Nucleophilic attack chiral enolate

If racemization were observed, it could only be due to a cleavage of one of die bonds to the chiral center prior to carbon-nitrogen bond formation or subsequent to it. This could occur by (a) enolization of the starting tridate, (b) an ionization of tridate to a carbocation and dien nucleophilic attack by die azide, or (c) enolization in the azido product. The fact that clean inversion occurs means not only that the substitution by azide occurs with inversion but also diat none of diese odier processes is signidcant under the reaction conditions since they would lead to racemized product. 

The stereochemistry of conjugate additions requires similar considerations to those used to predict nucleophilic attack on a carbonyl. Acyclic substrates may yield up to three contiguous chiral centres (Scheme 18). The relative stereochemistry of carbons C(l) and C(2) will depend upon the approach of the two reagents. The stereochemistry of carbon C(3) will depend upon the lifetime of the intermediate 30 if it has even a short lifetime it will take up the most stable conformation. For example, the base-catalysed additions of ethanol-d and 2-methyl-2-propanethiol-d to ethyl crotonate give a (2R, 3R )/(2R, 3S ) diastereoisomeric ratio of the addition products of approximately 10 190. The authors90 suggest the reaction proceeds in two steps and the protonation of the enolate determines the stereoselectivity. 

Similar to the addition reactions of acceptor-substituted dienes (Scheme 16), the outcome of the transformation depends on the regioselectivity of the nucleophilic attack of the organocopper reagent (1,4- vs. 1,6-addition) and of the electrophilic capture of the enolate formed. The allenyl enolate obtained by 1,6-addition can afford either a conjugated diene or an allene upon reaction with a soft electrophile, and thus opens up the possibility to create axial chirality. The first copper-mediated addition reactions to Michael acceptors of this type, for example, 3-alkynyl-2-cyclopentenone 75,... 

The enantioselectivity associated with quaternary allylation is connected with scenario 5 above (one of the five points associated in the catalytic cycles shown by Schemes 12.10a and b where chirality could be induced), which is where enantioselection of one of two faces of the nucleophile (the enolate ion) occurs. Theoretical studies of the transformation using the PHOX ligand have shown support for an inner sphere mechanism, where nucleophilic attack of the enolate onto the rf-allyl ligand occurs from the Pd-bound enolate and not from an external nucleophile.74 These studies have not been able to definitively determine the step that defines the enantioselectivity of the reaction, and it is not clear how these results would carry over to reactions involving the Trost ligands. At this time, selection of which ligand one should use not only to induce enantioselectivity but also to predict the sense of absolute configuration of any asymmetric Tsuji-Trost allylation is mostly based on empirical results. Work continues on this... 

The preceding reactions dealt with the use of chiral auxiliaries linked to the electrophilic arene partner. The entering nucleophile can also serve as a chiral controller in diastereoselective SjjAr reactions. This approach was successfully employed for the arylation of enolates derived from amino acids. To illustrate the potential of the method, two examples have been selected. Arylation of Schollkopf s bislactim ether 75 with aryne 77 as electrophilic arylation reagent was demonstrated by Barrett to provide substitution product 81 with good yield (Scheme 8.18) [62, 63]. Aryne 77 arises from the orf/jo-lithiation of 76 between the methoxy and the chlorine atom followed by elimination of LiCl. Nucleophilic attack of 77 by the lithiated species 78 occurs by the opposite face to that carrying the i-Pr substituent. Inter- or intramolecnlar proton transfer at the a-face of the newly formed carbanion 79 affords the anionic species 80. Subsequent diastereoselective reprotonation with the bulky weak acid 2,6-di-f-butyl-4-methyl-phenol (BHT) at the less hindered face provides the syn product 81. Hydrolysis and N-Boc protection give the unnatural arylated amino acid 82. The proposed mechanism is supported by a deuterium-labeling experiment. Unnatural arylated amino acids have found application as intermediates for the construction of pharmaceutically important products such as peptidomi-metics, enzyme inhibitors, etc. [64, 65]. 

