Carboxylic esters, conjugated formation

Heterocyclic carboxylic esters (708) are as reactive as formate and acetate esters. Extended to 1-substituted biguanides, the reaction is promoted by metal alkoxides. Since the heterocyclic ring must be five-or six-membered and contains a conjugated system of double bonds, the reaction resembles formally that involving a,p-unsaturated esters (see below). Several successful examples are on record (599, 606). 

Whereas the Markovnikov addition of carboxylic acids to propargylic alcohols produces P-ketoesters, resulting from intramolecular transesterification [30, 31], the addition to propargylic alcohols in the presence of Ru(methallyl)2(dppe) 1 at 65 °C leads to hydroxylated alk-l-en-l-yl esters via formation of a hydroxy vinylidene intermediate [32, 33]. The stereoselectivities are lo ver than those obtained from non-hydroxylated substrates. These esters, which are protected forms of aldehydes, can easily be cleaved under thermal or acidic conditions to give conjugated enals, corresponding to the formal isomerization products of the starting alcohols (Scheme 10.6). 

Some properties of diethyl allylphosphonate have been investigated, in particular the behaviour of its anion (500) towards < /t-unsaturated ketones and carboxylic esters. Although in. some cases the conjugate addition of the anion has been observed, e.g. in the formation of (501) and (502), in most ca.ses the reaction leads to carbocyclic products. y-Nucleophilicity, with addition-elimination, has been observed in reactions with e.g. ( )-4-methoxybut-3-en-2-one, when the final product is (503), following expulsion of the methoxy group. A third mode of reaction consists of multiple addition ... 

For the conjugation of the chelator to the biomolecule, the activation of a carboxylate group of the chelator via an active ester and the reaction with a primary amine of the biomolecule (side-chain of a lysine residue or N-terminal amine of a peptide) leads to a stable attachment via a peptide bond. This peptide bond is highly stable under physiological conditions. One popular example of activation of the carboxylate is the formation of N-hydroxysuccinimide (NHS) esters (O Fig. 45.21). NHS-activated esters are selective for primary amines in aqueous... 

In 2010, Hoveyda and coworkers disclosed a Cu-catalyzed method for enantio-selective boronate conjugate additions to trisubstituted alkenes of acyclic a.P Unsaturated carboxylic esters, ketones, and thioesters, resulting in the formation of p-substituted quaternary carbon stereogenic centers (Scheme 3.65) [94]. By using 5 mol% of a chiral monodentate NHC 103 copper complex at low temperature, the products were obtained in good yields (up to 98%) and enantiose-lectivities (up to 96% ee). Moreover, transformations involving unsaturated thioesters gave the best enantiocontrol. 

Figure 16 Conjugation of an amine and a carboxylic acid via the (V-hydroxysuccinimide (NHS)-activated ester method. NHS esters may be isolated and characterized and are stable to long term storage as the powder. Alternatively, the NHS esters may be used immediately upon formation without isolation. Details of the reaction are given in Table 4...

Copper-catalyzed cyclopropanation of benzene and its derivatives by a diazoacetic ester yields a norcaradiene 230 which undergoes spontaneous ring opening to cyclo-heptariene 231. At the temperatures needed for successful cyclopropanation, sigma-tropic H-shifts leading to conjugated isomers of cycloheptatriene carboxylates cannot be avoided. The situation is complicated by the formation of regioisomers upon cyclopropanation of substituted benzenes, and separation of the cycloheptatriene isomers may became tedious if not impossible. 

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