Stereochemistry chelation control

Thus chelation control " may lead to either product, depending on the relative stabilities of the respective ot- and /(-chelates. In cases with predominant formation of the anri-diastereomer, it is often difficult to establish whether the formation of a /(-chelate or an open-chain Felkin - Anh transition state is responsible for the observed stereochemistry the decision usually rests on plausibility considerations. Thus, with regard to the results obtained for a-alkoxy carbonyl... 

In the case of the amide 11 (R = CI13) derived from 2-oxopropanoic amid and amine G the chelation-controlled product is predominantly formed with all organometallic reagents. No reversal of the stereochemistry is observed, presumably for the same steric reason as with the corresponding pyruvic amides derived from amines E and F. 

The choice of Lewis acid can determine if a chelated or open TS is involved. For example, all four possible stereoisomers of 1 were obtained by variation of the Lewis acid and the stereochemistry in the reactant.92 The BF3-catalyzed reactions occur through an open TS, whereas the TiCl4 reactions are chelation controlled. 

Ketosulfoxides are subject to chelation control when reduced by DiBAlH in the presence of ZnCl2.141 This allows the use of chirality of the sulfoxide group to control the stereochemistry at the ketone carbonyl. 

Entry 2 was reported as part of a study of the stereochemistry of addition of allyltrimethylsilane to protected carbohydrates. Use of BF3 as the Lewis acid, as shown, gave the product from an open TS, whereas TiCl4 led to the formation of the alternate stereoisomer through chelation control. Similar results were reported for a protected galactose. 

Herein, the stereogenic center in 2-12 controls the stereochemistry in the way that the Michael addition occurs from the less-hindered a-face of the enolate to the si-side of the crotonate 2-13 according to transition structure 2-16. The second Michael addition occurs from the same face, again under chelation control, followed by an axial protonahon of the formed enolate to give the cis-compound 2-14a. It should be noted that after the usual aqueous work-up procedure an inseparable... 

On the other hand, a double asymmetric version where both radical fragments are chiral has been investigated (equation 12) . The stereochemistry of the rearrangement products 20a and 20b is not the result of chelation control, but is determined by the stereochemistry of the hthium-bearing terminus. The significant difference in the stereospecificity of 19a and 19b reveals that a substantial level of mutal recognition of the radical enantiomers takes place during the recombination process. 

Product stereochemistries can be greatly influenced by these chelation control effects. This was first observed by Cram.10 There are many controversies about this topic, and the issue remains a topic of investigative interest.11 Without kinetic data, it has been suggested that it is impossible to distinguish the following two mechanistic types 12... 

An intramolecular variant of this reaction was reported in 1988 by Molander and Kenny (Table l)37. These reactions proceeded in reasonable yields and exhibited extremely high diasteroselectivity (200 1). It was suggested that the aldehyde functionality is first reduced, allowing chelation control of the stereochemistry (e.g. 3). 

The cycloaddition of a nitrile oxide with a chiral allylic ether affords an isoxazoline with selectivity for the pre/-isomer. This selectivity increases with the size of the alkyl substituent and is insensitive to the size of the allyl oxygen substituent. However, allyl alcohols tend to form the / ar/ isomcr preferentially, although the selectivity is often low.427"434 The product of dipolar cycloadditions based on nitrile oxides, the isoxazoline moiety, can be converted into a large variety of functional groups under relatively mild conditions.3 Among other products, the addition can be used to prepare P-hydroxy ketones (Scheme 26.17).435 The isoxazoline moiety can be used to control the relative stereochemistry through chelation control.436,437... 

Variation of 2-alkyl substituent exerted an effect upon diastereoselectivity. The best diastereoselection was obtained when incorporating a 2-ethyl substituent for acyl dithiane oxides (Table 3.6). The diastereoselectivity and the sense of induced stereochemistry can be rationalized on the basis of a simple chelation control model. 

In contrast, the diastereoselectivities of Figure 8.10 can be observed for many additions of hydride donors to carbonyl compounds which contain a stereocenter in the a position with an O or N atom bound to it. One of the product diastereomers and the relative configuration of its stereocenters is called the Felkin-Anh product. The other diastereomer and its stereochemistry are referred to as the so-called Cram chelate product. If the latter is produced preferentially, one also talks about the occurrence of chelation control or—only in laboratory jargon—of the predominance of the chelation-controlled product. ... 

The BF3-catalyzed reaction of a-aminoaldehydes with 10 is valuable for highly stereoselective synthesis of 2,3,5-trisubstituted pyrrolidines with all -cis configurations (Equation (50)).197 The stereochemical outcome like chelation-controlled stereochemistry might result from the inherent conformational arrangement of the aldehyde-BF3 complex. />-Quinoneimines, o-quinones, and a-alkoxyhydroperoxides undergo similar types of [3 + 2]-cycloadditions with allylsilanes to afford dihydro indoles, dihydrobenzofurans, and 1,2-dioxolanes, respectively.164,175,198... 

