Esters lateral lithiation

Corydalic acid methyl ester lateral lithiation 366... 

These reactions have been used in the synthesis of aikaioids such as corydalic acid methyi ester 502 (Scheme i95). Isoiated from Corydalis incisa, 502 is derived from a proposed biosynthetic intermediate in the route to the tetrahydroprotoberberine aikaioids. The 1,2,3,4-tetrasubstituted ring of 502 demands control by an ortholithiation strategy, and the synthetic route proposed by Clark and Jahangir employs a lateral lithiation of 503 and addition to an imine as the key disconnection at the centre of the molecule. 

The reduced electrophUicity of indole-3-carboxylic esters (they are vinylogous carbamates) means that they are much more versatile directors of lateral lithiation than the comparable benzoates, as illustrated by the synthesis of 564 (Scheme 221... 

Remarkably, ethyl otolylsulfonate 456 can be laterally lithiated by BuLi at -78 °C 410 With the methyl ester, the expected substitution at the methyl group takes place. The -substituted ester also undergoes lithiation at the methyl group, suggesting that the sulfonate group acts substantially by conjugation. 

Meyers and co-workers" also investigated lateral lithiation of a 2-methyloxazole derivative during their synthesis of the oxazole dienyl amine moiety 1203, common to 1183 and 1184. The authors proposed a retrosynthetic path, wherein selective functionalization of a 2-methyl-4-oxazolecarboxylic acid ester would be the starting point for 1203 (Scheme 1.305). 

Lateral LithiationP Laterally metalated o-toluic acids (eq 48), esters (eq 49), and amides (eq 50) are important intermediates for chain extension and carbo- and hetero-ring annulation. Remote lateral lithiation of 2-methyl-2 -carboxaminobiaryls constitutes a general regiospecific synthesis of 9-phenanthrols (eq 51). ... 

As first described by Krizan and Martin,6 the in situ trapping protocol, i.e., having the base and electrophile present in solution simultaneously, makes it possible to lithiate substrates that are not applicable in classical ortho-lithiation reactions.7 Later, Caron and Hawkins utilized the compatibility of lithium diisopropylamide and triisopropyl borate to synthesize arylboronic acid derivatives of bulky, electron deficient neopentyl benzoic acid esters.8 As this preparation illustrates, the use of lithium tetramethylpiperidide instead of lithium diisopropylamide broadens the scope of the reaction, and makes it possible to functionalize a simple alkyl benzoate.2... 

Lateral metallation at C-2(a) of l-/ftt-butoxycarbonyl-2-methylimidazoline 709 (Scheme 173) with r f-BuLi results in the formation of a bright yellow lithiated intermediate that reacts with alkyl halides, diphenyldiselenide, and phosphoryl chlorides to give 710. In the case of reaction with esters, the conjugated ketones 711 are formed <2000T2061>. In the case of acylation with esters, conjugated enamino-ketones were the tautomer isolated. Further alkylation is also possible under similar conditions, to give 712. 

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