Aldol Reactions of Chiral Glycinates

Alternative routes to labeled anri-/3-hydroxy-a-amino acids of the a//o-threonine type are described in Section 11.3.9. They involve aldol reactions of haloacetyl-Evans and -Oppolzer auxiliaries to give iyn-/3-hydroxy-a-halo derivatives, whose a-halo groups are then inverted by nucleophilic displacement with azide ion.  

In contrast to the linear glycinates discussed above, the utility of lithium or titanium enolates of the cyclic glycinates 229. 230 and 231 for the preparation of e.p. isotopically labeled /3-hydroxy-a-amino acids of the threonine type has been documented by several examplesi  

The lithium enolate of (R)- or (S)-l-benzoyl-2-ferf-butyl-3-methylimidazolidin-4-one (Seebach s reagent, 229), for example, furnishes the respective primary aldol adducts in excellent diastereoselectivities (d.e. 90%). Their hydrolysis to the free acids, however, requires such drastic reaction conditions (6N HCI, 150 °C, sealed tube) that these building blocks are of very limited use. For this reason the corresponding (R)- and (5)-l,3-oxazolidin-5-ones 230 are recommended as more useful alternatives. In their case hydrolysis of the primary adducts can be accomplished under very mild reaction conditions, namely hydrogenolytic removal of benzyloxycarbonyl function followed by hydrolytic cleavage of the heterocyclic system with LiOH/aq. THF or IN HCI at room temperature.  

This procedure has been successfiilly applied to the synthesis of [ C]SM-11044 (235), a /3-adrenoceptor agonist . The primary adduct 233, obtained from reaction of the enolate of 230 and 3,4-methylenedioxybenz[ C]aldehyde (232), was cleaved following the recommended sequence to furnish (25,3R)-2-amino-3-(3,4-methylenedioxyphenyl)-3-hy-droxy[3- C]propionic acid (234) in 61% radiochemical yield and 99% enantiomeric 

For success with this method two issues must be taken into account. First, the lithium 

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