Malic acid from chiral acetate

Hydroxyproline is abundant but hydroxylysine is not. Fortunately it can be made59 from an abundant member of the chiral pool - malic acid 34. Borane reduction gives the triol 332 and anisaldehyde gives the diequatorial acetal 333 under thermodynamic control. 

The stereochemistry of these steps is of course controlled by the original chiral centre derived from malic acid. The acetate prefers to adopt a pseudo-equatorial position in the cation 105 and the conformational drawings 105a-107a show that a chair conformation for the [3,3] step with equatorial substituents gives the first two new chiral centres and a pseudo-equatorial position for the isopropyl substituent in the ionic cyclisation gives the third. 

By far the most widely used chiral intermediates derived from malic acid are acetals of 1,2,4-butanetriol. Triol 370 is by its nature capable of forming acetals with either the C-1 and C-2 hydroxyls, thus producing a 5-membered ring, or with the C-2 and C-4 hydroxyls to give a... 

The malic acid is isolated and incubated with fumarase until no further loss of carbon-bound tritium results. [The enzyme catalyses trans removal of water, as (1.28) t L30).] For the samples of malate derived from (/ )-acetic acid, the minor product L29) loses TOH. For the material derived from (5 )-acetic acid it is the major product 1.33) which loses TOH. So for (/2)-acetic acid a higher retention of tritium (ca. 75%) is observed in the fumarase equilibration and for (5)-acetic acid a lower value (ca. 25%). With the method of analysis established for samples of acetic acid of known chirality it can be used to determine the configuration of samples of acetic acid of unknown chirality derived from biological reactions (for examples see Section 4.2 and 4.4, and [14]). 

Lactonization of a hydroxy-acid to a butyrolactone is achieved, using dimethyl-formamide dineopentyl acetal, during a synthesis of oxygenated nor-heliango-lides. The chiral lactone (164) is prepared from (iJ)-malic acid, its dianion is alkylated at carbon to give the /ra/i5-disubstituted lactone (165) in moderate yield, and this is used in a synthesis of (—)-aplysistatin (Scheme 94). An independent, biogenetically patterned synthesis of this natural product, using tetronic acid intermediates, has been described. ... 

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