Its
structure was confirmed by an XSA. N-containing derivatives of phlomisoic acid that contained amines,
hydrazides, and methyl esters of amino acids on the C-18 atom in addition to (2-oxo-2-aminoacetyl)-substituted
derivatives of the C-16 methyl ester of phlomisoic acid were prepared.
Keywords: phlomisoic acid, lambertianic acid, amides, XSA, synthesis.
15,16-Epoxylabda-8(9),13(16),14-trien-18-oic (phlomisoic) acid (1) is a product from enzymatic hydrolysis of plant
glycosides found in medicinal plants of the family Lamiaceae, Phlomis spp. and Eremostachys spp. [2–4], and exhibiting a
variety of biological activity [2, 3]. An examination of the structure of 1 suggested that it could be prepared from lambertianic
acid (2), which is produced by Siberian pine Pinus sibirica R. Mayr. [5] and was used successfully by us earlier to synthesize
pharmacologically valuable agents [6–9]. Herein we report the preparation of phlomisoic acid (1) and its amides and
16-acetylamido-substituted derivatives of phlomisoic acid methyl ester for subsequent studies of their pharmacological properties.
We found that 2 treated with p-toluenesulfonic acid in boiling benzene isomerized smoothly into 1 (86% yield)
(Scheme 1). This regent was used successfully for isomerization of labdane diterpenoids in the total synthesis of drimane
sesquitpenoids [10].
O
O
13
13
11
11
Cl
20
O
O
O
O
17
1
1
9
17
a
b
15
15
9
10
10
+
5
5
7
7
3
3
H
H
H
H
CO H
CO H
COCl
COCl
2
2
18
18
4
2
1
3
O
O
Cl
O
O
c
H
H
CO CH
2
CO CH
2
3
3
5
6
a. p-TsOH, C H , ꢁ; b. (COCl) , CH Cl , Et N, 0°C; c. (COCl) , CH Cl , Et N
6
6
2
2
2
3
2
2
2
3
Scheme 1
______
*For No. XX, see Ref. [1].
1) Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, 630090,
Novosibirsk, fax: (383) 330 97 52, e-mail: schultz@nioch.nsc.ru; 2) Novosibirsk State University, 630090, Novosibirsk,
ul. Pirogova, 2. Translated from Khimiya Prirodnykh Soedinenii, No. 2, pp. 194–200, March–April, 2010. Original article
submitted October 21, 2009.
©
0009-3130/10/4602-0233 2010 Springer Science+Business Media, Inc.
233

Amides of 1 were synthesized by reaction of phlomisoic acid chloride (3) with amines or methyl esters of amino
acids. Acid chloride 3 was prepared by reaction of 1 with oxalylchloride under Ar at 0°C. If 1 was reacted with an excess of
oxalylchloride (2 equiv.) under these conditions, the product from acylation of the furan ring, 16-(2-chloro-2-oxoacetyl)-
15,16-epoxylabda-8(9),13(16),14-trien-18-oic acid chloride (4), also formed. The ease with which the acylation occurred was
confirmed by studying the action of oxalylchloride on the methyl ester of 1 (5) [11] under the reported conditions. The main
product from the reaction was methyl 16-(2-chloro-2-oxoacetyl)-15,16-epoxylabda-8(9),13(16),14-trienoate (6).
Condensation of 3 with amines (benzylamine, tyramine) and with the methyl esters of alanine, valine, methionine,
9-aminopelargonic acid, and 3-amino-3-phenylpropionic acid (used as the hydrochlorides) produced 7a-g, which had secondary
or tertiary amines on C-18 (Scheme 2). The amines were selected for either their intrinsic activity or structural features that
enabled additional pharmacophores to be introduced into the diterpenoid molecule. The reaction was carried out at room
temperature in anhydrous CH Cl in the presence of triethylamine. The yields were 39–74%. Reaction of 3 with 2-hydrazinyl-
2
2
2-oxo-N-phenylacetamide produced the corresponding hydrazide of phlomisoic acid 7h. The yields of amides 7a-g and
hydrazide 7h were calculated for starting 1, i.e., were in fact total yields from two steps.
O
a
b
H
R
CO CH
2
3
H
N
COCl
C
O
N
1
C
O
C
H
R
1
7a - c, g, h
3
7d - f
R = CH Ph (7a); (CH ) -C H -OH (7b); (CH ) CO Me (7c); R = CH (7d), CH(CH ) (7e)
1
2
2 2
6
4
2 8
2
1
3
3 2
(CH ) SCH (7f); CH(Ph)CH CO Me (7g); HNCOCONHPh (7h)
2 2
3
2
2
+
-
a. H N-R ; b. [H NCHR CO CH ] Cl
2
1
3
1
2
3
Scheme 2
We showed earlier that introducing aminomethyl and benzylaminomethyl substituents at the C-16 position of
furanolabdanoids produced effective neurotropic agents and antioxidants [9, 12, 13]. We used the reaction of 6 with benzylamine
or the methyl ester of 3-amino-3-phenylpropionic acid in order to introduce a 2-oxo-2-aminoacetyl substituent into the C-16
position of phlomisoic acid derivatives. Carrying out the condensation in CH Cl in the presence of triethylamine produced
2
2
the corresponding 16-(2-oxo-2-aminoacetyl)-derivatives of the methyl ester of phlomisoic acid 8a and b in 64–67% yields
(calculated for 5) (Scheme 3).
Ph
H
O
O
O
O
O
N
H
C
O
N
H
CH
2
Cl
CH
2
Ph
O
O
H NCHCH CO CH
H NCH Ph
O
C
2
2
2
3
2
2
O
OCH
3
H
CO CH
6
2
3
8a
8b
Scheme 3
13
The structures of the synthesized compounds were elucidated by IR, PMR, and C NMR spectroscopy in addition to
high-resolution mass spectrometry. The structure of 1 was also confirmed by an x-ray structure analysis (XSA).
