Synthesis of cyclohexyl analogs of restricticin, a novel type of antifungal agent from (-)-R-carvone and their in vitro antifungal activity are described. Restricticin (1), and lanomycin (2) were isolated from cultured broth of Penicillium sp. and Pycnidiophora sp. by Merck,¹) Bristol-Myers Squibb,²) and Roche,³) as novel antifungal substances which inhibit lanosterol C14 demethylase.²,⁴) In a previous paper,⁵) we reported that the synthesis of restricticin derivatives led to the identification of Ro09-1571 (3) which showed improved chemical stability and in vitro antifungal activity relative to restricticin (1). In this communication, we wish to report the design and synthesis of cyclohexyl analogs (4) of (1) with superior antifungal properties relative to (1) and (3). The mechanism by which (1) and its analogs inhibit P450 lanosterol C14 demethylase involves binding of their primary amino group to the P450 heme iron atom.⁴) However, the glycine ester of (1) and its analogs were easily hydrolyzed both chemically and enzymatically. Thus, the chemical modification of this group was needed to develop a clinically useful antifungal agent. We introduced an azolylmethyl moiety at the C-3β position as a conformationally restricted and stable bioisostere of the glycine ester moiety where amino nitrogen and carbonyl oxygen atoms in the glycine moiety are fixed with one additional carbon atom forming a five-membered ring. Actually, we synthesized cyclohexyl analogs (4) of (1) having an azolylmethyl group at the C-3 position. Many azole derivatives are known to inhibit lanosterol C14 demethylase and some of these are clinically useful antifungal agents.⁶) We chose (-)-R-carvone as a starting material, which has a cyclohexane ring with absolute configuration corresponding to that of C-2β of target compound (4). Treatment of (-)-R-carvone with K-selectride followed by methylation of the resulting enolate with methyl iodide afforded (5).⁷) Introduction of a carbomethoxy group at the C-3β position was carried out by the use of dimethyl carbonate and sodium hydride in pyridine at 80°C to give (6) in 89% yield. Reduction of ketone (6) with sodium borohydride in the presence of cerium (III) chloride followed by O-methylation gave the desired equatorial methyl ether (8) in 74% yield. After the reduction of the carbomethoxy group of compound (8) by lithium aluminum hydride, the resulting primary alcohol was protected with a benzyl group to give a benzyl ether (9) in 82% yield. For the introduction of various aralkyl groups at the C-2β position, (9) was converted into aldehyde (12) by following four-step procedure. Thus, the ozonolysis of compound (9) followed by the haloform reaction of the resulting methyl ketone (10) with sodium hypobromite gave carboxylic acid (11) in a good yield. The reduction of carboxylic acid (11) with lithium aluminum hydride followed by oxidation of the resulting primary alcohol with PCC gave aldehyde (12). Wittig olefination of aldehyde (12) gave an olefin (13) in 71% yield. After removal of the benzyl group of (13) by catalytic hydrogenolysis, the resulting alcohol (14) was converted to the mesylate. Finally, the mesylate group was substituted with the 1,2,4-triazole sodium salt or the imidazole sodium salt in DMF to give the desired derivative Ro 09-2056 and 2127 respectively. The in vitro antifungal activity of Ro 09-2056 and 2127 is summarized in Table 1 in comparison with those of itraconazole, fluconazole and Ro 09-1571. Ro 09-2056 and 2127 were found to have much more potent in vitro antifungal activity against Candida albicans and Cryptococcus neoformans when compared with fluconazole and Ro 09-1571, but were somewhat inferior to those of itraconazole. Detailed structure-activity relationships of a series of derivative (4) will be reported elsewhere. In summary, we have accomplished the synthesis of cyclohexyl analogs of restricticin (1), Ro 09-2056 and 2127 with potent antifungal activity starting from (-)-R-carvone.