Chiral acrylates

The catalyst played an important role in the asymmetric synthesis of Corey lactone based on high diastereofacial selective Diels-Alder reaction between chiral acrylate 37 and 5-benzyloxymethylcyclopentadiene [41] (Equation 3.9). The cycloadduct 38 was then converted into chiral Corey lactone [42] by a three-step procedure. 

Clay-catalyzed asymmetric Diels-Alder reactions were investigated by using chiral acrylates [10]. Zn(II)- and Ti(IV)-K-10 montmorillonite, calcined at 55 °C, did not efficiently catalyze the cycloadditions of cyclopentadiene (1) with acrylates that incorporate large-size chiral auxiliaries such as cA-3-neopentoxyisobornyl acrylate (2) and (-)-menthyl acrylate (3, R = H) (Figure 4.1). This result was probably due to diffusion problems. 

Asymmetric base-catalyzed Diels-Alder reaction of 3-hydroxy-2-pyrone with chiral acrylate derivatives [106]... 

The ene reaction of fuUerene (C o) with 3-methylene-2,3-dihydrofuran gives an easily isolated addition product in good yield <96JOC2559>. There is a continuous need for chiral acrylate esters for asymmetric Diels-Alder reactions with high diastereoselectivity. Lewis acid promoted Diels-Alder reactions of acrylate esters from monobenzylated isosorbide 28 (or isomannide) and cyclopentadiene provided exclusively e db-adducts with good yields and high diastereoselectivity <96TL7023>. 

Dipolar addition is closely related to the Diels-Alder reaction, but allows the formation of five-membered adducts, including cyclopentane derivatives. Like Diels-Alder reactions, 1,3-dipolar cycloaddition involves [4+2] concerted reaction of a 1,3-dipolar species (the An component and a dipolar In component). Very often, condensation of chiral acrylates with nitrile oxides or nitrones gives only modest diastereoselectivity.82 1,3-Dipolar cycloaddition between nitrones and alkenes is most useful and convenient for the preparation of iso-xazolidine derivatives, which can then be readily converted to 1,3-amino alcohol equivalents under mild conditions.83 The low selectivity of the 1,3-dipolar reaction can be overcome to some extent by introducing a chiral auxiliary to the substrate. As shown in Scheme 5-51, the reaction of 169 with acryloyl chloride connects the chiral sultam to the acrylic acid substrate, and subsequent cycloaddition yields product 170 with a diastereoselectivity of 90 10.84... 

Hansen and colleagues177 used (+)-pantolactone as a chiral auxiliary to achieve asymmetric induction in the first step toward their synthesis of d.v-perhydroisoq uinol inc 278. The titanium tetrachloride catalyzed reaction between 1,3-cyclohexadiene (275) and chiral acrylate 276 proceeded with high diastereofacial selectivity to give 277 (94% de) in 75% yield (equation 77). 

Nieman and Keay198 reported the use of c/.v,c/s-spiro 4,4]nonanc-1, 6-diol as a new chiral auxiliary to be used in asymmetric Diels-Alder reactions. Their best results in a series of reactions between chiral acrylates and cyclopentadiene were obtained when the pivalate ester of ds,ds-spiro[4,4]nonane-l,6-diol was used as the chiral auxiliary. When 318 was treated with cyclopentadiene, the expected endo adduct 319 was obtained with more than 97% de (equation 88). 

SCHEME 8. Stereodichotomy of the Lewis acid catalysed Diels-Alder reactions of a chiral acrylic ester and cyclopentadiene... 

