Asymmetric induction solvent effect

A characteristic solvent effect on the asymmetric induction is observed. 

Structural and Solvent Effects in the Asymmetric Induction of Chalcone Epoxides... 

As is the case in all other quinine-catalyzed reactions, the quininium-salt-catalyzed phase-transfer reactions are subject to strong solvent effects (Table 8) (81). The fact that, in the presence of water, polar solvents lower the e.e., whereas apolar solvents raise the e.e., indicates that these are true phase-transfer reactions in which the ion pairs within the organic layer are responsible for the asymmetric induction. 

Catalyst 329, prepared from trimethylaluminum and 3,3/-bis(triphenylsily 1)-1,1 /-bi-2-naphthol, allowed the preparation of the endo cycloadduct (2S )-327 with 67% ee. The use of non-polar solvents raised the ee, but lowered the chemical yield213. Recently, it was reported that the reaction to form 327 exhibited autoinduction when mediated by catalyst 326214. This was attributed to a co-operative interaction of the cycloadduct with the catalyst, generating a more selective catalytic species. A wide variety of carbonyl ligands were tested for their co-operative effect on enantioselectivity. Sterically crowded aldehydes such as pivaldehyde provided the best results. Surprisingly, 1,3-dicarbonyl compounds were even more effective than monocarbonyl compounds. The asymmetric induction increased from 82 to 92% ee when di(l-adamantyl)-2,2-dimethylmalonate was added while at the same time the reaction temperature was allowed to increase by 80 °C, from -80 °C to 0°C. 

A marked solvent effect on the sense of asymmetric induction was observed. For example, reduction of acetophenone with 65 in refluxing ether gave the (R)-alcohol in 48% optical yield, and reduction in boiling THF gave die (S)-alcohol in 9.5% optical yield. A number of other similar reversals were observed. In ether solvent, an empirical relationship can be drawn between the configuration of the alcohol used for preparation of the reducing complex and the configuration of the enantiomeric product alcohol formed in excess. The relationship depends on the type of substrate used and is summarized in Table 8. 

The optical yield was found to be very sensitive to structural modifications of the achiral agent. For example, use of the more bulky FV or Bu substituents in the 3,5-positions of phenol resulted in lower optical yields. In some cases a reversal of the sense of asymmetric induction was observed. Systematic variation of reaction conditions using the best achiral component, 3,5-xylenol, established that optimum results were obtained in ether solvent at about - 15°C. There was also a minor but definite influence of the rate of addition of ketone as well as an effect of concentration on optical yield, with a slower rate being advantageous. The results of reduction of aryl alkyl ketones are shown in Table 9, along with comparative results of reduction with similar chiral auxiliary reagents. 

An example of the solvent effect is also seen in the reaction of 3-acryloyl-l,3-oxazolidin-2-one (15b) which did not give sufficient asymmetric induction by the previous method.(18) The reaction of 15b with butadiene in 1,3,5-TMB gives the 3-cyclohexenecarboxylic acid derivative 22 in 77% optical purity. 

The C-H activation of allylic and benzylic C-H bonds has considerable application in organic synthesis. Studies by Muller [131] and Davies [130] on reactions with cyclohexene revealed that Rh2(S-DOSP)4 in a hydrocarbon solvent is the optimum system for high asymmetric induction (Tab. 14.13). Although this particular example gives a mixture of the C-H activation product 179 and cyclopropane 180, similar reactions with ethyl diazoacetate gave virtually no C-H activation product. Some of the other classic chiral dirhodium catalysts 181 and 182 were also effective in this chemistry, but the en-antioselectivity with these catalysts (45% ee and 55% ee) [131] was considerably lower than with Rh2(S-DOSP)4 (93% ee) [130]. 

Electron-deficient oxazoline thiourea 222 turned out to be the most effective catalyst concerning activity (93% yield/48h/THF) and asymmetric induction (88% ee/rt) in contrast to 218-221, which gave poor results (Figure 6.62). The solvent screening revealed aprotic THF to be the solvent of choice, while polar prohc... 

