Asymmetric reactions chiral auxiliaries

Asymmetric DieJs-Alder Reactions - Chiral Auxiliaries... 

To control the stereochemistry of 1,3-dipolar cycloaddition reactions, chiral auxiliaries are introduced into either the dipole-part or dipolarophile. A recent monograph covers this topic extensively 70 therefore, only typical examples are presented here. Alkenes employed in asymmetric 1,3-cycloaddition can be divided into three main groups (1) chiral allylic alcohols, (2) chiral amines, and (3) chiral vinyl sulfoxides or vinylphosphine oxides.63c... 

In the above asymmetric aldol reaction, the introduction and the removal of the chiral auxiliary are carried out by simple procedures, and high asymmetric induction is achieved even at ice—bath temperature. However, at least a stoichiometric amount of a chiral auxiliary is required in such a stereo-differentiating reaction (chiral auxiliary is attached to the reactant.). 

In terms of versatility in asymmetric synthesis, chiral auxiliary methodology is often favored over a substrate-controlled process, since the preexisting stereogenicity can be removed (and recovered) subsequent to reaction. This leads, in end effect, to an enantioselective rather than diastereoselective transformation. This section discusses the advances achieved in chiral auxiliary technology for metal-mediated [3 + 2] cycloadditions to electron-deficient olefins68,69. 

The first practical method for asymmetric epoxidation of primary and secondary allylic alcohols was developed by K.B. Sharpless in 1980 (T. Katsuki, 1980 K.B. Sharpless, 1983 A, B, 1986 see also D. Hoppe, 1982). Tartaric esters, e.g., DET and DIPT" ( = diethyl and diisopropyl ( + )- or (— )-tartrates), are applied as chiral auxiliaries, titanium tetrakis(2-pro-panolate) as a catalyst and tert-butyl hydroperoxide (= TBHP, Bu OOH) as the oxidant. If the reaction mixture is kept absolutely dry, catalytic amounts of the dialkyl tartrate-titanium(IV) complex are suflicient, which largely facilitates work-up procedures (Y. Gao, 1987). Depending on the tartrate enantiomer used, either one of the 2,3-epoxy alcohols may be obtained with high enantioselectivity. The titanium probably binds to the diol grouping of one tartrate molecule and to the hydroxy groups of the bulky hydroperoxide and of the allylic alcohol... 

Chiral oxazolines developed by Albert I. Meyers and coworkers have been employed as activating groups and/or chiral auxiliaries in nucleophilic addition and substitution reactions that lead to the asymmetric construction of carbon-carbon bonds. For example, metalation of chiral oxazoline 1 followed by alkylation and hydrolysis affords enantioenriched carboxylic acid 2. Enantioenriched dihydronaphthalenes are produced via addition of alkyllithium reagents to 1-naphthyloxazoline 3 followed by alkylation of the resulting anion with an alkyl halide to give 4, which is subjected to reductive cleavage of the oxazoline moiety to yield aldehyde 5. Chiral oxazolines have also found numerous applications as ligands in asymmetric catalysis these applications have been recently reviewed, and are not discussed in this chapter. ... 

Asymmetric reactions using nonnatural chiral auxiliaries with participation and formation of heterocycles 98YGK386. 

Asymmetric Diels-Alder reactions using a dienophile containing a chiral auxiliary were developed more than 20 years ago. Although the auxiliary-based Diels-Alder reaction is still important, it has two drawbacks - additional steps are necessary, first to introduce the chiral auxiliary into the starting material, and then to remove it after the reaction. At least an equimolar amount of the chiral auxiliary is, moreover, necessary. After the discovery that Lewis acids catalyze the Diels-Alder reaction, the introduction of chirality into such catalysts has been investigated. The Diels-Alder reaction utilizing a chiral Lewis acid is truly a practical synthetic transformation, not only because the products obtained are synthetically useful, but also because a catalytic amount of the chiral component can, in theory, produce a huge amount of the chiral product. 

The landmark report by Winstein et al. (Scheme 3.6) on the powerful accelerating and directing effect of a proximal hydroxyl group would become one of the most critical in the development of the Simmons-Smith cyclopropanation reactions [11]. A clear syw directing effect is observed, implying coordination of the reagent to the alcohol before methylene transfer. This characteristic served as the basis of subsequent developments for stereocontrolled reactions with many classes of chiral allylic cycloalkenols and indirectly for chiral auxiliaries and catalysts. A full understanding of this phenomenon would not only be informative, but it would have practical applications in the rationalization of asymmetric catalytic reactions. 