234

O1
C15
C14
C16
C13
C12
C11
C17
Ñ5
C4
C4A
C3
C2
C6
C20
1.794
1.832
C7
C1 C8A
C18
C8
O3
O2
C19
Fig. 1.
Fig. 2.
Fig.1. Molecular structure of one of the two independent molecules of phlomisoic acid (1) in the crystal.
Fig. 2. Molecular packing of phlomisoic acid in the crystal.
The asymmetric unit of 1 contained two molecules, the geometry and molecular structure of which agreed within 3ꢂ.
Figure 1 shows the molecular structure of one of them. The furan rings were planar with a mean-square deviation of the atoms
°
from the plane of one molecule of 0.004; of the other, –0.003 A. The cyclohexane rings had the chair conformation; the
cyclohexene ring, a half-chair. The molecules in the crystal formed dimers through strong “forked” H-bonds (Fig. 2). The
intermolecular distances O2...H and O2A...H are given in Fig. 2. The distances O2...O3A and O2A...O3 were 2.665(2) and
°
2.622(2) A, angles O–H...O 171 and 168°, respectively.
The positions of H atoms in 1 were calculated geometrically and refined using a “rider” model (parameters of H
atoms were calculated in each refinement cycle from coordinates of the corresponding C atoms). The final refinement of the
2
structure over all F gave wR = 0.1180 and S = 0.97. A total of 415 parameters was refined (R = 0.0443 for 4717 F > 4ꢂ). The
2
Flack parameter for determining the absolute configuration of 1 was –0.88(1.06). However, despite the large uncertainty,
refinement of the inverted structure gave a Flack parameter 1.87(1.06), which indirectly confirmed the absolute configuration
of 1.
13
Chemical shifts of H and C resonances of 1 in PMR and C NMR spectra in CDCl differed slightly from those
3
reported [2] (spectra taken in C D N). However, we observed all couplings in two-dimensional spectra obtained in COLOC
5
5
and NOESY modes that were previously reported [2].
The presence of amides in 7a-h and 8a and b was confirmed by absorption bands for C=O bonds in IR spectra at
–1
–1
1637–1680 cm and broad bands for N–H stretching vibrations at 3238–3451 cm . IR spectra of the synthesized acid
–1
chlorides 3, 4, and 6 had absorption bands at 1788–1805 cm that corresponded to stretching vibrations of the COCl carbonyls.
Introducing a COCOCl substituent into the furan ring caused a weak-field shift of H-14 and H-15 in the PMR spectrum
of 4 and 6 (for 6, ꢃ 6.60 and 7.63 ppm, respectively) compared with the position of the corresponding protons in 1 (ꢃ 6.31 and
13
7.37 ppm, respectively). The C NMR spectrum of 6 had two characteristic singlets at 165.01 and 169.60 ppm that corresponded
to the oxo-acid chloride and a singlet at 143.80 ppm for C-16, which appeared in 5 as a doublet at 142.67 ppm [11].
Introducing primary amines and esters of amino acids into 1 and 5 produced a set of characteristic resonances in the
13
PMR and C NMR spectra that corresponded to the substituent. Resonances of certain protons in PMR spectra of amides
7e, f, and g with amino acids were doubled, in particular, resonances for 17-CH , 19-CH , 20-CH , and OCH and NCH
3
3
3
3
groups were doubled. This was related to the use in the reaction of the corresponding amino-acid esters as a mixture of optical
isomers (D and L).
Thus, we synthesized phlomisoic acid and prepared its derivatives that are of interest as pharmacologically valuable
compounds.
235

13
TABLE 1. Chemical Shifts of C Atoms in C NMR Spectra of 1, 6, 7a–h, 8a, and 8b (ꢃ, ppm)
C atom*
1
6
7a
7b
7c
7d
1
2
3
36.72 t
19.06 t
36.92 t
36.94 t
19.44 t
37.54 t
37.61 t
19.83 t
38.02 t
37.06 t
19.23 t
37.39 t
37.47 t
19.70 t
37.89 t
37.38 t
19.51 t
37.78 t
4
5
6
7
43.38 s
53.13 d
20.26 t
43.74 s
53.33 d
20.65 t
43.76 s
53.84 d
21.42 t
43.39 s
53.31 d
20.86 t
43.61 s
53.58 d
21.30 t
43.66 s
53.41 d
21.20 t
33.79 t
34.22 t
34.49 t
33.88 t
33.89 t
34.38 t
8
9
126.91 s
138.38 s
39.32 s
28.48 t
128.40 s
137.56 s
39.54 s
27.50 t
