Stereoselectivity inversion

Stereoselective inverse-demand hetero (4 + 2) cycloadditions. A Chiral Template for C-Aryl Glycoside Synthesis. Chiral allenamides2 4 had been used in highly stereoselective inverse-demand hetero (4 + 2) cycloaddition reactions with heterodienes.5 These reactions lead to stereoselective synthesis of highly functionalized pyranyl heterocycles. Further elaboration of these cycloadducts provides a unique entry to C-aryl-glycosides and pyranyl structures that are common in other natural products (Scheme 1). 

O-benzylidene-L-ribono-l,5-lactone [27]. Thus, in both examples a stereoselective inversion at C-4 had taken place. 

The reactivity of 47/-benzopyran-4-ones in Diels-Alder reactions is well documented <1987T3075>, and recently high asymmetric induction has been achieved in the reaction of 3-alkoxycarbonyl-substituted chromones with chiral auxiliaries and Danishefsky s diene <1991JOC2058>. It should be noted that 3-formylchromones can react as heterodienes in the stereoselective inverse electron Diels-Alder reaction with enol ethers <1994T11755> to provide a route to pyrano[4,3-A][l]benzopyrans a heterocyclic nucleus which occurs naturally in the fungal metabolite fulvic acid <1984CC1565>. The thermal Diels-Alder reaction of 477-pyran-4-one 405 in the presence of an excess of Danishefsky s diene 404 provided cycloadduct 406 (Equation 32) <1996H(43)745>. 

Various arylpropionic acids show similar specificity. For most, if not all, the (5) enantiomer is the pharmacologically active one, whereas the R) enantiomer is usually much less active, although the ratio of iS)/ R) activity varies from drug to drug (and species to species). Only one of these drugs, however, is administered as the separated (S) enantiomer (naproxen, Naprosyn ). Normally these drugs are considered safe, and one cannot readily differentiate between the relative activities of the (S) and (R) forms because the in vivo half-life is very short, typically one or two hours. In patients with impaired renal function, where clearance is much slower, however, problems can arise. From in vivo studies of ibuprofen, it was established that the (S)-(-l-) isomer was responsible for antiinflammatory activity. In vivo, however, the (/ )-(-) isomer may become active because there is stereoselective inversion from R) to (S) (but not from 5 to R) in vivo with a half-life of about two hours. This inversion apparently proceeds by stereoselective formation of the coenzyme A (CoA) ester of the (f )-(-)-arylpropionic acid, followed by epimerization and release of the (S)-(+)-enantiomer. This epimerization is observed in vivo before the oxidative metabolism. Such inversion from (R) to (S) in vivo is also known for fenoprofen and benoxa-profen, and is expected to occur for most of the drugs of this series. ... 

Athene synthesis. Alcohols can be alkylated or arylated by treatment with organolithium compounds and 1 (equation 1). The main interest in this synthesis is the reaction of allylic alcohols to form alkenes. The reaction is regioselective and stereoselective (inversion of configuration). 

More recently, Chen and co-workers reported an organocatalytic regio- and stereoselective inverse-electron-demand aza-Diels-Alder reaction of a,p-unsaturated aldehydes 28 and iV-tosyl-l-aza-1,3-butadienes 88, providing the enantiomerically pure piperidine derivatives 89, Scheme 3.33 [48]. 

Stereoselective Inversion of Configuration at More Than One Carbon... 

When o>-activated aldonolactones with six or more carbon atoms are treated with strong aqueous base, the primary epoxides of the polyhydroxy carboxylic acids first formed may rearrange to secondary epoxides, which can finally be opened at C-4 by the carboxylate in a five-membered transition state. The driving force, and thus the success of the stereoselective inversion at more carbon atoms in the polyhydroxy acids, is the final opening of an epoxide at C-4. The method has been used to prepare a number of less available aldonic adds/lac-tones, as illustrated in the following examples. 

Chen and coworkers presented a highly stereoselective inverse-electron-demand aza-hetero-Diels-Alder reaction of aldehydes 137 and a, 3-unsaturated imines 136 with the use of a chiral secondary amine 36 through enamine activation [62]. Excellent enantioselectivities can be achieved for a broad range of substrates (Scheme 38.40). Water is helpful in the hydrolysis of intermediate P to release... 

By employing the dienamine-catalysis strategy, Chen and coworkers accomplished an unprecedented and highly regio- and stereoselective inverse-electron-demand aza-hetero-Diels-Alder reaction of a,P-unsaturated imines 136 with a,P-unsaturated aldehydes 143 [66]. Various multifunctional piperidine derivatives 144 and 145 can be obtained, with excellent levels of enantioselectivity, that are potentially useful in the synthesis of natural products and medicinal chemistry (Scheme 38.43). 

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