Controlling, stereoselectivity

Substraie-Controlled Stereoselection Reageni-Controlled Stereoseleciion ... 

In addition to the problems of substrate- or reagent-controlled stereoselectivity, the problem of simple synjanti diastereoselectivity arises. Most studies have been performed on the crotyl derivatives. Table 2 summarizes some of these under the latter aspect. Essentially all types of reagents related to the appropriate 2-propenylmetal reagents collected in Table 1 are known. 

With Reagent-Controlled Stereoselectivity With Auxiliary Control... 

Aldol Reactions of Boron Enolates. The matter of increasing stereoselectivity in the addition step can be addressed by using other reactants. One important version of the aldol reaction involves the use of boron enolates.15 A cyclic TS similar to that for lithium enolates is involved, and the same relationship exists between enolate configuration and product stereochemistry. In general, the stereoselectivity is higher than for lithium enolates. The O-B bond distances are shorter than for lithium enolates, and this leads to a more compact structure for the TS and magnifies the steric interactions that control stereoselectivity. 

Entry 10 is an example of the application of chelate-controlled stereoselectivity using TiCl4. Entry 11 also involves stereodirection by a (3-O-methoxybenzyloxy) substituent. In this case, the BF3-catalyzed reaction should proceed through an open TS and the (3-polar effect described on p. 96 prevails, resulting in the anti-3,5-isomer. 

As is the case for aldol addition, chiral auxiliaries and catalysts can be used to control stereoselectivity in conjugate addition reactions. Oxazolidinone chiral auxiliaries have been used in both the nucleophilic and electrophilic components under Lewis acid-catalyzed conditions. (V-Acyloxazolidinones can be converted to nucleophilic titanium enolates with TiCl3(0-/-Pr).320... 

Reagent-controlled stereoselectivity can provide stereochemical relationships over several centers when a combination of acyclic and chelation control and cyclic TS resulting from transmetallation is utilized. In reactions mediated by BF3 or MgBr2 the new centers are syn. Indium reagents can be used to create an anti relationship between two new chiral centers. The indium reagents are formed by transmetallation and react... 

Reactions through chelated TS Reactions of a- or (3-oxy-substituted aldehydes often show chelation-controlled stereoselectivity with Lewis acids that can accommodate five or six ligands. Chelation with substituents in the allylic reactant can also occur. The overall stereoselectivity depends on steric and stereoelectronic effects in the chelated TS. 

Extension of this strategy enables syntheses of both protected D-threonine and L-allo-threonine, in which reagent-controlled stereoselective epoxidation of a common intermediate is the key step (Scheme 4.8).53... 

The mechanisms for chain-end stereoselectivity (isospecific and syndiospecific) for primary monomer insertion (Section 4.1.1) present relevant analogies with the well-established mechanism of chiral site controlled stereoselectivity (Section 3). In fact, for both mechanisms, the selection between the two... 

The research group of Van Leeuwen has focused on catalysis at the core of a carbosilane dendrimer in an effort to be able to control stereoselectivity [10]. To this end, a ferrocenyl diphosphine backbone was functionalized with different generations of carbosilane dendrons producing a series of dendrimer phosphine ligands with an increasing steric demand (see 7 for an example, Scheme 6). In situ... 

In summary, a number of effective chiral reducing agents have been developed based on the modification of LAH. Excellent results have been obtained with aryl alkyl ketones and a,p-acetylenic ketones. However, dialkyl ketones are reduced in much lower enantiomeric excess. This clearly indicates that steric effects alone do not control stereoselectivity in these reductions. Systematic studies have been carried out with the objective of designing improved reagents. A better understanding of the mechanisms and knowledge of the active species is required in order to provide more accurate models of the transition states of the key reduction steps. 

Selective labelling of the two diastereotopic methyl groups of i-leucine (144) has enabled their fates during secondary metabolic reactions to be elucidated [66]. Moreover, in the context of protein interactions, differentiation of the leucine pro-R and pro-S methyl groups in protein NMR spectra allows molecular recognition phenomena to be studied [67]. Recently, efficient routes to both forms of Relabeled leucine, based on application of an auxiliary-controlled stereoselective conjugate addition reaction (Scheme 6.27) have been described [68]. Thus, starting... 

Scheme 6.27. Auxiliary-controlled stereoselective cuprate addition as the key step for the construction of both diastereomeric forms of [5-"q-leucine 144.

I. Solvent-Dependent, Kinetically Controlled Stereoselective Synthesis of 3- and 4-Thioglycosides... 

The neighboring group participation mechanism requires two conditions a neighboring ester group and traas-configmation. For example, in the course of 3- and 4-thioglycoside synthesis, a solvent-dependent kinetically controlled stereoselective mechanism was found (Figure 8). 

Figure 8. Solvent-dependent kinetically controlled stereoselective mechanism a) kinetic control in toluene b) neighboring group participation in DMF.

In this section an approach is discussed whereby absolute configurational assignment is based on auxiliary- or reagent-controlled stereoselective key reactions. The stereochemical outcome of the reaction used for the assignment must be predictable, from either the absolute configuration of the auxiliary or the reagent, by a rule or (better) a well-defined model of the transition state220. 

In the cases where auxiliary- or reagent-controlled stereoselectivity is employed for the assignment of absolute configurations, it must always be considered that the normal stereochemical outcome of the particular reaction may be reversed depending on both the structure of the starting material and/or the reaction conditions. Some examples are discussed ... 

Asymmetric transamination.2 This planar chiral pyridoxamine analog in the presence of Zn(C104), (l/Zn(C104)2 = 1.0.5) converts a-keto acids into (R)-amino tieids in 60 96%ee. Use of (R)-l in place of (S)-l produces (S)-amino acids with the wime elliciency. Chemical yields range from 50 75%. The preferred solvent is tnel li.mol. The pyridoxal-type analog is recovered in 75-85%yield. The transamination is considered to involve kinetically controlled stereoselective protonation of an octahedral Ztr 1 chelate intermediate. 

This reaction played a key role in a highly stereocontrolled synthesis of the aliphatic segment 1 of the antibiotic rifamycin S (2),2 as formulated in equation (III). In each of the two Cr(II) mediated reactions, the desired aldol is essentially the only product isolated. Further studies3 indicate that the 2,3-stereoselectivity is sensitive to the large substituent a to the aldehyde. A cyclic acetal group appears to play a specific role in contrast to an acyclic group, but the factors controlling stereoselectivity are not well understood. 

The Denmark phosphoramide organocatalyst has recently been applied in the first catalytic, diastereoselective, and enantioselective crossed-aldol reaction of aldehydes [86]. It is worthy of note that such controlled stereoselective selfcondensation of aldehydes has previously found no general application, because of many side-reactions, e.g. polyaldolization, and dehydration of the products. Several previously developed solutions have limitations. In a first step the Denmark group developed a procedure for generation of stereodefined trichlorosilyl enolates of aldehydes with high geometrical purity. Use of these geometrically pure (Z) and... 

Controlling Stereoselectivity with the Aid of a Reagent-Directing Croup... 

An example is the rhodium catalyzed hydroformylation reaction, which is an industrially important homogenous catalytic process [3]. In contrast, it is amazing that such an important transition-metal catalyzed C/C bond-forming process has been employed only rarely in organic synthesis [4]. Part of the reason stems from the difficulty in controlling stereoselectivity. Even though some recently developed chiral rhodium catalysts allow for enantio- and diastereoselective hydroformylation of certain specific classes of alkenes [5, 6], only little is known about the diastereoselective hydroformylation of acyclic olefins [7, 8]. 

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