Chain extension malonate

A large number of trialkylacetic acid esters have been prepared by mixed Kolbe electrolysis of ethyl malonates [164]. Crossed-coupling is also used for chain extension. Extension by two carbon atoms is achieved with benzyl succinates [153, 180-182], whereby the purification of the chain extended fatty acid is simphfied by using the benzyl half ester [181a]. 

Chain extension.1 An alternative lo the malonic ester synthesis involves ttlkylnliim of r-bmyl lithioacetate, Yields arc improved by preparation of the enolate With l.il( A (4, 306) ui 78. Alkylaliun proceeds in highesl yields at -78 to -35"... 

Chaulmoogric and hydnocarpic acids (Figure 3.15) are cyclopentenyl fatty acids found in chaul-moogra oil expressed from seeds of Hydnocar-pus wightiana (Flacourtiaceae). These acids are known to arise by malonate chain extension of the... 

Anthranilic acid (2-aminobenzoic acid) (see page 126) is another shikimate-derived compound which, as its CoA ester anthraniloyl-CoA, can act as a starter unit for malonate chain extension. Aromatization of the acetate-derived portion then leads to quinoline or acridine alkaloids, according to the number of acetate units incorporated (Figure 3.47). These products are similarly discussed elsewhere, under alkaloids (Chapter 6, page 376). 

Cinnamic acids, as their coenzyme A esters, may also function as starter units for chain extension with malonyl-CoA units, thus combining elements of the shikimate and acetate pathways (see page 80). Most commonly, three C2 units are added via malonate giving rise to flavonoids and stilbenes, as described in the next section (page 149). However, there are several examples of products formed from a cinnamoyl-CoA starter... 

The piperic acid portion is derived from a cinnamoyl-CoA precursor, with chain extension using acetate/malonate (compare flavonoids, page 149), and combines as its CoA ester with piperidine. 

Claisen reaction malonate chain extension of anthraniloyl starter... 

This strategy did not appeal to Ruppert and White9 who preferred to make 36 by a chain extension route. A Reformatsky reagent gave 39 and dehydration and alkylation of malonate gave 36. Treatment with oxalyl chloride (COCl)2 followed by reaction with diazomethane gave... 

Figure 22 Altering chain extension by DEBS 1. (a) A hybrid PKS was constructed by introducing a malonate-specific AT from RAPS in place of the methylmalonate-specific ATi in DEBS 1-TE. The resultant triketide lactones lacked a methyl group at C-4, consistent with the expected change in AT specificity, (b) A hybrid PKS was constructed by introducing a malonate-specific AT from RAPS in place of the methylmalonate-specific AT2 in DEBS 1+TE. The resultant lactone lacked a methyl group at C-2, consistent with the expected change in AT specificity.

Figure 23 Altering chain extension by DEBS. A hybrid PKS was constructed by introducing malonate-specific ATs in place of the methylmalonate-specific AT, of DEBS. The resultant erythromycin analog lacked both the C-12 methyl and C-12 hydroxyl groups of the parent antibiotic.

The rate limiting step in fatty acid synthesis is catalyzed by acetyl-CoA carboxylase to produce malonyl-CoA at the expense of one ATP.31 Malonate and acetate are transferred from CoA to acyl carrier protein in the cytosolic fatty acid synthetase complex, where chain extension leads to the production of palmitate. Palmitate can then be transferred back to CoA, and the chain can be extended two carbons at a time through the action of a fatty acid elongase system located in the endoplasmic reticulum. The >-hydroxylation that produces the >-hydroxyacids of the acylceramides is thought to be mediated by a cytochrome p450 just when the fatty acid is long enough to span the endoplasmic reticular membrane. 

Two-carbon chain extension at the carboxyl end, mimicking biosynthesis, uses the malonic ester route (102). After reduction of the carboxyl to an alcohol, the readily displaced mesylate is prepared and reacted with sodium diethylmalonate. Saponification and decarboxylation gives the chain extended product in high yield. 

