Enolates anti-aromatic

The rate of enolate-carbonyl equilibration " is dependent on the forward and backward rates of proton exchange. Proton exchange from a carbon-based acid is known to be slower than that of a more electronegative atom donor (in particular, O and N atoms) . For a series of closely related molecules usually the more acidic a given molecule is, the faster the rate of proton transfer (high kreu note that thermodynamic and kinetic parameters are not related). For example, benzocyclobutanone (10) is less acidic and the rate of deprotonation is substantially slower (10 times) than the related benzocyclopentanone (12) due to its enolate (11) having unfavourable anti-aromatic character. Deprotonation of the simplest cyclobutanone (13) clearly does not lead to an unfavourable anti-aromatic enolate (14) . By assuming the internal strain of 14 is similar to that of 11, cyclobutanone (13) is evidently 10 " times more acidic than benzocyclopentanone (12). By the same vain, the more acidic propanone (15) has a faster rate of deprotonation (10 times) than the less acidic ethyl acetate (16) . ... 

Arjona and Plumet recently contributed to the study of the use of non-aromatic enol and thioenol ethers as dienophiles with inverse electronic demand [140]. Cydoadditions using 76a also proved to be endo-selective and regiospecific (Figure 25). The regioisomers obtained were those having the heteroatom of the dienophile component adjacent (ortho) and anti to the carbonyl function, rather than ortho and anti to the dimethyl ketal function, as in the... 

Boryl enolates prepared from A-propionylsultam reacted with aliphatic, aromatic and a,/Tunsaturated aldehydes to provide diastereomerically pure. qw-aldols (Equation (174), whereas the presence of TiCl4 caused complete reversal of the diastereoface selectivity giving anti-aldols (Equation (175)).676-678 Camphor-derived chiral boryl enolates 423 were highly reactive and highly anti-selective enolate synthon system in aldol addition reactions promoted by TiCl4 or SnCl4 co-catalyst (Equation (176)).679... 

Through the use of a tin(iv) enolate with benzaldehyde it was possible to generate the anti A diastereomer 47 with high selectivity (Entry 5). With tin(n) etiolates a highly substituent-dependent outcome was observed. Low selectivities resulted with para-substituted aromatic aldehydes, but good selectivities were observed for ortho-substituted aromatic aldehydes (Entries 7-9). Simultaneous re-... 

For acyclic systems, the anti diastereoselectivity of the (i )-enolates is lower than the syn diastereoselectivity of comparable (Z)-enolates. For example, carboxylic acid esters, which form predominantly ( )-enolates, react with aldehydes with high anti selectivity only in those cases where bulky aromatic substituents are in the alcoholic part of the ester22 25. 

In summary, boryl enolate 38 can be obtained via in situ O-borylation of N-propionylsultam 37 and converted to aldol product 40 upon treatment with aliphatic, aromatic, or a,/l-unsaturatcd aldehdyes at - 78°C in the presence of TiCU- As aldol product 40 can normally be obtained in crystalline form, in most cases diastereomerically pure anti- Ao 40 can also be obtained after the recrystallization. 

On the other hand, the method of Mukaiyama can be succesfully applied to silyl enol ethers of acetic and propionic acid derivatives. For example, perfect stereochemical control is attained in the reaction of silyl enol ether of 5-ethyl propanethioate with several aldehydes including aromatic, aliphatic and a,j5-unsaturated aldehydes, with syir.anti ratios of 100 0 and an ee >98%, provided that a polar solvent, such as propionitrile, and the "slow addition procedure " are used. Thus, a typical experimental procedure is as follows [32e] to a solution of tin(II) triflate (0.08 mmol, 20 mol%) in propionitrile (1 ml) was added (5)-l-methyl-2-[(iV-l-naphthylamino)methyl]pyrrolidine (97b. 0.088 mmol) in propionitrile (1 ml). The mixture was cooled at -78 °C, then a mixture of silyl enol ether of 5-ethyl propanethioate (99, 0.44 mmol) and an aldehyde (0.4 mmol) was slowly added to this solution over a period of 3 h, and the mixture stirred for a further 2 h. After work-up the aldol adduct was isolated as the corresponding trimethylsilyl ether. Most probably the catalytic cycle is that shown in Scheme 9.30. 

