Enolates facial selectivity

The facial selectivity of a number of more specialized enolates has also been explored, sometimes with surprising results. Schultz and co-workers compared the cyclic enolate H with I." Enolate H presents a fairly straightforward picture. Groups such as methyl, allyl, and benzyl all give selective (3-alkylation, and this is attributed to steric factors. Enolate I can give either a- or (3-alkylation, depending on the conditions. The presence of NH3 or use of LDA favors a-alkylation, whereas the use... 

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. 

Among the most useful carbonyl derivatives are (V-acyloxazolidinones, and as we shall see in Section 2.3.4, they provide facial selectivity in aldol addition reactions. l,3-Thiazoline-2-thiones constitute another useful type of chiral auxiliary, and they can be used in conjunction with Bu2B03SCF3,44 Sn(03SCF3)2,45 or TiCl446 for generation of enolates. The stereoselectivity of the reactions is consistent with formation of a Z-enolate and reaction through a cyclic TS. 

In the discussion of the stereochemistry of aldol and Mukaiyama reactions, the most important factors in determining the syn or anti diastereoselectivity were identified as the nature of the TS (cyclic, open, or chelated) and the configuration (E or Z) of the enolate. If either the aldehyde or enolate is chiral, an additional factor enters the picture. The aldehyde or enolate then has two nonidentical faces and the stereochemical outcome will depend on facial selectivity. In principle, this applies to any stereocenter in the molecule, but the strongest and most studied effects are those of a- and (3-substituents. If the aldehyde is chiral, particularly when the stereogenic center is adjacent to the carbonyl group, the competition between the two diastereotopic faces of the carbonyl group determines the stereochemical outcome of the reaction. 

Stereochemical Control by the Aldehyde. A chiral center in an aldehyde can influence the direction of approach by an enolate or other nucleophile. This facial selectivity is in addition to the simple syn, anti diastereoselectivity so that if either the aldehyde or enolate contains a stereocenter, four stereoisomers are possible. There are four possible chairlike TSs, of which two lead to syn product from the Z-enolate and two to anti product from the A-enolate. The two members of each pair differ in the facial approach to the aldehyde and give products of opposite configuration at both of the newly formed stereocenters. If the substituted aldehyde is racemic, the enantiomeric products will be formed, making a total of eight stereoisomers possible. 

E- and Z-silyl thioketene acetals give the 2,3-anti product. The 3,4-syn ratio is 50 1, and is consistent with the Felkin model. When this nucleophile reacts with 2-benzyloxypropanal (Entry 8), a chelation product results. The facial selectivity with respect to the methyl group is now reversed. Both isomers of the silyl thioketene acetal give mainly the 2,3-syn-3A-syn product. The ratio is higher than 30 1 for the Z-enolate but only 3 1 for the F-enolate. 

Stereochemical Control by the Enolate or Enolate Equivalent. The facial selectivity of aldol addition reactions can also be controlled by stereogenic centers in the nucleophile. A stereocenter can be located at any of the adjacent positions on an enolate or enolate equivalent. The configuration of the substituent can influence the direction of approach of the aldehyde. 

Polar effects appear to be important for 3 -alkoxy substituents in enolates. 3-Benzyloxy groups enhance the facial selectivity of /(-boron enolates, and this is attributed to a TS I in which the benzyloxy group faces toward the approaching aldehyde. This structure is thought to be preferable to an alternate conformation J, which may be destabilized by electron pair repulsions between the benzyloxy oxygen and the enolate oxygen.109... 

In summary, the same factors that operate in the electrophile, namely steric, chelation, and polar effects, govern facial selectivity for enolates. The choice of the Lewis acid can determine if the enolate reacts via a chelate. The final outcome depends upon the relative importance of these factors within the particular TS. 

Scheme 2.4 provides some specific examples of facial selectivity of enolates. Entry 1 is a case of steric control with Felkin-like TS with approach anti to the cyclohexyl group. 

Scheme 2.5 gives some additional examples of double stereodifferentiation. Entry 1 combines the steric (Felkin) facial selectivity of the aldehyde with the facial selectivity of the enolate, which is derived from chelation. In reaction with the racemic aldehyde, the (R)-enantiomer is preferred. 

