Simple diastereoselectivity aldehydes

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. 

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... 

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... 

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 ... 

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. 

When a mixture of aldehydes and (Z)-l-ethylthio-l-trimethylsilyloxy-l-propene is added slowly to a solution of tin(Il) triflate and 10-20 mol% of the chiral diamine 4 in acetonitrile, /1-silyloxy thioesters 5 are obtained in high simple diastereoselection and induced stereoselectivity. Thus, the chiral auxiliary reagent can be used in substoichiometric amount. A rationale is given by the catalytic cycle shown below, whereby the chiral tin(II) catalyst 6 is liberated once the complex 7 has formed33. 

The exchange of tert-butyl for a smaller group, e.g., alkyl or 4-methylpheny], causes a decrease in the induced diastereoselectivity70. If a prostereogenic aldehyde is used, in addition. the problem of simple diastereoselectivity arises and four diastereomeric products are... 

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 E-crotylboronate derivatives 28 and 75 behave similarly. As shown in Eqs. 61 and 62, these reagents were successfully tested with simple ahphatic aldehydes and benzaldehyde and provide very high levels of stereoselectivity in the formation of anti-propionate products. Although the a-methoxy derivative 75 is more diastereoselective, it provides lower enantioselectivity because it can be obtained only in 90% ee from enantiopure 28 via an Sn2 displacement that canses some erosion of the enantiomeric purity. 

Simple diastereoselectivity in intermolecular reactions, such as the addition of allenyl- or alkynylmetal complexes to aldehydes and ketones90 91, has remained until recently virtually unexplored92-94. 

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. 

In addition to simple diastereoselectivity, high levels of induced diastereoselectivity may be obtained, for example, with racemic 2-phenylpropanal, where the induced diastereoselectivity due to diastereoface differentiating attack of the organometallic reagent on the aldehyde is 82 18. 

Catalysis with Bisoxazoline Complexes of Sn(II) and Cu(II). The bisoxazoline Cu(IT) and Sn(II) complexes 81-85 that have proven successful in the acetate additions with aldehydes 86,87, 88 also function as catalysts for the corresponding asymmetric propionate Mukaiyama aldol addition reactions (Scheme 8B2.8) [27]. It is worth noting that eithersyn or anti simple diastereoselectivity may be obtained by appropriate selection of either Sn(II) or Cu(II) complexes (Table 8B2.12). 

A simple diastereoselective route to 2,3,6-trisubstituted-2,3-dihydro-4-pyridones from a diketoester, aryl aldehydes, and ammonium acetate has been reported (Equation 168) <2005TL5511>. 

Fig. 11.15. Analysis of the overall stereoselectivity of a Still—Gennari olefination such as the one in Figure 11.13 simple diastereoselectivity of the formation of the alkoxide intermediate from the achiral phosphonate A and the achiral aldehyde B. For both reagents the terms "back face" and "front face" refer to the selected projection.

Let us now consider the stereostructures C/ent-C of the two enantiomeric Still-Gennari intermediates of Figure 11.15 from another point of view. The simple diastereoselectivity (see Section 11.1.3) with which the phosphonate A and the aldehyde B must combine in order for the alkoxides C and ent-C to be produced is easy to figure out. If we use the formulas as written in the figure, this simple diastereoselectivity can be described as follows the phosphonate ion A and the aldehyde B react with each other in such a way that a back facephosphonate/back faceaidehyde linkaSe (formation of alkoxide C) and a front facephosphonate/front facealdehyde linkage (formation of alkoxide ent-C) take place concurrently. 

Fig. 11.16. Analysis of the simple diastereoselectivity of a Still-Gennari olefination that starts from the enantiomeri-cally pure phosphonate A and the achiral aldehyde B.

The simple diastereoselectivity of aldol reactions was first studied in detail for the Ivanov reaction (Figure 13.45). The Ivanov reaction consists of the addition of a carboxylate enolate to an aldehyde. In the example of Figure 13.45, the diastereomer of the /1-hydroxycarboxylic acid product that is referred to as the and-diastereomer is formed in a threefold excess in comparison to the. vy/j-diastereoisomer. Zimmerman and Traxler suggested a transition state model to explain this selectivity, and their transition state model now is referred to as the Zimmer-man-Traxler model (Figure 13.46). This model has been applied ever since with good success to explain the simple diastereoselectivities of a great variety of aldol reactions. 

The simple diastereoselectivity of the photocycloaddition of electronically excited carbonyl compounds with electron rich olefins was studied as a function of the substituent size—at identical starting conditions ignoring the electronic state involved in the reaction mechanism [123], The [2+2] photocycloaddition of 2,3-dihydrofuran with different aldehydes in the nonpolar solvent benzene resulted in oxetanes 118 with high regioselectivity and suprising simple diastereoselectivites the addition to acetaldehyde resulted in 45 55 mixture of endo and exo diastereoisomer, with increasing the size of the ot-carbonyl substituent (Me, Et, i-Bu, t-Bu), the simple diastereoselectivity increased with preferential formation of the endo stereoisomer (Sch. 37). 

Recently, the effect of hydrogen bonding in the first excited singlet vs. the first excited triplet state of aliphatic aldehydes in the photocycloaddition to allylic alcohols and acetates (147) was compared (Sch. 51) [147]. The simple diastereoselectivity was nearly the same, but the presence of... 

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