The range of suitable aldehydes was investigated using the organocatalyst (S,S)-52 and the cyclohexanone-derived trichlorosilyl enolate 51 as prototypical ( )-enolate (Scheme 6.27) [84], Irrespective of the aldehyde used high yields of 90 to 98% were obtained. The diastereoselectivity was excellent for aromatic and unsaturated aldehydes, with anti/syn ratios between 61 1 and >99 1. Enantioselectivity for the anti enantiomer was high, between 88 and 97% ee. Selected examples are given in Scheme 6.27. The acetylenic aldehyde led to somewhat lower diastereo- and enantioselectivity (anti/syn ratio 5.3 1 anti-adduct 82% ee). 

The reaction also proceeds efficiently with (Z)-enolates, as has been demonstrated with the trichlorosilyl enolate derived from propiophenone, (Z)-58 (Scheme 6.28). With aromatic and olefinic aldehydes the syn products syn-59-63 were formed as preferred diastereomers in high yields (89 to 97%) and with moderate to high syn/anti ratio (3.0 1 to 18 1). Enantioselectivity for the preferred syn diaster-... 

For satisfactory diemo- and stereoselectivity, most catalytic, direct cross-aldol methods are limited to the use of non enolizable (aromatic, a-tert-alkyl) or kineti-cally non enolizable (highly branched, ,/funsaturated) aldehydes as acceptor carbonyls. With aromatic aldehydes, however, enantioselectivity is sometimes moderate, and the dehydration side-product may be important. With regard to the donor counterpart, the best suited pronucleophile substrates for these reactions are symmetric ketones (acetone) and ketones with only one site amenable for enolization (acetophenones). With symmetric cyclic or acyclic ketones superior to acetone, syn/anti mixtures of variable composition are obtained [8b, 11, 19a]. Of particularly broad scope is the reaction of N-propionylthiazolidinethiones with aldehydes, which regularly gives high enantioselectivity of the syn aldol adduct of aromatic, a,fi-unsaturated, branched, and unbranched aldehydes [13]. 

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... 

Friedel-Crafts alkylation has been used in an important synthesis of aryl C-glycosides, which are potent anti-tumor agents, from glycosyl fluorides (equation 99)65 661. The reaction takes place rapidly in dichloromethane, at room temperature using a novel zirconium complex and silver perchlorate combination catalyst. A similar alkylation has been performed by replacing the aromatic compound with either a silyl enol ether or an allylic compound using silver triflate as the catalyst662,663. 

Both the nature of solvent and the temperature influenced the stereochemistry of boron enolates, with the solvent effect being greater than that of the temperature. Aliphatic and alicyclic hydrocarbon solvent favored the formation of yy/z-aldols at — 78 °C, whereas aromatic and chlorinated aliphatic solvents favored the formation of anti-dXdoh at 0-25 °C (Equation (179)).682 683... 

The second Heck reaction involves a naphthyl iodide (Ar2 = 2-naphthyl) but the initial mechanism is much the same. However, the enol ether has two diastereotopic faces syn or anti to the aromatic substituent (Ar1) introduced in the first step. Palladium is very sensitive to steric effects and generally forms less hindered complexes where possible. Thus coordination of the palladium(II) intermediate occurs on the face of the enol ether anti to Ar1. This in turn controls all the subsequent steps, which must be syn, leading to the trans product. The requirement for syn p-hydride elimination also explains the regiochemical preference of the elimination. In this cyclic structure there is only one hydrogen (green) that is syn the one on the carbon bearing the naphthyl substituent is anti to the palladium and cannot be eliminated.. ... 

