The silyl‐protected allylhydropentalenone derivative 9, derived from the Weiss diketone, was functionalized by enantioselective deprotonation in the presence of lithium bis(1‐phenylethyl)amide/LiCl as the chiral base, which was generated in situ from bis(1‐phenylethyl)ammonium chloride [(R,R)‐ or (S,S)‐14] and BuLi, and trapping of the resulting enolate with alkyl halide electrophiles to give pseudo‐C2 or ‐Cs‐symmetrical bicyclo[3.3.0]octanones 10 and 11. The influence of the chiral base and electrophiles on the regioselectivity and double stereodifferentiation was investigated. Taking the double stereocontrol into account, a matched selectivity for the pseudo‐C2 pair (1R,4R)‐10/(1S,4R)‐10 and a mismatched selectivity for the pseudo‐Cs pair (1S,6R)‐11/(1R,6R)‐11 were observed in the presence of (R,R)‐14. The use of (S,S)‐14, however, produced a mismatched selectivity for (1R,4R)‐10/(1S,4R)‐10 and a matched selectivity for (1S,6R)‐11/(1R,6R)‐11 with complementary diastereoselectivity depending on the electrophile. Furthermore, the hydropentalenone derivative 10a provided an alternative route to the bicyclo[3.3.0]octene core of the macrocyclic tetramic acid lactam, cylindramide (5).

The functionalization of differently substituted hydropentalenone derivatives 9, derived from the Weiss diketone (8) by enantioselective deprotonation in the presence of lithium (R,R)‐bis(1‐phenylethyl)amide/LiCl (11·LiCl) as the chiral base is described. In the first route the resulting enolate was treated directly with alkyl halides as electrophiles to give the target α‐alkylhydropentalenones 12, whereas in the second route the enolate was trapped as one of the triethylsilyl enol ethers 17, from which the enolate was regenerated by treatment with MeLi prior to alkylation with alkyl halides. The substituents on 9 seemed to influence which strategy is favored: for the OTBS‐substituted hydropentalenone 9a the direct deprotonation/alkylation is preferred, whereas for the acetal‐substituted hydropentalenone 9b the silyl enol ether route is more suitable. In all cases the α‐alkylated hydropentalenones 12 and 15 were isolated with good diastereoselectivities.

CitationSAR studies on hydropentalene derivatives--Important core units of biologically active tetramic acid macrolactams and ptychanolides. 2014, 22 (13)

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