A study on the combined use of a chiral substrate obtained by alcoholysis of a 4-benzylidene-5(4//)-oxazolone with a chiral alcohol coupled with hydrogenation using a chiral catalyst has also been described. This work shows that the matching effect of double asymmetric induction in hydrogenation can be modulated by a solvent effect. 

Some aspects of the chemistry of helicenes require still more attention. Since the interpretation of the mass spectrum of hexahelicene by Dougherty 159) no further systematic work has been done on the mass spectroscopy of helicenes, to verify the concept of an intramolecular Diels-Alder reaction in the molecular ion. Though the optical rotation of a number of helicenes is known and the regular increase of the optical rotation with increasing number of benzene rings has been shown, the dependence of the rotation on the helicity is still unknown. The asymmetric induction in the synthesis of helicenes by chiral solvents, or in liquid crystals, though small, deserves still more attention because application to other organic compounds will be promoted when the explanation of observed effects is more improved. 

Complex LSB 9 is readily prepared either by the reaction of La(0 Pr)3 with 3 equiv. of B1NOL followed by the addition of NaO Bu (3 equiv.) or by the reaction of LaCl nfLO with sodium binaphthoxide. The complex 9 is stable to oxygen and moisture and has been proven to be effective in the catalytic Michael reaction of various enones with either malonates or p-keto esters. The Michael adducts with up to 92% ee were obtained in almost quantitative yield. Typical results with malonates are summarized in Table 8D.1 (Ln = lanthanide) [18], In general, the use of THF as solvent gave the best results except for the case of the LSB-catalyzed reaction of rmns-chalcone with dimethyl malonate, wherein the use of toluene was essential to give the adduct with good enantiomeric excess. The effects of the central metal (La, Pr, and Gd) on asymmetric induction were also examined in the same reaction, and LSB was found to be the best catalyst. 

When (PPh3)3PdCl2 is used as the catalyst precursor and optically active alcohols are used as the hydrogen donors, a small asymmetric induction occurs (see Table II) which could be due to a solvent effect (25). However, the large influence of the alcohol structure on re-gioselectivity suggests that the alcohol residue is present in (at least one of) the catalytic complexes. 

Kotsuki et al.909 have developed a method to effect the Michael addition of [3-ketoesters with ethyl acrylate in the presence of triflic acid under solvent-free conditions [Eq. (5.335)]. Nonactivated cyclohexanones as Michael donors and a,/3-unsaturated ketones as acceptors are also reactive. The use of menthyl acrylates did not result in any significant asymmetric induction. 

The choice of solvent has had little, if any, influence on the majority of Diels-Alder reactions.210,211 Although the addition of a Lewis acid might be expected to show more solvent dependence, generally there appears to be little effect on asymmetric induction.118129 However, a dramatic effect of solvent polarity has been observed for chiral metallocene triflate complexes.212 The use of polar solvents, such as nitromethane and nitropropane, leads to a significant improvement in the catalytic properties of a copper Lewis acid complex in the hetero Diels-Alder reaction of glyoxylate esters with dienes.213... 

An alternative access to L-amino acids was found by using chloroform as solvent in the asymmetric Strecker synthesis with galactosyl imines [24], This interesting reverse of asymmetric induction compared to the reactions shown in Scheme 5 can be explained by considering the zinc complex A as the crucial reactive species. Due to the exo anomeric effect, which is a delocalization of the 7r-electrons into the a of the ring C-O-bond, the imines adopt the conformation represented in Scheme 8. 

Coupling attempts conducted with (R,S)-214 led to lower enantioselection upon C-C bond formation, an observation that points to the significant role played by the relative configuration (R,R) of the binaphthyl and ethylenediamine units in promoting asymmetric induction. This complex was found to be the most efficient among several different structural variations. Solvent effects on this transformation were also studied (Table 35), with toluene and chlorobenzene giving the best results. Low solubility of the catalyst (diethyl ether and diiso-... 

