Diastereofacial selectivity aldol reaction

A highly diastereofacial /7-selective aldol reaction by using ester derivatives of norephedrine as a chiral auxiliary has been recently reported by Kurosu and Lorca (Scheme 38).138 This practical and general method proceeds via initial ( )-selective substrate enolization and provides access to a broad range of optically active 2-alkyl-3-hydroxycarboxylic acid esters of type 91. 

As with the above pyrrolidine, proline-type chiral auxiliaries also show different behaviors toward zirconium or lithium enolate mediated aldol reactions. Evans found that lithium enolates derived from prolinol amides exhibit excellent diastereofacial selectivities in alkylation reactions (see Section 2.2.32), while the lithium enolates of proline amides are unsuccessful in aldol condensations. Effective chiral reagents were zirconium enolates, which can be obtained from the corresponding lithium enolates via metal exchange with Cp2ZrCl2. For example, excellent levels of asymmetric induction in the aldol process with synj anti selectivity of 96-98% and diastereofacial selectivity of 50-200 116a can be achieved in the Zr-enolate-mediated aldol reaction (see Scheme 3-10). 

Although the results are easily rationalised in the case of the a-alkylation (attack of the electrophile at the Re face, i.e., attack from the less hindered a face), in the aldol condensation it is somewhat more difficult to rationalise and several factors should be considered. According to Evans [14] one possible explanation for the diastereofacial selection observed for these chiral enolates is illustrated in Scheme 9.14. In the aldol reactions, the more basic carbonyl group of the aldehyde partner interacts with the chelated boron enolate 45 to give the "complex" A which may... 

Darzens reaction of (-)-8-phenylmethyl a-chloroacetate (and a-bromoacetate) with various ketones (Scheme 2) yields ctT-glycidic esters (28) with high geometric and diastereofacial selectivity which can be explained in terms of both open-chain or non-chelated antiperiplanar transition state models for the initial aldol-type reaction the ketone approaches the Si-f ce of the Z-enolate such that the phenyl ring of the chiral auxiliary and the enolate portion are face-to-face. Aza-Darzens condensation reaction of iV-benzylideneaniline has also been studied. Kinetically controlled base-promoted lithiation of 3,3-diphenylpropiomesitylene results in Z enolate ratios in the range 94 6 (lithium diisopropylamide) to 50 50 (BuLi), depending on the choice of solvent and temperature. ... 

An interesting class of chiral enolates are allenyl enolates. These ambident nucleophiles bear an axis of chirality. Krause and coworkers have found that an axis to center chirality transfer takes place in the aldol reaction of chiral magnesium allenyl enolate with pivalic aldehyde . The aldol reaction proceeds with good diastereofacial selectivity if... 

Asymmetric aldol reactions5 (11, 379-380). The lithium enolate of the N-propionyloxazolidinone (1) derived from L-valine reacts with aldehydes with low syn vs. anti-selectivity, but with fair diastereofacial selectivity attributable to chelation. Transmetallation of the lithium enolate with ClTi(0-i-Pr)3 (excess) provides a titanium enolate, which reacts with aldehydes to form mainly the syn-aldol resulting from chelation, the diastereomer of the aldol obtained from reactions of the boron enolate (11, 379-380). The reversal of stereocontrol is a result of chelation in the titanium reaction, which is not possible with boron enolates. This difference is of practical value, since it can result in products of different configuration from the same chiral auxiliary. 

In 1992 Ghosh and co-workers provided the first example of the utility of rigid cis-1 -amino-2-indanol-derived oxazolidinone 36 as the chiral auxiliary in the asymmetric. vv//-aldol reaction.60-61 Aldol condensation of the boron enolate of 37 with various aldehydes proceeded with complete diastereofacial selectivity. Effective removal and recovery of the chiral auxiliary was carried out under mild hydrolysis conditions (Scheme 24.6). As both enantiomers of the chiral auxiliary were readily available, both enantiomers of the. yyn-aldol could be prepared with equal asymmetric induction. 

