Starter Groups Other Than Acetate

In the examples so far discussed, the basic carbon skeleton has been derived from an acetate starter group, with malonate acting as the chain extender. The molecule has then, in some cases, been made more elaborate by the inclusion of other carbon atoms, principally via alkylation reactions. However, the range of natural product structures that are at least partly derived from acetate is increased enormously by altering the nature of the

CO2H

orsellinic acid oxidative cleavage OMe of 1,4-quinone OMe

CO2H

orsellinic acid

HO2C HO

penicillic acid hemiketal OMe /->.

penicillic acid

Figure 3.45

reduction OMe

Figure 3.45

CoAS.J1 O

4-hydroxycinnamoyl-CoA

3 x malonyl-CoA

Michael-type nucleophilic addition on to a, ß-unsaturated ketone

Hydroxycinnamoyl Coa Esters
OH

OH O

OH O

CO2H OH lunularic acid

OH O

naringenin (a flavonoid)

OH O

naringenin (a flavonoid)

Figure 3.46

Y%-SEnz

Hydroxycinnamoyl Coa Esters
OH

resveratrol (a stilbene)

resveratrol (a stilbene)

starter group from acetate to a different carboxylate system, as its coenzyme A ester, with malonyl-CoA again providing the chain extender. There is less detailed knowledge here about the precise nature of how substrates are bound to the enzyme, and whether coenzyme A esters are initially transformed into thio esters of the ACP type.

Flavonoids and stilbenes are simple examples of molecules in which a suitable cinnamoyl-CoA C6C3 precursor from the shikimate pathway (see page 130) has acted as a starter group. Thus, if 4-hydroxycinnamoyl-CoA (Figure 3.46) is chain extended with three malonyl-CoA units, the poly-P-keto chain can then be folded in two ways, allowing aldol or Claisen-type cyclizations to occur, respectively. The six-membered hetero-cyclic ring characteristic of most flavonoids, e.g. naringenin, is formed by nucleophilic attack of a phenol group from the acetate-derived ring on to the a,P-unsaturated ketone. Stilbenes, such as

resveratrol, incorporate the carbonyl carbon of the cinnamoyl unit into the aromatic ring, and typically lose the end-of-chain carboxyl by a decarboxylation reaction. Although some related structures, e.g. lunularic acid from the liverwort Lunularia cruciata, still contain this carboxyl, in general it is lost in a pre-cyclization modification, and intermediates of the type shown in brackets are not produced. Flavonoids and stilbenes are discussed in more detail in Chapter 4 (see page 149).

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).

Fatty acyl-CoA esters are similarly capable of participating as starter groups. Fatty acid biosynthesis and aromatic polyketide biosynthesis are distinguished by the sequential reductions as the chain length increases in the former, and by the stabilization of a reactive poly-^-keto chain in the latter, with little or no reduction involved. It is thus interesting to see natural product structures containing both types of acetate - malonate-derived chains. In plants of the Anacardiaceae, e.g. poison ivy* (Rhus radicans) and poison oak* (Rhus toxicodendron ), contact allergens called urushiols are encountered, which derive from just such a pathway. Thus, palmitoleoyl-CoA (A9-hexadecenoyl-CoA) can act as starter group for extension by three malonyl-CoA units, with a reduction step during chain extension (Figure 3.48). Aldol cycliza-tion then gives anacardic acid, which is likely to be the precursor of urushiol by decarboxyla-tion/hydroxylation. It is likely that different fatty acyl-CoAs can participate in this sequence, since urushiols from poison ivy can contain up to three double bonds in the C15 side-chain, whilst those from poison oak also have variable unsaturation

anthraniloyl-CoA

2 x malonyl-CoA

3 x malonyl-CoA

O SCoA

quinoline alkaloid

quinoline alkaloid

O OH

O OH

acridine alkaloid

CoAS

acridine alkaloid

Figure 3.47

3 x malonyl-CoA .SCoA

palmitoleoyl-CoA

Figure 3.47

3 x malonyl-CoA .SCoA

palmitoleoyl-CoA

urushiol

reduction urushiol

HO2C

anacardic acid OH

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