Stereoselective Metallation

Ugi has coined the term stereorelating synthesis for the sequence lithiation/reac-tion with electrophiles [62,118], and used this technique as a method for the chemical correlation of the structure and for the determination of the enantiomeric purity of many 1,2-disubstituted ferrocene derivatives obtained either by resolution or by asymmetric synthesis (for a compilation, see [118]). It is important to note that all stereochemical features discussed above for central chiral compounds, such as retentive nucleophilic substitution, remain valid when more substituents are present at the ferrocene ring and the conversion of functional groups in planar chiral ferrocenes can be achieved by the same methods as described. 

A first attempt towards an asymmetric synthesis by the lithiation reaction used (— )-spartein as a chiral additive [12,13], but the enantioselectivity was disappointing. With the chiral (S)-M-ferrocenylmethyl-2-methylpiperidine, a high diastereoselec-tivity was observed [12, 13, 112] (note that the polemic about the structure of the product is due to different stereochemical nomenclature, i.e., central vs. planar , as discussed in Sect. 4.1). A breakthrough was achieved by the readily resolvable 

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The above literature review gives a comparison of different ways to control selectivity for both homogeneous and heterogeneous catalytic reactions. There are several common features for the four areas of stereoselectivity metal clusters, alloys and poisoning shape selectivity and reaction pathway control. In fact, many times more than one of these areas may be involved in a catalytic system. Some common features for all of these areas include precise control of the structural and compositional properties of the catalysts. This paper serves as an overview for the other manuscripts in this book. Specific review chapters on each of the four areas can be found in reviews that follow by D. Forster et al., K. J. Klabunde et al., M. E. Davis et al., and H. C. Foley and M. Klein et al. 

Regio- and stereoselective metal-mediated l,3-butadien-2-ylation reactions between 1,4-dibromo-2-butyne or l,4-bis(methanesulfonyl)-2-butyne and optically pure azetidine-2,3-diones in aqueous media offers a convenient asymmetric entry to potentially bioactive 3-substituted-3-hydroxy-p-lactams 19 <02JOC1925>. In addition, 2-azetidinone-tethered 1,3-butadienes can easily be transformed into other functionalities via Diels-Alder reaction. 

A new approach to /3-alkyl substituted a-methoxy vinyllithiums 540 with Z-configuration involved the stereoselective metallation of a-bromo vinyl ethers 539, prepared from acetylenes 538, with f-BuLi at — 78 °C (Scheme 145)821. These anions react with different electrophiles to give the corresponding vinyl ethers in good yields. The /3-isobutyl substituted derivative as cuprate has been added to an enone in the total synthesis of the anticancer natural product OSW-1822. 

In addition to stereoselective metalation, other methods have been applied for the synthesis of enantiomerically pure planar chiral compounds. Many racemic planar chiral amines and acids can be resolved by both classical and chromatographic techniques (see Sect. 4.3.1.1 for references on resolution procedures). Some enzymes have the remarkable ability to differentiate planar chiral compounds. For example, horse liver alcohol dehydrogenase (HLADH) catalyzes the oxidation of achiral ferrocene-1,2-dimethanol by NAD to (S)-2-hydroxymethyl-ferrocenealdehyde with 86% ee (Fig. 4-2la) and the reduction of ferrocene-1,2-dialdehyde by NADH to (I )-2-hydroxymethyl-ferrocenealdehyde with 94% ee (Fig. 4-2lb) [14]. Fermenting baker s yeast also reduces ferrocene-1,2-dialdehyde to (I )-2-hydroxymethyl-ferro-cenealdehyde [17]. HLADH has been used for a kinetic resolution of 2-methyl-ferrocenemethanol, giving 64% ee in the product, (S)-2-methyl-ferrocenealdehyde... 

It is useful to classify stereoselective reactions as a preliminary step to identifying the factors influencing stereoselectivity. Metals are intimately involved in almost all highly stereoselective reactions, so our classification will begin there. 

This work represents a landmark in the area of stereoselective metal-free (i.e., aminocatalysis) alkylation of benzenes based on Michael-type condensation via covalent catalyst-substrate interaction [22]. Subsequently, asymmetric acid catalysis based on hydrogen bond catalyst-substrate recognitions has found elegant applications in 1,4-conjugated additions and direct condensation of arenes with carbonyl compounds. The following sections will be organized based on the reactivity exploited in the arene functionalization. 

Trofimov, B. A., Andriyankova, L. V., Nikitina, L. P., Belyaeva, K. V., Mai kina, A. G., Afonin, A. V., and Ushakov, I. A. (2012). Stereoselective metal-fiee reaction of imidazoles with isothiocyanates involving cyanophenylacetylraie A shortcut to iV-(Z-alkenyl)imidazole-2-carbothioamides. Synlett, 23, 2069-2072. 

As we will see in the following, different groups have been interested in developing stereoselective metal-catalyzed methods to reach this framework. 

The second part of this chapter is dedicated to stereoselective, metal-assisted MBFTs leading to spirocyclic compounds containing an a-heteroatom-substituted spirocenter (Figure 9.3). 

Having highlighted the different stereoselective metal-mediated MBFT approaches to reach aza- or oxa-spirocyclic compounds, we now review the different strategies to build, in a step-economical manner, spiroacetal and aminal derivatives. As stated earlier, the last part of this chapter is dedicated to the organometallic stereoselective... 

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