Erythro-threo diastereoselectivity

Extensive investigations have been directed toward the development of chiral ester enolates that might exhibit practical levels of aldol asymmetric induction. Much of the early work in this area has been reviewed (111). In general, metal enolates derived from chiral acetate and propionate esters exhibit low levels of aldol asymmetric induction that rarely exceed 50% enantiomeric excess. The added problems associated with the low levels of aldol diastereoselection found with most substituted ester enolates (cf. Table 11) further detract from their utility as effective chiral enolates for the aldol process. Recent studies have examined the potential applications of the chiral propionates 121 to 125 in the aldol condensation (eq. [94]), and the observed erythro-threo diastereoselection and diastere-oface selection for these enolates are summarized in Table 31. For the six lithium enolates the threo diastereoselection was found to be... 

The aldol condensation, one of the oldest organic reactions, is emerging as a powerful method for control of relative and absolute stereochemistry in the synthesis of conformationally flexible compounds. Some of the research which has been carried out at Berkeley over the past five years is reviewed in this article. Points discussed are the factors that control simple erythro, threo diastereoselection, the use of double stereodifferentiation to influence the "Cram s rule" preference shown by chiral aldehydes, and some recent experiments that shed light on the role that the solvent and other nucleophilic ligands play in determining the stereochemistry of the reaction. 

Owing to the fully reversible equilibrium nature of the aldol addition process, enzymes with low diastereoselectivity will typically lead to a thermodynamically controlled mixture of erythro/threo-isomers that are difficult to separate. The thermodynamic origin of poor threo/erythro selectivity has most recently been turned to an asset by the design of a diastereoselective dynamic kinetic resolution process by coupling of L-ThrA and a diastereoselective L-tyrosine decarboxylase (Figure 10.47)... 

A related strategy was used to prepare D-allosamine (134). Cycloaddition of the dipole derived from nitroacetal (129) to (S )-vinyl dioxolane (74) afforded a mixture of erythro/threo isoxazolines 130 131 (Scheme 6.72). The erythro isoxazoline was subjected to hydroxylation as described above, to give 4-hydroxyisoxazoline 132 with high diastereoselectivity. Lithium aluminium hydride reduction furnished a single diastereomer of aminodiol 133, which could be deprotected to give the hydrochloride salt of D-allosamine (134) (141). 

Chiral ketone catalysts of the Yang-type (5a and 5b, see above) and of the Shi-type (10, Scheme 10.2) have been successfully used for kinetic resolution of several racemic olefins, in particular allylic ethers (Scheme 10.4) [28, 29]. Remarkable and synthetically quite useful S values of up to 100 (ketone 5b) and above 100 (ketone 10) were achieved. Epoxidation of the substrates shown in Scheme 10.4 proceeds with good diastereoselectivity. For the cyclic substrates investigated with ketone 10 the trans-epoxides are formed predominantly and cis/trans-ratios were usually better than 20 1 [29]. For the linear substrates shown in Scheme 10.4 epoxidation catalyzed by ketone 5b resulted in the predominant formation of the erythro-epoxides (erythro/threo-ratio usually better than 49 1) [28]. 

In most cases, the Reformatsky reaction is not very stereospecific and mixtures of erythro- and threo-p-hydroxyesters are obtained when asymmetric a-haloesters are used as reagents (equation 79). The erythro threo ratio appears to depend on the solvent polarity and the reaction time. However, it is of current interest to develop highly stereocontrolled asymmetric Reformatsky reactions. To date, high diastereoselectivities could be achieved only in a few cases either by substitution of zinc with other metal... 

There are a few reports of hetero-Diels-Alder Reactions promoted by LPDE. Intriguing stereoselectivity is observed for the [4 + 2] cyclization between Danishefsky s diene 77 and a-heteroatom-substituted aldehydes. For example, reaction of 77 with N-Boc-protected a-aminoaldehyde with 76 gave the threo isomer selectively, a result in keeping with a chelation-controUed process. In contrast, the threo diastereoselectivity observed could be reversed by changing the amino protecting group from A-Boc to A,A(-dibenzyl. In this instance, the erythro isomer was generated exclusively via a non-chelation-controlled transition state (Sch. 38) [89]. 

Crotyl-titanocene and -zirconocene complexes, like bis(cyclopentadienyl)-Ti and -Zr derivatives (llland) react (equation 44) with aldehydes (Table 9) with pronounced threo diastereoselectivity (>90 <10 threo.-erythro (112) (113) for Ti reagents and approximately 80 20 for their Zr analogs). ... 

Threo diastereoselectivity is consistent with a chelation-controlled (Cram cyclic model) organolithium addition (Figure 8a). Since five-membered chelation of lithium is tenuous, an alternative six-membered chelate involving the dimethylamino nitrogen atom of the thermodynamically less stable (Z)-hydrazone (in equilibrium with the ( )-isomer) cannot be discounted. The trityl ether (entry 4, Table 9) eliminates the chelation effect of the oxygen atom such that the erythro diastereomer predominates (via normal Felkin-Ahn addition) (Figure 8b). 

Heathcock et al. described the process that formed diastereomers in the aldol condensation, from precursors that do not contain a chiral center, as simple diastereoselectivity.209,210 Naming protocols to describe the diastereomers produced in the aldol condensation include the erythro/threo nomenclature, as well as the syn/anti nomenclature was discussed in Section I.4.B. Using this latter convention, diastereomers 340 and 343 were designated as anti and diastereomers 341 and 342 were designated as syn. 

When neither the enolate 29 nor the aldehyde contains stereogenic units, both reactants have enantiotopic faces and 30a and 30b are enantiomers. The same is true for the pair 31a and 31b. However, 30 and 31 form a pair of diastereomers. When an aldol addition leads to an excess of one of these diastereomers 30 or 31, it is said to exhibit simple diastereoselectivity. Several notations that assign descriptors to diastereomeric aldols are found in the literature. The classical erythro/threo nomenclature, which is based on Fischer projection formulas [62], will not be used in this chapter, because it can cause considerable confusion with branched carbon chains. Among the... 

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