Natural products Knoevenagel reaction

Tietze L. F. Domino-Reactions the Tandem-Knoevenagel-Hetero-Diels-Alder Reaction and Its Application in Natural Product Synthesis J. Heterocycl. Chem. 1990 27 47-69... 

The domino Knoevenagel/hetero-Diels-Alder reaction is a prominent example of the great advantage of domino processes as it not only allows the efficient synthesis of complex compounds such as natural products starting from simple substrates, but also permits the preparation of highly diversified molecules. Due to the vast number of reports that have been made, only a few recent publications can be discussed here, although several excellent reviews on this topic have been produced that provide a more detailed insight into this useful method [372]. 

The domino process probably involves the chiral enamine intermediate 2-817 formed by reaction of ketone 2-813 with 2-815. With regard to the subsequent cy-doaddition step of 2-817 with the Knoevenagel condensation product 2-816, it is interesting to note that only a normal Diels-Alder process operates with the 1,3-bu-tadiene moiety in 2-817 and not a hetero-Diels-Alder reaction with the 1-oxa-l,3-butadiene moiety in 2-816. The formed spirocydic ketones 2-818/2-819 can be used in natural products synthesis and in medidnal chemistry [410]. They have also been used in the preparation of exotic amino adds these were used to modify the physical properties and biological activities of peptides, peptidomimetics, and proteins... 

Both natural and non-natural compounds with a 2ff,5ff-pyrano[4,3-fc]pyran-5-one skeleton are of interest in medicinal chemistry. Several natural products, such as the pyripyropenes, incorporate this bicyclic ring system. The group of Beifuss has described an efficient microwave-promoted domino synthesis of the 2ff,5H-pyr-ano[4,3-fo]pyran-5-one skeleton by condensation of a,/3-unsaturated aldehydes with 4-hydroxy-6-methyl-2]-f-pyran-2-one (Scheme 6.244) [428]. It is assumed that in the presence of an amino acid catalyst a Knoevenagel condensation occurs first, which is then followed by a 6jr-electron electrocyclization to the pyran ring. While the conventional thermal protocol required a reaction time of up to 25 h (refluxing ethyl... 

Tietze LF (1990) Domino-reactions - the tandem-Knoevenagel-hetero-Diels-Alder reaction and its application in natural product synthesis. J Heterocycl Chem 27 47-69... 

Tetrahydroalstonine 7-7, a heteroyohimboid alkaloid, has been synthesised in enantiopure form by Martin et al. by means of an oxa Diels-Alder reaction as key step. The trienic precursor 7-5 underwent a thermal intramolecular cycloaddition to form a 5 1 mixture of 7-6 and its 15/J-epimer. The main cycloadduct was then subjected to a straightforward sequence to yield the natural product 7-7 (Fig. 7-2) [483-485]. In earlier work, Ogasawara et al. have employed a con-ceptionally different domino Knoevenagel-hetero Diels-Alder approach to this alkaloid and other natural products [486-488]. 

Snider et al. have synthesised the antiinsectan ( )-leporin [496] 7-26 using the domino-Knoevenagel-hetero Diels-Alder sequence. The intermediate 1-oxa-1,3-butadiene 7-25 was formed in situ by condensation of the pyridone 7-23 and the dienal 7-24. Subsequently, a hetero Diels-Alder reaction occurred accompanied by minor side reactions. Thus, the desired cycloadduct 7-27 was formed only in moderate yield as 5 1 mixture with its trans-fused diastereomer (Fig. 7-6). Functionalisation of the nitrogen atom yielded the natural product. A similar reaction sequence occurred in the synthesis of the structurally related free radical scavenger ( )-pyridoxatin, however, in this approach the hetero Diels-Alder reaction represented only a side reaction competing with the desired intramolecular ene reaction [497]. 

The Knoevenagel reaction is a synthetic method with a broad scope. The educts are simple and cheap, reaction conditions are mild, and a wide variety of solvents can be used. In addition, the Knoevenagel products are reactive compounds and may be employed in sequential transformations (see also Section 1.1.1.4). This is why the Knoevenagel reaction is widely employed, especially in the formation of heterocycles. The most used active methylene in these reactions is malonodinitrile. In many syntheses of natural products, drugs, dyes and other compounds, the condensation of a carbonyl group with an activated methylene compound is found. It is beyond the scope of this review to discuss all examples described in the literature, so only a few recent examples are given in this section. 

In nature, the intramolecular condensation of a 1,3-dicarbonyl moiety with a keto group in polyketides is an important step in the biosynthesis of aromatic compounds. Biomimetic transformations of this type have been intensively investigated by Harris. (For a discussion, see Chapter 1.5, this volume.) In the following, the synthesis of some natural products and biologically active compounds using the Knoevenagel reaction will be described. 

J,V-Unsaturated carboxylic acids and their derivatives are valuable synthetic intermediates for various natural products. Two typical multi-step processes for the synthesis of p.y-unsaturated acids, Knoevenagel reaction/isomerization with base and allylic cyanide/hydrolysis,3 are those most commonly used. Other new methods have been developed 4-7 however, there is a problem with E/Z stereoselectivity. One straightforward way to obtain p,y-unsaturated acids is by the carboxylation of an allyl metal Intermediate. In the substituted allylic series, the reaction usually occurs at the more sterically hindered terminus. A stereospecific route for the synthesis of homogeranlo acid and homoneric acid by carboxylation of the lithiated allylic sulfone... 

Deoxyloganin (24) has previously been synthesized by Tietze and coworkers, utilizing an intramolecular hetero-Diels-Alder reaction to construct the iridoid core (Scheme 10). The synthesis commenced with conversion of (5)-citronellal (47) to enol ether 48 in seven steps. Knoevenagel condensation of the aldehyde with Meldrum s acid, followed by in situ intramolecular hetero-Diels-Alder reaction afforded pyran 49, with all the carbons required for the natural product core installed. Conversion of 49a, via methanolysis and a reduction/elimination sequence, to lactol acetate 50, was achieved in four steps. Finally, glycosylation and deprotection provided the natural product in a total of 14 steps. 

One of the most versatile domino reactions involving a cycloaddition step is the domino Knoevenagel/hetero Diels-Alder reaction, which was developed by Tietze et al. It has been used for the efficient synthesis of innumerous heterocycles and many natural products. A novel example is the preparation of the amino sugar D-forosamin by Tietze et al. using a three-component reaction, which is described in detail in Chapter 14 [60]. 

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