126.91 s
139.21 s
39.78 s
29.62 t
126.59 s
138.37 s
40.54 s
28.45 t
126.79 s
139.03 s
39.33 s
28.88 t
126.90 s
139.00 s
39.69 s
28.75 t
10
11
12
13
14
15
16
17
18
19
20
25.27 t
26.57 t
25.68 t
25.25 t
25.55 t
25.54 t
125.09 s
110.35 d
142.21 d
137.94 d
19.29 q
184.31 s
28.17 q
17.41 q
142.14 s
115.41 d
149.13 d
143.80 s
19.60 q
177.93 s
28.31 q
17.61 q
125.49 s
110.73 d
147.70 d
146.06 d
19.66 q
176.70 s
29.72 q
18.18 q
125.07 s
110.32 d
142.23 d
137.94 d
19.29 q
177.23 s
29.34 q
17.62 q
125.38 s
110.65 d
142.52 d
138.23 d
19.59 q
176.63 s
29.69 q
19.97 q
125.36 s
110.64 d
142.51 d
138.22 d
19.58 q
176.24 s
28.75 q
18.17 q
C atom*
7e
7f
7g
7h
8a
8b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
39.21 t
21.35 t
39.45 t
45.83 s
53.09 d
23.09 t
37.19 t
19.44 t
37.73 t
43.66 s
53.32 d
20.82 t
37.83 t
19.53 t
37.94 t
36.75 t
19.22 t
36.97 t
43.33 s
53.77 d
20.54 t
36.91 t
19.48 t
37.57 t
43.74 s
53.38 d
20.68 t
36.95 t
20.69 t
37.60 t
43.77 s
53.08 d
20.37 t
34.26 t
127.63 s
138.09 s
39.55 s
27.61 s
27.05 t
142.24 s
114.32
147.61 d
146.01 s
19.61 q
177.90 s
28.31 q
17.62 q
43.82 s
53.49 d, 53.72 d
21.18 t
36.13 t
34.19 t
34.43 t
33.89 t
34.23 t
128.76 s
140.92 s
41.55 s
30.82 t
126.65 s
138.72 s
39.51 s
29.77 t
126.84 s
139.01 s
39.51 s
28.77 t
25.55 t
125.40 s
110.67 d
142.56 d
138.26 d
19.62 q
126.64 s
138.44 s
39.30 s
28.45 t
127.96 s
138.02 s
39.54 s
27.70 t
27.34 t
25.36 t
25.19 t
27.08 t
127.27 s
112.26 d
144.49 d
140.17 d
20.65 q
174.41 s
30.55 q
19.30 q
125.17 s
110.47 d
142.31 d
138.02 d
19.41 q
176.59 s
29.31 q
17.95 q
125.07 s
110.25 d
142.18 d
137.86 d
19.01 q
175.94 s
28.69 q
17.78 q
142.30 s
114.41 d
147.70 d
146.06 s
19.59 q
177.94 s
28.32 q
17.59 q
176.08 s
29.55 q, 29.69 q
17.98 q, 18.13 q
______
*Atom numbering of the diterpene skeleton given in the structure of 2 (Scheme 1) is used. *For 6: 51.00 q (OCH ), 165.01 s (COCOCl),
3
169.60 s (COCl); 7a: 28.87 t (NHCH ), 127.35 d (C-4ꢀ), 127.93 d (C-3ꢀ,5ꢀ), 128.63 d (C-2ꢀ,6ꢀ), 138.52 s (C-1ꢀ); 7b: 34.02 t (CH Ar), 39.33
2
2
t (NHCH ), 115.28 d (C-3ꢀ,5ꢀ), 129.21 d (C-2ꢀ,6ꢀ), 129.27 s (C-1ꢀ), 154.97 s (C-4ꢀ); 7c: 24.73 t (C-4ꢀ,5ꢀ), 26.88 t (C-6ꢀ), 28.75 t (C-3ꢀ), 28.96
2
t (C-7ꢀ), 29.22 t (C-2ꢀ), 34.38 t (C-1ꢀ), 39.66 t (C-8ꢀ), 51.29 q (OCH ), 174.12 s (CO CH ); 7d: 29.49 q (SHCH ), 52.23 q (OCH ), 53.62
3
2
3
3
3
d (NHCH), 173.86 s (CO CH ); 7e: 20.27 q (CH(CH ) ), 32.48 d (CH(CH ) ), 55.86 q (OCH ), 59.77 d (NHCH), 180.12 s (CO CH );
2
3
3 2
3 2
3
2
3
7f: 15.12 q (SCH ), 28.58 t (CH SCH ), 31.21 t (CH CH SCH ), 51.12 d (NHCH), 52.09 q (OCH ), 172.41 s (CO CH ); 7g: 37.44 t
3
2
3
2
2
3
3
2
3
(CH CO CH ), 49.29 d (SHPh), 51.70 q, 51.74 q (OCH ), 126.07 d (C-4ꢀ), 126.99 s (C-1ꢀ), 127.34 d (C-4ꢀ,5ꢀ), 128.54 d (C-2ꢀ,6ꢀ), 171.91
2
2
3
3
s (CO CH ); 7 h: 119.75 d (C-4ꢀ), 124.91 d (C-3ꢀ,5ꢀ), 128.54 d (C-2ꢀ,6ꢀ), 135.94 s (C-1ꢀ), 156.33 s (CONHPh), 158.02 s (NHCO); CH
2
3
3
(on C-2ꢀꢀ) – 14.48 q; 8a: 50.97 q (OCH ), 127.65 d (C-4ꢀ), 127.87 d (C-3ꢀ,5ꢀ), 128.63 d (C-2ꢀ,6ꢀ), 137.05 s (C-1ꢀ), 161.41 s (COCONH),
3
176.41 s (CONH); 8b: 39.55 d (CH ), 49.65 d (CH), 50.92, 51.73 (both q, OCH ), 126.30 q (C-4ꢀ), 127.78 d (C-3ꢀ,5ꢀ), 127.93 s (C-8),
2
3
128.68 d (C-2ꢀ,5ꢀ), 139.57 s (C-1ꢀ), 160.83 s (CO CH ), 170.85 s (CONH), 176.22 s (COCO).
2
3
236

EXPERIMENTAL
NMR spectra were taken on Bruker AV-300 [operating frequency 300.13 ( H) and 75.47 MHz ( C)] and Bruker
1
13
1
13
13
DRX-500 [operating frequency 500.13 ( H) and 125.76 MHz ( C)] instruments. Multiplicity of resonances in C NMR
spectra were determined using standard methods for recording spectra in J-modulation (JMOD) and with off-resonance
13
suppression of protons. Table 1 lists C NMR spectra of 1, 6, 7a-h, 8a, and 8b. Mass spectra were obtained in a DFS high-
resolution mass spectrometer. Specific rotation was measured on a Polar 3005 polarimeter at room temperature (20–23°C).