The use of chiral auxiliaries to induce (or even control) diastereoselectivity in the cycloaddition of nitrile oxides with achiral alkenes to give 5-substituted isoxazolines has been investigated by a number of groups. With chiral acrylates, this led mostly to low or modest diastereoselectivity, which was explained in terms of the conformational flexibility of the vinyl-CO linkage of the ester (Scheme 6.33) (179). In cycloadditions to chiral acrylates (or acrylamides), both the direction of the facial attack of the dipole as well as the conformational preference of the rotamers need to be controlled in order to achieve high diastereoselection. Although the attack from one sector of space may well be directed or hindered by the chiral auxiliary, a low diastereomer ratio would result due to competing attack to the respective 7i-faces of both the s-cis and s-trans rotamers of the acrylate or amide. 

The camphor-derived chiral acrylate 160a was used in reactions with nitrones by Olsson (272) (Scheme 12.51). They observed low endo/exo-selectivity, but excellent diastereofacial discrimination in the reactions of cyclic nitrones with 160a. They also studied the reactions of nitrile oxides with 160a,b. Fair selectivity of up to 68-75% de was obtained. However, for the reaction of the crotonyl derivative 160b with nitrile oxides, mixtures of regiomers were obtained. 

The chiral acrylate 164 was used in a 1,3-dipolar cycloaddition with a nitrile imine. Bis(trityl)nitrile imine was found to undergo a diastereoselective 1,3-dipolar cycloaddition with (f )-a-(acyloxy)-p,p-dimethyl-y-butyrolactone 164 to give the 2-pyrazoline product with a de of 50% (Scheme 12.51) (275). 

Enantioselective Diels-Alder reaction,3 The reaction of the chiral acrylate ester 1 with butadiene catalyzed with this Lewis acid followed by hydride reduction gives the alcohol 2 in 70% chemical yield and 86-91% ee. A1C13 and SnCl4 are inferior in terms of either the chemical or optical yield. The product (2) was used for a chiral synthesis of (R)-(- )-sarkomycin (4). 

Most of the approaches outlined in Figure 15.10 have been successfully realized on insoluble supports, either with the alkene or alkyne linked to the support, or with support-bound 1,3-dipoles (Table 15.16). Nitrile oxides are highly reactive 1,3-dipoles and react smoothly with both electron-poor and electron-rich alkenes, including enol ethers [200]. The addition of resin-bound nitrile oxides to alkenes (Entries 5 and 6, Table 15.16) has also been accomplished enantioselectively under catalysis by diisopropyl tartrate and EtMgBr [201], The diastereoselectivity of the addition of nitrile oxides and nitrones to resin-bound chiral acrylates has been investigated [202], Intramolecular 1,3-dipolar cycloadditions of nitrile oxides and nitrones to alkenes have been used to prepare polycyclic isoxazolidines on solid phase (Entries 7 and 9, Table 15.16). 

A photo-induced [6+2] cycloaddition of the chiral acrylate 28 with the chromium carbonyl complex 27 afforded the endo- AAuct 29 in high diastereomeric excess (Equation 3) <1995JOC7392>. 

The first examples of the diastereoselective aminohydroxylation of chiral acryl amides, R3CH=C(R2)CONHCH (Me)R1, have been reported. The reaction is believed to proceed within the so-called second catalytic cycle with diastereoisomeric excesses (g) reaching >99 1. The reaction relies solely on the stereochemical information provided by the enantiomerically pure starting materials. A stereochemical model for the observed asymmetric induction has been proposed.128... 

Carbonyl compounds have also been used as electrophiles with the intermediate 719 to afford a-allenic alcohols758,783 788 1016 1030,1033-1051 and, after hydrolysis, the corresponding hydroxy enones1034 1037 1051. The chiral acrylate equivalent endo-2-acryloylisoborneol (726), used in metal-free Diels-Alder reactions, has been prepared by reaction of (-El-camphor with compound 7191039 (Scheme 190). 

Evans DA, Chapman KT, Bisaha J (1984) New asymmetric Diels-Alder cycloaddition reactions. Chiral a,fS-unsaturated carboximides as practical chiral acrylate and crotonate dienophile synthons. J Am Chem Soc 106 4261-4263... 

