Nucleophilic addition reactions stereocontrol

We reasoned that some cyclic enone sulfoxides should form an even more rigid chelate than that formed from the corresponding acyclic alkenyl sulfoxides when complexed with metal ions model exemplifies the case for a cyclopentenone sulfoxide and suggests a high degree of stereocontrol during the nucleophilic addition reaction. 

The proposed biosyntheses of ether-containing natural products employ enzymes to introduce epoxide groups with complete stereocontrol and, in some cases, to dictate the regioselectivity of the nucleophilic addition reactions. Chemical mimicry of these pathways reqnires extensive understanding of the fundamental structural relationships for epoxide reactivity toward tetherednucleophiles. Additionally,... 

Addition of Heterocyclic Compounds Stereocontrolled nucleophilic addition of heterocyclic compounds to chiral nitrones is of great synthetic importance in the synthesis of natural and biologically active compounds. In these reactions, the nitrone group serves as an amino group precursor and the heterocycle furnishes the formyl group (from thiazole) (192, 195, 214, 215, 579) or the carboxyl group (fromfuran) (194-196, 580-584) (Scheme 2.149). 

The introduction of umpoled synthons 177 into aldehydes or prochiral ketones leads to the formation of a new stereogenic center. In contrast to the pendant of a-bromo-a-lithio alkenes, an efficient chiral a-lithiated vinyl ether has not been developed so far. Nevertheless, substantial diastereoselectivity is observed in the addition of lithiated vinyl ethers to several chiral carbonyl compounds, in particular cyclic ketones. In these cases, stereocontrol is exhibited by the chirality of the aldehyde or ketone in the sense of substrate-induced stereoselectivity. This is illustrated by the reaction of 1-methoxy-l-lithio ethene 56 with estrone methyl ether, which is attacked by the nucleophilic carbenoid exclusively from the a-face —the typical stereochemical outcome of the nucleophilic addition to H-ketosteroids . Representative examples of various acyclic and cyclic a-lithiated vinyl ethers, generated by deprotonation, and their reactions with electrophiles are given in Table 6. 

The activation of the carbonyl group by Lewis acids was another leap made in the 1960s as typified by Mukaiyama-aldol reaction. In sharp contrast to the conventional carbonyl addition reactions that had been run under basic conditions, this new method allowed the addition of various nucleophiles under acidic conditions with high chemo- and stereocontrol and, consequently, the scope of the carbonyl addition reaction was extensively expanded. The Lewis acid-promoted ally-lation with allylmetals and ene reaction also received as much attention as the aldol-type reaction. It should be further pointed out that the catalytic versions of asymmetric reactions, which represent one of the most exciting topics in recent synthetic chemistry, owe their development strongly to the Lewis acid activation protocol. The design of a variety of chiral ligands for metals has produced luxuriant fruits in this field. 

Hydride abstraction from dienyl tricarbonyl iron complexes furnishes cationic dienyl tricarbonyl iron complexes. For example, reaction of the diene - iron tricarbonyl complex (115) with triphenylmethyl hexafluorophosphate followed by trimethylsilyl cyanide furnished with excellent regio- and stereoselectivity a new diene-iron tricarbonyl complex (116) (Scheme 170). Excellent regio- and stereoselectivity is seen upon reaction of the cationic complex (116) with trimethylsilyl cyanide (TMS-CN) (Scheme 170). Reduction of the nitrile affords a spirocyclic lactam complex. Intramolecular cyclization of in situ formed enols furnishes spirocyclic compounds again with excellent stereocontrol (Scheme 171). An interesting example of hydride transfer from a cyclohexadiene ring to a pendant aldehyde followed by nucleophilic addition is seen in Scheme 172. 

Alkylideneindolones are particularly good electrophiles, especially toward Michael additions, and therefore constitute excellent starting materials for the synthesis of spirooxindoles by multiple bond-forming approaches. The general strategy of the cascade reactions consists of an initial Michael reaction followed by a nucleophilic addition of the in situ formed enolate intermediate to various electrophiles. In the last years, several electrophilic partners with different scaffolds that lead to formal cyclizations, such as [3+2] cycloadditions [8a], Diels-Alder reactions [8b], and cyclopropanation [8c], have been used to afford a plethora of new spirooxindole scaffolds with excellent stereocontrol. 

Nucleophilic addition to the C-O double bond of carbonyl derivatives is one of the most widely used C-C-bond forming reactions in organic synthesis. The synthetic value of this process lies particularly on the stereocontrolled formation of a new C-O-chiral center when aldehydes or ketones are used. On the other hand, carbonyl derivatives themselves can serve as nucleophiles leading to new carbon-carbon bonds and thus expanding the synthetic scope of these functional groups. The explanation of the underlying basic principles in terms of reactivity and stereochemical models is beyond the scope of this book and will not be discussed in the following chapter since many textbooks cover these issues. Instead, we wish to provide the practitioner with examples that detail the delicate relationship of an individual, unique structure with its special reactivity delineated thereof... 

Lewis acid 71. This procedure gave the corresponding seven-membered products 72 with high enantio- and diastereoselectivity (Scheme 49) [83]. This reaction involves (1) the nucleophilic addition of 70 to acid activated cyclohexanones and (2) the subsequent 1,2-skeletal rearrangement of diazonium intermediate with the evolution of nitrogen. It should be noted that this protocol overcame the difficulty of stereocontrolled addition to symmetric ketones without a prochiral face. 

Recently, Lin et al. demonstrated that the propargyl alcohol could participate in such a transformation for the synthesis of chiral dihydrofurans [53]. The reaction began with a challenging oxa-Michael addition to cinnamaldehyde derivatives, which was followed by a secondary amine/Pd complex-catalyzed nucleophilic addition/ isomerization of the alkyne moiety in excellent yields and enantioseleclivities (Scheme 9.58). Since the oxa-Michael addition of propargyl alcohol to 0[,P-unsaturated aldehydes was a slow process, this cascade reaction proceeded through a dynamic kinetic asymmetric transformation (DYKAT) process, whereby it made the overall reaction proceed efficiently and with high stereocontrol using the second reaction with precise stereocontrol to shift the first reversible oxa-Michael addition selectively. 

Nucleophilic additions to a,3-dialkoxy aldehydes via allyl silanes (eq 3) or silyl ketene acetals (Mukaiyama reaction) (eq 4) exhibit similarly high selectivities. a-Thio aldehydes also react under MgBr2-catalyzed Mukaiyama conditions with efficient stereocontrol (eq 5). ... 

The organochromium complex 47 provides a good example of remote addition to an j " complex (Scheme 14.18) with stereocontrolled reaction with the nucleophile and trapping the anion [198]. Similar examples have been reported by Uemura s group [199], establishing the general principles of remote nucleophile addition to tf Cr(CO)3 complexes. An example from Muller in Munich has used this effect to add PrS" to an allenylbenzene ligand [200]. 

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