IR spectra were recorded in KBr on a Vector-22 instrument. UV absorption spectra were recorded on an HP 8453 UV Vis
–4
spectrometer in EtOH (c 10 M).
The course of reactions and purity of products were monitored by TLC on Silufol UV-254 plates using CHCl :EtOH
3
(3:1) and petroleum ether:EtOAc (10:1). Spots were developed by spraying plates with aqueous H SO (10%) with subsequent
2
4
heating to 100°C or using UV illumination.
Lambertianic acid (2) was isolated by the literature method [14]. The synthesis of the methyl ester of phlomisoic acid
(5) was reported by us earlier [11].
(1S,4aS,5S,8aR)-5-[2-(Furan-3-yl)ethyl]-1,4a,6-trimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-carbonic
Acid [15,16-Epoxylabda-8(9),13(16),14-trien-18-oic Acid, Phlomisoic Acid] (1). A solution of lambertianic acid (2, 8.88 g,
28.1 mmol) in benzene (30 mL) was treated with p-toluenesulfonic acid (0.24 g, 1.4 mmol) and refluxed for 8 h. Solvent was
evaporated in vacuo. The solid was chromatographed over a column of silica gel (CHCl eluent). Crystallization of product
3
25
14
fractions from hexane afforded 1 (7.66 g, 86%), mp 119–122°C, [ꢄ] +181.5° (c 0.23, CHCl ) {lit. [2] [ꢄ] +116.9° (c 0.31,
D
3
D
CH OH)}. UV spectrum (EtOH, ꢅ , nm, log ꢆ): 203 (4.05).
3
max
PMR spectrum (ꢃ, ppm, J/Hz): 0.91 (3H, s, 20-CH ), 1.06 (1H, td, J = 13.9, 4.6, H-3), 1.24 (1H, t, J = 13.1, H-1), 1.30
3
(3H, s, 19-CH ), 1.41 (1H, d, J = 11.9, H-5), 1.58 (2H, dm, J = 11.0, H-2), 1.66 (3H, s, 17-CH ), 1.82 (1H, td, J = 12.3, 5.5,
3
3
H-6), 1.93 (2H, dm, J = 13.3, H-6,1), 2.01 (1H, d, J = 5.7, H-7), 2.07–2.34 (4H, m, H-3,11,11,7), 2.47 (2H, t, J = 7.0, H-12),
6.31 (1H, dd, J = 1.7, 1.0, H-14), 7.25 (1H, dd, J = 1.3, 1.0, H-16), 7.37 (1H, dd, J = 1.3, 1.7, H-15).
Mass spectrum (m/z, I , %): 317 (21), 316 (94), 301 (22), 235 (37), 234 (36), 221 (31), 189 (100), 188 (36), 133 (62),
rel
+
119 (45), 105 (33), 91 (35), 82 (39), 81 (60), 56 (37), 43 (61). Found: [M] 316.2040. C H O . Calcd: 316.2033.
20 28
3
Acid Chloride of (1S,4aS,8aR)-1,4a,6-Trimethyl-5-[2-(furan-3-yl)ethyl]-1,2,3,4,4a,7,8,8a-octahydronaphthalen-
1-carboxylic Acid (Phlomisoic Acid Chloride) (3). Phlomisoic acid (1, 1.00 g, 3.2 mmol) in CH Cl (10 mL) under Ar was
2
2
cooled by ice, stirred vigorously, and treated dropwise with oxalylchloride (0.28 mL, 3.2 mmol) in CH Cl (10 mL). The
2
2
temperature was raised to ambient. Stirring was continued for 5 h. Solvent was evaporated in vacuo. The solid was treated
with CH Cl (10 mL) and again evaporated. This procedure was repeated four times. The solid afforded 3, which was used
2
2
immediately to synthesize the amides.
PMR spectrum (ꢃ, ppm, J/Hz): 0.95 (3H, s, 20-CH ), 1.10 (1H, d, J = 12.2, H-3), 1.22 (1H, td, J = 14.0, 3.4, H-1), 1.40
3
(3H, s, 19-CH ), 1.52 (1H, m, H-5), 1.61 (2H, s, H-2), 1.67 (3H, s, 17-CH ), 1.71–1.89 (2H, m, H-6), 1.91-2.37 (6H, m,
3
3
H-1,3,7,7,11,11), 2.41–2.49 (2H, m, H-12), 6.31 (1H, s, H-14), 7.25 (1H, s, H-16), 7.37 (1H, s, H-15).
(1S,4aS,8aR)-Methyl 1,4a,6-trimethyl-5-{2-[2-(2-chloro-2-oxoacetyl)furan-3-yl]-ethyl}-1,2,3,4,4a,7,8,8a-
octahydronaphthalen-1-carboxylate (6). Methyllabdatriene (5, 1.00 g, 3.0 mmol) in CH Cl (15 mL) under Ar was cooled
2
2
to 0°C and treated dropwise with oxalylchloride (0.53 mL, 6.0 mmol) in CH Cl (6 mL). The temperature was raised to
2
2
ambient. Stirring was continued for 5 h. Solvent was evaporated. The solid was treated with CH Cl (10 mL) and again
2
2
–1
evaporated. This procedure was repeated another two times. The solid affored 6 as an oil. IR spectrum ( , cm ): 1788, 1726,
1670, 1576, 1380, 1230, 1160, 1148, 1038, 982, 889, 782, 722, 682.