The commonly accepted mechanism for the Steglich rearrangement, depicted in Scheme 40.2, involves a fast and reversible attack of the nucleophilic catalyst to the acyl of alkoxycarbonyl group, leading to an ion pair that in a slow irreversible step leads to the formation of the C4- or C2-substituted azlactone. If the nucleophile is chiral, the acyl cation can discriminate between the two enantiotopic faces of the azlactone enolate, affording enantiomerically enriched products. 

Analogous results were obtained for enol ether bromination. The reaction of ring-substituted a-methoxy-styrenes (ref. 12) and ethoxyvinylethers (ref. 10), for example, leads to solvent-incorporated products in which only methanol attacks the carbon atom bearing the ether substituent. A nice application of these high regio-and chemoselectivities is found in the synthesis of optically active 2-alkylalkanoic acids (ref. 13). The key step of this asymmetric synthesis is the regioselective and chemoselective bromination of the enol ether 4 in which the chiral inductor is tartaric acid, one of the alcohol functions of which acts as an internal nucleophile (eqn. 2). 

The conversion of an a, -unsaturated aldehyde or ketone into an allylic acetal or ketal, followed by SN2 -type attack of a nucleophile, leads, after hydrolysis of an initially formed enol ether, to a fi-sub-stituted carbonyl compound. The overall sequence (Scheme 23) is equivalent to a direct conjugate addition, but has the advantage that it allows the temporary introduction of a chiral auxiliary group if a chiral (C2-symmetric) diol is used in the acetalization step, die subsequent nucleophilic addition leads to a mix-... 

The two 7t-faces of an aldehyde or of a ketone with at least one stereogenic center are diastereotopic. As a result, the Re and Si attack by an achiral nucleophile (i.e., L1A1H4, EtMgBr, PhLi) or an achiral enolate ion differ in energy, so unequal amounts of products are formed (A B 1). The ratio of products reflects the bias of the chiral substrate to undergo preferential addition on one diastereotopic face. 

Addition to C=N. Imine derivatives which contain a chirality center adjacent to, or one atom away from the nitrogen atom are attacked by nucleophiles enantioselectively. Examples include p-toluenesulfinimines " and 42, 43, and 447 Reaction of lithium ester enolates with imines in the presence of the Cj-symmetric dimethoxybibenzyl leads to P-lactams in good ee, and a bis(aziridine) ligand is useful for enantioselective addition of RLi to imines. ... 

A wide variety of nucleophiles add to an -rf-allyl ligand. Desirable nucleophiles typically include stabilized carbanions such as CH(COOR)2 or 1° and II0 amines. Unstabilized nucleophiles such as MeMgBr or MeLi often attack the metal first and then combine with the n-allyl by reductive elimination. The Tsuji-Trost reaction, which is typified by the addition of stabilized carbanions to T 3—allyl ligands complexed to palladium followed by loss of the resulting substituted alk-ene, comprises an extremely useful method of constructing new C-C bonds, and many applications of this reaction have appeared in the literature.61 Equation 8.43 illustrates an example of a Pd-catalyzed addition of a stabilized enolate to an allyl acetate.62 The initial step in the catalytic cycle is oxidative addition of the allyl acetate to the Pd(0) complex, followed by nq1 to nq3—allyl isomerization, and then attack by the nucleophile to a terminal position of the T 3—allyl ligand. We will discuss the Tsuji-Trost reaction, especially in regard to its utility in chiral synthesis,63 more extensively in Chapter 12. 

Decide how the reaction influences symmetry. Is symmetry created, destroyed or even left unchanged If a molecule contains a mirror plane, for instance, and the new bonds are made within the mirror plane we can expect the symmetry element to be retained. However, attack at one side or other of the mirror plane will naturally destroy it. Ketone 65 has mirror plane that slices through the ring 65a. The mirror plane contains the carbonyl and the central carbon of the tert-butyl group. If we attack the carbonyl with a nucleophile, the nucleophile will have a line of attack that is within the mirror plane and the resulting alcohol 67 will retain the mirror plane. This is not the case if we make an enolate 66. The proton must be removed from one side or the other and this will destroy the mirror plane. Notice that when this happens a chiral centre is formed where the tert-butyl group connects to the ring. 

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