Diastereoselectivity in the aldol reaction

Tab. 3.2. Diastereoselectivity in the aldol reactions between ( )- or (Z)-/ -silyl ester enolates and aldehydes (Scheme 3.7).

FIGURE 14. Selected sterically demanding non racemic alcohols allowing high diastereoselectivities in the aldol reaction of their lithium enol acetates555,556... 

Fig. 1 Enantio- and diastereoselectivities in the aldol reaction using rare earth metal triflates and ionic diameters (eight-coordination for Sc, nine-coordination for other metals) of the metal cations (M3+). ee ((2R,3R)% - (2S,3S)%) yields 49-95%.

The foregoing reactions bear a resemblance to the reactions of 3-keto ester dianions vide supra, equation 32), in that reaction occurs at C-4 instead of C-2. The only study of simple diastereoselection in the aldol reactions of 3-keto ester dianions shows a stereochemical similarity as well. As shown in equation (84), the dianions of a series of 3-keto esters react with aldehydes to give largely the trans lactone (126) data are summarized in Table 10. ° ... 

Table 11 Enantioselectivity and Diastereoselectivity in the Aldol Reactions of Methyl Isocyanoacetate Under Catalysis by Chiral Ferrocenylphosphine-Gold Complexes (equation 22)...

In order to reverse the diastereoselectivity in the aldol reaction, the Lewis acid-catalyzed silyl enol ether addition (73) (Mukaiyama aldol reaction) was examined. Since the Mukaiyama aldol reaction is assumed to be proceeded via an acyclic transition state, a chelation controled aldol reaction of the a-alkoxy aldehyde should be possible (74). In the presence of TiCU, the silyl enol ether derived from 14 was reacted with aldehyde 13, followed by desilylation to afford the desired anti-Felkin product 122a as a single adduct (Scheme 21). Based on precedents for chelation-controlled Mukaiyama aldol reaction (74), the exceptional high selectivity in this reaction would be accounted for by chelation of TiCl4 with the C23-methoxy group of the aldehyde 13 (eq. 13). On the other hand, when the lithium enolate derived from 14 was treated with the aldehyde 13, followed by desilylation, it gave a 1 4 ratio of the two epimers in favour of the undesired (22S)-aldol product... 

Hagiwara, H., K. Kimura, and H. Uda High Diastereoselection in the Aldol Reaction of the Bistrimethylsilyl Enol Ether of Methyl Acetoacetate with 2-Benzyloxy-hexanal Synthesis of (-)-Pestalotin. J. Chem. Soc. (London) Perkin Trans. 1, 693 (1992). 

The enantiomers are obtained as a racemic mixture if no asymmetric induction becomes effective. The ratio of diastereomers depends on structural features of the reactants as well as the reaction conditions as outlined in the following. By using properly substituted preformed enolates, the diastereoselectivity of the aldol reaction can be controlled. Such enolates can show E-ot Z-configuration at the carbon-carbon double bond. With Z-enolates 9, the syn products are formed preferentially, while fi-enolates 12 lead mainly to anti products. This stereochemical outcome can be rationalized to arise from the more favored transition state 10 and 13 respectively ... 

Scheme 2.3 shows reactions of several substituted aldehydes of varying complexity that illustrate aldehyde facial diastereoselectivity in the aldol and Mukaiyama reactions. The stereoselectivity of the new bond formation depends on the effect that reactant substituents have on the detailed structure of the TS. The 3,4-syn stereoselectivity of Entry 1 derives from a Felkin-type acyclic TS. 

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. 

Even greater diastereoselectivity in die aldol reaction can be achieved using boron etiolates as the carbon nucleophile. Boron etiolates are easily prepared from aldehydes and ketones, and the syn and die anti isomers can be separated as pure compounds. They react with aldehydes and ketones to give aldol products by a similar transition state. The difference is fliat boron oxygen bonds are shorter than lidiium oxygen bonds, and thus steric interactions in the transition state are magnified and result in greater diastereoselectivity. 

For an excellent discussion of diastereoselectivity in the aldol and related reactions see M. B. Smith, Organic Synthesis, McGraw-Hill, New York, 1994, Chapter 9, pp. 857-964. 

Asymmetric induction in the aldol reaction of enolsilane and metal enolate nucleophiles with yS-substituted aldehydes gives rise to both excellent yields and good diastereoselectivities (equation 128)507. The best diastereoselectivity was obtained using a trimethylsilyl enolate in the presence of boron trifluoride-etherate (92 8 anti. syn). The key step in the synthesis of the N-terminal amino acid analogue of nikkomycin B and Bx (nucleoside peptide antibiotics) has been performed using this type of methodology508. 