PMR spectrum (ꢃ, ppm, J/Hz): 0.76 (3H, s, 20-CH ), 1.00 (1H, td, J = 13.3, 4.4, H-3), 1.18 (1H, m, H-1), 1.19 (3H,
3
s, 19-CH ), 1.33 (1H, dd, J = 12.6, 2.5, H-5), 1.54 (2H, dm, J = 13.9, H-2), 1.65 (3H, s, 17-CH ), 1.69–2.32 (8H, m,
3
3
H-1,3,6,6,7,7,11,11), 2.88 (2H, t, J = 8.1, H-12), 3.61 (3H, s, OCH ), 6.60 (1H, d, J = 1.5, H-14), 7.63 (1H, d, J = 1.5, H-15).
3
Mass spectrum (m/z, Irel, %): 420 (1), 405 (2), 357 (11), 235 (37), 330 (16), 316 (13), 301 (15), 189 (100), 175 (54),
+
133 (52), 121 (41), 119 (46), 105 (44), 91 (36), 81 (30), 55 (31). Found: [M] 420.1707. C H O Cl. Calcd: 420.1698.
23 29
5
General Method for Preparing Amides of 8(9),13(16),14-labdatrien-18-oic Acid 7a-h. A solution of 3 (1.10 g,
3.2 mmol) in CH Cl (15 mL) was treated in portions with amine (3.8 mmol) (hydrochlorides for methyl esters of amino acids)
2
2
and then with triethylamine (2.11 mL, 15.2 mmol). The reaction mixture was left at room temperature with periodic stirring
for 2 d. Solvent was evaporated in vacuo. The solid was treated with Et O. The resulting precipitate of triethylammonium
2
237

chloride was filtered off. The mother liquor was evaporated. The solid was purified by column chromatography over silica gel
(20:1, CHCl :CH OH, 100:1) to afford amides 7a-h.
3
3
(1S,4aS,8aR)-N-Benzyl-5-[2-(furan-3-yl)ethyl]-1,4a,6-trimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-
carboxamide (7a). Reaction of 3 (0.54 g, 1.6 mmol) with benzylamine in the presence of Et N afforded 7a (0.41 g, 64%),
3
25
–1
[ꢄ] +105.6° (c 1.64, CHCl ). IR spectrum ( , cm ): 3377, 1696, 1649, 1640, 1515, 1259, 1025, 874, 778, 724, 699.
D
3
PMR spectrum (ꢃ, ppm, J/Hz): 0.85, 0.87 (3H, both s, 20-CH ), 0.97 (1H, td, J = 13.9, 4.6, H-3), 1.09 (1H, td,
3
J = 13.9, 4.6, H-1), 1.21, 1.25 (3H, both s, 19-CH ), 1.37 (1H, dd, J = 12.5, 2.8, H-5), 1.53–1.56 (2H, m, H-2), 1.62 (3H, s,
3
17-CH ), 1.71–2.27 (8H, m, H-1,3,6,6,7,7,11,11), 2.36–2.48 (2H, m, H-12), 4.34, 4.42 (2H, AB-X, J = 5.2, NHCH ), 5.80
3
2
(1H, s, NH), 6.27 (1H, s, H-14), 7.21–7.33 (7H, m, H-15,16 and 5H, Ph–H).
Mass spectrum (m/z, I , %): 405.27 (17), 324 (36), 189 (46), 175 (22), 133 (31), 119 (30), 105 (21), 95 (30),
rel
+
91 (100), 57 (52), 55 (38). Found: [M] 405.2663, C H NO . Calcd: 405.2668.
27 35
2
(1S,4aS,8aR)-N-(4-Hydroxyphenethyl)-5-[2-(furan-3-yl)ethyl]-1,4a,6-trimethyl-1,2,3,4,4a,7,8,8a-
octahydronaphthalen-1-carboxamide (7b). Reaction of 3 (2.10 g, 6.3 mmol) with tyramine in the presence of Et N afforded
3
25
–1
7b (1.72 g, 63%) as an amorphous solid, mp 162–165°C, [ꢄ] +74.6° (c 1.17, CHCl ). IR spectrum ( , cm ): 3255, 1660,
D
3
1638, 1594, 1560, 1515, 1365, 1231, 1105, 1024, 873, 830, 777.
PMR spectrum (ꢃ, ppm, J/Hz): 0.81 (3H, s, 20-CH ), 0.85–1.09 (2H, m, H-1,3), 1.13 (3H, s, 19-CH ), 1.16–1.32 (1H,
3
3
m, H-5), 1.50 (2H, dm, J = 13.8, H-2), 1.60 (3H, s, 17-CH ), 1.64–2.27 (8H, m, H-1,3,6,6,7,7,11,11), 2.41 (2H, m, H-12), 2.71
3
(2H, t, J = 7.0, CH Ar), 3.39–3.48 (2H, m, NHCH ), 5.68 (1H, br.s, NH), 6.26 (1H, s, H-14), 6.81 (2H, d, J = 8.5, H-2ꢀ,6ꢀ), 6.99
2
2
(2H, d, J = 8.5, H-3ꢀ,5ꢀ), 7.20 (1H, s, H-16), 7.32 (1H, s, H-15).
+
Mass spectrum (m/z, I , %): 435.3 (6), 354 (22), 189 (100), 120 (83), 133 (71), 81 (62). Found: [M] 435.2766.
rel
C H NO . Calcd: 435.2768.
28 37
3
(1S,4aS,8aR)-N-[(9-Methoxycarbonyl)nonyl]-5-[2-(furan-3-yl)ethyl]-1,4a,6-trimethyl-1,2,3,4,4a,7,8,8a-
octahydronaphthalen-1-carboxamide (7c). Reaction of 3 (1.10 g, 3.2 mmol) with the hydrochloride of 9-aminopelargonic
25
–1
acid methyl ester in the presence of Et N afforded 7c (0.54 g, 35%), [ꢄ] +77.1° (c 0.74, CHCl ). IR spectrum ( , cm ):
3
D
3
3391, 1738, 1644, 1520, 1249, 1196, 1170, 1063, 1025, 980, 873, 777, 755, 723.
