Aldol addition reactions biological

The group of Samuel Danishefsky at the Sloan-Kettering Institute for Cancer Research in New York has also been active in the synthesis of the natural epothilones and biologically active analogs. One of these syntheses also uses the olefin metathesis reaction (not shown). The synthesis in Scheme 13.51 uses an alternative approach to create the macrocycle. One of the key steps is a Suzuki coupling carried out at step H-(l,2) between a vinylborane and vinyl iodide. The macrocyclization is an aldol addition reaction at step H-4. The enolate of the acetate adds to the aldehyde, creating the C(2)-C(3) bond of the macrolactone and also establishing the stereocenter at C-3. 

This is a type of aldol addition (known as biological aldol addition) and is one of the reaction in the metabolism of carbohydrates by the glycolic pathway. 

By using the neutral enamine as the carbon nucleophile rather than an eno-late anion, the biological system avoids the need for strongly basic reaction conditions in aldol addition. 

By the reaction of D-glyceraldehyde and 1,3-dihydroxypropane (both as monophosphate ester), D-fructose as the 1,6-diphosphate ester is formed. The process is readily reversible and is catalysed by an enzyme known as aldolase. This is a type of aldol addition (known as biological aldol addition) and is one of the reaction in the metabolism of carbohydrates by the glycolic pathway. 

Trimethylsilyloxy)furan can also be used as a functionalized silyl enol ether for the asymmetric catalytic aldol-type reaction. Figadere has reported that the reaction of aliphatic aldehydes with the siloxyfuran catalyzed by BINOL-derived titanium complex provides the diastereomeric mixtures with high enantioselectivity (Sch. 42) [107], The addition reaction proceeds at the y position of the siloxyfuran to give butenolides of biological and synthetic importance. 

The catalytic version of this type of reaction was realized by using acetoacetate derived O-silyl dienolate as nucleophiles in the presence of Carreira s catalyst, giving acetoacetate y-adducts in high yields and enantiomeric excesses [119] (Scheme 14.42). The products are ubiquitous structural subunits in biologically active natural products such as the polyene macrolide antibiotic and medicinally important HMG-CoA reductase inhibitors. This aldol addition can also be catalyzed by BINOL-Ti complex in the presence of 4A MS with moderate to good enantioselectivity [120]. The same catalyst system was also efficient in the asymmetric aldol reaction between the aldehydes and Chan s diene [ 1,3-bis-(trimethylsilyloxy)-l-methoxy-buta-1,3-diene] and other related silyl enol ethers [121, 122] (Scheme 14.43) or the functionalized silyl enol ether such as 2-(trimethylsilyloxy)furan with good to excellent enantioselectivities [123]. 

Since the first report on aldol additions of the chiral acetate 173, the reagent has been applied frequently in syntheses of natural products and biologically active compounds. In the course of these synthesis, it was noticed by several research groups that the extremely low temperatures are not always necessary and the diastereoselectivity in the aldol addition is only slightly diminished when the reactions are run at -78 °C or higher temperature. Among the applications of the acetate S) or (5 )-174 are inter alia y-amino-P-oxy-butanoic acid ( GABOB )... 

Aldol reactions occur in many biological pathways, but are particularly important in carbohydrate metabolism, where enzymes called aldolases catalyze the addition of a ketone enolate ion to an aldehvde. Aldolases occur in all organisms and are of two types. Type 1 aldolases occur primarily in animals and higher plants type II aldolases occur primarily in fungi and bacteria. Both types catalyze the same kind of reaction, but type 1 aldolases operate place through an enamine, while type II aldolases require a metal ion (usually 7n2+) as Lewis acid and operate through an enolate ion. 

Enantioselective organocatalytic conjugate additions such as Michael and aldol reactions have been intensely studied under new catalysts. However, only a few organocatalyzed Michael reactions have been developed. The reaction involves construction of a new C-N bond that is very attractive for syntheses of molecules with biological properties. 

The alkyllithium reagents to be used in tandem reactions can be prepared by direct alkylation or by an aldol reaction involving nucleophilic addition of the alkyllithium as the first step. Several complex heteroaromatic compounds, which can serve as pivotal intermediates in synthetic strategy of biologically active species, could be synthesized by this procedure. The preparation of polysubstituted pyridines has been an active research area for many years181. The synthesis of 2-alkyl- or 2-aryl-5-hydrazinopyridines 327 has never been performed directly from pyridine. The reported methods involve several steps... 

Carbon-carbon bond formation is a reaction of fundamental importance to the cellular metabolism of all living systems and includes alkylation reactions involving one and five carbon fragments as well as carboxylation reactions. In addition, a very common method of generating carbon-carbon bonds in biology includes the reactions of enolates and their equivalents (such as enamines) with aldehydes, ketones, keto acids, and esters. Reactions in which the enolate derives from an acyl thioester are Claisen condensations, whereas the remainder are classified as aldol reactions. 

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