Variants diastereoselective

Whereas the halogen-lithium exchange is of limited importance for the generation of a-lithiated ethers, the reductive lithiation of 0/S-acetals has been applied more frequently, the versatility being enhanced by remarkable diastereoselective variants. Thus, a single diastereomer of the lithium carbenoid 52 results from the diastereomeric mixture 51 (equation 34) . Representative examples of a-lithiated ethers generated by this method and their reactions with electrophiles are given in Table 4. 

An accelerated diastereoselective variant of the amide acetal Claisen rearrangement is the reaction between the lithium alkoxide of ( )- or (Z)-2-butenol with salts derived from alkylation of propanamides or fluoroacetamides with methyl triflate or dimethyl sulfate. This reaction yields directly the [3,3] sigmatropic rearrangement products of the corresponding N.O-ketene acetals at room temperature, e.g., formation of 7/8 and 12/13 (Table 8)4fiI-462. 

The inter molecular nickel-catalyzed reductive coupling of aldehydes and alkynes has largely been examined with the reaction variants involving either EtaB with monodentate phosphines [22] or EtaSiH with NHCs [21]. Substantial advances in simple couplings, large fragment couplings, diastereoselective variants, directed processes, and asymmetric variants have been made and are detailed below. 

Most attempts to construct diastereoselective variants of the Passerini reaction have met with a certain degree of failure. Undoubtedly, the numerous uncertainties of the reaction mechanism have contributed to these difficulties. The usual low levels of control for the Passerini reaction have also impeded efforts to establish empirical trends in the diastereofacial selectivity. This is exemplified in the construction of peptidomimetics, a class of molecules which has stimulated numerous applications of the Passerini reaction, where the diastereoselectivity is typically in the range of 1 1 to 4 1, A survey of results of the diastereofacial selectivity of carbonyl addition does not consistently follow a clear trend of either the Felkin-Anh or chelation-controlled models of carbonyl addition. ... 

The development of catalytic, enantioselective C-H insertion reactions has been relatively slow in comparison with the diastereoselective variants described in Section 15.7. It was only in 1990 that McKervey reported the first such example in the context of an intramolecular ring closure (Equation 28) [51]. Exposure of 169 to chiral rhodium catalyst 170 thus afforded 171 in 12% ee. 

A similar but asymmetric variant of the reaction, involving the radical addition of alkyl iodides and trialkylboranes to chiral azirine esters derived from 8-phenyl-menthol and camphorsultam, in the presence of a Cu(i) catalyst, has subsequently been reported [64]. The diastereoselectivity of the addition is variable (0-92% de)... 

Bode and co-workers have extended the synthetic ntility of homoenolates to the formation of enantiomerically enriched IV-protected y-butyrolactams 169 from saccharin-derived cyclic sulfonylimines 167. While racemic products have been prepared from a range of P-alkyl and P-aryl substitnted enals and substitnted imi-nes, only a single example of an asymmetric variant has been shown, affording the lactam prodnct 169 with good levels of enantioselectivity and diastereoselectivity (Scheme 12.36) [71], As noted in the racemic series (see Section 12.2.2), two mechanisms have been proposed for this type of transformation, either by addition of a homoenolate to the imine or via an ene-type mechanism. 

Nair and co-workers have demonstrated NHC-catalysed formation of spirocyclic diketones 173 from a,P-unsaturated aldehydes 174 and snbstitnted dibenzylidine-cyclopentanones 175. Where chalcones and dibenzylidene cyclohexanones give only cyclopentene products (as a result of P-lactone formation then decarboxylation), cyclopentanones 175 give only the spirocychc diketone prodncts 173 [73]. Of particular note is the formation of an all-carbon quaternary centre and the excellent level of diastereoselectivity observed in the reaction. An asymmetric variant of this reaction has been demonstrated by Bode using chiral imidazolium salt 176, obtaining the desymmetrised product with good diastereo- and enantioselectivity, though in modest yield (Scheme 12.38) [74],... 

