E. V. Tret'yakova

Synthesis and Antiviral Activity of Betulonic Acid Amides and Conjugates with Amino Acids

Betulonic acid amides with aliphatic and heterocyclic amines and with L-amino acids were synthesized by the acid chloride method. Betulonic acid amide and L-methionine derivatives of betulonic acid and its 3-oxime effectively inhibit the influenza A virus. Betulonic acid octadecylamide is active against the herpes simplex Type 1 virus. The conjugate of betulonic acid 3-oxime with L-methionine is also active toward HIV-1. The tested compounds mainly show no activity toward the ECHO6 virus, which is devoid of a coat.

SYNTHESIS AND PHARMACOLOGICAL ACTIVITY OF ACYLATED BETULONIC ACID OXIDES AND 28-OXO-ALLOBETULONE

In recent years, the chemical transformations and biological activity of triterpenoids of the lupane group have received much attention. It was found that betulin acylates possess antitumor properties [1], while lupeol esters with palmitic and linolic acids produce antiarrhythmic action [2]. The most promising inhibitors of HIV replication include 3-O-(3,3-dimethylsuccinate) of betulinic acid and 3-O(3,3-dimethylsuccinate)-28-O-(2,2-dimethylsuccinate) of betulin [3]. Recently, Kashiwada et al. [4] reported on the synthesis of derivatives of 3-alkylamino-3-deoxo-betulinic acid possessing anti-HIV-1 properties [4]. Another promising compound is betulin 3,28-di-O-nicotinate, which shows hepatoprotector, antiulcer, antiinflammatory, wound-healing, anti-HIV, and immunomodulant activity [5]. An analysis of published data suggests that the class of lupane triterpenoids and related compounds containing acyl groups is a promising source of new biologically active substances. Below we report on the first synthesis of acylated oximes based on betulonic acid (Ia), its methyl ester (IIa), and 28-oxo-allobetulone (IIIa). In the first step, boiling 3-oxo-triterpenoids (Ia, IIa, IIIa) with hydroxylamine hydrochloride in anhydrous pyridine led to a quantitative yield of the corresponding 3-oximes (Ib, IIb, IIIb). By acylating these compounds in anhydrous benzene with excess acetic, succinic, and phthalic anhydrides at room temperature in the presence of triethylamine, we obtained acylated oximes (Ic – Ie, IIc – IIe, IIIc – IIIe) with a yield of 64 – 78% after purification of the products by column chromatography (Table 1).

Synthetic Transformations of Higher Terpenoids: XI. Synthesis of A-Nor-5bH-19b,28-epoxy-18a-olean-3-one Derivatives

Starting with allobetulin triterpenoid A-nor-derivatives with a cis-junction of A/B rings were prepared for the first time.

Synthesis of 1,2,3-Thiadiazolo Terpenoids on the Basis of Cyclopentanonopimaric and Betulonic Acids

The Hurd-Mori reaction with derivatives of cyclopentanonopimaric and betulonic acids afforded mostly the corresponding 1,2,3-thiadiazoles and small amounts of thioketone oxides.

Synthesis of 2-Amino-4-aryl-3-cyano-4H-pyrano and 2-Amino-3-cyanothieno Derivatives of Cyclopentanonopimaric Acid

Condensation of cyclopentanonopimaric acid with malononitrile in the presence of p-methoxybenzaldehyde or elemental sulfur gave the corresponding fused 2-amino-3-cyano-4-(4-methoxyphenyl)-4H-pyrano and 2-amino-3-cyanothieno derivatives.

Synthesis of 1,6-Dihydro- and 4-(4-Nitrophenyl)-1,2,3,4-tetrahydropyrimidine, 1H- and 1-Phenyl-1H-pyrazole, and Isoxazole Derivatives on the Basis of Cyclopentanonopimaric Acid

Reactions of cyclopentanonopimaric acid dimethyl ester with phosphoryl chloride, ethyl formate, and p-nitrobenzaldehyde afforded Δ15(16)-16-formyl-15-chloro, 16-hydroxymethylene-15-oxo, and 16-nitrobenzylidene-15-oxo derivatives which were subjected to heterocyclizations to obtain new diterpene pyrimidine, pyrazole, and oxazole derivatives.

Synthesis and Antiinflammatory Activity of Quinopimaric Acid Amides

As is known, pine galipot contains a large number of biologically active substances [1]. One of the main components of this resin is levopimaric acid (I), the derivatives of which were reported to possess antibacterial activity and antifungal activity [2]. Acid I readily forms adducts of diene synthesis with benzo-, acetamido-, thienonaphtho-, -, and -quinones and naphthazarin [3 – 6]. We have synthesized a series of derivatives of quinopimaric acid (IIa) and studied their antiinflammatory activity. Quinopimaric acid, together with chloroquinopimaric acid (IIb), were isolated from pine galipot as described in [4]. Compound IIb was found to form regiospecifically with a yield of 50%. The structure of diterpenoid IIb was established using the data of H NMR spectroscopy. According to these, H-12 proton ( = 2.85 ppm) is characterized by two trans coupling constants, with H-11 (axial) and H-1a protons (J 1 = J 2 = 13.6 Hz), and one cis constant with H-11 (equatorial) proton (J = 4.5 Hz). The signals from H-1a and H-4a protons, observed at = 2.40 ppm (dd) and 2.48 ppm (d), respectively, are characterized by the cis constant (J = 9 Hz). Calculations performed by the additive schemes with increments showed that the chemical shifts of H-1a and H-4a protons correspond to a chlorine atom in the C-3 position. In an alternative structure with chlorine at C-2, the chemical shift of H-1a would be greater than that of H-14a [7]. It should be noted that the spectrum of adduct IIb exhibits a weak-field shift of the signal of the H-4a proton ( = 2.48 ppm) relative to the analogous signal in the spectrum of IIa ( = 1.93 ppm) [4]. The above spin – spin coupling constants of IIb indicate that the E cycle is cis to the C cycle and syn to the D cycle, as manifested by a shift of the signal of the H-4 proton toward stronger field (from = 5.68 ppm in IIa to 5.47 ppm in IIb). The aforementioned regiospecificity of the interaction between chlorobenzoquinone and acid I is related to the influence of chlorine – an electron acceptor favoring the formation of a transition state by closing a hydrogen bond between carboxy group and carbonyl oxygen in the C-1 position [4, 8]. This leads to a product containing a substituent at C-3.

Synthesis of Phenyl-2,3-oxazine Derivatives of Chrysenequinonecarboxylic Acid

A mixture of isomeric phenyloxazines (2, 3) in a 5:4 ratio was synthesized via a [4 + 2] addition reaction of a heterocyclic diene-precursor prepared from bromoacetophenone oxime and the methyl ester of chrysenequinonecarboxylic acid (1). The structures of the synthesized compounds were confirmed using spectral methods.

Beckmann Rearrangement of Dimethylcyclopentanonepimarate Oxime

Beckmann rearrangement of dimethylcyclopentanonepimarate-15-oxime 2 was used to produce lactam 3 or seco-nitrile 4, depending on the conditions. The structures of the synthesized compounds were confirmed by IR and NMR spectroscopies.

Synthesis of a diterpene 1,3,4-oxadiazolin-2'-one from dimethylcyclopentenonepimarate

A diterpene 1,3,4-oxadiazolin-2′-one was synthesized by lead-tetraacetate oxidation of 16,17- epoxydimethylcyclpentenonepimarate. The structures of the synthesized compounds were confirmed by IR and NMR spectroscopies.