Diastereoselectivity simple

The stereochemical outcome of nucleophilic addition reactions to cyclic ketones is the subject of numerous experimental and theoretical studies, with substituted cyclohexanones and cy-clopcntanones having been intensively studied. In addition reactions to substituted cyclohexanones 1 the problem of simple diastereoselectivity is manifested in the predominance of cither axial attack of a nucleophile, leading to the equatorial alcohol 2 A. or equatorial attack of the nucleophile which leads to the axial alcohol 2B. 

The carbonyl addition reactions of benzylmetals, compared to the allylic counterparts, have found few applications in stereoselective synthesis, apparently for the following reasons The carbonyl addition of alkali metal salts (M = Li, Na, K, Cs) of benzyl anions, with few exceptions, usually proceeds with low levels of simple diastereoselectivity affording mixtures of syn- or <7 / -diastereomers (see Section 1.3.2.3.1.). 

I.3.2.3. Stereoselective Carbonyl Addition 1.3.2.3.1. With Simple Diastereoselectivity... 

In order to demonstrate the limited simple diastereoselectivity in most of these addition reactions, some selected examples are collected below. 

Dibenzylamino)-3-phenylpropanal adds benzyllithium reagents with virtually complete steric approach controlled selectivity again the simple diastereoselectivity is poor (approx. 1 11 2)5. 

The 1,3-oxathiane 8, derived from (5)-l,2,4-butanetriol, is lithiated to form the equatorial anion 9, which adds benzaldehyde with high induced but moderate simple diastereoselectivity (4 1) to form the alcohols 10 and 1117. The selectivity is enhanced to 7 1 by metal exchange by means of magnesium bromide. Deprotection affords (5)-2-hydroxy-l,2-diphenylethanone with 75% ee. It is expected that the method could be extended to aliphatic aldehydes. 

With prostereogenic carbonyl components, the problem of simple diastereoselectivity arises, which is unsatisfactorily solved at present21. Both the intermediate alkoxides rearrange by migration of the carbonyl group at a different rate21 22, which might be used for the enrichment of one diastereomer. 

For a successful application in synthesis, several problems have to be solved regioselectivity, whether the C-C bond is formed with the 1- or 3-position in an unsymmetrical ambident anion, EjZ selectivity in the formation of the double bond, and simple diastereoselectivity, since two new stereogenic centers are created from prostereogenic compounds. Further, different types of induced stereoselectivity or enantioselectivity may be required. Allylmetals with a wide choice of substituents are accessible by various methods (Sections D. 1.3.3.3.1.-10.). 

With reagent-induced diastereoselectivity. d 3-Substituted reagent with simple diastereoselectivity. 

Table 2. Simple Diastereoselectivity in the Reaction of 2-Butenylmetal Reagents with Aldehydes8...

Cation/ Section D. Typical Configur- Simple Diastereoselectivity Chiral... 

Simple Diastereoselectivity Substrate-Induced Diastereoselectivity Reagent-Induced Stereoselectivity... 

Phosphonamide-stabilized allylic anions react y-selectively and serve as homocnolate reagents86 in the reaction with aldehydes only moderate simple diastereoselectivity is observed. 

Simple 1-hetero-substituted allyllithium derivatives, such as 1-alkoxy-94"96, 1-alkyl-thio-50,97, 1-phenylselenyl-54,98 show insufficient regio- and simple diastereoselectivity in their reaction with aldehydes. The rcgiosclectivity is greatly enhanced in favor of the a-products by in... 

An interesting case of product-controlled simple diastereoselectivity has been reported103. [l-[Methyl(nitrosoamino)]-2-propenyl]lithium adds to benzaldehyde at — 78°C to give the amino alcohol with an anti/syn ratio of 65 35, but equilibration of the reversible reaction at room temperature leads exclusively to the more stable, vv -product. 

Simple allyl alkali metal compounds have only a small capability for discriminating between diastereotopic faces of carbonyl compounds. Although a matter of simple diastereoselectivity, this can be concluded from the reaction of conformationally locked 4-/erf-butylcyclohexanone... 

Enantiomerically enriched l-(diisopropylaminocarbonyloxy)allyllithium derivatives (Section 1.3.3.3.1.2.) add to carbonyl compounds with syn-l,3-chirality transfer21, giving good evidence for a pericyclic transition state in the main reaction path (Section 1.3.3.1.). However, since the simple diastereoselectivity and the degree of chirality transfer are low, for synthetic purposes a metal exchange with titanium reagents or trialkyltin halides (Section D.1.3.3.3.8.2.3.) is recommended. 

