Chemistry of Zerumbone. 1. Simplified Isolation, Conjugate Addition Reactions, and a Unique Ring Contracting Transannular Reaction of Its Dibromide

Abstract

Zerumbone (1) was isolated from fresh rhizomes of Zingiber zerumbet Smith in yields of 0.3-0.4% by simple steam distillation and recrystallization. 1 accepted 2 equiv of hydrogen cyanide at the C6 and C9 double bonds of the cross-conjugated dienone system to give a mixture of diastereomers 3a-d. In the presence of potassium cyanide, the dominant isomer 3a was isomerized to a mixture of 3a-d. Under controlled conditions, 1 added one mole of methanol regio- and stereoselectively at the C6 double bond to give adduct 4a. With potassium cyanide, 4a was transformed to the mixture of 3a-d. 1 took up one mole of bromine at C6 double bond to give a diastereomeric mixture of adducts 5a and 5b. Treatment of 5a with potassium cyanide gave a mixture of cyclopropanecarboxylic acid 6a and 6b. This unique ring-contracting cyclopropane formation is pictured as a sequential Favorskii type reaction. alpha-Cyclodextrin improved the selectivity and yields of the reactions conducted in an aqueous medium.

Zerumbone-loaded nanostructured lipid carriers: preparation, characterization, and antileukemic effect

“…1,2 Zerumbone has been shown to possess antitumor, anti-inflammatory, antioxidant, antimicrobial, antinociceptive, hepatoprotective, and immunomodulatory activity. This compound also significantly suppresses tumor promoter 12-O-tetradecanoylphorbol-13-acetate-induced Epstein-Barr virus activation in Raji cells and free radical (superoxide anion) generation in cancer cell lines, and strongly inhibits platelet aggregation induced by arachidonic acid, collagen, and adenosine diphosphate.…”

Zerumbone abolishes NF-κB and IκBα kinase activation leading to suppression of antiapoptotic and metastatic gene expression, upregulation of apoptosis, and downregulation of invasion

“…According to a recent report by Newman et al, as many as 65% (48 out of 74) of formally synthetic drugs in the antihypertensive medicine are plant based (Newman et al, 2003). Zerumbone (2,6,9,9-tetramethyl-[2E,6E, 10E]-cycloundeca-2,6,10-trien-1-one; Figure 1) was first isolated in 1956 from the essential oil of rhizomes of a wild ginger, Zingiber zerumbet Smith, which is widespread in Southeast Asia (Dev, 1956;Kitayama et al, 1999). Over the years, a wide variety of activities have been assigned to this compound (Ozaki et al, 1991;Murakami et al, 1999Murakami et al, , 2002Murakami et al, , 2003aMurakami et al, , 2004Tanaka et al, 2001;Kirana et al, 2003).…”

Attractive Reactivity of a Natural Product, Zerumbone

“…The flexible nature of the large ring made it impossible to determine the configuration of 3 by NMR, even though NOEs of almost the same value were observed between the methoxy protons and those at C3 and C2, and no NOE was seen between the C2 methyl protons and the methoxy protons at C3. 7) In an attempt to add a cyanide ion to the remaining conjugated double bond, treatment of 3 with KCN resulted quantitatively in a mixture of the four diastereomeric dinitriles (2a-d) in the same ratio as above. The smooth substitution of the cyano for the methoxy group represents a reversal of the addition of methanol, and again illustrates the strong propensity of cyanide for conjugate addition.…”

“…The smooth substitution of the cyano for the methoxy group represents a reversal of the addition of methanol, and again illustrates the strong propensity of cyanide for conjugate addition. 7) Common primary and secondary amines reacted with 1 and 6,7-epoxide (4), which was prepared from 1 and MCPBA, at or below room temperature to give conjugate-added products at C3, and sometimes at C3 and C10 of the substrates. 8) In a tightly sealed container, 1 was stirred with excess concentrated aqueous ammonia in acetonitrile at room temperature to yield monoamine 5.…”

“…We built the foundations for the industrial use of 1 by establishing novel methods, including conjugate addition, 7) transannular reaction, 7,8) ring cleavage, [8][9][10] ring expansion, 11) and asymmetric induction. [12][13][14][15][16][17] For example, since many useful polycyclic compounds exist in nature, the development of the transannular reaction and the construction of various transannular products are very important in organic and material chemistry.…”