Diels asymmetric variants

The aza-Diels-Alder reaction is an important and versatile tool for the preparation of nitrogen-containing heterocycles present in numerous natural products and drug candidates. It involves the [4 + 2] cycloaddition of either an imine with an electron-rich diene or an azabutadiene with an electron-rich alkene (inverse electron demand). Catalytic asymmetric variants employing not only metal complexes, but also organic molecules were disclosed over the last few years. 

Chiral metal alkoxides M(OR)4 have been developed as asymmetric variants of ordinary Lewis acids, such as A1C13 and ZrCU, and are used as catalysts for selective carbon-carbon bond formation. Thus, starting from bidentate l,l -bi-2-naphthol derivatives (BINOL) and SnCU, a series of chiral tin(iv) aryloxides 221 (Figure 7) was prepared and successfully applied to the enantioselective Diels-Alder reaction <2006TL873>. Similar silocanes obtained from menthone- or camphor-derived 2,2 -biphenols have been obtained and their configuration was analyzed by NOE differential spectroscopy (NOEDS) <1997JOC7156>. 

Kobayashi and coworkers exploited the use of lanthanide Lewis acid catalysts in various achiral reactions as described in the previous section, and they also successfully extended some of them into asymmetric variants. A series of their works commenced with catalytic asymmetric Diels-Alder reactions [50, 51]. The reaction was performed with a chiral ytterbium catalyst prepared from Yb(OTf)3, (R)-l,l -bi-2-naphthol (BINOL), and tertiary amine. The amine significantly influenced enantioselectivity of the reaction, and cis-l,2,6-trimethylpiperidine combined with 4 A molecular sieves (MS 4 A) aflhrded the best results (endo/exo = 89/11, endo = 95% ee, Yb catalyst A) (Scheme 13.20). Later, Nakagawa and coworkers improved reactivity and selectivity of the Yb catalyst by modification of chiral ligand. Use of l,l -(2,2 -bisacylamino)binaphthalene (Yb catalyst B) gave product in >98%ee [52]. 

The asymmetric Diels-Alder addition is a powerful tool of organic chemistry therefore, its variant using diaza dienophiles has also been studied. When chiral diene 562, derived from (A)-phenylethylamine, is allowed to react... 

The stereocontrolled synthesis of a-hydroxyakylated piperidines, a motif frequently encountered in natural products, represents a difficult synthetic challenge that was recently tackled by Hall and co-workers using the aza-variant of the Vaultier-Lallemand three-component reaction described in Scheme 12.14 [62]. One interesting feature of this reaction is the use of hydrazines, as masked amines, which allows the hetero-Diels-Alder reaction to operate on a normal electron demand manifold. Toure and Hall recently applied this powerful MCR to the asymmetric synthesis of (—)-methyl dihydropalustramate 192 [91], a degradation product and postulated biosynthetic precursor of (+)-palustrine (Scheme 12.27) [92]. 

The intramolecular Diels-Alder reaction is most frequently used in natural product total synthesis, and numerous examples will be described in the synthetic utility section. As with the intermolecular variant, intramolecular reactions are highly regioselective and stereoselective and participate in hetero, inverse electron demand, and asymmetric Diels-Alder reactions. One report from 2008 describes the investigation of an intramolecular hetero Diels-Alder reaction in ionic liquids. ... 

The versatility of the hetero-Diels-Alder reaction for the construction of a wide range of substituted, six-membered heterocycles has spurred intense investigations to develop enantioselective variants of this transformation [37]. The first reports of the use of chiral Lewis acids for the enantioselective catalysis of hetero-Diels-Alder reactions stem from investigations by Danishefsky [119, 120], During these studies, use of the chiral europium complex Eu(hfc)5 (204) as catalyst was found to result in significant asymmetric induction, as illustrated by the formation of cycloadduct 240 in 58% ee (Equation 24) [119]. 

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