PMR spectrum (ꢃ, ppm, J/Hz): 0.85 (3H, s, 20-CH ), 1.06 (1H, td, J = 13.6, 4.0, H-3), 1.15 (3H, s, 19-CH ),
3
3
1.16–1.27 (9H, m, H-1,3ꢀ,3ꢀ,4ꢀ,4ꢀ,5ꢀ,5ꢀ,6ꢀ,6ꢀ), 1.32 (1H, dd, J = 12.6, 2.8, H-5), 1.48 (2H, m, H-7ꢀ), 1.57–1.62 (4H, m,
H-2,2,2ꢀ,2ꢀ), 1.62 (3H, s, 19-CH ), 1.70–1.91 (4H, m, H-1,7,6,6), 1.98–2.12 (2H, m, H-7,11), 2.23–2.29 (4H, m, H-3,11,1ꢀ,1ꢀ),
3
2.42 (2H, m, H-12), 3.18 (2H, m, H-8ꢀ), 3.64 (3H, s, OCH ), 5.56 (1H, br.s, NH), 6.27 (1H, s, H-14), 7.21 (1H, s, H-16), 7.32
3
(1H, s, H-15).
+
Mass spectrum (m/z, I , %): 485 (45), 404 (100), 81 (50), 55 (49). Found: [M] 485.3508. C H NO .
rel
30 47
4
Calcd: 485.3499.
(1S,4aS,8aR)-N-(3-Methoxycarbonylpropan-2-yl)-5-[2-(furan-3-yl)ethyl]-1,4a,6-trimethyl-1,2,3,4,4a,7,8,8a-
octahydronaphthalen-1-carboxamide (7d). Reaction of 3 (1.10 g, 3.2 mmol) with the hydrochloride of D,L-alanine methyl
25
–1
ester in the presence of Et N afforded 7d (0.73 g, 57%), [ꢄ] +145.9° (c 0.84, CHCl ). IR spectrum ( , cm ): 3448, 3134,
3
D
3
1741, 1654, 1503, 1449, 1311, 1214, 1191, 1175, 1096, 1063, 1025, 980, 874, 825, 777, 755, 600.
PMR spectrum (ꢃ, ppm, J/Hz): 0.83, 0.84 (3H, both s, 20-CH ), 1.02–1.12 (1H, m, H-3), 1.18, 1.19 (3H, both s,
3
19-CH ), 1.16-1.23 (2H, m, H-1,5), 1.36, 1.38 (3H, both d, J = 7.0, CH ), 1.56 (2H, dt, J
= 11.3, H-2), 1.62 (3H, s, 17-CH ),
3
3
gem
3
1.74–1.96 (4H, m, H-1,7,6,6), 2.01–2.14 (2H, m, H-7,11), 2.18–2.26 (2H, m, H-3,11), 2.40–2.44 (2H, m, H-12), 3.72 (3H, s,
OCH ), 4.56 (1H, qd, J = 7.3, 4.8, CH), 6.17, 6.24 (1H, both d, J = 7.0, NH), 6.26 (1H, s, H-14), 7.20 (1H, s, H-16), 7.32 (1H,
3
s, H-15).
+
Mass spectrum (m/z, I , %): 477 (30), 271 (100), 189 (95), 201 (77), 107 (37). Found: [M] 401.2550. C H NO .
rel
24 35
4
Calcd: 401.2561.
(1S,4aS,8aR)-N-(2-Methyl-4-methoxycarbonylbutan-3-yl)-5-[2-(furan-3-yl)ethyl]-1,4a,6-trimethyl-
1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-carboxamide (7e). Reaction of 3 (1.10 g, 3.2 mmol) with the hydrochloride
25
of D,L-valine methyl ester in the presence of Et N afforded 7e (0.65 g, 47%), [ꢄ] +70.0° (c 0.67, CHCl ).
3
D
3
–1
IR spectrum ( , cm ): 3451, 1739, 1669, 1502, 1466, 1371, 1306, 1265, 1206, 1154, 1063, 1025, 994, 874, 775 (NH).
PMR spectrum (ꢃ, ppm, J/Hz): 0.82, 0.84 (3H, both s, 20-CH ), 0.87, 0.90, 0.91, 0.92 [6H, all d, CH(CH ) ],
3
3 2
0.90–1.18 (2H, m, H-3,1), 1.21, 1.23 (3H, both s, 19-CH ), 1.38 (1H, m, H-5), 1.53–1.57 (2H, m, H-2), 1.62 (3H, s, 17-CH ),
3
3
238

2.39–2.42 (9H, m, H-1,3,6,6,7,7,11,11), 2.45 [1H, m, CH(CH ) ], 2.39–2.45 (2H, m, H-12), 3.70, 3.71 (3H, both s, OCH ),
3 2
3
4.51–4.56 (1H, m, NHCH), 6.03, 6.06 (1H, both d, NH), 6.27 (1H, s, H-14), 7.20 (1H, s, H-16), 7.32 (1H, s, H-15).
+
Mass spectrum (m/z, I , %): 429 (14), 189 (100), 57 (58), 149 (48), 175 (41). Found: [M] 429.2871. C H NO .
rel
26 39
4
Calcd: 429.2879.
(1S,4aS,8aR)-N-[(1-Methylthio)-4-methoxycarbonylbutan-2-yl]-5-[2-(furan-3-yl)-ethyl]-1,4a,6-trimethyl-
1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-carboxamide (7f). Reaction of 3 (1.10 g, 3.2 mmol) with the hydrochloride of
25
D, L-methionine methyl ester in the presence of Et N afforded 7f (0.56 g, 39%), [ꢄ] +104.3° (c 0.49, CHCl ). IR spectrum
3
D
3
–1
( , cm ): 3442, 3387, 1741, 1660, 1504, 1344, 1300, 1261, 1225, 1175, 1100, 1063, 1024, 873, 800, 756, 667.