Although methods for stereocontrol of the aldol reaction are well documented, including diastereofacial selectivity in reactions of chiral enolates,25 stereocontrol in Mannich reactions appears to have received relatively little attention.26-30... 

The most direct method for the preparation of polyol frameworks is without doubt the aldol reaction. The diastereofacial selectivity of the reaction can be controlled by /J-alkoxy groups in both the methylketone enolate and the aldehyde. As investigations by Evans [6] and Paterson [7] and their groups have demonstrated, the correct selection of enolization conditions and the protective group for the )8-hydroxy group are important for the stereocontrol of the reaction. 

Chiral Auxiliary for Asymmetric Induction. Numerous derivatives of (—)-8-phenylmenthol have been utilized for asymmetric induction studies. These include inter- and intramolecular Diels-Alder reactions, dihydroxylations, and intramolecular ene reactions of a,p-unsaturated 8-phenylmenthol esters. These reactions usually proceed in moderate to good yield with high diastereofacial selectivity. a-Keto esters of 8-phenylmenthol (see 8-Phenylmenthyl Pyruvate) have been used for asymmetric addition to the keto group, as well as for asymmetric [2 -F 2] photoadditions and nucleophilic alkylation. Ene reactions of a-imino esters of 8-phenylmenthol with alkenes provide a direct route to a-amino acids of high optical purity. Vinyl and butadienyl ethers of 8-phenylmenthol have been prepared and the diastereofacial selectivity of nitrone and Diels-Alder cycloadditions, respectively, have been evaluated. a-Anions of 8-phenylmenthol esters also show significant diastereofacial selectivity in aldol condensations and enantiose-lective alkene formation by reaction of achiral ketones with 8-phenylmenthyl phosphonoacetate gives de up to 90%. ... 

There is a dichotomy in the sense of syn-anti diastereofacial preference, dictated by the bulkiness of the migrating group [94]. The sterically demanding silyl group results in syn diastereofacial preference but the less demanding proton leads to anti preference (Sch. 35). The anti diastereoselectivity in carbonyl-ene reactions can be explained by the Felkin-Anh-like cyclic transition-state model (Ti) (Sch. 36). In the aldol reaction, by contrast, the now inside-crowded transition state (Ti ) is less favorable than Tg, because of steric repulsion between the trimethylsilyl group and the inside methyl group of aldehyde (Ti ). The syn-diastereofacial selectivity is, therefore, visualized in terms of the anti-Felkin-like cyclic transition-state model (T2 )-... 

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. 

Gennari, C., Vieth, S., Comotti, A., Vulpetti, A., Goodman, J. M., Paterson, I. Diastereofacial selectivity in the aldol reactions of chiral a-methyl aldehydes a computer modelling approach. Tetrahedron 1992, 48,4439-4458. 

The utility of BF3-OEt2, a monodentate Lewis acid, for acyclic stereocontrol in the Mukaiyama aldol reaction has been demonstrated by Evans et al. (Scheme 10.3) [27, 28]. The BF3-OEt2-mediated reaction of silyl enol ethers (SEE, ketone silyl enolates) with a-unsubstituted, /falkoxy aldehydes affords good 1,3-anti induction in the absence of internal aldehyde chelation. The 1,3-asymmetric induction can be reasonably explained by consideration of energetically favorable conformation 5 minimizing internal electrostatic and steric repulsion between the aldehyde carbonyl moiety and the /i-substituents. In the reaction with anti-substituted a-methyl-/ -alkoxy aldehydes, the additional stereocontrol (Felkin control) imparted by the a-substituent achieves uniformly high levels of 1,3-anti-diastereofacial selectivity. 

