Enantioselective equivalents

As a result of the many advantages of the allyl p-ketoesters, we were able to quickly prepare a large number of substrates and demonstrate that the reaction gave yields and enantioselectivities equivalent to the other classes of substrates (Table 9). Additionally, we were able to access a number of products that we had not been able to access previously, such as enantioenriched tertiary fluorides, vinylogous esters and thioesters, nitrogen heterocycles, and compounds containing multiple quaternary stereocenters. These advances comprised the bulk of our secmid paper in the field [25]. 

Because the Corey synthesis has been extensively used in prostaglandin research, improvements on the various steps in the procedure have been made. These variations include improved procedures for the preparation of norbomenone (24), alternative methods for the resolution of acid (26), stereoselective preparations of (26), improved procedures for the deiodination of iodolactone (27), alternative methods for the synthesis of Corey aldehyde (29) or its equivalent, and improved procedures for the stereoselective reduction of enone (30) (108—168). For example, a catalytic enantioselective Diels-Alder reaction has been used in a highly efficient synthesis of key intermediate (24) in 92% ee (169). 

Since cbiral sulfur ylides racemize rapidly, they are generally prepared in situ from chiral sulfides and halides. The first example of asymmetric epoxidation was reported in 1989, using camphor-derived chiral sulfonium ylides with moderate yields and ee (< 41%) Since then, much effort has been made in tbe asymmetric epoxidation using sucb a strategy without a significant breakthrough. In one example, the reaction between benzaldehyde and benzyl bromide in the presence of one equivalent of camphor-derived sulfide 47 furnished epoxide 48 in high diastereoselectivity (trans cis = 96 4) with moderate enantioselectivity in the case of the trans isomer (56% ee). ... 

The nickel and cohalt aqua complexes were even more effective, both for catalytic activity and enantioselectivity, than the corresponding anhydrous complexes (Scheme 7.5). Addition of three equivalents of water to the anhydrous nickel complex recovered the catalytic efficiency. DBFOX/Ph complexes derived from manga-nese(II), iron(II), copper(II), and zinc(II) perchlorates, both anhydrous and vef. 

Effect of water additive was examined in the asymmetric Diels-Alder reactions catalyzed by the J ,J -DBF0X/Ph-Ni(C104)2 complex. After addition of an appropriate amount of water to the anhydrous complex A, the reaction with an excess amount of cyclopentadiene was performed at room temperature. Enantioselectivity was as high as 93% ee for the endo cycloadduct up to five equivalents of water added and the satisfactory level of 88% ee was maintained when 10 equivalents were added. However, enantioselectivity gradually decreased with the increased amounts of water added 83 and 55% ee from 15 and 50 equivalents, respectively (Scheme 7.11). When the reaction temperature went down to -40 °C, the enantioselectivity as high as 98% ee resulted up to 15 equivalents of water additive. The effect of methanol at room temperature was even more surprising. In the presence of 15 and 100 equivalents of methanol, high levels of enantioselectivities of 88% and 83% ee, respectively, were recorded for the reactions at room temperature. 

Accordingly, cyclic nitronates can be a useful synthetic equivalent of functionalized nitrile oxides, while reaction examples are quite limited. Thus, 2-isoxazoline N-oxide and 5,6-dihydro-4H-l,2-oxazine N-oxide, as five- and six-membered cyclic nitronates, were generated in-situ by dehydroiodination of 3-iodo-l-nitropropane and 4-iodo-l-nitrobutane with triethylamine and trapped with monosubstituted alkenes to give 5-substituted 3-(2-hydroxyethyl)isoxazolines and 2-phenylperhydro-l,2-oxazino[2,3-fe]isoxazole, respectively (Scheme 7.26) [72b]. Upon treatment with a catalytic amount of trifluoroacetic acid, the perhydro-l,2-oxazino[2,3-fe]isoxazole was quantitatively converted into the corresponding 2-isoxazoline. Since a method for catalyzed enantioselective nitrone cycloadditions was established and cyclic nitronates should behave like cyclic nitrones in reactivity, there would be a good chance to attain catalyzed enantioselective formation of 2-isoxazolines via nitronate cycloadditions. 

In order to obtain good yields, it is important to use dry solvent and reagents. The commercially available t-butyl hydroperoxide contains about 30% water for stabilization. For the use in a Sharpless epoxidation reaction the water has to be removed first. The effect of water present in the reaction mixture has for example been investigated by Sharpless et al. for the epoxidation of (E)-a-phenylcinnamyl alcohol, the addition of one equivalent of water led to a decrease in enantioselectivity from 99% e.e. to 48% e.e. 

