Large Lactone synthesis

The production of polyesters from lactones (cyclic esters) avoids the problems usually encountered in traditional polyester synthesis due to esterification equilibrium and water production. In fact, they yield in a single step, in the presence of ROP catalysts, high molecular weight polymers endowed with optimum mechanical properties. This is particularly true when large lactones are used as starting monomers. On the other hand, one of the main drawbacks connected with their use lies in their high cost. 

Another efficient method is the electrochemical oxidation of NADH at 0.585 V vs Ag/AgCl by means of ABTS2- (2,2,-azinobis(3-ethylbenzothiazoline-6-sulfonate)) as an electron transfer mediator [96]. Due to the unusual stability of the radical cation ABTS, the pair ABTS2 /ABTS is a useful mediator for application in large-scale synthesis even under basic conditions. Basic conditions are favorable for dehydrogenase catalyzed reactions. This electrochemical system for the oxidation of NADH using ABTS2 as mediator was successfully coupled with HLADH to catalyze the oxidation of a meso-diol (ws >-3,4-dihydroxymethylcyclohex-l-ene) to a chiral lactone ((3aA, 7aS )-3a,4,7,7a-tetrahydro-3//-isobenzofurane- l-one) with a yield of 93.5% and ee >99.5% (Fig. 18). 

Hydrocarboxylation of alkenes or alkynes involves the formal addition of a carboxylic acid O—H bond across a C=C or C=C bond (Scheme 2.25) [63]. In particular, intramolecular hydrocarboxylation provides an atom economical strategy for lactone synthesis. The aforementioned reaction is thermodynamically favorable but there is a large intrinsic kinetic barrier for this type of cydization, thus requiring the addition of a catalyst. Catalysts for hydrocarboxylation typically facilitate addition by alkene or alkyne binding. This process increases the inherent electrophilicity of the C=C and C=C bonds, respectively. Subsequent protonolysis (or 3-H elimination under Pd catalysis) regenerates the catalytic spedes. 

When the amide (4) was treated under Mitsunobu conditions, cyclization occurred through oxygen to give the L-xylono-1,4-lactone derivative (5). A convenient large-scale synthesis of D-ribono-1,4-lactone from D-ribose has been described, and 5-0-glucopyranosylarabinonic acid can be obtained selectively by oxidative removal of C-1 from isomaltulose. Rate constants for the hydrolysis of D-glucono-1,5-lactone, and for the reverse reaction, have been determined. ... 

These antibiotics (erythromycin, spiramycin, carbomycin, oleandomycin) are very effective in inhibiting protein synthesis. They are called macrolides because they contain a large lactone ring (Fig. 5). 

Synthesis of large ring alkanes and lactones from smaHer ring ketones via peroxides... 

An interesting footnote to the general synthesis of macrocyclic crown ether-type esters is found in the work of Ors and Srinivasan . These workers used cinnamate esters and diesters as precursors to large ring lactones. Depending on orientation, either truxil-... 

The hydroxy lactams are postulated to be intermediates in transformations of enol lactones to ene lactams. This hypothesis was proved by synthesis. For example, treatment of N-methylhydrastine (98) with dilute ammonium hydroxide resulted in hydroxy lactam 148, which by the action of hydrochloric acid underwent dehydration to produce fumaridine (113) (5). Similarily, fumschleicherine (120) in reaction with trifluoroacetic acid gave fumaramine (111) 121). Narceine amide (149) was prepared from (Z)-narceine enol lactone (101) in likewise fashion 100,122) and dehydrated to narceine imide (116). A large number of N-alkylated narceine amides was synthesized from (Z)-narceine enol lactone (101) and primary amines by Czech investigators for... 

The diversity of the Ugi-MCR mainly arises from the large number of available acids and amines, which can be used in this transformation. A special case is the reaction of an aldehyde 9-26 and an isocyanide 9-28 with an a-amino acid 9-25 in a nucleophilic solvent HX 9-30 (Scheme 9.5). Again, initially an iminium ion 9-27 is formed, which leads to the a-adduct 9-29. This does not undergo a rearrangement as usual, but the solvent HX 9-30 attacks the lactone moiety. Such a process can be used for the synthesis of aminodicarboxylic acid derivatives such as 9-31 [3, 30],... 

Phase-transfer catalysis can be used to mimic high dilution reaction conditions and has been utilized to good effect in the synthesis of large ring lactones [67J. Macrocyclic nitrolactones have also been obtained by rearrangement of 2-(3-hydroxy-propyI)-2-nitrocycloalkanones using a stoichiometric amount of tetra-n-butyl-ammonium fluoride [68]. 

Strategy should also be applicable to paraconic acids, and indeed, the synthesis of (+)-phaseolinic acid (6) as well as (-)-methylenolactocin (11) has successfully been achieved this way (Scheme 24) [61]. This approach is especially advantageous if the precursors are readily available on large scale to compensate for the principle loss of at least 50% caused by the presence of the undesired enantiomer. Thus, a mixture of the lactones ( )-151 and ( )-152 is available in a single step from the ketodiester 150 [5c, 62] via a reduc-tion-lactonization sequence. After separation, ( )-151 was transformed into racemic ( )-153, which was hydrolyzed by pig liver esterase (PLE) to yield (+)-phaseolinic acid ((+)-6) in up to 94% ee. Alternatively, the remaining (-)-153 could be obtained in up to 96% ee, which could be hydrolyzed to (-)-phaseolinic acid ((-)-6). 

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