Amination intermolecular-asymmetric

Intermolecular asymmetric aminations are at an early stage of development, and consequently much lower turnover frequencies and catalytic yields have been observed at this stage. In the example shown, a key aspect is the activation of the iridium complex catalyst by fluoride ion [111] (Scheme 38). 

One of the most studied processes is the direct intermolecular asymmetric aldol condensation catalysed by proline and primary amines, which generally uses DMSO as solvent. The same reaction has been demonstrated to also occur using mechanochemical techniques, under solvent-free ball-milling conditions. This chemistry is generally referred to as enamine catalysis , since the electrophilic substitution reactions in the a-position of carbonyl compounds occur via enamine intermediates, as outlined in the catalytic cycle shown in Scheme 1.1. A ketone or an a-branched aldehyde, the donor carbonyl compound, is the enamine precursor and an aromatic aldehyde, the acceptor carbonyl compound, acts as the electrophile. Scheme 1.1 shows the TS for the ratedetermining enamine addition step, which is critical for the achievement of enantiocontrol, as calculated by Houk. ... 

The first amine-catalyzed, asymmetric intermolecular aldol reactions were developed by List et al. in 2000 [29-33]. Initially it was found that excess acetone in DMSO containing sub-stoichiometric amounts of (S)-proline reacted with some aromatic aldehydes and isobutyraldehyde to give the corresponding acetone aldols (134) with good yields and enantioselectivity (Scheme 4.25). Particularly high ee were achieved with a-branched aldehydes. Similarly to the intramolecular enolendo variant, the only side-product in proline-catalyzed intermolecular aldol reactions are the condensation products (Scheme 4.25). 

Intermolecular asymmetric hydroamination provides chiral acyclic amines, whereas intramolecular asymmetric hydroamination provides chiral cyclic amines. 

Scheme 9.21 Sequential intermolecular and intramolecular asymmetric allylic aminations.

Oxidative amination of carbamates, sulfamates, and sulfonamides has broad utility for the preparation of value-added heterocyclic structures. Both dimeric rhodium complexes and ruthenium porphyrins are effective catalysts for saturated C-H bond functionalization, affording products in high yields and with excellent chemo-, regio-, and diastereocontrol. Initial efforts to develop these methods into practical asymmetric processes give promise that such achievements will someday be realized. Alkene aziridina-tion using sulfamates and sulfonamides has witnessed dramatic improvement with the advent of protocols that obviate use of capricious iminoiodinanes. Complexes of rhodium, ruthenium, and copper all enjoy application in this context and will continue to evolve as both achiral and chiral catalysts for aziridine synthesis. The invention of new methods for the selective and efficient intermolecular amination of saturated C-H bonds still stands, however, as one of the great challenges. 

It is true that highly enantioselective reactions are possible with proline in the asymmetric a-amination of aldehydes by azodicarboxylates and in a-oxidation with nitrosobenzene. However, good rather than excellent yields and enantioselectivities are more common in intermolecular Michael and aldol reactions. Moreover, the high catalyst loadings required for proline-catalyzed aldol reactions (up to 30%), and low TOFs (from hours to days to achieve a good conversion, even at a high catalyst... 

Surprisingly, the catalytic potential of proline (1) in asymmetric aldol reactions was not explored further until recently. List et al. reported pioneering studies in 2000 on intermolecular aldol reactions [14, 15]. For example, acetone can be added to a variety of aldehydes, affording the corresponding aldols in excellent yields and enantiomeric purity. The example of iso-butyraldehyde as acceptor is shown in Scheme 1.4. In this example, the product aldol 13 was obtained in 97% isolated yield and with 96% ee [14, 15]. The remarkable chemo- and enantioselectivity observed by List et al. triggered massive further research activity in proline-catalyzed aldol, Mannich, Michael, and related reactions. In the same year, MacMillan et al. reported that the phenylalanine-derived secondary amine 5 catalyzes the Diels-Alder reaction of a,/>-un saturated aldehydes with enantioselectivity up to 94% (Scheme 1.4) [16]. This initial report by MacMillan et al. was followed by numerous further applications of the catalyst 5 and related secondary amines. 

Asymmetric intermolecular Pauson Khand reactions have been reahzed using a number of chiral auxiliaries chelating to the metal and/or attached to the alkyne. One example using a camphor-derived hgand is seen in Scheme 253. Moderate asymmetric induction has been observed using chiral amine A-oxides as the promoter. For example, (-F)-indohzino[3,4-b]quinoline A-oxide gave up to 53% ee. 

In the crystal of CpSnCl, the tin is unsymmetrically associated by one intramolecular short bond and two intermolecular long bonds to three chlorine atoms as shown in 21-65.106 Similarly, the cyclopentadienyl ring in the tin amine 21-66 is asymmetrically r -bonded.107... 

As already mentioned, there has been significant progress in the development of chiral catalysts for asymmetric hydroamination reactions over the last decade. However, significant challenges remain, such as asymmetric intermolecular hydro aminations of simple nonactivated alkenes and the development of a chiral catalyst, which is applicable to a wide variety of substrates with consistent high stereochemical induction and tolerance of a multitude of functional groups as well as air and moisture. Certainly, late transition metal based catalysts show promising leads that could fill this void, but to date, early transition metal based catalysts (in particular, rare earth metals) remain the most active and most versatile catalyst systems. 

This chapter will highlight recent efforts to develop metal-mediated processes for selective C-H amination. Other excellent, comprehensive reviews can be found on this topic [3, 8-10]. To distinguish this discourse from prior works, we have opted to focus attention on the diversity of catalysts that are now known to mediate racemic and asymmetric intra- and intermolecular oxidation reactions. Where possible, mechanistic insights that elucidate the role of the metal catalyst and the details of the defining bond-forming event will be presented. It is our hope that this analysis will serve to inspire additional inventive discoveries in this rapidly progressing field - advances that may change the art and practice of complex molecule assembly. 

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