Allylboron compounds have proven to be an exceedingly useful class of allylmetal reagents for the stereoselective synthesis of homoallylic alcohols via reactions with carbonyl compounds, especially aldehydes1. The reactions of allylboron compounds and aldehydes proceed by way of cyclic transition states with predictable transmission of olefinic stereochemistry to anti (from L-alkene precursors) or syn (from Z-alkene precursors) relationships about the newly formed carbon-carbon bond. This stereochemical feature, classified as simple diastereoselection, is general for Type I allylorganometallicslb. 

Simple diastereoselection in the reactions of 2-butenylboron compounds and aldehydes is critically dependent on the configurational stability of the reagentslb. As a general rule, most 2-bulenylorganometallics arc sensitive to sequential 1,3-metal shifts (1,3-metallotropic rearrangements) that result in E- to Z-olefin isomerization via the l-methyl-2-propenylmetal isomer. 

On the basis of this analysis, it may be anticipated that the extent of aldehyde diastereofa-cial selectivity will depend on the difference in size of the R3 aldehyde substituent relative to that of the methyl group. The examples summarized in Table 2 are generally supportive of this thesis, particularly the reactions of (F)-2-butenylboronntc. The data cited for reactions of 3-methoxymethoxy-2-methylbutanal with (Z)-2-butenylboronate and 2-propenylboronate, however, also show that diastereoselectivity depends on the stereochemistry at C-3 of the chiral aldehydes. These data imply that simple diastereoselectivity depends not simply on reduced mass considerations, but rather on the stereochemistry and conformation of the R3 substituent in the family of potentially competing transition states21,60. The dependence of aldehyde diastcrcofacial selectivity on the stereochemistry of remote positions of chiral aldehydes has also been documented for reactions involving the ( )-2-butenylchromium reagent62. 

I.3.3.3.3.2.2. Simple Diastereoselection Reactions of Racemic -Substituted Allylboron Reagents with Achiral Aldehydes and Ketones... 

The addition of 2-butenyl(triisopropoxy)titanium was applied in the total synthesis of the pyridone fragment of the antibiotics aurodox and efrotomycin57. 2-Alkenyltitanium(IV) reagents exhibit outstanding simple diastereoselectivity in reactions with methyl ketones52,58 (see Table 2). 

High nonchclation-controlled induced and simple diastereoselectivity are also reported for a 2-butenyl titanium reagent for example65 92 ... 

Surprisingly, sense and degree of simple diastereoselectivity are not influenced by methyl groups in the and y-position of these chromium reagents13. 

Simple diastereoselectivity does not arise when an a-unsubstituted enolate or an cnolate with two identical a-substituents is combined with an aldehyde. Provided that neither the aldehyde nor the enolate are chiral molecules, the products 6a and 6b are enantiomers. 

If, on the other hand, the aldol addition is performed using either enolates with stereogenic units, which may be located in the a-substituent Y or in the ipso-substituent X, or using chiral aldehydes, the aldol products 4a, 5a and 6a arc diastcreomers with respect to 4b, 5b and 6b. Thus, both significant simple diastereoselectivity and induced stereoselectivity are highly desirable when ... 

In a number of kinctically controlled aldol additions, simple diastereoselectivity is related to the geometry of the enolate (Z)-enolates furnish syn-aldols and (/f)-cnolatcs give //-aldols as the main products. 

With (Z)-amide enolates and (Z)-thioamide enolates a strong preference for sm-adducts is also observed. In general, boron or zirconium (Z)-enolates of ketones and amides display a higher simple diastereoselectivity in favor of syn-products than the corresponding lithium or magnesium enolates6,7. 

A stereoconvergent reaction without any correlation between the geometry of the enolate and simple diastereoselectivity occurs when fluoride ions are used to induce an aldol addition of enolsilanes to aldehydes. For example, both a 99 1 and a 9 91 mixture of the following (Z)/( )-enolsilane lead predominantly to the formation of the. un-adduct in a highly selective manner, when the addition is mediated by tris(diethylamino)sulfonium difluorotrimethylsili-conate27,28. 

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