Tsuji has completed three syntheses of zearalenone (119), all by quite similar routes. The first, shown in Scheme 1.28, began with acetate 59b, the minor product from the telomerization of butadiene in acetic acid. Cleavage to the alcohol and gas-phase dehydrogenation led to enone 141. Chain extension to 142 was accomplished in 70% yield by way of Michael addition of diethyl malonate to enone 141. Decarboalkoxylation and protection of the ketone then gave 143 (63%). Conversion of the ester to the primary tosylate 144 was achieved by conventional methods in 62% yield. A Wacker oxidation of the terminal olefin followed by reduction and exchange of the tosylate for an iodide then provided the aliphatic segment 145 in 64% yield. 

Some acids are conveniently made by a combination of isolation and synthesis. For example, dihomogammalinolenic acid (20 3 n—6) is best obtained from gammalinolenic acid (18 3 n—6), itself isolated from evening primrose oil, by chain extension by two carbon atoms (malonation). 

Once a H-labelled compound has been made it can be incorporated into a long-chain acid by chain extension (via the nitrile, by malonation, or by enamine synthesis) or by involvement in a Wittig or acetylenic synthesis as in the following synthesis of methyl 11-dideutero-oleate. 

There are other synthetic transformations of phenylalanine, including conversion of the acid moiety to a halide (5.78), that allow a chain extension reaction by coupling with the anion of dimethyl malonate. S In this case, the amino group was incorporated in the starting material rather than using an amine surrogate. This... 

The basic principle of polyketide assembly is highly related to that of fatty acid biosynthesis [14, 16]. In both biosynthetic systems, an acyl-primed ketosynthase (KS) catalyzes chain extension by decarboxylative Claisen condensation with malonate activated by its attachment to coenzyme A or an acyl carrier protein (ACP) via a thioester bond (Scheme 2.2). hi fatty acid synthases (FASs), the resulting ketone is rednced to the corresponding alcohol by a ketore-ductase (KR), dehydrated by action of a dehydratase (DH) to give the alkene with snbseqnent donble-bond reduction by an enoyl rednctase (ER) yielding the saturated system (cf. Section 3.2). The latter can then be transferred onto the KS domain and enter the next cycle of chain extension and complete rednction. This homologation process facilitates the assembly of long-chain satnrated fatty acids, for example, palmitic acid, after seven cycles, which will ultimately be released from the catalytic system by saponification of the... 

Figure 6.7 Chain extension of aryl methyl [ " C]ketones via malonic ester synthesis...

Furthermore, catalytic hydrogenation of the a,/3-unsaturated acids has been introduced as a convenient alternative to the two carbon chain extension sequence effected by alkylation of dialkyl malonates with primary alkyl and aryl alkyl halides, as exemplified... 

PKSs are characterized by their ability to catalyze the formation of polyketide chains from the sequential condensation of acetate units from malonate thioesters. In plants they produce a range of natural products with varied in vivo and pharmacological properties. PKSs of particular note include acridone synthase, bibenzyl synthase, 2-pyrone synthase, and stilbene synthase (STS). STS forms resveratrol, a plant defense compound of much interest with regard to human health. STS shares high sequence identity with CHS, and is considered to have evolved from CHS more than once. ° Knowledge of the molecular structure of the CHS-like enzymes has allowed direct engineering of CHS and STS to alter their catalytic activities, including the number of condensations carried out (reviewed in Refs. 46, 51, 52). These reviews also present extensive, and superbly illustrated, discussions of CHS enzyme structure and reaction mechanism. 

The tetracyclines (Table 3.3) are a group of broad spectrum, orally active antibiotics produced by species of Streptomyces, and several natural and semi-synthetic members are used clinically. They contain a linear tetracyclic skeleton of polyketide origin in which the starter group is malonamyl-CoA (Figure 3.54), i.e. the coenzyme A ester of malonate semi-amide. Thus, in contrast to most acetate-derived compounds, malonate supplies all carbon atoms of the tetracycline skeleton, the starter group as well as the chain extenders. The main features of the pathway (Figure 3.54) were deduced from extensive studies of mutant strains of Streptomyces aureofaciens with genetic blocks... 

---