2018 Springer Science+Business Media, LLC
Chemistry of Natural Compounds, Vol. 54, No. 3, May, 2018
SYNTHESIS AND STRUCTURE OF DRIMANE SESQUITERPENOIDS
CONTAINING PYRIMIDINE, PYRAZINE, 1,2,4-TRIAZOLE,
AND CARBAZOLE RINGS
A. N. Aricu,
K. I. Kuchkova,
E. S. Secara,
A. N. Barba,
I. P. Dragalin,
N. D. Ungur,
and V. Kh. Kravtsov
Drimenic acid was synthesized in six steps from norambreinolide. Reaction of drimenic acid with oxalyl
chloride produced iso-drimenic acid chloride, which reacted with heterocyclic amines (2-aminopyrimidine,
2-aminopyrazine, 4-aminopyrimidine, N-aminocarbazole, and 3-amino-1,2,4-triazole) to form amides
of iso-drimenic and albicanic acids. The structures of the amides were elucidated by spectral methods and
an X-ray structure analysis.
Keywords: sesquiterpenoids, heterocyclic amines, amides, drimenic acid, iso-drimenic acid, synthesis.
Several drimane and homodrimane sesquiterpenoids, including N-containing ones, are known to have a variety of
biological activities [1, 2]. Diazine heterocycles (pyrimidines and pyrazines) exhibit broad spectra of biological activities
such as antimicrobial, antiviral, antifungal, antituberculosis, antitumor, anti-inflammatory, etc. [3–7]. 1,2,4-Triazole derivatives
are well known as antiviral, antimicrobial, antifungal, antitumor, anticonvulsant, antimalarial, and anti-inflammatory agents
. Carbazole derivatives exhibited antifungal and antitumor activities [9, 10].
A series of N-containing drimane, homodrimane, and dihomodrimane derivatives were synthesized by us earlier in
order to discover new biologically active compounds and to find a structure–activity relationship [11–16]. They included
-bicyclohomofarnesenic acid containing pyrimidine and pyrazine rings and possessed significant antimicrobial
activity according to biotesting . Amides of
-bicyclohomofarnesenic acid that were synthesized later included
1,2,4-triazole and carbazole rings and exhibited antioxidant activity [18–20].
In continuation of this research, amides of drimenic acid containing the aforementioned heterocycles were prepared
by us for biotesting.
Drimenic acid was synthesized from norambreinolide (1) (in six steps) in overall yield 55%. The key steps were
oxidation of drimenol (2), which was obtained from 1 [21, 22], by P
and DMSO into aldehyde 3 followed by its oxidation
into drimenic acid (4). Reaction of 4 with (COCl)
produced in situ acid chloride 5, which reacted with amines
6a–c, 9, and 12 to give the corresponding amides 7a–c, 10, 11, and 13 (Scheme 1).
double bond obviously isomerized into the C
position during the reaction of 4 with oxalyl chloride.
Subsequent reaction of resulting acid chloride 5 with 2-aminopyrimidine (6a), 2-aminopyrazine (6b), and N-aminocarbazole
(6c) formed iso-drimenic acid amides 7a–c in yields of 29, 14, and 49%, respectively. A mixture of amides 10 and 11
(2:3 ratio) resulted from the reaction of the intermediate acid chloride with 4-aminopyrimidine (9). Spectral data of products
from the reaction with 3-amino-1,2,4-triazole (12) showed that a tautomer of this amine reacted with 5 to produce amide 13
(53% yield) with an NH
group and a semicyclic C
double bond. Furthermore, column chromatography of the reaction
products of amines 6a–c, 9, and 12 with acid chloride 5, which was obtained from drimenic acid (4), isolated iso-drimenic acid
(8) in addition to amides 7a–c, 10, 11, and 13.
1) Institute of Chemistry, Academy of Sciences of Moldova, 3 Akademicheskaya St., MD-2028, Kishinev, Republic
of Moldova; e-mail: email@example.com; 2) Institute of Applied Physics, Academy of Sciences of Moldova,
5 Akademicheskaya St., MD-2028, Kishinev, Republic of Moldova. Translated from Khimiya Prirodnykh Soedinenii, No. 3,
May–June, 2018, pp. 386–390. Original article submitted November 10, 2017.