Doing it Twice: Asymmetric Deprotonation/Alkylation of Weiss Diketone Derivatives as Key Steps in the Functionalization of Bicyclo[3.3.0]octanes

Abstract

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).

Role of Regioisomeric Bicyclo[3.3.0]octa-2,5-diene Ligands in Rh Catalysis: Synthesis, Structural Analysis, Theoretical Study, and Application in Asymmetric 1,2- and 1,4-Additions

“…While enantioselective desymmetrizations of meso -ketones with chiral bases are long known and sequential deprotonation/electrophilic trapping sequences for bicyclo[3.3.0]­octane precursors of natural products have been reported, , the simultaneous deprotonation/electrophilic trapping of two oxo functions remained elusive.…”

“…In order to obtain racemic products as analytical reference samples, Weiss diketone 5 was deprotonated with 2.25 equiv of KHMDS in THF at −78 °C for 1 h, followed by quenching with 2-pyridyltriflimide and warming the solution to 0 °C over 4 h. After workup, a (33:67) mixture of C 2 -symmetric ( 7 ) and C S -symmetric bis­(enoltriflate) 8 was isolated in 49% combined yield (Table , entry 1). Replacing KHMDS with the chiral base ( S,S )- 6a· LiCl, which was generated in situ from the ( S )-1-phenylethylamine-derived ( S , S )-bis­(1-phenylethyl)­ammonium chloride and BuLi, ,, inverted the ratio of regioisomers 7 and 8 in favor of the desired C 2 -symmetric product 7 giving a 79:21 mixture in 74% yield (entry 2). The isomeric ratio was found to be influenced by the addition rate of 5 , i.e., the slower its addition the higher the amount of 7 , resulting in a 89:11 mixture of 7 / 8 (entry 4).…”

Adventures and Detours in the Synthesis of Hydropentalenes

“…83 Luckily, initial experiments with -methyl and -allyl bicyclo[3.3.0]octanone tosylhydrazones 120a and 120b, respectively, revealed an excellent regioselectivity in favor of the less-substituted C=C double bond (Scheme 30). 84 However, for the -allyl-substituted elimination product 121b, a significant degree of racemization was observed (56% ee) in contrast to the corresponding methyl-substituted product 121a, where the stereochemistry was almost retained (80% ee). Presumably, the erosion of optical purity of 121b was due to a thermal [3,3]-sigmatropic Cope rearrangement of the alkene.…”

Bamford‐Stevens and Shapiro Reactions in Organic Synthesis

“…Bicyclo[3.3.0]octanes are an integral part of several natural products such as carbacycline, ptychenolide, and cylindramide. Laschat and co‐workers worked on functionalization of Weiss diketone ( 92 ) in order to provide a synthetic approach for natural products possessing bicyclo[3.3.0]octanes [35] . A representative example for the functionalization is shown in scheme 18.…”

“…Laschat and co-workers worked on functionalization of Weiss diketone (92) in order to provide a synthetic approach for natural products possessing bicyclo[3.3.0]octanes. [35] A representative example for the functionalization is shown in scheme 18.…”