Dicarboxylic acids with cyclopropane rings

Witten et al. (1973) identified adipic and 3-methyladipic acids and also reported the presence in urine, using GC-MS, of aconitic and isocitric acids in addition to citrate. Mamer et al, (1971) reported the occurrence of several hydroxyaliphatic acids in addition to those already identified by other workers, and Mamer and Tjoa have identified 2-ethylhydracrylic acid in urine derived from isoleucine metabolism (Mamer and Tjoa, 1974). Urine from healthy children and adults may contain low amounts of aliphatic dicarboxylic acids of chain length C4-C8 (Lawson et ai, 1976). Pettersen and Stokke (1973) reported a series of 3-methyl-branched C4-C8 dicarboxylic acids in urine from normal subjects, and Lindstedt and co-workers have identified other dicarboxylic acids with cyclopropane rings and acetylenic bonds as well as a series of cis and trans mono-unsaturated aliphatic dicarboxylic acids (Lindstedt et al., 1974,1976 Lindstedt and Steen, 1975). 

Chiral 1,2-cycloalkanedicarboxylic acids.1 This ring system can be obtained by coupling 1,co-dihalides or -ditosylates with the dienolate of d- or /-menthyl succinate (1). The dienolate generated with lithium 2,2,6,6-tetramethylpiperidide is mainly the (E,E)-isomer, whereas deprotonation with LDA and HMPT generates mainly the (Z,Z)-isomer. Thus reaction of 1 (R = /-menthyl) with LiTMP in THF at -78° with CH2BrCl results in (S,S)-( - )-dimenthyl cyclopropane-frww-1,2-dicarboxylate (2) in 58% chemical yield and 99% de. A similar reaction of 1, R = d-menthyl, results in (R,R)-2 in 60% yield and 80% de. 

Alkylation of malonic ester with an equimolar ponion of ethylene bromide or trimethylene bromide produces ring closure to give diethyl esters of 1,1-cyclopropane- and 1,1-cyclobutane-dicarboxylic acids, respectively. Five- and six-membered rings also have been formed in this manner. ... 

When the spiro-activated cyclopropane (479) is heated with aqueous acetone a 9 1 mixture of the lactone (482) and the dicarboxylic acid (480) is obtained. Thus, with water as a nucleophile, ring cleavage is faster than acylal cleavage. Presumably, the spiroacylal functions as an active ester in the cyclization of the initially formed 1,5-adduct (481) (equation 164) °. ... 

Various cyclopropanecarboxylic acids and esters have been converted to various amides, TV-alkylated amides, and hydrazides by treatment with ammonia, alkylamines, - and hydrazines, respectively. In many cases the acids have been converted via the corresponding acid chlorides generated in situ. Diethyl esters of a variety of cyclopropane-1,1-dicarboxylic acids also react with urea. Generally, all these reactions proceed smoothly and in fairly good yield and give only very small amounts of byproducts due to opening of the cyclopropane ring. 

A carbonyl function in the a-position relative to the cyclopropane ring renders the adjacent endocyclic bond susceptible to cleavage by nucleophiles. The reactivity can be greatly increased when the polarity of the carbonyl group is enhanced by the addition of electrophiles such as protons or Lewis acids. This is exemplified by the reaction of cyclopropane dicarboxylic acid (2a) with sulfuric acid which leads to (2-hydroxyethyl)malonic acid (3a) if water is present. In a similar fashion, 2-phenylcyclopropane-l, 1-dicarboxylate (2b) gives dimethyl (2-methoxy-2-phenylethyl)malonate (3b) when treated with sulfuric acid in methanol. ... 

The Lewis acid-promoted reactions of l-seleno-2-silylethene with a-enones and 1-phosphonoacrylates give cyclopropane products (Scheme 10.203) [534]. The [24-1] cycloaddition would proceed via 1,2-silyl migration of a-seleno-/ -silylcarbenium ion intermediate 146 and subsequent ring-closure. Interestingly, dimethyl 1,1-di-cyanoethene-2,2-dicarboxylate, a highly electron-deficient alkene, undergoes [24-2] cycloaddition under similar conditions [535]. 

---