Substrate Control with Chiral Carbonyl Compounds

43 Substrate Control with Chiral Carbonyl Compounds 

Aldol additions to chiral carbonyl compounds or with chiral enolates not bearing an auxiliary can also lead to products with high levels of diastereoin-duction. The approach naturally leads to concise syntheses, because no added steps to introduce and remove chiral auxiliaries are necessary. The aldol addition reaction is acutely responsive to alterations in reaction parameters, and fine tuning of conditions can lead to high induction. 

In the addition of an achiral enolate to an aldehyde bearing a stereogenic center at Ca, the jr-facial selectivity can usually be predicted by the Felkin-Anh model (158 see also Chapter 2) [83]. However, simple 1,2-diastereoin-duction with enolates derived from typical metals such as lithium, boron, and titanium is often insufficient to be synthetically useful [16, 20). Higher levels of diastereoselectivity are generally obtained by use of enol silanes [34], as reported by Heathcock (Equation 14) [84]. 

The presence of a polar /3-substituent in the aldehyde can significantly influence the stereochemical outcome of nucleophilic addition. The observed selectivity has been attributed to the intermediacy of an acyclic transition state structure proposed by Evans (Equation 15) [85, 86]. The key characteristics of the model are (1) attenuation of dipole effects by orientation of C(3-0 and C = 0 in an antiparallel arrangement, and (2) the minimization of non-covalent interactions as the C=0 undergoes rehybridization. Thus, over the course of nucleophilic addition, the preferred conformer 162 is transformed into a product with He- PGO and OM - H interactions, whereas the alternative conformer 163 accrues the energetically more costly interaction between PGO and MO [86]. 

Asymmetric aldol additions involving chiral ketones generally furnish products with much higher levels of induction [16, 20], These processes offer an attractive alternative to auxiliary-based methods since additional steps for auxiliary introduction and removal can thus be avoided. In particular, boron enolates have been extensively used. High stereoselectivity obtained with boron enolates is ascribed to the highly ordered nature of the cyclic chair-like transition states involved. The shorter C-B and 0-B bond distances give rise to tighter transition states, in which unfavorable non-bonded interactions between substituents are maximized, in contrast to those formed from other metal enolates [13]. Furthermore, additions of boron enolates are stereospecific, such that cis-boron enolates preferentially furnish 1,2-syn products and trans-boron enolates the 1,2-anti products [13, 14, 16]. 

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Carbonyl Allylation and Propargylation. Boron complex (8), derived from the bis(tosylamide) compound (3), transmeta-lates allylstannanes to form allylboranes (eq 12). The allylboranes can be combined without isolation with aldehydes at —78°C to afford homoallylic alcohols with high enantioselectivity (eq 13). On the basis of a single reported example, reagent control might be expected to overcome substrate control in additions to aldehydes containing an adjacent asymmetric center. The sulfonamide can be recovered by precipitation with diethyl ether during aqueous workup. Ease of preparation and recovery of the chiral controller makes this method one of the more useful available for allylation reactions. 

To date, many electrophilic reagents, such as alkyl halides, alkenes, alkynes, carbonyl compounds, epoxides, alcohols, and ethers, have been investigated in AFC alkylation reactions. On the other hand, the reactive 5-membered heteroaromatic compounds, such as indole, pyrrole, furan, and thiophene derivatives, and electron-rich benzene derivatives have been successfully applied in AFC alkylation reactions. Indole and pyrrole derivatives are most popular substrates due to their high reactivity and account for almost 80% of the published methodologies. A variety of chiral organometal-lic catalysts and organocatalysts are employed in the catalytic AFC alkylation reactions with high enantiomeric control. 

Allylborane 235 exhibits excellent reagent control and provides high ee s for a wide range of carbonyl compounds regardless of the substrate stereochemistry. For example, in the reaction of a-chiral aldehydes S-237 and / -237 with allylboranes (-f-)-235 (-)-235, the prodnct stereochemistry entirely depends on the antipode of the reagent used and not on the substrate stereochemistry (Scheme 25.37). 

Chiral (3-hydroxy esters are versatile synthons in organic synthesis specifically in the preparation of natural products [68-70]. The asymmetrical reduction of carbonyl compounds using baker s yeast has been demonstrated and reviewed [5,71,72]. In the stereoselective reduction of P-keto ester of 4-chloro- and 4-bromo-3-oxobutanoic acid, specifically 4-chloro-3-oxobutanoic acid methyl ester, Sih and Chen [73] demonstrated that the stereoselectivity of yeast-catalyzed reductions may be altered by manipulating the size of ester group using y-chloroacetoacetate as substrate. They also indicated that the e.e. of the alcohol produced depended on the concentration of the substrate used. Nakamura et al. [74] demonstrated the reduction of p-keto ester with baker s yeast and controlled... 

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