PMR spectrum (ꢃ, ppm, J/Hz): 0.80 (3H, s, 20-CH ), 0.85–0.92 (1H, m, H-3), 1.05 (1H, td, J = 13.7, 3.9, H-1), 1.18
3
(3H, s, 19-CH ), 1.20–1.58 (3H, m, H-2,2,5), 1.59 (3H, s, 17-CH ), 1.70–2.02 (8H, m, 6H, H-1,6,6,7,7,11 and 2H, CH SCH ),
3
3
2
3
2.05 (3H, s, SCH ), 2.06–2.25 (2H, m, H-3,11), 2.48 (2H, m, CH ), 2.52 (2H, m, H-12), 3.71 (3H, s, OCH ), 4.67 (1H, m, CH),
3
2
3
6.25 (1H, s, H-14), 6.30, 6.38 (1H, both d, NH), 7.18 (1H, s, H-16), 7.30 (1H, s, H-15). C H NO S.
26 39
4
(1S,4aS,8aR)-N-(3-Methoxy-1-phenylpropyl)-5-[2-(furan-3-yl)ethyl]-1,4a,6-trimethyl-1,2,3,4,4a,7,8,8a-
octahydronaphthalen-1-carboxamide (7g). Reaction of 3 (1.10 g, 3.2 mmol) with the hydrochloride of 3-amino-
25
3-phenylpropionic acid methyl ester in the presence of Et N afforded 7g (1.12 g, 74%), [ꢄ] +100.7° (c 0.91, CHCl ).
3
D
3
–1
IR spectrum ( , cm ): 3435, 1731, 1658, 1628, 1600, 1504, 1438, 1369, 1281, 1211, 1165, 1064, 1025, 980, 874, 756, 720,
700, 666.
PMR spectrum (ꢃ, ppm, J/Hz): 0.78, 0.81 (3H, both s, 20-CH ), 1.02–1.17 (2H, m, H-3,1), 1.20, 1.22 (3H, both s,
3
19-CH ), 1.35 (1H, m, H-5), 1.58 (2H, m, H-2), 1.62, 1.63 (3H, both s, 17-CH ), 1.71–2.26 (8H, m, H-1,3,6,6,7,7,11,11), 2.42
3
3
(2H, m, H-12), 2.77, 2.94 (2H, both m, CH ), 3.60, 3.62 (3H, both s, OCH ), 5.42 (1H, m, CH), 6.27 (1H, s, H-14), 6.77, 6.82
2
3
(1H, both d, J = 8.3, NH), 7.20 (1H, s, H-16), 7.21–7.30 (5H, m, Ph–H), 7.36 (1H, s, H-15).
Mass spectrum (m/z, I , %): 477 (30), 121 (100), 189 (73), 396 (55), 175 (41). Found: [M] 477.2879. C H NO .
+
rel
30 39
4
Calcd: 477.2874.
(1S,4aS,8aR)-1,4a,6-Trimethyl-1-{2-[2-oxo-2-(phenylamino)acetyl]hydrazinocarbonyl}-5-[2-(furan-3-yl)ethyl]-
1,2,3,4,4a,7,8,8a-octahydronaphthalene (7h). Reaction of 3 (1.10 g, 3.2 mmol) with 2-oxo-2-(phenylamino)acetohydrazide
(0.74 g, 4.1 mmol) in the presence of Et N under the conditions for synthesizing amides 7a-g afforded 7h (0.36 g, 24%),
3
25
–1
mp 153°C (ether), [ꢄ] +39.6° (c 0.92, dioxane). IR spectrum ( , cm ): 3437, 1702, 1672, 1658, 1625, 1602, 1535, 1500,
D
1320, 1225, 1103, 1053, 1021, 750, 691.
PMR spectrum (ꢃ, ppm, J/Hz): 0.86 (3H, s, 20-CH ), 1.08 (1H, dt, J
= 13.6, H-3), 1.21 (1H, m, H-1), 1.28 (3H, s,
gem
3
19-CH ), 1.42 (1H, dd, J = 12.6, 2.8, H-5), 1.62 (2H, m, H-2), 1.64 (3H, s, 17-CH ), 1.71–1.95 (4H, m, H-1,7,6,6), 1.99–2.13
3
3
(2H, m, H-7,11), 2.16–2.28 (2H, m, H-3,11), 2.42 (2H, m, H-12), 6.27 (1H, s, H-14), 7.15 (1H, m, H-4ꢀ), 7.20 (1H, s, H-16),
7.33 (1H, s, H-15), 7.37 (2H, m, H-3ꢀ,5ꢀ), 7.58–7.66 (2H, m, H-2ꢀ,6ꢀ), 8.25 (1H, t, J = 7, CONHPh), 9.10 (1H, br.s, NHNH),
9.29 (1H, br.s, NHNH).
+
Mass spectrum (m/z, I , %): 477 (30), 271 (100), 201 (77), 189 (95), 107 (37). Found: [M] 477.2619. C H N O .
rel
28 35 3 4
Calcd: 477.2622.
(1S,4aS,8aR)-Methyl-5-{2-[2-(2-oxo-2-benzylaminoacetyl)furan-3-yl]ethyl}-1,4a,6-trimethyl-1,2,3,4,4a,7,8,8a-
octahydronaphthalen-1-carboxylate (8a). Compound 5 (1.00 g, 3.0 mmol) in CH Cl (8 mL) was treated with benzylamine
2
2
(0.68 mL, 6.0 mmol) and Et N (0.62 mL, 4.5 mmol) and stirred at room temperature for 1 d. Solvent was evaporated in vacuo.