Entry 2 involves the use of a sterically biased enol boronate with an a-substituted aldehyde. The reaction, which gives 40 1 facial selectivity, was used in the synthesis of 6-deoxyerythronolide B and was one of the early demonstrations of the power of double diastereoselection in synthesis. In Entry 3, the syn selectivity is the result of a chelated TS, in which the (3-p-methoxybenzyl substituent interacts with the tin ion.120... 

Entry 4 has siloxy substituents in both the (titanium) enolate and the aldehyde. The TBDPSO group in the aldehyde is in the large Felkin position, that is, perpendicular to the carbonyl group.121 The TBDMS group in the enolate is nonchelated but exerts a steric effect that governs facial selectivity.122 In this particular case, the two effects are matched and a single stereoisomer is observed. 

Titanium enolates also can be prepared from /V-acyloxazolidinones. These Z-enolates, which are chelated with the oxazolidinone carbonyl oxygen,128 show syn stereoselectivity, and the oxazolidinone substituent exerts facial selectivity. 

The boron enolates of a-substituted thiol esters also give excellent facial selectivity.135 CH(CH3)2 (CHg"/ -CH2)2BCI... 

The facial selectivity in these chiral boron enolates has its origin in the steric effects of the boron substituents. 

With titanium enolates it was found that use of excess (3 equiv.) of the titanium reagent reversed facial selectivity of oxazolidinone enolates.140 This was attributed to generation of a chelated TS in the presence of the excess Lewis acid. The chelation rotates the oxazolidinone ring and reverses the facial preference, while retaining the Z-configuration syn diastereoselectivity. 

Scheme 2.7 gives some examples of the control of stereoselectivity by use of additional Lewis acid and related methods. Entry 1 shows the effect of the use of excess TiCl4. Entry 2 demonstrates the ability of (C2H5)2A1C1 to shift the boron enolate toward formation of the 2,3-anti diastereomer. Entries 3 and 4 compare the use of one versus two equivalents of TiCl4 with an oxazoldine-2-thione auxiliary. There is a nearly complete shift of facial selectivity. Entry 5 shows a subsequent application of this methodology. Entries 6 and 7 show the effect of complexation of the aldehyde... 

Summary of Facial Stereoselectivity in Aldol and Mukaiyama Reactions. The examples provided in this section show that there are several approaches to controlling the facial selectivity of aldol additions and related reactions. The E- or Z-configuration of the enolate and the open, cyclic, or chelated nature of the TS are the departure points for prediction and analysis of stereoselectivity. The Lewis acid catalyst and the donor strength of potentially chelating ligands affect the structure of the TS. Whereas dialkyl boron enolates and BF3 complexes are tetracoordinate, titanium and tin can be... 

The facial selectivity of the aldehydes 22A and 22B is dependent on both the configuration at the fi-ccnter and the nature of the enolate as indicated by the data below. Consider possible transition structures for these reactions and offer a rationale for the observed facial selectivity. 

Dicarbonyl donors bearing a thioester has been applied in the Mannich reaction to A -tosyl imines. Ricci presented an enantioselective decarboxylative addition of malonic half thioester 37 to imine 38. In the Mannich-type addition, catalyst 36 deprotonates the malonic acid thioester followed by decarboxylation to generate a stabilized thioacetate enolate. This stabilized anion reacts with facial selectivity to the imine due to steric-tuning from 36 [47] (Scheme 8). 

Considerable effort has been devoted to finding Lewis acid or other catalysts that could induce high enantioselectivity in the Mukaiyama reaction. As with aldol addition reactions involving enolates, high diastereoselectivity and enantioselectivity requires involvement of a transition state with substantial facial selectivity with respect to the electrophilic reactant and a preferred orientation of the nucleophile. Scheme 2.4 shows some examples of enantioselective catalysts. 

