Enantioselective chiral inductor

Asymmetric additions of Reformatsky-type reagents to nitrones 258a and 258b have also been reported (Scheme 139). The reagents were prepared in situ from ZnEt2 and the corresponding iodoacetic acid ester. Diisopropyl (R,R)-tartrate 262 was employed as a chiral inductor. Enantioselectivities varied significantly the best results were obtained at 0 °C when a nitrone was added to the reaction mixture over a 2 h period. 

The enantioselectivity of [3+ 2]-cycloaddition reactions is determined by the preference of a particular facial attack of the reagents containing chiral inductors. Most of such reactions proceed in the absence of a catalyst and, consequently, the inductor should be present in either the dipole or the dipolarophile. 

In more recent times interest has been shown in the effects of constrained environment on the outcome of such reactions. Some enantioselectivity in the product 308 has been reported following the irradiation of benzonorbornadiene 309 in a T1Y zeolite. (—)-Ephedrine was used as the chiral inductor and sensitization brought about the reaction in 30 min. An ee of about 14% was obtained168. 

The enantioselective oxidation of prochiral sulfides with DMD has been achieved by using bovine serum albumin (BSA) as the chiral inductor Moderate to good enan-tioselectivities have been reported in the presence of this protein, for which a typical example is shown in equation 22 . As yet, however, no enantioselective oxidation of a prochiral sulfide has been documented by employing an optically active dioxirane. We have tried the enantioselective oxidation of methyl phenyl sulfide with the dioxirane generated from the ketone 7 (Shi s ketone), but an ee value of only ca 5% was obtained. One major hurdle that needs to be overcome with such enantioselective dioxirane oxidations is the suppression of the background oxidation of the sulfide substrate by Caroate, an unavoidable feature of the in-situ mode. 

Figure 42 Results on the enantioselective Norrish-Yang photocyclization of trans-A-terf-butyl-1-methy Icy clo hexyl aryl ketone. Note that the same isomer of the chiral inductor favors opposite isomers within NaY and NaX zeolites.

In the above-discussed examples, a chiral inductor is used to induce chirality on the product of a reaction. In the absence of any specific interaction between a chiral inductor and a reactant, it is unable to force every reactant molecule close to the chiral agent. This is one of the main reasons for poor enantioselectivity. The 69% ee obtained in the case of tropolone phenylethyl ether/ephedrine/NaY (dry) despite this limitation is remarkable. In an effort to reduce this limitation and to maintain closeness between the chiral center and the reaction site, Ramamurthy et... 

Ramamurthy et al. have examined enantioselective and diastereoselective ODPM rearrangements of cyclohexadienone and naphthalenone derivatives within MY zeolites, where M is an alkali ion [38, 39]. For example, in Scheme 4.27, in NaY in the presence of several chiral inductors such as ephedrine, pseudoephedrine, and camphorquinone-3-oxime, an enantioselective ODPM rearrangement of 65 and 66 took place to afford 68 in 30% ee yield. In the frame of the chiral auxiliary approach, the compound 67 linked to (S)-ephedrine was irradiated within NaY to give 68 in moderate diastereoselective excess (de) (59%). Interestingly, the reaction media of KY, RbY, and CsY reverse the diastereoselectivities. The cation-dependent diastereo-meric switch has been discussed with respect to the N- or O-functional group in 67 [39]. Recently, Arumugan reported that the irradiation of naphthalenones 65 linked chiral auxiliaries (R3 = COO(—)-Ment or (S)-NHCH(Me)Ph) in Li+ or Na + Nafion resulted in chiral products ( 14% de) [40],... 

All these results indicate that enantioselective photocycloadditions of s thetic interest should be possible with the help of a removable chiral auxilii as soon as the right chiral auxiliaries could be defined. In order to test the limit of this strategy, functionalized cyclohexenones and cyclopentenones were si lected to look for new chiral inductors. When co-alkenyl substituents were attach to the cyclic enone through an enamide, a carboxamide, or an ester group (Schei... 

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. 

In a more recent study, the enamide photocyclization with very similar photosubstrates was examined in the presence of chiral amino alcohols and chiral amines as asymmetric inductors [47]. The achieved enantioselectivities are in the same range as the ones reported by Ninomiya and Naito, but in this approach the asymmetric induction was more effective for the cis products. In cyclopentane at — 40°C, 0.1 equivalents of the most effective inductor, (— )-ephedrine (entity, gave the cis cyclization products with up to 37% ee and the trans products with only 2% ee. The role of the chiral inductor as a Br0nsted acid was supported by flash photolysis experiments. The presence of the chiral amino alcohol led to an increase in the rate of disappearance of a transient that was assigned to the primary cyclization intermediate of type 29, i.e., the chiral inductor accelerates the protonation/deprotonation sequence that reestablishes the aromatic ring. 

In summary, chiral Br0nsted acids have been used to protonate prochiral intermediates that were photochemically produced. Optimization of the chiral amino alcohols and the conditions led to excellent enantioselectivities of up to 91% ee employing only 0.1 equivalent of chiral inductor with respect to the substrate. These results demonstrate that the desirable goal of chiral amplification can be reached with chiral templates. The asymmetric induction varies strongly for different substrates, and therefore the general applicability as a synthetic tool seems to be limited. 

V. ENANTIOSELECTIVITY WITHIN ZEOLITES THROUGH THE USE OF NONREACTIVE CHIRAL INDUCTORS... 

The irradiation of phenyl-2-methyltricyclo[3.3.1.1]dec-2-yl methanone 54a (Scheme 37) included in faujasite was carried out in presence of chiral inductors. The maximum enantioselectivity obtained using the chiral inductor approach was 32% ee both with (— )-pseudoephedrine and with ( + )-2-amino-3-methoxy-l-phenyl-1-propanol [302], Similar studies were done for l-(4-fluorophenyl)-2 methyltricyclo[3.3.1. l]dec-2-yl methanone 54b. The maximum enantioselectivity obtained in this case was 30% ee with (— )-pseudoephedrine. 

While zeolites are themselves rarely chiral, adsorption of chiral inductors can enable enantioselective or diastereoselective reactions. For instance, Y zeolites have been modified with chiral dithiane oxides (47) Ramamurthy and his group have... 

An enantioselective method for the synthesis of 3-functionalized 2,3-dihydrobenzofuran derivatives via an intramolecular carbolithiation reaction of allyl 2-lithioaryl ethers uses (—)-sparteine as a chiral inductor. A variety of electrophiles can be reacted with the cyclized organolithium intermediate. With certain substrates, however, /3-elimination occurs instead (Equation 140) <2005CEJ5397>. 

The nucleophilic addition on substituted ketenes is a well-known method to generate a prochiral enolate that can be further protonated by a chiral source of proton. Metallic nucleophiles are used under anhydrous conditions therefore, the optically pure source of proton must be added then (often in a stoichiometric amount) to control the protonation. In the case of a protic nucleophile, an alcohol, a thiol, or an amine, the chiral inductor is usually present at the beginning of the reaction since it also catalyzes the addition of the heteroatomic nucleophile before mediating the enantioselective protonation (Scheme 7.5). The use of a chiral tertiary amine as catalyst generates a zwitterionic intermediate B by nucleophilic addition on ketene A, followed by a rapid diastereoselective protonation of the enolate to acylammonium C, and then the release of the catalyst via its substitution by the nucleophile ends this reaction sequence. 

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