Polyketides aldol condensation

The addition of allenyl metal reagents to aldehydes affords homopropargylic alcohols with contiguous OH- and Me-substituted stereocenters, which serves as a complementary approach to the aldol condensation for polyketide synthesis. Marshall has developed this method extensively and this work is the subject of a more detailed review (cf. Chapter 9) [50]. The applications of this method to the synthesis of naturally occurring compounds have also been wide-ranging and a few are highlighted below. 

Most of the pigments of flowers arise from a single polyketide precursor. Phenylalanine is converted to trans-cinnamic acid (Eq. 14-45) and then to cinnamoyl-CoA. The latter acts as the starter piece for chain elongation via malonyl-CoA (step a in the accompanying scheme). The resulting (3-polyketone derivative can cyclize in two ways. The aldol condensation (step b) leads to stilbenecar-boxylic acid and to such compounds as pinosylvin of pine trees. The Claisen condensation (step c) produces chalcones, flavonones, and flavones. These, in turn, can be converted to the yellow fla-vonol pigments and to the red, purple, and blue anthocyanidins.3 c... 

Stilbenoids are derived from cinnamic acid and three acetate units from mal-onyl coenzym A. The first part of the biosynthesis is in common to flavonoids. The two biosynthetic routes are diverging at the point of cyclization of a styryl-3,5,7-triketoheptanoic acid. A C-acylation produces a chalcone and subsequent modifications lead to the flavonoids. An aldol condensation of the same intermediate polyketide produces a stilbene-2-carboxylic acid that is unstable and constitutes a range of structures known as stilbenoids. Figure 9C.5 shows an overview of the biosynthetic pathway (Gorham 1995). 

In order to confirm the structures of solanapyrones, chemical synthesis of these phytotoxins were attempted based on biogenetic consideration [55], The retro synthesis envisaged intramolecular Diels-Alder reaction of the achiral polyketide triene (a), a key intermediate, which is further divided into a pyrone moiety (b) and a diene moiety (c). The moieties a and b were prepared from dehydroacetic acid and hexadienyl acetate, respectively. Aldol condensation of the aldehyde (72) with the dithioacetal (73) gave a dienol, which was further converted to a triene (74). The intramolecular Diels-Alder reaction of 74 in toluene at 170-190 °C for 1 hr in a sealed tube yielded a mixture of the adducts (75) and (76) in a ratio of 1 2. This product ratio depends on the solvents, i.e. in water (1 7), and should be useful in differentiating between artificial and enzymatic reactions in biosynthetic studies. Removal of the thioacetal groups in 75 and 76 yielded solanapyrone A (67) and D (70) in a ratio of 3 5. Though solanapyrone D (70) had not been isolated from the natural resources at this stage, the structure and stereochemistry were confirmed by H NMR spectrum. 

It was proposed that both the naphthalene and isoquinoline moieties of these compounds could arise from a common polyketide precursor 9 (Scheme I). Aldol condensation of 9 could provide diketone 10 or a reduction/aldol sequence could provide the C-6 deoxygenated analogue... 

Ozonolysis of diene 19 provides the reduced polyketide 20 which is cyclised to phenol 21 (ref. 13) (Seheme 3). Methylation and a further aldol condensation gives the naphthalene segment 12 while methylation followed by condensation with ammonia yields the C-6 deoxygenated... 

The formation of orcin 7 in addition to 6 is the result of a subsequent deprotonation of 6 to the enolate 8 which recyclizes by an intramolecular aldol condensation. This reaction gave rise to the hypothesis of the biosynthesis of aromatic compounds from polyketides (Collie 1907) [34]. 

Intramolecular aldol condensation of a slightly longer polyketide chain gives orsellinic acid. 

The chain length of the polyketide intermediate increases by units of two carbon atoms to various lengths. Cyclization of intermediates occurs by one of two pathways. An intramolecular aldol condensation produces aromatic rings with one substitution pattern (Fig. 5.2) and an intramo-... 

This and other information show that nine Cg units from malonyl-coenzyme A and one C3 unit from propionyl-coenzyme A condense to form the linear polyketide intermediate shown below. These units are joined by acylation reactions that are the biosynthetic equivalent of the malonic ester synthesis we studied in Section 18.7. These reactions are also similar to the acylation steps we saw in fatty acid biosynthesis (Special Topic E in WileyPLUS). Once formed, the linear polyketide cyclizes by enzymatic reactions akin to intramolecular aldol additions and dehydrations (Section 19.6). These steps form the tetracyclic core of akiavinone. Phenolic hydroxyl groups in akiavinone arise by enolization of ketone carbonyl groups present after the aldol condensation steps. Several other transformations ultimately lead to daunomycin ... 

The spatial arrangement of the polyketo acids leads to cyclization by aldol condensations, i.e., reaction of carbonyl groups with acidic CHg-groups, or by Claisen condensation, i.e., reaction of the ester group at the head of the molecule with one of the acidic CHg-groups. The actual type of condensation depends on the nature of the polyketide synthetase in question and the spatial arrangement of the polyketo acid directed by the enzyme. Thus several cyclic structures... 

Intramolecular aldol condensations also serve as the key step in bio-mimetic syntheses of polyketides, synthetic strategies that try to imitate in vitro a proven or an assumed biosynthetic path vay [30]. Although the first attempts in this direction go back to the early 20th century [31], practical and efficient syntheses based on this concept vere elaborated much later. 

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