One of the factors directing the alkylation of an enolate is the Jt-facial selectivity. The differences in reactivity of the two diastereotopic faces of the enolate, due to steric and electronic features, contribute to the steric control of the alkylation (for extensive reviews, see refs 1, 4, and 30). Likewise, stereoelectronic features are important control elements for C- versus O-alkylation, as illustrated by the cyclization of enolates 1 and 3 via intramolecular nucleophilic substitution 39. 

The opportunity for chelation in the various enolate intermediates offers a possible explanation for the observed diastereoselectivities. In the dianions derived from l-acyl-2-pyrrolidinemethanols strong chelation of both of the lithium cations should lead to a rigid enolate structure 9. It is reasonable to assume that the pyrrolidine ring is locked in one conformation. Since, according to models, it is difficult to attribute the observed high diastereoselectivity to steric hindrance, it is probable that the lone pair on the nitrogen directs the facial selectivity of electrophilic attack (see Section 1.1.1.3.3.1.) to one side of the enolate a-carbon. 

In the reaction of a simple ketone enolate with a chiral aldehyde, the use of a zinc enolate may offer advantages in terms of facial selectivity with respect to the use of a lithium enolate. This is exactly the result recorded in the condensation of the kinetic enolate of 2-undecanone 140 with 141, the key step in a total synthesis of (-l-)-preussin 142, a fermentation product with antifungal and antibacterial activity (equation 77)169. While 2-undecanone Li enolate did not display stereocontrol when added to 141, an acceptable syn diastereoselectivity was displayed by the Zn enolate 140. 

The idea that the stereochemical outcome of an intramolecular enolate alkylation is determined by chelation in the transition state was recently demonstrated by Denmark and Henke, who observed a marked preference for a "closed transition state (coordination of the cationic counterion to an enolate and the developing alcohol) resulting in a syn product. For example, the highest syn anti ratio (89 11) was obtained in toluene and the lowest syn.anti ratio (2 98) was obtained with a crown ether. These observations parallel the facial selectivities described herein and in ref 11 on the intramolecular SN2 reaction see (a) Denmark, S. A. Henke, B. R. J. Am. Chem. Soc. 1991, 113, 2177. (b) Denmark, S. A. Henke, B. R. J. Am. Chem. Soc. 1989, 111, 8022. 

Excellent (3-facial selectivity on the enolate was observed, but there was a lower facial selectivity on the aldehyde partner. The cation was of tremendous importance, as seen from the reversal of selectivity when going from lithium to zinc or magnesium enolates [12] (Scheme 40). This is explained by a Zimmerman-Traxler model in which a... 

The yields ranged from good to excellent, and the syn-2,6-disubstituted tetrahy-dropyran products 203 were formed stereoselectively. The facial selectivity in the addition to the aldehyde, however, was minimal, as might be expected considering the distance between the reactive end of the enol function and the stereogenic center in enols 200 and 201. 

The facial selectivity of the dihydroxylation can reliably be predicted using the mnemonic device 42. The smallest substituent on the olefin (generally the hydrogen) is always placed in the south-east quadrant (H), which is the most hindered space in the asymmetric environment. The south-west quadrant (RL) is especially attractive for large aliphatic groups in the case of PYR 39 and for aromatic groups in the case of PHAL 43. Use of DHQD 40 causes dihydroxylation from the /9-side. Treatment of enol ether 9 with the common (DHQD)2PHAL-system provides only 32 % ee. 

The alternative strategy of using d,v-aminoindanol as a chiral auxiliary on the Michael donor has also been explored.81 Chiral amide enolates were reacted with a,P-unsaturated ester 70, and the resultant adducts were reduced and cyclized to 8-lactones 73 to determine the facial selectivity on the Michael acceptor. It is interesting that protected amino alcohol 71 did not lead to significant diastereofacial discrimination, whereas 72 afforded lactone 73 with high 4-(,S )-selectivity (Scheme 24.15). 

The N—Li bond of azaenolate D lies outside the plane of the enolate. The structure created via chelation is a rigid polycyclic species. In this structure, the 4 and 5 carbons of the pyrollidine ring block one side of the azaenolate, resulting in facial selectivity during alkylation. The alkylation product E is formed preferentially with the -configuration shown. Only traces of the 3 -configured product are formed. 

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