Deprotonation chiral substrates

A different mechanism operates in the direct a-heteroatom functionalization of carbonyl compounds when chiral bases such as cinchona alkaloids are used as the catalysts. The mechanism is outlined in Scheme 2.26 for quinine as the chiral catalyst quinine can deprotonate the substrate when the substituents have strong electron-withdrawing groups. This reaction generates a nucleophile in a chiral pocket (see Fig. 2.6), and the electrophile can thus approach only one of the enantiotopic faces. 

A similar case of enolatc-controlled stereochemistry is found in aldol additions of the chiral acetate 2-hydroxy-2.2-triphenylethyl acetate (HYTRA) when both enantiomers of double deprotonated (R)- and (S)-HYTRA are combined with an enantiomerically pure aldehyde, e.g., (7 )-3-benzyloxybutanal. As in the case of achiral aldehydes, the deprotonated (tf)-HYTRA also attacks (independent of the chirality of the substrate) mainly from the /te-side to give predominantly the t/nii-carboxylic acid after hydrolysis. On the other hand, the (S)-reagcnt attacks the (/ )-aldebyde preferably from the. S7-side to give. s wz-carboxylic acids with comparable selectivity 6... 

In some cases the yields were poor due to competing deprotonation of the substrate by the organolithium reagent. Deprotonation was the predominant reaction with methyllithium or when (Z)-2-(l-alkenyl)-4,5-dihydrooxazoles were employed. The stereochemical outcome has been rationalized as occurring from a chelated transition state. The starting chiral amino alcohol auxiliary can also be recovered without racemization for reuse. 

Enantioselective deprotonations of meso substrates such as ketones or epoxides are firmly entrenched as a method in asymmetric synthesis, although the bulk of this work involves stoichiometric amounts of the chiral reagent. Nevertheless, a handful of reports have appeared detailing a catalytic approach to enantioselective deprotonation. The issue that ultimately determines whether an asymmetric deprotonation may be rendered catalytic is a balance of the stoichiometric base s ability... 

Preliminary mechanistic studies show no polymerization of the unsaturated aldehydes under Cinchona alkaloid catalysis, thereby indicating that the chiral tertiary amine catalyst does not act as a nucleophilic promoter, similar to Baylis-Hilhnan type reactions (Scheme 1). Rather, the quinuclidine nitrogen acts in a Brpnsted basic deprotonation-activation of various cychc and acyclic 1,3-dicarbonyl donors. The conjugate addition of the 1,3-dicarbonyl donors to a,(3-unsaturated aldehydes generated substrates with aU-carbon quaternary centers in excellent yields and stereoselectivities (Scheme 2) Utility of these aU-carbon quaternary adducts was demonstrated in the seven-step synthesis of (H-)-tanikolide 14, an antifungal metabolite. 

A ferrocenyloxazoline with only one adjacent position available for deprotonation will lithiate at that position irrespective of stereochemistry. This means that the same oxazoline can be used to form ferrocenes with either sense of planar chirality. The synthesis of the diastereoisomeric ligands 311 and 313 illustrates the strategy (Scheme 143), which is now commonly used with other substrates to control planar chirality by lithiation (see below). Ferrocene 311 is available by lithiation of 305 directly, but diastereoselective silylation followed by a second lithiation (best carried out in situ in a single pot) gives the diastereoisomeric phosphine 313 after deprotection by protodesilylation ". ... 

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. 

D. Deprotonation of Achiral Substrates with a Chiral Base and... 

A much more efficient procedure consists in the deprotonation of prochiral substrates 4 by chiral base 5 (equation 2). The removal of the enantiotopic protons in 4 proceeds through diastereotopic transition states having different energies AG and thus yielding the diastereomeric carbanions 6 and epi-6 in unequal amounts (equation 2). 

The asymmetric (—)-sparteine-mediated deprotonation of alkyl carbamates was unprecedented until discovered in 1990 °. For the first time, protected 1-alkanols could be transformed generally to the corresponding carbanionic species by a simple deprotonation protocol. Moreover, an efficient differentiation between enantiotopic protons in the substrate took place and the extent of stereoselection could be stored in a chiral ion pair, bearing the chiral information at the carbanionic centre. 

The first example of enantioselective allylzincation of an alkene was also reported for the cyclopropenone ketal 78 as substrate. The chiral allylzinc complex 135 was prepared from the corresponding bis-oxazoline derived from (,V)-valine by deprotonation with n-BuLi and transmetallation with allylzinc bromide. This reagent reacted with 78 and afforded the allylated product 136 with high optical purity ( = 99%) (equation 66)101. 

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