Cyclopropanation of betulin and its diacetate with dihalocarbenes

Abstract

Reactions of betulin, its diacetate, and 17-acetoxy-28-norlupan-3-one with dichlorocarbene generated from chloroform follow the [1 + 2]-cycloaddition pattern leading to the corresponding adducts in moderate to quantitative yield. In the reaction with betulin, [1 + 2]-cycloaddition is accompanied by dichlorocarbene attack on the primary hydroxy group to give the corresponding halogen derivative and formate. The addition of dichlorocarbene to betulin is strictly stereoselective, while the reaction with betulin diacetate affords a mixture of two diastereoisomers at a ratio of 95 : 5. The reaction of betulin diacetate with dibromocarbene yields dibromocyclopropane derivative which can be converted into the the corresponding diol.Compounds containing a cyclopropane fragment were found among various naturally occurring biologically active substances, including steroids and terpenoids. The synthetic and biological potentials of these compounds are difficult to overestimate [1,2]. The presence of an isopropenyl group in molecules of lupane triterpenoids makes it possible to introduce a functionalized cyclopropane moiety into the side chain, thus opening wide prospects in modifying the lupane skeleton at C 20 and giving rise to new approaches to design of complex molecules on the basis of accessible lupane triterpenoids and to search for new kinds of biological activity in the series of these compounds. Among lupane derivatives containing a cyclopropane fragment, esters derived from betulin (Ia) and tetramethylcyclopropanecarboxylic and permetrinic acids have been reported [3].The double bond in compound Ia and its derivatives can be involved in isomerization, oxidation, reduction, and allylic bromination [4][5][6][7][8]. However, despite wide synthetic potential, cyclopropanation of betulin (Ia) was not studied. In particular, such experimentally simple and convenient procedure as dihalocyclopropanation of double bond under conditions of phase-transfer catalysis was not applied to betulin [9].While performing the present study, a publication appeared [10], where a high antituberculous activity was predicted by computer simulation for 20,29-dichloromethanolupane-3β,28-diol and a procedure was proposed for the synthesis of this compound in 35% yield from betulin (Ia) in one step under conditions of phase-transfer catalysis. However, no spectral data were given, and the melting point reported therein, 293-294°C, considerably differed from the melting point of a sample prepared by us.We have found that the reaction of betulin (Ia) with dichlorocarbene generated from CHCl 3 by the action of 50% aqueous sodium hydroxide in the presence of benzyltriethylammonium chloride at room temperature gives a mixture of dichlorocyclopropanated diol II, formate III, and chloride IV (Scheme 1). The reaction follows the [1 + 2]-cycloaddition pattern and is accompanied by dichlorocarbene attack on unshared electron pair on the oxygen atom of the primary hydroxy group [11,12]. Diol II was isolated in 55% yield by column chromatography. Formate...

Recent advances in the syntheses, transformations and applications of 1,1-dihalocyclopropanes

“…12 The lupan triterpenoid betulin 8a on treatment with dichlorocarbene generated from CHCl 3 and NaOH under PTC conditions afforded the dichlorocyclopropane derivative 9a in 55% yield along with some side products (Scheme 3). 12 The lupan triterpenoid betulin 8a on treatment with dichlorocarbene generated from CHCl 3 and NaOH under PTC conditions afforded the dichlorocyclopropane derivative 9a in 55% yield along with some side products (Scheme 3).…”

“…The preparation of gem-dihalocyclopropane derivatives of some triterpenoids of lupan series under PTC was reported. 12 The lupan triterpenoid betulin 8a on treatment with dichlorocarbene generated from CHCl 3 and NaOH under PTC conditions afforded the dichlorocyclopropane derivative 9a in 55% yield along with some side products (Scheme 3). However, the diacetate of betulin 8b under similar reaction conditions afforded quantitative yield of the product 9b with high diastereoselectivity (95 : 5).…”

Oxidative Decarboxylation of Triterpene C-28 Acids of Lupane Series

“…( 1 H-1 H COSY and 13 C-1 H correlations) of the oxidative decarboxylation products and also of compounds described earlier [5][6][7][8][9][10], allowed us to make the unambiguous and full assignment of all carbon and hydrogen atom signals in these spectra and to reveal a criterion for the determination of the stereochemistry of the C-17 atom, which are complementary. One of the criteria is the value of the chemical shift of the C-13 signal.…”

Cyclopropanation of betulonic acid and its methyl ester with dichlorocarbene generated under phase transfer catalysis conditions

“…Previously, 5 it was shown that the addition of dichloro carbene to the C(20)-C(29) double bond of betulin diacetate affords two diastereomers (95 : 5 ratio); one of these was isolated in a pure state by recrystallization, while the second was obtained as a 1 : 1 mixture with the first one. In this study, compounds 2, 3, and 5 are formed as individual diastereomers.…”