Vicinal quaternary stereocenters

A catal34ic asymmetric Nazarov cyclisation of fully-substituted die-nones (297) that provided cyclopentenone derivatives (298) with vicinal quaternary stereocenters in high optical purity and as single diastereo-isomers, has been carried out in the presence ofiV-triflyl phosphoramide (299) (Scheme 80). ... 

A direct catalytic asymmetric aldol-type reaction of 3-substituted-2-oxindoles with glyoxal derivatives was catalyzed by a similar chiral )V,A -dioxide-Sc(OTf)3 complex (eq 33). The complex efficiently catalyzed the aldol reaction affording the 3-(a-hydroxy-/3-carbonyl) oxindoles with vicinal quaternary-tertiary stereocenters, in up to 93% yield, 99 1 dr, and >99% ee under mild conditions. 

The first step of the proposed synthesis is the intermolecular Michael reaction of 2-substituted p-ketoesters and p-substituted enones, which results in vicinal quaternary and tertiary stereocenters. Michael reactions of this type are challenging, due to the increased sterics. In fact, only a few asymmetric examples have been reported to constract these motifs (Scheme The only success-... 

With the catalyst of choice and optimal reaction conditions identified, the scope and limitations of the enantioselective Michael reaction were investigated (Schemes 6-10). As examples of asymmetric Michael reactions of 2-substituted p-ketoesters and p-substituted enones resulting in vicinal quaternary and tertiary stereocenters are limited (vide supra), demonstrating the utility of these reaction conditions would be beneficial. 

Such reactions would generate Michael adducts possessing vicinal aU-carbon quaternary stereocenters. In the literature, transformations of this type are unprecedented under ambient conditions. These Michael reactions can happen only under ultrahigh pressures (>15kbar) with stoichiometric base as a promoter however, the Michael adducts are typically unstable under these conditions and further cyclize to form functionalized cyclohexenone. For example, the Dauben group explored a DBN-promoted Michael reaction of 20 and mesityl oxide (21a) that resulted in the formation of cyclohexenone 23 through the intermediacy of Michael adduct 22 (Scheme 9). This reaction did not proceed at ambient pressure and happened only when the reaction vessel containing the solution of 20 and 21a with DBN was compressed to 15 kbar with hydraulic press. 

Remarkably, bis(oxazoline)copper(II) complex H was found to catalyze a reaction of mesityl oxide 21a and structurally similar ketone 22b and ethyl 2-oxocyclopentane-l-carboxylate (Scheme 10). This transformation proceeded at ambient pressure and temperature in synthetically useful yields in 72 h. Compared to examples that generated Michael adducts with vicinal quaternary and tertiary stereocenters, the formation of vicinal all-carbon quaternary stereocenters was accomplished in lower enantiomeric excess. However, cOTisidering the unprecedented mode of reactivity achieved with Cu(II) catalysts in these studies, this reaction is clearly of great synthetic utility. 

Studies reporting substituent effects on the palladium- and copper-catalysed Sonogashira coupling reaction between an aryl iodide and an alkyne the 5 2 allylic substitution reactions between benzyl amine and racemic allyl carbonates substituted with a j -X-Ph- group on C(l) in the presence of a Rh(15,15, 2/ ,2/ -tangphos)(COD)Bp4 catalyst the stereoselective 5 2 reactions between a-substituted linear 0-ketoesters and meta- and /Jura-substituted cinnamyl carbonates generating vicinal quaternary and tertiary stereocenters in the presence of an Ir-V-arylphosphoramidite catalyst, TBD, and LiOBu-t identity vinyl halide reactions the S N... 

In addition to protonation, a postdoc in the lab, Jan Streuff, explored the use of our catalytically generated enolate in the context of conjugate additions [31]. While the scope of Michael acceptors reactive enough to be intercepted by our chiral enolate complex was limited, we were able to demonstrate a highly diastereo- and enantioselective S3mthesis of vicinal quaternary and tertiary stereocenters with a number of allyl p-ketoesters. In particular, the most enantio- and diastereoselective reactions of this type were observed with 4-piperidinone-derived pronucleophiles (Scheme 10). 

The resulting derivatives (269) can be considered as strategically important intermediates in the synthesis of glycosidase inhibitors and carbocyclic nucleosides (150). A new approach to the stereoselective synthesis of the piperidine ring with the use of [4+ 2] [3+ 2]-cycloaddition from specially prepared substrates is also very interesting (431)b, c. In the context of this problem, the conditions for the formation of systems containing quaternary vicinal stereocenters were found. 

As a key intermediate in an approach to the communesins, Weitrreb and co-workers have constructed the all-carbon quaternary center of oxindole 166. The tandem Heck cyclization/carbonylation sequence illustrated in Scheme 41 provided 165 as a single stereoisomer in 79% yield [95]. Further manipulation of 165 revealed the vicinal pair of all-carbon stereocenters housed within 166. An approach to the synthesis of ( )-cotnmrmesin F has been reported by the same group [96]. 

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