Chiral building blocks reaction

This catalyst was successfully applied to the Diels-Alder reaction of propargyl aldehydes as dienophUes [12] (Scheme 1.21, Table 1.8). Though 2-hutyn-l-al and 2-oc-tyn-l-al are unreactive dienophUes, silyl- and stannyl-suhstituted a,/ -acetylenic aldehydes react with cydopentadiene readily in the presence of 20 mol% of the catalyst at low temperature to give hicyclo[2.2.1]heptadiene derivatives in high optical purity these derivatives are synthetically useful chiral building blocks. 

The reaction has wide scope in respect of the dienophUe / -substituent. The representative less reactive dienophiles, crotonoyl- and cinnamoyl-oxazolidinone, react with cyclopentadiene at -15 °C and 25 °C for 20 h and 24 h giving cycloadducts in 99% ee and 96% ee, respectively. The 3-chloropropenoyl derivative also affords the adduct in high optical purity (96% ee) this adduct is transformed to 2-(methoxycar-bonyl)norbornadiene, a useful chiral building block. Thus, the 3-chloropropenoyl derivative can be regarded as a synthetic equivalent of an acetylene dienophile. 

Hydroxy-L-prolin is converted into a 2-methoxypyrrolidine. This can be used as a valuable chiral building block to prepare optically active 2-substituted pyrrolidines (2-allyl, 2-cyano, 2-phosphono) with different nucleophiles and employing TiQ as Lewis acid (Eq. 21) [286]. Using these latent A -acylimmonium cations (Eq. 22) [287] (Table 9, No. 31), 2-(pyrimidin-l-yl)-2-amino acids [288], and 5-fluorouracil derivatives [289] have been prepared. For the synthesis of p-lactams a 4-acetoxyazetidinone, prepared by non-Kolbe electrolysis of the corresponding 4-carboxy derivative (Eq. 23) [290], proved to be a valuable intermediate. 0-Benzoylated a-hydroxyacetic acids are decarboxylated in methanol to mixed acylals [291]. By reaction of the intermediate cation, with the carboxylic acid used as precursor, esters are obtained in acetonitrile (Eq. 24) [292] and surprisingly also in methanol as solvent (Table 9, No. 32). Hydroxy compounds are formed by decarboxylation in water or in dimethyl sulfoxide (Table 9, Nos. 34, 35). 

The cationic pathway allows the conversion of carboxylic acids into ethers, acetals or amides. From a-aminoacids versatile chiral building blocks are accessible. The eliminative decarboxylation of vicinal diacids or P-silyl carboxylic acids, combined with cycloaddition reactions, allows the efficient construction of cyclobutenes or cyclohexadienes. The induction of cationic rearrangements or fragmentations is a potent way to specifically substituted cyclopentanoids and ring extensions by one-or four carbons. In view of these favorable qualities of Kolbe electrolysis, numerous useful applications of this old reaction can be expected in the future. 

Even if hundreds of chiral catalysts have been developed to promote the enantioselective addition of alkylzinc reagents to aldehydes with enantioselectivities over 90% ee, the addition of organozinc reagents to aldehydes is not a solved problem. For example, only very few studies on the addition of vinyl groups or acetylides and even arylzinc reagents to aldehydes have been published, in spite of the fact that the products of these reactions, chiral allylic, propargylic and aryl alcohols, are valuable chiral building blocks. 

These enzymes catalyze a variety of oxidative reactions in natural product biosynthesis with two C—Hhydroxylation examples shown in Figure 13.24 [72,73]. It should be noted thatC—H activation by nonheme iron oxygenases, such as aromatic dioxygenases, is an important pathway in degradation of aromatics into m-dibydrodiols, which are important chiral building blocks for chemical synthesis [74,75]. 

The optically active isoxazolidines obtained in these cycloaddition reactions can be easily transformed into biologically active 3 -amino acids, into j3-lactams and into important chiral building blocks such as y-amino alcohols. The multitude of synthetic results in these reactions is of course expected by the wide variety... 