An enantioselective variant of the diene cydization reaction has been developed by application of chiral zirconocene derivatives, such as Brintzinger s catalyst (12) [10]. Mori and co-workers demonstrated that substituted dial-lylbenzylamine 25 could be cyclized to pyrrolidines 26 and 27 in a 2 1 ratio using chiral complex 12 in up to 79% yield with up to 95% ee (Eq. 4) [ 17,18]. This reaction was similarly applied to 2-substituted 1,6-dienes, which provided the analogous cyclopentane derivatives in up to 99% ee with similar diastereoselectivities [19]. When cyclic, internal olefins were used, spirocyclic compounds were isolated. The enantioselection in these reactions is thought to derive from either the ate or the transmetallation step. The stereoselectivity of this reaction has been extended to the selective reaction of enantiotopic olefin compounds to form bicyclic products such as 28, in 24% yield and 59% ee after deprotection (Eq. 5) [20]. 

An interesting variant involves the use of an allylic alcohol as the alkene component. In this process, re-oxidation of the catalyst is unnecessary since the cyclization occurs with /Uoxygen elimination of the incipient cr-Pd species to effect an SN2 type of ring closure. Both five- and six-membered oxacycles have been prepared in this fashion using enol, hemiacetal, and aliphatic alcohol nucleophiles.439,440 With a chiral allylic alcohol substrate, the initial 7r-complexation may be directed by the hydroxyl group,441 as demonstrated by the diastereoselective cyclization used in the synthesis of (—)-laulimalide (Equation (120)).442 Note that the oxypalladation takes place with syn-selectivity, in analogy with the cyclization of phenol nucleophiles (1vide supra). 

The first chapter in this volume is a particularly timely one given the recent surge of activity in natural product synthesis based upon stereocontrolled Aldol Condensations. D. A. Evans, one of the principal protagonists in this effort, and his associates, J. V. Nelson and T. R. Taber, have surveyed the several modem variants of the Aldol Condensation and discuss models to rationalize the experimental results, particularly with respect to stereochemistry, in a chapter entitled Stereoselective Aldol Condensations. The authors examine Aldol diastereoselection under thermodynamic and kinetic control as well as enantioselection in Aldol Condensations involving chiral reactants. 

The ability to produce 1,3-dipoles, through the rhodium-catalyzed decomposition of diazo carbonyl compounds, provides unique opportunities for the accomplishment of a variety of cycloaddition reactions, in both an intra- and intermolecular sense. These transformations are often highly regio- and diastereoselective, making them extremely powerful tools for synthetic chemistry. This is exemplified in the number of applications of this chemistry to the construction of heterocyclic and natural-product ring systems. Future developments are likely to focus on the enantioselective and combinatorial variants of these reactions. 

The use of chiral Br0nsted acids is illustrated in Eq. 93 as a method for catalyst-controlled double diastereoselective additions of pinacol allylic boronates. Aside from circumventing the need for a chiral boronate, these additions can lead to very good amplification of facial stereoselectivity. For example, compared to both non-catalyzed (room temperature, Eq. 90) and SnCU-catalyzed variants, the use of the matched diol-SnCU enantiomer at a low temperature leads to a significant improvement in the proportion of the desired anti-syn diastereomer in the crotylation of aldehyde 117 with pinacolate reagent (Z)-7 (Eq. 93). Moreover, unlike reagent (Z)-ll (Eq. 91) none of the other diastereomers arising from Z- to E-isomerization is observed. 

Allylic chromium species can also add to aldehydes. In this regard, an efficient catalytic enantioselective variant using allylic halides as substrates and manganese as co-oxidant has been described recently (Eq. 117). This method provides high enantiomeric excesses in the simple allylation of a wide range of aliphatic, aromatic, and heteroaromatic aldehydes. Crotylation examples are also very enantioselective, albeit with modest anti/syn diastereoselectivity. 

The intramolecular variant of ester enolate alkylations is a very useful ring-forming reaction. It can often be carried out under milder conditions than the corresponding intermolecular alkylation. Yields and diastereoselectivities are usually high. 

Michael addition of a dithiane anion 20, generated from the dithiane 19 with butyllithium, to the butenolide 21 creates the enolate 22 which has been efficiently alkylated in situ by 3,4,5-trimethoxybenzyl chloride to give 24 (mp 146-146.5 °C) in 65% overall yield. Protona-tion of 22 furnished the Michael adduct 23, which again can be deprotonated16 with LDA at — 78 °C to give 22 and alkylated (trimethoxybenzyl chloride, THF, HMPA, 3 h at — 78 °C, 18 h at 20 °C) to yield 24. Both variants are equally completely diastereoselective giving rise to the trans- product. 

---