3
The solid was treated with Et O. The resulting precipitate was filtered off. The mother liquor was evaporated. The solid was
2
25
chromatographed over silica gel (CHCl eluent) to afford 8a as an oil (0.93 g, 67%), [ꢄ] +69.9° (c 0.87, CHCl ).
IR spectrum ( , cm ): 3350, 1723, 1680, 1618, 1572, 1526, 1497, 1230, 1160, 1140, 1130, 1113, 1065, 1037, 982, 881, 780,
3
D
3
–1
754, 700. UV spectrum (EtOH, ꢅ , nm, log ꢆ): 241 (3.62), 290 (3.97).
max
PMR spectrum (ꢃ, ppm, J/Hz): 0.76 (3H, s, 20-CH ), 0.99 (1H, td, J = 9.4, 4.0, H-3), 1.18 (3H, s, 19-CH ), 1.23 (1H,
3
3
m, H-1), 1.32 (1H, d, J = 11.7, H-5), 1.52 (2H, dm, J = 14.1, H-2), 1.65 (3H, s, 17-CH ), 1.69–2.29 (8H, m, H-1,3,6,6,7,7,11,11),
3
2.87 (2H, t, J = 8.9, H-12), 3.60 (3H, s, OCH ), 4.53 (2H, d, J = 6.9, CH Ph), 6.51 (1H, d, J = 1.6, H-14), 7.24–7.31 (5H, m,
3
2
Ph), 7.60 (1H, d, J = 1.6, H-15).
+
Mass spectrum (m/z, I , %): 491 (4), 243 (100), 91 (33), 152 (19), 244 (18). Found: [M] 491.2655. C H NO .
rel
30 37
5
Calcd: 491.2666.
239

(1S,4aS,8aR)-Methyl-5-{2-[2-(2-oxo-2-benzylaminoacetyl)furan-3-yl]ethyl}-1,4a,6-trimethyl-1,2,3,4,4a,7,8,8a-
octahydronaphthalen-1-carboxylate (8b). Compound 5 (1.00 g, 3.0 mmol) in CH Cl (8 mL) was treated with 3-amino-
2
2
3-phenylpropionic acid (0.97 g, 4.5 mmol) and Et N (0.83 mL, 6 mmol) and stirred at room temperature for 1 d. Solvent was
3
evaporated in vacuo. The solid was treated with Et O. The resulting precipitate was filtered off. The mother liquor was
2
25
evaporated. The solid was chromatographed over silica gel (CHCl eluent) to afford 8b as an oil (1.08 g, 64%), [ꢄ] +49.6°
(c 1.7, CHCl ). IR spectrum ( , cm ): 3380, 1720, 1675, 1620, 1575, 1530, 1498, 1240, 1165, 1140, 1135, 1110, 1048, 1013,
3
D
–1
3
982, 880, 780, 755, 702. UV spectrum (EtOH, ꢅ , nm, log ꢆ): 242 (3.89), 290 (4.05).
max
PMR spectrum (ꢃ, ppm, J/Hz): 0.76 (3H, s, 20-CH ), 1.00 (1H, td, J = 12.0, 4.0, H-3), 1.18 (3H, s, 19-CH ), 1.24 (1H,
3
3
m, H-1), 1.32 (1H, d, J = 12.0, H-5), 1.52 (2H, dm, J = 16.0, H-2), 1.64 (3H, s, 17-CH ), 1.70 (1H, dd, J = 12.0, 6.0, H-6), 1.82
3
(1H, dm, J = 12.0, H-6), 1.92 (1H, m, H-7), 1.95 (1H, m, H-1), 2.00 (1H, m, H-7), 2.10 (1H, m, H-11), 2.19 (1H, dm, J = 12.0,
H-3), 2.24 (1H, m, H-11), 2.87 (2H, dd, J = 12.0, 6.0, H-12), 2.92 (1H, d, J = 6.0, CH ), 3.02 (1H, dd, J = 18.0, 6.0, CH ), 3.60
2
2
(3H, s, OCH ), 5.50 (1H, dd, J = 12.0, 6.0, CH), 6.53 (1H, d, J = 1.5, H-14), 7.29–7.35 (5H, m, Ph), 7.60 (1H, d, J = 1.7, H-15),
3
7.80 (1H, d, J = 6.0, NH). C H NO .
33 41
7
XSA of 1. The XSA of 1 was performed on a Kappa Apex II diffractometer (Bruker) with a two-coordinate CCD
detector using ꢇ–ꢈ scanning at –100°C. A total of 16,568 reflections was measured in the range 2ꢉ < 51°. Of these, 6,308
were independent (R = 0.067). A colorless crystal (0.10 ꢊ 0.10 ꢊ 0.40 mm) was selected. The crystals were pseudo-
int
orthorhombic because averaging equivalent reflections for the orthorhombic system gave R = 36.6% (for 14,628 reflections);
int
for monoclinic, R = 7.1% (for 13,009 reflections). The unit-cell constants were a = 10.6941(4), b = 10.2198(8),
int
°
° 3
3
c = 16.221(2) A, ꢋ = 90.00(1)°, V = 1772.8(3) A , space group P2 , Z = 4, d
= 1.186 g/cm . Absorption corrections were
1
calc
applied using the SADABS program [15], which used multiple measurements of the same reflections at different crystal
orientations (transmission 0.62–0.75). The structure model was found by direct methods and refined with anisotropic thermal
factors for nonhydrogen atoms using the program set SHELXL [16]. The Cif file containing complete information on the
structure was deposited in the CCDC (CCDC 748547), from where it can be obtained free upon request to the following
internet site: www.ccdc.cam.ac.uk/data_request/cif.
ACKNOWLEDGMENT
The work was supported by the Russian Foundation for Basic Research (Projects No. 09-03-00183 and 08-03-90200-
Mong-a).
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