Asymmetric Di ls-Alder reactions. The chiral acrylate (2) of (IR)-l undergoes cycloaddition with cj clopentadiene to give the adduct (2R)-3 with high enr/o-selectivity and high asymmetric induction (99.3% de) in the presence of a mild Lewis acid catalyst. 

In reactions of the chiral acrylate and crotonate imides with cyclopentadiene, endo-products are formed almost exclusively, with diastereoselection of about 95%. Examples ... 

In addition to being an efficient chiral controller in a number of stereoselective transformations of chiral acrylates, (i.e. the Diels-Alder reaction, the conjugate reduction, the asymmetric dihydroxylation, and the nitrile oxide cycloaddition ) the bomanesultam (11) has been shown to be an exceptionally efficient chiral auxiliary for stereoselective aldol condensations (eqs eq 3 and eq 4). Depending upon the reaction conditions, A -propionylsultam can produce either the syn or anti aldol product with an excellent diastereoselectivity, Furthermore, good diastereoselectiv-ities are also observed for the corresponding acetate aldol reaction (eq 5), ... 

Cycloadditions. Oppolzer first used this chiral acrylate derivative as an auxiliary in the Diels-Alder reaction with cyclopen-tadiene. Promotion by Lewis acids such as TiCU SnCU, and Et2AlCl provides the adduct in greater than 90% de (eq 1). Lithium perchlorate-promoted [4 + 2] reaction between 1 and 1-acetoxybutadiene was similarly effective." More recently, an exo-selective Diels-Alder addition of 1 with 2-acylamino dienes provided a single diastereomer in 80% yield. Cyclopentane formation is possible through exposure of 1 to methylenecyclo-propane and Ni(0) (eq 2). An example of a higher-order cycloaddition with 1 gave only low diastereoselection (78 22) for the endo product. 

Table 19 Influence of Conditions Upon Diastereoselectivity in Cycloadditions to Chiral Acrylates...

Table 3 Cycloadditions of Methylenecydopropancs with Chiral Acrylic Acid Derivatives, Catalyzed by...

Asymmetric Diels-Alder reactions have been the subject of some of the more thorough mechanistic studies. Fairly reliable structural models for predicting the outcome of these reactions exist. In a review of the subject, it has been suggested that the stereochemical course of the reaction of a variety of chiral acrylates could be consistently predicted based on two models (Figures 39 and 40). Model A positions the complex in a (Z)-syn-s-trans conformation and presumes attack from the least-hindered face of the double bond. This model is consistent with almost all of the structural data for systems of this type (e.g. SnCWethyl cinnamate X-ray diffraction study). Contrapuntally, the large number of experimental observations that can be explained by this model support the assumption that the crystal structure conformation (26) is relevant to the course of these reactions. 

Reaction of ketyls. The carbonyl group reacts with Smlj to generate ketyl species which may be reduced further. Capture of the ketyls with suitable reactants expands the utility of the samarium chemistry. Important reactions include butyrolactone synthesis that is amenable to asymmetric induction when chiral acrylic esters are employed. The reagent system (catalytic in Smij) generated in situ from Smij and Zn-Hg is more economical. The system also contains Lil and MCjSiOTf, and in practice MejSiOTf is added to the mixture of the other components at just the rate to maintain a light blue color (indicating the presence of Smij). When Nilj is added as a catalyst, p-propiolactone instead of acrylic esters can be used. Sometimes steric factors preclude cyclization, and 7-hydroxy esters result. Ketyl addition to acrylamides opens a route to 1,4-amino alcohols. ... 

Reactions involving a variety of terpene-derived, chiral acrylic amides and esters at least partly lead to equally remarkable yields and diastereoselectivities (Table 2). A more detailed discussion including experimental procedures is available. ... 

Table 2. [3 -I- 2] Cycloadducts from the Nickel(0)-Catalyzed Reaction of Methylenecyclopropane with Chiral Acrylic Ester Derivatives ...

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