Recently, studies were carried out to explain the exo/endo selectivity the Patemo-Buchi reaction [30]. These studies were carried out mostly achiral or racemic substrates. Excited monocyclic aromatic aldehydes 33 re in their 3n,/rr state with cyclic enol ether derivatives like 2,3-dihydrofuran (Scheme 8) [31]. In these cases, the sterically disfavored endo isomer 35a obtained as major product. This result was explained by the fate of the trip biradical intermediate G. In order to favor cyclization to the oxetanes 35a,b, radical p-orbitals have to approach in a perpendicular fashion to increase spin-orbit coupling needed for the triplet to singlet intersystem crossing [32]. sterically most favored arrangement of this intermediate is depicted as G. encumbering Ar substituent is orientated upside and anti to the trihydrofur moiety. Cyclization from this conformation yields the major isomer 35a. 

Enolates derived from a-haloimides also exhibit metal-dependent syn/anti-d do diastereoselection. The derived Li, Sn, and Zn enolates afford the anti isomer in reactions with aromatic aldehydes, while the corresponding B and Sn enolates lead to the conventional syn products. The non-Evans syn adducts... 

For the propionate aldol reaction the Li enolate (7), generated by deprotonation of 2,6-dimethylphenyl propionate with Lithium Diisopropylamide in EtiO, was chosen. Transmetalation with 1.25 equiv of an ethereal solution of (1) takes 24 h at —78 °C. The completion of this step is evident by the disappearance of racemic anti-a do (9) in favor of optically active yw-isomer (10) (91-98% ee) upon reaction with an aldehyde (RCHO) and aqueous workup. At this point, 3-11% of anri-aldol (9) remaining in the reaction mixture is optically active as well (eq 2). This awri-isomer (9) (94-98% ee) becomes the major product if the reaction mixture, containing the putative ( )-titanium enolate derived from (7), is warmed for 4-5 h to —30°C before reaction with an aldehyde (RCHO) again at —78 °C. Isomerization to the (Z)-titanium enolate is a possible explanation of this behavior. Some substrates, aromatic and unsaturated aldehydes, behave exceptionally, as a high proportion of yn-isomer (10) (19-77%) of lower optical purity (47-66% ee) is formed in addition to (9) (94-98% ee). After hydrolysis of the acetonide (6) the products (9/10) are isolated and separated by chromatography in 50-87% yield. The reactions of pivalaldehyde (R = r-Bu) are sluggish at —78°C and have therefore been carried out at —50 to —30°C. 

Asymmetric synthesis of 1,2-diol derivatives based on asymmetric aldol reactions of a-alkoxy silyl enol ethers with aldehydes has been developed. The reaction of (Z)-2-benzyloxy-l-(5)-ethyl-l-trimethylsiloxyethene with benzaldehyde was conducted in dichloromethane at -78 °C with a chiral promoter consisting of Sn(OTf)2, (5)-l-ethyl-2-[(piperidin-l-yl)methyl]pyrrolidine, and Bu2Sn(OAc)2, to afford the corresponding aldol adduct in 83 % yield with 99 % anti preference. The enantiomeric excess of anti aldol is 96 % [38a]. In the aldol reaction of several kinds of aldehydes, e.g. aromatic,... 

Stereoselective Mukaiyama-Michael reactions, Heathcock et alJ have investigated the syn anti stereoselectivity in the reaction of twelve silyl enol ethers with a variety of acyclic and cyclic enones catalyzed by TiCh or SnCh. Preliminary results suggest that the stereoselectivity is independent of the geometry of the silyl enol ether, and that silyl enol ethers derived from aliphatic ketones show a preference for (2n /-addition ranging from 1.5 1 to 10 1. The preference for a/ift-addition is even higher in the case of (Z)-silyl enol ethers of aromatic ketones (10 1 to >20 1). However, high 5y/i-selectivity is observed with acyclic -butyl enones. 

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