Aldol reaction double diastereoselection

Methyl ketone enolates bearing a /1-heteroatom substituent have been designed to effect highly 1,5-diastereoselective additions to aldehyde electrophiles and used to achieve double-stereodifferentiating aldol reactions.30... 

P-Hydroxy carboxylic acids (12,3).2 This acetate on double deprotonation with LDA undergoes diastereoselective aldol reactions with aldehydes. The adducts are easily hydrolyzed to optically active P-hydroxycarboxylic acids with release of (R)-(+)-1,1,2-triphenyl-1,2-ethanediol, the precursor to 1. Optically pure acids can be obtained by crystallization of the salt with an optically active amine such as (S)-(—)-1 -pheny lethylamine. 

Highly diastereoselective acetate aldol additions using chlorotitanium enolates of mesityl-substituted JV-acetylthiazolidinethione 136 has been documented <07OL149>. These aldol reactions proceed in high yields and diastereoselectivities (94/6 to 98/2) for aliphatic, aromatic, and a,P-unsaturated aldehydes. Compound 136 also undergoes double diastereoselective aldol additions with chiral aldehyde 139 to give adduct 140 in high yields. 

Diastereoselective aldol reactions have been extensively utilized in the synthesis of complex natural products, including macrolides [4] and ionophores [5]. In this context, iterative approaches are often exploited to append propionate units one at a time. This approach leads to double stereodifferentiation [6] in tvhich the reactant pairs can be either matched or mismatched . The chirality of the t vo reactants reinforce each other if they are matched. As a result, the diastereoselectivity is often higher than vould... 

The enantiomers are obtained as a racemic mixture if no asymmetric induction becomes effective. The ratio of diastereomers depends on structural features of the reactants as well as the reaction conditions as outlined in the following. By using properly substituted preformed enolates, the diastereoselectivity of the aldol reaction can be controlled. Such enolates can show E-ot Z-configuration at the carbon-carbon double bond. With Z-enolates 9, the syn products are formed preferentially, while fi-enolates 12 lead mainly to anti products. This stereochemical outcome can be rationalized to arise from the more favored transition state 10 and 13 respectively ... 

Wang identified a series of Michael/Michael and Michael/aldol sequences catalysed by diarylprolinol ethers that led directly to densely functionalised five-mem-bered rings [172-174]. For example, highly diastereoselective and enantioselective double Michael addition reactions were achieved by treatment of a,p-unsaturated aldehydes with triester 113 catalysed by 30 (Scheme 45). Initial conjugate addition... 

There is an important difference between Horeau s and Heathcock s examples in that the aldol reaction generates two chirality elements in the bond-forming step. In principle, analysis of such a reaction requires evaluation of two aspects, i.e., the effect of double asymmetric induction on simple and induced diastereoselectivity. The aldol reaction is not particularly suited for this... 

Dicyclohexylchloroborane mediates aldol reactions between chiral aldehydes and a chiral ketone the reaction exhibits double diastereoselection.120... 

As depicted in Scheme 13, the SnCU-promoted vinylogous aldol reaction between silyloxy pyrrole 76 and D-glyceraldehyde 11 afforded the unsaturated lactam 77 in a good yield and excellent diastereoselectivity. Saturation of the carbon-carbon double bond within 77 using the NiC /NaBfLt mixture, followed by protection of the free secondary carbinol group as a TBS-ether and TV-Bn for TV-Boc protecting... 

Scheme 12. The C6-C7 aldol reaction has to proceed with double stereodifferentiation. The ratios refer to the anti-syn diastereoselectivity at the C7-C8 bond.

Such p-silyl enolate intermediates also react with aldehydes with high diastereoselectivity with respect to both new chiral centers being created, the relative stereochemistry in the aldol reaction being dependent upon the original geometry of the enolate double bond (Scheme 13). This aldol reaction has... 

The stereochemical outcome of an aldol reaction involving more than one chiral component is consistent with the rule of approximate multiplicativity of diastereofacial selectivities intrinsic to the chiral reactants. For a matched case, the diastereoselectivity approximates (substrate DS) X (reagent DS). For a mismatched case, the diastereoselectivity is (substrate DS) (reagent DS). Double asymmetric induction also can be used to enforce the inherent facial selectivity of a chiral aldehyde, as shown below. 

In accordance with this model one finds diastereoselectively anti products on reaction of aldehydes with ( )-allyl compounds, whereas allyl systems with the (Z)-configuration give mainly syn products and it is even possible to effect asymmetric induction. As the double bond of the product can be oxidatively cleaved to a CW3 group, the reaction can be regarded as a stereoselective aldol reaction, an aspect which explains the widespread interest in this type of reaction. With heterosubstituted allylic anions it is sometimes possible to effect predominantly y-attack with different electrophiles by the choice of the heteroatom.2 For instance it is well known that with sulfur substituents like —SR, —SOR or —SOjR the a-attack dominates, but doubly lithiated allenethiol possesses high y-reactivity and can be used as a homoenolate anion equivalent in reaction with electrophiles such as alkyl halides (Scheme 7). ... 

Woerpel has recently reported a tandem double asymmetric aldol/C=0 reduction sequence that diastereoselectively affords propionate stereo-triads and -pentads commonly found in polyketide-derived natural products (Scheme 8-2) [14], When the lithium enolate of propiophenone is treated with excess aldehyde, the expected aldolates 30/31 are formed however, following warming to ambient temperature a mono-protected diol 34 can be isolated. In a powerful demonstration of the method, treatment of 3-pentanone with 1.3 equiv of LDA and excess benzaldehyde yielded product in corporating five new stereocenters in 81% as an 86 5 5 3 mixture of diastereomers (Eq. (8.8)). A series of elegant experiments have shown that under the condition that the reaction is conducted, the aldol addition reaction is rapidly reversible with an irreversible intramolecular Tischenko reduction serving as the stereochemically determining step (32 34, Scheme 8-2). 

It is clear that the presence of the benzeneselenoethyl moiety in 21 or 22 is not required as a latent double bond in subsequent transformations. It would thus be synthetically more attractive to be able to prepare the unsaturated ketones directly. Reaction of AS-hexahy-dromandelic acid (3) with either (E)- or (Z)-propenyllithium followed by hydroxy silylation opens the way to both 34 and 35. Boron enolates of either 34 or 35, prepared in situ, undergo reaction with aldehydes to afford aldol products, albeit with low selectivity when R=TBS. Interestingly, the -isomer 34 provides mainly the 2,3-anti products 36 (1 3.5 syn. anti), while the Z-isomer 35 affords mainly the syn products 37 (3 1 to 10 1 syn anti). However, the corresponding O-triethylsilyl-protected boron enolates of 34 or 35 undergo smooth aldol reaction with aldehydes to yield the 1,3-syn products 37 with high diastereoselectivity (>100 1) (Scheme 6) [7]. 

The issue of simple diastereoselectivity arises when both the allyl and vinyl moieties of the ketene N,0-acetal intermediate 2 are substituted at their terminus, leading to vicinal stereocenters in the products (Scheme 7.22). In analogy to the aldol reaction, the stereochemical outcome can be predicted in terms of a Zimmermann-Traxler type chair-shaped transition state. Accordingly, the synlanti ratio of the products depends on double bond geometry. Whereas the geometry of the unsaturated alcohol is pre-determined and usually not subject to equilibration, the geometry of the ketene N,0-acetal moiety depends on the reaction conditions that lead to its in situ formation. 

Heathcock has demonstrated the utility of double stereodifferentiation to enhance 1,2-diastereoselectivity in aldol reactions. ... 

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