Enantioselectivity five-membered heterocyclic

Much work in the review period has concerned enantioselective substitution in five-membered heterocyclics. The enantioselective alkylation of some pyrroles by unsaturated 2-acylimidazoles catalysed by the bis(oxazolinyl)pyridine-scandium(in) triflate complex (31) has been reported.39 Compound (33) is formed in 98% yield and 94% ee from the 2-acylimidazole (32) and pyrrole at —40 °C. A series of enantiomer- ically pure aziridin-2-ylmethanols has been tested as catalysts in the alkylation of /V-mclhylpyrrolc and (V-methylindole by ,/l-unsalura(cd aldehydes.40 Enantiomeric excesses of up to 75% were observed for the alkylation of /V-mcthylpyrrole by ( >crotonaldehyde using (2.S ,3.S )-3-mclhylazirin-2-yl(diphenyl)methanol TFA salt as catalyst to form (34). 

Under the same conditions, diisopropyl ether as the solvent was found to give the best results in terms of chemical yield and enantioselectivity. The absolute configuration of the stereogenic center of the major enantiomer was determined to be (J ) by chemical correlations with previously reported compounds [46]. An example of tin-lithium exchange followed by intramolecular carboHthiation of a carbon-carbon double bond as an efficient entry to the asymmetric synthesis of 3-hydroxy-pyrrolidines was reported by Hoppe et al. [47]. When the easily accessible enantioenriched stannane 173 was treated with n-butyUithium at low temperature, the five-membered heterocycle 174 was obtained in nearly quantitative yield and with excellent diastereo- and enantioselectivity (Scheme 10.57). 

Unsaturated lactone 74 (Scheme 7.21) can be viewed as an oxygen heterocyclic analogue of 2-cyclohexenone, and it has recently been reported that catalytic 1,4-additions of Et2Zn to 74 can indeed be accomplished with high enantioselectivity. For adduct 76, Reetz achieved a remarkable 98% ee when employing ferrocene-based diphosphonate ligand 23 [48]. Using diphosphite 24, Chan et al. achieved an ee of 92% for the six-membered lactone 74 and a 56% ee for the five-membered lactone 25 [49c]. 

Palladium(II)-promoted oxidative cyclization of alkenes bearing tethered nucleophiles represents an intramolecular variant of the Wacker reaction. These reactions, which typically generate five- and six-membered heterocycles, have been the subject of considerable interest in organic chemistry [89-96]. Contemporary interest centers on the development of enantioselective examples [95,97] and reactions that employ dioxygen as the sole oxidant for the Pd catalyst [92-96]. 

An -carbonyi radicai cyciization was the key step in C.-K. Sha s enantioselective total synthesis of the alkaloid (-)-dendrobine. The five-membered nitrogen heterocycle was installed during the final stages of the synthetic effort. The bicyclic azido alcohol intermediate was oxidized using the Jones reagent to give the corresponding azido ketone, which was converted in three steps to the natural product. 

The Rh-BINAP-catalyzed intramolecular Alder-ene cycloisomerization is very rapid and, therefore, sequentially Rh-catalyzed sequences for the efficient enantioselective generation of five-membered carbo- and heterocycles were envisioned. Korber et al. [21] reported the enantioselective rhodium-catalyzed cycloisomerization of alkyl and (hetero)aryl alkynyl allyl alcohols for the generation of aldehyde-bearing chiral 4-alkyl 3-alkylidene THFs and tetrahydro-furanones, which were converted into a,P-unsaturated carbonyl side chains in a one-pot manner via a concluding Wittig olefination in good yields. 

Conjugated aza-addition to a,P-unsaturated compounds constitutes one of the most important methods in C-N bond forming reactions. It was not until 2007 that the highly stereocontroUed intramolecular aza-Michael addition was disclosed via iminium catalysis [15aj. The reaction of carbamates 31 bearing an ot,P-unsaturated aldehyde moiety took place with good yields and excellent ees by catalysis of Jorgensen s catalyst 30. This process provides an efficient way for the enantioselective preparation of several five- and six-membered heterocycles 32 (Scheme 36.9). 

Recent advances in the synthesis of imino sugars, comprising the preparation of five- and six-membered heterocycles containing an en-docyclic nitrogen atom, authored by Slawomir Jarosz and coworker (Chapter 9) and amino sugar synthesis, with emphasis on diastereo- and enantioselectivity (Chapter 10) authored by Zbigniew Witczak and Roman... 

In 1993, we reported that various unsaturated heterocycles can be alkylated with Et-, wPr- and nBuMgCl in the presence of optically pure (EBTHI)ZrCl2 (3a) or (EBTHI)Zr-binol (3b) to afford the derived unsaturated products in >90% ee (cf. 5 6, Scheme 2) [4a]. Many of the simpler five- and six-membered starting materials are available commercially or can be prepared by established procedures. In contrast, catalytic enantioselective reactions involving unsaturated medium ring hetero cycles were not a trivial undertaking the synthesis of these olefinic substrates, by the extant methods, was prohibitively cumbersome. 

A variety of methods are available for the synthesis of heterocyclic carbonyl compounds by radical cyclization. For example, the cyclization of alkoxycarbonyl radicals is particularly useful for the synthesis of five- and six-membered ring lactones [80]. Recent applications of this cyclization method include Zard s photoly-tical transformation of an alkoxycarbonyl dithiocarbonate having a double bond which can serve as a key step in the synthesis of ( )-cinnamolide and RA. Evans s enantioselective synthesis of 4-hydroxy butenolide terminus, which is applicable to the synthesis of mucocin [81J. Amidyl radical cyclizations are frequently utilized for the synthesis of five- and six-membered ring lactams [82]. However, this section only focuses on recent methods for heterocyclic carbonyl compounds by an n-i-1 type strategy based on radical carbonylations. 

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