High anti-diastereoselectivity is observed for several aromatic imines for ortho-substituted aromatic imines the two newly formed stereocenters are created with almost absolute stereocontrol. Aliphatic imines can also be used as substrates and the reaction is readily performed on the gram scale with as little as 0.25 mol% catalyst loading. Furthermore, the Mannich adducts are readily transformed to protected a-hydroxy-/8-amino acids in high yield. The absolute stereochemistry of the Mannich adducts revealed that Et2Zn-linked complex 3 affords Mannich and aldol adducts with the same absolute configuration (2 R). However, the diastereoselectiv-ity of the amino alcohol derivatives is anti, which is opposite to the syn-l,2-diol aldol products. Hence, the electrophiles approach the re face of the zinc enolate in the Mannich reactions and the si face in the aldol reactions. The anti selectivity is... 

Ghosh also took advantage of the C—2 hydroxyl moiety of aminoindanols as a handle in the aldol reaction. Chiral sulfonamide 41 was O-acylated to give ester 42. The titanium enolate of ester 42 was formed as a single isomer and added to a solution of aldehyde, precomplexed with titanium tetrachloride, to yield the anft -aldol product 43 in excellent diastereoselectivities.63 One additional advantage of the ester-derived chiral auxiliaries was their ease of removal under mild conditions. Thus, hydrolysis of 43 afforded a ft -a-methyl- 3-hydroxy acid 44 as a pure enantiomer and cis-1-/ -1 o I y I s u I f on a m i do- 2 - i n da n ol was recovered without loss of optical purity (Scheme 24.7).63... 

First, chemoselective (Chapter 24) conjugate addition of the silyl ketene acetal on the enone is preferred to direct aldol reaction with the aldehyde. Then an aldol reaction of the intermediate silyl enol ether on the benzaldehyde follows. The stereoselectivity results, firstly, from attack of benzalde-hyde on the less hindered face of the intermediate silyl enol ether, which sets the two side chains trans on the cyclohexanone, and, secondly, from the intrinsic diastereoselectivity of the aldol reaction (this is treated in some detail in Chapter 34). This is a summary mechanism. 

Such p-silyl enolate intermediates also react with aldehydes with high diastereoselectivity with respect to both new chiral centers being created, the relative stereochemistry in the aldol reaction being dependent upon the original geometry of the enolate double bond (Scheme 13). This aldol reaction has... 

Amide Enolates. The lithium (Z)-enolate can be generated from (5)-4-benzyl-3-propanoyl-2,2,5,5-tetra-methyloxazolidine and Lithium Diisopropylamide in THF at —78 °C. Its alkylations take place smoothly in the presence of Hexamethylphosphoric Triamide with high diastereoselec-tivity (eq 3), and its Michael additions to a,(3-unsaturated carbonyl compounds are also exclusively diastereoselective (eq 4). Synthetic applications have been made in the aldol reactions of the titanium (Z)-enolates of a-(alkylideneamino) esters. ... 

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 )-... 

Table XVII shows the maximum acid strength of Al-Mont catalyst in various organic solvents. In CHjClj or PhCHj, strongly acidic sites (//q < —8.2) were detected on Al-Mont. On the other hand, the acid strength of Al-Mont was weakened to -5.6 < Hq < -3.0 in DME. 1,2-Dimethoxyethane is a relatively basic molecule and thus interacts with the acid sites on montmoril-lonite to reduce their acid strength. The diastereoselectivity of the aldol reaction catalyzed by Al-Mont probably relates to the acid strength of Al-Mont because the degree of interaction between aldehydes (acetals) and acid sites on Al-Mont is affected by the acid strength of acid sites and influences the stabilities of the transition states which involve both enolsilane and aldehyde.

As mentioned previously, it can be more difficult to predict syn anti diastereoselectivity in Mukaiyama aldol reactions of substituted ketones. However, the reward of high stereocontrol in these reactions is attainable as shown in Scheme 9-12. While the second example shows disappointing aldehyde face selectivity, there is strong enolate facial bias 5-anti in both 32 and 33). Therefore,... 

The Sn(OTf)2-based chiral promoter system enables highly selective synthesis of both enantiomers of the aldol adducts by using similar types of chiral diamines derived from L-proline (Scheme 10.47). Diamines 50d and 50h are highly effective chiral sources for the synthesis of (2S,3K) and 2R,3S) adducts, respectively, from 52a [135]. In the aldol reaction of 52b, diamines 50f and 50g realize the selective synthesis of both enantiomers of the syn adducts [136]. The sense of diastereoselectivity can also be controlled by choice of the diamine ligands. The use of 50 g... 

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