Simple diastereoselectivity reactions

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

Simple diastereoselectivity comes into play when allenylmetal compounds are added to aldehydes, since adducts such as 1 a/b contain both an axis and a center of asymmetry. Hence, diastereomeric mixtures are produced. When chiral aldehydes are used in such reactions, the diastereoselectivity also depends on the relative rate by which the enantiomers of the racemic allenylmetallic species interconvert, i.e., relative to the rate of addition to the chiral aldehyde. Apart from reactions of allenyllithium and -titanium reagents with aldehydes90-94, few such intermolecular, simple diastereoselective reactions yielding allenes have been reported. 

The principal factor that was responsible for the rebirth of the venerable aldol reaction as a modem method of synthesis was the discovery that its stereochemistry can be controlled quite effectively through the use of preformed enolates. In this section is discussed simple diastereoselection, reactions between prochiral enolates and prochiral aldehydes (equation 37) the synJanti stereochemical notation is employed. ... 

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.). 

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

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

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. 

Stereoselective Carbonyl Addition Reactions I.3.3.3.2.2.I. With Simple Diastereoselectivity... 

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. 

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). 

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. 

A completely different dipolar cycloaddition model has been proposed39 in order to rationalize the stereochemical outcome of the addition of doubly deprotonated carboxylic acids to aldehydes, which is known as the Ivanov reaction. In the irreversible reaction of phenylacetic acid with 2,2-dimethylpropanal, metal chelation is completely unfavorable. Thus simple diastereoselectivity in favor of u f/-adducts is extremely low when chelating cations, e.g., Zn2 + or Mg- +, are used. Amazingly, the most naked dianions provide the highest anti/syn ratios as indicated by the results obtained with the potassium salt in the presence of a crown ether. 

A more effective control of both simple diastereoselectivity and induced stereoselectivity is provided by the titanium enolate generated in situ by transmetalation of deprotonated 2,6-dimethylphenyl propanoate with chloro(cyclopentadienyl)bis(l,2 5,6-di-0-isopropylidene-a-D-glucofuranos-3-0-yl)titanium. Reaction of this titanium enolate with aldehydes yields predominantly the. yyw-adducts (syn/anti 89 11 to 97 3). The chemical yields of the adducts are 24 87% while the n-u-products have 93 to 98% ee62. 

Asymmetric Bond Formation with Simple Diastereoselection 1.4.5.3.1. Intermolecular Reactions... 

Very recently a number of intermolecular a-amidoalkylation reactions related to the formation of C-C bonds with simple diastereoselection have been reported only activated 7t-nucle-ophiles, such as allylsilanes, enamines, enol ethers, etc. are used83 - 88. 

High, simple diastereoselection was also observed on the reaction of the anion of racemic (Z)-1-(phenylsulfinyl)-2-butene (2 equiv) with a nonracemic bicyclic chiral enone (1 equiv) giving a 7-1,4-adduct in 82% eeI5b. 

In a recent study, simple diastereoselectivities in the reactions of 2-butenylsilanes with cyclo-hexenone were reported24 25. As shown in the table below, the double-bond geometry plays a principal role in the stereochemical outcome of the reaction. In general, the ( )-2-butenylsi-lanes gave better selectivities, whereas the effect of the silyl substituents was hard to correlate with the changes in selectivity. 

Summary of the Relationship between Diastereoselectivity and the Transition Structure. In this section we considered simple diastereoselection in aldol reactions of ketone enolates. Numerous observations on the reactions of enolates of ketones and related compounds are consistent with the general concept of a chairlike TS.35 These reactions show a consistent E - anti Z - syn relationship. Noncyclic TSs have more variable diastereoselectivity. The prediction or interpretation of the specific ratio of syn and anti product from any given reaction requires assessment of several variables (1) What is the stereochemical composition of the enolate (2) Does the Lewis acid promote tight coordination with both the carbonyl and enolate oxygen atoms and thereby favor a cyclic TS (3) Does the TS have a chairlike conformation (4) Are there additional Lewis base coordination sites in either reactant that can lead to reaction through a chelated TS Another factor comes into play if either the aldehyde or the enolate, or both, are chiral. In that case, facial selectivity becomes an issue and this is considered in Section 2.1.5. 

If the substituents are nonpolar, such as an alkyl or aryl group, the control is exerted mainly by steric effects. In particular, for a-substituted aldehydes, the Felkin TS model can be taken as the starting point for analysis, in combination with the cyclic TS. (See Section 2.4.1.3, Part A to review the Felkin model.) The analysis and prediction of the direction of the preferred reaction depends on the same principles as for simple diastereoselectivity and are done by consideration of the attractive and repulsive interactions in the presumed TS. In the Felkin model for nucleophilic addition to carbonyl centers the larger a-substituent is aligned anti to the approaching enolate and yields the 3,4-syn product. If reaction occurs by an alternative approach, the stereochemistry is reversed, and this is called an anti-Felkin approach. 

Traditional models for diastereoface selectivity were first advanced by Cram and later by Felkin for predicting the stereochemical outcome of aldol reactions occurring between an enolate and a chiral aldehyde. [37] During our investigations directed toward a practical synthesis of dEpoB, we were pleased to discover an unanticipated bias in the relative diastereoface selectivity observed in the aldol condensation between the Z-lithium enolate B and aldehyde C, Scheme 2.6. The aldol reaction proceeds with the expected simple diastereoselectivity with the major product displaying the C6-C7 syn relationship shown in Scheme 2.7 (by ul addition) however, the C7-C8 relationship of the principal product was anti (by Ik addition). [38] Thus, the observed symanti relationship between C6-C7 C7-C8 in the aldol reaction between the Z-lithium enolate of 62 and aldehyde 63 was wholly unanticipated. These fortuitous results prompted us to investigate the cause for this unanticipated but fortunate occurrence. 

The analysis and prediction of the direction of preferred reaction depend on the same principles as for simple diastereoselectivity and are done by analysis of the attractive and repulsive interactions in the presumed transition state. 

Thus, in the example of the chiral olefin 3, there is simple diastereoselectivity of (m4a + m4b)/(m4c + m4d) and induced diastereoselectivities of m4a/m4b and m4c/m4d. It is not strictly necessary, but conversely there is no harm, in applying the term simple diastcrcosclcc-tivity to the first case, i.e., to a diastereoselective reaction of achiral reactants. In this volume the presentation of a given reaction type always begins with simple diastereoselectivity of achiral reactants. 

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