Based on the Kulinkovich reagent (Ti(OiPr)4/iPrMgCl), a new route to allyltita-niums has been devised by Sato and coworkers and this has allowed the synthesis of chiral allylTi reagents which, by reaction with aldehydes and imines provide diverse polyfunctional chiral building blocks. Thus, while a number of versatile and dependable Ti-based allyl-transfer reagents are now available, the development and employment of chiral allyltitaniums appears to be poised for new application. 

A number of enantiomerically pure chiral building-blocks, such as 292-294, have been prepared (270,271) by zinc-copper cleavage of 5-bromo-5-deoxy-2,3-0-isopropylidene-D-ribono-1,4-lactone, followed by reduction. Similarly, from the 5-iodo lactone analogue the enoic acid 295 was obtained by reaction with zinc/silver-graphite (272). 

Chiral Building Blocks Some drugs are made using chiral building blocks to generate the required chiral center in the drug. The introduction of chiral centers ensures that the reaction proceeds in the desired direction. The preparation of enalapril, an ACE inhibitor, is an example of the use of chiral building blocks. 

Both enantiomers of the bicyclic enone 78 and their derivatives have been proved to be useful chiral building blocks for the synthesis of natural products [29], among them y-butyrolactones. 78 is readily available in either enantiomeric form by a Diels-Alder reaction of furan with a-acetoxyacry-lonitrile and subsequent hydrolysis, followed by a resolution of the racemate... 

Another type of Cinchona alkaloid catalyzed reactions that employs azodicarbo-xylates includes enantioselective allylic amination. Jprgensen [51-53] investigated the enantioselective electrophilic addition to aUyhc C-H bonds activated by a chiral Brpnsted base. Using Cinchona alkaloids, the first enantioselective, metal-free aUyhc amination was reported using alkylidene cyanoacetates with dialkyl azodi-carboxylates (Scheme 12). The product was further functionalized and used in subsequent tandem reactions to generate useful chiral building blocks (52, 53). Subsequent work was applied to other types of allylic nitriles in the addition to a,P-unsaturated aldehydes and P-substituted nitro-olefins (Scheme 13). 

Other types of conjugate additions with chiral thioureas were also explored by Connon. P-Substituted nitro-olefms were used in the conjugate addition reaction with dimethyl chloromalonate 115 to generate chiral, functionalized nitrocyclopro-panes [73]. Utility of the nitrocyclopropanes was demonstrated in the one-step modification towards other functionalized chiral building blocks (Scheme 24). 

In the asymmetric addition to alkenylphosphonate 33 (Eq. 2) [25], the yield is dependent on the amount of water present. The combination of boroxine and water (1 equiv. relative to boron) gave a high yield of the desired product 34, with 96% enantiomeric excess. The alkylphosphonate 34 can be used as a chiral building block for the synthesis of optically active alkenes, using a Horner-Emmons type of reaction. 

The 2//-azirine may be optically active and therefore be regarded as a chiral building block for enatioselective synthesis. This opens a wide field of investigation and recently efforts have been made to produce optically pure azirines. Considering the anionic displacement as the main pathway (and not the nitrene pathway), the Neber reaction may be modified to serve as a synthetic tool for the production of optically active 2//-azirine intermediates. 

The hydrovinylation reaction, the codimerization of ethene and styrene (Scheme 2), provides easy access to chiral building blocks from inexpensive hydrocarbon feedstocks, which can be used further for the preparation of fine chemicals. Key problems in this reaction include the selectivity of the reaction and the stability of the catalyst. The main side reactions are oligomerization and isomerization of the product to internal achiral alkenes. The latter reaction can be suppressed by... 

For further work in the field of benzofurans see <99TA1521> (synthesis of TAK-218 using (i )-2-methylglycidyl tosylate as a chiral building block), <99SL495> (heterocyclic rubicene analogues) and <99S751> (synthesis of benzofuro[2,3-b]benzofuran derivatives under Hoesch reaction conditions). 

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