The stereoselectivity of the antibody-catalyzed addition of acetone to aldehyde 67 revealed that the ketone was added to the re-face of 67 regardless of the stereochemistry at C2 of this substrate. The aldol process follows a classical Cram-Felkin mode of attack on (S)-67 to generate the (4S,5S)-68 diastereomer and the anti-Cram-Felkin mode of attack on the (R)-67 to yield the (4S,5R)-69 diastereomer. The products are formed at a similar rate and yield, therefore there is no concomitant kinetic resolution of the racemic aldehyde. The two antibodies differ in their diastereofacial selectivity, reflecting the ability of the antibodies to orient the 67 on opposite sides of the prochiral faces of the nucleophilic antibody-enamine complex of acetone. Heath cock and Flippin [79] have shown that the chemical reaction of the lithium enolate of acetone with (S)-67 yields the (4S,5S)-68 diastereomer a 5% de for this Cram-Felkin product. The generation of the (4S,5R)-69 and (4R,5R)-70 products in a ratio of 11 1 by the... 

In connection with the synthesis of podophyllum lignans, ester (62) was deprotonated and the resulting enolate condensed with 3,4,5-trimethoxybenzaldehyde to give a 1 1 mixture of diastereomeric aldols (equation 68). The structure of (63) was established by X-ray analysis the other diastereomer was assigned the 2,3-anti relative stereochemistry (64) on circumstantial evidence. It was suggested that the 1 1 mixture of isomeric products results from a 1 1 mixture of the ( )- and (Z)-enolate, each of which shows complete simple and diastereofacial selectivity in its reactions with 3,4,5-trimethoxybenzaldehyde. For this to be true, it is also necessary that the ( )-enolate reacts through a non-Zimmerman , boat-like transition state, whereas the (Z)-enolate reacts through the normal chair-like transition state. 

The dianion of the hydroxybutyrolactone (87) reacts with aldehydes with high diastereofacial selectivity to give mixtures of dihydroxy lactones (88) and (89) (equation 76 Table 5). ° The lithium enolate shows little simple stereoselection with the sterically undemanding aldehydes phenylacetaldehyde and tetradecanal. Significant stereoselectivity is seen in the reaction with benzaldehyde, and pivalaldehyde gives only a single product. Because the aldol relative stereochemistry in the reactions with benzalde-... 

In the Woodward erythromycin synthesis, the lithium enolate of t-butyl thiopropionate was added to aldehyde (151) aldol (152) was obtained in 85% yield (equation 99). The remarkable diastereofacial selectivity observed in this reaction may be a general property of thioester enolates. (v/de infra). 

The major and minor products obtained in aldol reactions of chiral aldehyde (168 equation 109) are not those predicted by Cram s rule, presumably because the lithium cation is chelated by the alkoxy and aldehyde oxygens, leading to a rigid six-meml red intermediate that undergoes attack primarily from its unsubstituted face. " Similar behavior, with somewhat higher diastereofacial selectivity (5 1), is seen with the magnesium enolate (equation 50). 

Although alkylation of 3-hydFoxy ester dianions occurs with high diastereofacial selectivity, the aldol reaction of the dianion obtained from methyl 3-hydroxybutanoate with benzaldehyde gives all four dia-stereomeric aldols in a ratio of 43 34 14 9 (equation 117). On the other hand, dianions of 8-hydroxy esters show rather good diastereofacial preferences under the proper conditions. Deprotonation of t-butyl-5-hydroxyhexanoate with lithium diethylamide in the presence of lithium triflate gives an enolate that reacts with benzaldehyde to give aldols (196) and (197) in a ratio of 91 9 (equation 118). Use of the r-butyldimethylsilyl ether instead of the alcohol resulted in no facial preference. 

Chiral acetate (204) shows excellent diastereofacial selectivity and has obvious utility as a reagent for asymmetric aldol reactions. As shown in equation (122), reaction of (204) with benzaldehyde provides diastereomers (205) and (206). As shown in Table 23, entry 1, the diastereoselectivity is 83% if the lithium enolate is formed in the conventional manner and the aldol reaction is carried out in THF at -78 C. A significant improvement is obtained by using the magnesium enolate (Table 23, entry 5), and diastereoselectivity of up to 98% is obtained by the use of very low reaction temperatures (Table 23, entries 10-13). 

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