In the early stages of the project, we reasoned that the sulfoxide unit might be expected to influence the transition state geometry of the 2-acyl side chain, perhaps by chelation to a metal counterion, and hence control the stereochemistry of a wide range of functional group transformations. Indeed, a chelation control model of the reactivity of the 2-acyl dithiane 1-oxide systems has allowed us to rationalize, and predict, the stereochemical outcome of most of the reactions studied so far. These predictions have, in many cases, been confirmed by X-ray structure determination of the relative stereochemistries within product structures.1-4... 

It should be noted that in cases where the stereochemistry of the addition is dependent on chelation control, the presence of Lewis acids may profoundly influence the selectivity, e.g. [9],... 

The stereochemistry of addition of organomagnesium compounds to ketones is governed by similar factors to those influencing their addition to aldehydes (see Section 6.1.1). For addition of achiral organomagnesium compounds to a-chiral ketones, steric approach control is commonly observed, but chelation control may also operate [63, 64], It is noteworthy that a pioneering asymmetric synthesis — one of the first which could be regarded as virtually stereospecific, was of this type [65] ... 

Chelation control has also been implicated in conjugate addition reactions. For example, during a synthesis of the macrolide antibiotic 6-ep/-erythromycin, Mul-zer and co-workers86 found that the stereochemistry at the anomeric centre (l position) of the tetrahydropyranyl protecting group had a profound effect on the stereochemistry of conjugate addition of lithium dimethylcuprate to the ynone 49.1 [Scheme 1.49]. 

P-Keto esters and -keto amides, each substituted between the two carbonyl units with a 2-[2-(tri-methylsilyl)methyl] group, also undergo Lewis acid catalyzed, chelation-controlled cyclization. When titanium tetrachloride is used, only the product possessing a cis relationship between the hydroxy and ester (or amide) groups is product yields range from 65 to 88% (Table 8). While loss of stereochemistry in the product and equilibration of diastereomers could have occurred via a Lewis acid promoted retro aldol-aldol sequence, none was observed. Consequently, it is assumed that the reactions occur under kinetic, rather than thermodynamic, control. In contrast to the titanium tetrachloride promoted process, fluoride-induced cyclization produces a 2 1 mixture of diastereomeric products, and the nonchelating Lewis acid BF3-OEt2 leads to a 1 4.8 mixture of diastereomers. 

Additions of allyltributyltin to an a-oxygenated aldehyde are also influenced by the choice of Lewis acid (Table 7) [16]. The relative stereochemistry of the adduct is a result of the facial preference for attack on the aldehyde-Lewis acid complex by the stannane. The reaction involving BF3 OEta is subject to Felkin-Ahn/Comforth control whereas MgBr2 and TiCU in CH2CI2 proceed by chelation control. In THF the... 

For the preparation of aspartic proteinase inhibitors, Jones et al. [7] needed epimeric A -protected alcohols (see Table 1, entry 2). In this stereocontrolled synthesis of hydroxyethylene dipeptide isoteres, a chiral Grignard reagent was used in a reaction with a protected aminoaldehyde [7]. In this reaction, a 6 1 ratio of diastomers 4SAR) was obtained. The stereochemistry of the products was controlled by the complexation of the reagent with the protected amine the S-epimer predominates because of a chelation-controlled addition of the Grignard. 

The stereochemistry in the reactions mentioned above is consistent with a chelation-controlled addition of the organocerium reagents. On the other hand, nonchelation-controlled addition of alkylcerium reagents to carbonyl components has also been observed, as shown in Scheme... 

Despite the great deal of attention devoted to nucleophilic additions to a-chiral carbonyls, the source of stereoselectivity in these reactions (predicted by Cram s rules of asymmetric induction ) remains largely unresolved. Neither direct structural studies nor correlation of reactant and product stereochemistries have yielded any conclusive support for a single comprehensive model. Similarly, the effect of Lewis acids on these systems is only understood at the level of chelation-controlled additions (vide infra). 

An example of this type of effort is as follows. Complexation of the carbonyl oxygen of N/(-dibenzyl-a-amino aldehydes wiA Lewis acids such as BF3, ZnBr2 or SnCU, followed by ad tion of trimethylsilyl cyanide leads to adducts formed by a nonchelation-controlled process. Complexation with TiCU or MgBr2 affords the opposite stereochemistry preferentially, tl ugh a chelation-controlled process (Scheme 1). ... 

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