The cholesteric mesophase formed by cholesteryl p-nitrobenzoate at 200 °C has been used as the solvent to effect an asymmetric synthesis lrans-but-2-enyl p-tolyl ether gave the product of an ortho-Claisen rearrangement, 2-(but-1 -en-3 -yl)-4-methylphenol. This material exhibited circular dichroism, although neither the optical yield nor the configuration of the product is yet known.262 Decarboxylation of ethylphenylmalonic acid in cholesteryl benzoate at 160 °C (cholesteric liquid-crystalline phase) also proceeded with asymmetric induction to give (R)-(—)-2-phenylbutyric acid, with 18% optical yield.263 Electric dipole moments are reported for some esters of 5a-cholest-8(14)-en-3j8-ol there is some slight correlation with melting points.264... 

After early unsuccessful attempts to direct the photoreduction of ketones with chiral secondary alcohols [8-10]. Weiss et al. examined the sensitized cis-trans photoisomerization of 1,2-diphenylcyclopropane in chiral solvents but obtained the product without detectable optical rotation [11]. Seebach and coworkers were the first to achieve asymmetric induction for a photochemical reaction by a chiral solvent [12-15]. They examined the photopinacolization of aldehydes and ketones in the chiral solvent (S,S)-( + )-l,4-bis(dimethylamino)-2,3-dimethoxybutane (DDB, 4). Irradiation of acetophenone in the presence of 7.5 equiv. of DDB yielded a mixture of chiral d,/-pinacols 3/ent-3 and achiral meso-pinacol 2. At 25°C pinacol 3 was obtained with 8% ee, with the (R, / )-( + )-enantiomer prevailing. At lower temperatures the asymmetric induction was more effective, up to 23% ee at — 78°C in a 1 5 mixture of DDB and pentane (Scheme... 

In summary, chiral solvents have only induced limited enantioselectivity into different types of photochemical reactions as pinacolization, cyclization, and isomerization reactions. These studies are nevertheless very important, because they are among the early examples of chiral induction by an asymmetric environ ment. Based on our classification of chiral solvents as chiral inductors that only act as passive reaction matrices, effective asymmetric induction by this means seems to be intrinsically difficult. From the observed enantioselectivities it can be postulated that defined interactions with the prochiral substrate during the conversion to the product are a prerequisite for effective template induced enantioselectivity. 

Thus the hypothesis in Figure 3.4 is indeed effective for designing asymmetric synthesis. However, the main drawbacks in the transformation of 32 into 33 are low chemical yield and difficulty in removing the (V-mcthyl protective group. Further investigation of other (readily removable) nitrogen substituents and conditions for asymmetric induction are shown in Table 3.4. The best result was obtained with A-methoxymethyl(MOM)-A-Boc derivative 40. Treatment of 40 with KHMDS in toluene-THF (4 1) at —78°C for 30 minutes followed by the addition of methyl iodide afforded 41 in 96% yield and 81% ee (entry 9).27,28 Use of a toluene-THF (4 1) mixture as a solvent is crucial for both high yield and enantioselectivity (entries 7-9). 

A striking solvent effect was observed in the reduction of a chiral a-keto amide, C6H5-CO-CO-NR2 (NR2 = (5)-proline methyl ester), with sodium tetrahy-dridoborate, leading to mandelic acid after hydrolysis [704]. When the a-keto amide was reduced in pure tetrahydrofuran or methanol, the resulting enantiomeric excess of (5)-mandelic acid produced was 36% and 4%, respectively. However, when a tetrahydrofuran/methanol (99 1 cL/L) solvent mixture was used, the enantiomeric excess increased to 64% ( ). In other solvent mixtures, a catalytic amount of a protic solvent (CH3OH or H2O) was found to be necessary for good asymmetric induction [704]. 

Finally, examples of highly diastereoselective hydroxy enoate iodo-cyclizations will be mentioned. In the first case, the homoallylic asymmetric induction in the formation of 2,4-disubsti-tuted tetrahydrofurans was investigated41. When the ( )-substrates 3 were iodo-cyclized, the diastereomeric products 4 were formed in ca. 86% yield their relative abundance depended both on the nature of R and the solvent. The effect of the substituent R was interpreted by means of AM 1 calculations41. 

---