Most asymmetric induction processes with Chital auxiliaries involve a stereo-differentiating reaction that affords one diastereomet as the primary product To obtain the desired enantiomer, the Chiral auxiliary must be removed Highly dia-stereoselective reactions between otganocoppet reagents and allylic substrates with... 

Scheme 5 details the asymmetric synthesis of dimethylhydrazone 14. The synthesis of this fragment commences with an Evans asymmetric aldol condensation between the boron enolate derived from 21 and trans-2-pentenal (20). Syn aldol adduct 29 is obtained in diastereomerically pure form through a process which defines both the relative and absolute stereochemistry of the newly generated stereogenic centers at carbons 29 and 30 (92 % yield). After reductive removal of the chiral auxiliary, selective silylation of the primary alcohol furnishes 30 in 71 % overall yield. The method employed to achieve the reduction of the C-28 carbonyl is interesting and worthy of comment. The reaction between tri-n-butylbor-... 

Clearly it is advantageous to be able to use achiral starting materials and a chiral reagent to induce an asymmetric reaction, thus obviating the need to attach and remove a chiral auxiliary and permitting the recovery and reuse of the chiral reagent. 

Lewis acid-mediated asymmetric Diels-Alder reactions between 2H-azirines 59, bearing chiral auxiliaries, with enophiles such as 60 afforded mixtures of bicyclic aziridine-2-carboxylates 61 (Scheme 3.20) [68]. 8-Phenylmenthol appeared to be the auxiliary of choice in this reaction in terms of yield and diastereoselectivity. 

The reaction of methyl 4-formyl-2-mcthylpentanoate and the chiral (Z)-2-butenylboronate clearly shows 52b-103, however, that the chiral auxiliary is not sufficiently enantioselective to increase the diastereoselectivity to >90% in either the matched [( + )-auxiliary] or mismatched [(—)-auxiliary] case. This underscores the requirement that highly enantioselective chiral reagents be utilized in double asymmetric reactions. 

Chiral, nonracemic allylboron reagents 1-7 with stereocenters at Cl of the allyl or 2-butenyl unit have been described. Although these optically active a-substituted allylboron reagents are generally less convenient to synthesize than those with conventional auxiliaries (Section 1.3.3.3.3.1.4.), this disadvantage is compensated for by the fact that their reactions with aldehydes often occur with almost 100% asymmetric induction. Thus, the enantiomeric purity as well as the ease of preparation of these chiral a-substituted allylboron reagents are important variables that determine their utility in enantioselective allylboration reactions with achiral aldehydes, and in double asymmetric reactions with chiral aldehydes (Section 1.3.3.3.3.2.4.). 

Chiral imines derived from 1-phenylethanone and (I. Sj-exo-l, 7,7-trimethyIbicyclo-[2.2.1]heptan-2-amine [(S)-isobornylamine], (.S>1-phenylethanamine or (R)-l-(1-naphthyl) ethanamine are transformed into the corresponding (vinylamino)dichloroboranes (e.g., 3) by treatment with trichloroborane and triethylamine in dichloromethane. Reaction of the chiral boron azaenolates with aromatic aldehydes at 25 "C, and subsequent acidic hydrolysis, furnishes aldol adducts with enantiomeric excesses in the range of 2.5 to 47.7%. Significantly lower asymmetric inductions are obtained from additions of the corresponding lithium and magnesium azaenolates. Best results arc achieved using (.S )-isobornylamine as the chiral auxiliary 3. 

In Ugi four-component reactions (for mechanism, see Section 1.4.4.1.) all four components may potentially serve as the stereodifferentiating tool65. However, neither the isocyanide component nor the carboxylic acid have pronounced effects on the overall stereodiscrimination60 66. As a consequence, the factors influencing the stereochemical course of Ugi reactions arc similar to those in Strecker syntheses. The use of chiral aldehydes is commonly found in substrate-controlled syntheses whereas the asymmetric synthesis of new enantiomerically pure compounds via Ugi s method is restricted to the application of optically active amines as the chiral auxiliary group. 

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