Jacobsen has utilized [(salen)Co]-catalyzed kinetic resolutions of tenninal epoxides to prepare N-nosyl aziridines with high levels of enantioselectivity [72], A range of racemic aryl and aliphatic epoxides are thus converted into aziridines in a four-step process, by sequential treatment with water (0.55 equivalents), Ns-NH-BOC, TFA, Ms20, and carbonate (Scheme 4.49). Despite the apparently lengthy procedure, overall yields of the product aziridines are excellent and only one chromatographic purification is required in the entire sequence. 

The tridentate ligands C, L and M are effective catalysts for the enantioselective addition of dialkylzincs to aromatic aldehydes16,17. In particular, ligands L and M qualify as members of the chemical enzyme (chemzyme) class of synthetic reagents17, since they function in a predictable, clear-cut mechanistic way. As demonstrated by X-ray diffraction, the actual catalyst is a monomeric zinc chelate 2 formed in toluene at 50 C by reaction of L or M with one equivalent of diethylzinc. 

An application of this method is the enantioselective synthesis of a-amino acids [e.g., (5)-phenyl-glycine (11)]10. Hence, 8 can be regarded as a chiral synthetic equivalent of a carboxyl group. 

A -(l-Phenylpropyl)amidcs 3 are enantioselectively synthesized by alkylation of acylimines 2 generated in situ from N-(amidobenzyl)benzotriazoles 1 with diethylzinc in the presence of an enantiomerically pure promoter [(— )-(l/ 2.V)-A,A-dibutylnorcphcdrine, DBNE], The best results are obtained with one equivalent of 1, one equivalent of DBNE and two or three equivalents of diethylzinc in toluene at —78 =C with slow warming to room temperature before workup11. 

The enantioselective addition of organometallic reagents to, V-(trimethylsilyl)benzaldehyde imine (1) in the presence of enantiomerically pure modifiers has been investigated. The best result is obtained with butyllithium (the corresponding Grignard reagent affords both lower yield and selectivity, 1 fails to react with diethylzinc) and two equivalents of the enantiomerically pure diol 2 in diethyl ether. It should be noted that the choice of the solvent is crucial for the stereoselectivity of the reaction1 2 3 5 7 8 9. 

It should also be noted that the 5-exo-trig cyclization of achiral olefinic organolithiums has been found to proceed enantioselectively when conducted in the presence of a chiral ligand that serves to render the lithium atom stereogenic. Thus, for example, R) 1 -allyl-3-methylindolinc has been prepared in 86 % ee by cyclization of an achiral aryllithium in the presence of an equivalent of (-)-sparteine.15... 

The condensation of nitro compounds and imines, the so-called aza-Henry or nitro-Mannich reaction, has recently emerged as a powerful tool for the enantioselective synthesis of 1,2-diamines through the intermediate /3-amino nitro compounds. The method is based on the addition of a nitronate ion (a-nitro carbanion), generated from nitroalkanes, to an imine. The addition of a nitronate ion to an imine is thermodynamically disfavored, so that the presence of a protic species or a Lewis acid is required, to activate the imine and/or to quench the adduct. The acidic medium is compatible with the existence of the nitronate anion, as acetic acid and nitromethane have comparable acidities. Moreover, the products are often unstable, either for the reversibility of the addition or for the possible /3-elimination of the nitro group, and the crude products are generally reduced, avoiding purification to give the desired 1,2-diamines. Hence, the nitronate ion is an equivalent of an a-amino carbanion. 

As can be seen from the above examples, the decarboxylation reaction can be said to generate carbanion-equivalent, which is capable of undergoing the enantioselective reactions not only with a proton but also with a carbon electrophile in an aqueous medium. In the future extension of this field, this characteristic point should be utilized for the design of the unique reactions. 

These reactions were also performed by Jin et al. in the presence of chiral amino thioaeetate ligands derived from (-i-)-norephedrine." As shown in Scheme 3.5, quantitative yields and excellent enantioselectivities of up to >99% ee were obtained in almost all eases of aldehydes, even when using 1.1 equivalent of ZnEt2 instead of 2 equivalents as usually employed. More recently, these authors developed eorresponding chiral amino thiocyanate derivatives from (-)-norephedrine and tested these new aprotic ligands for... 

---